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Sample records for controls pten function

  1. Cell Cycle Control by PTEN.

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    Brandmaier, Andrew; Hou, Sheng-Qi; Shen, Wen H

    2017-07-21

    Continuous and error-free chromosome inheritance through the cell cycle is essential for genomic stability and tumor suppression. However, accumulation of aberrant genetic materials often causes the cell cycle to go awry, leading to malignant transformation. In response to genotoxic stress, cells employ diverse adaptive mechanisms to halt or exit the cell cycle temporarily or permanently. The intrinsic machinery of cycling, resting, and exiting shapes the cellular response to extrinsic stimuli, whereas prevalent disruption of the cell cycle machinery in tumor cells often confers resistance to anticancer therapy. Phosphatase and tensin homolog (PTEN) is a tumor suppressor and a guardian of the genome that is frequently mutated or deleted in human cancer. Moreover, it is increasingly evident that PTEN deficiency disrupts the fundamental processes of genetic transmission. Cells lacking PTEN exhibit cell cycle deregulation and cell fate reprogramming. Here, we review the role of PTEN in regulating the key processes in and out of cell cycle to optimize genomic integrity. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Cell-type specific roles for PTEN in establishing a functional retinal architecture.

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    Robert Cantrup

    Full Text Available The retina has a unique three-dimensional architecture, the precise organization of which allows for complete sampling of the visual field. Along the radial or apicobasal axis, retinal neurons and their dendritic and axonal arbors are segregated into layers, while perpendicular to this axis, in the tangential plane, four of the six neuronal types form patterned cellular arrays, or mosaics. Currently, the molecular cues that control retinal cell positioning are not well-understood, especially those that operate in the tangential plane. Here we investigated the role of the PTEN phosphatase in establishing a functional retinal architecture.In the developing retina, PTEN was localized preferentially to ganglion, amacrine and horizontal cells, whose somata are distributed in mosaic patterns in the tangential plane. Generation of a retina-specific Pten knock-out resulted in retinal ganglion, amacrine and horizontal cell hypertrophy, and expansion of the inner plexiform layer. The spacing of Pten mutant mosaic populations was also aberrant, as were the arborization and fasciculation patterns of their processes, displaying cell type-specific defects in the radial and tangential dimensions. Irregular oscillatory potentials were also observed in Pten mutant electroretinograms, indicative of asynchronous amacrine cell firing. Furthermore, while Pten mutant RGC axons targeted appropriate brain regions, optokinetic spatial acuity was reduced in Pten mutant animals. Finally, while some features of the Pten mutant retina appeared similar to those reported in Dscam-mutant mice, PTEN expression and activity were normal in the absence of Dscam.We conclude that Pten regulates somal positioning and neurite arborization patterns of a subset of retinal cells that form mosaics, likely functioning independently of Dscam, at least during the embryonic period. Our findings thus reveal an unexpected level of cellular specificity for the multi-purpose phosphatase, and

  3. PTENα, a PTEN isoform translated through alternative initiation, regulates mitochondrial function and energy metabolism.

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    Liang, Hui; He, Shiming; Yang, Jingyi; Jia, Xinying; Wang, Pan; Chen, Xi; Zhang, Zhong; Zou, Xiajuan; McNutt, Michael A; Shen, Wen Hong; Yin, Yuxin

    2014-05-06

    PTEN is one of the most frequently mutated genes in human cancer. It is known that PTEN has a wide range of biological functions beyond tumor suppression. Here, we report that PTENα, an N-terminally extended form of PTEN, functions in mitochondrial metabolism. Translation of PTENα is initiated from a CUG codon upstream of and in-frame with the coding region of canonical PTEN. Eukaryotic translation initiation factor 2A (eIF2A) controls PTENα translation, which requires a CUG-centered palindromic motif. We show that PTENα induces cytochrome c oxidase activity and ATP production in mitochondria. TALEN-mediated somatic deletion of PTENα impairs mitochondrial respiratory chain function. PTENα interacts with canonical PTEN to increase PINK1 protein levels and promote energy production. Our studies demonstrate the importance of eIF2A-mediated alternative translation for generation of protein diversity in eukaryotic systems and provide insights into the mechanism by which the PTEN family is involved in multiple cellular processes. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Selective neuronal PTEN deletion: can we take the brakes off of growth without losing control?

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    Erin A Gutilla

    2016-01-01

    Full Text Available The limited ability for injured adult axons to regenerate is a major cause for limited functional recovery after injury to the nervous system, motivating numerous efforts to uncover mechanisms capable of enhancing regeneration potential. One promising strategy involves deletion or knockdown of the phosphatase and tensin (PTEN gene. Conditional genetic deletion of PTEN before, immediately following, or several months after spinal cord injury enables neurons of the corticospinal tract (CST to regenerate their axons across the lesion, which is accompanied by enhanced recovery of skilled voluntary motor functions mediated by the CST. Although conditional genetic deletion or knockdown ofPTEN in neurons enables axon regeneration, PTEN is a well-known tumor suppressor and mutations of the PTEN gene disrupt brain development leading to neurological abnormalities including macrocephaly, seizures, and early mortality. The long-term consequences of manipulating PTEN in the adult nervous system, as would be done for therapeutic intervention after injury, are only now being explored. Here, we summarize evidence indicating that long-term deletion of PTEN in mature neurons does not cause evident pathology; indeed, cortical neurons that have lived without PTEN for over 1 year appear robust and healthy. Studies to date provide only a first look at potential negative consequences of PTEN deletion or knockdown, but the absence of any detectable neuropathology supports guarded optimism that interventions to enable axon regeneration after injury are achievable.

  5. Posttranslational regulation of phosphatase and tensin homolog (PTEN and its functional impact on cancer behaviors

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    Xu WT

    2014-10-01

    Full Text Available Wenting Xu,1 Zhen Yang,1 Shu-Feng Zhou,2 Nonghua Lu1 1Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 2Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA Abstract: The incidence of cancer is increasing worldwide, but the biochemical mechanisms for the occurrence of cancer is not fully understood, and there is no cure for advanced tumors. Defects of posttranslational modifications of proteins are linked to a number of important diseases, such as cancer. This review will update our knowledge on the critical role of posttranscriptional regulation of phosphatase and tensin homolog (PTEN and its activities and the functional impact on cancer behaviors. PTEN is a tumor suppressor gene that occupies a key position in regulating cell growth, proliferation, apoptosis, mobility, signal transduction, and other crucial cellular processes. The activity and function of PTEN are regulated by coordinated epigenetic, transcriptional, posttranscriptional, and posttranslational modifications. In particular, PTEN is subject to phosphorylation, ubiquitylation, somoylation, acetylation, and active site oxidation. Posttranslational modifications of PTEN can dynamically change its activity and function. Deficiency in the posttranslational regulation of PTEN leads to abnormal cell proliferation, apoptosis, migration, and adhesion, which are associated with cancer initiation, progression, and metastasis. With increasing information on how PTEN is regulated by multiple mechanisms and networked proteins, its exact role in cancer initiation, growth, and metastasis will be revealed. PTEN and its functionally related proteins may represent useful targets for the discovery of new anticancer drugs, and gene therapy and the therapeutic potentials should be fully explored. Keywords: phosphorylation, ubiquitination, acetylation, oxidation

  6. A phosphatase-independent gain-of-function mutation in PTEN triggers aberrant cell growth in astrocytes through an autocrine IGF-1 loop.

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    Fernández, S; Genis, L; Torres-Alemán, I

    2014-08-07

    Loss-of-function mutations in the phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome10) contribute to aberrant cell growth in part through upregulation of the mitogenic IGF-1/PI3K/Akt pathway. In turn, this pathway exerts a homeostatic feedback over PTEN. Using mutagenesis analysis to explore a possible impact of this mutual control on astrocyte growth, we found that truncation of the C-terminal region of PTEN (Δ51) associates with a marked increase in NFκB activity, a transcription factor overactivated in astrocyte tumors. Whereas mutations of PTEN are considered to lead to a loss-of-function, PTENΔ51, a truncation that comprises a region frequently mutated in human gliomas, displayed a neomorphic (gain-of-function) activity that was independent of its phosphatase activity. This gain-of-function of PTENΔ51 includes stimulation of IGF-1 synthesis through protein kinase A activation of the IGF-1 promoter. Increased IGF-1 originates an autocrine loop that activates Akt and NFκB. Constitutive activation of NFκB in PTENΔ51-expressing astrocytes leads to aberrant cell growth; astrocytes expressing this mutant PTEN generate colonies in vitro and tumors in vivo. Mutations converting a tumor suppressor such as PTEN into a tumor promoter through a gain-of-function involving IGF-1 production may further our understanding of the role played by this growth factor in glioma growth and help us define druggable targets for personalized therapy.

  7. Genomic rearrangements of PTEN in prostate cancer

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    Sopheap ePhin

    2013-09-01

    Full Text Available The phosphatase and tensin homolog gene on chromosome 10q23.3 (PTEN is a negative regulator of the PIK3/Akt survival pathway and is the most frequently deleted tumor suppressor gene in prostate cancer. Monoallelic loss of PTEN is present in up to 60% of localized prostate cancers and complete loss of PTEN in prostate cancer is linked to metastasis and androgen independent progression. Studies on the genomic status of PTEN in prostate cancer initially used a two-color fluorescence in-situ hybridization (FISH assay for PTEN copy number detection in formalin fixed paraffin embedded tissue preparations. More recently, a four-color FISH assay containing two additional control probes flanking the PTEN locus with a lower false-positive rate was reported. Combined with the detection of other critical genomic biomarkers for prostate cancer such as ERG, AR, and MYC, the evaluation of PTEN genomic status has proven to be invaluable for patient stratification and management. Although less frequent than allelic deletions, point mutations in the gene and epigenetic silencing are also known to contribute to loss of PTEN function, and ultimately to prostate cancer initiation. Overall, it is clear that PTEN is a powerful biomarker for prostate cancer. Used as a companion diagnostic for emerging therapeutic drugs, FISH analysis of PTEN is promisingly moving human prostate cancer closer to more effective cancer management and therapies.

  8. The role of PTEN in regulation of hepatic macrophages activation and function in progression and reversal of liver fibrosis

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    Cheng, Yahui; Tian, Yuanyao; Xia, Jialu; Wu, Xiaoqin; Yang, Yang; Li, Xiaofeng; Huang, Cheng; Meng, Xiaoming; Ma, Taotao; Li, Jun, E-mail: lj@ahmu.edu.cn

    2017-02-15

    Activation of Kupffer cells (KCs) plays a pivotal role in the pathogenesis of liver fibrosis. The progression and reversal of CCl{sub 4}-induced mouse liver fibrosis showed a mixed induction of hepatic classical (M1) and alternative (M2) macrophage markers. Although the role of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in modulating myeloid cell activation has recently been identified, its function in macrophage activation during hepatic fibrosis remains to be fully appreciated. In our study, PTEN expression of KCs was remarkably decreased in CCl{sub 4}-induced mice but increased to a near-normal level in reversed mice. Moreover, PTEN was significantly decreased in IL4-induced RAW 264.7 cells in vitro and lower expression of PTEN was observed in M2 macrophages in vivo. In addition, loss- and gain-of-function studies suggested that PTEN regulates M2 macrophages polarization via activation of PI3K/Akt/STAT6 signaling, but had a limited effect on M1 macrophages polarization in vitro. Additionally, Ly294002, a chemical inhibitor of PI3K/Akt, could dramatically down-regulate the hallmarks of M2 macrophages. In conclusion, PTEN mediates macrophages activation by PI3K/Akt/STAT6 signaling pathway, which provides novel compelling evidences on the potential of PTEN in liver injury and opens new cellular target for the pharmacological therapy of liver fibrosis. - Highlights: • CCl{sub 4} treatment triggered a mixed M1/M2 macrophage phenotype in fibrosis. • Lower expression of PTEN in murine M2 macrophages in vivo and vitro. • PTEN modulates M2 macrophages activation via PI3K/Akt/STAT6 signaling. • Provide a new cellular target modulate macrophage mediated hepatic fibrosis.

  9. PTEN C-Terminal Deletion Causes Genomic Instability and Tumor Development

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    Zhuo Sun

    2014-03-01

    Full Text Available Tumor suppressor PTEN controls genomic stability and inhibits tumorigenesis. The N-terminal phosphatase domain of PTEN antagonizes the PI3K/AKT pathway, but its C-terminal function is less defined. Here, we describe a knockin mouse model of a nonsense mutation that results in the deletion of the entire Pten C-terminal region, referred to as PtenΔC. Mice heterozygous for PtenΔC develop multiple spontaneous tumors, including cancers and B cell lymphoma. Heterozygous deletion of the Pten C-terminal domain also causes genomic instability and common fragile site rearrangement. We found that Pten C-terminal disruption induces p53 and its downstream targets. Simultaneous depletion of p53 promotes metastasis without influencing the initiation of tumors, suggesting that p53 mainly suppresses tumor progression. Our data highlight the essential role of the PTEN C terminus in the maintenance of genomic stability and suppression of tumorigenesis.

  10. Functional genomics identifies specific vulnerabilities in PTEN-deficient breast cancer.

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    Tang, Yew Chung; Ho, Szu-Chi; Tan, Elisabeth; Ng, Alvin Wei Tian; McPherson, John R; Goh, Germaine Yen Lin; Teh, Bin Tean; Bard, Frederic; Rozen, Steven G

    2018-03-22

    Phosphatase and tensin homolog (PTEN) is one of the most frequently inactivated tumor suppressors in breast cancer. While PTEN itself is not considered a druggable target, PTEN synthetic-sick or synthetic-lethal (PTEN-SSL) genes are potential drug targets in PTEN-deficient breast cancers. Therefore, with the aim of identifying potential targets for precision breast cancer therapy, we sought to discover PTEN-SSL genes present in a broad spectrum of breast cancers. To discover broad-spectrum PTEN-SSL genes in breast cancer, we used a multi-step approach that started with (1) a genome-wide short interfering RNA (siRNA) screen of ~ 21,000 genes in a pair of isogenic human mammary epithelial cell lines, followed by (2) a short hairpin RNA (shRNA) screen of ~ 1200 genes focused on hits from the first screen in a panel of 11 breast cancer cell lines; we then determined reproducibility of hits by (3) identification of overlaps between our results and reanalyzed data from 3 independent gene-essentiality screens, and finally, for selected candidate PTEN-SSL genes we (4) confirmed PTEN-SSL activity using either drug sensitivity experiments in a panel of 19 cell lines or mutual exclusivity analysis of publicly available pan-cancer somatic mutation data. The screens (steps 1 and 2) and the reproducibility analysis (step 3) identified six candidate broad-spectrum PTEN-SSL genes (PIK3CB, ADAMTS20, AP1M2, HMMR, STK11, and NUAK1). PIK3CB was previously identified as PTEN-SSL, while the other five genes represent novel PTEN-SSL candidates. Confirmation studies (step 4) provided additional evidence that NUAK1 and STK11 have PTEN-SSL patterns of activity. Consistent with PTEN-SSL status, inhibition of the NUAK1 protein kinase by the small molecule drug HTH-01-015 selectively impaired viability in multiple PTEN-deficient breast cancer cell lines, while mutations affecting STK11 and PTEN were largely mutually exclusive across large pan-cancer data sets. Six genes showed PTEN

  11. PTEN and PI-3 kinase inhibitors control LPS signaling and the lymphoproliferative response in the CD19+ B cell compartment

    International Nuclear Information System (INIS)

    Singh, Alok R.; Peirce, Susan K.; Joshi, Shweta; Durden, Donald L.

    2014-01-01

    Pattern recognition receptors (PRRs), e.g. toll receptors (TLRs) that bind ligands within the microbiome have been implicated in the pathogenesis of cancer. LPS is a ligand for two TLR family members, TLR4 and RP105 which mediate LPS signaling in B cell proliferation and migration. Although LPS/TLR/RP105 signaling is well-studied; our understanding of the underlying molecular mechanisms controlling these PRR signaling pathways remains incomplete. Previous studies have demonstrated a role for PTEN/PI-3K signaling in B cell selection and survival, however a role for PTEN/PI-3K in TLR4/RP105/LPS signaling in the B cell compartment has not been reported. Herein, we crossed a CD19cre and PTEN fl/fl mouse to generate a conditional PTEN knockout mouse in the CD19+ B cell compartment. These mice were further crossed with an IL-14α transgenic mouse to study the combined effect of PTEN deletion, PI-3K inhibition and expression of IL-14α (a cytokine originally identified as a B cell growth factor) in CD19+ B cell lymphoproliferation and response to LPS stimulation. Targeted deletion of PTEN and directed expression of IL-14α in the CD19+ B cell compartment (IL-14+PTEN-/-) lead to marked splenomegaly and altered spleen morphology at baseline due to expansion of marginal zone B cells, a phenotype that was exaggerated by treatment with the B cell mitogen and TLR4/RP105 ligand, LPS. Moreover, LPS stimulation of CD19+ cells isolated from these mice display increased proliferation, augmented AKT and NFκB activation as well as increased expression of c-myc and cyclinD1. Interestingly, treatment of LPS treated IL-14+PTEN-/- mice with a pan PI-3K inhibitor, SF1126, reduced splenomegaly, cell proliferation, c-myc and cyclin D1 expression in the CD19+ B cell compartment and normalized the splenic histopathologic architecture. These findings provide the direct evidence that PTEN and PI-3K inhibitors control TLR4/RP105/LPS signaling in the CD19+ B cell compartment and that pan PI-3

  12. PTEN and PI-3 kinase inhibitors control LPS signaling and the lymphoproliferative response in the CD19+ B cell compartment

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    Singh, Alok R. [UCSD Department of Pediatrics, Moores UCSD Cancer Center, University of California School of Medicine, San Diego, CA 92093 (United States); Peirce, Susan K. [Department of Pediatrics, Emory University School of Medicine, Atlanta, GA (United States); Joshi, Shweta [UCSD Department of Pediatrics, Moores UCSD Cancer Center, University of California School of Medicine, San Diego, CA 92093 (United States); Durden, Donald L., E-mail: ddurden@ucsd.edu [UCSD Department of Pediatrics, Moores UCSD Cancer Center, University of California School of Medicine, San Diego, CA 92093 (United States); Division of Pediatric Hematology-Oncology, UCSD Rady Children' s Hospital, La Jolla, CA (United States)

    2014-09-10

    Pattern recognition receptors (PRRs), e.g. toll receptors (TLRs) that bind ligands within the microbiome have been implicated in the pathogenesis of cancer. LPS is a ligand for two TLR family members, TLR4 and RP105 which mediate LPS signaling in B cell proliferation and migration. Although LPS/TLR/RP105 signaling is well-studied; our understanding of the underlying molecular mechanisms controlling these PRR signaling pathways remains incomplete. Previous studies have demonstrated a role for PTEN/PI-3K signaling in B cell selection and survival, however a role for PTEN/PI-3K in TLR4/RP105/LPS signaling in the B cell compartment has not been reported. Herein, we crossed a CD19cre and PTEN{sup fl/fl} mouse to generate a conditional PTEN knockout mouse in the CD19+ B cell compartment. These mice were further crossed with an IL-14α transgenic mouse to study the combined effect of PTEN deletion, PI-3K inhibition and expression of IL-14α (a cytokine originally identified as a B cell growth factor) in CD19+ B cell lymphoproliferation and response to LPS stimulation. Targeted deletion of PTEN and directed expression of IL-14α in the CD19+ B cell compartment (IL-14+PTEN-/-) lead to marked splenomegaly and altered spleen morphology at baseline due to expansion of marginal zone B cells, a phenotype that was exaggerated by treatment with the B cell mitogen and TLR4/RP105 ligand, LPS. Moreover, LPS stimulation of CD19+ cells isolated from these mice display increased proliferation, augmented AKT and NFκB activation as well as increased expression of c-myc and cyclinD1. Interestingly, treatment of LPS treated IL-14+PTEN-/- mice with a pan PI-3K inhibitor, SF1126, reduced splenomegaly, cell proliferation, c-myc and cyclin D1 expression in the CD19+ B cell compartment and normalized the splenic histopathologic architecture. These findings provide the direct evidence that PTEN and PI-3K inhibitors control TLR4/RP105/LPS signaling in the CD19+ B cell compartment and that pan PI

  13. Avian Reovirus Protein p17 Functions as a Nucleoporin Tpr Suppressor Leading to Activation of p53, p21 and PTEN and Inactivation of PI3K/AKT/mTOR and ERK Signaling Pathways.

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    Wei-Ru Huang

    Full Text Available Avian reovirus (ARV protein p17 has been shown to regulate cell cycle and autophagy by activation of p53/PTEN pathway; nevertheless, it is still unclear how p53 and PTEN are activated by p17. Here, we report for the first time that p17 functions as a nucleoporin Tpr suppressor that leads to p53 nuclear accumulation and consequently activates p53, p21, and PTEN. The nuclear localization signal (119IAAKRGRQLD128 of p17 has been identified for Tpr binding. This study has shown that Tpr suppression occurs by p17 interacting with Tpr and by reducing the transcription level of Tpr, which together inhibit Tpr function. In addition to upregulation of PTEN by activation of p53 pathway, this study also suggests that ARV protein p17 acts as a positive regulator of PTEN. ARV p17 stabilizes PTEN by stimulating phosphorylation of cytoplasmic PTEN and by elevating Rak-PTEN association to prevent it from E3 ligase NEDD4-1 targeting. To activate PTEN, p17 is able to promote β-arrestin-mediated PTEN translocation from the cytoplasm to the plasma membrane via a Rock-1-dependent manner. The accumulation of p53 in the nucleus induces the PTEN- and p21-mediated downregulation of cyclin D1 and CDK4. Furthermore, Tpr and CDK4 knockdown increased virus production in contrast to depletion of p53, PTEN, and LC3 reducing virus yield. Taken together, our data suggest that p17-mediated Tpr suppression positively regulates p53, PTEN, and p21 and negatively regulates PI3K/AKT/mTOR and ERK signaling pathways, both of which are beneficial for virus replication.

  14. Regulation of T Cell Homeostasis and Responses by Pten

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    Ryan H. Newton

    2012-06-01

    Full Text Available The generation of lipid products catalyzed by PI3K is critical for normal T cell homeostasis and a productive immune response. PI3K can be activated in response to antigen receptor, costimulatory, cytokine and chemokine signals. Moreover, dysregulation of this pathway frequently occurs in T cell lymphomas and is implicated in lymphoproliferative autoimmune disease. Akt acts as a central mediator of PI3K signals, downstream of which is the mTOR pathway, controlling cell growth and metabolism. Members of the Foxo family of transcription factors are also regulated by Akt, thus linking control over homing and migration of T cells, as well cell cycle entry, apoptosis, and DNA damage and oxidative stress responses, to PI3K signaling. PTEN, first identified as a tumor suppressor gene, encodes a lipid phosphatase that, by catalyzing the reverse of the PI3K reaction, directly opposes PI3K signaling. However, PTEN may have other functions as well, and recent reports have suggested roles for PTEN as a tumor suppressor independent of its effects on PI3K signaling. Through the use of models in which Pten is deleted specifically in T cells, it is becoming increasingly clear that control over autoimmunity and lymphomagenesis by PTEN involves multi-faceted functions of this molecule at multiple stages of T cell development.

  15. Pten Regulates Retinal Amacrine Cell Number by Modulating Akt, Tgfβ, and Erk Signaling.

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    Tachibana, Nobuhiko; Cantrup, Robert; Dixit, Rajiv; Touahri, Yacine; Kaushik, Gaurav; Zinyk, Dawn; Daftarian, Narsis; Biernaskie, Jeff; McFarlane, Sarah; Schuurmans, Carol

    2016-09-07

    All tissues are genetically programmed to acquire an optimal size that is defined by total cell number and individual cellular dimensions. The retina contains stereotyped proportions of one glial and six neuronal cell types that are generated in overlapping waves. How multipotent retinal progenitors know when to switch from making one cell type to the next so that appropriate numbers of each cell type are generated is poorly understood. Pten is a phosphatase that controls progenitor cell proliferation and differentiation in several lineages. Here, using a conditional loss-of-function strategy, we found that Pten regulates retinal cell division and is required to produce the full complement of rod photoreceptors and amacrine cells in mouse. We focused on amacrine cell number control, identifying three downstream Pten effector pathways. First, phosphoinositide 3-kinase/Akt signaling is hyperactivated in Pten conditional knock-out (cKO) retinas, and misexpression of constitutively active Akt (Akt-CA) in retinal explants phenocopies the reduction in amacrine cell production observed in Pten cKOs. Second, Akt-CA activates Tgfβ signaling in retinal explants, which is a negative feedback pathway for amacrine cell production. Accordingly, Tgfβ signaling is elevated in Pten cKO retinas, and epistatic analyses placed Pten downstream of TgfβRII in amacrine cell number control. Finally, Pten regulates Raf/Mek/Erk signaling levels to promote the differentiation of all amacrine cell subtypes, which are each reduced in number in Pten cKOs. Pten is thus a positive regulator of amacrine cell production, acting via multiple downstream pathways, highlighting its diverse actions as a mediator of cell number control. Despite the importance of size for optimal organ function, how individual cell types are generated in correct proportions is poorly understood. There are several ways to control cell number, including readouts of organ function (e.g., secreted hormones reach functional

  16. Molecular Mechanism of Nkx3.1 Deregulation and its Function in Murine Pten Prostate Cancer Model

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    2006-09-01

    One possible explanation is that Pten null cells have become ‘‘ addicted ’’ to high levels of PI3K/AKT activity and, consequently, are hypersensitive...H.H., Kertesz, N., Lesche, R., Whale , A.D., Martinez-Diaz, H., Rozengurt, N., Cardiff, R.D., et al. (2003). PTEN tumor suppressor regulates p53 protein

  17. Role of PTEN in TNFα induced insulin resistance

    International Nuclear Information System (INIS)

    Bulger, David A.; Conley, Jermaine; Conner, Spencer H.; Majumdar, Gipsy; Solomon, Solomon S.

    2015-01-01

    Aims/hypothesis: PTEN may play a reversible role in TNFα induced insulin resistance, which has been linked to obesity-associated insulin resistance (IR). Methods: Western blots for PTEN and p-Akt were performed on H-411E liver cells incubated with insulin, TNFα, and in selected experiments VO-OHpic vanadium complex in the presence and absence of PTEN siRNA. Total PTEN was compared to β-actin loading control and p-Akt was compared to total Akt. Results: Western blot and Real Time RT-PCR experiments showed increased PTEN after TNFα treatment (p = 0.04); slightly decreased PTEN after insulin treatment; and slightly increased PTEN after insulin + TNFα treatment. PTEN siRNA markedly inhibited the TNFα-induced increase in PTEN (p < 0.01) without significantly changing the p-Akt levels. The vanadium complex, exhibiting insulin-like effects, also significantly prevented the TNFα-induced increase in PTEN. Combining insulin and VO-OHpic was additive, providing both proof of concept and insight into mechanism. Discussion: The PTEN increase due to TNFα treatment was reversible by both PTEN siRNA knockdown and VO-OHpic treatment. Thus, PTEN is identified as a potential new therapeutic target for reducing IR in Type 2 DM. - Highlights: • TNFα treatment induced a significant increase in PTEN in H-411E liver cells. • PTEN siRNA knockdown prevented this effect. • VO-OHpic (vanadium complex) treatment, like insulin, decreased PTEN protein levels. • Thus, PTEN is identified as a potential therapeutic target in DM Type 2

  18. Role of PTEN in TNFα induced insulin resistance

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    Bulger, David A. [Departments of Medicine and Pharmacology, University of Tennessee Health Science Center, Memphis, TN 38163 (United States); Medicine and Research Services, Veterans Association Medical Center, Memphis, TN 38104 (United States); Wellcome Trust Medical Research Council Institute of Metabolic Science, Cambridge CB2 0QQ (United Kingdom); National Institute of Diabetes & Digestive & Kidney Disease, National Institutes of Health, Bethesda, MD 20892 (United States); Conley, Jermaine [Medicine and Research Services, Veterans Association Medical Center, Memphis, TN 38104 (United States); Conner, Spencer H.; Majumdar, Gipsy [Departments of Medicine and Pharmacology, University of Tennessee Health Science Center, Memphis, TN 38163 (United States); Medicine and Research Services, Veterans Association Medical Center, Memphis, TN 38104 (United States); Solomon, Solomon S., E-mail: ssolomon@uthsc.edu [Departments of Medicine and Pharmacology, University of Tennessee Health Science Center, Memphis, TN 38163 (United States); Medicine and Research Services, Veterans Association Medical Center, Memphis, TN 38104 (United States)

    2015-06-05

    Aims/hypothesis: PTEN may play a reversible role in TNFα induced insulin resistance, which has been linked to obesity-associated insulin resistance (IR). Methods: Western blots for PTEN and p-Akt were performed on H-411E liver cells incubated with insulin, TNFα, and in selected experiments VO-OHpic vanadium complex in the presence and absence of PTEN siRNA. Total PTEN was compared to β-actin loading control and p-Akt was compared to total Akt. Results: Western blot and Real Time RT-PCR experiments showed increased PTEN after TNFα treatment (p = 0.04); slightly decreased PTEN after insulin treatment; and slightly increased PTEN after insulin + TNFα treatment. PTEN siRNA markedly inhibited the TNFα-induced increase in PTEN (p < 0.01) without significantly changing the p-Akt levels. The vanadium complex, exhibiting insulin-like effects, also significantly prevented the TNFα-induced increase in PTEN. Combining insulin and VO-OHpic was additive, providing both proof of concept and insight into mechanism. Discussion: The PTEN increase due to TNFα treatment was reversible by both PTEN siRNA knockdown and VO-OHpic treatment. Thus, PTEN is identified as a potential new therapeutic target for reducing IR in Type 2 DM. - Highlights: • TNFα treatment induced a significant increase in PTEN in H-411E liver cells. • PTEN siRNA knockdown prevented this effect. • VO-OHpic (vanadium complex) treatment, like insulin, decreased PTEN protein levels. • Thus, PTEN is identified as a potential therapeutic target in DM Type 2.

  19. Pten Regulates Epithelial Cytodifferentiation during Prostate Development

    DEFF Research Database (Denmark)

    Lokody, Isabel B; Francis, Jeffrey C; Gardiner, Jennifer R

    2015-01-01

    that are shared with Pten mutant prostate cancer models, including a decrease in androgen receptor regulated genes. In depth analysis of the phenotype of these mice during development revealed that loss of Pten leads to the precocious differentiation of epithelial cells towards a luminal cell fate. This study......Gene expression and functional studies have indicated that the molecular programmes involved in prostate development are also active in prostate cancer. PTEN has been implicated in human prostate cancer and is frequently mutated in this disease. Here, using the Nkx3.1:Cre mouse strain and a genetic...... deletion approach, we investigate the role of Pten specifically in the developing mouse prostate epithelia. In contrast to its role in other developing organs, this gene is dispensable for the initial developmental processes such as budding and branching. However, as cytodifferentiation progresses...

  20. PPAR, PTEN, and the Fight against Cancer

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    Rosemary E. Teresi

    2008-01-01

    Full Text Available Peroxisome proliferator-activated receptor gamma (PPAR is a ligand-activated transcription factor, which belongs to the family of nuclear hormone receptors. Recent in vitro studies have shown that PPAR can regulate the transcription of phosphatase and tensin homolog on chromosome ten (PTEN, a known tumor suppressor. PTEN is a susceptibility gene for a number of disorders, including breast and thyroid cancer. Activation of PPAR through agonists increases functional PTEN protein levels that subsequently induces apoptosis and inhibits cellular growth, which suggests that PPAR may be a tumor suppressor. Indeed, several in vivo studies have demonstrated that genetic alterations of PPAR can promote tumor progression. These results are supported by observations of the beneficial effects of PPAR agonists in the in vivo cancer setting. These studies signify the importance of PPAR and PTEN's interaction in cancer prevention.

  1. PTEN status in advanced colorectal cancer treated with cetuximab

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    Negri, F V; Bozzetti, C; Lagrasta, C A; Crafa, P; Bonasoni, M P; Camisa, R; Pedrazzi, G; Ardizzoni, A

    2009-01-01

    Background: Loss of phosphatase and tensin homologue deleted in chromosome 10 (PTEN) function in advanced colorectal cancer (CRC) may represent one of the resistance mechanisms to cetuximab by interfering with the epidermal growth factor receptor signal transduction pathway. Methods: PTEN expression tested by indirect immunofluorescence was evaluated both on primary (n=43) and on metastatic (n=24) sites in CRC patients treated with cetuximab. Results: The loss of PTEN expression tested on metastatic sites was negatively associated with response (100% progressive disease (PD) in PTEN-negative cases vs 30% PD in PTEN-positive cases; P<0.05), PFS (0.8 vs 8.2 months; P<0.001) and OS (2.9 vs 14.2 months; P<0.001). Conclusion: A potential role of PTEN in the anti-tumour activity of cetuximab could be hypothesised. PMID:19953097

  2. Molecular and phenotypic abnormalities in individuals with germline heterozygous PTEN mutations and autism.

    Science.gov (United States)

    Frazier, T W; Embacher, R; Tilot, A K; Koenig, K; Mester, J; Eng, C

    2015-09-01

    PTEN is a tumor suppressor associated with an inherited cancer syndrome and an important regulator of ongoing neural connectivity and plasticity. The present study examined molecular and phenotypic characteristics of individuals with germline heterozygous PTEN mutations and autism spectrum disorder (ASD) (PTEN-ASD), with the aim of identifying pathophysiologic markers that specifically associate with PTEN-ASD and that may serve as targets for future treatment trials. PTEN-ASD patients (n=17) were compared with idiopathic (non-PTEN) ASD patients with (macro-ASD, n=16) and without macrocephaly (normo-ASD, n=38) and healthy controls (n=14). Group differences were evaluated for PTEN pathway protein expression levels, global and regional structural brain volumes and cortical thickness measures, neurocognition and adaptive behavior. RNA expression patterns and brain characteristics of a murine model of Pten mislocalization were used to further evaluate abnormalities observed in human PTEN-ASD patients. PTEN-ASD had a high proportion of missense mutations and showed reduced PTEN protein levels. Compared with the other groups, prominent white-matter and cognitive abnormalities were specifically associated with PTEN-ASD patients, with strong reductions in processing speed and working memory. White-matter abnormalities mediated the relationship between PTEN protein reductions and reduced cognitive ability. The Pten(m3m4) murine model had differential expression of genes related to myelination and increased corpus callosum. Processing speed and working memory deficits and white-matter abnormalities may serve as useful features that signal clinicians that PTEN is etiologic and prompting referral to genetic professionals for gene testing, genetic counseling and cancer risk management; and could reveal treatment targets in trials of treatments for PTEN-ASD.

  3. Overexpression of miR-21 in stem cells improves ovarian structure and function in rats with chemotherapy-induced ovarian damage by targeting PDCD4 and PTEN to inhibit granulosa cell apoptosis.

    Science.gov (United States)

    Fu, Xiafei; He, Yuanli; Wang, Xuefeng; Peng, Dongxian; Chen, Xiaoying; Li, Xinran; Wang, Qing

    2017-08-14

    Chemotherapy-induced premature ovarian failure (POF) is a severe complication affecting tumor patients at a childbearing age. Mesenchymal stem cells (MSCs) can partially restore the ovarian structure and function damaged by chemotherapy. miR-21 is a microRNA that can regulate cell apoptosis. This study discusses the repair effect and mechanism of MSCs overexpressing miR-21 on chemotherapy-induced POF. Rat MSCs and granulosa cells (GCs) were isolated in vitro. MSCs were transfected with miR-21 lentiviral vector (LV-miR-21) to obtain MSCs stably expressing miR-21 (miR-21-MSCs). The microenvironment of an ovary receiving chemotherapy was mimicked by adding phosphamide mustard (PM) into the cellular culture medium. The apoptosis rate and the mRNA and protein expression of target genes PTEN and PDCD4 were detected in MSCs. Apoptosis was induced by adding PM into the culture medium for GCs, which were cocultured with miR-21-MSCs. The apoptosis rate and the mRNA and protein expression of PTEN and PDCD4 were detected. The chemotherapy-induced POF model was built into rats by intraperitoneal cyclophosphamide injection. miR-21-MSCs were transplanted into the bilateral ovary. The rats were sacrificed at 15, 30, 45, and 60 days after the last injection. The ovarian weights, follicle count, estrous cycle, and sex hormone levels (estradiol (E2) and follicle-stimulating hormone (FSH)) were detected. Apoptosis of GCs was determined by TUNEL assay. The miR-21 and mRNA and protein expression of PTEN and PDCD4 were determined. The apoptosis decreased in MSCs transfected with miR-21. The mRNA and protein expression of target genes PTEN and PDCD4 was downregulated. GCs cocultured with miR-21-MSCs showed a decreased apoptosis, an upregulation of miR-21, and a downregulation of PTEN and PDCD4. Following the injection of miR-21-MSCs, the ovarian weight and follicle counts increased; E 2 levels increased while FSH levels decreased, with less severe apoptosis of GCs. The miR-21 expression

  4. Expression patterns and role of PTEN in rat peripheral nerve development and injury.

    Science.gov (United States)

    Chen, Hui; Xiang, Jianping; Wu, Junxia; He, Bo; Lin, Tao; Zhu, Qingtang; Liu, Xiaolin; Zheng, Canbin

    2018-05-29

    Studies have suggested that phosphatase and tensin homolog (PTEN) plays an important role in neuroprotection and neuronal regeneration. To better understand the potential role of PTEN with respect to peripheral nerve development and injury, we investigated the expression pattern of PTEN at different stages of rat peripheral nerve development and injury and subsequently assessed the effect of pharmacological inhibition of PTEN using bpV(pic) on axonal regeneration in a rat sciatic nerve crush injury model. During the early stages of development, PTEN exhibits low expression in neuronal cell bodies and axons. From embryonic day (E) 18.5 and postnatal day (P)5 to adult, PTEN protein becomes more detectable, with high expression in the dorsal root ganglia (DRG) and axons. PTEN expression is inhibited in peripheral nerves, preceding myelination during neuronal development and remyelination after acute nerve injury. Low PTEN expression after nerve injury promotes Akt/mammalian target of rapamycin (mTOR) signaling pathway activity. In vivo pharmacological inhibition of PTEN using bpV(pic) promoted axonal regrowth, increased the number of myelinated nerve fibers, improved locomotive recovery and enhanced the amplitude response and nerve conduction velocity following stimulation in a rat sciatic nerve crush injury model. Thus, we suggest that PTEN may play potential roles in peripheral nerve development and regeneration and that inhibition of PTEN expression is beneficial for nerve regeneration and functional recovery after peripheral nerve injury. Copyright © 2018 Elsevier B.V. All rights reserved.

  5. Intermittent fasting uncovers and rescues cognitive phenotypes in PTEN neuronal haploinsufficient mice.

    Science.gov (United States)

    Cabral-Costa, J V; Andreotti, D Z; Mello, N P; Scavone, C; Camandola, S; Kawamoto, E M

    2018-06-05

    Phosphatase and tensin homolog (PTEN) is an important protein with key modulatory functions in cell growth and survival. PTEN is crucial during embryogenesis and plays a key role in the central nervous system (CNS), where it directly modulates neuronal development and synaptic plasticity. Loss of PTEN signaling function is associated with cognitive deficits and synaptic plasticity impairment. Accordingly, Pten mutations have a strong link with autism spectrum disorder. In this study, neuronal Pten haploinsufficient male mice were subjected to a long-term environmental intervention - intermittent fasting (IF) - and then evaluated for alterations in exploratory, anxiety and learning and memory behaviors. Although no significant effects on spatial memory were observed, mutant mice showed impaired contextual fear memory in the passive avoidance test - an outcome that was effectively rescued by IF. In this study, we demonstrated that IF modulation, in addition to its rescue of the memory deficit, was also required to uncover behavioral phenotypes otherwise hidden in this neuronal Pten haploinsufficiency model.

  6. Molecular Analysis of AFP and HSA Interactions with PTEN Protein

    Directory of Open Access Journals (Sweden)

    Mingyue Zhu

    2015-01-01

    Full Text Available Human cytoplasmic alpha-fetoprotein (AFP has been classified as a member of the albuminoid gene family. The protein sequence of AFP has significant homology to that of human serum albumin (HSA, but its biological characteristics are vastly different from HSA. The AFP functions as a regulator in the phosphatidylinositol 3-kinase (PI3K/protein kinase B (AKT pathway, but HSA plays a key role as a transport protein. To probe their molecular mechanisms, we have applied colocalization, coimmunoprecipitation (co-IP, and molecular docking approaches to analyze the differences between AFP and HSA. The data from colocalization and co-IP displayed a strong interaction between AFP and PTEN (phosphatase and tensin homolog, demonstrating that AFP did bind to PTEN, but HSA did not. The molecular docking study further showed that the AFP domains I and III could contact with PTEN. In silicon substitutions of AFP binding site residues at position 490M/K and 105L/R corresponding to residues K490 and R105 in HSA resulted in steric clashes with PTEN residues R150 and K46, respectively. These steric clashes may explain the reason why HSA cannot bind to PTEN. Ultimately, the experimental results and the molecular modeling data from the interactions of AFP and HSA with PTEN will help us to identify targets for designing drugs and vaccines against human hepatocellular carcinoma.

  7. An inducible knockout mouse to model the cell-autonomous role of PTEN in initiating endometrial, prostate and thyroid neoplasias

    Science.gov (United States)

    Mirantes, Cristina; Eritja, Núria; Dosil, Maria Alba; Santacana, Maria; Pallares, Judit; Gatius, Sónia; Bergadà, Laura; Maiques, Oscar; Matias-Guiu, Xavier; Dolcet, Xavier

    2013-01-01

    SUMMARY PTEN is one of the most frequently mutated tumor suppressor genes in human cancers. The role of PTEN in carcinogenesis has been validated by knockout mouse models. PTEN heterozygous mice develop neoplasms in multiple organs. Unfortunately, the embryonic lethality of biallelic excision of PTEN has inhibited the study of complete PTEN deletion in the development and progression of cancer. By crossing PTEN conditional knockout mice with transgenic mice expressing a tamoxifen-inducible Cre-ERT under the control of a chicken actin promoter, we have generated a tamoxifen-inducible mouse model that allows temporal control of PTEN deletion. Interestingly, administration of a single dose of tamoxifen resulted in PTEN deletion mainly in epithelial cells, but not in stromal, mesenchymal or hematopoietic cells. Using the mT/mG double-fluorescent Cre reporter mice, we demonstrate that epithelial-specific PTEN excision was caused by differential Cre activity among tissues and cells types. Tamoxifen-induced deletion of PTEN resulted in extremely rapid and consistent formation of endometrial in situ adenocarcinoma, prostate intraepithelial neoplasia and thyroid hyperplasia. We also analyzed the role of PTEN ablation in other epithelial cells, such as the tubular cells of the kidney, hepatocytes, colonic epithelial cells or bronchiolar epithelium, but those tissues did not exhibit neoplastic growth. Finally, to validate this model as a tool to assay the efficacy of anti-tumor drugs in PTEN deficiency, we administered the mTOR inhibitor everolimus to mice with induced PTEN deletion. Everolimus dramatically reduced the progression of endometrial proliferations and significantly reduced thyroid hyperplasia. This model could be a valuable tool to study the cell-autonomous mechanisms involved in PTEN-loss-induced carcinogenesis and provides a good platform to study the effect of anti-neoplastic drugs on PTEN-negative tumors. PMID:23471917

  8. A role for Pten in paediatric intestinal dysmotility disorders.

    LENUS (Irish Health Repository)

    O'Donnell, Anne-Marie

    2012-02-01

    PURPOSE: The enteric nervous system (ENS) is a network of neurons and glia that lies within the gut wall. It is responsible for the normal regulation of gut motility and secretory activities. Hirschsprung\\'s disease (HD) is a congenital defect of the ENS, characterised by an absence of ganglia in the distal colon. Intestinal neuronal dysplasia (IND) is a condition that clinically resembles HD, characterised by hyperganglionosis, giant and ectopic ganglia, resulting in intestinal dysmotility. Intestinal ganglioneuromatosis is characterised by hyperplasia and hypertrophy of enteric neuronal cells and causes chronic intestinal pseudo-obstruction (CIPO). Phosphatase and tensin homolog deleted on chromosome 10 (Pten) is a phosphatase that is critical for controlling cell growth, proliferation and cell death. A recent study of Pten knockout mice showed evidence of ganglioneuromatosis in the ENS suggesting a role for this protein in ENS development. Ganglioneuromatosis patients have also been shown to have a decreased level of Pten expression in the colon. The aim of our study was to investigate Pten expression in the ENS of HD and IND patients compared to normal controls. METHODS: Resected tissue from 10 HD and 10 IND type B patients was fixed and embedded in paraffin wax. Normal control colon tissue was obtained from ten patients who underwent a colostomy closure for imperforate anus. Sections were cut and immunohistochemistry was carried out using a Pten antibody. Results were analysed by light microscopy. RESULTS: Staining showed that Pten was strongly expressed in ganglia of both the submucosal and myenteric plexus of normal and HD specimens from the ganglionic colon. Pten expression was significantly reduced in the giant ganglia in IND patients in both the myenteric and submucosal plexuses compared to the normal controls. Specimens from the aganglionic region of HD did not show Pten expression. CONCLUSION: To the best of our knowledge, this is the first study

  9. Characterization of novel non-clonal intrachromosomal rearrangements between the H4 and PTEN genes (H4/PTEN) in human thyroid cell lines and papillary thyroid cancer specimens

    International Nuclear Information System (INIS)

    Puxeddu, Efisio; Zhao Guisheng; Stringer, James R.; Medvedovic, Mario; Moretti, Sonia; Fagin, James A.

    2005-01-01

    mechanism for loss-of-function of PTEN, other thyroid neoplastic phenotypes and eventually other cancer types need to be screened for clonal H4/PTEN rearrangements

  10. Characterization of novel non-clonal intrachromosomal rearrangements between the H4 and PTEN genes (H4/PTEN) in human thyroid cell lines and papillary thyroid cancer specimens

    Energy Technology Data Exchange (ETDEWEB)

    Puxeddu, Efisio [Division of Endocrinology and Metabolism, University of Cincinnati College of Medicine, PO Box 670547, Cincinnati, OH 45267-0547 (United States); Zhao Guisheng [Division of Endocrinology and Metabolism, University of Cincinnati College of Medicine, PO Box 670547, Cincinnati, OH 45267-0547 (United States); Stringer, James R. [Department of Molecular Genetics, University of Cincinnati College of Medicine, PO Box 670547, Cincinnati, OH 45267-0547 (United States); Medvedovic, Mario [Center for Biostatistic Service, University of Cincinnati College of Medicine, PO Box 670547, Cincinnati, OH 45267-0547 (United States); Moretti, Sonia [Dipartimento di Medicina Interna, Universita degli Studi di Perugia, Via E. dal Pozzo, Perugia 06126, (Italy); Fagin, James A. [Division of Endocrinology and Metabolism, University of Cincinnati College of Medicine, PO Box 670547, Cincinnati, OH 45267-0547 (United States)]. E-mail: james.fagin@uc.edu

    2005-02-15

    plausible mechanism for loss-of-function of PTEN, other thyroid neoplastic phenotypes and eventually other cancer types need to be screened for clonal H4/PTEN rearrangements.

  11. Germline disruption of Pten localization causes enhanced sex-dependent social motivation and increased glial production.

    Science.gov (United States)

    Tilot, Amanda K; Gaugler, Mary K; Yu, Qi; Romigh, Todd; Yu, Wanfeng; Miller, Robert H; Frazier, Thomas W; Eng, Charis

    2014-06-15

    PTEN Hamartoma Tumor Syndrome (PHTS) is an autosomal-dominant genetic condition underlying a subset of autism spectrum disorder (ASD) with macrocephaly. Caused by germline mutations in PTEN, PHTS also causes increased risks of multiple cancers via dysregulation of the PI3K and MAPK signaling pathways. Conditional knockout models have shown that neural Pten regulates social behavior, proliferation and cell size. Although much is known about how the intracellular localization of PTEN regulates signaling in cancer cell lines, we know little of how PTEN localization influences normal brain physiology and behavior. To address this, we generated a germline knock-in mouse model of cytoplasm-predominant Pten and characterized its behavioral and cellular phenotypes. The homozygous Pten(m3m4) mice have decreased total Pten levels including a specific drop in nuclear Pten and exhibit region-specific increases in brain weight. The Pten(m3m4) model displays sex-specific increases in social motivation, poor balance and normal recognition memory-a profile reminiscent of some individuals with high functioning ASD. The cytoplasm-predominant protein caused cellular hypertrophy limited to the soma and led to increased NG2 cell proliferation and accumulation of glia. The animals also exhibit significant astrogliosis and microglial activation, indicating a neuroinflammatory phenotype. At the signaling level, Pten(m3m4) mice show brain region-specific differences in Akt activation. These results demonstrate that differing alterations to the same autism-linked gene can cause distinct behavioral profiles. The Pten(m3m4) model is the first murine model of inappropriately elevated social motivation in the context of normal cognition and may expand the range of autism-related behaviors replicated in animal models. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  12. The microbiome in PTEN hamartoma tumor syndrome.

    Science.gov (United States)

    Byrd, Victoria; Getz, Ted; Padmanabhan, Roshan; Arora, Hans; Eng, Charis

    2018-03-01

    Germline PTEN mutations defining PTEN hamartoma tumor syndrome (PHTS) confer heritable predisposition to breast, endometrial, thyroid and other cancers with known age-related risks, but it remains impossible to predict if any individual will develop cancer. In the general population, gut microbial dysbiosis has been linked to cancer, yet is unclear whether these are associated in PHTS patients. In this pilot study, we aimed to characterize microbial composition of stool, urine, and oral wash from 32 PTEN mutation-positive individuals using 16S rRNA gene sequencing. PCoA revealed clustering of the fecal microbiome by cancer history ( P  = 0.03, R 2  = 0.04). Fecal samples from PHTS cancer patients had relatively more abundant operational taxonomic units (OTUs) from family Rikenellaceae and unclassified members of Clostridia compared to those from non-cancer patients, whereas families Peptostreptococcaceae, Enterobacteriaceae, and Bifidobacteriaceae represented relatively more abundant OTUs among fecal samples from PHTS non-cancer patients. Functional metagenomic prediction revealed enrichment of the folate biosynthesis, genetic information processing and cell growth and death pathways among fecal samples from PHTS cancer patients compared to non-cancer patients. We found no major shifts in overall diversity and no clustering by cancer history among oral wash or urine samples. Our observations suggest the utility of an expanded study to interrogate gut dysbiosis as a potential cancer risk modifier in PHTS patients. © 2018 The authors.

  13. BMP suppresses PTEN expression via RAS/ERK signaling.

    Science.gov (United States)

    Beck, Stayce E; Carethers, John M

    2007-08-01

    Bone morphogenetic protein (BMP), a member of the transforming growth factor beta family, classically utilizes the SMAD signaling pathway for its growth suppressive effects,and loss of this signaling cascade may accelerate cell growth. In the colon cancer predisposition syndrome Juvenile Polyposis, as well as in the late progression stages of nonsyndromic colorectal cancers, SMAD4 function is typically abrogated. Here, we utilized the SMAD4-null SW480 colon cancer cell line to examine BMPs effect on a potential target gene, PTEN, and how its expression might be regulated. Initial treatment of the SMAD4-null cells with BMP resulted in mild growth suppression, but with prolonged exposure to BMP, the cells become growth stimulatory, which coincided with observed decreases in transcription and translation of PTEN, and with corresponding increases in phospho-AKT protein levels. BMP-induced PTEN suppression was mediated via the RAS/ERK pathway, as pharmacologic inhibition of RAS/ERK, or interference with protein function in the cytosol by DN-RAS prevented BMP-induced growth promotion and changes in PTEN levels, as did treatment with noggin, a BMP ligand inhibitor. Thus, BMP downregulates PTEN via RAS/ERK in a SMAD4-null environment that contributes to cell growth, and constitutes a SMAD4-independent but BMP-responsive signaling pathway.

  14. The Involvement of Phosphatase and Tensin Homolog Deleted on Chromosome Ten (PTEN in the Regulation of Inflammation Following Coronary Microembolization

    Directory of Open Access Journals (Sweden)

    Jiangyou Wang

    2014-06-01

    Full Text Available Background/Aims: Growing evidence shows that phosphatase and tensin homolog deleted on chromosome ten (PTEN is involved in regulating inflammation in different pathological conditions. Therefore, we hypothesized that the upregulation of PTEN correlates with the impairment of cardiac function in swine following coronary microembolization (CME. Methods: To possibly disclose an anti-inflammatory effect of PTEN, we induced swine CME by injecting inertia plastic microspheres (42 μm in diameter into the left anterior descending coronary artery and analyzed the myocardial tissue by immunochemistry, qRT-PCR and western blot analyses. In addition, we downregulated PTEN using siRNA. Results: Following CME, PTEN mRNA and protein levels were elevated as early as 3 h, peaked at 12 h, and then continuously decreased at 24 h and 48 h but remained elevated. Through linear correlation analysis, the PTEN protein level positively correlated with cTnI and TNF-α but was negatively correlated with LVEF. Furthermore, PTEN siRNA reduced the microinfarct volume, improved cardiac function (LVEF, reduced the release of cTnI, and suppressed PTEN and TNF-α protein expression. Conclusion: This study demonstrated, for the first time, that PTEN is involved in CME-induced inflammatory injury. The data generated from this study provide a rationale for the development of PTEN-based anti-inflammatory strategies.

  15. Hyperactivity of newborn Pten knock-out neurons results from increased excitatory synaptic drive.

    Science.gov (United States)

    Williams, Michael R; DeSpenza, Tyrone; Li, Meijie; Gulledge, Allan T; Luikart, Bryan W

    2015-01-21

    Developing neurons must regulate morphology, intrinsic excitability, and synaptogenesis to form neural circuits. When these processes go awry, disorders, including autism spectrum disorder (ASD) or epilepsy, may result. The phosphatase Pten is mutated in some patients having ASD and seizures, suggesting that its mutation disrupts neurological function in part through increasing neuronal activity. Supporting this idea, neuronal knock-out of Pten in mice can cause macrocephaly, behavioral changes similar to ASD, and seizures. However, the mechanisms through which excitability is enhanced following Pten depletion are unclear. Previous studies have separately shown that Pten-depleted neurons can drive seizures, receive elevated excitatory synaptic input, and have abnormal dendrites. We therefore tested the hypothesis that developing Pten-depleted neurons are hyperactive due to increased excitatory synaptogenesis using electrophysiology, calcium imaging, morphological analyses, and modeling. This was accomplished by coinjecting retroviruses to either "birthdate" or birthdate and knock-out Pten in granule neurons of the murine neonatal dentate gyrus. We found that Pten knock-out neurons, despite a rapid onset of hypertrophy, were more active in vivo. Pten knock-out neurons fired at more hyperpolarized membrane potentials, displayed greater peak spike rates, and were more sensitive to depolarizing synaptic input. The increased sensitivity of Pten knock-out neurons was due, in part, to a higher density of synapses located more proximal to the soma. We determined that increased synaptic drive was sufficient to drive hypertrophic Pten knock-out neurons beyond their altered action potential threshold. Thus, our work contributes a developmental mechanism for the increased activity of Pten-depleted neurons. Copyright © 2015 the authors 0270-6474/15/350943-17$15.00/0.

  16. Genomic Deletion at 10q23 in Prostate Cancer: More Than PTEN Loss?

    Directory of Open Access Journals (Sweden)

    Raghavendra Tejo Karthik Poluri

    2018-06-01

    Full Text Available The PTEN gene encodes for the phosphatase and tensin homolog; it is a tumor suppressor gene that is among the most frequently inactivated genes throughout the human cancer spectrum. The most recent sequencing approaches have allowed the identification of PTEN genomic alterations, including deletion, mutation, or rearrangement in about 50% of prostate cancer (PCa cases. It appears that mechanisms leading to PTEN inactivation are cancer-specific, comprising gene mutations, small insertions/deletions, copy number alterations (CNAs, promoter hypermethylation, and RNA interference. The examination of publicly available results from deep-sequencing studies of various cancers showed that PCa appears to be the only cancer in which PTEN is lost mostly through CNA. Instead of inactivating mutations, which are seen in other cancers, deletion of the 10q23 locus is the most common form of PTEN inactivation in PCa. By investigating the minimal deleted region at 10q23, several other genes appear to be lost simultaneously with PTEN. Expression data indicate that, like PTEN, these genes are also downregulated upon loss of 10q23. These analyses raise the possibility that 10q23 is lost upon selective pressure not only to inactivate PTEN but also to impair the expression of surrounding genes. As such, several genes from this deleted region, which represents about 500 kb, may also act as tumor suppressors in PCa, requiring further studies on their respective functions in that context.

  17. The PTEN protein: cellular localization and post-translational regulation.

    Science.gov (United States)

    Leslie, Nick R; Kriplani, Nisha; Hermida, Miguel A; Alvarez-Garcia, Virginia; Wise, Helen M

    2016-02-01

    The phosphatase and tensin homologue deleted on chromosome 10 (PTEN) phosphatase dephosphorylates PIP3, the lipid product of the class I PI 3-kinases, and suppresses the growth and proliferation of many cell types. It has been heavily studied, in large part due to its status as a tumour suppressor, the loss of function of which is observed through diverse mechanisms in many tumour types. Here we present a concise review of our understanding of the PTEN protein and highlight recent advances, particularly in our understanding of its localization and regulation by ubiquitination and SUMOylation. © 2016 Authors; published by Portland Press Limited.

  18. Tumor suppressor PTEN affects tau phosphorylation: deficiency in the phosphatase activity of PTEN increases aggregation of an FTDP-17 mutant Tau

    Directory of Open Access Journals (Sweden)

    Zhang Xue

    2006-07-01

    Full Text Available Abstract Background Aberrant hyperphosphorylation of tau protein has been implicated in a variety of neurodegenerative disorders. Although a number of protein kinases have been shown to phosphorylate tau in vitro and in vivo, the molecular mechanisms by which tau phosphorylation is regulated pathophysiologically are largely unknown. Recently, a growing body of evidence suggests a link between tau phosphorylation and PI3K signaling. In this study, phosphorylation, aggregation and binding to the microtubule of a mutant frontal temporal dementia and parkinsonism linked to chromosome 17 (FTDP-17 tau in the presence of tumor suppressor PTEN, a major regulatory component in PI3K signaling, were investigated. Results Phosphorylation of the human mutant FTDP-17 tau, T40RW, was evaluated using different phospho-tau specific antibodies in the presence of human wild-type or phosphatase activity null mutant PTEN. Among the evaluated phosphorylation sites, the levels of Ser214 and Thr212 phospho-tau proteins were significantly decreased in the presence of wild-type PTEN, and significantly increased when the phosphatase activity null mutant PTEN was ectopically expressed. Fractionation of the mutant tau transfected cells revealed a significantly increased level of soluble tau in cytosol when wild-type PTEN was expressed, and an elevated level of SDS-soluble tau aggregates in the presence of the mutant PTEN. In addition, the filter/trap assays detected more SDS-insoluble mutant tau aggregates in the cells overexpressing the mutant PTEN compared to those in the cells overexpressing wild-type PTEN and control DNA. This notion was confirmed by the immunocytochemical experiment which demonstrated that the overexpression of the phosphatase activity null mutant PTEN caused the mutant tau to form aggregates in the COS-7 cells. Conclusion Tumor suppressor PTEN can alleviate the phosporylation of the mutant FTDP-17 tau at specific sites, and the phosphatase activity

  19. A recessive form of extreme macrocephaly and mild intellectual disability complements the spectrum of PTEN hamartoma tumour syndrome.

    Science.gov (United States)

    Schwerd, Tobias; Khaled, Andrea V; Schürmann, Manfred; Chen, Hannah; Händel, Norman; Reis, André; Gillessen-Kaesbach, Gabriele; Uhlig, Holm H; Abou Jamra, Rami

    2016-06-01

    PTEN hamartoma tumour syndrome (PHTS) is caused by heterozygous variants in PTEN and is characterised by tumour predisposition, macrocephaly, and cognition impairment. Bi-allelic loss of PTEN activity has not been reported so far and animal models suggest that bi-allelic loss of PTEN activity is embryonically lethal. Here, we report the identification of a novel homozygous variant in PTEN, NM_000314.4; c.545T>C; p.Leu182Ser, in two adolescent siblings with severe macrocephaly and mild intellectual disability. The variant is predicted to be damaging and is associated with significantly increased phospho-S6 downstream of PTEN. The absence of tumours in the two homozygous siblings as well as lack of symptoms of PHTS in the heterozygous carriers of the family suggest that this particular variant is functionally hypomorphic rather than deleterious.

  20. Conditional Deletion of Pten Causes Bronchiolar Hyperplasia

    OpenAIRE

    Davé, Vrushank; Wert, Susan E.; Tanner, Tiffany; Thitoff, Angela R.; Loudy, Dave E.; Whitsett, Jeffrey A.

    2007-01-01

    Tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a lipid phosphatase that regulates multiple cellular processes including cell polarity, migration, proliferation, and carcinogenesis. In this work, we demonstrate that conditional deletion of Pten (PtenΔ/Δ) in the respiratory epithelial cells of the developing mouse lung caused epithelial cell proliferation and hyperplasia as early as 4 to 6 weeks of age. While bronchiolar cell differentiation was normal, as in...

  1. Studies of variability in the PTEN gene among Danish caucasian patients with Type II diabetes mellitus

    DEFF Research Database (Denmark)

    Hansen, L; Jensen, J N; Ekstrøm, C T

    2001-01-01

    Phosphatase and tensin homologue deleted from chromosome ten (PTEN) has recently been characterized as a novel member in the expanding network of proteins regulating the intracellular effects of insulin. By dephosphorylation of phosphatidyl-inositol-(3, 4, 5)-trisphosphate (PIP3) the PTEN protein...... regulates the insulin-dependent phosphoinositide 3-kinase (PI3K) signalling cassette and accordingly might function as a regulator of insulin sensitivity in skeletal muscle and adipose tissue. In this study we tested PTEN as a candidate gene for insulin resistance and late-onset Type II (non...

  2. Endogenous S-sulfhydration of PTEN helps protect against modification by nitric oxide

    International Nuclear Information System (INIS)

    Ohno, Kazuki; Okuda, Kosaku; Uehara, Takashi

    2015-01-01

    Highlights: • PTEN is S-sulfhydrated endogenously in SH-SY5Y human neuroblastoma cells. • Preventing this modification by knocking down CBS renders PTEN sensitive to NO. • pAkt levels are increased significantly in CBS siRNA-transfected cells. • H 2 S functions as an endogenous regulator of PTEN in neuronal cells. - Abstract: Hydrogen sulfide (H 2 S) is a gaseous regulatory factor produced by several enzymes, and plays a pivotal role in processes such as proliferation or vasodilation. Recent reports demonstrated the physiological and pathophysiological functions of H 2 S in neurons. PTEN is a target of nitric oxide (NO) or hydrogen peroxide, and the oxidative modification of cysteine (Cys) residue(s) attenuates its enzymatic activity. In the present study, we assessed the effect of H 2 S on the direct modification of PTEN and the resulting downstream signaling. A modified biotin switch assay in SH-SY5Y human neuroblastoma cells revealed that PTEN is S-sulfhydrated endogenously. Subsequently, site-directed mutagenesis demonstrated that both Cys71 and Cys124 in PTEN are targets for S-sulfhydration. Further, the knockdown of cystathionine β-synthetase (CBS) using siRNA decreased this modification in a manner that was correlated to amount of H 2 S. PTEN was more sensitive to NO under these conditions. These results suggest that the endogenous S-sulfhydration of PTEN via CBS/H 2 S plays a role in preventing the S-nitrosylation that would inhibition its enzymatic activity under physiological conditions

  3. Endogenous S-sulfhydration of PTEN helps protect against modification by nitric oxide

    Energy Technology Data Exchange (ETDEWEB)

    Ohno, Kazuki; Okuda, Kosaku; Uehara, Takashi, E-mail: uehara@pharm.okayama-u.ac.jp

    2015-01-02

    Highlights: • PTEN is S-sulfhydrated endogenously in SH-SY5Y human neuroblastoma cells. • Preventing this modification by knocking down CBS renders PTEN sensitive to NO. • pAkt levels are increased significantly in CBS siRNA-transfected cells. • H{sub 2}S functions as an endogenous regulator of PTEN in neuronal cells. - Abstract: Hydrogen sulfide (H{sub 2}S) is a gaseous regulatory factor produced by several enzymes, and plays a pivotal role in processes such as proliferation or vasodilation. Recent reports demonstrated the physiological and pathophysiological functions of H{sub 2}S in neurons. PTEN is a target of nitric oxide (NO) or hydrogen peroxide, and the oxidative modification of cysteine (Cys) residue(s) attenuates its enzymatic activity. In the present study, we assessed the effect of H{sub 2}S on the direct modification of PTEN and the resulting downstream signaling. A modified biotin switch assay in SH-SY5Y human neuroblastoma cells revealed that PTEN is S-sulfhydrated endogenously. Subsequently, site-directed mutagenesis demonstrated that both Cys71 and Cys124 in PTEN are targets for S-sulfhydration. Further, the knockdown of cystathionine β-synthetase (CBS) using siRNA decreased this modification in a manner that was correlated to amount of H{sub 2}S. PTEN was more sensitive to NO under these conditions. These results suggest that the endogenous S-sulfhydration of PTEN via CBS/H{sub 2}S plays a role in preventing the S-nitrosylation that would inhibition its enzymatic activity under physiological conditions.

  4. DAF-18/PTEN signals through AAK-1/AMPK to inhibit MPK-1/MAPK in feedback control of germline stem cell proliferation.

    Directory of Open Access Journals (Sweden)

    Patrick Narbonne

    2017-04-01

    Full Text Available Under replete growth conditions, abundant nutrient uptake leads to the systemic activation of insulin/IGF-1 signalling (IIS and the promotion of stem cell growth/proliferation. Activated IIS can stimulate the ERK/MAPK pathway, the activation of which also supports optimal stem cell proliferation in various systems. Stem cell proliferation rates can further be locally refined to meet the resident tissue's need for differentiated progeny. We have recently shown that the accumulation of mature oocytes in the C. elegans germ line, through DAF-18/PTEN, inhibits adult germline stem cell (GSC proliferation, despite high systemic IIS activation. We show here that this feedback occurs through a novel cryptic signalling pathway that requires PAR-4/LKB1, AAK-1/AMPK and PAR-5/14-3-3 to inhibit the activity of MPK-1/MAPK, antagonize IIS, and inhibit both GSC proliferation and the production of additional oocytes. Interestingly, our results imply that DAF-18/PTEN, through PAR-4/LKB1, can activate AAK-1/AMPK in the absence of apparent energy stress. As all components are conserved, similar signalling cascades may regulate stem cell activities in other organisms and be widely implicated in cancer.

  5. A Critical Role of the PTEN/PDGF Signaling Network for the Regulation of Radiosensitivity in Adenocarcinoma of the Prostate

    Energy Technology Data Exchange (ETDEWEB)

    Christensen, Michael, E-mail: mechristense@uwalumni.com [Department of Radiation Oncology, Wayne State University School of Medicine, Barbara Ann Karmanos Cancer Center, Detroit, Michigan (United States); Najy, Abdo J. [Department of Pathology, Wayne State University School of Medicine, Barbara Ann Karmanos Cancer Center, Detroit, Michigan (United States); Snyder, Michael; Movilla, Lisa S. [Department of Radiation Oncology, Wayne State University School of Medicine, Barbara Ann Karmanos Cancer Center, Detroit, Michigan (United States); Kim, Hyeong-Reh Choi [Department of Pathology, Wayne State University School of Medicine, Barbara Ann Karmanos Cancer Center, Detroit, Michigan (United States)

    2014-01-01

    that PDGF D represents a potentially promising target for PCa treatment resistance in the absence of PTEN function, and warrants further laboratory evaluation and clinical study.

  6. PTEN-induction in U251 glioma cells decreases the expression of insulin-like growth factor binding protein-2

    International Nuclear Information System (INIS)

    Levitt, Randy J.; Georgescu, Maria-Magdalena; Pollak, Michael

    2005-01-01

    PTEN is a tumor suppressor gene whose loss of function is observed in ∼40-50% of human cancers. Although insulin-like growth factor binding protein-2 (IGFBP-2) was classically described as a growth inhibitor, multiple recent reports have shown an association of overexpression and/or high serum levels of IGFBP-2 with poor prognosis of several malignancies, including gliomas. Using an inducible PTEN expression system in the PTEN-null glioma cell line U251, we demonstrate that PTEN-induction is associated with reduced proliferation, increased apoptosis, and a substantial reduction of the high levels of IGFBP-2 expression. The PTEN-induced decrease in IGFBP-2 expression could be mimicked with the PI3-kinase inhibitor LY294002, indicating that the lipid phosphatase activity of PTEN is responsible for the observed effect. However, the rapamycin analog CCI-779 did not affect IGFBP-2 expression, suggesting that the PTEN-induced decrease in IGFBP-2 expression is not attributable to decreased mTOR signalling. Recombinant human IGFBP-2 was unable to rescue U251-PTEN cells from the antiproliferative effects of PTEN, and IGFBP-2 siRNA did not affect the IGF-dependent or -independent growth of this cell line. These results suggest that the clinical data linking IGFBP-2 expression to poor prognosis may arise, at least in part, because high levels of IGFBP-2 expression correlate with loss of function of PTEN, which is well known to lead to aggressive behavior of gliomas. Our results motivate translational research regarding the relationship between IGFBP-2 expression and loss of function of PTEN

  7. Fish oil suppresses cell growth and metastatic potential by regulating PTEN and NF-κB signaling in colorectal cancer.

    Directory of Open Access Journals (Sweden)

    Shevali Kansal

    Full Text Available Homeostasis in eukaryotic tissues is tightly regulated by an intricate balance of the prosurvival and antisurvival signals. The tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10, a dual-specificity phosphatase, plays a functional role in cell cycle arrest and apoptosis. NF-κB and its downstream regulators (such as VEGF play a central role in prevention of apoptosis, promotion of inflammation and tumor growth. Therefore, we thought to estimate the expression of PTEN, Poly-ADP-ribose polymerase (PARP, NF-κBp50, NF-κBp65 and VEGF to evaluate the effect of supplementation of fish oil on apoptotic and inflammatory signaling in colon carcinoma. Male wistar rats in Group I received purified diet while Group II and III received modified diet supplemented with FO∶CO(1∶1&FO∶CO(2.5∶1 respectively. These were further subdivided into controls receiving ethylenediamine-tetra acetic-acid and treated groups received dimethylhydrazine-dihydrochloride (DMH/week for 4 weeks. Animals sacrificed 48 hours after last injection constituted initiation phase and that sacrificed after 16 weeks constituted post-initiation phase. We have analysed expression of PTEN, NF-κBp50, NF-κBp65 by flowcytometer and nuclear localization of NF-κB by immunofluorescence. PARP and VEGF were assessed by immunohistochemistry. In the initiation phase, animals receiving DMH have shown increased % of apoptotic cells, PTEN, PARP, NF-κBp50, NF-κBp65 and VEGF however in post-initiation phase no significant alteration in apoptosis with decreased PTEN and increased PARP, NF-κBp50, NF-κBp65 and VEGF were observed as compared to control animals. On treatment with both ratios of fish oil in both the phases, augmentation in % of apoptotic cells, decreased PTEN, PARP, NF-κBp50, NF-κBp65 and VEGF were documented with respect to DMH treated animals with effect being more exerted with higher ration in post-initiation phase. Hence, fish oil activates

  8. Interaction of E-cadherin and PTEN regulates morphogenesis and growth arrest in human mammary epithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Fournier, Marcia V.; Fata, Jimmie E.; Martin, Katherine J.; Yaswen, Paul; Bissell, Mina J.

    2009-06-03

    PTEN is a dual function phosphatase with tumor suppressor function compromised in a wide spectrum of cancers. Because tissue polarity and architecture are crucial modulators of normal and malignant behavior, we postulated that PTEN may play a role in maintenance of tissue integrity. We used two non-malignant human mammary epithelial cell lines (HMECs) that form polarized, growth-arrested structures (acini) when cultured in 3-dimensional laminin-rich extracellular matrix gels (3D lrECM). As acini begin to form, PTEN accumulates in both the cytoplasm, and at cell-cell contacts where it colocalizes with E-cadherin/{beta}-catenin complex. Reduction of PTEN levels by shRNA in lrECM prevents formation of organized breast acini and disrupts growth arrest. Importantly, disruption of acinar polarity and cell-cell contact by E-cadherin function-blocking antibodies reduces endogenous PTEN protein levels and inhibits its accumulation at cell-cell contacts. Conversely, in SKBR3 breast cancer cells lacking endogenous E-cadherin expression, exogenous introduction of E-cadherin gene causes induction of PTEN expression and its accumulation at sites of cell interactions. These studies provide evidence that E-cadherin regulates both the PTEN protein levels and its recruitment to cell-cell junctions in 3D lrECM indicating a dynamic reciprocity between architectural integrity and the levels and localization of PTEN. This interaction thus appears to be a critical integrator of proliferative and morphogenetic signaling in breast epithelial cells.

  9. Interaction of IGF2 and PTEN in ( M alignant Breast T issues

    Directory of Open Access Journals (Sweden)

    Preetha J Shetty

    2012-07-01

    Full Text Available Background: Breast Cancer (BC is one of the leading malignancies affecting women worldwide. Epigenetic mechanisms regulate gene expression playing an important role in the pathophysiology of cancer. In the present study IGF2 and PTEN genes in AKT pathway were selected for evaluation. Objective: To investigate the role of methylation and interaction of IGF2 and PTEN and in the pathoetiology of BC. Methods: Paraffin embedded archival breast tumor and adjacent normal tissue samples were used for carrying out PCR based methylation assay, genomic PCR, immunohistochemistry and qRT PCR. Results: In-Silico study indicated the absence of hormone responsive elements in the promoters of the selected genes. Methylation results indicated significant loss of methylation in IGF2 exon 9 CpG cluster and significant gain of PTEN promoter methylation in tumors. Immunohistochemistry revealed enhanced cytoplasmic expression o f IGF2 protein (p< 0.0001 and decreased nuclear localization of PTEN protein (p=0.0069 in the breast tumors. RT-PCR results indicated an increased IGF2 (p=0.024 and decreased PTEN transcripts (p<0.0001 in the tumors. Conclusion: Increased IGF2 in normal tissues increases PTEN which acts as a negative regulator of AKT pathway in the cytoplasm controlling excessive proliferation while in tumors this regulation is lost. PTEN acts as a negative regulator of MAPK pathway in the nucleus, plays an important role in cell cycle arrest in normal breast tissue. Reduction of PTEN in tumor tissue affects this pathway leading to cell survival. IGF2 and PTEN have a role in breast cancer and these molecular factors can be used for targeting therapy in future.

  10. Control functions in MFM

    DEFF Research Database (Denmark)

    Lind, Morten

    2011-01-01

    Multilevel Flow Modeling (MFM) has been proposed as a tool for representing goals and functions of complex industrial plants and suggested as a basis for reasoning about control situations. Lind presents an introduction to MFM but do not describe how control functions are used in the modeling....... The purpose of the present paper is to serve as a companion paper to this introduction by explaining the basic principles used in MFM for representation of control functions. A theoretical foundation for modeling control functions is presented and modeling examples are given for illustration....

  11. Supplementary data: Variation in the PTEN-induced putative kinase ...

    Indian Academy of Sciences (India)

    Variation in the PTEN-induced putative kinase 1 gene associated with the increase risk of type 2 diabetes in northern Chinese. Yanchun Qu, Liang Sun, Ze Yang and Ruifa Han. J. Genet. 90, 125–128. Table 1. Clinical characteristics of cases and controls. Phenotype. T2DM. Controls. P value. Age (years). 49.5 ± 11.1. 50.4 ± ...

  12. PTEN phosphatase-independent maintenance of glandular morphology in a predictive colorectal cancer model system.

    Science.gov (United States)

    Jagan, Ishaan C; Deevi, Ravi K; Fatehullah, Aliya; Topley, Rebecca; Eves, Joshua; Stevenson, Michael; Loughrey, Maurice; Arthur, Kenneth; Campbell, Frederick Charles

    2013-11-01

    Organotypic models may provide mechanistic insight into colorectal cancer (CRC) morphology. Three-dimensional (3D) colorectal gland formation is regulated by phosphatase and tensin homologue deleted on chromosome 10 (PTEN) coupling of cell division cycle 42 (cdc42) to atypical protein kinase C (aPKC). This study investigated PTEN phosphatase-dependent and phosphatase-independent morphogenic functions in 3D models and assessed translational relevance in human studies. Isogenic PTEN-expressing or PTEN-deficient 3D colorectal cultures were used. In translational studies, apical aPKC activity readout was assessed against apical membrane (AM) orientation and gland morphology in 3D models and human CRC. We found that catalytically active or inactive PTEN constructs containing an intact C2 domain enhanced cdc42 activity, whereas mutants of the C2 domain calcium binding region 3 membrane-binding loop (M-CBR3) were ineffective. The isolated PTEN C2 domain (C2) accumulated in membrane fractions, but C2 M-CBR3 remained in cytosol. Transfection of C2 but not C2 M-CBR3 rescued defective AM orientation and 3D morphogenesis of PTEN-deficient Caco-2 cultures. The signal intensity of apical phospho-aPKC correlated with that of Na(+)/H(+) exchanger regulatory factor-1 (NHERF-1) in the 3D model. Apical NHERF-1 intensity thus provided readout of apical aPKC activity and associated with glandular morphology in the model system and human colon. Low apical NHERF-1 intensity in CRC associated with disruption of glandular architecture, high cancer grade, and metastatic dissemination. We conclude that the membrane-binding function of the catalytically inert PTEN C2 domain influences cdc42/aPKC-dependent AM dynamics and gland formation in a highly relevant 3D CRC morphogenesis model system.

  13. PTEN Phosphatase-Independent Maintenance of Glandular Morphology in a Predictive Colorectal Cancer Model System

    Directory of Open Access Journals (Sweden)

    Ishaan C. Jagan

    2013-11-01

    Full Text Available Organotypic models may provide mechanistic insight into colorectal cancer (CRC morphology. Three-dimensional (3D colorectal gland formation is regulated by phosphatase and tensin homologue deleted on chromosome 10 (PTEN coupling of cell division cycle 42 (cdc42 to atypical protein kinase C (aPKC. This study investigated PTEN phosphatase-dependent and phosphatase-independent morphogenic functions in 3D models and assessed translational relevance in human studies. Isogenic PTEN-expressing or PTEN-deficient 3D colorectal cultures were used. In translational studies, apical aPKC activity readout was assessed against apical membrane (AM orientation and gland morphology in 3D models and human CRC. We found that catalytically active or inactive PTEN constructs containing an intact C2 domain enhanced cdc42 activity, whereas mutants of the C2 domain calcium binding region 3 membrane-binding loop (M-CBR3 were ineffective. The isolated PTEN C2 domain (C2 accumulated in membrane fractions, but C2 M-CBR3 remained in cytosol. Transfection of C2 but not C2 M-CBR3 rescued defective AM orientation and 3D morphogenesis of PTEN-deficient Caco-2 cultures. The signal intensity of apical phospho-aPKC correlated with that of Na+/H+ exchanger regulatory factor-1 (NHERF-1 in the 3D model. Apical NHERF-1 intensity thus provided readout of apical aPKC activity and associated with glandular morphology in the model system and human colon. Low apical NHERF-1 intensity in CRC associated with disruption of glandular architecture, high cancer grade, and metastatic dissemination. We conclude that the membrane-binding function of the catalytically inert PTEN C2 domain influences cdc42/aPKC-dependent AM dynamics and gland formation in a highly relevant 3D CRC morphogenesis model system.

  14. Effects of PTEN inhibition on the regulation of Tau phosphorylation in rat cortical neuronal injury after oxygen and glucose deprivation.

    Science.gov (United States)

    Zhao, Jing; Chen, Yurong; Xu, Yuxia; Pi, Guanghuan

    2016-01-01

    This report investigated the involvement of the PTEN pathway in the regulation of Tau phosphorylation using an oxygen and glucose deprivation (OGD) model with rat cortical neurons. Primary cortical neurons were used to establish the oxygen and glucose deprivation (OGD) model in vitro. These were randomly divided into control, OGD, bpV+OGD, As+OGD, Se+OGD and Mock treatment groups. The neuron viability was assessed by MTT, the cell apoptosis was detected using TUNEL staining. The expression of Phospho-PTEN/PTEN, Phospho-Tau/Tau, Phospho-Akt/Akt and Phospho-GSK-3β/GSK-3β were detected by Western blotting. OGD induced Tau phosphorylation through PTEN and glycogen synthase kinase-3β (GSK-3β) activation, together with a decrease in AKT activity. Pre-treatment with bpv, a potent PTEN inhibitor, and PTEN antisense nucleotides decreased PTEN and GSK-3β activity and caused alterations in Tau phosphorylation. Neuronal apoptosis was also reduced. The PTEN/Akt/GSK-3β/Tau pathway is involved in the regulation of neuronal injury, providing a novel route for protecting neurons following neonatal HI.

  15. Suppression of PTEN transcription by UVA

    Science.gov (United States)

    Zhao, Baozhong; Ming, Mei; He, Yu-Ying

    2012-01-01

    Although UVA has different physical and biological targets than UVB, the contribution of UVA to skin cancer susceptibility and its molecular basis remain largely unknown. Here we show that chronic UVA radiation suppresses PTEN expression at the mRNA level. Subchronic and acute UVA radiation also down-regulated PTEN in normal human epidermal keratinocytes, skin culture and mouse skin. At the molecular level, chronic UVA radiation decreased the transcriptional activity of the PTEN promoter in a methylation-independent manner, while it had no effect on the protein stability or mRNA stability of PTEN. In contrast, we found that UVA-induced activation of the Ras/ERK/AKT and NF-κB pathways plays an important role in UV-induced PTEN down-regulation. Inhibiting ERK or AKT increases PTEN expression. Our findings may provide unique insights into PTEN down-regulation as a critical component of UVA’s molecular impact during keratinocyte transformation. PMID:23129115

  16. PTEN gene and phosphorylation of Akt protein expression in the LPS-induced lung fibroblast

    Directory of Open Access Journals (Sweden)

    Mao-lin HUANG

    2014-09-01

    Full Text Available Objective: To investigate PTEN gene expression and the Akt phosphorylation of protein expression in the LPS-induced lung fibroblast, to initially reveal the relation between PTEN gene and the Akt phosphorylated proteins to LPS-induced lung fibroblast proliferation mechanism. Methods: BrdU experiments was performed to evaluate the LPS-induced lung fibroblast proliferation,  RT-PCR and Western Blot analysis were used to analyze the PTEN gene expression and Western blot was performed to analyze Akt phosphorylated protein expression. Results: PTEN mRNA level of the experimental group were significantly lower than the control group (P<0.05 with LPS simulation for 24h and 72h , and there were no significant difference between the experimental group and control group the experimental group and control group (P>0.05 . PTEN protein expression levels of the experimental group were significantly lower than the control group (P<0.05 , at 72h, and PTEN mRNA levels had no significant differences between these of the experimental and control group at 6h,12h and 24h(p>0.05. Phosphorylation Akt protein level (relative to total Akt protein was significantly higer than the control group (P<0.05 at 24h and 72h, and phosphorylation Akt protein levels had no significant differences between these of the experimental and control group at 6h and 12h (P>0.05 .Conclusion: PTEN gene and phosphorylation Akt protein involve in LPS-induced lung fibroblast proliferation signal transduction pathway.

  17. PTEN deletion from adult-generated dentate granule cells disrupts granule cell mossy fiber axon structure.

    Science.gov (United States)

    LaSarge, Candi L; Santos, Victor R; Danzer, Steve C

    2015-03-01

    Dysregulation of the mTOR-signaling pathway is implicated in the development of temporal lobe epilepsy. In mice, deletion of PTEN from hippocampal dentate granule cells leads to mTOR hyperactivation and promotes the rapid onset of spontaneous seizures. The mechanism by which these abnormal cells initiate epileptogenesis, however, is unclear. PTEN-knockout granule cells develop abnormally, exhibiting morphological features indicative of increased excitatory input. If these cells are directly responsible for seizure genesis, it follows that they should also possess increased output. To test this prediction, dentate granule cell axon morphology was quantified in control and PTEN-knockout mice. Unexpectedly, PTEN deletion increased giant mossy fiber bouton spacing along the axon length, suggesting reduced innervation of CA3. Increased width of the mossy fiber axon pathway in stratum lucidum, however, which likely reflects an unusual increase in mossy fiber axon collateralization in this region, offsets the reduction in boutons per axon length. These morphological changes predict a net increase in granule cell innervation of CA3. Increased diameter of axons from PTEN-knockout cells would further enhance granule cell communication with CA3. Altogether, these findings suggest that amplified information flow through the hippocampal circuit contributes to seizure occurrence in the PTEN-knockout mouse model of temporal lobe epilepsy. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. Cystic Fibrosis Transmembrane Conductance Regulator Attaches Tumor Suppressor PTEN to the Membrane and Promotes Anti Pseudomonas aeruginosa Immunity.

    Science.gov (United States)

    Riquelme, Sebastián A; Hopkins, Benjamin D; Wolfe, Andrew L; DiMango, Emily; Kitur, Kipyegon; Parsons, Ramon; Prince, Alice

    2017-12-19

    The tumor suppressor PTEN controls cell proliferation by regulating phosphatidylinositol-3-kinase (PI3K) activity, but the participation of PTEN in host defense against bacterial infection is less well understood. Anti-inflammatory PI3K-Akt signaling is suppressed in patients with cystic fibrosis (CF), a disease characterized by hyper-inflammatory responses to airway infection. We found that Ptenl -/- mice, which lack the NH 2 -amino terminal splice variant of PTEN, were unable to eradicate Pseudomonas aeruginosa from the airways and could not generate sufficient anti-inflammatory PI3K activity, similar to what is observed in CF. PTEN and the CF transmembrane conductance regulator (CFTR) interacted directly and this interaction was necessary to position PTEN at the membrane. CF patients under corrector-potentiator therapy, which enhances CFTR transport to the membrane, have increased PTEN amounts. These findings suggest that improved CFTR trafficking could enhance P. aeruginosa clearance from the CF airway by activating PTEN-mediated anti-bacterial responses and might represent a therapeutic strategy. Published by Elsevier Inc.

  19. Multifocal demyelinating motor neuropathy and hamartoma syndrome associated with a de novo PTEN mutation.

    Science.gov (United States)

    Bansagi, Boglarka; Phan, Vietxuan; Baker, Mark R; O'Sullivan, Julia; Jennings, Matthew J; Whittaker, Roger G; Müller, Juliane S; Duff, Jennifer; Griffin, Helen; Miller, James A L; Gorman, Grainne S; Lochmüller, Hanns; Chinnery, Patrick F; Roos, Andreas; Swan, Laura E; Horvath, Rita

    2018-05-22

    To describe a patient with a multifocal demyelinating motor neuropathy with onset in childhood and a mutation in phosphatase and tensin homolog ( PTEN ), a tumor suppressor gene associated with inherited tumor susceptibility conditions, macrocephaly, autism, ataxia, tremor, and epilepsy. Functional implications of this protein have been investigated in Parkinson and Alzheimer diseases. We performed whole-exome sequencing in the patient's genomic DNA validated by Sanger sequencing. Immunoblotting, in vitro enzymatic assay, and label-free shotgun proteomic profiling were performed in the patient's fibroblasts. The predominant clinical presentation of the patient was a childhood onset, asymmetric progressive multifocal motor neuropathy. In addition, he presented with macrocephaly, autism spectrum disorder, and skin hamartomas, considered as clinical criteria for PTEN-related hamartoma tumor syndrome. Extensive tumor screening did not detect any malignancies. We detected a novel de novo heterozygous c.269T>C, p.(Phe90Ser) PTEN variant, which was absent in both parents. The pathogenicity of the variant is supported by altered expression of several PTEN-associated proteins involved in tumorigenesis. Moreover, fibroblasts showed a defect in catalytic activity of PTEN against the secondary substrate, phosphatidylinositol 3,4-trisphosphate. In support of our findings, focal hypermyelination leading to peripheral neuropathy has been reported in PTEN-deficient mice. We describe a novel phenotype, PTEN-associated multifocal demyelinating motor neuropathy with a skin hamartoma syndrome. A similar mechanism may potentially underlie other forms of Charcot-Marie-Tooth disease with involvement of the phosphatidylinositol pathway. Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

  20. Conditional deletion of Pten causes bronchiolar hyperplasia.

    Science.gov (United States)

    Davé, Vrushank; Wert, Susan E; Tanner, Tiffany; Thitoff, Angela R; Loudy, Dave E; Whitsett, Jeffrey A

    2008-03-01

    Tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a lipid phosphatase that regulates multiple cellular processes including cell polarity, migration, proliferation, and carcinogenesis. In this work, we demonstrate that conditional deletion of Pten (Pten(Delta/Delta)) in the respiratory epithelial cells of the developing mouse lung caused epithelial cell proliferation and hyperplasia as early as 4 to 6 weeks of age. While bronchiolar cell differentiation was normal, as indicated by beta-tubulin and FOXJ1 expression in ciliated cells and by CCSP expression in nonciliated cells, cell proliferation (detected by expression of Ki-67, phospho-histone-H3, and cyclin D1) was increased and associated with activation of the AKT/mTOR survival pathway. Deletion of Pten caused papillary epithelial hyperplasia characterized by a hypercellular epithelium lining papillae with fibrovascular cores that protruded into the airway lumens. Cell polarity, as assessed by subcellular localization of cadherin, beta-catenin, and zonula occludens-1, was unaltered. PTEN is required for regulation of epithelial cell proliferation in the lung and for the maintenance of the normal simple columnar epithelium characteristics of bronchi and bronchioles.

  1. DNA methylation of PTEN gene promoter region is not correlated ...

    African Journals Online (AJOL)

    Tumor suppressor gene PTEN plays an important role in cell cycle. Disorder of PTEN protein can cause cell growth and division in an uncontrolled way, which can lead to the formation of tumors. It has been proven that epigenetic mechanisms, such as promoter hypermethylation, may account for inactivation of PTEN in a ...

  2. Reciprocal positive regulation between TRPV6 and NUMB in PTEN-deficient prostate cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sung-Young; Hong, Chansik; Wie, Jinhong [Department of Physiology, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Kim, Euiyong [Department of Physiology, College of Medicine, Inje University, Busan 614-735 (Korea, Republic of); Kim, Byung Joo [Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan 626-870 (Korea, Republic of); Ha, Kotdaji [Department of Physiology, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Cho, Nam-Hyuk; Kim, In-Gyu [Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Jeon, Ju-Hong [Department of Physiology, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); So, Insuk, E-mail: insuk@snu.ac.kr [Department of Physiology, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of)

    2014-04-25

    Highlights: • TRPV6 interacts with tumor suppressor proteins. • Numb has a selective effect on TRPV6, depending on the prostate cancer cell line. • PTEN is a novel regulator of TRPV6–Numb complex. - Abstract: Calcium acts as a second messenger and plays a crucial role in signaling pathways involved in cell proliferation. Recently, calcium channels related to calcium influx into the cytosol of epithelial cells have attracted attention as a cancer therapy target. Of these calcium channels, TRPV6 is overexpressed in prostate cancer and is considered an important molecule in the process of metastasis. However, its exact role and mechanism is unclear. NUMB, well-known tumor suppressor gene, is a novel interacting partner of TRPV6. We show that NUMB and TRPV6 have a reciprocal positive regulatory relationship in PC-3 cells. We repeated this experiment in two other prostate cancer cell lines, DU145 and LNCaP. Interestingly, there were no significant changes in TRPV6 expression following NUMB knockdown in DU145. We revealed that the presence or absence of PTEN was the cause of NUMB–TRPV6 function. Loss of PTEN caused a positive correlation of TRPV6–NUMB expression. Collectively, we determined that PTEN is a novel interacting partner of TRPV6 and NUMB. These results demonstrated a novel relationship of NUMB–TRPV6 in prostate cancer cells, and show that PTEN is a novel regulator of this complex.

  3. Uniting Control Lyapunov and Control Barrier Functions

    NARCIS (Netherlands)

    Romdlony, Zakiyullah; Jayawardhana, Bayu

    2014-01-01

    In this paper, we propose a nonlinear control design for solving the problem of stabilization with guaranteed safety. The design is based on the merging of a Control Lyapunov Function and a Control Barrier Function. The proposed control method allows us to combine the design of a stabilizer based on

  4. Role of PTEN in the Tumor Microenvironment

    Science.gov (United States)

    2009-06-01

    themselves, as well as the matrix that holds these cells together. Because the entire system is so complex, we plan to study how the Pten gene behaves as...Rev. 17, 501-519 8. Gould HJ, Sutton BJ. (2008). IgE in allergy and asthma today. Nat. Rev. Immunol. 8, 205-217. 9. Granucci F, Petralia F, Urbano M

  5. Characterization of Heterogeneous Prostate Tumors in Targeted Pten Knockout Mice.

    Directory of Open Access Journals (Sweden)

    Hanneke Korsten

    Full Text Available Previously, we generated a preclinical mouse prostate tumor model based on PSA-Cre driven inactivation of Pten. In this model homogeneous hyperplastic prostates (4-5m developed at older age (>10m into tumors. Here, we describe the molecular and histological characterization of the tumors in order to better understand the processes that are associated with prostate tumorigenesis in this targeted mouse Pten knockout model. The morphologies of the tumors that developed were very heterogeneous. Different histopathological growth patterns could be identified, including intraductal carcinoma (IDC, adenocarcinoma and undifferentiated carcinoma, all strongly positive for the epithelial cell marker Cytokeratin (CK, and carcinosarcomas, which were negative for CK. IDC pattern was already detected in prostates of 7-8 month old mice, indicating that it could be a precursor stage. At more than 10 months IDC and carcinosarcoma were most frequently observed. Gene expression profiling discriminated essentially two molecular subtypes, denoted tumor class 1 (TC1 and tumor class 2 (TC2. TC1 tumors were characterized by high expression of epithelial markers like Cytokeratin 8 and E-Cadherin whereas TC2 tumors showed high expression of mesenchyme/stroma markers such as Snail and Fibronectin. These molecular subtypes corresponded with histological growth patterns: where TC1 tumors mainly represented adenocarcinoma/intraductal carcinoma, in TC2 tumors carcinosarcoma was the dominant growth pattern. Further molecular characterization of the prostate tumors revealed an increased expression of genes associated with the inflammatory response. Moreover, functional markers for senescence, proliferation, angiogenesis and apoptosis were higher expressed in tumors compared to hyperplasia. The highest expression of proliferation and angiogenesis markers was detected in TC2 tumors. Our data clearly showed that in the genetically well-defined PSA-Cre;Pten-loxP/loxP prostate tumor

  6. MiR-155 promotes cell proliferation and inhibits apoptosis by PTEN signaling pathway in the psoriasis.

    Science.gov (United States)

    Xu, Longjiang; Leng, Hong; Shi, Xin; Ji, Jiang; Fu, Jinxiang; Leng, Hong

    2017-06-01

    MicroRNAs (miRNAs) have been demonstrated to contribute to malignant progression in psoriasis development. The purposes of the study was to evaluated the effects of miRNA-155 on cell proliferation, migration and apoptosis in psoriasis development via PTEN singaling pathway and identify its direct target protein. Quantitative real-time RT-PCR (qRT-PCR) was performed to examine the level of miR-155 in psoriasis cells, miR-155 was downregulated in a psoriasis cell line Hacat by transfected with small interfering RNA (siRNA), respectively. Cell survival was detected by the MTT assay and colony formation assay. Cell migration and invasion were measured via wound-healing assayand transwell assay. In addition, cell cycle and apoptosis about psoriasis cells was measured by flow cytometry. In this study, qRT-PCR assay showed that the expressions of miR-155 mRNA in psoriasis tissues were significantly higher than that in normal tissues. The assays about cell growth and proliferation showed that miR-155 knockdown led to a significant decrease in cell proliferation which was determined by MTT assay and colony formation assay compared to those of Lv-NC cells. Flow cytometry analysis showed that depletion of miR-155 could cause cell cycle change and the number of apoptotic cells was significantly increased in Lv-miR155 cells compared with control cells. In addition, the expression of several apoptosis-related factors were dramatically changed, such as PTEN, PIP 3 , AKT, p-AKT, Bax and Bcl-2. Our findings indicate that down-regulation of miR-155 significantly inhibits proliferation, migration, invasion and promotes apoptosis through PTEN singaling pathway in psoriasis cells. miR-155 might function as an oncogene miRNA in the progress of psoriasis. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  7. Atorvastatin Inhibits Myocardial Apoptosis in a Swine Model of Coronary Microembolization by Regulating PTEN/PI3K/Akt Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Jiangyou Wang

    2016-01-01

    Full Text Available Background/Aims: Phosphatase and tensin homolog deleted on chromosome ten (PTEN has been recognized as a promoter of apoptosis in various tissues, and revealed to be up-regulated in circumstances of coronary microembolization (CME. However, whether this functional protein could be modified by pretreatment of atorvastatin in models of CME has not been disclosed yet. Methods: Swine CME was induced by intra-coronary injection of inertia plastic microspheres (diameter 42 μm into left anterior descending coronary, with or without pretreatment of atorvastatin or PTEN siRNA. Echocardiologic measurements, pathologic examination, TUNEL staining and western blotting were applied to assess their functional, morphological and molecular effects in CME. Results: PTEN were aberrantly up-regulated in cardiomyocytes following CME, with both the mRNA and protein levels increased after CME modeling. Pretreatment with atorvastatin could attenuate the induction of PTEN. Furthermore, down-regulation of PTEN in vivo via siRNA was associated with an improved cardiac function, attenuated myocardial apoptosis, and concomitantly inhibited expressions of key proapoptotic proteins such as Bax, cleaved-caspase-3. Interestingly, atorvastatin could markedly attenuate PTEN expression and therefore partially reverse cardiac dysfunction and attenuate the apoptosis of the myocardium following CME. Conclusion: Modulation of PTEN was probably as a potential mechanism involved in the beneficial effects of pretreatment of atorvastatin to cardiac function and apoptosis in large animal models of CME.

  8. Organizational Control: Two Functions

    Science.gov (United States)

    Ouchi, William G.; Maguire, Mary Ann

    1975-01-01

    Distinguishes between two modes of organizational control, personal surveillance (behavior control) and the measurement of outputs (output control). Output control occurs in response to a manager's need to provide legitimate evidence of performance, while behavior control is exerted when means-ends relations are known and appropriate instruction…

  9. MicroRNA-221 and -222 Regulate Radiation Sensitivity by Targeting the PTEN Pathway

    International Nuclear Information System (INIS)

    Zhang Chunzhi; Kang Chunsheng; Wang Ping; Cao Yongzhen; Lv Zhonghong; Yu Shizhu; Wang Guangxiu; Zhang Anling; Jia Zhifan; Han Lei; Yang Chunying; Ishiyama, Hiromichi; Teh, Bin S.; Xu Bo; Pu Peiyu

    2011-01-01

    Purpose: MicroRNAs (miRNAs) are noncoding RNAs inhibiting expression of numerous target genes by posttranscriptional regulation. miRNA-221 and miRNA-222 (miRNA-221/-222) expression is elevated in radioresistant tumor cell lines; however, it is not known whether and how miRNAs control cellular responses to ionizing irradiation. Methods and Materials: We used bioinformatic analyses, luciferase reporter assay, and genetic knockdown and biochemical assays to characterize the regulation pathways of miRNA-221/-222 in response to radiation treatment. Results: We identified the PTEN gene as a target of miRNA-221/-222. Furthermore, we found that knocking down miRNA-221/-222 by antisense oligonucleotides upregulated PTEN expression. Upregulated PTEN expression suppressed AKT activity and increased radiation-induced apoptosis, resulting in enhancement of radiosensitivity in tumor cells. Conclusions: miRNA-221/-222 control radiation sensitivity by regulating the PTEN/AKT pathway and can be explored as novel targets for radiosensitization.

  10. Role of PTEN in the Tumor Microenvironment

    Science.gov (United States)

    2010-06-01

    fibroblasts (Fig. 2f, g), presumably owing to the constitutive Pten-independent activation of Erk1/2 by serum -stimulation23. Among the many expression...and provide rigorous validation proof. Using man- ual ground- truth , we compare the performance of the tensor classification framework with the k...tive hues in the standard H&E histological staining protocol. In an earlier effort, Pan and Huang (2005) devised a Bayesian supervised segmentation

  11. PTEN Sequence Analysis in Endometrial Hyperplasia and Endometrial Carcinoma in Slovak Women

    Directory of Open Access Journals (Sweden)

    H. Gbelcová

    2015-01-01

    Full Text Available Phosphatase and tensin homolog (PTEN is a protein that acts as a tumor suppressor by dephosphorylating the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate. Loss of PTEN function has been implicated in the pathogenesis of a number of different tumors, particularly endometrial carcinoma (ECa. ECa is the most common neoplasia of the female genital tract. Our study evaluates an association between the morphological appearance of endometrial hyperplasia and endometrial carcinoma and the degree of PTEN alterations. A total of 45 endometrial biopsies from Slovak women were included in present study. Formalin-fixed and paraffin-embedded tissue samples with simple hyperplasia (3, complex hyperplasia (5, atypical complex hyperplasia (7, endometrioid carcinomas G1 (20 and G3 (5, and serous carcinoma (5 were evaluated for the presence of mutations in coding regions of PTEN gene, the most frequently mutated tumor suppressor gene in endometrial carcinoma. 75% of the detected mutations were clustered in exons 5 and 8. Out of the 39 mutations detected in 24 cases, 20 were frameshifts and 19 were nonsense, missense, or silent mutations. Some specimens harboured more than one mutation. The results of current study on Slovak women were compared to a previous study performed on Polish population. The two sets of results were similar.

  12. The melatonin-MT1 receptor axis modulates tumor growth in PTEN-mutated gliomas.

    Science.gov (United States)

    Ma, Huihui; Wang, Zhen; Hu, Lei; Zhang, Shangrong; Zhao, Chenggang; Yang, Haoran; Wang, Hongzhi; Fang, Zhiyou; Wu, Lijun; Chen, Xueran

    2018-02-19

    More than 40% of glioma patients have tumors that harbor PTEN (phosphatase and tensin homologue deleted on chromosome ten) mutations; this disease is associated with poor therapeutic resistance and outcome. Such mutations are linked to increased cell survival and growth, decreased apoptosis, and drug resistance; thus, new therapeutic strategies focusing on inhibiting glioma tumorigenesis and progression are urgently needed. Melatonin, an indolamine produced and secreted predominantly by the pineal gland, mediates a variety of physiological functions and possesses antioxidant and antitumor properties. Here, we analyzed the relationship between PTEN and the inhibitory effect of melatonin in primary human glioma cells and cultured glioma cell lines. The results showed that melatonin can inhibit glioma cell growth both in culture and in vivo. This inhibition was associated with PTEN levels, which significantly correlated with the expression level of MT1 in patients. In fact, c-fos-mediated MT1 was shown to be a key modulator of the effect of melatonin on gliomas that harbor wild type PTEN. Taken together, these data suggest that melatonin-MT1 receptor complexes represent a potential target for the treatment of glioma. Copyright © 2018 Elsevier Inc. All rights reserved.

  13. A unified nomenclature and amino acid numbering for human PTEN

    NARCIS (Netherlands)

    Pulido, Rafael; Baker, Suzanne J; Barata, Joao T; Carracedo, Arkaitz; Cid, Victor J; Chin-Sang, Ian D; Davé, Vrushank; den Hertog, Jeroen; Devreotes, Peter; Eickholt, Britta J; Eng, Charis; Furnari, Frank B; Georgescu, Maria-Magdalena; Gericke, Arne; Hopkins, Benjamin; Jiang, Xeujun; Lee, Seung-Rock; Lösche, Mathias; Malaney, Prerna; Matias-Guiu, Xavier; Molina, María; Pandolfi, Pier Paolo; Parsons, Ramon; Pinton, Paolo; Rivas, Carmen; Rocha, Rafael M; Rodríguez, Manuel S; Ross, Alonzo H; Serrano, Manuel; Stambolic, Vuk; Stiles, Bangyan; Suzuki, Akira; Tan, Seong-Seng; Tonks, Nicholas K; Trotman, Lloyd C; Wolff, Nicolas; Woscholski, Rudiger; Wu, Hong; Leslie, Nicholas R

    2014-01-01

    The tumor suppressor PTEN is a major brake for cell transformation, mainly due to its phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3] phosphatase activity that directly counteracts the oncogenicity of phosphoinositide 3-kinase (PI3K). PTEN mutations are frequent in tumors and in the germ line

  14. Simvastatin and metformin inhibit cell growth in hepatitis C virus infected cells via mTOR increasing PTEN and autophagy.

    Directory of Open Access Journals (Sweden)

    José A Del Campo

    Full Text Available Hepatitis C virus (HCV infection has been related to increased risk of development of hepatocellular carcinoma (HCC while metformin (M and statins treatment seemed to protect against HCC development. In this work, we aim to identify the mechanisms by which metformin and simvastatin (S could protect from liver cancer. Huh7.5 cells were infected with HCV particles and treated with M+S. Human primary hepatocytes were treated with M+S. Treatment with both drugs inhibited Huh7.5 cell growth and HCV infection. In non-infected cells S increased translational controlled tumor protein (TCTP and phosphatase and tensin homolog (PTEN proteins while M inhibited mammalian target of rapamycin (mTOR and TCTP. Simvastatin and metformin co-administered down-regulated mTOR and TCTP, while PTEN was increased. In cells infected by HCV, mTOR, TCTP, p62 and light chain 3B II (LC3BII were increased and PTEN was decreased. S+M treatment increased PTEN, p62 and LC3BII in Huh7.5 cells. In human primary hepatocytes, metformin treatment inhibited mTOR and PTEN, but up-regulated p62, LC3BII and Caspase 3. In conclusion, simvastatin and metformin inhibited cell growth and HCV infection in vitro. In human hepatocytes, metformin increased cell-death markers. These findings suggest that M+S treatment could be useful in therapeutic prevention of HCV-related hepatocellular carcinoma.

  15. Klf5 deletion promotes Pten deletion-initiated luminal-type mouse prostate tumors through multiple oncogenic signaling pathways.

    Science.gov (United States)

    Xing, Changsheng; Ci, Xinpei; Sun, Xiaodong; Fu, Xiaoying; Zhang, Zhiqian; Dong, Eric N; Hao, Zhao-Zhe; Dong, Jin-Tang

    2014-11-01

    Krüppel-like factor 5 (KLF5) regulates multiple biologic processes. Its function in tumorigenesis appears contradictory though, showing both tumor suppressor and tumor promoting activities. In this study, we examined whether and how Klf5 functions in prostatic tumorigenesis using mice with prostate-specific deletion of Klf5 and phosphatase and tensin homolog (Pten), both of which are frequently inactivated in human prostate cancer. Histologic analysis demonstrated that when one Pten allele was deleted, which causes mouse prostatic intraepithelial neoplasia (mPIN), Klf5 deletion accelerated the emergence and progression of mPIN. When both Pten alleles were deleted, which causes prostate cancer, Klf5 deletion promoted tumor growth, increased cell proliferation, and caused more severe morphologic and molecular alterations. Homozygous deletion of Klf5 was more effective than hemizygous deletion. Unexpectedly, while Pten deletion alone expanded basal cell population in a tumor as reported, Klf5 deletion in the Pten-null background clearly reduced basal cell population while expanding luminal cell population. Global gene expression profiling, pathway analysis, and experimental validation indicate that multiple mechanisms could mediate the tumor-promoting effect of Klf5 deletion, including the up-regulation of epidermal growth factor and its downstream signaling molecules AKT and ERK and the inactivation of the p15 cell cycle inhibitor. KLF5 also appears to cooperate with several transcription factors, including CREB1, Sp1, Myc, ER and AR, to regulate gene expression. These findings validate the tumor suppressor function of KLF5. They also yield a mouse model that shares two common genetic alterations with human prostate cancer-mutation/deletion of Pten and deletion of Klf5.

  16. Architecture of conference control functions

    Science.gov (United States)

    Kausar, Nadia; Crowcroft, Jon

    1999-11-01

    Conference control is an integral part in many-to-many communications that is used to manage and co-ordinate multiple users in conferences. There are different types of conferences which require different types of control. Some of the features of conference control may be user invoked while others are for internal management of a conference. In recent years, ITU (International Telecommunication Union) and IETF (Internet Engineering Task Force) have standardized two main models of conferencing, each system providing a set of conference control functionalities that are not easily provided in the other one. This paper analyzes the main activities appropriate for different types of conferences and presents an architecture for conference control called GCCP (Generic Conference Control Protocol). GCCP interworks different types of conferencing and provides a set of conference control functions that can be invoked by users directly. As an example of interworking, interoperation of IETF's SIP and ITU's H.323 call control functions have been examined here. This paper shows that a careful analysis of a conferencing architecture can provide a set of control functions essential for any group communication model that can be extensible if needed.

  17. Establishment of pten knockout medaka with transcription activator-like effector nucleases (TALENs as a model of PTEN deficiency disease.

    Directory of Open Access Journals (Sweden)

    Yuriko Matsuzaki

    Full Text Available Phosphatase and tensin homolog (PTEN is a lipid and protein phosphatase that antagonizes signaling by the phosphatidylinositol 3-kinase (PI3K-AKT signaling pathway. The PTEN gene is a major tumor suppressor, with mutations of this gene occurring frequently in tumors of humans and mice. We have now developed mutant medaka deficient in PTEN with the use of transcription activator-like effector nuclease (TALEN technology. Medaka possesses two pten genes, ptena and ptenb, similar to zebrafish. We established 16 ptena mutant lines and two ptenb mutant lines. Homozygous single pten mutants were found to be viable and fertile. In contrast, pten double-knockout (dko embryos manifested severe abnormalities in vasculogenesis, eye size, and tail development at 72 hours post fertilization(hpf and died before hatching. Immunoblot analysis revealed that the ratio of phosphorylated to total forms of AKT (pAKT/AKT in pten dko embryos was four times that in wild-type embryos, indicative of up-regulation of signaling by the PI3K-AKT pathway. Treatment of pten dko embryos with the PI3K inhibitor LY294002 reduced the pAKT/AKT ratio by about one-half and partially rescued the defect in vasculogenesis. Additional inhibitors of the PI3K-AKT pathway, including rapamycin and N-α-tosyl-L-phenylalanyl chloromethyl ketone, also partially restored vasculogenesis in the dko embryos. Our model system thus allows pten dko embryos to be readily distinguished from wild-type embryos at an early stage of development and is suitable for the screening of drugs able to compensate for PTEN deficiency.

  18. The PTEN/NRF2 Axis Promotes Human Carcinogenesis

    DEFF Research Database (Denmark)

    Rojo, Ana I; Rada, Patricia; Mendiola, Marta

    2014-01-01

    and tumorigenic advantage. Tissue microarrays from endometrioid carcinomas showed that 80% of PTEN-negative tumors expressed high levels of NRF2 or its target heme oxygenase-1 (HO-1). INNOVATION: These results uncover a new mechanism of oncogenic activation of NRF2 by loss of its negative regulation by PTEN/GSK-3....../β-TrCP that may be relevant to a large number of tumors, including endometrioid carcinomas. CONCLUSION: Increased activity of NRF2 due to loss of PTEN is instrumental in human carcinogenesis and represents a novel therapeutic target. Antioxid. Redox Signal. 21, 2498-2514....

  19. Lycium barbarum Polysaccharide Promotes Nigrostriatal Dopamine Function by Modulating PTEN/AKT/mTOR Pathway in a Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Murine Model of Parkinson's Disease.

    Science.gov (United States)

    Wang, Xiaohong; Pang, Lei; Zhang, Yanqing; Xu, Jiang; Ding, Dongyi; Yang, Tianli; Zhao, Qian; Wu, Fan; Li, Fei; Meng, Haiwei; Yu, Duonan

    2018-04-01

    To investigate the effects of Lycium barbarum polysaccharide (LBP) on pathological symptoms and behavioral deficits in a Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) mouse model. The therapeutic effects of LBP were monitored with an Open field test, a Rotarod test and a Morris water maze test. We also investigated the mechanisms with qRT-PCR and Western blotting analyses. After a relatively short-term LBP treatment, the total distance and walking time of PD mice significantly increased. The staying duration on the rod of PD mice increased in the Rotarod test. LBP can up-regulate levels of SOD2, CAT and GPX1 and inhibit the abnormal aggregation of α-synuclein induced by MPTP. LBP treatment can also up-regulate the phosphorylation of AKT and mTOR, and may play its protective role by activating the PTEN/AKT/mTOR signaling axis. These results suggest that LBP can effectively alleviate the degeneration in the nigrostriatal system induced by MPTP treatment. It may be a potential candidate for the treatment of Parkinson's disease.

  20. MiR-21/PTEN Axis Promotes Skin Wound Healing by Dendritic Cells Enhancement.

    Science.gov (United States)

    Han, Zhaofeng; Chen, Ya; Zhang, Yile; Wei, Aizhou; Zhou, Jian; Li, Qian; Guo, Lili

    2017-10-01

    A number of miRNAs associated with wound repair have been identified and characterized, but the mechanism has not been fully clarified. MiR-21 is one of wound-related lncRNAs, and the study aimed to explore the functional involvement of miR-21 and its concrete mechanism in wound healing. In this study, the rat model of skin wounds was established. The expression of miR-21, PTEN and related molecules of wound tissues or cells was determined by quantitative real-time PCR and Western blot, respectively. The regulatory role of miR-21 on PTEN was examined by luciferase reporter gene assay. Flow cytometry assay was applied to measure cell number changes. MiR-21 was upregulated at 6, 24, 48, 72 h after model establishment, and the increase reached a maximum at 24 h in wound tissues. MMP-9 expression presented the same tread as miR-21 and was significantly enhanced within 6 h of wound formation, and then remained to be increased to the maximum at 24 h. The increase of miR-21 was accompanied by the increase of cell total number and DCs ratio in wound fluids. MiR-21 overexpression significantly improved the healing of skin wounds and increased the ratio of DCs in rats. The results of using FL confirmed that miR-21 overexpression obviously promoted DCs differentiation. Additionally, miR-21 could activate AKT/PI3K signaling pathway via inhibition of PTEN. MiR-21 contributes to wound healing via inhibition of PTEN that activated AKT/PI3K signaling pathway to increase DCs. J. Cell. Biochem. 118: 3511-3519, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  1. MicroRNA-22 promotes cell survival upon UV radiation by repressing PTEN

    International Nuclear Information System (INIS)

    Tan, Guangyun; Shi, Yuling; Wu, Zhao-Hui

    2012-01-01

    Highlights: ► miR-22 is induced in cells treated with UV radiation. ► ATM is required for miR-22 induction in response to UV. ► miR-22 targets 3′-UTR of PTEN to repress its expression in UV-treated cells. ► Upregulated miR-22 inhibits apoptosis in cells exposed to UV. -- Abstract: DNA damage response upon UV radiation involves a complex network of cellular events required for maintaining the homeostasis and restoring genomic stability of the cells. As a new class of players involved in DNA damage response, the regulation and function of microRNAs in response to UV remain poorly understood. Here we show that UV radiation induces a significant increase of miR-22 expression, which appears to be dependent on the activation of DNA damage responding kinase ATM (ataxia telangiectasia mutated). Increased miR-22 expression may result from enhanced miR-22 maturation in cells exposed to UV. We further found that tumor suppressor gene phosphatase and tensin homolog (PTEN) expression was inversely correlated with miR-22 induction and UV-induced PTEN repression was attenuated by overexpression of a miR-22 inhibitor. Moreover, increased miR-22 expression significantly inhibited the activation of caspase signaling cascade, leading to enhanced cell survival upon UV radiation. Collectively, these results indicate that miR-22 is an important player in the cellular stress response upon UV radiation, which may promote cell survival via the repression of PTEN expression.

  2. Genetic variations in a PTEN/AKT/mTOR axis and prostate cancer risk in a Chinese population.

    Directory of Open Access Journals (Sweden)

    Jiawei Chen

    Full Text Available Genetic variations in a PTEN/AKT/mTOR signaling axis may influence cellular functions including cell growth, proliferation and apoptosis, and then increase the individual's risk of cancer. Accordingly, we explore the association between single nucleotide polymorphisms (SNPs of these genes and prostate cancer (PCa in our Chinese population.Subjects were recruited from 666 PCa patients and 708 cancer-free controls, and eight SNPs in the PTEN/AKT/mTOR axis were determined by the TaqMan assay. Odds ratios (OR and 95% confidence intervals (95% CI were evaluated by logistic regression.We observed significant associations between PCa risk and mTOR rs2295080 [P = 0.027, OR = 0.85, 95%CI = 0.74-0.98], and AKT2 rs7254617 (P = 0.003, OR = 1.35, 95%CI = 1.11-1.64. When estimated these two SNPs together, the combined genotypes with 2-4 risk alleles (rs2295080 T and rs7254617 A alleles were associated with an increased risk of PCa compared with 0-1 risk alleles, which was more pronounced among subgroups of age >71 years, smokers, drinkers and no family history of cancer. Results of stratified analyses by cliniopathological parameters revealed that the frequencies of the combined genotypes with 2-4 risk alleles in advanced stage were significantly higher than in localized stage (P = 0.022, but there was no significant association in Gleason score and PSA level.Our results indicate, for the first time that the two variants in AKT2 and mTOR, particularly the joint genotypes with 2-4 risk alleles may influence PCa susceptibility and progression in Chinese, and the association appeared to be more strong in the subgroup of smokers and drinkers.

  3. Protein Kinase C Epsilon Cooperates with PTEN Loss for Prostate Tumorigenesis through the CXCL13-CXCR5 Pathway

    Directory of Open Access Journals (Sweden)

    Rachana Garg

    2017-04-01

    Full Text Available Summary: PKCε, an oncogenic member of the PKC family, is aberrantly overexpressed in epithelial cancers. To date, little is known about functional interactions of PKCε with other genetic alterations, as well as the effectors contributing to its tumorigenic and metastatic phenotype. Here, we demonstrate that PKCε cooperates with the loss of the tumor suppressor Pten for the development of prostate cancer in a mouse model. Mechanistic analysis revealed that PKCε overexpression and Pten loss individually and synergistically upregulate the production of the chemokine CXCL13, which involves the transcriptional activation of the CXCL13 gene via the non-canonical nuclear factor κB (NF-κB pathway. Notably, targeted disruption of CXCL13 or its receptor, CXCR5, in prostate cancer cells impaired their migratory and tumorigenic properties. In addition to providing evidence for an autonomous vicious cycle driven by PKCε, our studies identified a compelling rationale for targeting the CXCL13-CXCR5 axis for prostate cancer treatment. : Garg et al. find that PKCε overexpression cooperates with Pten loss to promote prostate cancer in mice. These two alterations together confer enhanced growth, tumorigenic, migratory and invasive capabilities to prostate epithelial cells, and promote the release of CXCL13, an effect that is mediated by the non-canonical NF-κB pathway. Keywords: PKCε, PTEN, CXCL13, NF-κB, prostate cancer, CXCR5, migration, proliferation, transgenic mice

  4. MiR-20a Induces Cell Radioresistance by Activating the PTEN/PI3K/Akt Signaling Pathway in Hepatocellular Carcinoma

    International Nuclear Information System (INIS)

    Zhang, Yuqin; Zheng, Lin; Ding, Yi; Li, Qi; Wang, Rong; Liu, Tongxin; Sun, Quanquan; Yang, Hua; Peng, Shunli; Wang, Wei; Chen, Longhua

    2015-01-01

    Purpose: To investigate the role of miR-20a in hepatocellular carcinoma (HCC) cell radioresistance, which may reveal potential strategies to improve treatment. Methods and Materials: The expression of miR-20a and PTEN were detected in HCC cell lines and paired primary tissues by quantitative real-time polymerase chain reaction. Cell radiation combined with colony formation assays was administrated to discover the effect of miR-20a on radiosensitivity. Bioinformatics prediction and luciferase assay were used to identify the target of miR-20a. The phosphatidylinositol 3-kinase inhibitor LY294002 was used to inhibit phosphorylation of Akt, to verify whether miR-20a affects HCC cell radioresistance through activating the PTEN/PI3K/Akt pathway. Results: MiR-20a levels were increased in HCC cell lines and tissues, whereas PTEN was inversely correlated with it. Overexpression of miR-20a in Bel-7402 and SMMC-7721 cells enhances their resistance to the effect of ionizing radiation, and the inhibition of miR-20a in HCCLM3 and QGY-7701 cells sensitizes them to it. PTEN was identified as a direct functional target of miR-20a for the induction of radioresistance. Overexpression of miR-20a activated the PTEN/PI3K/Akt signaling pathway. Additionally, the kinase inhibitor LY294002 could reverse the effect of miR-20a–induced radioresistance. Conclusion: MiR-20a induces HCC cell radioresistance by activating the PTEN/PI3K/Akt pathway, which suggests that miR-20a/PTEN/PI3K/Akt might represent a target of investigation for developing effective therapeutic strategies against HCC

  5. Increased plasma levels of FABP4 and PTEN is associated with more severe insulin resistance in women with gestational diabetes mellitus.

    Science.gov (United States)

    Li, Yuan-yuan; Xiao, Rui; Li, Cai-ping; Huangfu, Jian; Mao, Jiang-feng

    2015-02-08

    The aim of this study was to investigate the relationship between plasma fatty acid binding protein 4 (FABP4), phosphatase and tensin homolog (PTEN), and insulin resistance in patients with gestational diabetes mellitus (GDM). Plasma FABP4 and PTEN were determined by ELISA in GDM patients (GDM group, n=30) and in euglycemic pregnant women (control group, n=30). The clinical features, body mass index (BMI), homeostasis model assessment of insulin resistance (HOMA-IR), and lipid profiles were compared between the 2 groups. The influence of risk factors on insulin resistance, including BMI, lipid profiles, FABP4, and PTEN, were further investigated by multiple-factor stepwise regression analysis. Higher levels of BMI, ΔBMI, triglyceride (TG), fasting plasma glucose (FPG), 2-hour plasma glucose (2hPG), fasting insulin, HOMA-IR, FABP4, PTEN, and lower level of high-density lipoprotein cholesterol (HDL-C) were found in the GDM patients than in the controls (all Pinsulin resistance. GDM patients have more severe insulin resistance compared to euglycemic pregnant women. Higher levels of plasma FABP4 and PTEN are associated with increased insulin resistance and may participate in the pathogenesis of insulin resistance during gestation.

  6. The tumor suppressor PTEN inhibits EGF-induced TSP-1 and TIMP-1 expression in FTC-133 thyroid carcinoma cells

    International Nuclear Information System (INIS)

    Soula-Rothhut, Mahdhia; Coissard, Cyrille; Sartelet, Herve; Boudot, Cedric; Bellon, Georges; Martiny, Laurent; Rothhut, Bernard

    2005-01-01

    Thrombospondin-1 (TSP-1) is a multidomain extracellular macromolecule that was first identified as natural modulator of angiogenesis and tumor growth. In the present study, we found that epidermal growth factor (EGF) up-regulated TSP-1 expression in FTC-133 (primary tumor) but not in FTC-238 (lung metastasis) thyroid cancer cells. Both EGF and TSP-1 induced expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) in a mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and phosphatidylinositol 3-kinase (PI3-kinase)-dependent manner. In FTC-133 cells, EGF induced proliferation in a TSP-1- and TIMP-1-dependent manner. In addition, we determined that re-expression of the tumor suppressor protein PTEN induced cell death, an effect that correlated with a block of Akt kinase phosphorylation. EGF-induced TSP-1 and TIMP-1 promoter activity and protein expression were inhibited in FTC-133 cells stably expressing wtPTEN but not in cells expressing mutant PTEN. Furthermore, we found that wtPTEN inhibited EGF-but not TSP-1-stimulated FTC-133 cell migration and also inhibited invasion induced by EGF and by TSP-1. Finally, an antibody against TSP-1 reversed EGF-stimulated FTC-133 cell invasion as well as the constitutive invasive potential of FTC-238 cells. Overall, our results suggest that PTEN can function as an important modulator of extracellular matrix proteins in thyroid cancer. Therefore, analyzing differential regulation of TSP-1 by growth factors such as EGF can be helpful in understanding thyroid cancer development

  7. Activating PTEN by COX-2 inhibitors antagonizes radiation-induced AKT activation contributing to radiosensitization

    Energy Technology Data Exchange (ETDEWEB)

    Meng, Zhen [Central Laboratory, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081 (China); Department of Oral & Maxillofacial Surgery, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081 (China); Gan, Ye-Hua, E-mail: kqyehuagan@bjmu.edu.cn [Central Laboratory, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081 (China); Department of Oral & Maxillofacial Surgery, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081 (China)

    2015-05-01

    Radiotherapy is still one of the most effective nonsurgical treatments for many tumors. However, radioresistance remains a major impediment to radiotherapy. Although COX-2 inhibitors can induce radiosensitization, the underlying mechanism is not fully understood. In this study, we showed that COX-2 selective inhibitor celecoxib enhanced the radiation-induced inhibition of cell proliferation and apoptosis in HeLa and SACC-83 cells. Treatment with celecoxib alone dephosphorylated phosphatase and tensin homolog deleted on chromosome ten (PTEN), promoted PTEN membrane translocation or activation, and correspondingly dephosphorylated or inactivated protein kinase B (AKT). By contrast, treatment with radiation alone increased PTEN phosphorylation, inhibited PTEN membrane translocation and correspondingly activated AKT in the two cell lines. However, treatment with celecoxib or another COX-2 selective inhibitor (valdecoxib) completely blocked radiation-induced increase of PTEN phosphorylation, rescued radiation-induced decrease in PTEN membrane translocation, and correspondingly inactivated AKT. Moreover, celecoxib could also upregulate PTEN protein expression by downregulating Sp1 expression, thereby leading to the activation of PTEN transcription. Our results suggested that COX-2 inhibitors could enhance radiosensitization at least partially by activating PTEN to antagonize radiation-induced AKT activation. - Highlights: • COX-2 inhibitor, celecoxib, could enhance radiosensitization. • Radiation induced PTEN inactivation (phosphorylation) and AKT activation. • COX-2 inhibitor induced PTEN expression and activation, and inactivated AKT. • COX-2 inhibitor enhanced radiosensitization through activating PTEN.

  8. PTEN overexpression improves cisplatin-resistance of human ovarian cancer cells through upregulating KRT10 expression

    International Nuclear Information System (INIS)

    Wu, Huijuan; Wang, Ke; Liu, Wenxin; Hao, Quan

    2014-01-01

    Highlights: • Overexpression of PTEN enhanced the sensitivity of C13K cells to cisplatin. • KRT10 is a downstream molecule of PTEN involved in the resistance-reversing effect. • Overexpression of KRT10 enhanced the chemosensitivity of C13K cells to cisplatin. - Abstract: Multi-drug resistance (MDR) is a common cause of the failure of chemotherapy in ovarian cancer. PTEN, a tumor suppressor gene, has been demonstrated to be able to reverse cisplatin-resistance in ovarian cancer cell line C13K. However, the downstream molecules of PTEN involved in the resistance-reversing effect have not been completely clarified. Therefore, we screened the downstream molecules of PTEN and studied their interactions in C13K ovarian cancer cells using a 3D culture model. Firstly, we constructed an ovarian cancer cell line stably expressing PTEN, C13K/PTEN. MTT assay showed that overexpression of PTEN enhanced the sensitivity of C13K cells to cisplatin, but not to paclitaxel. Then we examined the differently expressed proteins that interacted with PTEN in C13K/PTEN cells with or without cisplatin treatment by co-immunoprecipitation. KRT10 was identified as a differently expressed protein in cisplatin-treated C13K/PTEN cells. Further study confirmed that cisplatin could induce upregulation of KRT10 mRNA and protein in C13K/PTEN cells and there was a directly interaction between KRT10 and PTEN. Forced expression of KRT10 in C13K cells also enhanced cisplatin-induced proliferation inhibition and apoptosis of C13K cells. In addition, KRT10 siRNA blocked cisplatin-induced proliferation inhibition of C13K/PTEN cells. In conclusion, our data demonstrate that KRT10 is a downstream molecule of PTEN which improves cisplatin-resistance of ovarian cancer and forced KRT10 overexpression may also act as a therapeutic method for overcoming MDR in ovarian cancer

  9. Inhibition of PTEN and activation of Akt by menadione.

    Science.gov (United States)

    Yoshikawa, Kyoko; Nigorikawa, Kiyomi; Tsukamoto, Mariko; Tamura, Namiko; Hazeki, Kaoru; Hazeki, Osamu

    2007-04-01

    Menadione (vitamin K(3)) has been shown to activate Erk in several cell lines. This effect has been shown to be due to the activation of EGF receptors (EGFR) as a result of inhibition of some protein tyrosine phosphatases. In the present study, we examined the effects of menadione on Akt in Chinese hamster ovary cells. The phosphorylation of Akt by menadione was not inhibited by AG1478, an inhibitor of EGFR. Menadione inhibited the lipid phosphatase activity of PTEN in a cell-free system. In an intact cell system, menadione inhibited the effect of transfected PTEN on Akt. Thus, one mechanism of its action was considered the accelerated activation of Akt through inhibition of PTEN. This was not the sole mechanism responsible for the EGFR-independent activation of Akt, because menadione attenuated the rate of Akt dephosphorylation even in PTEN-null PC3 cells. The decelerated inactivation of Akt, probably through inhibition of some tyrosine phosphatases, was considered another mechanism of its action.

  10. Expanding Internal Control Functionality Scope

    Directory of Open Access Journals (Sweden)

    Mykola M. Vuitsiv

    2012-08-01

    Full Text Available The article reviews the influence of «western» concepts of the information needs of management process provisions on forming and developing the up-to-date model of Internal Control. An attempt has been made to develop the approach to solve urgent management tasks by applying the ideas of controlling and management accounting via the traditional national approach to the content of control. The place of control in the enterprise management information system has also been reviewed.

  11. Control functions in nonseparable simultaneous equations models

    OpenAIRE

    Blundell, R.; Matzkin, R. L.

    2014-01-01

    The control function approach (Heckman and Robb (1985)) in a system of linear simultaneous equations provides a convenient procedure to estimate one of the functions in the system using reduced form residuals from the other functions as additional regressors. The conditions on the structural system under which this procedure can be used in nonlinear and nonparametric simultaneous equations has thus far been unknown. In this paper, we define a new property of functions called control function ...

  12. Heterozygosity for Pten promotes tumorigenesis in a mouse model of medulloblastoma.

    Directory of Open Access Journals (Sweden)

    Robert C Castellino

    Full Text Available BACKGROUND: Recent publications have described an important role for cross talk between PI-3 kinase and sonic hedgehog signaling pathways in the pathogenesis of medulloblastoma. METHODOLOGY/PRINCIPAL FINDINGS: We crossed mice with constitutive activation of Smoothened, SmoA1, with Pten deficient mice. Both constitutive and conditional Pten deficiency doubled the incidence of mice with symptoms of medulloblastoma and resulted in decreased survival. Analysis revealed a clear separation of gene signatures, with up-regulation of genes in the PI-3 kinase signaling pathway, including downstream activation of angiogenesis in SmoA1+/-; Pten +/- medulloblastomas. Western blotting and immunohistochemistry confirmed reduced or absent Pten, Akt activation, and increased angiogenesis in Pten deficient tumors. Down-regulated genes included genes in the sonic hedgehog pathway and tumor suppressor genes. SmoA1+/-; Pten +/+ medulloblastomas appeared classic in histology with increased proliferation and diffuse staining for apoptosis. In contrast, Pten deficient tumors exhibited extensive nodularity with neuronal differentiation separated by focal areas of intense staining for proliferation and virtually absent apoptosis. Examination of human medulloblastomas revealed low to absent PTEN expression in over half of the tumors. Kaplan-Meier analysis confirmed worse overall survival in patients whose tumor exhibited low to absent PTEN expression. CONCLUSIONS/SIGNIFICANCE: This suggests that PTEN expression is a marker of favorable prognosis and mouse models with activation of PI-3 kinase pathways may be important tools for preclinical evaluation of promising agents for the treatment of medulloblastoma.

  13. Dermal Delivery of Constructs Encoding Cre Recombinase to Induce Skin Tumors in PtenLoxP/LoxP;BrafCA/+ Mice

    Directory of Open Access Journals (Sweden)

    Marcel A. Deken

    2016-12-01

    Full Text Available Current genetically-engineered mouse melanoma models are often based on Tyr::CreERT2-controlled MAPK pathway activation by the BRAFV600E mutation and PI3K pathway activation by loss of PTEN. The major drawback of these models is the occurrence of spontaneous tumors caused by leakiness of the Tyr::CreERT2 system, hampering long-term experiments. To address this problem, we investigated several approaches to optimally provide local delivery of Cre recombinase, including injection of lentiviral particles, DNA tattoo administration and particle-mediated gene transfer, to induce melanomas in PtenLoxP/LoxP;BrafCA/+ mice lacking the Tyr::CreERT2 allele. We found that dermal delivery of the Cre recombinase gene under the control of a non-specific CAG promoter induced the formation of melanomas, but also keratoacanthoma and squamous cell carcinomas. Delivery of Cre recombinase DNA under the control of melanocyte-specific promoters in PtenLoxP/LoxP;BrafCA/+ mice resulted in sole melanoma induction. The growth rate and histological features of the induced tumors were similar to 4-hydroxytamoxifen-induced tumors in Tyr::CreERT2;PtenLoxP/LoxP;BrafCA/+ mice, while the onset of spontaneous tumors was prevented completely. These novel induction methods will allow long-term experiments in mouse models of skin malignancies.

  14. PTEN expression is consistent in colorectal cancer primaries and metastases and associates with patient survival

    International Nuclear Information System (INIS)

    Atreya, Chloe E; Sangale, Zaina; Xu, Nafei; Matli, Mary R; Tikishvili, Eliso; Welbourn, William; Stone, Steven; Shokat, Kevan M; Warren, Robert S

    2013-01-01

    Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) negatively regulates the phosphoinositide-3-kinase (PI3K) signaling pathway. In colorectal cancer (CRC), observed frequencies of loss of PTEN expression, concordant expression in primary tumors and metastases, and the association of PTEN status with outcome vary markedly by detection method. We determined the degree to which PTEN expression is consistent in 70 matched human CRC primaries and liver metastases using a validated immunohistochemistry assay. We found loss of PTEN expression in 12.3% of assessable CRC primaries and 10.3% of assessable liver metastases. PTEN expression (positive or negative) was concordant in 98% of matched colorectal primaries and liver metastases. Next we related PTEN status to mutations in RAS and PI3K pathway genes (KRAS, NRAS, BRAF, and PIK3CA) and to overall survival (OS). PTEN expression was not significantly associated with the presence or absence of mutations in RAS or PI3K pathway genes. The median OS of patients whose tumors did not express PTEN was 9 months, compared to 49 months for patients whose tumors did express PTEN (HR = 6.25, 95% confidence intervals (CI) (1.98, 15.42), P = 0.0017). The association of absent PTEN expression with increased risk of death remained significant in multivariate analysis (HR = 6.31, 95% CI (2.03, 17.93), P = 0.0023). In summary, PTEN expression was consistent in matched CRC primaries and in liver metastases. Therefore, future investigations of PTEN in metastatic CRC can use primary tumor tissue. In patients with liver-only metastases, loss of PTEN expression predicted poor OS. We observed concordant PTEN expression in 98% of colorectal cancer (CRC) primary and liver metastasis pairs using a validated immunohistochemistry assay. Consistent PTEN expression at both disease sites is significant because tumor tissue is usually available from CRC primaries but not metastases. Loss of PTEN expression associated with poor survival of

  15. Hydrocephalus caused by conditional ablation of the Pten or beta-catenin gene

    Directory of Open Access Journals (Sweden)

    Ohtoshi Akihira

    2008-10-01

    Full Text Available Abstract To investigate the roles of Pten and β-Catenin in the midbrain, either the Pten gene or the β-catenin gene was conditionally ablated, using Dmbx1 (diencephalon/mesencephalon-expressed brain homeobox gene 1-Cre mice. Homozygous disruption of the Pten or β-catenin gene in Dmbx1-expressing cells caused severe hydrocephalus and mortality during the postnatal period. Conditional deletion of Pten resulted in enlargement of midbrain structures. β-catenin conditional mutant mice showed malformation of the superior and inferior colliculi and stenosis of the midbrain aqueduct. These results demonstrate that both Pten and β-Catenin are essential for proper midbrain development, and provide the direct evidence that mutations of both Pten and β-catenin lead to hydrocephalus.

  16. RNA interference mediated pten knock-down inhibit the formation of polycystic ovary.

    Science.gov (United States)

    Ouyang, Jie-Xiu; Luo, Tao; Sun, Hui-Yun; Huang, Jian; Tang, Dan-Feng; Wu, Lei; Zheng, Yue-Hui; Zheng, Li-Ping

    2013-08-01

    Pten (phosphatase and tensin homolog deleted on chromosome 10), a kind of tumor suppressor gene, plays important roles in female reproductive system. But its expression and roles in the formation of polycystic ovaries are yet to be known. In this study, we constructed a rat model of PCOS using norethindrone and HCG injections and found the expressions of pten mRNA and PTEN protein increased significantly in the polycystic ovary tissue by immunohistochemistry, RT-PCR, and western blot. Furthermore, the results showed that in vivo ovaries could be effectively transfected by lentiviral vectors through the ovarian microinjection method and indicated that pten shRNA may inhibit the formation of polycystic ovaries by pten down-regulation. Our study provides new information regarding the role of PTEN in female reproductive disorders, such as polycystic ovary syndrome.

  17. Developing a PTEN-ERG Signature to Improve Molecular Risk Stratification in Prostate Cancer

    Science.gov (United States)

    2017-10-01

    AWARD NUMBER: W81XWH-16-1-0737 TITLE: Developing a PTEN-ERG Signature to Improve Molecular Risk Stratification in Prostate Cancer PRINCIPAL...AND SUBTITLE 5a. CONTRACT NUMBER Developing a PTEN-ERG Signature to Improve Molecular Risk Stratification in Prostate Cancer 5b. GRANT NUMBER W81XWH...that there exist distinctive molecular correlates of PTEN loss in the context of ETS-negative versus ETS-positive human prostate cancers and that

  18. Adenovirus mediated homozygous endometrial epithelial Pten deletion results in aggressive endometrial carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Joshi, Ayesha; Ellenson, Lora Hedrick, E-mail: lora.ellenson@med.cornell.edu

    2011-07-01

    Pten is the most frequently mutated gene in uterine endometriod carcinoma (UEC) and its precursor complex atypical hyperplasia (CAH). Because the mutation frequency is similar in CAH and UEC, Pten mutations are thought to occur relatively early in endometrial tumorigenesis. Previous work from our laboratory using the Pten{sup +/-} mouse model has demonstrated somatic inactivation of the wild type allele of Pten in both CAH and UEC. In the present study, we injected adenoviruses expressing Cre into the uterine lumen of adult Pten floxed mice in an attempt to somatically delete both alleles of Pten specifically in the endometrium. Our results demonstrate that biallelic inactivation of Pten results in an increased incidence of carcinoma as compared to the Pten{sup +/-} mouse model. In addition, the carcinomas were more aggressive with extension beyond the uterus into adjacent tissues and were associated with decreased expression of nuclear ER{alpha} as compared to associated CAH. Primary cultures of epithelial and stromal cells were prepared from uteri of Pten floxed mice and Pten was deleted in vitro using Cre expressing adenovirus. Pten deletion was evident in both the epithelial and stromal cells and the treatment of the primary cultures with estrogen had different effects on Akt activation as well as Cyclin D3 expression in the two purified components. This study demonstrates that somatic biallelic inactivation of Pten in endometrial epithelium in vivo results in an increased incidence and aggressiveness of endometrial carcinoma compared to mice carrying a germline deletion of one allele and provides an important in vivo and in vitro model system for understanding the genetic underpinnings of endometrial carcinoma.

  19. Adenovirus mediated homozygous endometrial epithelial Pten deletion results in aggressive endometrial carcinoma

    International Nuclear Information System (INIS)

    Joshi, Ayesha; Ellenson, Lora Hedrick

    2011-01-01

    Pten is the most frequently mutated gene in uterine endometriod carcinoma (UEC) and its precursor complex atypical hyperplasia (CAH). Because the mutation frequency is similar in CAH and UEC, Pten mutations are thought to occur relatively early in endometrial tumorigenesis. Previous work from our laboratory using the Pten +/- mouse model has demonstrated somatic inactivation of the wild type allele of Pten in both CAH and UEC. In the present study, we injected adenoviruses expressing Cre into the uterine lumen of adult Pten floxed mice in an attempt to somatically delete both alleles of Pten specifically in the endometrium. Our results demonstrate that biallelic inactivation of Pten results in an increased incidence of carcinoma as compared to the Pten +/- mouse model. In addition, the carcinomas were more aggressive with extension beyond the uterus into adjacent tissues and were associated with decreased expression of nuclear ERα as compared to associated CAH. Primary cultures of epithelial and stromal cells were prepared from uteri of Pten floxed mice and Pten was deleted in vitro using Cre expressing adenovirus. Pten deletion was evident in both the epithelial and stromal cells and the treatment of the primary cultures with estrogen had different effects on Akt activation as well as Cyclin D3 expression in the two purified components. This study demonstrates that somatic biallelic inactivation of Pten in endometrial epithelium in vivo results in an increased incidence and aggressiveness of endometrial carcinoma compared to mice carrying a germline deletion of one allele and provides an important in vivo and in vitro model system for understanding the genetic underpinnings of endometrial carcinoma.

  20. Complicated biallelic inactivation of Pten in radiation-induced mouse thymic lymphomas

    Energy Technology Data Exchange (ETDEWEB)

    Yamaguchi, Yu [Department of Biology, Graduate School of Science, Chiba University, Yayoicho, Inage-ku, Chiba 263-8522 (Japan); Experimental Radiobiology for Children' s Health Research Group, Research Center for Radiation Protection, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555 (Japan); Takabatake, Takashi; Kakinuma, Shizuko; Amasaki, Yoshiko; Nishimura, Mayumi; Imaoka, Tatsuhiko; Yamauchi, Kazumi; Shang, Yi [Experimental Radiobiology for Children' s Health Research Group, Research Center for Radiation Protection, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555 (Japan); Miyoshi-Imamura, Tomoko [Experimental Radiobiology for Children' s Health Research Group, Research Center for Radiation Protection, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555 (Japan); Genetic Counseling Program, Graduate School of Humanities and Sciences, Ochanomizu University, 2-1-1 Otsuka, Bunkyou-ku, Tokyo 112-8610 (Japan); Nogawa, Hiroyuki [Department of Biology, Graduate School of Science, Chiba University, Yayoicho, Inage-ku, Chiba 263-8522 (Japan); Kobayashi, Yoshiro [Department of Biomolecular Science, Faculty of Science, Toho University, Miyama 2-2-1, Funabashi, Chiba 274-8510 (Japan); Shimada, Yoshiya, E-mail: y_shimad@nirsgo.jp [Experimental Radiobiology for Children' s Health Research Group, Research Center for Radiation Protection, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555 (Japan)

    2010-04-01

    Inactivation of the phosphatase and tensin homolog gene (Pten) occurs via multiple tissue-dependent mechanisms including epigenetic silencing, point mutations, insertions, and deletions. Although frequent loss of heterozygosity around the Pten locus and plausible involvement of epigenetic silencing have been reported in radiation-induced thymic lymphomas, the proportion of lymphomas with inactivated Pten and the spectrum of causal aberrations have not been extensively characterized. Here, we assessed the mode of Pten inactivation by comprehensive analysis of the expression and alteration of Pten in 23 radiation-induced thymic lymphomas developed in B6C3F1 mice. We found no evidence for methylation-associated silencing of Pten; rather, complex structural abnormalities comprised of missense and nonsense mutations, 1- and 3-bp insertions, and focal deletions were identified in 8 of 23 lymphomas (35%). Sequencing of deletion breakpoints suggested that aberrant V(D)J recombination and microhomology-mediated rearrangement were responsible for the focal deletions. Seven of the 8 lymphomas had biallelic alterations, and 4 of them did not express Pten protein. These Pten aberrations coincided with downstream Akt phosphorylation. In conclusion, we demonstrate that Pten inactivation is frequently biallelic and is caused by a variety of structural abnormalities (rather than by epigenetic silencing) and is involved in radiation-induced lymphomagenesis.

  1. Understanding the tumor suppressor PTEN in chronic alcoholism and hepatocellular carcinoma.

    Science.gov (United States)

    Shearn, Colin T; Petersen, Dennis R

    2015-01-01

    The tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a phosphatidylinositol (PtdIns) phosphatase that regulates Akt activation via PtdIns 3 kinase. Changes in PTEN expression and/or activity have been identified in a variety of chronic hepatocellular disorders including obesity, NAFLD, NASH, and alcoholism. In cancer biology, PTEN is frequently mutated or deleted in a wide variety of tumors. Mutations, decreased promoter activity, and decreased expression in PTEN are frequently identified in patients with hepatocellular carcinoma. While the majority of research on PTEN concerns obesity and NASH, PTEN clearly has a role in hepatic insulin sensitivity and in the development of steatosis during chronic alcoholism. Yet, in chronic alcoholics and HCC, very little is known concerning PTEN mutation/deletion or low PTEN expression. This review is focused on an overview of the current knowledge on molecular mechanisms of dysregulation of PTEN expression/activity in the liver and their relationship to development of ethanol-induced hepatocellular damage and cancer.

  2. Redox Regulation of the Tumor Suppressor PTEN by Hydrogen Peroxide and Tert-Butyl Hydroperoxide

    Directory of Open Access Journals (Sweden)

    Ying Zhang

    2017-05-01

    Full Text Available Organic peroxides and hydroperoxides are skin tumor promoters. Free radical derivatives from these compounds are presumed to be the prominent mediators of tumor promotion. However, the molecular targets of these species are unknown. Phosphatase and tensin homologs deleted on chromosome 10 (PTEN are tumor suppressors that play important roles in cell growth, proliferation, and cell survival by negative regulation of phosphoinositol-3-kinase/protein kinase B signaling. PTEN is reversibly oxidized in various cells by exogenous and endogenous hydrogen peroxide. Oxidized PTEN is converted back to the reduced form by cellular reducing agents, predominantly by the thioredoxin (Trx system. Here, the role of tert-butyl hydroperoxide (t-BHP in redox regulation of PTEN was analyzed by using cell-based and in vitro assays. Exposure to t-BHP led to oxidation of recombinant PTEN. In contrast to H2O2, PTEN oxidation by t-BHP was irreversible in HeLa cells. However, oxidized PTEN was reduced by exogenous Trx system. Taken together, these results indicate that t-BHP induces PTEN oxidation and inhibits Trx system, which results in irreversible PTEN oxidation in HeLa cells. Collectively, these results suggest a novel mechanism of t-BHP in the promotion of tumorigenesis.

  3. Documenting control system functionality for digital control implementations

    International Nuclear Information System (INIS)

    Harber, J.; Borairi, M.; Tikku, S.; Josefowicz, A.

    2006-01-01

    In past CANDU designs, plant control was accomplished by a combination of digital control computers, analogue controllers, and hardwired relay logic. Functionality for these various control systems, each using different hardware, was documented in varied formats such as text based program specifications, relay logic diagrams, and other various specification documents. The choice of formats was influenced by the hardware used and often required different specialized skills for different applications. The programmable electronic systems in new CANDU designs are realized in a manner consistent with latest international standards (e.g., the IEC 61513 standard). New CANDU designs make extensive use of modern digital control technology, with the benefit that functionality can be implemented on a limited number of control platforms, reducing development and maintenance cost. This approach can take advantage of tools that allow the plant control system functional and performance requirements to be documented using graphical representations. Modern graphical methods supplemented by information databases can be used to provide a clear and comprehensive set of requirements for software and system development. Overview diagrams of system functionality provide a common understanding of the system boundaries and interfaces. Important requirements are readily traced through the development process. This improved reviewability helps to ensure consistency with the safety and and production design requirements of the system. Encapsulation of commonly used functions into custom-defined function blocks, such as typical motor control centre interfaces, process interlocks, median selects etc, eases the burden on designers to understand and analyze the detailed functionality of each instance of use of this logic. A library of encapsulated functions will be established for complex functions that are reused in the control logic development. By encapsulation and standardisation of such

  4. A Chimeric Protein PTEN-L-p53 Enters U251 Cells to Repress Proliferation and Invasion.

    Science.gov (United States)

    Xiao, Man; An, Yang; Wang, Fengling; Yao, Chao; Zhang, Chu; Xin, Junfang; Duan, Yongjian; Zhao, Xiaofang; Fang, Na; Ji, Shaoping

    2018-05-23

    PTEN, a well-known tumor suppressor, dephosphorylates PIP3 and inhibits AKT activity. A translational variant of PTEN has been identified and termed PTEN-Long (PTEN-L). The additional 173 amino acids (PTEN-L leader) at the N-terminal constitute a potential signal peptide. Differing from canonical PTEN, PTEN-L is secreted into the extracellular fluid and re-enters recipient cells, playing the similar roles as PTEN in vivo and in vitro. This character confers the PTEN-L a therapeutic ability via directly protein delivering instead of traditional DNA and RNA vector options. In the present study, we employed PTEN-L leader to assemble a fusion protein, PTEN-L-p53, inosculated with the transcriptional regulator TP53, which is another powerful tumor suppressor. We overexpressed PTEN-L-p53 in HEK293T cells and detected it in both the cytoplasm and nucleus. Subsequently, we found that PTEN-L-p53 was secreted outside of the cells and detected in the culture media by immunoblotting. Furthermore, we demonstrated that PTEN-L-p53 freely entered the cells and suppressed the viability of U251cells (p53 R273H , a cell line with p53 R273H-mutation). PTEN-L-p53 is composed of endogenous protein/peptide bearing low immunogenicity, and only the junction region between PTEN-L leader and p53 can act as a new immune epitope. Accordingly, this fusion protein can potentially be used as a therapeutic option for TP53-abnormality cancers. Copyright © 2018. Published by Elsevier Inc.

  5. Maximizing Function through Intelligent Robot Actuator Control

    Data.gov (United States)

    National Aeronautics and Space Administration — Maximizing Function through Intelligent Robot Actuator Control Successful missions to Mars and beyond will only be possible with the support of high-performance...

  6. Transfer Function Control for Biometric Monitoring System

    Science.gov (United States)

    Chmiel, Alan J. (Inventor); Humphreys, Bradley T. (Inventor); Grodinsky, Carlos M. (Inventor)

    2015-01-01

    A modular apparatus for acquiring biometric data may include circuitry operative to receive an input signal indicative of a biometric condition, the circuitry being configured to process the input signal according to a transfer function thereof and to provide a corresponding processed input signal. A controller is configured to provide at least one control signal to the circuitry to programmatically modify the transfer function of the modular system to facilitate acquisition of the biometric data.

  7. Pten regulates spindle pole movement through Dlg1-mediated recruitment of Eg5 to centrosomes

    NARCIS (Netherlands)

    Ree, J.H. van; Nam, H.J.; Jeganathan, K.B.; Kanakkanthara, A.; Deursen, J.M.A. van

    2016-01-01

    Phosphatase and tensin homologue (Pten) suppresses neoplastic growth by negatively regulating PI(3)K signalling through its phosphatase activity. To gain insight into the actions of non-catalytic Pten domains in normal physiological processes and tumorigenesis, we engineered mice lacking the

  8. Explaining Biological Functionality: Is Control Theory Enough ...

    African Journals Online (AJOL)

    I argue that the etiological approach, as understood in terms of control theory, suffers from a problem of symmetry, by which function can equally well be placed in the environment as in the organism. Focusing on the autonomy view, I note that it can be understood to some degree in terms of control theory in its version called ...

  9. Inhibition of PTEN and activation of Akt by menadione

    OpenAIRE

    Yoshikawa, Kyoko; Nigorikawa, Kiyomi; Tsukamoto, Mariko; Tamura, Namiko; Hazeki, Kaoru; Hazeki, Osamu

    2007-01-01

    Menadione (vitamin K3) has been shown to activate Erk in several cell lines. This effect has been shown to be due to the activation of EGF receptors (EGFR) as a result of inhibition of some protein tyrosine phosphatases. In the present study, we examined the effects of menadione on Akt in Chinese hamster ovary cells. The phosphorylation of Akt by menadione was not inhibited by AG1478, an inhibitor of EGFR. Menadione inhibited the lipid phosphatase activity of PTEN in a cell-free system. In an...

  10. Voltage-sensing phosphatase: its molecular relationship with PTEN.

    Science.gov (United States)

    Okamura, Yasushi; Dixon, Jack E

    2011-02-01

    Voltage-sensing phosphoinositide phosphatase (VSP) contains voltage sensor and cytoplasmic phosphatase domains. A unique feature of this protein is that depolarization-induced motions of the voltage sensor activate PtdIns(3,4,5)P(3) and PtdIns(4,5)P(2) phosphatase activities. VSP exhibits remarkable structural similarities with PTEN, the phosphatase and tensin homolog deleted on chromosome 10. These similarities include the cytoplasmic phosphatase region, the phosphoinositide binding region, and the putative membrane interacting C2 domain.

  11. Improved fuzzy PID controller design using predictive functional control structure.

    Science.gov (United States)

    Wang, Yuzhong; Jin, Qibing; Zhang, Ridong

    2017-11-01

    In conventional PID scheme, the ensemble control performance may be unsatisfactory due to limited degrees of freedom under various kinds of uncertainty. To overcome this disadvantage, a novel PID control method that inherits the advantages of fuzzy PID control and the predictive functional control (PFC) is presented and further verified on the temperature model of a coke furnace. Based on the framework of PFC, the prediction of the future process behavior is first obtained using the current process input signal. Then, the fuzzy PID control based on the multi-step prediction is introduced to acquire the optimal control law. Finally, the case study on a temperature model of a coke furnace shows the effectiveness of the fuzzy PID control scheme when compared with conventional PID control and fuzzy self-adaptive PID control. Copyright © 2017 ISA. Published by Elsevier Ltd. All rights reserved.

  12. Loss of PTEN causes SHP2 activation, making lung cancer cells unresponsive to IFN-γ

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Chia-Ling [Translational Research Center, Taipei Medical University, Taipei 110, Taiwan (China); Chiang, Tzu-Hui; Tseng, Po-Chun [Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan (China); Wang, Yu-Chih [Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan (China); Lin, Chiou-Feng, E-mail: cflin2014@tmu.edu.tw [Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan (China); Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan (China)

    2015-10-23

    Src homology-2 domain-containing phosphatase (SHP) 2, an oncogenic phosphatase, inhibits type II immune interferon (IFN)-γ signaling by subverting signal transducers and activators of transcription 1 tyrosine phosphorylation and activation. For cancer immunoediting, this study aimed to investigate the decrease of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a tumor suppressor protein, leading to cellular impairment of IFN-γ signaling. In comparison with human lung adenocarcinoma A549 cells, the natural PTEN loss in another human lung adenocarcinoma line, PC14PE6/AS2 cells, presents reduced responsiveness in IFN-γ-induced IFN regulatory factor 1 activation and CD54 expression. Artificially silencing PTEN expression in A549 cells also caused cells to be unresponsive to IFN-γ without affecting IFN-γ receptor expression. IFN-γ-induced inhibition of cell proliferation and cytotoxicity were demonstrated in A549 cells but were defective in PC14PE6/AS2 cells and in PTEN-deficient A549 cells. Aberrant activation of SHP2 by ROS was specifically shown in PC14PE6/AS2 cells and PTEN-deficient A549 cells. Inhibiting ROS and SHP2 rescued cellular responses to IFN-γ-induced cytotoxicity and inhibition of cell proliferation in PC14PE6/AS2 cells. These results demonstrate that a decrease in PTEN facilitates ROS/SHP2 signaling, causing lung cancer cells to become unresponsive to IFN-γ. - Highlights: • This study demonstrates that PTEN decrease causes cellular unresponsive to IFN-γ. • Lung cancer cells with PTEN deficiency show unresponsive to IFN-γ signaling. • PTEN decrease inhibits IFN-γ-induced CD54, cell proliferation inhibition, and cytotoxicity. • ROS-mediated SHP2 activation makes PTEN-deficient cells unresponsive to IFN-γ.

  13. Loss of CDH1 and Pten accelerates cellular invasiveness and angiogenesis in the mouse uterus.

    Science.gov (United States)

    Lindberg, Mallory E; Stodden, Genna R; King, Mandy L; MacLean, James A; Mann, Jordan L; DeMayo, Francesco J; Lydon, John P; Hayashi, Kanako

    2013-07-01

    E-cadherin (CDH1) is a cell adhesion molecule that coordinates key morphogenetic processes regulating cell growth, cell proliferation, and apoptosis. Loss of CDH1 is a trademark of the cellular event epithelial to mesenchymal transition, which increases the metastatic potential of malignant cells. PTEN is a tumor-suppressor gene commonly mutated in many human cancers, including endometrial cancer. In the mouse uterus, ablation of Pten induces epithelial hyperplasia, leading to endometrial carcinomas. However, loss of Pten alone does not affect longevity until around 5 mo. Similarly, conditional ablation of Cdh1 alone does not predispose mice to cancer. In this study, we characterized the impact of dual Cdh1 and Pten ablation (Cdh1(d/d) Pten(d/d)) in the mouse uterus. We observed that Cdh1(d/d) Pten(d/d) mice died at Postnatal Days 15-19 with massive blood loss. Their uteri were abnormally structured with curly horns, disorganized epithelial structure, and increased cell proliferation. Co-immunostaining of KRT8 and ACTA2 showed invasion of epithelial cells into the myometrium. Further, the uteri of Cdh1(d/d) Pten(d/d) mice had prevalent vascularization in both the endometrium and myometrium. We also observed reduced expression of estrogen and progesterone receptors, loss of cell adherens, and tight junction molecules (CTNNB1 and claudin), as well as activation of AKT in the uteri of Cdh1(d/d) Pten(d/d) mice. However, complex hyperplasia was not found in the uteri of Cdh1(d/d) Pten(d/d) mice. Collectively, these findings suggest that ablation of Pten with Cdh1 in the uterus accelerates cellular invasiveness and angiogenesis and causes early death.

  14. Feeding, evaluating, and controlling rumen function.

    Science.gov (United States)

    Lean, Ian J; Golder, Helen M; Hall, Mary Beth

    2014-11-01

    Achieving optimal rumen function requires an understanding of feeds and systems of nutritional evaluation. Key influences on optimal function include achieving good dry matter intake. The function of feeds in the rumen depends on other factors including chemical composition, rate of passage, degradation rate of the feed, availability of other substrates and cofactors, and individual animal variation. This article discusses carbohydrate, protein, and fat metabolism in the rumen, and provides practical means of evaluation of rations in the field. Conditions under which rumen function is suboptimal (ie, acidosis and bloat) are discussed, and methods for control examined. Copyright © 2014 Elsevier Inc. All rights reserved.

  15. Deletion of the N-terminus of IKKγ induces apoptosis in keratinocytes and impairs the AKT/PTEN signaling pathway

    International Nuclear Information System (INIS)

    Leis, Hugo; Sanchis, Ana; Perez, Paloma

    2007-01-01

    The regulatory subunit IKKγ/NEMO is crucial for skin development and function and although devoid of kinase activity, loss of IKKγ function completely abolishes the activation of NF-κB by all pro-inflammatory cytokines. To inhibit the IκB kinase (IKK) complex in keratinocytes, we have used a dominant negative approach by generating stable transfectants of an N-terminal deletion of IKKγ (IKKγ-DN97) that uncouples formation of the IKK complex. Expression of this mutant in PB keratinocytes (PB-IKKγ-DN97) delayed growth kinetics, caused morphological changes and dramatically augmented apoptosis even in the absence of pro-apoptotic stimuli, as determined by cell morphology, TUNEL and caspase-3 cleavage. Moreover, in PB-IKKγ-DN97 cells, TNF-α and IL-1 treatment failed to induce degradation of IκBα, phosphorylation of p65 on Ser 536 and nuclear translocation which, consequently, reduced κB-binding activity. In PB-IKKγ-DN97 cells, accumulation of IκBα correlated with a downregulation of AKT activity and an increase of PTEN protein levels whereas pro-apoptotic p53 target genes Bax and Puma were upregulated. These effects were most likely mediated through IKK since coexpression of the wild-type form of IKKγ in keratinocytes partially reversed apoptosis and reduced PTEN expression. Thus, our data suggest a negative cross-talk mechanism involving PTEN and NF-κB, critical for the anti-apoptotic role of NF-κB in keratinocytes

  16. Controlled functionalization of nanoparticles & practical applications

    Science.gov (United States)

    Rashwan, Khaled

    With the increasing use of nanoparticles in both science and industry, their chemical modification became a significant part of nanotechnology. Unfortunately, most commonly used procedures provide just randomly functionalized materials. The long-term objective of our work is site- and stoichiometrically-controlled functionalization of nanoparticles with the utilization of solid supports and other nanostructures. On the examples of silica nanoparticles and titanium dioxide nanorods, we have obtained results on the solid-phase chemistry, method development, and modeling, which advanced us toward this goal. At the same time, we explored several applications of nanoparticles that will benefit from the controlled functionalization: imaging of titanium-dioxide-based photocatalysts, bioimaging by fluorescent nanoparticles, drug delivery, assembling of bone implants, and dental compositions. Titanium dioxide-based catalysts are known for their catalytic activity and their application in solar energy utilization such as photosplitting of water. Functionalization of titanium dioxide is essential for enhancing bone-titanium dioxide nanotube adhesion, and, therefore, for its application as an interface between titanium implants and bones. Controlled functionalization of nanoparticles should enhance sensitivity and selectivity of nanoassemblies for imaging and drug delivery applications. Along those lines, we studied the relationship between morphology and surface chemistry of nanoparticles, and their affinity to organic molecules (salicylic and caffeic acid) using Langmuir adsorption isotherms, and toward material surfaces using SEM- and TEM-imaging. We focused on commercial samples of titanium dioxide, titanium dioxide nanorods with and without oleic acid ligands, and differently functionalized silica nanoparticles. My work included synthesis, functionalization, and characterization of several types of nanoparticles, exploring their application in imaging, dentistry, and bone

  17. Secondary control for microgrids using potential functions

    Energy Technology Data Exchange (ETDEWEB)

    Mehrizi-Sani, A.; Iravani, R. [Toronto Univ., ON (Canada)

    2009-07-01

    Issues with power grids include reliability, aging infrastructure, limited use of communications, efficiency, and low asset utilization. The smart grid involves a vision of the future electric system. Core elements of the smart grid include information technology, communication, and power electronic devices. This presentation discussed and compared the current grid with the smart grid and presented operational requirements of the microgrid. The concept of potential functions for secondary control based on availability of communication within the microgrid was introduced. The smart grid vision requires the microgrid to remain in operation even when islanded. The existing primary control does not guarantee stable islanded operation. Other topics that were discussed included primary and secondary control; proposed secondary control; the control hierarchy; and advantages and differences over conventional methods. A case study involving different scenarios was presented. It was concluded that the microgrid central controller minimizes each potential function to determine the set points of the corresponding distributed energy resources unit associated with the minimum of the potential function. tabs., figs.

  18. Reduced expression levels of PTEN are associated with decreased sensitivity of HCC827 cells to icotinib.

    Science.gov (United States)

    Zhai, Yang; Zhang, Yanjun; Nan, Kejun; Liang, Xuan

    2017-05-01

    The clinical resistance of non-small cell lung cancer (NSCLC) to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has been linked to EGFR T790M resistance mutations or MET amplifications. Additional mechanisms underlying EGFR-TKI drug resistance remain unclear. The present study demonstrated that icotinib significantly inhibited the proliferation and increased the apoptosis rate of HCC827 cells; the cellular mRNA and protein expression levels of phosphatase and tensin homolog (PTEN) were also significantly downregulated. To investigate the effect of PTEN expression levels on the sensitivity of HCC827 cells to icotinib, PTEN expression was silenced using a PTEN-specific small interfering RNA. The current study identified that the downregulation of PTEN expression levels may promote cellular proliferation in addition to decreasing the apoptosis of HCC827 cells, and may reduce the sensitivity of HCC827 cells to icotinib. These results suggested that reduced PTEN expression levels were associated with the decreased sensitivity of HCC827 cells to icotinib. Furthermore, PTEN expression levels may be a useful marker for predicting icotinib resistance and elucidating the resistance mechanisms underlying EGFR-mutated NSCLC.

  19. Regulation of the activity of the tumor suppressor PTEN by thioredoxin in Drosophila melanogaster

    International Nuclear Information System (INIS)

    Song, Zuohe; Saghafi, Negin; Gokhale, Vijay; Brabant, Marc; Meuillet, Emmanuelle J.

    2007-01-01

    Human Thioredoxin-1 (hTrx-1) is a small redox protein with a molecular weight of 12 kDa that contains two cysteine residues found in its catalytic site. HTrx-1 plays an important role in cell growth, apoptosis, and cancer patient prognosis. Recently, we have demonstrated that hTrx-1 binds to the C2 domain of the human tumor suppressor, PTEN, in a redox dependent manner. This binding leads to the inhibition of PTEN lipid phosphatase activity in mammalian tissue culture systems. In this study, we show that over-expression of hTrx-1 in Drosophila melanogaster promotes cell growth and proliferation during eye development as measured by eye size and ommatidia size. Furthermore, hTrx-1 rescues the small eye phenotype induced by the over-expression of PTEN. We demonstrate that this rescue of the PTEN-induced eye size phenotype requires cysteine-218 in the C2 domain of PTEN. We also show that hTrx-1 over-expression results in increased Akt phosphorylation in fly head extracts supporting our observations that the hTrx-1-induced eye size increase results from the inhibition of PTEN activity. Our study confirms the redox regulation of PTEN through disulfide bond formation with the hTrx-1 in Drosophila and suggests conserved mechanisms for thioredoxins and their interactions with the phosphatidylinositol-3-kinase signaling pathway in humans and fruit flies

  20. Bregman storage functions for microgrid control

    NARCIS (Netherlands)

    De Persis, Claudio; Monshizadeh, Nima

    In this paper, we contribute a theoretical framework that sheds a new light on the problem of microgrid analysis and control. The starting point is an energy function comprising the “kinetic” energy associated with the elements that emulate the rotating machinery and terms taking into account the

  1. The significance of PTEN and AKT aberrations in pediatric T-cell acute lymphoblastic leukemia

    Science.gov (United States)

    Zuurbier, Linda; Petricoin, Emanuel F.; Vuerhard, Maartje J.; Calvert, Valerie; Kooi, Clarissa; Buijs-Gladdines, Jessica G.C.A.M.; Smits, Willem K.; Sonneveld, Edwin; Veerman, Anjo J.P.; Kamps, Willem A.; Horstmann, Martin; Pieters, Rob; Meijerink, Jules P.P.

    2012-01-01

    Background PI3K/AKT pathway mutations are found in T-cell acute lymphoblastic leukemia, but their overall impact and associations with other genetic aberrations is unknown. PTEN mutations have been proposed as secondary mutations that follow NOTCH1-activating mutations and cause cellular resistance to γ-secretase inhibitors. Design and Methods The impact of PTEN, PI3K and AKT aberrations was studied in a genetically well-characterized pediatric T-cell leukemia patient cohort (n=146) treated on DCOG or COALL protocols. Results PTEN and AKT E17K aberrations were detected in 13% and 2% of patients, respectively. Defective PTEN-splicing was identified in incidental cases. Patients without PTEN protein but lacking exon-, splice-, promoter mutations or promoter hypermethylation were present. PTEN/AKT mutations were especially abundant in TAL- or LMO-rearranged leukemia but nearly absent in TLX3-rearranged patients (P=0.03), the opposite to that observed for NOTCH1-activating mutations. Most PTEN/AKT mutant patients either lacked NOTCH1-activating mutations (P=0.006) or had weak NOTCH1-activating mutations (P=0.011), and consequently expressed low intracellular NOTCH1, cMYC and MUSASHI levels. T-cell leukemia patients without PTEN/AKT and NOTCH1-activating mutations fared well, with a cumulative incidence of relapse of only 8% versus 35% for PTEN/AKT and/or NOTCH1-activated patients (P=0.005). Conclusions PI3K/AKT pathway aberrations are present in 18% of pediatric T-cell acute lymphoblastic leukemia patients. Absence of strong NOTCH1-activating mutations in these cases may explain cellular insensitivity to γ-secretase inhibitors. PMID:22491738

  2. RAS/ERK modulates TGFbeta-regulated PTEN expression in human pancreatic adenocarcinoma cells.

    Science.gov (United States)

    Chow, Jimmy Y C; Quach, Khai T; Cabrera, Betty L; Cabral, Jennifer A; Beck, Stayce E; Carethers, John M

    2007-11-01

    Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is rarely mutated in pancreatic cancers, but its regulation by transforming growth factor (TGF)-beta might mediate growth suppression and other oncogenic actions. Here, we examined the role of TGFbeta and the effects of oncogenic K-RAS/ERK upon PTEN expression in the absence of SMAD4. We utilized two SMAD4-null pancreatic cell lines, CAPAN-1 (K-RAS mutant) and BxPc-3 (WT-K-RAS), both of which express TGFbeta surface receptors. Cells were treated with TGFbeta1 and separated into cytosolic/nuclear fractions for western blotting with phospho-SMAD2, SMAD 2, 4 phospho-ATP-dependent tyrosine kinases (Akt), Akt and PTEN antibodies. PTEN mRNA levels were assessed by reverse transcriptase-polymerase chain reaction. The MEK1 inhibitor, PD98059, was used to block the downstream action of oncogenic K-RAS/ERK, as was a dominant-negative (DN) K-RAS construct. TGFbeta increased phospho-SMAD2 in both cytosolic and nuclear fractions. PD98059 treatment further increased phospho-SMAD2 in the nucleus of both pancreatic cell lines, and DN-K-RAS further improved SMAD translocation in K-RAS mutant CAPAN cells. TGFbeta treatment significantly suppressed PTEN protein levels concomitant with activation of Akt by 48 h through transcriptional reduction of PTEN mRNA that was evident by 6 h. TGFbeta-induced PTEN suppression was reversed by PD98059 and DN-K-RAS compared with treatments without TGFbeta. TGFbeta-induced PTEN expression was inversely related to cellular proliferation. Thus, oncogenic K-RAS/ERK in pancreatic adenocarcinoma facilitates TGFbeta-induced transcriptional down-regulation of the tumor suppressor PTEN in a SMAD4-independent manner and could constitute a signaling switch mechanism from growth suppression to growth promotion in pancreatic cancers.

  3. SURFACE TEXTURE ANALYSIS FOR FUNCTIONALITY CONTROL

    DEFF Research Database (Denmark)

    De Chiffre, Leonardo; Andreasen, Jan Lasson; Tosello, Guido

    This document is used in connection with three exercises of 3 hours duration as a part of the course VISION ONLINE – One week course on Precision & Nanometrology. The exercises concern surface texture analysis for functionality control, in connection with three different case stories. This docume...... contains a short description of each case story, 3-D roughness parameters analysis and relation with the product’s functionality.......This document is used in connection with three exercises of 3 hours duration as a part of the course VISION ONLINE – One week course on Precision & Nanometrology. The exercises concern surface texture analysis for functionality control, in connection with three different case stories. This document...

  4. Metformin inhibits inflammatory response via AMPK–PTEN pathway in vascular smooth muscle cells

    International Nuclear Information System (INIS)

    Kim, Sun Ae; Choi, Hyoung Chul

    2012-01-01

    Highlights: ► PTEN was induced by metformin and inhibited by compound C and AMPK siRNA. ► Metformin suppressed TNF-α-induced COX-2 and iNOS mRNA expression. ► Compound C and bpv (pic) increased iNOS and COX-2 protein expression. ► NF-κB activation was restored by inhibiting AMPK and PTEN. ► AMPK and PTEN regulated TNF-α-induced ROS production in VSMCs. -- Abstract: Atherosclerosis is a chronic inflammation of the coronary arteries. Vascular smooth muscle cells (VSMCs) stimulated by cytokines and chemokines accelerate the inflammatory response and migrate to the injured endothelium during the progression of atherosclerosis. Activation of AMP activated protein kinase (AMPK), a key sensor maintaining metabolic homeostasis, suppresses the inflammatory response. However, how AMPK regulates the inflammatory response is poorly understood. To identify the mechanism of this response, we focused on phosphatase and tensin homolog (PTEN), which is a negative regulator of inflammation. We investigated that activation of AMPK-induced PTEN expression and suppression of the inflammatory response through the AMPK–PTEN pathway in VSMCs. We treated with the well-known AMPK activator metformin to induce PTEN expression. PTEN was induced by metformin (2 mM) and inhibited by compound C (10 μM) and AMPK siRNA. Tumor necrosis factor-alpha (TNF-α) was used to induce inflammation. The inflammatory response was confirmed by cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS) expression, and activation of nuclear factor (NF)-κB. Metformin suppressed COX-2 and iNOS mRNA and protein expression dose dependently. Treatment with compound C and bpv (pic) in the presence of metformin, iNOS and COX-2 protein expression increased. NF-κB activation decreased in response to metformin and was restored by inhibiting AMPK and PTEN. Inhibiting AMPK and PTEN restored ROS levels stimulated with TNF-α. Taken together, PTEN could be a possible downstream regulator of AMPK, and the

  5. Metformin inhibits inflammatory response via AMPK-PTEN pathway in vascular smooth muscle cells

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sun Ae [Department of Pharmacology, Aging-Associated Vascular Disease Research Center, College of Medicine, Yeungnam University, Daegu 705-717 (Korea, Republic of); Choi, Hyoung Chul, E-mail: hcchoi@med.yu.ac.kr [Department of Pharmacology, Aging-Associated Vascular Disease Research Center, College of Medicine, Yeungnam University, Daegu 705-717 (Korea, Republic of)

    2012-09-07

    Highlights: Black-Right-Pointing-Pointer PTEN was induced by metformin and inhibited by compound C and AMPK siRNA. Black-Right-Pointing-Pointer Metformin suppressed TNF-{alpha}-induced COX-2 and iNOS mRNA expression. Black-Right-Pointing-Pointer Compound C and bpv (pic) increased iNOS and COX-2 protein expression. Black-Right-Pointing-Pointer NF-{kappa}B activation was restored by inhibiting AMPK and PTEN. Black-Right-Pointing-Pointer AMPK and PTEN regulated TNF-{alpha}-induced ROS production in VSMCs. -- Abstract: Atherosclerosis is a chronic inflammation of the coronary arteries. Vascular smooth muscle cells (VSMCs) stimulated by cytokines and chemokines accelerate the inflammatory response and migrate to the injured endothelium during the progression of atherosclerosis. Activation of AMP activated protein kinase (AMPK), a key sensor maintaining metabolic homeostasis, suppresses the inflammatory response. However, how AMPK regulates the inflammatory response is poorly understood. To identify the mechanism of this response, we focused on phosphatase and tensin homolog (PTEN), which is a negative regulator of inflammation. We investigated that activation of AMPK-induced PTEN expression and suppression of the inflammatory response through the AMPK-PTEN pathway in VSMCs. We treated with the well-known AMPK activator metformin to induce PTEN expression. PTEN was induced by metformin (2 mM) and inhibited by compound C (10 {mu}M) and AMPK siRNA. Tumor necrosis factor-alpha (TNF-{alpha}) was used to induce inflammation. The inflammatory response was confirmed by cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS) expression, and activation of nuclear factor (NF)-{kappa}B. Metformin suppressed COX-2 and iNOS mRNA and protein expression dose dependently. Treatment with compound C and bpv (pic) in the presence of metformin, iNOS and COX-2 protein expression increased. NF-{kappa}B activation decreased in response to metformin and was restored by inhibiting AMPK

  6. When "altering brain function" becomes "mind control".

    Science.gov (United States)

    Koivuniemi, Andrew; Otto, Kevin

    2014-01-01

    Functional neurosurgery has seen a resurgence of interest in surgical treatments for psychiatric illness. Deep brain stimulation (DBS) technology is the preferred tool in the current wave of clinical experiments because it allows clinicians to directly alter the functions of targeted brain regions, in a reversible manner, with the intent of correcting diseases of the mind, such as depression, addiction, anorexia nervosa, dementia, and obsessive compulsive disorder. These promising treatments raise a critical philosophical and humanitarian question. "Under what conditions does 'altering brain function' qualify as 'mind control'?" In order to answer this question one needs a definition of mind control. To this end, we reviewed the relevant philosophical, ethical, and neurosurgical literature in order to create a set of criteria for what constitutes mind control in the context of DBS. We also outline clinical implications of these criteria. Finally, we demonstrate the relevance of the proposed criteria by focusing especially on serendipitous treatments involving DBS, i.e., cases in which an unintended therapeutic benefit occurred. These cases highlight the importance of gaining the consent of the subject for the new therapy in order to avoid committing an act of mind control.

  7. Algebras of holomorphic functions and control theory

    CERN Document Server

    Sasane, Amol

    2009-01-01

    This accessible, undergraduate-level text illustrates the role of algebras of holomorphic functions in the solution of an important engineering problem: the stabilization of a linear control system. Its concise and self-contained treatment avoids the use of higher mathematics and forms a bridge to more advanced treatments. The treatment consists of two components: the algebraic framework, which serves as the abstract language for posing and solving the problem of stabilization; and the analysis component, which examines properties of specific rings of holomorphic functions. Elementary, self-co

  8. Functional Neuroanatomy for Posture and Gait Control

    Directory of Open Access Journals (Sweden)

    Kaoru Takakusaki

    2017-01-01

    Full Text Available Here we argue functional neuroanatomy for posture- gait control. Multi-sensory information such as somatosensory, visual and vestibular sensation act on various areas of the brain so that adaptable posture- gait control can be achieved. Automatic process of gait, which is steady-state stepping movements associating with postural reflexes including headeye coordination accompanied by appropriate alignment of body segments and optimal level of postural muscle tone, is mediated by the descending pathways from the brainstem to the spinal cord. Particularly, reticulospinal pathways arising from the lateral part of the mesopontine tegmentum and spinal locomotor network contribute to this process. On the other hand, walking in unfamiliar circumstance requires cognitive process of postural control, which depends on knowledges of self-body, such as body schema and body motion in space. The cognitive information is produced at the temporoparietal association cortex, and is fundamental to sustention of vertical posture and construction of motor programs. The programs in the motor cortical areas run to execute anticipatory postural adjustment that is optimal for achievement of goal-directed movements. The basal ganglia and cerebellum may affect both the automatic and cognitive processes of posturegait control through reciprocal connections with the brainstem and cerebral cortex, respectively. Consequently, impairments in cognitive function by damages in the cerebral cortex, basal ganglia and cerebellum may disturb posture-gait control, resulting in falling.

  9. Functional graphical languages for process control

    International Nuclear Information System (INIS)

    1996-01-01

    A wide variety of safety systems are in use today in the process industries. Most of these systems rely on control software using procedural programming languages. This study investigates the use of functional graphical languages for controls in the process industry. Different vendor proprietary software and languages are investigated and evaluation criteria are outlined based on ability to meet regulatory requirements, reference sites involving applications with similar safety concerns, QA/QC procedures, community of users, type and user-friendliness of the man-machine interface, performance of operational code, and degree of flexibility. (author) 16 refs., 4 tabs

  10. APT LLRF control system functionality and architecture

    International Nuclear Information System (INIS)

    Regan, A.H.; Rohlev, A.S.; Ziomek, C.D.

    1996-01-01

    1% amplitude and l degree phase. The feedback control system requires a phase-stable RF reference subsystem signal to correctly phase each cavity. Also, instead of a single klystron RF source for individual accelerating cavities, multiple klystrons will drive a string of resonantly coupled cavities, based on input from a single LLRF feedback control system. To achieve maximum source efficiency, we will be employing single fast feedback controls around individual klystrons such that the gain and phase characteristics of each will be ''identical.'' In addition, resonance control is performed by providing a proper drive signal to structure cooling water valves in order to keep the cavity resonant during operation. To quickly respond to RF shutdowns, and hence rapid accelerating cavity cool- down, due to RF fault conditions, drive frequency agility in the main feedback control subsystem will also be incorporated. Top level block diagrams will be presented and described for each of the aforementioned subsystems as they will first be developed and demonstrated on the Low Energy Demonstrator Accelerator (LEDA) The low-level RF (LLRF) control system for the Accelerator Production of Tritium (APT) will perform various functions. Foremost is the feedback control of the accelerating fields within the cavity in order to maintain field stability within

  11. A functional overview of conservation biological control

    DEFF Research Database (Denmark)

    Begg, Graham S; Cook, Samantha M; Dye, Richard

    2017-01-01

    Conservation biological control (CBC) is a sustainable approach to pest management that can contribute to a reduction in pesticide use as part of an Integrated Pest Management (IPM) strategy. CBC is based on the premise that countering habitat loss and environmental disturbance associated...... CBC prescriptions have proved elusive. To tackle this, we consolidate existing knowledge of CBC using a simple conceptual model that organises the functional elements of CBC into a common, unifying framework. We identify and integrate the key biological processes affecting natural enemies...... and their biological control function across local and regional scales, and consider the interactions, interdependencies and constraints that determine the outcome of CBC strategies. Conservation measures are often effective in supporting natural enemy populations but their success cannot be guaranteed; the greatest...

  12. A study of the dynamics of PTEN proteins in living cells using in vivo fluorescence correlation spectroscopy

    Science.gov (United States)

    Du, Zhixue; Dong, Chaoqing; Ren, Jicun

    2017-06-01

    PTEN (phosphatase and tensin homolog on chromosome 10) is one of the most important tumor-suppressor proteins, which plays a key role in negative regulation of the PI3K/AKT pathway, and governs many cellular processes including growth, proliferation, survival and migration. The dynamics of PTEN proteins in single living cells is as yet unclear owing to a shortage of suitable in vivo approaches. Here, we report a single-molecule method for in vivo study of the dynamics of PTEN proteins in living cells using fluorescence correlation spectroscopy (FCS). First, we established a monoclonal H1299 stable cell line expressing enhanced green fluorescent protein (EGFP) and PTEN (EGFP-PTEN) fusion proteins; we then developed an in vivo FCS method to study the dynamics of EGFP-PTEN both in the nucleus and the cytoplasm. We investigated the diffusion behaviors of EGFP and EGFP-PTEN in solution, nucleus and cytosol, and observed that the motion of PTEN in living cells was restricted compared with EGFP. Finally, we investigated the protein dynamics in living cells under oxidative stress stimulation and a cellular ATP depletion treatment. Under oxidative stress stimulation, the EGFP-PTEN concentration increased in the nucleus, but slightly decreased in the cytoplasm. The diffusion coefficient and alpha value of EGFP-PTEN reduced significantly both in the nucleus and cytoplasm; the significantly decreased alpha parameter indicates a more restricted Brownian diffusion behavior. Under the cellular ATP depletion treatment, the concentration of EGFP-PTEN remained unchanged in the nucleus and decreased significantly in cytosol. The diffusion coefficient of EGFP-PTEN decreased significantly in cytosol, but showed no significant change in the nucleus; the alpha value decreased significantly in both the nucleus and cytoplasm. These results suggest that the concentration and mobility of PTEN in the nucleus and cytoplasm can be regulated by stimulation methods. Our approach provides a unique

  13. A common variation of the PTEN gene is associated with peripheral insulin resistance

    DEFF Research Database (Denmark)

    Grinder-Hansen, L; Ribel-Madsen, R; Wojtaszewski, Jørgen

    2016-01-01

    . RESULTS: The minor G allele of PTEN rs11202614 was associated with elevated fasting plasma insulin levels and a decreased peripheral glucose disposal rate, but not with the hepatic insulin resistance index or insulin secretion measured as the first-phase insulin response and disposition index. The single...... nucleotide polymorphism was not associated with either PI3K or Akt activities. CONCLUSION: A common PTEN variation is associated with peripheral insulin resistance and subsequent risk of developing T2D. However, the association with insulin resistance is not explained by decreased proximal insulin signalling......AIM: Phosphatase and tensin homologue (PTEN) reduces insulin sensitivity by inhibiting the phosphatidylinositol 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homologue (Akt) pathway. This study investigated how a common single nucleotide polymorphism near PTEN, previously associated...

  14. Broad spectrum of neuropsychiatric phenotypes associated with white matter disease in PTEN hamartoma tumor syndrome.

    Science.gov (United States)

    Balci, Tugce B; Davila, Jorge; Lewis, Denice; Boafo, Addo; Sell, Erick; Richer, Julie; Nikkel, Sarah M; Armour, Christine M; Tomiak, Eva; Lines, Matthew A; Sawyer, Sarah L

    2018-01-01

    White matter lesions have been described in patients with PTEN hamartoma tumor syndrome (PHTS). How these lesions correlate with the neurocognitive features associated with PTEN mutations, such as autism spectrum disorder (ASD) or developmental delay, has not been well established. We report nine patients with PTEN mutations and white matter changes on brain magnetic resonance imaging (MRI), eight of whom were referred for reasons other than developmental delay or ASD. Their clinical presentations ranged from asymptomatic macrocephaly with normal development/intellect, to obsessive compulsive disorder, and debilitating neurological disease. To our knowledge, this report constitutes the first detailed description of PTEN-related white matter changes in adult patients and in children with normal development and intelligence. We present a detailed assessment of the neuropsychological phenotype of our patients and discuss the relationship between the wide array of neuropsychiatric features and observed white matter findings in the context of these individuals. © 2017 Wiley Periodicals, Inc.

  15. Effects of AdR-siPTEN on learning capability, memory and ...

    African Journals Online (AJOL)

    USER

    2010-07-12

    Jul 12, 2010 ... protein expression of a phosphatase and tensin homolog deleted on chromosome 10 (PTEN), ... disease (AD) and refers to a step-wise deterioration in cognitive ..... Pappas BA, de la Torre JC, Davidson CM (1996).Chronic ...

  16. Kaempferol Promotes Apoptosis in Human Bladder Cancer Cells by Inducing the Tumor Suppressor, PTEN

    Directory of Open Access Journals (Sweden)

    Liqun Zhou

    2013-10-01

    Full Text Available Kaempferol (Kae, a natural flavonoid, is widely distributed in fruits and vegetables. Previous studies have identified Kae as a possible cancer preventive and therapeutic agent. We found Kae to exhibit potent antiproliferation and anti-migration effects in human bladder cancer EJ cells. Kaempferol robustly induced apoptosis in EJ cells in a dose-dependent manner, as evidenced by increased cleavage of caspase-3. Furthermore, we found Kae-induced apoptosis in EJ cells to be associated with phosphatase and the tensin homolog deleted on the chromosome 10 (PTEN/PI3K/Akt pathway. Kae significantly increased PTEN and decreased Akt phosphorylation. Kae-induced apoptosis was partially attenuated in PTEN-knockdown cells. Our findings indicate that Kae could be an alternative medicine for bladder cancer, based on a PTEN activation mechanism.

  17. The Functional Connectome of Speech Control.

    Directory of Open Access Journals (Sweden)

    Stefan Fuertinger

    2015-07-01

    Full Text Available In the past few years, several studies have been directed to understanding the complexity of functional interactions between different brain regions during various human behaviors. Among these, neuroimaging research installed the notion that speech and language require an orchestration of brain regions for comprehension, planning, and integration of a heard sound with a spoken word. However, these studies have been largely limited to mapping the neural correlates of separate speech elements and examining distinct cortical or subcortical circuits involved in different aspects of speech control. As a result, the complexity of the brain network machinery controlling speech and language remained largely unknown. Using graph theoretical analysis of functional MRI (fMRI data in healthy subjects, we quantified the large-scale speech network topology by constructing functional brain networks of increasing hierarchy from the resting state to motor output of meaningless syllables to complex production of real-life speech as well as compared to non-speech-related sequential finger tapping and pure tone discrimination networks. We identified a segregated network of highly connected local neural communities (hubs in the primary sensorimotor and parietal regions, which formed a commonly shared core hub network across the examined conditions, with the left area 4p playing an important role in speech network organization. These sensorimotor core hubs exhibited features of flexible hubs based on their participation in several functional domains across different networks and ability to adaptively switch long-range functional connectivity depending on task content, resulting in a distinct community structure of each examined network. Specifically, compared to other tasks, speech production was characterized by the formation of six distinct neural communities with specialized recruitment of the prefrontal cortex, insula, putamen, and thalamus, which collectively

  18. APT LLRF control system functionality and architecture

    International Nuclear Information System (INIS)

    Regan, A.H.; Rohlev, A.S.; Ziomek, C.D.

    1996-01-01

    The low-level RF (LLRF) control system for the Accelerator Production of Tritium (APT) will perform various functions. Foremost is the feedback control of the accelerating fields within the cavity in order to maintain field stability within ± 1% amplitude and 1 degree phase. The feedback control system requires a phase-stable RF reference subsystem signal to correctly phase each cavity. Also, instead of a single klystron RF source for individual accelerating cavities, multiple klystrons will drive a string of resonantly coupled cavities, based on input from a single LLRF feedback control system. To achieve maximum source efficiency, we will be employing single fast feedback controls around individual klystrons such that the gain and phase characteristics of each will be 'identical'. In addition, the resonance condition of the cavities is monitored and maintained. To quickly respond to RF shutdowns, and hence rapid accelerating cavity cool-down, due to RF fault conditions, drive frequency agility in the main feedback control subsystem will also be incorporated. Top level block diagrams will be presented and described as they will first be developed and demonstrated on the Low Energy Demonstrator Accelerator (LEDA). (author)

  19. Synergistic action of Smad4 and Pten in suppressing pancreatic ductal adenocarcinoma formation in mice.

    Science.gov (United States)

    Xu, X; Ehdaie, B; Ohara, N; Yoshino, T; Deng, C-X

    2010-02-04

    Mutations of SMAD4/DPC4 are found in about 60% of human invasive pancreatic ductal adenocarcinomas (PDACs); yet, the manner in which SMAD4 deficiency enhances tumorigenesis remains elusive. Using a Cre-LoxP approach, we generated a mutant mouse carrying a targeted deletion of Smad4 in the pancreas. We showed that the absence of Smad4 alone did not trigger pancreas tumor formation; however, it increased the expression of an inactivated form of Pten, suggesting a role of Pten in preventing Smad4-/- cells from undergoing malignancy. To investigate this, we disrupted both Pten and Smad4. We showed that Pten deficiency initiated widespread premalignant lesions, and a low tumor incidence that was significantly accelerated by Smad4-deficiency. The absence of Smad4 in a Pten-mutant background enhanced cell proliferation and triggered transdifferentiation from acinar, centroacinar and islet cells, accompanied by activation of Notch1 signaling. We showed that all tumors developed in the Smad4/Pten-mutant pancreas exhibited high levels of pAKT and mTOR, and that about 50 and 83% of human pancreatic cancers examined showed increased pAKT and pmTOR, respectively. Besides the similarity in gene expression, the pAKT and/or pmTOR-positive human PDACs and mouse pancreatic tumors also shared some histopathological similarities. These observations indicate that Smad4/Pten-mutant mice mimic the tumor progression of human pancreatic cancers that are driven by activation of the AKT-mTOR pathway, and uncovered a synergistic action of Smad4 and Pten in repressing pancreatic tumorigenesis.

  20. PTEN drives Th17 cell differentiation by preventing IL-2 production.

    Science.gov (United States)

    Kim, Hyeong Su; Jang, Sung Woong; Lee, Wonyong; Kim, Kiwan; Sohn, Hyogon; Hwang, Soo Seok; Lee, Gap Ryol

    2017-11-06

    T helper 17 (Th17) cells are a CD4 + T cell subset that produces IL-17A to mediate inflammation and autoimmunity. IL-2 inhibits Th17 cell differentiation. However, the mechanism by which IL-2 is suppressed during Th17 cell differentiation remains unclear. Here, we show that phosphatase and tensin homologue (PTEN) is a key factor that regulates Th17 cell differentiation by suppressing IL-2 production. Th17-specific Pten deletion ( Pten fl/fl Il17a cre ) impairs Th17 cell differentiation in vitro and ameliorated symptoms of experimental autoimmune encephalomyelitis (EAE), a model of Th17-mediated autoimmune disease. Mechanistically, Pten deficiency up-regulates IL-2 and phosphorylation of STAT5, but reduces STAT3 phosphorylation, thereby inhibiting Th17 cell differentiation. PTEN inhibitors block Th17 cell differentiation in vitro and in the EAE model. Thus, PTEN plays a key role in Th17 cell differentiation by blocking IL-2 expression. © 2017 Kim et al.

  1. PTEN and DMBT1 homozygous deletion and expression in medulloblastomas and supratentorial primitive neuroectodermal tumors.

    Science.gov (United States)

    Inda, María Mar; Mercapide, Javier; Muñoz, Jorge; Coullin, Philippe; Danglot, Giséle; Tuñon, Teresa; Martínez-Peñuela, José María; Rivera, José María; Burgos, Juan J; Bernheim, Alain; Castresana, Javier S

    2004-12-01

    Medulloblastoma, which accounts for 20-25% of all childhood brain tumors, is defined as a primitive neuroectodermal tumor (PNET) located in the cerebellum. Supratentorial PNET are less frequent than medulloblastoma. But their clinical outcome is worse than in medulloblastomas. Chromosome 10q contains at least 2 tumor suppressor genes that might play a role in brain tumor development: PTEN and DMBT1. The aim of this study was to compare the status of homozygous deletion and expression of PTEN and DMBT1 genes in PNET primary tumor samples and cell lines. Homozygous deletions of PTEN and DMBT1 were studied in 32 paraffin-embedded PNET samples (23 medulloblastomas and 9 supratentorial PNET) and in 7 PNET cell lines, by differential PCR and by FISH. PTEN homozygous losses were demonstrated in 7 medulloblastomas (32%) and in no supratentorial PNET, while homozygous deletions of DMBT1 appeared in 1 supratentorial PNET (20%) and in 7 medulloblastomas (33%). No homozygous deletion of PTEN or DMBT1 was detected in any of the PNET cell lines either by differential PCR or by FISH. Expression study of the 2 genes was performed in the 7 PNET cell lines by RT-PCR. One PNET cell line lacked PTEN and DMBT1 expression, while 2 medulloblastoma cell lines did not express DMBT1. Our results add some positive data to the hypothesis that supratentorial PNETs and medulloblastomas might be genetically different.

  2. Hesperitin derivative-11 suppress hepatic stellate cell activation and proliferation by targeting PTEN/AKT pathway

    International Nuclear Information System (INIS)

    Li, Wan-xia; Chen, Xin; Yang, Yang; Huang, Hui-min; Li, Hai-di; Huang, Cheng; Meng, Xiao-ming; Li, Jun

    2017-01-01

    Hesperitin derivative (HD-11) is a monomeric compound derived from Hesperidin, which is a naturally occurring flavanone glycoside that exerts extensive clinical effects such as anti-inflammatory, anti-oxidant and anti-angiogenic. However, the role and fundamental mechanism of HD-11 in hepatic fibrosis are still unrevealed. In this study, HD-11 not only alleviates ECM deposition in rats with liver fibrosis, but also reduces the expression of α-SMA and col1a1 in TGF-β1-induced HSC-T6 cells. Moreover, it was demonstrated that HD-11 significantly promoted the expression of PTEN in vivo and in vitro. In order to evaluate the involvement of HD-11 in TGF-β1-induced HSC-T6 activation, a specific blocking agent of PTEN (bpv) and PTEN small interfering (si)-RNA-mediated silencing were used. Interestingly, HD-11 treatment couldn’t inhibit α-SMA and col1a1 expression on the basis of PTEN knockdown. On the contrary, over-expression of PTEN had an opposite effect on the expression of α-SMA and col1a1 in TGF-β1-induced HSC-T6 cells after treatment of HD-11. In addition, HD-11 remarkably inhibited the expression of p-AKT in vivo and in vitro. Taken together, all the above results indicate that HD-11 may play the part of an effective modulator of PTEN/AKT signaling pathway.

  3. PTEN Signaling in the Postnatal Perivascular Progenitor Niche Drives Medulloblastoma Formation.

    Science.gov (United States)

    Zhu, Guo; Rankin, Sherri L; Larson, Jon D; Zhu, Xiaoyan; Chow, Lionel M L; Qu, Chunxu; Zhang, Jinghui; Ellison, David W; Baker, Suzanne J

    2017-01-01

    Loss of the tumor suppressor gene PTEN exerts diverse outcomes on cancer in different developmental contexts. To gain insight into the effect of its loss on outcomes in the brain, we conditionally inactivated the murine Pten gene in neonatal neural stem/progenitor cells. Pten inactivation created an abnormal perivascular proliferative niche in the cerebellum that persisted in adult animals but did not progress to malignancy. Proliferating cells showed undifferentiated morphology and expressed the progenitor marker Nestin but not Math1, a marker of committed granule neuron progenitors. Codeletion of Pten and Trp53 resulted in fully penetrant medulloblastoma originating from the perivascular niche, which exhibited abnormal blood vessel networks and advanced neuronal differentiation of tumor cells. EdU pulse-chase experiments demonstrated a perivascular cancer stem cell population in Pten/Trp53 double mutant medulloblastomas. Genetic analyses revealed recurrent somatic inactivations of the tumor suppressor gene Ptch1 and a recapitulation of the sonic hedgehog subgroup of human medulloblastomas. Overall, our results showed that PTEN acts to prevent the proliferation of a progenitor niche in postnatal cerebellum predisposed to oncogenic induction of medulloblastoma. Cancer Res; 77(1); 123-33. ©2016 AACR. ©2016 American Association for Cancer Research.

  4. The GAS5/miR-222 Axis Regulates Proliferation of Gastric Cancer Cells Through the PTEN/Akt/mTOR Pathway.

    Science.gov (United States)

    Li, Yanhua; Gu, Junjiao; Lu, Hong

    2017-12-01

    Several lines of evidence have indicated that growth arrest-specific transcript 5 (GAS5) functions as a tumor suppressor and is aberrantly expressed in multiple cancers. GAS5 was found to be downregulated in gastric cancer (GC) tissues, and ectopic expression of GAS5 inhibited GC cell proliferation. The present study aimed to explore the underlying mechanisms of GAS5 involved in GC cell proliferation. GAS5 and miR-222 expressions in GC cell lines were estimated by quantitative real-time polymerase chain reaction. The effects of GAS5 and miR-222 on GC cell proliferation were assessed by MTT assay and 5-bromo-2-deoxyuridine (BrdU) incorporation assays. The interaction between GAS5 and miR-222 was confirmed by luciferase reporter assay and RNA immunoprecipitation assay. The protein levels of the phosphatase and tensin homolog (PTEN), phosphorylated protein kinase B (Akt) (p-Akt), Akt, phosphorylated mammalian target of rapamycin (mTOR) (p-mTOR), and mTOR were determined by western blot. GAS5 was downregulated and miR-222 was upregulated in GC cells. GAS5 directly targeted and suppressed miR-222 expression. GAS5 overexpression and miR-222 inhibition suppressed cell proliferation, increased PTEN protein level and decreased p-Akt and p-mTOR protein levels in GC cells while GAS5 knockdown and miR-222 overexpression exhibited the opposite effects. Moreover, mechanistic analyses revealed that GAS5 regulated GC cell proliferation through the PTEN/Akt/mTOR pathway by negatively regulating miR-222. GAS5/miR-222 axis regulated proliferation of GC cells through the PTEN/Akt/mTOR pathway, which facilitated the development of lncRNA-directed therapy against this deadly disease.

  5. Differential Requirements for c-Myc in Chronic Hematopoietic Hyperplasia and Acute Hematopoietic Malignancies in Pten-null Mice

    Science.gov (United States)

    Zhang, Jun; Xiao, Yechen; Guo, Yinshi; Breslin, Peter; Zhang, Shubin; Wei, Wei; Zhang, Zhou; Zhang, Jiwang

    2011-01-01

    Myeloproliferative disorders (MPDs), lymphoproliferative disorders (LPDs), acute T-lymphocytic or myeloid leukemia and T-lymphocytic lymphoma were developed in inducible Pten-knockout (Pten−/−) mice. The appearance of these multiple diseases in one animal model provides an opportunity to study the pathogenesis of multiple diseases simultaneously. To study whether Myc function is required for the development of these hematopoietic disorders in Pten−/− mice, we generated inducible Pten/Myc double-knockout mice (Pten−/−/Myc−/−). By comparing the hematopoietic phenotypes of these double-knockout mice with those of Pten−/− mice, we found that both sets of animals developed MPDs and LPDs. However, none of the compound-mutant mice developed acute leukemia or lymphoma. Interestingly, in contrast to the MPDs which developed in Pten−/− mice which are dominated by granulocytes, megakaryocytes predominate in the MPDs of Pten−/−/Myc−/− mice. Our study suggests that the deregulation of PI3K/Akt signaling in Pten−/− hematopoietic cells protects these cells from apoptotic cell death, resulting in chronic proliferative disorders. But due to the differential requirement for Myc in granulocyte as compared to megakaryocyte proliferation, Myc deletion converts Pten−/− MPDs from granulocyte-dominated to megakaryocyte-dominated conditions. Myc is absolutely required for the development of acute hematopoietic malignancies. PMID:21926961

  6. Conditional Loss of Pten in Myogenic Progenitors Leads to Postnatal Skeletal Muscle Hypertrophy but Age-Dependent Exhaustion of Satellite Cells.

    Science.gov (United States)

    Yue, Feng; Bi, Pengpeng; Wang, Chao; Li, Jie; Liu, Xiaoqi; Kuang, Shihuan

    2016-11-22

    Skeletal muscle stem cells (satellite cells [SCs]) are normally maintained in a quiescent (G 0 ) state. Muscle injury not only activates SCs locally, but also alerts SCs in distant uninjured muscles via circulating factors. The resulting G Alert SCs are adapted to regenerative cues and regenerate injured muscles more efficiently, but whether they provide any long-term benefits to SCs is unknown. Here, we report that embryonic myogenic progenitors lacking the phosphatase and tensin homolog (Pten) exhibit enhanced proliferation and differentiation, resulting in muscle hypertrophy but fewer SCs in adult muscles. Interestingly, Pten null SCs are predominantly in the G Alert state, even in the absence of an injury. The G Alert SCs are deficient in self-renewal and subjected to accelerated depletion during regeneration and aging and fail to repair muscle injury in old mice. Our findings demonstrate a key requirement of Pten in G 0 entry of SCs and provide functional evidence that prolonged G Alert leads to stem cell depletion and regenerative failure. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  7. Cancer/testis Antigen-Plac1 Promotes Invasion and Metastasis of Breast Cancer through Furin/NICD/PTEN Signaling Pathway.

    Science.gov (United States)

    Li, Yongfei; Chu, Jiahui; Li, Jun; Feng, Wanting; Yang, Fan; Wang, Yifan; Zhang, Yanhong; Sun, Chunxiao; Yang, Mengzhu; Vasilatos, Shauna N; Huang, Yi; Fu, Ziyi; Yin, Yongmei

    2018-04-28

    Plac1 is a cancer-testis antigen that plays a critical role in promoting cancer initiation and progression. However, the clinical significance and mechanism of Plac1 in cancer progression remains elusive. Here we report that Plac1 is an important oncogenic and prognostic factor which physically interacts with Furin to drive breast cancer invasion and metastasis. We have shown that Plac1 expression positively correlates with clinical stage, lymph node metastasis, HR status and overall patient survival. Overexpression of Plac1 promoted invasion and metastasis of breast cancer cells in vitro and in vivo. Co-immunoprecipitation and immunofluorescence cell staining assays revealed that interaction of Plac1 and Furin degraded Notch1 and generated Notch1 intracellular domain (NICD) that could inhibit PTEN activity. These findings are consistent with the results of microarray study in MDA-MB-231 cells overexpressing Plac1. A rescue study showed that inhibition of Furin and overexpression of PTEN in Plac1 overexpression cells blocked Plac1-induced tumor cell progression. Taken together, our findings suggest that functional interaction between Plac1 and Furin enhances breast cancer invasion and metastasis and the Furin/NICD/PTEN axis may act as an important therapeutic target for breast cancer treatment. Molecular Oncology (2018) © 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

  8. MDM2 regulates hypoxic hypoxia-inducible factor 1α stability in an E3 ligase, proteasome, and PTEN-phosphatidylinositol 3-kinase-AKT-dependent manner.

    Science.gov (United States)

    Joshi, Shweta; Singh, Alok R; Durden, Donald L

    2014-08-15

    Hypoxia-inducible factor 1 (HIF1) is a heterodimeric transcription factor containing an inducibly expressed HIF1α subunit and a constitutively expressed HIF1β subunit. Under hypoxic conditions, the HIF1α subunit accumulates because of a decrease in the rate of proteolytic degradation, and the resulting HIF1α-HIF1β heterodimers undergo post-translational modifications that promote transactivation. Previous reports suggest that amplified signaling through PI3K enhances HIF1-dependent gene expression; however, its role is controversial, and the mechanism is unclear. Using genetically engineered PTEN-deficient cell lines, we demonstrate that PTEN specifically inhibited the accumulation of HIF1α in response to hypoxia. Furthermore, we report that in glioblastoma cell lines, inhibition of PI3K pathway, using pan as well as isoform-specific PI3K inhibitors SF1126, PF4691502, BEZ-235, GDC0941, and TGX221 blocked the induction of HIF1α protein and its targets vascular endothelial growth factor, HK1, and GLUT1 mRNA in response to hypoxia. Herein, we describe the first evidence that HIF1α can be degraded under hypoxic conditions via the 26 S proteasome and that MDM2 is the E3 ligase that induces the hypoxic degradation of HIF1α. Moreover, the action of MDM2 on HIF1α under hypoxia occurs in the cytoplasm and is controlled by the PTEN-PI3K-AKT signaling axis. These data strongly suggest a new role for PTEN in the regulation of HIF1α and importantly that PI3K-AKT activation is required for the hypoxic stabilization of HIF1α and that hypoxia alone is not sufficient to render HIF1α resistant to proteasomal cleavage and degradation. Moreover, these findings suggest new therapeutic considerations for PI3K and/or AKT inhibitors for cancer therapeutics. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  9. MDM2 Regulates Hypoxic Hypoxia-inducible Factor 1α Stability in an E3 Ligase, Proteasome, and PTEN-Phosphatidylinositol 3-Kinase-AKT-dependent Manner*

    Science.gov (United States)

    Joshi, Shweta; Singh, Alok R.; Durden, Donald L.

    2014-01-01

    Hypoxia-inducible factor 1 (HIF1) is a heterodimeric transcription factor containing an inducibly expressed HIF1α subunit and a constitutively expressed HIF1β subunit. Under hypoxic conditions, the HIF1α subunit accumulates because of a decrease in the rate of proteolytic degradation, and the resulting HIF1α–HIF1β heterodimers undergo post-translational modifications that promote transactivation. Previous reports suggest that amplified signaling through PI3K enhances HIF1-dependent gene expression; however, its role is controversial, and the mechanism is unclear. Using genetically engineered PTEN-deficient cell lines, we demonstrate that PTEN specifically inhibited the accumulation of HIF1α in response to hypoxia. Furthermore, we report that in glioblastoma cell lines, inhibition of PI3K pathway, using pan as well as isoform-specific PI3K inhibitors SF1126, PF4691502, BEZ-235, GDC0941, and TGX221 blocked the induction of HIF1α protein and its targets vascular endothelial growth factor, HK1, and GLUT1 mRNA in response to hypoxia. Herein, we describe the first evidence that HIF1α can be degraded under hypoxic conditions via the 26 S proteasome and that MDM2 is the E3 ligase that induces the hypoxic degradation of HIF1α. Moreover, the action of MDM2 on HIF1α under hypoxia occurs in the cytoplasm and is controlled by the PTEN-PI3K-AKT signaling axis. These data strongly suggest a new role for PTEN in the regulation of HIF1α and importantly that PI3K-AKT activation is required for the hypoxic stabilization of HIF1α and that hypoxia alone is not sufficient to render HIF1α resistant to proteasomal cleavage and degradation. Moreover, these findings suggest new therapeutic considerations for PI3K and/or AKT inhibitors for cancer therapeutics. PMID:24982421

  10. Histone methyltransferase SETDB1 maintains survival of mouse spermatogonial stem/progenitor cells via PTEN/AKT/FOXO1 pathway.

    Science.gov (United States)

    Liu, Tiantian; Chen, Xiaoxu; Li, Tianjiao; Li, Xueliang; Lyu, Yinghua; Fan, Xiaoteng; Zhang, Pengfei; Zeng, Wenxian

    2017-10-01

    Spermatogonial stem cells (SSCs) possess the capacity of self-renewal and differentiation, which are the basis of spermatogenesis. In maintenance of SSC homeostasis, intrinsic/extrinsic factors and various signaling pathways tightly control the fate of SSCs. Methyltransferase SETDB1 (Set domain, bifurcated 1) catalyzes histone H3 lysine 9 (H3K9) trimethylation and represses gene expression. SETDB1 is required for maintaining the survival of spermatogonial stem cells in mice. However, the underlying molecular mechanism remains unclear. In the present study, we found that Setdb1 regulates PTEN/AKT/FOXO1 pathway to inhibit SSC apoptosis. Co-immunoprecipitation and reporter gene assay revealed that SETDB1 interacted and coordinated with AKT to regulate FOXO1 activity and expression of the downstream target genes Bim and Puma. Among the SETDB1-bound genes, the H3K9me3 levels on the promoter regions of Bim and Pten decreased in Setdb1-KD group; in contrast, H3K9me3 status on promoters of Bax and Puma remained unchanged. Therefore, SETDB1 was responsible for regulating the transcription activity of genes in the apoptotic pathway at least in part through modulating H3K9me3. This study replenishes the research on the epigenetic regulation of SSC survival, and provides a new insight for the future study of epigenetic regulation of spermatogenesis. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. ATM inhibition induces synthetic lethality and enhances sensitivity of PTEN-deficient breast cancer cells to cisplatin.

    Science.gov (United States)

    Li, Ke; Yan, Huaying; Guo, Wenhao; Tang, Mei; Zhao, Xinyu; Tong, Aiping; Peng, Yong; Li, Qintong; Yuan, Zhu

    2018-05-01

    PTEN deficiency often causes defects in DNA damage repair. Currently, effective therapies for breast cancer are lacking. ATM is an attractive target for cancer treatment. Previous studies suggested a synthetic lethality between PTEN and PARP. However, the synthetically lethal interaction between PTEN and ATM in breast cancer has not been reported. Moreover, the mechanism remains elusive. Here, using KU-60019, an ATM kinase inhibitor, we investigated ATM inhibition as a synthetically lethal strategy to target breast cancer cells with PTEN defects. We found that KU-60019 preferentially sensitizes PTEN-deficient MDA-MB-468 breast cancer cells to cisplatin, though it also slightly enhances sensitivity of PTEN wild-type breast cancer cells. The increased cytotoxic sensitivity is associated with apoptosis, as evidenced by flow cytometry and PARP cleavage. Additionally, the increase of DNA damage accumulation due to the decreased capability of DNA repair, as indicated by γ-H2AX and Rad51 foci, also contributed to this selective cytotoxicity. Mechanistically, compared with PTEN wild-type MDA-MB-231 cells, PTEN-deficient MDA-MB-468 cells have lower level of Rad51, higher ATM kinase activity, and display the elevated level of DNA damage. Moreover, these differences could be further enlarged by cisplatin. Our findings suggest that ATM is a promising target for PTEN-defective breast cancer. Copyright © 2018 Elsevier Inc. All rights reserved.

  12. Region-specific role for Pten in maintenance of epithelial phenotype and integrity

    Science.gov (United States)

    Flodby, Per; Sunohara, Mitsuhiro; Castillo, Dan R.; McConnell, Alicia M.; Krishnaveni, Manda S.; Banfalvi, Agnes; Li, Min; Stripp, Barry; Zhou, Beiyun; Crandall, Edward D.; Minoo, Parviz

    2017-01-01

    Previous studies have demonstrated resistance to naphthalene-induced injury in proximal airways of mice with lung epithelial-specific deletion of the tumor-suppressor gene Pten, attributed to increased proliferation of airway progenitors. We tested effects of Pten loss following bleomycin injury, a model typically used to study distal lung epithelial injury, in conditional PtenSFTPC-cre knockout mice. Pten-deficient airway epithelium exhibited marked hyperplasia, particularly in small bronchioles and at bronchoalveolar duct junctions, with reduced E-cadherin and β-catenin expression between cells toward the luminal aspect of the hyperplastic epithelium. Bronchiolar epithelial and alveolar epithelial type II (AT2) cells in PtenSFTPC-cre mice showed decreased expression of epithelial markers and increased expression of mesenchymal markers, suggesting at least partial epithelial-mesenchymal transition at baseline. Surprisingly, and in contrast to previous studies, mutant mice were exquisitely sensitive to bleomycin, manifesting rapid weight loss, respiratory distress, increased early mortality (by day 5), and reduced dynamic lung compliance. This was accompanied by sloughing of the hyperplastic airway epithelium with occlusion of small bronchioles by cellular debris, without evidence of increased parenchymal lung injury. Increased airway epithelial cell apoptosis due to loss of antioxidant defenses, reflected by decreased expression of superoxide dismutase 3, in combination with deficient intercellular adhesion, likely predisposed to airway sloughing in knockout mice. These findings demonstrate an important role for Pten in maintenance of airway epithelial phenotype integrity and indicate that responses to Pten deletion in respiratory epithelium following acute lung injury are highly context-dependent and region-specific. PMID:27864284

  13. miR-367 promotes proliferation and invasion of hepatocellular carcinoma cells by negatively regulating PTEN

    Energy Technology Data Exchange (ETDEWEB)

    Meng, Xiangrui, E-mail: mengxiangruibb2008@163.com [Oncology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou (China); Lu, Peng [Gastrointestinal Surgery Department, People' s Hospital of Zhengzhou, Zhengzhou (China); Fan, Qingxia [Oncology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou (China)

    2016-01-29

    MicroRNAs play important roles in the carcinogenesis of many types of cancers by inhibiting gene expression at posttranscriptional level. However, the roles of microRNAs in hepatocellular carcinoma, are still unclear. Here, we identified that miR-367 promotes hepatocellular carcinoma (HCC) cell proliferation by negatively regulates its target gene PTEN. The expression of miR-367 and PTEN are significantly inverse correlated in 35 HCC patients. In HCC cell line, CCK-8 proliferation assay indicated that the cell proliferation was promoted by miR-367, while miR-367 inhibitor significantly inhibited the cell proliferation. Transwell assay showed that miR-367 mimics significantly promoted the migration and invasion of HCC cells, whereas miR-367 inhibitors significantly reduced cell migration and invasion. Luciferase assays confirmed that miR-367 directly bound to the 3'untranslated region of PTEN, and western blotting showed that miR-367 suppressed the expression of PTEN at the protein levels. This study indicated that miR-367 negatively regulates PTEN and promotes proliferation and invasion of HCC cells. Thus, miR-367 may represent a potential therapeutic target for HCC intervention. - Highlights: • miR-367 mimics promote the proliferation and invasion of HCC cells. • miR-367 inhibitors inhibit the proliferation and invasion of HCC cells. • miR-367 targets 3′UTR of PTEN in HCC cells. • miR-367 negatively regulates PTEN in HCC cells.

  14. The effect of intense intermittent training with and without taking vitamin E on mRNA expression of p53/PTEN tumor suppressing genes in prostate glands of male rats

    Directory of Open Access Journals (Sweden)

    Mohammad Esmaeil Afzalpour

    2016-11-01

    Full Text Available Physical activity and diet are the most important modifiable determinants of cancer risk. The objective of this study was to examine the effect of intense intermittent training with and without taking vitamin E on expression of p53 and PTEN tumor suppressing genes in the prostate gland of male rats. For this purpose, 50 Sprague-Dawley male rats were randomly assigned into 5 groups: [1] control (CON, n = 10, [2] sham (S, n = 10, [3] intense intermittent training (IIT, n = 10, [4] intense intermittent training + vitamin E (IIT + VE, n = 10, [5] vitamin E (VE, n = 10. Protocol of this study was implemented for 6 days per week for 6 weeks, with observing the overload principle on the motorized treadmill. After implementing training protocol, expression rate of p53 and PTEN genes reduced significantly (p<0.000, p<0.031, respectively. Taking vitamin E with intermittent training caused significant reduction in p53 expression (p<0.013, while it caused significant increase in expression of PTEN (p<0.035. These results showed that intense intermittent training reduces expression of p53 and PTEN tumor suppressing genes and taking supplementation vitamin E along with this type of training could cause different effects in expression of these tumor suppressor genes.

  15. Effects of PTEN transfer on cell cycle progression and expression of P27kipl followed by X-ray irradiation

    International Nuclear Information System (INIS)

    Tian Mei; Wu Congmei; Liu Linlin; Piao Chunji; Li Xiuyi

    2007-01-01

    Objective: To investigate the effect of pEgr-hPTEN stable transfer combined with irradiation on the cell cycle progression and the expression of cell cycle kinase inhibitor P27 kipl protein of SHG-44 human glioma cells. Methods: pEgr-hPTEN vector containing the exogenous wild type PTEN gene was transfected into SHG-44 cells under mediation of lipofectamine in vitro, the positive cell clones were selected and amplified by using G418. Western blotting was used to measure the expression of PTEN protein. Transmission electron microscope was adopted to detect the cell ultrastructural changes and flow cytometry was adopted to analysis the changes of cell cycle progression and the expression of P27 kipl in SHG-44-sPTEN cells followed by different doses of X-ray irradiation. Results: Egr-1 promoter could be induced and activated by irradiation and then enhanced the expression of downstream PTEN gene within 5 Gy. The ultrastructure of SHG-44-sPTEN cells had many degenerative changes and many early apoptotic changes including the chromosome condensate around the nuclear envelope. pEgr-hPTEN stable transfer combined with X-ray irradiation could significantly induce G 1 arrest. The expression of P27 kipl proteins increased in SHG-44-sPTEN stable transfected cells. Conclusion: PTEN stable transfer combined with irradiation can significantly induce G 1 arrest. The molecular basis may be correlated with the enhanced expression of PTEN induced by irradiation and increased expression of cell cycle kinase inhibitor P27 kipl . (authors)

  16. Cisplatin-induced caspase activation mediates PTEN cleavage in ovarian cancer cells: a potential mechanism of chemoresistance

    International Nuclear Information System (INIS)

    Singh, Mohan; Chaudhry, Parvesh; Fabi, Francois; Asselin, Eric

    2013-01-01

    The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor protein is a central negative regulator of the PI3K/AKT signaling cascade and suppresses cell survival as well as cell proliferation. PTEN is found to be either inactivated or mutated in various human malignancies. In the present study, we have investigated the regulation of PTEN during cisplatin induced apoptosis in A2780, A270-CP (cisplatin resistant), OVCAR-3 and SKOV3 ovarian cancer cell lines. Cells were treated with 10μM of cisplatin for 24h. Transcript and protein levels were analysed by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and western blotting, respectively. Immunofluorescence microscopy was used to assess the intracellular localization of PTEN. Proteasome inhibitor and various caspases inhibitors were used to find the mechanism of PTEN degradation. PTEN protein levels were found to be decreased significantly in A2780 cells; however, there was no change in PTEN protein levels in A2780-CP, OVCAR-3 and SKOV3 cells with cisplatin treatment. The decrease in PTEN protein was accompanied with an increase in the levels of AKT phosphorylation (pAKT) in A2780 cells and a decrease of BCL-2. Cisplatin treatment induced the activation/cleavage of caspase-3, -6, -7, -8, -9 in all cell lines tested in this study except the resistant variant A2780-CP cells. In A2780 cells, restoration of PTEN levels was achieved upon pre-treatment with Z-DEVD-FMK (broad range caspases inhibitor) and not with MG132 (proteasome inhibitor) and by overexpression of BCL-2, suggesting that caspases and BCL-2 are involved in the decrease of PTEN protein levels in A2780 cells. The decrease in pro-apoptotic PTEN protein levels and increase in survival factor pAKT in A2780 ovarian cancer cells suggest that cisplatin treatment could further exacerbate drug resistance in A2780 ovarian cancer cells

  17. Cisplatin-induced caspase activation mediates PTEN cleavage in ovarian cancer cells: a potential mechanism of chemoresistance.

    Science.gov (United States)

    Singh, Mohan; Chaudhry, Parvesh; Fabi, Francois; Asselin, Eric

    2013-05-10

    The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor protein is a central negative regulator of the PI3K/AKT signaling cascade and suppresses cell survival as well as cell proliferation. PTEN is found to be either inactivated or mutated in various human malignancies. In the present study, we have investigated the regulation of PTEN during cisplatin induced apoptosis in A2780, A270-CP (cisplatin resistant), OVCAR-3 and SKOV3 ovarian cancer cell lines. Cells were treated with 10μM of cisplatin for 24h. Transcript and protein levels were analysed by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and western blotting, respectively. Immunofluorescence microscopy was used to assess the intracellular localization of PTEN. Proteasome inhibitor and various caspases inhibitors were used to find the mechanism of PTEN degradation. PTEN protein levels were found to be decreased significantly in A2780 cells; however, there was no change in PTEN protein levels in A2780-CP, OVCAR-3 and SKOV3 cells with cisplatin treatment. The decrease in PTEN protein was accompanied with an increase in the levels of AKT phosphorylation (pAKT) in A2780 cells and a decrease of BCL-2. Cisplatin treatment induced the activation/cleavage of caspase-3, -6, -7, -8, -9 in all cell lines tested in this study except the resistant variant A2780-CP cells. In A2780 cells, restoration of PTEN levels was achieved upon pre-treatment with Z-DEVD-FMK (broad range caspases inhibitor) and not with MG132 (proteasome inhibitor) and by overexpression of BCL-2, suggesting that caspases and BCL-2 are involved in the decrease of PTEN protein levels in A2780 cells. The decrease in pro-apoptotic PTEN protein levels and increase in survival factor pAKT in A2780 ovarian cancer cells suggest that cisplatin treatment could further exacerbate drug resistance in A2780 ovarian cancer cells.

  18. Von Hippel-Lindau status influences phenotype of liver cancers arising from PTEN loss

    Directory of Open Access Journals (Sweden)

    Sendor AB

    2015-02-01

    Full Text Available Adam B Sendor,1 Kathryn E Hacker,1 Shufen Chen,1 Armando L Corona,1 Oishee Sen,1 Derek Y Chiang,1 Anna Snavely,1 Arlin B Rogers,2 Stephanie A Montgomery,1 W Kimryn Rathmell,1 Autumn J McRee11Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA; 2Section of Pathology, Department of Biomedical Sciences, Cummings School of Veterinary Medicine, Tufts University, Boston, MA, USABackground: PTEN loss contributes to the development of liver diseases including hepatic steatosis and both hepatocellular carcinoma (HCC and cholangiocarcinoma (CC. The factors that influence the penetrance of these conditions are unclear. We explored the influence of sustained hypoxia signaling through co-deletion of Pten and Vhl in a murine model.Methods: We used a CreER-linked Keratin 18 mouse model to conditionally delete Pten, Vhl or both in somatic cells of adult mice, evaluating the resultant tumors by histology and gene expression microarray. Existing sets of gene expression data for human HCC and CC were examined for pathways related to those observed in the murine tumors, and a cohort of human CC samples was evaluated for relationships between HIF-1α expression and clinical outcomes.Results: Both Pten deletion genotypes developed liver tumors, but with differing phenotypes. Pten deletion alone led to large hepatic tumors with widespread hepatosteatosis. Co-deletion of Pten and Vhl with the Keratin 18 promoter resulted in reduced steatosis and a reduced tumor burden that was characterized by a trabecular architecture similar to CC. Genes associated with hepatic steatosis were coordinately expressed in the human HCC dataset, while genes involved in hypoxia response were upregulated in tumors from the human CC dataset. HIF-1α expression and overall survival were examined in an independent cohort of human CC tumors with no statistical differences uncovered.Conclusion: Pten deletion in Keratin 18 expressing cells leads to

  19. A Dictyostelium secreted factor requires a PTEN-like phosphatase to slow proliferation and induce chemorepulsion.

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    Sarah E Herlihy

    Full Text Available In Dictyostelium discoideum, AprA and CfaD are secreted proteins that inhibit cell proliferation. We found that the proliferation of cells lacking CnrN, a phosphatase and tensin homolog (PTEN-like phosphatase, is not inhibited by exogenous AprA and is increased by exogenous CfaD. The expression of CnrN in cnrN cells partially rescues these altered sensitivities, suggesting that CnrN is necessary for the ability of AprA and CfaD to inhibit proliferation. Cells lacking CnrN accumulate normal levels of AprA and CfaD. Like cells lacking AprA and CfaD, cnrN cells proliferate faster and reach a higher maximum cell density than wild type cells, tend to be multinucleate, accumulate normal levels of mass and protein per nucleus, and form less viable spores. When cnrN cells expressing myc-tagged CnrN are stimulated with a mixture of rAprA and rCfaD, levels of membrane-associated myc-CnrN increase. AprA also causes chemorepulsion of Dictyostelium cells, and CnrN is required for this process. Combined, these results suggest that CnrN functions in a signal transduction pathway downstream of AprA and CfaD mediating some, but not all, of the effects of AprA and CfaD.

  20. A Dictyostelium secreted factor requires a PTEN-like phosphatase to slow proliferation and induce chemorepulsion.

    Science.gov (United States)

    Herlihy, Sarah E; Tang, Yitai; Gomer, Richard H

    2013-01-01

    In Dictyostelium discoideum, AprA and CfaD are secreted proteins that inhibit cell proliferation. We found that the proliferation of cells lacking CnrN, a phosphatase and tensin homolog (PTEN)-like phosphatase, is not inhibited by exogenous AprA and is increased by exogenous CfaD. The expression of CnrN in cnrN cells partially rescues these altered sensitivities, suggesting that CnrN is necessary for the ability of AprA and CfaD to inhibit proliferation. Cells lacking CnrN accumulate normal levels of AprA and CfaD. Like cells lacking AprA and CfaD, cnrN cells proliferate faster and reach a higher maximum cell density than wild type cells, tend to be multinucleate, accumulate normal levels of mass and protein per nucleus, and form less viable spores. When cnrN cells expressing myc-tagged CnrN are stimulated with a mixture of rAprA and rCfaD, levels of membrane-associated myc-CnrN increase. AprA also causes chemorepulsion of Dictyostelium cells, and CnrN is required for this process. Combined, these results suggest that CnrN functions in a signal transduction pathway downstream of AprA and CfaD mediating some, but not all, of the effects of AprA and CfaD.

  1. Phenotype selection reveals coevolution of muscle glycogen and protein and PTEN as a gate keeper for the accretion of muscle mass in adult female mice.

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    Mandy Sawitzky

    Full Text Available We have investigated molecular mechanisms for muscle mass accretion in a non-inbred mouse model (DU6P mice characterized by extreme muscle mass. This extreme muscle mass was developed during 138 generations of phenotype selection for high protein content. Due to the repeated trait selection a complex setting of different mechanisms was expected to be enriched during the selection experiment. In muscle from 29-week female DU6P mice we have identified robust increases of protein kinase B activation (AKT, Ser-473, up to 2-fold if compared to 11- and 54-week DU6P mice or controls. While a number of accepted effectors of AKT activation, including IGF-I, IGF-II, insulin/IGF-receptor, myostatin or integrin-linked kinase (ILK, were not correlated with this increase, phosphatase and tensin homologue deleted on chromosome 10 (PTEN was down-regulated in 29-week female DU6P mice. In addition, higher levels of PTEN phosphorylation were found identifying a second mechanism of PTEN inhibition. Inhibition of PTEN and activation of AKT correlated with specific activation of p70S6 kinase and ribosomal protein S6, reduced phosphorylation of eukaryotic initiation factor 2α (eIF2α and higher rates of protein synthesis in 29-week female DU6P mice. On the other hand, AKT activation also translated into specific inactivation of glycogen synthase kinase 3ß (GSK3ß and an increase of muscular glycogen. In muscles from 29-week female DU6P mice a significant increase of protein/DNA was identified, which was not due to a reduction of protein breakdown or to specific increases of translation initiation. Instead our data support the conclusion that a higher rate of protein translation is contributing to the higher muscle mass in mid-aged female DU6P mice. Our results further reveal coevolution of high protein and high glycogen content during the selection experiment and identify PTEN as gate keeper for muscle mass in mid-aged female DU6P mice.

  2. PLZF mediates the PTEN/AKT/FOXO3a signaling in suppression of prostate tumorigenesis.

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    JingPing Cao

    Full Text Available Promyelocytic leukemia zinc finger (PLZF protein expression is closely related to the progression of human cancers, including prostate cancer (PCa. However, the according context of a signaling pathway for PLZF to suppress prostate tumorigenesis remains greatly unknown. Here we report that PLZF is a downstream mediator of the PTEN signaling pathway in PCa. We found that PLZF expression is closely correlated with PTEN expression in a cohort of prostate cancer specimens. Interestingly, both PTEN rescue and phosphoinositide 3-kinase (PI3K inhibitor LY294002 treatment increase the PLZF expression in prostate cancer cell lines. Further, luciferase reporter assay and chromatin immunoprecipitation assay demonstrate that FOXO3a, a transcriptional factor phosphorylated by PI3K/AKT, could directly bind to the promoter of PLZF gene. These results indicate that PTEN regulates PLZF expression by AKT/FOXO3a. Moreover, our animal experiments also demonstrate that PLZF is capable of inhibiting prostate tumorigenesis in vivo. Taken together, our study defines a PTEN/PLZF pathway and would shed new lights for developing therapeutic strategy of prostate cancer.

  3. Differential role of PTEN in transforming growth factor β (TGF-β) effects on proliferation and migration in prostate cancer cells.

    Science.gov (United States)

    Kimbrough-Allah, Mawiyah N; Millena, Ana C; Khan, Shafiq A

    2018-04-01

    Transforming growth factor-β (TGF-β) acts as a tumor suppressor in normal epithelial cells but as a tumor promoter in advanced prostate cancer cells. PI3-kinase pathway mediates TGF-β effects on prostate cancer cell migration and invasion. PTEN inhibits PI3-kinase pathway and is frequently mutated in prostate cancers. We investigated possible role(s) of PTEN in TGF-β effects on proliferation and migration in prostate cancer cells. Expression of PTEN mRNA and proteins were determined using RT-PCR and Western blotting in RWPE1 and DU145 cells. We also studied the role of PTEN in TGF-β effects on cell proliferation and migration in DU145 cells after transient silencing of endogenous PTEN. Conversely, we determined the role of PTEN in cell proliferation and migration after over-expression of PTEN in PC3 cells which lack endogenous PTEN. TGF-β1 and TGF-β3 had no effect on PTEN mRNA levels but both isoforms increased PTEN protein levels in DU145 and RWPE1 cells indicating that PTEN may mediate TGF-β effects on cell proliferation. Knockdown of PTEN in DU145 cells resulted in significant increase in cell proliferation which was not affected by TGF-β isoforms. PTEN overexpression in PC3 cells inhibited cell proliferation. Knockdown of endogenous PTEN enhanced cell migration in DU145 cells, whereas PTEN overexpression reduced migration in PC3 cells and reduced phosphorylation of AKT in response to TGF-β. We conclude that PTEN plays a role in inhibitory effects of TGF-β on cell proliferation whereas its absence may enhance TGF-β effects on activation of PI3-kinase pathway and cell migration. © 2018 Wiley Periodicals, Inc.

  4. Association of promoter methylation and 32-bp deletion of the PTEN gene with susceptibility to metabolic syndrome.

    Science.gov (United States)

    Hashemi, Mohammad; Rezaei, Hamzeh; Eskandari-Nasab, Ebrahim; Kaykhaei, Mahmoud-Ali; Taheri, Mohsen

    2013-01-01

    Metabolic syndrome (MeS), a cluster of several metabolic disorders, is increasingly being recognized as a risk factor for type II diabetes (T2D) and cardiovascular disease. Genetic and epigenetic alteration of the phosphatase and tensin homolog deleted on chromosome ten (PTEN) has been associated with components of MeS. The aim of the present study was to investigate the possible association of a 32-bp deletion polymorphism and promoter methylation of the PTEN gene with MeS. DNA was extracted from the peripheral blood of 151 subjects with and 149 subjects without MeS. The 32-bp deletion variant of PTEN was detected by polymerase chain reaction (PCR) and PTEN promoter methylation was defined by a nested methylation‑specific PCR (MSP) method. No significant differences were found in the allelic and genotypic frequencies of the 32-bp deletion variant of PTEN between the groups [odds ratio (OR), 0.77; 95% confidence interval (CI), 0.41-1.45; P=0.431]. However, patients with MeS were identified to have lower levels of PTEN promoter hypermethylation than subjects without MeS. Promoter methylation may be a protective factor against susceptibility to MeS (OR, 0.52; 95% CI, 0.29-0.92; P=0.029). Our findings suggest that PTEN promoter methylation may be a mechanism for PTEN downregulation or silencing in MeS, which remains to be fully clarified.

  5. PTEN expression as a predictor for the response to trastuzumab-based therapy in Her-2 overexpressing metastatic breast cancer.

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    Daphne Gschwantler-Kaulich

    Full Text Available Even though trastuzumab is an effective therapy in early stage Her-2+ breast cancer, 40-50% of advanced Her-2+ breast cancer patients develop trastuzumab resistance. A potential resistance mechanism is aberrant downstream signal transmission due to loss of phosphatase and tensin homologue (PTEN. This study investigated the relationship between the expression of PTEN and trastuzumab response in Her-2 overexpressing metastatic breast cancer patients.Between 2000 and 2007, 164 patients with Her-2+ metastatic breast cancer received trastuzumab-based therapy in our institution. We analyzed PTEN status by immunohistochemistry of 115 available tumor tissues and analyzed associations with other histopathological parameters, response rate, progression free survival (PFS and overall survival (OS with a median follow-up of 60 months.Eighty patients were PTEN positive (69.6% and 35 patients PTEN negative (30.4%. We found a significant association of the expression of PTEN and p53 (p = 0.041, while there was no association with grading, hormone receptor status, IGFR or MIB. We found significantly more cases with progressive disease under trastuzumab-based therapy in patients with PTEN positive breast cancers (p = 0.018, while there was no significant correlation with PFS or OS.In Her-2-positive metastatic breast cancers, PTEN positivity was significantly associated with progressive disease, but not with PFS or OS.

  6. Model predictive control using fuzzy decision functions

    NARCIS (Netherlands)

    Kaymak, U.; Costa Sousa, da J.M.

    2001-01-01

    Fuzzy predictive control integrates conventional model predictive control with techniques from fuzzy multicriteria decision making, translating the goals and the constraints to predictive control in a transparent way. The information regarding the (fuzzy) goals and the (fuzzy) constraints of the

  7. Exosomes promote cetuximab resistance via the PTEN/Akt pathway in colon cancer cells.

    Science.gov (United States)

    Zhang, S; Zhang, Y; Qu, J; Che, X; Fan, Y; Hou, K; Guo, T; Deng, G; Song, N; Li, C; Wan, X; Qu, X; Liu, Y

    2017-11-13

    Cetuximab is widely used in patients with metastatic colon cancer expressing wildtype KRAS. However, acquired drug resistance limits its clinical efficacy. Exosomes are nanosized vesicles secreted by various cell types. Tumor cell-derived exosomes participate in many biological processes, including tumor invasion, metastasis, and drug resistance. In this study, exosomes derived from cetuximab-resistant RKO colon cancer cells induced cetuximab resistance in cetuximab-sensitive Caco-2 cells. Meanwhile, exosomes from RKO and Caco-2 cells showed different levels of phosphatase and tensin homolog (PTEN) and phosphor-Akt. Furthermore, reduced PTEN and increased phosphorylated Akt levels were found in Caco-2 cells after exposure to RKO cell-derived exosomes. Moreover, an Akt inhibitor prevented RKO cell-derived exosome-induced drug resistance in Caco-2 cells. These findings provide novel evidence that exosomes derived from cetuximab-resistant cells could induce cetuximab resistance in cetuximab-sensitive cells, by downregulating PTEN and increasing phosphorylated Akt levels.

  8. Stabilization with guaranteed safety using Control Lyapunov–Barrier Function

    NARCIS (Netherlands)

    Romdlony, Muhammad Zakiyullah; Jayawardhana, Bayu

    2016-01-01

    We propose a novel nonlinear control method for solving the problem of stabilization with guaranteed safety for nonlinear systems. The design is based on the merging of the well-known Control Lyapunov Function (CLF) and the recent concept of Control Barrier Function (CBF). The proposed control

  9. PTEN genomic deletion predicts prostate cancer recurrence and is associated with low AR expression and transcriptional activity

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    Choucair Khalil

    2012-11-01

    Full Text Available Abstract Background Prostate cancer (PCa, a leading cause of cancer death in North American men, displays a broad range of clinical outcome from relatively indolent to lethal metastatic disease. Several genomic alterations have been identified in PCa which may serve as predictors of progression. PTEN, (10q23.3, is a negative regulator of the phosphatidylinositol 3-kinase (PIK3/AKT survival pathway and a tumor suppressor frequently deleted in PCa. The androgen receptor (AR signalling pathway is known to play an important role in PCa and its blockade constitutes a commonly used treatment modality. In this study, we assessed the deletion status of PTEN along with AR expression levels in 43 primary PCa specimens with clinical follow-up. Methods Fluorescence In Situ Hybridization (FISH was done on formalin fixed paraffin embedded (FFPE PCa samples to examine the deletion status of PTEN. AR expression levels were determined using immunohistochemistry (IHC. Results Using FISH, we found 18 cases of PTEN deletion. Kaplan-Meier analysis showed an association with disease recurrence (P=0.03. Concurrently, IHC staining for AR found significantly lower levels of AR expression within those tumors deleted for PTEN (PPTEN deleted. We confirmed the predictive value of PTEN deletion in disease recurrence (P=0.03. PTEN deletion was also linked to diminished expression of PTEN (PP=0.02. Furthermore, gene set enrichment analysis revealed a diminished expression of genes downstream of AR signalling in PTEN deleted tumors. Conclusions Altogether, our data suggest that PTEN deleted tumors expressing low levels of AR may represent a worse prognostic subset of PCa establishing a challenge for therapeutic management.

  10. Loss of PTEN expression is associated with aggressive behavior and poor prognosis in Middle Eastern triple-negative breast cancer.

    Science.gov (United States)

    Beg, Shaham; Siraj, Abdul K; Prabhakaran, Sarita; Jehan, Zeenath; Ajarim, Dahish; Al-Dayel, Fouad; Tulbah, Asma; Al-Kuraya, Khawla S

    2015-06-01

    PTEN is a tumor suppressor that negatively regulates the PI3 K-AKT signaling pathway which is involved in the pathogenesis of many different tumor types and serves as a prognostic marker in breast cancer. However, the significance of the role of PTEN in Middle Eastern ethnic breast cancer has not been explored especially with the fact that breast cancer originating from this ethnic population tend to behave more aggressively than breast cancer in the west. In this study, we analyzed PTEN alteration in a tissue microarray format containing more than 1000 primary breast cancers with clinical follow-up data. Tissue Microarray sections were analyzed for protein expression and copy number change using immunohistochemistry and fluorescence in situ hybridization. Loss of PTEN immunostaining was observed in 77 % of the cases. PTEN loss was significantly associated with large tumor size (p = 0.0030), high grade (p = 0.0281), tumor recurrence (p = 0.0333), and triple-negative breast cancers (p = 0.0086). PTEN loss in triple-negative breast cancers was significantly associated with rapid tumor cell proliferation (p = 0.0396) and poor prognosis (p = 0.0408). PTEN deletion was found only in 60 cases (6.4 %). Loss of PTEN protein expression occurs at high frequency in Middle Eastern breast cancer. PTEN inactivation may potentially lead to an aggressive behavior of tumor cells through stimulation of tumor cell proliferation. Furthermore, PTEN signaling pathway might be used as potential therapeutic target in triple-negative breast cancers since loss of its expression is shown to be significantly associated with this aggressive subtype of breast cancer.

  11. RAS/ERK modulates TGFβ-regulated PTEN expression in human pancreatic adenocarcinoma cells

    OpenAIRE

    Chow, Jimmy Y.C.; Quach, Khai T.; Cabrera, Betty L.; Cabral, Jennifer A.; Beck, Stayce E.; Carethers, John M.

    2007-01-01

    Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is rarely mutated in pancreatic cancers, but its regulation by transforming growth factor (TGF)-β might mediate growth suppression and other oncogenic actions. Here, we examined the role of TGFβ and the effects of oncogenic K-RAS/ERK upon PTEN expression in the absence of SMAD4. We utilized two SMAD4-null pancreatic cell lines, CAPAN-1 (K-RAS mutant) and BxPc-3 (WT-K-RAS), both of which express TGFβ surface receptors. Cells were t...

  12. A novel deleterious PTEN mutation in a patient with early-onset bilateral breast cancer

    International Nuclear Information System (INIS)

    Pradella, Laura Maria; Gasparre, Giuseppe; Turchetti, Daniela; Evangelisti, Cecilia; Ligorio, Claudia; Ceccarelli, Claudio; Neri, Iria; Zuntini, Roberta; Amato, Laura Benedetta; Ferrari, Simona; Martelli, Alberto Maria

    2014-01-01

    An early age at Breast Cancer (BC) onset may be a hallmark of inherited predisposition, but BRCA1/2 mutations are only found in a minority of younger BC patients. Among the others, a fraction may carry mutations in rarer BC genes, such as TP53, STK11, CDH1 and PTEN. As the identification of women harboring such mutations allows for targeted risk-management, the knowledge of associated manifestations and an accurate clinical and family history evaluation are warranted. We describe the case of a woman who developed an infiltrating ductal carcinoma of the right breast at the age of 32, a contralateral BC at age 36 and another BC of the right breast at 40. When she was 39 years-old, during a dermatological examination, mucocutaneous features suggestive of Cowden Syndrome, a disorder associated to germ-line PTEN mutations, were noticed. PTEN genetic testing revealed the novel c.71A > T (p.Asp24Val) mutation, whose deleterious effect, suggested by conservation data and in silico tools, was definitely demonstrated by the incapacity of mutant PTEN to inhibit Akt phosphorylation when used to complement PTEN-null cells. In BC tissue, despite the absence of LOH or somatic mutations of PTEN, Akt phosphorylation was markedly increased in comparison to normal tissue, thus implying additional somatic events into the deregulation of the PI3K/Akt/mTOR pathway and, presumably, into carcinogenesis. Hence, known oncogenic mutations in PIK3CA (exons 10 and 21) and AKT1 (exon 2) were screened in tumor DNA with negative results, which suggests that the responsible somatic event(s) is a different, uncommon one. This case stresses the importance of clinical/genetic assessment of early-onset BC patients in order to identify mutation carriers, who are at high risk of new events, so requiring tailored management. Moreover, it revealed a novel PTEN mutation with pathogenic effect, pointing out, however, the need for further efforts to elucidate the molecular steps of PTEN

  13. Effect of Jianpi Jiedu Recipe on angiogenesis and the PTEN/PI3K/AKT signaling pathway in the course of Helicobacter pylori-induced gastric cancer in C57BL/6 mice

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    Ning-Ning Liu

    2018-01-01

    Full Text Available Objective: To reveal the effect of Jianpi Jiedu recipe (JPJDR on angiogenesis and the PTEN (Phosphatase and tensin homolog deleted on chromosome ten/PI3K/AKT signaling pathway in the course of H. pylori infection-induced carcinogenesis of gastric mucosa in C57BL/6 mice. Methods: Two-hundred C57BL/6 mice were randomly divided into five groups (control group, model group, JPJDR low-dose group, JPJDR medium-dose group, and JPJDR high-dose group, 40 in each group. A mouse model of gastric cancer, induced by H. pylori standard strain infection, was established. The mice of JPJDR low-dose, middle-dose, and high-dose groups were intragastrically administered 250, 500, and 1000 mg/kg JPJDR per day, respectively. After 72 weeks, the H. pylori infection in gastric mucosa of the mice was analyzed by rapid urease test; the pathological changes in the gastric mucosa of mice were assessed by histopathological examination, and micro-vessel density (MVD, vascular endothelial growth factor (VEGF, and PTEN/PI3K/AKT levels were determined. Results: The incidence of gastric cancer in each group (control group, model group, JPJDR low-dose, medium-dose, high-dose group was 0%, 26.3%, 13.2%, 10%, and 7.5% respectively. The incidence of gastric cancer in the Chinese medicine group was significantly lower than that of the model group (P = 0.020, P = 0.023, P = 0.007. The expression of MVD and VEGF in the model group was significantly higher than that in the control group (P = 0.002, P < 0.001, while the expression of MVD and VEGF decreased in the Chinese medicine group. The expression of p-PTEN and p-AKT in the model group was significantly higher than that in the control group (All P < 0.001, while Chinese medicine could reduce the expression of p-PTEN and p-AKT to varying extents. Conclusion: Long-term infection of C57BL/6 mice with H. pylori induces gastric carcinogenesis, by increasing gastric mucosal MVD, promoting the expression of VEGF, inhibiting the activity of

  14. Machine function based control code algebras

    NARCIS (Netherlands)

    Bergstra, J.A.

    Machine functions have been introduced by Earley and Sturgis in [6] in order to provide a mathematical foundation of the use of the T-diagrams proposed by Bratman in [5]. Machine functions describe the operation of a machine at a very abstract level. A theory of hardware and software based on

  15. β-catenin is required for prostate development and cooperates with Pten loss to drive invasive carcinoma.

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    Jeffrey C Francis

    Full Text Available Prostate cancer is a major cause of male death in the Western world, but few frequent genetic alterations that drive prostate cancer initiation and progression have been identified. β-Catenin is essential for many developmental processes and has been implicated in tumorigenesis in many tissues, including prostate cancer. However, expression studies on human prostate cancer samples are unclear on the role this protein plays in this disease. We have used in vivo genetic studies in the embryo and adult to extend our understanding of the role of β-Catenin in the normal and neoplastic prostate. Our gene deletion analysis revealed that prostate epithelial β-Catenin is required for embryonic prostate growth and branching but is dispensable in the normal adult organ. During development, β-Catenin controls the number of progenitors in the epithelial buds and regulates a discrete network of genes, including c-Myc and Nkx3.1. Deletion of β-Catenin in a Pten deleted model of castration-resistant prostate cancer demonstrated it is dispensable for disease progression in this setting. Complementary overexpression experiments, through in vivo protein stabilization, showed that β-Catenin promotes the formation of squamous epithelia during prostate development, even in the absence of androgens. β-Catenin overexpression in combination with Pten loss was able to drive progression to invasive carcinoma together with squamous metaplasia. These studies demonstrate that β-Catenin is essential for prostate development and that an inherent property of high levels of this protein in prostate epithelia is to drive squamous fate differentiation. In addition, they show that β-Catenin overexpression can promote invasive prostate cancer in a clinically relevant model of this disease. These data provide novel information on cancer progression pathways that give rise to lethal prostate disease in humans.

  16. Concurrent deletion of 16q23 and PTEN is an independent prognostic feature in prostate cancer.

    Science.gov (United States)

    Kluth, Martina; Runte, Frederic; Barow, Philipp; Omari, Jazan; Abdelaziz, Zaid M; Paustian, Lisa; Steurer, Stefan; Christina Tsourlakis, Maria; Fisch, Margit; Graefen, Markus; Tennstedt, Pierre; Huland, Hartwig; Michl, Uwe; Minner, Sarah; Sauter, Guido; Simon, Ronald; Adam, Meike; Schlomm, Thorsten

    2015-11-15

    The deletion of 16q23-q24 belongs to the most frequent chromosomal changes in prostate cancer, but the clinical consequences of this alteration have not been studied in detail. We performed fluorescence in situ hybridization analysis using a 16q23 probe in more than 7,400 prostate cancers with clinical follow-up data assembled in a tissue microarray format. Chromosome 16q deletion was found in 21% of cancers, and was linked to advanced tumor stage, high Gleason grade, accelerated cell proliferation, the presence of lymph node metastases (p Deletion was more frequent in ERG fusion-positive (27%) as compared to ERG fusion-negative cancers (16%, p deletions including phosphatase and tensin homolog (PTEN) (p deletion of 16q was linked to early biochemical recurrence independently from the ERG status (p deletion of 16q alone. Multivariate modeling revealed that the prognostic value of 16q/PTEN deletion patterns was independent from the established prognostic factors. In summary, the results of our study demonstrate that the deletion of 16q and PTEN cooperatively drives prostate cancer progression, and suggests that deletion analysis of 16q and PTEN could be of important clinical value particularly for preoperative risk assessment of the clinically most challenging group of low- and intermediated grade prostate cancers. © 2015 UICC.

  17. High-calorie diet exacerbates prostate neoplasia in mice with haploinsufficiency of Pten tumor suppressor gene

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    Jehnan Liu

    2015-03-01

    Conclusion: High-calorie diet promotes prostate cancer progression in the genetically susceptible Pten haploinsufficient mouse while preserving insulin sensitivity. This appears to be partly due to increased inflammatory response to high-caloric intake in addition to increased ability of insulin to promote lipogenesis.

  18. Homozygous deletion and expression of PTEN and DMBT1 in human primary neuroblastoma and cell lines.

    Science.gov (United States)

    Muñoz, Jorge; Lázcoz, Paula; Inda, María Mar; Nistal, Manuel; Pestaña, Angel; Encío, Ignacio J; Castresana, Javier S

    2004-05-01

    Neuroblastoma is the most common pediatric solid tumor. Although many allelic imbalances have been described, a bona fide tumor suppressor gene for this disease has not been found yet. In our study, we analyzed 2 genes, PTEN and DMBT1, mapping 10q23.31 and 10q25.3-26.1, respectively, which have been found frequently altered in other kinds of neoplasms. We screened both genes for homozygous deletions in 45 primary neuroblastic tumors and 12 neuroblastoma cell lines. Expression of these genes in cell lines was assessed by RT-PCR analysis. We could detect 2 of 41 (5%) primary tumors harboring PTEN homozygous deletions. Three of 41 (7%) primary tumors and 2 of 12 cell lines presented homozygous losses at the g14 STS on the DMBT1 locus. All cell lines analyzed expressed PTEN, but lack of DMBT1 mRNA expression was detected in 2 of them. We tried to see whether epigenetic mechanisms, such as aberrant promoter hypermethylation, had any role in DMBT1 silencing. The 2 cell lines lacking DMBT1 expression were treated with 5-aza-2'-deoxycytidine; DMBT1 expression was restored in only one of them (MC-IXC). From our work, we can conclude that PTEN and DMBT1 seem to contribute to the development of a small fraction of neuroblastomas, and that promoter hypermethylation might have a role in DMBT1 gene silencing. Copyright 2004 Wiley-Liss, Inc.

  19. miR-1297 mediates PTEN expression and contributes to cell progression in LSCC

    International Nuclear Information System (INIS)

    Li, Xin; Wang, Hong-liang; Peng, Xin; Zhou, Hui-fang; Wang, Xin

    2012-01-01

    Highlights: ► miR-1297 was found to be overexpressed in LSCC and contribute to the cell progression. ► PTEN was confirmed to be a target gene of miR-1297. ► Downregulation of PTEN can rescue the proliferation and invasion ability of miR-1297 downregulated Hep-2 cells. ► Downregulation of miR-1297 inhibits tumor growth in vivo. -- Abstract: MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression after transcription, and are involved in cancer development. Laryngeal squamous cell carcinoma (LSCC) is one of the most common malignant neoplasms with increasing incidence in recent years. In this paper, we report the overexpression of miR-1297 in LSCC and Hep-2 cells. In addition, PTEN was identified to be directly regulated by miR-1297 through western blot and luciferase activity assay. Furthermore, downregulation of miR-1297 in Hep-2 cells was shown to inhibit cancer cell proliferation, migration, and tumor genesis. Our results document a new epigenetic mechanism for PTEN regulation in LSCC, which is crucial for the development of these tumors.

  20. MicroRNA-103 Promotes Colorectal Cancer by Targeting Tumor Suppressor DICER and PTEN

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    Li Geng

    2014-05-01

    Full Text Available MicroRNAs (miRNAs are a class of small, noncoding RNAs that act as key regulators in various physiological and pathological processes. However, the regulatory mechanisms for miRNAs in colorectal cancer remain largely unknown. Here, we found that miR-103 is up-regulated in colorectal cancer and its overexpression is closely associated with tumor proliferation and migration. In addition, repressing the expression of miR-103 apparently inhibits colorectal cancer cell proliferation and migration in vitro and HCT-116 xenograft tumor growth in vivo. Subsequent software analysis and dual-luciferase reporter assay identified two tumor suppressor genes DICER and PTEN as direct targets of miR-103, and up-regulation of DICER and PTEN obtained similar results to that occurred in the silencing of miR-103. In addition, restoration of DICER and PTEN can inhibit miR-103-induced colorectal cancer cell proliferation and migration. Our data collectively demonstrate that miR-103 is an oncogene miRNA that promotes colorectal cancer proliferation and migration through down-regulation of the tumor suppressor genes DICER and PTEN. Thus, miR-103 may represent a new potential diagnostic and therapeutic target for colorectal cancer treatment.

  1. Variable phenotypes associated with 10q23 microdeletions involving the PTEN and BMPR1A genes.

    NARCIS (Netherlands)

    Menko, F.H.; Kneepkens, C.M.; Leeuw, N. de; Peeters, E.A.; Maldergem, L. van; Kamsteeg, E.J.; Davidson, R.; Rozendaal, L.; Lasham, C.A.; Peeters-Scholte, C.M.; Jansweijer, M.C.E.; Hilhorst-Hofstee, Y.; Gille, J.J.P.; Heins, Y.M.; Nieuwint, A.W.; Sistermans, E.A.

    2008-01-01

    Infantile juvenile polyposis is a rare disease with severe gastrointestinal symptoms and a grave clinical course. Recently, 10q23 microdeletions involving the PTEN and BMPR1A genes were found in four patients with infantile juvenile polyposis. It was hypothesized that a combined and synergistic

  2. Deletion of PTEN Produces Deficits in Conditioned Fear and Increases Fragile X Mental Retardation Protein

    Science.gov (United States)

    Lugo, Joaquin N.; Smith, Gregory D.; Morrison, Jessica B.; White, Jessika

    2013-01-01

    The phosphatase and tensin homolog detected on chromosome 10 (PTEN) gene product modulates activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. The PI3K pathway has been found to be involved in the regulation of the fragile X mental retardation protein, which is important for long-term depression and in the formation of new…

  3. Alterations in PTEN and PIK3CA in colorectal cancers in the EPIC Norfolk study: associations with clinicopathological and dietary factors

    International Nuclear Information System (INIS)

    Naguib, Adam; Arends, Mark J; Cooke, James C; Happerfield, Lisa; Kerr, Lucy; Gay, Laura J; Luben, Robert N; Ball, Richard Y; Mitrou, Panagiota N; McTaggart, Alison

    2011-01-01

    The PTEN tumour suppressor gene and PIK3CA proto-oncogene encode proteins which contribute to regulation and propagation of signal transduction through the PI3K/AKT signalling pathway. This study investigates the prevalence of loss of PTEN expression and mutations in both PTEN and PIK3CA in colorectal cancers (CRC) and their associations with tumour clinicopathological features, lifestyle factors and dietary consumptions. 186 adenocarcinomas and 16 adenomas from the EPIC Norfolk study were tested for PTEN and PIK3CA mutations by DNA sequencing and PTEN expression changes by immunohistochemistry. Dietary and lifestyle data were collected prospectively using seven day food diaries and lifestyle questionnaires. Mutations in exons 7 and 8 of PTEN were observed in 2.2% of CRC and PTEN loss of expression was identified in 34.9% CRC. Negative PTEN expression was associated with lower blood low-density lipoprotein concentrations (p = 0.05). PIK3CA mutations were observed in 7% of cancers and were more frequent in CRCs in females (p = 0.04). Analysis of dietary intakes demonstrated no link between PTEN expression status and any specific dietary factor. PTEN expression negative, proximal CRC were of more advanced Dukes' stage (p = 0.02) and poor differentiation (p < 0.01). Testing of the prevalence of PIK3CA mutations and loss of PTEN expression demonstrated that these two events were independent (p = 0.55). These data demonstrated the frequent occurrence (34.9%) of PTEN loss of expression in colorectal cancers, for which gene mutations do not appear to be the main cause. Furthermore, dietary factors are not associated with loss of PTEN expression. PTEN expression negative CRC were not homogenous, as proximal cancers were associated with a more advanced Dukes' stage and poor differentiation, whereas distal cancers were associated with earlier Dukes' stage

  4. Controlling Function and Structure with DNA

    DEFF Research Database (Denmark)

    Tørring, Thomas

    2011-01-01

    and ideas are presented. The second research topic concerns our contributions to the field of DNA origami. This includes investigations of single molecule reactions on a DNA origami platform. The reaction between an amine and an activated ester, as well as the Huisgen-Meldal-Sharpless reaction were...... investigated on a two dimensional DNA origami platform. This was done by incorporating functional groups on the surface of the origami, and reacting these with biotin analogues carrying the complementary functional groups. Successful reactions could then be observed using atomic force microscopy after addition...... of the protein streptavidin. While the implementation of chemical functionalities on origami can be achieved during automated DNA synthesis, this is laborious and costly. In a separate research project we aimed at improving the accessibility by applying an enzymatic labelling method. We demonstrated that the DNA...

  5. Loss of Cdh1 and Pten Accelerates Cellular Invasiveness and Angiogenesis in the Mouse Uterus1

    Science.gov (United States)

    Lindberg, Mallory E.; Stodden, Genna R.; King, Mandy L.; MacLean, James A.; Mann, Jordan L.; DeMayo, Francesco J.; Lydon, John P.; Hayashi, Kanako

    2013-01-01

    ABSTRACT E-cadherin (CDH1) is a cell adhesion molecule that coordinates key morphogenetic processes regulating cell growth, cell proliferation, and apoptosis. Loss of CDH1 is a trademark of the cellular event epithelial to mesenchymal transition, which increases the metastatic potential of malignant cells. PTEN is a tumor-suppressor gene commonly mutated in many human cancers, including endometrial cancer. In the mouse uterus, ablation of Pten induces epithelial hyperplasia, leading to endometrial carcinomas. However, loss of Pten alone does not affect longevity until around 5 mo. Similarly, conditional ablation of Cdh1 alone does not predispose mice to cancer. In this study, we characterized the impact of dual Cdh1 and Pten ablation (Cdh1d/d Ptend/d) in the mouse uterus. We observed that Cdh1d/d Ptend/d mice died at Postnatal Days 15–19 with massive blood loss. Their uteri were abnormally structured with curly horns, disorganized epithelial structure, and increased cell proliferation. Co-immunostaining of KRT8 and ACTA2 showed invasion of epithelial cells into the myometrium. Further, the uteri of Cdh1d/d Ptend/d mice had prevalent vascularization in both the endometrium and myometrium. We also observed reduced expression of estrogen and progesterone receptors, loss of cell adherens, and tight junction molecules (CTNNB1 and claudin), as well as activation of AKT in the uteri of Cdh1d/d Ptend/d mice. However, complex hyperplasia was not found in the uteri of Cdh1d/d Ptend/d mice. Collectively, these findings suggest that ablation of Pten with Cdh1 in the uterus accelerates cellular invasiveness and angiogenesis and causes early death. PMID:23740945

  6. α(V)β(6) integrin expression is induced in the POET and Pten(pc-/-) mouse models of prostatic inflammation and prostatic adenocarcinoma.

    Science.gov (United States)

    Garlick, David S; Li, Jing; Sansoucy, Brian; Wang, Tao; Griffith, Leeanne; Fitzgerald, Tj; Butterfield, Julie; Charbonneau, Bridget; Violette, Shelia M; Weinreb, Paul H; Ratliff, Timothy L; Liao, Chun-Peng; Roy-Burman, Pradip; Vietri, Michele; Lian, Jane B; Stein, Gary S; Altieri, Dario C; Languino, Lucia R

    2012-01-01

    Chronic inflammation is proposed to prime the development of prostate cancer. However, the mechanisms of prostate cancer initiation and development are not completely understood. The α(v)β(6) integrin has been shown to play a role in epithelial development, wound healing and some epithelial cancers [1, 2]. Here, we investigate the expression of α(v)β(6) in mouse models of prostatic inflammation and prostate cancer to establish a possible relationship between inflammation of the prostate, α(v)β(6) expression and the progression of prostate cancer. Using immunohistochemical techniques, we show expression of α(v)β(6) in two in vivo mouse models; the Pten(pc)-/- model containing a prostate- specific Pten tumor suppressor deletion that causes cancer, and the prostate ovalbumin-expressing transgenic (POET) inflammation mouse model. We show that the α(v)β(6) integrin is induced in prostate cancer and inflammation in vivo in these two mouse models. α(v)β(6) is expressed in all the mice with cancer in the Pten(pc-/-) model but not in age-matched wild-type mice. In the POET inflammation model, α(v)β(6) is expressed in mice injected with activated T-cells, but in none of the control mice. In the POET model, we also used real time PCR to assess the expression of Transforming Growth Factor Beta 1 (TGFβ1), a factor in inflammation that is activated by α(v)β(6). In conclusion, through in vivo evidence, we conclude that α(v)β(6) integrin may be a crucial link between prostatic inflammation and prostatic adenocarcinoma.

  7. Applications of functional analysis to optimal control problems

    International Nuclear Information System (INIS)

    Mizukami, K.

    1976-01-01

    Some basic concepts in functional analysis, a general norm, the Hoelder inequality, functionals and the Hahn-Banach theorem are described; a mathematical formulation of two optimal control problems is introduced by the method of functional analysis. The problem of time-optimal control systems with both norm constraints on control inputs and on state variables at discrete intermediate times is formulated as an L-problem in the theory of moments. The simplex method is used for solving a non-linear minimizing problem inherent in the functional analysis solution to this problem. Numerical results are presented for a train operation. The second problem is that of optimal control of discrete linear systems with quadratic cost functionals. The problem is concerned with the case of unconstrained control and fixed endpoints. This problem is formulated in terms of norms of functionals on suitable Banach spaces. (author)

  8. Core functions of the Web-of-Cells control scheme

    DEFF Research Database (Denmark)

    Evenblij, Berend; Rikos, Evangelos; Heussen, Kai

    In order to maintain frequency (balancing) and voltage control in the future power system, the ELECTRA Web-of-Cells (WoC) control scheme introduces six high-level use cases, which are Balance Restoration Control (BRC), Frequency Containment Control (FCC), Inertia Response Power Control (IRPC), Ba......), Balance Steering Control (BSC), Primary Voltage Control (PVC) and Post Primary Voltage Control (PPVC). This document presents the detailed description of the core functions that are needed and sufficient for controlling the grid in a Web-of-Cells architecture....

  9. miR-494 up-regulates the PI3K/Akt pathway via targetting PTEN and attenuates hepatic ischemia/reperfusion injury in a rat model.

    Science.gov (United States)

    Su, Song; Luo, De; Liu, Xiangdong; Liu, Jiang; Peng, Fangyi; Fang, Cheng; Li, Bo

    2017-10-31

    A rat HIRI model was constructed and treated with an intraperitoneal injection of agomir- miR-494 or agomir-NC (negative control) for 7 days after the surgery. The pathophysiological changes in sham-operated rats, HIRI, HIRI + agomir- miR-494 , and HIRI + agomir-NC were compared. The effect of miR-494 was also assessed in an H 2 O 2 -induced apoptosis model. Hepatic AML12 cells were transfected with mimics NC or miR-494 mimics, followed by 6-h H 2 O 2 treatment. Cell proliferation and apoptosis were detected by CCK8 assay and flow cytometry, respectively. Further, the miR-494 target gene was identified by luciferase reporter assay, and verified both in vitro and in vivo experiments. The activity of AKT pathway was further analyzed in vivo by Western blot. HIRI + agomir- miR-494 rats exhibited significantly higher miR-494 expression, lower serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and glutamate dehydrogenase (GLDH) level, lower hepatic MDA, TOA, and OSI, alleviated hepatic necrosis, reduced hepatocyte apoptosis, and decreased expression of apoptosis-related proteins, when compared with HIRI + agomir-NC rats ( P <0.05 or 0.01). After H 2 O 2 treatment, AML-12 cells transfected with miR-494 mimics had significantly higher proliferation and lower apoptosis rate compared with mimics NC group ( P <0.01). PTEN was identified as an miR-494 target gene. PTEN expression was significantly down-regulated in AML12 cells transfected with miR-494 mimics, and was up-regulated by treatment of miR-494 inhibitor ( P <0.01). Moreover, HIRI + agomir- miR-494 rats exhibited significantly lower PTEN expression, and higher p-AKT, p-mTOR, and p-p70S6K levels compared with HIRI + agomir-NC rats. Therefore, miR-494 protected rats against hepatic ischemia/reperfusion (I/R) injury through down-regulating its downstream target gene PTEN , leading to the activation of PI3K/AKT signaling pathway. © 2017 The Author(s).

  10. Evaluation-Function-based Model-free Adaptive Fuzzy Control

    Directory of Open Access Journals (Sweden)

    Agus Naba

    2016-12-01

    Full Text Available Designs of adaptive fuzzy controllers (AFC are commonly based on the Lyapunov approach, which requires a known model of the controlled plant. They need to consider a Lyapunov function candidate as an evaluation function to be minimized. In this study these drawbacks were handled by designing a model-free adaptive fuzzy controller (MFAFC using an approximate evaluation function defined in terms of the current state, the next state, and the control action. MFAFC considers the approximate evaluation function as an evaluative control performance measure similar to the state-action value function in reinforcement learning. The simulation results of applying MFAFC to the inverted pendulum benchmark verified the proposed scheme’s efficacy.

  11. Formation control of marine craft using constraint functions

    DEFF Research Database (Denmark)

    Ihle, Ivar-Andre F.; Jouffroy, Jerome; Fossen, Thor I.

    This article presents a method for formation control of marine surface vessels inspired by Lagrangian mechanics. The desired formation configuration is given as a set of constraint functions. The functions are treated analytically and by using feedback from the imposed constraint functions, const...

  12. Catalog of Window Taper Functions for Sidelobe Control

    Energy Technology Data Exchange (ETDEWEB)

    Doerry, Armin W.

    2017-04-01

    Window taper functions of finite apertures are well-known to control undesirable sidelobes, albeit with performance trades. A plethora of various taper functions have been developed over the years to achieve various optimizations. We herein catalog a number of window functions, and com pare principal characteristics.

  13. Function analysis and function assignment of NPP advanced main control room

    International Nuclear Information System (INIS)

    Zheng Mingguang; Xu Jijun

    2001-01-01

    The author addresses the requirements of function analysis and function assignment, which should be carried out in the design of main control room in nuclear power plant according to the design research of advanced main control room, then states its contents, functions, importance and necessity as well as how to implement these requirements and how to do design verification and validation in the design of advanced main control room of nuclear power plant

  14. Induction of intrahepatic cholangiocellular carcinoma by liver-specific disruption of Smad4 and Pten in mice

    OpenAIRE

    Xu, Xiaoling; Kobayashi, Shogo; Qiao, Wenhui; Li, Cuiling; Xiao, Cuiying; Radaeva, Svetlana; Stiles, Bangyan; Wang, Rui-Hong; Ohara, Nobuya; Yoshino, Tadashi; LeRoith, Derek; Torbenson, Michael S.; Gores, Gregory J.; Wu, Hong; Gao, Bin

    2006-01-01

    Cholangiocellular carcinoma (CC), the second most common primary liver cancer, is associated with a poor prognosis. It has been shown that CCs harbor alterations of a number of tumor-suppressor genes and oncogenes, yet key regulators for tumorigenesis remain unknown. Here we have generated a mouse model that develops CC with high penetrance using liver-specific targeted disruption of tumor suppressors SMAD4 and PTEN. In the absence of SMAD4 and PTEN, hyperplastic foci emerge exclusively from ...

  15. Synthetic RNA Controllers for Programming Mammalian Cell Fate and Function

    Science.gov (United States)

    2015-11-04

    Final report for “Synthetic RNA controllers for programming mammalian cell fate and function” Principal Investigator: Christina D. Smolke...SUBTITLE Synthetic RNA controllers for programming mammalian cell fate and function 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER...Form 298 (Rev. 8-98) Prescribed by ANSI Std Z39-18   2 Synthetic RNA controllers for programming mammalian cell fate and function Task 1

  16. High-incidence of PTEN mutations in Chinese patients with primary small cell carcinoma of the esophagus

    International Nuclear Information System (INIS)

    Zhang, Zhimin; Wang, Ge; Xiao, Hualiang; Xie, Fei; Zhang, Hui; Chen, Chuan; Xiao, He; Yang, Zhenzhou; Wang, Dong; Li, Zengpeng

    2014-01-01

    Primary small cell carcinoma of the esophagus (PSCCE) is a rare and aggressive tumor with poor prognosis. The aim of this study was to investigate the existence of EGFR, KRAS, PIK3CA and PTEN mutations in PSCCE. Clinical–pathological data and paraffin-embedded specimens were collected from 38 patients. Exons 18 to 21 of EGFR, KRAS and PIK3CA status were analyzed by real-time PCR based on ARMS and Scorpion technology in all patients, and the PTEN gene was also screened using real-time PCR and high-resolution melting curve analysis (HRMA). Only 1 (2.63%) out of 38 patients had EGFR mutations in L858R missense, and KRAS and PIK3CA were not found in the mutational spot in all patients. However, PTEN mutations presented in 14 (36.84%) out of 38 patients, including exon 5 coding for PTEN missense mutation (n =4, 10.53%), exon 6 (n =7, 18.42%), concurrent exon 5 and exon 6 (n =2, 5.26%), and exon 8 (n =1, 2.63%). Concurrent mutations of these genes were not detected in all samples. No statistically significant associations were found between the clinicopathological features and the mutation status of PTEN. The incidence of PTEN mutations in Chinese patients with PSCCE was higher than that of previous reports in other histological subtypes of esophageal cancer

  17. Exploring Prostate Cancer Genome Reveals Simultaneous Losses of PTEN, FAS and PAPSS2 in Patients with PSA Recurrence after Radical Prostatectomy

    Directory of Open Access Journals (Sweden)

    Chinyere Ibeawuchi

    2015-02-01

    Full Text Available The multifocal nature of prostate cancer (PCa creates a challenge to patients’ outcome prediction and their clinical management. An approach that scrutinizes every cancer focus is needed in order to generate a comprehensive evaluation of the disease, and by correlating to patients’ clinico-pathological information, specific prognostic biomarker can be identified. Our study utilized the Affymetrix SNP 6.0 Genome-wide assay to investigate forty-three fresh frozen PCa tissue foci from twenty-three patients. With a long clinical follow-up period that ranged from 2.0–9.7 (mean 5.4 years, copy number variation (CNV data was evaluated for association with patients’ PSA status during follow-up. From our results, the loss of unique genes on 10q23.31 and 10q23.2–10q23.31 were identified to be significantly associated to PSA recurrence (p < 0.05. The implication of PTEN and FAS loss (10q23.31 support previous reports due to their critical roles in prostate carcinogenesis. Furthermore, we hypothesize that the PAPSS2 gene (10q23.2–10q23.31 may be functionally relevant in post-operative PSA recurrence because of its reported role in androgen biosynthesis. It is suggestive that the loss of the susceptible region on chromosome 10q, which implicates PTEN, FAS and PAPSS2 may serve as genetic predictors of PSA recurrence after radical prostatectomy.

  18. Exploring Prostate Cancer Genome Reveals Simultaneous Losses of PTEN, FAS and PAPSS2 in Patients with PSA Recurrence after Radical Prostatectomy

    Science.gov (United States)

    Ibeawuchi, Chinyere; Schmidt, Hartmut; Voss, Reinhard; Titze, Ulf; Abbas, Mahmoud; Neumann, Joerg; Eltze, Elke; Hoogland, Agnes Marije; Jenster, Guido; Brandt, Burkhard; Semjonow, Axel

    2015-01-01

    The multifocal nature of prostate cancer (PCa) creates a challenge to patients’ outcome prediction and their clinical management. An approach that scrutinizes every cancer focus is needed in order to generate a comprehensive evaluation of the disease, and by correlating to patients’ clinico-pathological information, specific prognostic biomarker can be identified. Our study utilized the Affymetrix SNP 6.0 Genome-wide assay to investigate forty-three fresh frozen PCa tissue foci from twenty-three patients. With a long clinical follow-up period that ranged from 2.0–9.7 (mean 5.4) years, copy number variation (CNV) data was evaluated for association with patients’ PSA status during follow-up. From our results, the loss of unique genes on 10q23.31 and 10q23.2–10q23.31 were identified to be significantly associated to PSA recurrence (p < 0.05). The implication of PTEN and FAS loss (10q23.31) support previous reports due to their critical roles in prostate carcinogenesis. Furthermore, we hypothesize that the PAPSS2 gene (10q23.2–10q23.31) may be functionally relevant in post-operative PSA recurrence because of its reported role in androgen biosynthesis. It is suggestive that the loss of the susceptible region on chromosome 10q, which implicates PTEN, FAS and PAPSS2 may serve as genetic predictors of PSA recurrence after radical prostatectomy. PMID:25679447

  19. Rac1-mediated membrane raft localization of PI3K/p110β is required for its activation by GPCRs or PTEN loss

    Science.gov (United States)

    Cizmecioglu, Onur; Ni, Jing; Xie, Shaozhen; Zhao, Jean J; Roberts, Thomas M

    2016-01-01

    We aimed to understand how spatial compartmentalization in the plasma membrane might contribute to the functions of the ubiquitous class IA phosphoinositide 3-kinase (PI3K) isoforms, p110α and p110β. We found that p110β localizes to membrane rafts in a Rac1-dependent manner. This localization potentiates Akt activation by G-protein-coupled receptors (GPCRs). Thus genetic targeting of a Rac1 binding-deficient allele of p110β to rafts alleviated the requirement for p110β-Rac1 association for GPCR signaling, cell growth and migration. In contrast, p110α, which does not play a physiological role in GPCR signaling, is found to reside in nonraft regions of the plasma membrane. Raft targeting of p110α allowed its EGFR-mediated activation by GPCRs. Notably, p110β dependent, PTEN null tumor cells critically rely upon raft-associated PI3K activity. Collectively, our findings provide a mechanistic account of how membrane raft localization regulates differential activation of distinct PI3K isoforms and offer insight into why PTEN-deficient cancers depend on p110β. DOI: http://dx.doi.org/10.7554/eLife.17635.001 PMID:27700986

  20. Study on construction of pEgr-hPTEN expression vector induced by irradiation and its anti-tumor effect in vitro

    International Nuclear Information System (INIS)

    Tian Mei; Jin Guanghui; Piao Chunji; Li Xiuyi; Liu Linlin

    2003-01-01

    Objective: To clone the cDNA of human tumor suppressor gene-PTEN, construct pEgr-hPTEN expression vector induced by irradiation and study its inhibitory effect on proliferation of malignant glioma cell line SHG-44 transfected steadily with pEgr-hPTEN after different doses of X-ray irradiation. Methods: A DNA fragment about 1200 bp, PTEN, was amplified from human placenta tissues by using RT-nested PCR and was cloned into pUCm-T vector after automatic sequencing, then the fragment was inserted into a vector pcD-NA3.1-Egr to construct an expression vector pEgr-hPTEN. pEgr-hPTEN was transfected into SHG-44 cells in vitro. Stably transfected cell line SHG-44-sPTEN was selected through G418. The inhibitor effect on SHG-44-sPTEN was observed after different doses of X-ray irradiation in vitro. Results: The PTEN cDNA has been cloned correctly and its expression vector pEgr-hPTEN was also constructed. Growth of SHG-44 cells was inhibited significantly by stable pEgr-hPTEN transfection combined with X-ray irradiation. With the increase of dose, the inhibitory effect was enhanced within 5 Gy. Conclusion: Human tumor suppressor gene-PTEN cDNA has been cloned and its expression vector has been constructed. The tumor was inhibited significantly by gene-radiotherapy in vitro. The result provides the theoretical and experimental basis for improvement of clinical radiotherapeutic effect on tumors

  1. Alteration of major vault protein in human glioblastoma and its relation with EGFR and PTEN status.

    Science.gov (United States)

    Navarro, L; Gil-Benso, R; Megías, J; Muñoz-Hidalgo, L; San-Miguel, T; Callaghan, R C; González-Darder, J M; López-Ginés, C; Cerdá-Nicolás, M J

    2015-06-25

    Glioblastoma (GBM) is the most frequent and malignant primary brain tumor. Conventional therapy of surgical removal, radiation and chemotherapy is largely palliative. Major vault protein (MVP), the main component of the vault organelle has been associated with multidrug resistance by reducing cellular accumulation of chemotherapeutic agents. With regard to cancer, MVP has been shown to be overexpressed in drug resistance development and malignant progression. The aim of the present study was to evaluate the MVP gene dosage levels in 113 archival samples from GBM and its correlation with patients' survival and epidermal growth factor receptor (EGFR) and phosphatase and tensin homolog (PTEN) gene dosages. Fluorescent in situ hybridization revealed polysomy of chromosome 7 in 76.1% of the GBMs and EGFR amplification in a 64.6% of the tumors. Genetic status of EGFR, PTEN and MVP copies was determined by multiplex ligation-dependent probe amplification (MLPA) technique. 31% of the tumors showed the EGFR is variant III mutation (EGFRvIII) mutation and 74.3% of them presented amplification of MVP gene. Amplification of EGFR and MVP was found in a 63.7% and 56.6% of the GBM, respectively. An inverse correlation between MVP and PTEN dosage values was observed. Besides, an inverse relationship between the survival of the patients treated with chemotherapy and the levels of MVP copies was determined. In conclusion, our study reveals an important role of MVP, together with EGFRvIII and PTEN, in the progression of GBM and proposes it as a novel and interesting target for new treatment approaches. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  2. Potential value of PTEN in predicting cetuximab response in colorectal cancer: An exploratory study

    International Nuclear Information System (INIS)

    Razis, Evangelia; Galanidi, Eleni; Bai, Maria; Gikonti, Ioanna; Koukouma, Alona; Kafiri, Georgia; Papakostas, Pavlos; Kalogeras, Konstantine T; Kosmidis, Paris; Fountzilas, George; Briasoulis, Evangelos; Vrettou, Eleni; Skarlos, Dimosthenis V; Papamichael, Dimitrios; Kostopoulos, Ioannis; Samantas, Epaminontas; Xanthakis, Ioannis; Bobos, Mattheos

    2008-01-01

    The epidermal growth factor receptor (EGFR) is over-expressed in 70–75% of colorectal adenocarcinomas (CRC). The anti-EGFR monoclonal antibody cetuximab has been approved for the treatment of metastatic CRC, however tumor response to cetuximab has not been found to be associated with EGFR over-expression by immunohistochemistry (IHC). The aim of this study was to explore EGFR and the downstream effector phosphatase and tensin homologue deleted on chromosome 10 (PTEN) as potential predictors of response to cetuximab. CRC patients treated with cetuximab by the Hellenic Cooperative Oncology group, whose formalin-fixed paraffin-embedded tumor tissue was available, were included. Tissue was tested for EGFR and PTEN by IHC and fluorescence in situ hybridization (FISH). Eighty-eight patients were identified and 72 were included based on the availability of tissue blocks with adequate material for analysis on them. All patients, except one, received cetuximab in combination with chemotherapy. Median follow-up was 53 months from diagnosis and 17 months from cetuximab initiation. At the time of the analysis 53% of the patients had died. Best response was complete response in one and partial response in 23 patients. In 16 patients disease stabilized. Lack of PTEN gene amplification was associated with more responses to cetuximab and longer time to progression (p = 0.042). PTEN could be one of the molecular determinants of cetuximab response. Due to the heterogeneity of the population and the retrospective nature of the study, our results are hypothesis generating and should be approached with caution. Further prospective studies are needed to validate this finding

  3. Exploring the Hypersensitivity of PTEN Deleted Prostate Cancer Stem Cells to WEE1 Tyrosine Kinase Inhibitors

    Science.gov (United States)

    2015-12-01

    performed the clonogenic survival assay using LAPC4 as a model as these cell form well defined colonies compared to C42B cells. This assay revealed that...cells. Future studies with other PTEN deficient models are important to validate the effectiveness of WEE1 inhibitors to tackle recurrent PC...Amplifications and missense mutations Cixutumumab (IMC-A12), Dalotuzumab (MK-0646; h7C10), Linsitinib ( OSI -906) EPHA5 12% LAC, 10% SCLC, 9% SAC, Lung

  4. Developing a PTEN-ERG Signature to Improve Molecular Risk Stratification in Prostate Cancer

    Science.gov (United States)

    2017-10-01

    performed exploratory data analysis on all clinically annotated prostate cancer datasets available from the public domain and through the collaboration...with GenomeDX. We used statistical summaries and data visualizations techniques (e.g., principal component analysis , hierarchical clustering) to...associated with PTEN loss on genetically homogeneous ERG-positive and ERG- negative backgrounds. Timeline (Months) Major Task 2: Perform CAGE analysis

  5. Exploring the Hypersensitivity of PTEN Deleted Prostate Cancer Stem Cells to WEE1 Tyrosine Kinase Inhibitors

    Science.gov (United States)

    2015-12-01

    AWARD NUMBER: W81XWH-14-1-0251 TITLE: Exploring the Hypersensitivity of PTEN Deleted Prostate Cancer Stem Cells to WEE1 Tyrosine Kinase... Tyrosine Kinase Inhibitors 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-14-1-0251 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Kiran Mahajan 5d...ABSTRACT Central to all cycling cells-including prostate cancer stem cells- is the expression of WEE1 tyrosine kinase. WEE1 monitors duplication of

  6. Constitutive insulin sensitivity and obesity my be caused by PTEN mutations

    Directory of Open Access Journals (Sweden)

    E A Pigarova

    2012-12-01

    Full Text Available Реферат по статье: Pal A, Barber TM, Van de Bunt M, Rudge SA, Zhang Q, Lachlan KL, Cooper NS, Linden H, Levy JC, Wakelam MJ, Walker L, Karpe F, Gloyn AL. PTEN mutations as a cause of constitutive insulin sensitivity and obesity. N Engl J Med. 2012 Sep 13;367(11:1002-11.

  7. Locomotor Sub-functions for Control of Assistive Wearable Robots

    Directory of Open Access Journals (Sweden)

    Maziar A. Sharbafi

    2017-09-01

    Full Text Available A primary goal of comparative biomechanics is to understand the fundamental physics of locomotion within an evolutionary context. Such an understanding of legged locomotion results in a transition from copying nature to borrowing strategies for interacting with the physical world regarding design and control of bio-inspired legged robots or robotic assistive devices. Inspired from nature, legged locomotion can be composed of three locomotor sub-functions, which are intrinsically interrelated: Stance: redirecting the center of mass by exerting forces on the ground. Swing: cycling the legs between ground contacts. Balance: maintaining body posture. With these three sub-functions, one can understand, design and control legged locomotory systems with formulating them in simpler separated tasks. Coordination between locomotor sub-functions in a harmonized manner appears then as an additional problem when considering legged locomotion. However, biological locomotion shows that appropriate design and control of each sub-function simplifies coordination. It means that only limited exchange of sensory information between the different locomotor sub-function controllers is required enabling the envisioned modular architecture of the locomotion control system. In this paper, we present different studies on implementing different locomotor sub-function controllers on models, robots, and an exoskeleton in addition to demonstrating their abilities in explaining humans' control strategies.

  8. Locomotor Sub-functions for Control of Assistive Wearable Robots.

    Science.gov (United States)

    Sharbafi, Maziar A; Seyfarth, Andre; Zhao, Guoping

    2017-01-01

    A primary goal of comparative biomechanics is to understand the fundamental physics of locomotion within an evolutionary context. Such an understanding of legged locomotion results in a transition from copying nature to borrowing strategies for interacting with the physical world regarding design and control of bio-inspired legged robots or robotic assistive devices. Inspired from nature, legged locomotion can be composed of three locomotor sub-functions, which are intrinsically interrelated: Stance : redirecting the center of mass by exerting forces on the ground. Swing : cycling the legs between ground contacts. Balance : maintaining body posture. With these three sub-functions, one can understand, design and control legged locomotory systems with formulating them in simpler separated tasks. Coordination between locomotor sub-functions in a harmonized manner appears then as an additional problem when considering legged locomotion. However, biological locomotion shows that appropriate design and control of each sub-function simplifies coordination. It means that only limited exchange of sensory information between the different locomotor sub-function controllers is required enabling the envisioned modular architecture of the locomotion control system. In this paper, we present different studies on implementing different locomotor sub-function controllers on models, robots, and an exoskeleton in addition to demonstrating their abilities in explaining humans' control strategies.

  9. Superoxide anion radicals induce IGF-1 resistance through concomitant activation of PTP1B and PTEN

    Science.gov (United States)

    Singh, Karmveer; Maity, Pallab; Krug, Linda; Meyer, Patrick; Treiber, Nicolai; Lucas, Tanja; Basu, Abhijit; Kochanek, Stefan; Wlaschek, Meinhard; Geiger, Hartmut; Scharffetter-Kochanek, Karin

    2015-01-01

    The evolutionarily conserved IGF-1 signalling pathway is associated with longevity, metabolism, tissue homeostasis, and cancer progression. Its regulation relies on the delicate balance between activating kinases and suppressing phosphatases and is still not very well understood. We report here that IGF-1 signalling in vitro and in a murine ageing model in vivo is suppressed in response to accumulation of superoxide anions () in mitochondria, either by chemical inhibition of complex I or by genetic silencing of -dismutating mitochondrial Sod2. The -dependent suppression of IGF-1 signalling resulted in decreased proliferation of murine dermal fibroblasts, affected translation initiation factors and suppressed the expression of α1(I), α1(III), and α2(I) collagen, the hallmarks of skin ageing. Enhanced led to activation of the phosphatases PTP1B and PTEN, which via dephosphorylation of the IGF-1 receptor and phosphatidylinositol 3,4,5-triphosphate dampened IGF-1 signalling. Genetic and pharmacologic inhibition of PTP1B and PTEN abrogated -induced IGF-1 resistance and rescued the ageing skin phenotype. We thus identify previously unreported signature events with , PTP1B, and PTEN as promising targets for drug development to prevent IGF-1 resistance-related pathologies. PMID:25520316

  10. Diffuse Gastric Ganglioneuromatosis: Novel Presentation of PTEN Hamartoma Syndrome—Case Report and Review of Gastric Ganglioneuromatous Proliferations and a Novel PTEN Gene Mutation

    Directory of Open Access Journals (Sweden)

    Alexander J. Williams

    2018-01-01

    Full Text Available Gastrointestinal ganglioneuromatous proliferations are rare, most often found in the colon, and are three types: polypoid ganglioneuromas, ganglioneuromatous polyposis, and diffuse ganglioneuromatosis. We present a case of diffuse ganglioneuromatosis in the posterior gastric wall in a nine-year-old female. To our knowledge, this is the first reported case of diffuse ganglioneuromatosis located in the stomach. Only six cases of gastric ganglioneuromatous proliferations have previously been reported, two in English and none were diffuse ganglioneuromatosis. A diagnosis of diffuse ganglioneuromatosis is relevant for patient care because, unlike sporadic polypoid ganglioneuromas or ganglioneuromatous polyposis, most are syndromic. Diffuse ganglioneuromatosis is commonly associated with neurofibromatosis type 1, multiple endocrine neoplasia type 2b, and Cowden Syndrome, one of the phenotypes of PTEN hamartoma tumor syndrome. The patient had the noted gastric diffuse ganglioneuromatosis, as well as other major and minor criteria for Cowden syndrome. Genetic testing revealed a novel frameshift mutation in the PTEN gene in the patient, her father, paternal aunt, and the aunt’s son who is a paternal first cousin of the patient.

  11. DMA mitigates ionizing radiation induced damage in Balb/c mice through Akt/NFκB/PTEN pathway

    International Nuclear Information System (INIS)

    Tiwari, Vinod; Ranjan, Atul; Tandon, Vibha

    2014-01-01

    Ionizing radiation is associated with massive apoptosis in tumor as well as in radiosensitive organs. DMA, (5-(4-methylpiperazin-1-yl)-2-(2'-(3,4-dimethoxy-phenyl)-5'-benzimidazolyl) a cytoprotective radiomodulator, work in dual mode of action as free radical quencher and modifier of genomic instability caused by radiation. We observed 34% radioprotection with 50 mg/Kg bw intravenous dose of DMA in Balb/c mice at 8 Gy. DMA treatment before irradiation restored the normal crypts and villi architecture in Balb/c mice. The villi height was restored equivalent to control group in DMA treated animals, whereas, it was degenerated in irradiated animals. IR-induced apoptosis was reduced in spleen in presence of DMA as a result of preservation of splenic lymphocytes from radiation. This clearly exhibits the radioprotective ability of DMA to mitigate radiation induced tissue damage. IR-induced S phase check point was overcome by DMA. DMA promoted activation and phosphorylation of GSK3β through the activation of Akt in Balb/c mice. There was reduction in PTEN level in DMA pretreated mice where as it was upregulated in irradiated mice. Relative enhanced kinase activity of Akt was observed in DMA treated Balb/c mice and irradiated A549, MRC5 cell lines. There was no significant radioprotection in DMA treated Akt siRNA transfected cells in comparison to only Akt siRNA transfected cells with increasing dose of radiation. Akt activation was found in a dose-dependent manner by DMA through Luciferase reporter assay. We observed that DMA treated HEK cells transfected with control siRNA, resulted in less early apoptotic cells within 24h, but radiation (5 Gy) treated cells showed 20% early apoptotic cells within 3 h which were reduced to 12% at 3 h, 9% at 6 h and 8% at 24 h in DMA+radiation treated cells determined by Annexin V binding assay. Further molecular mRNA expression analysis of key regulatory genes unveil that DMA inhibited p21 and augmented Akt and Gadd45 in

  12. The Investigation of NPP Control and Monitoring Functional Analysis Applied to Functional Displays’ Implementation

    International Nuclear Information System (INIS)

    Yan, J.

    2015-01-01

    NPP Control and Monitoring System has been recognised as extreme and safe as well as large scale product, thus it was one of the most major design activities that fully, accurately and operationally functional analysis. The results of functional analysis would be employed as initial instruction through the whole lifecycle of NPP Control and Monitoring System. In this paper, it was discovered that several disadvantages of present functional analysis methods included FAST, The Subtract and Operate Procedure and Functional Procedure Method; owing to the identity methods enveloped here was the combination of Functional Tree and System Structure, as well as its decomposition steps; and RCS Inventory Control function which is defined as one of the most significant control functions in Advanced Light Water Reactor Utility Requirement Document has been employed to demonstrate the feasibility of this method; the analysis results of RCS Inventory function has been applied to direct the design and implementation of related displays, here the functional display of RCS Inventory Control function has been implemented on NuCON which is originated by SNPAS. Owing to the analyzing results, it would be ensured that the accuracy of information displayed to operators, thus the operator would be aware the condition of systems and then make the proper move to ensure the safety and productivity of NPP based on the received data. (author)

  13. An integrative genomic and proteomic analysis of PIK3CA, PTEN and AKT mutations in breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Stemke-Hale, Katherine; Gonzalez-Angulo, Ana Maria; Lluch, Ana; Neve, Richard M.; Kuo, Wen-Lin; Davies, Michael; Carey, Mark; Hu, Zhi; Guan, Yinghui; Sahin, Aysegul; Symmans, W. Fraser; Pusztai, Lajos; Nolden, Laura K.; Horlings, Hugo; Berns, Katrien; Hung, Mien-Chie; van de Vijver, Marc J.; Valero, Vicente; Gray, Joe W.; Bernards, Rene; Mills, Gordon B.; Hennessy, Bryan T.

    2008-05-06

    Phosphatidylinositol-3-kinase (PI3K)/AKT pathway aberrations are common in cancer. By applying mass spectroscopy-based sequencing and reverse phase protein arrays to 547 human breast cancers and 41 cell lines, we determined the subtype specificity and signaling effects of PIK3CA, AKT and PTEN mutations, and the effects of PIK3CA mutations on responsiveness to PI3K inhibition in-vitro and on outcome after adjuvant tamoxifen. PIK3CA mutations were more common in hormone receptor positive (33.8%) and HER2-positive (24.6%) than in basal-like tumors (8.3%). AKT1 (1.4%) and PTEN (2.3%) mutations were restricted to hormone receptor-positive cancers with PTEN protein levels also being significantly lower in hormone receptor-positive cancers. Unlike AKT1 mutations, PIK3CA (39%) and PTEN (20%) mutations were more common in cell lines than tumors, suggesting a selection for these but not AKT1 mutations during adaptation to culture. PIK3CA mutations did not have a significant impact on outcome in 166 hormone receptor-positive breast cancer patients after adjuvant tamoxifen. PIK3CA mutations, in comparison with PTEN loss and AKT1 mutations, were associated with significantly less and indeed inconsistent activation of AKT and of downstream PI3K/AKT signaling in tumors and cell lines, and PTEN loss and PIK3CA mutation were frequently concordant, suggesting different contributions to pathophysiology. PTEN loss but not PIK3CA mutations rendered cells sensitive to growth inhibition by the PI3K inhibitor LY294002. Thus, PI3K pathway aberrations likely play a distinct role in the pathogenesis of different breast cancer subtypes. The specific aberration may have implications for the selection of PI3K-targeted therapies in hormone receptor-positive breast cancer.

  14. A multicenter study shows PTEN deletion is strongly associated with seminal vesicle involvement and extracapsular extension in localized prostate cancer.

    Science.gov (United States)

    Troyer, Dean A; Jamaspishvili, Tamara; Wei, Wei; Feng, Ziding; Good, Jennifer; Hawley, Sarah; Fazli, Ladan; McKenney, Jesse K; Simko, Jeff; Hurtado-Coll, Antonio; Carroll, Peter R; Gleave, Martin; Lance, Raymond; Lin, Daniel W; Nelson, Peter S; Thompson, Ian M; True, Lawrence D; Brooks, James D; Squire, Jeremy A

    2015-08-01

    Loss of the phosphatase and tensin homolog (PTEN) tumor suppressor gene is a promising marker of aggressive prostate cancer. Active surveillance and watchful waiting are increasingly recommended to patients with small tumors felt to be low risk, highlighting the difficulties of Gleason scoring in this setting. There is an urgent need for predictive biomarkers that can be rapidly deployed to aid in clinical decision-making. Our objectives were to assess the incidence and ability of PTEN alterations to predict aggressive disease in a multicenter study. We used recently developed probes optimized for sensitivity and specificity in a four-color FISH deletion assay to study the Canary Retrospective multicenter Prostate Cancer Tissue Microarray (TMA). This TMA was constructed specifically for biomarker validation from radical prostatectomy specimens, and is accompanied by detailed clinical information with long-term follow-up. In 612 prostate cancers, the overall rate of PTEN deletion was 112 (18.3%). Hemizygous PTEN losses were present in 55/612 (9.0%) of cancers, whereas homozygous PTEN deletion was observed in 57/612 (9.3%) of tumors. Significant associations were found between PTEN status and pathologic stage (P free survival (number of events = 189), pre-operative prostate specific antigen (PSA) (P free survival in multivariate models, as were seminal vesicle invasion, extracapsular extension, and Gleason score, and preoperative PSA. Furthermore, these data demonstrate that the assay can be readily introduced at first diagnosis in a cost effective manner analogous to the use of FISH for analysis of HER2/neu status in breast cancer. Combined with published research beginning 17 years ago, both the data and tools now exist to implement a PTEN assay in the clinic. © 2015 The Authors. The Prostate, published by Wiley Periodicals, Inc.

  15. Finger functionality and joystick design for complex hand control

    NARCIS (Netherlands)

    Grinten, M.P. van der; Krause, F.

    2006-01-01

    Joysticks and similar multi-directional controls are increasingly applied in machines, instruments and consumer goods. Operational complexity rises through miniaturization and additional control functions on the joystick. With this the effort for the finger, hand and arm, and for the perceptive and

  16. Control architecture of power systems: Modeling of purpose and function

    DEFF Research Database (Denmark)

    Heussen, Kai; Saleem, Arshad; Lind, Morten

    2009-01-01

    Many new technologies with novel control capabilities have been developed in the context of “smart grid” research. However, often it is not clear how these capabilities should best be integrated in the overall system operation. New operation paradigms change the traditional control architecture...... of power systems and it is necessary to identify requirements and functions. How does new control architecture fit with the old architecture? How can power system functions be specified independent of technology? What is the purpose of control in power systems? In this paper, a method suitable...... for semantically consistent modeling of control architecture is presented. The method, called Multilevel Flow Modeling (MFM), is applied to the case of system balancing. It was found that MFM is capable of capturing implicit control knowledge, which is otherwise difficult to formalize. The method has possible...

  17. Cooperative Control for Multiple Autonomous Vehicles Using Descriptor Functions

    Directory of Open Access Journals (Sweden)

    Marta Niccolini

    2014-01-01

    Full Text Available The paper presents a novel methodology for the control management of a swarm of autonomous vehicles. The vehicles, or agents, may have different skills, and be employed for different missions. The methodology is based on the definition of descriptor functions that model the capabilities of the single agent and each task or mission. The swarm motion is controlled by minimizing a suitable norm of the error between agents’ descriptor functions and other descriptor functions which models the entire mission. The validity of the proposed technique is tested via numerical simulation, using different task assignment scenarios.

  18. A Goal-Function Approach to Analysis of Control Situations

    DEFF Research Database (Denmark)

    Lind, Morten

    2010-01-01

    The concept of situations plays a central role in all theories of meaning and context. and serve to frame or group events and other occurrences into coherent meaningful wholes. Situations are typed, may be interconnected and organized into higher level structures. In operation of industrial...... processes situations should identify operational aspects relevant for control agent’s decision making in plant supervision and control. Control situations can be understood as recurrent and interconnected patterns of control with important implications for control and HMI design. Goal-Function approaches...

  19. Functional Dual Adaptive Control with Recursive Gaussian Process Model

    International Nuclear Information System (INIS)

    Prüher, Jakub; Král, Ladislav

    2015-01-01

    The paper deals with dual adaptive control problem, where the functional uncertainties in the system description are modelled by a non-parametric Gaussian process regression model. Current approaches to adaptive control based on Gaussian process models are severely limited in their practical applicability, because the model is re-adjusted using all the currently available data, which keeps growing with every time step. We propose the use of recursive Gaussian process regression algorithm for significant reduction in computational requirements, thus bringing the Gaussian process-based adaptive controllers closer to their practical applicability. In this work, we design a bi-criterial dual controller based on recursive Gaussian process model for discrete-time stochastic dynamic systems given in an affine-in-control form. Using Monte Carlo simulations, we show that the proposed controller achieves comparable performance with the full Gaussian process-based controller in terms of control quality while keeping the computational demands bounded. (paper)

  20. Recombinant adenovirus-mediated overexpression of PTEN and KRT10 improves cisplatin resistance of ovarian cancer in vitro and in vivo.

    Science.gov (United States)

    Wu, H; Wang, K; Liu, W; Hao, Q

    2015-06-18

    Drug resistance is a major cause of treatment failure in ovarian cancer patients, and novel therapeutic strategies are urgently needed. Overexpression of phosphatase and tensin homolog (PTEN) has been shown to preserve the cisplatin-resistance of ovarian cancer cells, while cisplatin-induced keratin 10 (KRT10) overexpression mediates the resistance-reversing effect of PTEN. However, whether overexpression of PTEN or KRT10 can improve the cisplatin resistance of ovarian cancer in vivo has not been investigated. Therefore, we investigated the effects of adenovirus-mediated PTEN or KRT10 overexpression on the cisplatin resistance of ovarian cancer in vivo. Recombinant adenoviruses carrying the gene for PTEN or KRT10 were constructed. The effects of overexpression of PTEN and KRT10 on cisplatin resistance of ovarian cancer cells were examined using the 3(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide (MTT) and TdT-mediated dUTP nick-end labeling (TUNEL) assays in vitro. Subcutaneously transplanted nude mice, as a model of human ovarian cancer, were used to test the effects of PTEN and KRT10 on cisplatin resistance of ovarian cancer in vivo. The MTT assay showed that recombinant adenovirus-mediated overexpression of KRT10 and PTEN enhanced the proliferation inhibition effect of cisplatin on C13K cells. Recombinant adenovirus-mediated overexpression of KRT10 and PTEN also increased the cisplatin-induced apoptosis rate of C13K cells. Furthermore, recombinant adenovirus-mediated overexpression of KRT10 and PTEN enhanced the inhibitory effect of cisplatin on C13K xenograft tumor growth. Thus, recombinant adenovirus-mediated overexpression of KRT10 and PTEN may improve the cisplatin resistance of ovarian cancer in vitro and in vivo.

  1. Lung function and functional capacity among foundry workers using effective risk control measures.

    Science.gov (United States)

    Bernardes, Rosane Andrea Bretas; Chiavegato, Luciana Dias; de Moraes, Mônica Vasconcelos; Negreiros, Alexandher; Padula, Rosimeire Simprini

    2015-01-01

    Inhaled dust in the environment can trigger specific reactions in the airways and cause various respiratory diseases. Evaluate the lung function and functional capacity of foundry workers who are exposed to metals and use effective control measures. A cross-sectional study was realized with 108 workers at a bronze foundry and machining plant and in maintenance at a private university, both in Brazil. The workers were divided into two groups: the study group exposed to metals but using risk control measues and a control group not exposed to metal work. The Medical Research Council Questionnaire on Respiratory Symptoms and the International Physical Activity Questionnaire were administered, and lung function and functional capacity were evaluated. Comparative statistics were used to identify differences in the outcome measures between the two groups. The groups had similar personal and anthropometric characteristics and time on the job. Spirometry and peak expiratory flow presented no significant differences between the groups. And there was also no statistically significant difference between groups in functional capacity as assessed by performance on the six-minute walk test. Foundry industry workers in Brazil who were exposed to metal but used risk control measures had similar lung function and functional capacity when compared to the control group who were not exposed to metal. This is a positive results and maybe related to age, time exposure and control of occupational hazards. However, these workers need to continue being monitored in longitudinal studies.

  2. Failure of the PTEN/aPKC/Lgl Axis Primes Formation of Adult Brain Tumours in Drosophila

    Directory of Open Access Journals (Sweden)

    Simona Paglia

    2017-01-01

    Full Text Available Different regions in the mammalian adult brain contain immature precursors, reinforcing the concept that brain cancers, such as glioblastoma multiforme (GBM, may originate from cells endowed with stem-like properties. Alterations of the tumour suppressor gene PTEN are very common in primary GBMs. Very recently, PTEN loss was shown to undermine a specific molecular axis, whose failure is associated with the maintenance of the GBM stem cells in mammals. This axis is composed of PTEN, aPKC, and the polarity determinant Lethal giant larvae (Lgl: PTEN loss promotes aPKC activation through the PI3K pathway, which in turn leads to Lgl inhibition, ultimately preventing stem cell differentiation. To find the neural precursors responding to perturbations of this molecular axis, we targeted different neurogenic regions of the Drosophila brain. Here we show that PTEN mutation impacts aPKC and Lgl protein levels also in Drosophila. Moreover, we demonstrate that PI3K activation is not sufficient to trigger tumourigenesis, while aPKC promotes hyperplastic growth of the neuroepithelium and a noticeable expansion of the type II neuroblasts. Finally, we show that these neuroblasts form invasive tumours that persist and keep growing in the adult, leading the affected animals to untimely death, thus displaying frankly malignant behaviours.

  3. Age-related clinical and biological features of PTEN abnormalities in T-cell acute lymphoblastic leukaemia.

    Science.gov (United States)

    Tesio, M; Trinquand, A; Ballerini, P; Hypolite, G; Lhermitte, L; Petit, A; Ifrah, N; Baruchel, A; Dombret, H; Macintyre, E; Asnafi, V

    2017-12-01

    The tumour suppressor gene PTEN is commonly altered in T-cell acute lymphoblastic leukaemia but its prognostic impact is still debated. We screened a cohort of 573 fully characterised adult and paediatric T-cell acute lymphoblastic leukaemia (T-ALL) patients for genomic PTEN abnormalities. PTEN-inactivating mutations and/or deletions were identified in 91 cases (16%), including 18% of paediatric (49/277) and 14% of adult cases (42/296). Thirty-four patients harboured only mutations, 12 cases demonstrated only large deletions and 9 only microdeletions. About 36 patients had combined alterations. Different mechanisms of PTEN inactivation predicted differences in the clinical outcome for both adult and paediatric patients treated according to the GRAALL03/05 and FRALLE2000 protocols. Whereas large deletions predicted lower 5-year overall survival (P=0.0053 in adults, P=0.001 in children) and disease-free survival (P=0.0009 in adults, P=0.0002 in children), mutations were not associated with a worse prognosis. The prognostic impact of PTEN loss is therefore linked to the underlying type of genomic abnormality, both in adult and paediatric T-ALLs, demonstrating that detailed analysis of the type of abnormality type would be useful to refine risk stratification.

  4. Induction of intrahepatic cholangiocellular carcinoma by liver-specific disruption of Smad4 and Pten in mice.

    Science.gov (United States)

    Xu, Xiaoling; Kobayashi, Shogo; Qiao, Wenhui; Li, Cuiling; Xiao, Cuiying; Radaeva, Svetlana; Stiles, Bangyan; Wang, Rui-Hong; Ohara, Nobuya; Yoshino, Tadashi; LeRoith, Derek; Torbenson, Michael S; Gores, Gregory J; Wu, Hong; Gao, Bin; Deng, Chu-Xia

    2006-07-01

    Cholangiocellular carcinoma (CC), the second most common primary liver cancer, is associated with a poor prognosis. It has been shown that CCs harbor alterations of a number of tumor-suppressor genes and oncogenes, yet key regulators for tumorigenesis remain unknown. Here we have generated a mouse model that develops CC with high penetrance using liver-specific targeted disruption of tumor suppressors SMAD4 and PTEN. In the absence of SMAD4 and PTEN, hyperplastic foci emerge exclusively from bile ducts of mutant mice at 2 months of age and continue to grow, leading to tumor formation in all animals at 4-7 months of age. We show that CC formation follows a multistep progression of histopathological changes that are associated with significant alterations, including increased levels of phosphorylated AKT, FOXO1, GSK-3beta, mTOR, and ERK and increased nuclear levels of cyclin D1. We further demonstrate that SMAD4 and PTEN regulate each other through a novel feedback mechanism to maintain an expression balance and synergistically repress CC formation. Finally, our analysis of human CC detected PTEN inactivation in a majority of p-AKT-positive CCs, while about half also lost SMAD4 expression. These findings elucidate the relationship between SMAD4 and PTEN and extend our understanding of CC formation.

  5. C-reactive protein inhibits survivin expression via Akt/mTOR pathway downregulation by PTEN expression in cardiac myocytes.

    Directory of Open Access Journals (Sweden)

    Beom Seob Lee

    Full Text Available C-reactive protein (CRP is one of the most important biomarkers for arteriosclerosis and cardiovascular disease. Recent studies have shown that CRP affects cell cycle and inflammatory process in cardiac myocytes. Survivin is also involved in cardiac myocytes replication and apoptosis. Reduction of survivin expression is associated with less favorable cardiac remodeling in animal models. However, the effect of CRP on survivin expression and its cellular mechanism has not yet been studied. We demonstrated that treatment of CRP resulted in a significant decrease of survivin protein expression in a concentration-dependent manner in cardiac myocytes. The upstream signaling proteins of survivin, such as Akt, mTOR and p70S6K, were also downregulated by CRP treatment. In addition, CRP increased the protein and mRNA levels of PTEN. The siRNA transfection or specific inhibitor treatment for PTEN restored the CRP-induced downregulation of Akt/mTOR/p70S6K pathway and survivin protein expression. Moreover, pretreatment with a specific p53 inhibitor decreased the CRP-induced PTEN expression. ERK-specific inhibitor also blocked the p53 phosphorylation and PTEN expression induced by CRP. Our study provides a novel insight into CRP-induced downregulation of survivin protein expression in cardiac myocytes through mechanisms that involved in downregulation of Akt/mTOR/p70S6K pathway by expression of PTEN.

  6. Selective deletion of Pten in theca-interstitial cells leads to androgen excess and ovarian dysfunction in mice.

    Science.gov (United States)

    Lan, Zi-Jian; Krause, M S; Redding, S D; Li, X; Wu, G Z; Zhou, H X; Bohler, H C; Ko, C; Cooney, A J; Zhou, Junmei; Lei, Z M

    2017-03-15

    Theca cell-selective Pten mutation (tPtenMT) in mice resulted in increases in PDK1 and Akt phosphorylation, indicating an over-activation of PI3K signaling in the ovaries. These mice displayed elevated androgen levels, ovary enlargement, antral follicle accumulation, early fertility loss and increased expression of Lhcgr and genes that are crucial to androgenesis. These abnormalities were partially reversed by treatments of PI3K or Akt inhibitor. LH actions in Pten deficient theca cells were potentiated. The phosphorylation of Foxo1 was increased, while the binding of Foxo1 to forkhead response elements in the Lhcgr promoter was reduced in tPtenMT theca cells, implying a mechanism by which PI3K/Akt-induced upregulation of Lhcgr in theca cells might be mediated by reducing the inhibitory effect of Foxo1 on the Lhcgr promoter. The phenotype of tPtenMT females is reminiscent of human PCOS and suggests that dysregulated PI3K cascade in theca cells may be involved in certain types of PCOS pathogenesis. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Qualitative Functional Decomposition Analysis of Evolved Neuromorphic Flight Controllers

    Directory of Open Access Journals (Sweden)

    Sanjay K. Boddhu

    2012-01-01

    Full Text Available In the previous work, it was demonstrated that one can effectively employ CTRNN-EH (a neuromorphic variant of EH method methodology to evolve neuromorphic flight controllers for a flapping wing robot. This paper describes a novel frequency grouping-based analysis technique, developed to qualitatively decompose the evolved controllers into explainable functional control blocks. A summary of the previous work related to evolving flight controllers for two categories of the controller types, called autonomous and nonautonomous controllers, is provided, and the applicability of the newly developed decomposition analysis for both controller categories is demonstrated. Further, the paper concludes with appropriate discussion of ongoing work and implications for possible future work related to employing the CTRNN-EH methodology and the decomposition analysis techniques presented in this paper.

  8. Controllability for Semilinear Functional and Neutral Functional Evolution Equations with Infinite Delay in Frechet Spaces

    International Nuclear Information System (INIS)

    Agarwal, Ravi P.; Baghli, Selma; Benchohra, Mouffak

    2009-01-01

    The controllability of mild solutions defined on the semi-infinite positive real interval for two classes of first order semilinear functional and neutral functional differential evolution equations with infinite delay is studied in this paper. Our results are obtained using a recent nonlinear alternative due to Avramescu for sum of compact and contraction operators in Frechet spaces, combined with the semigroup theory

  9. Mathematic-Graphical Formalization of Switch Point Control Circuit Function

    Directory of Open Access Journals (Sweden)

    Juraj Zdansky

    2004-01-01

    Full Text Available This article describes authors designed method then enables mathematic – graphical formalization of system’s functional specification. The result of this method is algebraic system – finite automata that is written in transition table. This transition table is possible to overwrite to graphic form (state diagram or to mathematic form (transition and output function. This method is described by example of switch point control circuit.

  10. Predictive Function Control for Communication-Based Train Control (CBTC Systems

    Directory of Open Access Journals (Sweden)

    Bing Bu

    2013-01-01

    Full Text Available In Communication-Based Train Control (CBTC systems, random transmission delays and packet drops are inevitable in the wireless networks, which could result in unnecessary traction, brakes or even emergency brakes of trains, losses of line capacity and passenger dissatisfaction. This paper applies predictive function control technology with a mixed H2/∞ control approach to improve the control performances. The controller is in the state feedback form and satisfies the requirement of quadratic input and state constraints. A linear matrix inequality (LMI approach is developed to solve the control problem. The proposed method attenuates disturbances by incorporating H2/∞ into the control scheme. The control command from the automatic train operation (ATO is included in the reward function to optimize the train's running profile. The influence of transmission delays and packet drops is alleviated through improving the performances of the controller. Simulation results show that the method is effective to improve the performances and robustness of CBTC systems.

  11. Swarm formation control utilizing elliptical surfaces and limiting functions.

    Science.gov (United States)

    Barnes, Laura E; Fields, Mary Anne; Valavanis, Kimon P

    2009-12-01

    In this paper, we present a strategy for organizing swarms of unmanned vehicles into a formation by utilizing artificial potential fields that were generated from normal and sigmoid functions. These functions construct the surface on which swarm members travel, controlling the overall swarm geometry and the individual member spacing. Nonlinear limiting functions are defined to provide tighter swarm control by modifying and adjusting a set of control variables that force the swarm to behave according to set constraints, formation, and member spacing. The artificial potential functions and limiting functions are combined to control swarm formation, orientation, and swarm movement as a whole. Parameters are chosen based on desired formation and user-defined constraints. This approach is computationally efficient and scales well to different swarm sizes, to heterogeneous systems, and to both centralized and decentralized swarm models. Simulation results are presented for a swarm of 10 and 40 robots that follow circle, ellipse, and wedge formations. Experimental results are included to demonstrate the applicability of the approach on a swarm of four custom-built unmanned ground vehicles (UGVs).

  12. Systematic Product Development of Control and Diagnosis Functionalities

    Science.gov (United States)

    Stetter, R.; Simundsson, A.

    2017-01-01

    In the scientific field of systematic product development a wide range of helpful methods, guidelines and tools were generated and published in recent years. Until now little special attention was given to design guidelines aiming at supporting product development engineers to design products that allow and support control or diagnosis functions. The general trend to ubiquitous computing and the first development steps towards cognitive systems as well as a general trend toward higher product safety, reliability and reduced total cost of ownership (TCO) in many engineering fields lead to a higher importance of control and diagnosis. In this paper a first attempt is made to formulate general valid guidelines how products can be developed in order to allow and to achieve effective and efficient control and diagnosis. The guidelines are elucidated on the example of an automated guided vehicle. One main concern of this paper is the integration of control and diagnosis functionalities into the development of complete systems which include mechanical, electrical and electronic subsystems. For the development of such systems the strategies, methods and tools of systematic product development have attracted significant attention during the last decades. Today, the functionality and safety of most products is to a large degree dependent on control and diagnosis functionalities. Still, there is comparatively little research concentrating on the integration of the development of these functionalities into the overall product development processes. The paper starts with a background describing Systematic Product Development. The second section deals with the product development of the sample product. The third part clarifies the notions monitoring, control and diagnosis. The following parts summarize some insights and formulate first hypotheses concerning control and diagnosis in Systematic Product Development.

  13. PTEN Loss in E-Cadherin-Deficient Mouse Mammary Epithelial Cells Rescues Apoptosis and Results in Development of Classical Invasive Lobular Carcinoma

    NARCIS (Netherlands)

    Boelens, M.C.; Nethe, M.; Klarenbeek, S.; de Ruiter, J.R.; Schut, E.; Bonzanni, N.; Zeeman, A.L.; Wientjens, E.; van der Burg, E.; Wessels, L.; van Amerongen, R.; Jonkers, J.

    2016-01-01

    Invasive lobular carcinoma (ILC) is an aggressive breast cancer subtype with poor response to chemotherapy. Besides loss of E-cadherin, a hallmark of ILC, genetic inactivation of PTEN is frequently observed in patients. Through concomitant Cre-mediated inactivation of E-cadherin and PTEN in mammary

  14. Controlling fungal biofilms with functional drug delivery denture biomaterials.

    Science.gov (United States)

    Wen, Jianchuan; Jiang, Fuguang; Yeh, Chih-Ko; Sun, Yuyu

    2016-04-01

    Candida-associated denture stomatitis (CADS), caused by colonization and biofilm-formation of Candida species on denture surfaces, is a significant clinical concern. We show here that modification of conventional denture materials with functional groups can significantly increase drug binding capacity and control drug release rate of the resulting denture materials for potentially managing CADS. In our approach, poly(methyl methacrylate) (PMMA)-based denture resins were surface grafted with three kinds of polymers, poly(1-vinyl-2-pyrrolidinone) (PNVP), poly(methacrylic acid) (PMAA), and poly(2-hydroxyethyl methacrylate) (PHEMA), through plasma-initiated grafting polymerization. With a grafting yield as low as 2 wt%, the three classes of new functionalized denture materials showed significantly higher drug binding capacities toward miconazole, a widely used antifungal drug, than the original PMMA denture resin control, leading to sustained drug release and potent biofilm-controlling effects against Candida. Among the three classes of functionalized denture materials, PNVP-grafted resin provided the highest miconazole binding capability and the most powerful antifungal and biofilm-controlling activities. Drug binding mechanisms were studied. These results demonstrated the importance of specific interactions between drug molecules and functional groups on biomaterials, shedding lights on future design of CADS-managing denture materials and other related devices for controlled drug delivery. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. Brookhaven Reactor Experiment Control Facility, a distributed function computer network

    International Nuclear Information System (INIS)

    Dimmler, D.G.; Greenlaw, N.; Kelley, M.A.; Potter, D.W.; Rankowitz, S.; Stubblefield, F.W.

    1975-11-01

    A computer network for real-time data acquisition, monitoring and control of a series of experiments at the Brookhaven High Flux Beam Reactor has been developed and has been set into routine operation. This reactor experiment control facility presently services nine neutron spectrometers and one x-ray diffractometer. Several additional experiment connections are in progress. The architecture of the facility is based on a distributed function network concept. A statement of implementation and results is presented

  16. PTP1B promotes aggressiveness of breast cancer cells by regulating PTEN but not EMT.

    Science.gov (United States)

    Liu, Xue; Chen, Qian; Hu, Xu-Gang; Zhang, Xian-Chao; Fu, Ti-Wei; Liu, Qing; Liang, Yan; Zhao, Xi-Long; Zhang, Xia; Ping, Yi-Fang; Bian, Xiu-Wu

    2016-10-01

    Metastasis is a complicated, multistep process and remains the major cause of cancer-related mortality. Exploring the molecular mechanisms underlying tumor metastasis is crucial for development of new strategies for cancer prevention and treatment. In this study, we found that protein tyrosine phosphatase 1B (PTP1B) promoted breast cancer metastasis by regulating phosphatase and tensin homolog (PTEN) but not epithelial-mesenchymal transition (EMT). By detecting PTP1B expression of the specimens from 128 breast cancer cases, we found that the level of PTP1B was higher in breast cancer tissues than the corresponding adjacent normal tissues. Notably, PTP1B was positively associated with lymph node metastasis (LNM) and estrogen receptor (ER) status. In vitro, disturbing PTP1B expression obviously attenuated cell migration and invasion. On the contrary, PTP1B overexpression significantly increased migration and invasion of breast cancer cells. Mechanistically, PTP1B knockdown upregulated PTEN, accompanied with an abatement of AKT phosphorylation and the expression of matrix metalloproteinase 2 (MMP2) and MMP7. Conversely, forced expression of PTP1B reduced PTEN and increased AKT phosphorylation as well as the expression of MMP2 and MMP7. Notably, neither EMT nor stemness of breast cancer cells was regulated by PTP1B. We also found that PTP1B acted as an independent prognostic factor and predicted poor prognosis in ER-positive breast cancer patients. Taken together, our findings provide advantageous evidence for the development of PTP1B as a potential therapeutic target for breast cancer, especially for ER-positive breast cancer patients.

  17. The safe use of a PTEN inhibitor for the activation of dormant mouse primordial follicles and generation of fertilizable eggs.

    Directory of Open Access Journals (Sweden)

    Deepak Adhikari

    Full Text Available Primordial ovarian follicles, which are often present in the ovaries of premature ovarian failure (POF patients or are cryopreserved from the ovaries of young cancer patients who are undergoing gonadotoxic anticancer therapies, cannot be used to generate mature oocytes for in vitro fertilization (IVF. There has been very little success in triggering growth of primordial follicles to obtain fertilizable oocytes due to the poor understanding of the biology of primordial follicle activation.We have recently reported that PTEN (phosphatase and tensin homolog deleted on chromosome ten prevents primordial follicle activation in mice, and deletion of Pten from the oocytes of primordial follicles leads to follicular activation. Consequently, the PTEN inhibitor has been successfully used in vitro to activate primordial follicles in both mouse and human ovaries. These results suggest that PTEN inhibitors could be used in ovarian culture medium to trigger the activation of primordial follicle. To study the safety and efficacy of the use of such inhibitors, we activated primordial follicles from neonatal mouse ovaries by transient treatment with a PTEN inhibitor bpV(HOpic. These ovaries were then transplanted under the kidney capsules of recipient mice to generate mature oocytes. The mature oocytes were fertilized in vitro and progeny mice were obtained after embryo transfer.Long-term monitoring up to the second generation of progeny mice showed that the mice were reproductively active and were free from any overt signs or symptoms of chronic illnesses. Our results indicate that the use of PTEN inhibitors could be a safe and effective way of generating mature human oocytes for use in novel IVF techniques.

  18. Four MicroRNAs Promote Prostate Cell Proliferation with Regulation of PTEN and Its Downstream Signals In Vitro

    Science.gov (United States)

    Xue, Jing-lun; Chen, Jin-zhong

    2013-01-01

    Background Phosphatase and tensin homologue (PTEN), as a tumor suppressor, plays vital roles in tumorigenesis and progression of prostate cancer. However, the mechanisms of PTEN regulation still need further investigation. We here report that a combination of four microRNAs (miR-19b, miR-23b, miR-26a and miR-92a) promotes prostate cell proliferation by regulating PTEN and its downstream signals in vitro. Methodology/Principal Findings We found that the four microRNAs (miRNAs) could effectively suppress PTEN expression by directly interacting with its 3’ UTR in prostate epithelial and cancer cells. Under-expression of the four miRNAs by antisense neutralization up-regulates PTEN expression, while overexpression of the four miRNAs accelerates epithelial and prostate cancer cell proliferation. Furthermore, the expression of the four miRNAs could, singly or jointly, alter the expression of the key components in the phosphoinositide 3-kinase (PI3K)/Akt pathway, including PIK3CA, PIK3CD, PIK3R1 and Akt, along with their downstream signal, cyclin D1. Conclusions These results suggested that the four miRNAs could promote prostate cancer cell proliferation by co-regulating the expression of PTEN, PI3K/Akt pathway and cyclin D1 in vitro. These findings increase understanding of the molecular mechanisms of prostate carcinogenesis and progression, even provide valuable insights into the diagnosis, prognosis, and rational design of novel therapeutics for prostate cancer. PMID:24098737

  19. Design of Connectivity Preserving Flocking Using Control Lyapunov Function

    Directory of Open Access Journals (Sweden)

    Bayu Erfianto

    2016-01-01

    Full Text Available This paper investigates cooperative flocking control design with connectivity preserving mechanism. During flocking, interagent distance is measured to determine communication topology of the flocks. Then, cooperative flocking motion is built based on cooperative artificial potential field with connectivity preserving mechanism to achieve the common flocking objective. The flocking control input is then obtained by deriving cooperative artificial potential field using control Lyapunov function. As a result, we prove that our flocking protocol establishes group stabilization and the communication topology of multiagent flocking is always connected.

  20. Computer functions in overall plant control of candu generating stations

    International Nuclear Information System (INIS)

    Chou, Q.B.; Stokes, H.W.

    1976-01-01

    System Planning Specifications form the basic requirements for the performance of the plant including its response to abnormal situations. The rules for the computer control programs are devised from these, taking into account limitations imposed by the reactor, heat transport and turbine-generator systems. The paper outlines these specifications and the limitations imposed by the major items of plant equipment. It describes the functions of each of the main programs, their interactions and the control modes used in the existing Ontario Hydro's nuclear station or proposed for future stations. Some simulation results showing the performance of the overall unit control system and plans for future studies are discussed. (orig.) [de

  1. BMP Suppresses PTEN Expression via RAS/ERK Signaling

    OpenAIRE

    Beck, Stayce E.; Carethers, John M.

    2007-01-01

    Bone morphogenetic protein (BMP), a member of the transforming growth factor β family, classically utilizes the SMAD signaling pathway for its growth suppressive effects, and loss of this signaling cascade may accelerate cell growth. In the colon cancer predisposition syndrome Juvenile Polyposis, as well as in the late progression stages of nonsyndromic colorectal cancers, SMAD4 function is typically abrogated. Here, we utilized the SMAD4-null SW480 colon cancer cell line to examine BMPs effe...

  2. Requirements for VICTORIA Class Fire Control System: Contact Management Function

    Science.gov (United States)

    2014-07-01

    Requirements for VICTORIA Class Fire Control System Contact Management Function Tab Lamoureux CAE Integrated Enterprise Solutions...Contract Report DRDC-RDDC-2014-C190 July 2014 © Her Majesty the Queen in Right of Canada, as represented by the...i Abstract …….. The VICTORIA Class Submarines (VCS) are subject to a continuing program of technical upgrades. One such program is

  3. On the functional aspects of variability in postural control

    NARCIS (Netherlands)

    Van Emmerik, Richard E.A.; Van Wegen, Erwin E.H.

    2002-01-01

    Current research in nonlinear dynamics and chaos theory has challenged traditional perspectives that associate high variability with performance decrement and pathology. It is argued that variability can play a functional role in postural control and that reduction of variability is associated with

  4. Bioinformatics prediction of miR-30a targets and its inhibition of cell proliferation of osteosarcoma by up-regulating the expression of PTEN

    Directory of Open Access Journals (Sweden)

    Biao Zhong

    2017-11-01

    Full Text Available Abstract Background MiRNAs are frequently abnormally expressed in the progression of human osteosarcoma. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN is one of the tumor suppressors in various types of human cancer. In the present study, we detected how hsa-miR-30a-3p regulated PTEN and further tested the role of hsa-miR-30a-3p in the cell proliferation of osteosarcoma cells. Methods The levels of miR-30a were determined by real time PCR. The expression of PTEN was tested by western blotting analysis. Cell distribution of PTEN was observed with confocal laser scanning microscope. Cell viability was determined by MTT assay. Results The expression of miR-30a and PTEN was obviously decreased in MG-63, 143B and Saos-2 cells compared with primary osteoblasts. TargetScan analysis data showed miR-30a might bind with position 30-57 of 3’UTR of PTEN. Transfection with miR-30a-3p increased the level of PTEN in MG-63 cells, while transfection with miR-30a-3p inhibitor significantly decreased the expression of PTEN in osteosarcoma cells. Transfection with miR-30a-3p significantly inhibited cell proliferation of osteosarcoma cells, while miR-30a inhibitor obviously promoted cell viability of MG63 cells and Saos-2 cells. Inhibition of PTEN eliminated the proliferation inhibitory effect of miR-30a-3p. Conclusion Thus, all these findings revealed the anti-tumor effects of miR-30a in human osteosarcoma cells, which could be mediated by regulating the level of PTEN.

  5. Heterogeneity of PTEN and ERG expression in prostate cancer on core needle biopsies: implications for cancer risk stratification and biomarker sampling.

    Science.gov (United States)

    Shah, Rajal B; Bentley, James; Jeffery, Zach; DeMarzo, Angelo M

    2015-05-01

    ERG and PTEN biomarkers are increasingly being analyzed on prostate core biopsies (NBXs); ERG as a marker of clonality and number of separately arising tumor foci and PTEN for prognostic information. Yet, in patients with multiple biopsy cores positive for cancer (PCa), there is no standardized approach for interrogation of these biomarkers in terms of the number of positive cores to evaluate. A total of 194 NBX cases containing more than one positive core with cancer were evaluated for ERG overexpression and PTEN loss by immunostaining (immunohistochemistry) of all positive cores. ERG overexpression or PTEN loss in at least one cancer core was present in 111 (57%) and 69 (36%) cases respectively. ERG overexpression was significantly associated with PTEN loss (P < .0001), and PTEN loss was associated with a high Gleason score (P < .0001). Inter- and intra-tumor core staining heterogeneity for ERG overexpression occurred in 42% and 5% cases and for PTEN loss both intra- and inter-tumor core heterogeneity was 68%. PTEN staining was highly discordant between PCa sites regardless of laterality. When the Gleason score was non-uniform across PCa sites, the combination of cores showing the highest Gleason score and largest tumor volume provided the best representation of ERG overexpression (92%) and PTEN loss (98%). When grades were uniform across cancer sites, the highest tumor volume core was generally representative of ERG overexpression (90%) but was less representative for PTEN loss (76%). Our results suggest that knowledge of this heterogeneity is critical for developing optimal yet cost-effective strategies to identify these underlying molecular abnormalities. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. Cyberneticization of the sense function in an intellectual control system

    Directory of Open Access Journals (Sweden)

    G. G. Vorob’ev

    2017-01-01

    Full Text Available In the present work, from the standpoint of cybernetics, a sensible psychic function is considered, proposed by K.Jung in the framework of analytical psychology. The peculiarities of this function enabled Jung to distinguish it as an independent equivalent function of thinking, feeling and intuition, and to describe perceptive psychological types (extraverted and introvert. The special research in this work is carried out in view of the practical lack of similar materials by other researchers and the need to understand the meaning and role of the sensation function in the intellectual control system of the new generation, as a cybernetic system, expressing the ideas of analytical psychology. This work is based on the publications of well-known practicing psychologists and specialists in the field of cybernetics, as well as on the results of previous studies by the authors. An in-depth analysis of the properties of the sensory function, undertaken according to the given psychological descriptions, made it possible to correlate these properties with the positions of cybernetics in the part of information transmission and control. In order to correctly describe the action of the sensory function, two operations are proposed: diffusion (blurring and contraction (concentration of sensory images. The results of this study indicate that in natural systems, the sensory function operates already in the sensory perception of objective reality, and the operation of the sensible function determines the modes of operation of mental functions in any intellectual system that satisfies the provisions of analytical psychology. The meaning and role of the tangible function in the intellectual control system go well beyond the limits of only “simple transmission of images”, indicated by Jung. Analysis of the results of the study showed that it was the sensible function that could be provided for the psychic attitudes “extraversion” and

  7. Bilingualism Alters Children's Frontal Lobe Functioning for Attentional Control

    Science.gov (United States)

    Arredondo, Maria M.; Hu, Xiao-Su; Satterfield, Teresa; Kovelman, Ioulia

    2017-01-01

    Bilingualism is a typical linguistic experience, yet relatively little is known about its impact on children's cognitive and brain development. Theories of bilingualism suggest early dual-language acquisition can improve children's cognitive abilities, specifically those relying on frontal lobe functioning. While behavioral findings present much conflicting evidence, little is known about its effects on children's frontal lobe development. Using functional Near-Infrared Spectroscopy (fNIRS), the findings suggest that Spanish-English bilingual children (n=13, ages 7-13) had greater activation in left prefrontal cortex during a non-verbal attentional control task relative to age-matched English monolinguals. In contrast, monolinguals (n=14) showed greater right prefrontal activation than bilinguals. The present findings suggest early bilingualism yields significant changes to the functional organization of children's prefrontal cortex for attentional control and carry implications for understanding how early life experiences impact cognition and brain development. PMID:26743118

  8. Safeguarding the functions and performance of instrumentation and control systems

    International Nuclear Information System (INIS)

    Koehler, M.; Schoerner, O.

    1996-01-01

    Based on an analysis of the existing nuclear power plant control technology, the necessity of providing in the medium-term advanced and future-oriented, digital control system, both for normal operation and for safety-relevant tasks of the reactor and safety control systems. Siemens KWU has been promoting the development, review and marketing of the digital instrumentation and control systems called TELEPERM XS and TELEPERM XP in addition to the measures taken for safeguarding the functions of existing, wired systems. The paper briefly explains the performance and advantages of digital systems and the progress in approval and pioneering of the TELEPERM XS safety control system. Many examples discussed show the diversity of applications of the systems both in new reactor plants and as retrofitting measures, for KWU power plants and those of other manufacturers. (orig.) [de

  9. The control function of the National Bank of Serbia

    Directory of Open Access Journals (Sweden)

    Golubović Srđan

    2016-01-01

    Full Text Available The functioning of a modern economy cannot be conceived without activities of banks and non-banking financial institutions. As financial intermediaries, these institutions issue various financial instruments to mobilize and further allocate free financial funds in appropriate financial investments. By performing this function, financial institutions concurrently affect economic activity, economic structure, employment and macroeconomic stability. Due to their importance for economic relations in any country, most countries prescribe very strict requirements that must be fulfilled in order for an organization to perform financial intermediation activities. These conditions are most often related to the specific requirements regarding activities of financial institutions and their establishment, balance sheet, and requirements in terms of capital adequacy. An integral part of the financial sector regulation is definition of the prudential supervision framework (an effective system of supervision, precisely defined competences of the bodies involved in the supervision, their operational independence, transparency, proceedings for the control of solvency and legality of financial institutions' activities and the implementation of corrective and coercive measures. The paper analyzes the control function of the National Bank of Serbia which, in addition to monitoring and controlling the banking sector, exercises the supervision and control of non-banking financial institutions. The analysis of this issue aims to highlight the importance of the financial institutions' control for curtailing the excessive risk-taking practices by financial institutions, minimizing of systemic risk, and strengthening and preserving the financial system stability.

  10. A smart pH-responsive nano-carrier as a drug delivery system for the targeted delivery of ursolic acid: suppresses cancer growth and metastasis by modulating P53/MMP-9/PTEN/CD44 mediated multiple signaling pathways.

    Science.gov (United States)

    Jiang, Kai; Chi, Ting; Li, Tao; Zheng, Guirong; Fan, Lulu; Liu, Yajun; Chen, Xiufen; Chen, Sijia; Jia, Lee; Shao, Jingwei

    2017-07-13

    Ursolic acid (UA) has been recently used as a promising anti-tumor and cancer metastatic chemo-preventive agent due to its low toxicity and liver-protecting property. However, the low bioavailability and nonspecific tumor targeting restrict its further clinical application. To address the problem, a silica-based mesoporous nanosphere (MSN) controlled-release drug delivery system (denoted UA@M-CS-FA) was designed and successfully synthesized, and was functionalized with folic acid (FA) and pH-sensitive chitosan (CS) for the targeted delivery of UA to folate receptor (FR) positive tumor cells. UA@M-CS-FA were spherical with mean diameter below 150 nm, and showed about -20 mV potential. Meanwhile, UA@M-CS-FA exhibited a pH-sensitive release manner and high cellular uptake in FR over-expressing HeLa cancer cells. Also, in vitro cellular assays suggested that UA@M-CS-FA inhibited cancer cell growth, invasion and migration. Mechanistically, UA@M-CS-FA induced cancer cell apoptosis and inhibited migration via cell cycle arrest in the G0/G1 stage, regulating the PARP/Bcl-2/MMP-9/CD44/PTEN/P53. Importantly, in vivo experiments further confirmed that UA@M-CS-FA significantly suppressed the tumor progression and lung metastasis in tumor-bearing nude mice. Immunohistochemical analysis revealed that UA@M-CS-FA treatment regulated CD44, a biomarker of cancer metastasis. Overall, our data demonstrated that a CS and FA modified MSN controlled-release drug delivery system could help broaden the usage of UA and reflect the great application potential of the UA as an anticancer or cancer metastatic chemopreventive agent.

  11. A fuzzy controller with a robust learning function

    International Nuclear Information System (INIS)

    Tanji, Jun-ichi; Kinoshita, Mitsuo

    1987-01-01

    A self-organizing fuzzy controller is able to use linguistic decision rules of control strategy and has a strong adaptive property by virture of its rule learning function. While a simple linguistic description of the learning algorithm first introduced by Procyk, et al. has much flexibility for applications to a wide range of different processes, its detailed formulation, in particular with control stability and learning process convergence, is not clear. In this paper, we describe the formulation of an analytical basis for a self-organizing fuzzy controller by using a method of model reference adaptive control systems (MRACS) for which stability in the adaptive loop is theoretically proven. A detailed formulation is described regarding performance evaluation and rule modification in the rule learning process of the controller. Furthermore, an improved learning algorithm using adaptive rule is proposed. An adaptive rule gives a modification coefficient for a rule change estimating the effect of disturbance occurrence in performance evaluation. The effect of introducing an adaptive rule to improve the learning convergency is described by using a simple iterative formulation. Simulation tests are presented for an application of the proposed self-organizing fuzzy controller to the pressure control system in a Boiling Water Reactor (BWR) plant. Results with the tests confirm the improved learning algorithm has strong convergent properties, even in a very disturbed environment. (author)

  12. Salivary function and glycemic control in older persons with diabetes.

    Science.gov (United States)

    Chavez, E M; Taylor, G W; Borrell, L N; Ship, J A

    2000-03-01

    There is no consensus on the possible association between diabetes and salivary dysfunction in older persons with diabetes. This study's purpose was to investigate the effect of diabetes and glycemic control on salivary function in an older population. Twenty nine persons with type 2 diabetes and 23 nondiabetic control subjects participated (age range, 54-90 years). Diabetic status was determined by a glycosylated hemoglobin (HbA(1c)) test and a 2-hour glucose tolerance test. Poor glycemic control was defined as HbA(1c) >9%. Unstimulated whole saliva, unstimulated parotid, and stimulated parotid flow rates were measured, and subjects completed a standardized xerostomia questionnaire. Persons with poorly controlled diabetes had lower (P =.01) stimulated parotid flow rates than persons with well-controlled diabetes and nondiabetic control subjects. There were no significant differences in xerostomic complaints based on diabetic or glycemic control status or salivary flow rates. These results provide some evidence that poorly controlled diabetes may be associated with salivary dysfunction in older adults who have no concomitant complaints of xerostomia.

  13. Cytoplasm-predominant Pten associates with increased region-specific brain tyrosine hydroxylase and dopamine D2 receptors in mouse model with autistic traits.

    Science.gov (United States)

    He, Xin; Thacker, Stetson; Romigh, Todd; Yu, Qi; Frazier, Thomas W; Eng, Charis

    2015-01-01

    Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by impairment in social communication/interaction and inflexible/repetitive behavior. Several lines of evidence support genetic factors as a predominant cause of ASD. Among those autism susceptibility genes that have been identified, the PTEN tumor suppressor gene, initially identified as predisposing to Cowden heritable cancer syndrome, was found to be mutated in a subset of ASD patients with extreme macrocephaly. However, the ASD-relevant molecular mechanism mediating the effect of PTEN mutations remains elusive. We developed a Pten knock-in murine model to study the effects of Pten germline mutations, specifically altering subcellular localization, in ASD. Proteins were isolated from the hemispheres of the male littermates, and Western blots were performed to determine protein expression levels of tyrosine hydroxylase (TH). Immunohistochemical stains were carried out to validate the localization of TH and dopamine D2 receptors (D2R). PC12 cells ectopically expressing either wild-type or missense mutant PTEN were then compared for the differences in TH expression. Mice carrying Pten mutations have high TH and D2R in the striatum and prefrontal cortex. They also have increased phosphorylation of cAMP response element-binding protein (CREB) and TH. Mechanistically, PTEN downregulates TH production in PC12 cells via inhibiting the phosphoinositide 3-kinase (PI3K)/CREB signaling pathway, while PTEN reduces TH phosphorylation via suppressing MAPK pathway. Unlike wild-type PTEN but similar to the mouse knock-in mutant Pten, three naturally occurring missense mutations of PTEN that we previously identified in ASD patients, H93R, F241S, and D252G, were not able to suppress TH when overexpressed in PC12 cells. In addition, two other PTEN missense mutations, C124S (pan phosphatase dead) and G129E (lipid phosphatase dead), failed to suppress TH when ectopically expressed in PC12 cells

  14. Electromyographic control of functional electrical stimulation in selected patients.

    Science.gov (United States)

    Graupe, D; Kohn, K H; Basseas, S; Naccarato, E

    1984-07-01

    The paper describes initial results of above-lesion electromyographic (EMG) controlled functional electrical stimulation (FES) of paraplegics. Such controlled stimulation is to provide upper-motor-neuron paraplegics (T5 to T12) with self-controlled standing and some walking without braces and with only the help of walkers or crutches. The above-lesion EMG signal employed serves to map the posture of the patient's upper trunk via a computerized mapping of the temporal patterns of that EMG. Such control also has an inherent safety feature in that it prevents the patient from performing a lower-limb movement via FES unless his trunk posture is adequate. Copyright 2013, SLACK Incorporated.

  15. PIK3CA, HRAS and PTEN in human papillomavirus positive oropharyngeal squamous cell carcinoma

    International Nuclear Information System (INIS)

    Chiosea, Simion I; Nikiforova, Marina N; Grandis, Jennifer R; Lui, Vivian W Y; Diergaarde, Brenda; Maxwell, Jessica H; Ferris, Robert L; Kim, Seungwon W; Luvison, Alyssa; Miller, Megan

    2013-01-01

    Recent genomic evidence suggests frequent phosphatidylinositide 3-kinase (PI3K) pathway activation in human papillomavirus (HPV) positive oropharyngeal squamous cell carcinoma. Mutations/amplification of the gene encoding p110α catalytic subunit of phosphoinositide 3-kinase (PIK3CA), loss of phosphatase and tensin homolog (PTEN) and HRAS mutations are known to activate PI3K pathway. PIK3CA mutations were identified by Sanger sequencing in 23 of 75 (31%) HPV-positive oropharyngeal carcinomas, including exon 9 (p.E545K [n = 10] and p.E542K [n = 5]) or exon 20 (p.H1047Y, n = 2) mutations. Five rare and one novel (p.R537Q) PIK3CA mutations were identified. HRAS mutation (p.Q61L) was detected in 1 of 62 tested cases. PIK3CA amplification by fluorescence in situ hybridization (FISH) was identified in 4 cases (4/21, 20%), while PTEN loss was seen in 7 (7/21, 33%) cases (chromosome 10 monosomy [n = 4], homozygous deletion [n = 3]). Overall, genetic alterations that likely lead to PI3K pathway activation were identified in 34 of 75 cases (45%) and did not correlate with disease specific survival. These findings offer a molecular rationale for therapeutic targeting of PI3K pathway in patients with HPV-positive oropharyngeal carcinoma

  16. High frequency of PTEN mutations in nevi and melanomas from xeroderma pigmentosum patients.

    Science.gov (United States)

    Masaki, Taro; Wang, Yun; DiGiovanna, John J; Khan, Sikandar G; Raffeld, Mark; Beltaifa, Senda; Hornyak, Thomas J; Darling, Thomas N; Lee, Chyi-Chia R; Kraemer, Kenneth H

    2014-05-01

    We examined nevi and melanomas in 10 xeroderma pigmentosum (XP) patients with defective DNA repair. The lesions had a lentiginous appearance with markedly increased numbers of melanocytes. Using laser capture microdissection, we performed DNA sequencing of 18 benign and atypical nevi and 75 melanomas (melanoma in situ and invasive melanomas). The nevi had a similar high frequency of PTEN mutations as melanomas [61% (11/18) versus 53% (39/73)]. Both had a very high proportion of UV-type mutations (occurring at adjacent pyrimidines) [91% (10/11) versus 92% (36/39)]. In contrast to melanomas in the general population, the frequency of BRAF mutations (11%, 7/61), NRAS mutations (21%, 13/62), and KIT mutations (21%, 6/28) in XP melanomas was lower than for PTEN. Phospho-S6 immunostaining indicated activation of the mTOR pathway in the atypical nevi and melanomas. Thus, the clinical and histological appearances and the molecular pathology of these UV-related XP nevi and melanomas were different from nevi and melanomas in the general population. © 2014 Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

  17. Loss of Mel-18 induces tumor angiogenesis through enhancing the activity and expression of HIF-1α mediated by the PTEN/PI3K/Akt pathway.

    Science.gov (United States)

    Park, J H; Lee, J Y; Shin, D H; Jang, K S; Kim, H J; Kong, Gu

    2011-11-10

    Mel-18 has been implicated in several processes in tumor progression, in which the Akt pathway is involved as an important key molecular event. However, the function of Mel-18 in human cancers has not been fully established yet. Here, we examined the effect of Mel-18 on tumor angiogenesis in human breast cancer, and found that Mel-18 was a novel regulator of HIF-1α. Mel-18 negatively regulated the HIF-1α expression and its target gene VEGF transcription during both normoxia and hypoxia. We demonstrated that Mel-18 regulated the HIF-1α expression and activity via the PI3K/Akt pathway. Loss of Mel-18 downregulated Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression, consequently activating the PI3K/Akt/MDM2 pathway, and leading to an increase of HIF-1α protein level. Mel-18 modulated the HIF-1α transcriptional activity via regulating the cytoplasmic retention of FOXO3a, a downstream effector of Akt, and recruitment of HIF-1α/CBP complex to the VEGF promoter. Furthermore, our data shows that Mel-18 blocked tumor angiogenesis both in vitro and in vivo. Mel-18 overexpression inhibited in vitro tube formation in human umbilical endothelial cells (HUVECs). Xenografts in NOD/SCID mice derived from stably Mel-18 knocked down MCF7 human breast cancer cells showed increased tumor volume, microvessel density, and phospho-Akt and HIF-1α expression levels. In conclusion, our findings provide that Mel-18 is a novel regulator of tumor angiogenesis through regulating HIF-1α and its target VEGF expressions mediated by the PTEN/PI3K/Akt pathway, suggesting a new tumor-suppressive role of Mel-18 in human breast cancer.

  18. Alcohol Dehydrogenase Protects against Endoplasmic Reticulum Stress-Induced Myocardial Contractile Dysfunction via Attenuation of Oxidative Stress and Autophagy: Role of PTEN-Akt-mTOR Signaling.

    Directory of Open Access Journals (Sweden)

    Jiaojiao Pang

    Full Text Available The endoplasmic reticulum (ER plays an essential role in ensuring proper folding of the newly synthesized proteins. Aberrant ER homeostasis triggers ER stress and development of cardiovascular diseases. ADH is involved in catalyzing ethanol to acetaldehyde although its role in cardiovascular diseases other than ethanol metabolism still remains elusive. This study was designed to examine the impact of ADH on ER stress-induced cardiac anomalies and underlying mechanisms involved using cardiac-specific overexpression of alcohol dehydrogenase (ADH.ADH and wild-type FVB mice were subjected to the ER stress inducer tunicamycin (1 mg/kg, i.p., for 48 hrs. Myocardial mechanical and intracellular Ca(2+ properties, ER stress, autophagy and associated cell signaling molecules were evaluated.ER stress compromised cardiac contractile function (evidenced as reduced fractional shortening, peak shortening, maximal velocity of shortening/relengthening, prolonged relengthening duration and impaired intracellular Ca(2+ homeostasis, oxidative stress and upregulated autophagy (increased LC3B, Atg5, Atg7 and p62, along with dephosphorylation of PTEN, Akt and mTOR, all of which were attenuated by ADH. In vitro study revealed that ER stress-induced cardiomyocyte anomaly was abrogated by ADH overexpression or autophagy inhibition using 3-MA. Interestingly, the beneficial effect of ADH was obliterated by autophagy induction, inhibition of Akt and mTOR. ER stress also promoted phosphorylation of the stress signaling ERK and JNK, the effect of which was unaffected by ADH transgene.Taken together, these findings suggested that ADH protects against ER stress-induced cardiac anomalies possibly via attenuation of oxidative stress and PTEN/Akt/mTOR pathway-regulated autophagy.

  19. Methodology for allocating nuclear power plant control functions to human or automatic control

    International Nuclear Information System (INIS)

    Pulliam, R.; Price, H.E.; Bongarra, J.; Sawyer, C.R.; Kisner, R.A.

    1983-08-01

    This report describes a general method for allocating control functions to man or machine during nuclear power plant (NPP) design, or for evaluating their allocation in an existing design. The research examined some important characeristics of the systems design process, and the results make it clear that allocation of control functions is an intractable problem, one which increases complexity of systems. The method is reported in terms of specific steps which should be taken during early stages of a new system design, and which will lead to an optimal allocation at the functional design level of detail

  20. Is function-based control room design human-centered?

    International Nuclear Information System (INIS)

    Norros, L.; Savioja, P.

    2006-01-01

    Function-based approaches to system interface design appears an appealing possibility in helping designers and operators to cope with the vast amount of information needed to control complex processes. In this paper we provide evidence of operator performance analyses showing that outcome-centered performance measures may not be sufficiently informative for design. We need analyses indicating habitual patterns of using information, operator practices. We argue that practices that portray functional orienting to the task support mastery of the process. They also create potential to make use of function-based information presentation. We see that functional design is not an absolute value. Instead, such design should support communication of the functional significance of the process information to the operators in variable situations. Hence, it should facilitate development of practices that focus to interpreting this message. Successful function-based design facilitates putting operations into their contexts and is human-centered in an extended sense: It aids making sense in the complex, dynamic and uncertain environment. (authors)

  1. Memory intensive functional architecture for distributed computer control systems

    International Nuclear Information System (INIS)

    Dimmler, D.G.

    1983-10-01

    A memory-intensive functional architectue for distributed data-acquisition, monitoring, and control systems with large numbers of nodes has been conceptually developed and applied in several large-scale and some smaller systems. This discussion concentrates on: (1) the basic architecture; (2) recent expansions of the architecture which now become feasible in view of the rapidly developing component technologies in microprocessors and functional large-scale integration circuits; and (3) implementation of some key hardware and software structures and one system implementation which is a system for performing control and data acquisition of a neutron spectrometer at the Brookhaven High Flux Beam Reactor. The spectrometer is equipped with a large-area position-sensitive neutron detector

  2. Water hammer prediction and control: the Green's function method

    Science.gov (United States)

    Xuan, Li-Jun; Mao, Feng; Wu, Jie-Zhi

    2012-04-01

    By Green's function method we show that the water hammer (WH) can be analytically predicted for both laminar and turbulent flows (for the latter, with an eddy viscosity depending solely on the space coordinates), and thus its hazardous effect can be rationally controlled and minimized. To this end, we generalize a laminar water hammer equation of Wang et al. (J. Hydrodynamics, B2, 51, 1995) to include arbitrary initial condition and variable viscosity, and obtain its solution by Green's function method. The predicted characteristic WH behaviors by the solutions are in excellent agreement with both direct numerical simulation of the original governing equations and, by adjusting the eddy viscosity coefficient, experimentally measured turbulent flow data. Optimal WH control principle is thereby constructed and demonstrated.

  3. Objective function choice for control of a thermocapillary flow using an adjoint-based control strategy

    International Nuclear Information System (INIS)

    Muldoon, Frank H.; Kuhlmann, Hendrik C.

    2015-01-01

    Highlights: • Suppression of oscillations in a thermocapillary flow is addressed by optimization. • The gradient of the objective function is obtained by solving the adjoint equations. • The issue of choosing an objective function is investigated. - Abstract: The problem of suppressing flow oscillations in a thermocapillary flow is addressed using a gradient-based control strategy. The physical problem addressed is the “open boat” process of crystal growth, the flow in which is driven by thermocapillary and buoyancy effects. The problem is modeled by the two-dimensional unsteady incompressible Navier–Stokes and energy equations under the Boussinesq approximation. The goal of the control is to suppress flow oscillations which arise when the driving forces are such that the flow becomes unsteady. The control is a spatially and temporally varying temperature gradient boundary condition at the free surface. The control which minimizes the flow oscillations is found using a conjugate gradient method, where the gradient of the objective function with respect to the control variables is obtained from solving a set of adjoint equations. The issue of choosing an objective function that can be both optimized in a computationally efficient manner and optimization of which provides control that damps the flow oscillations is investigated. Almost complete suppression of the flow oscillations is obtained for certain choices of the objective function.

  4. Regulatory Mechanisms Controlling Maturation of Serotonin Neuron Identity and Function.

    Science.gov (United States)

    Spencer, William C; Deneris, Evan S

    2017-01-01

    The brain serotonin (5-hydroxytryptamine; 5-HT) system has been extensively studied for its role in normal physiology and behavior, as well as, neuropsychiatric disorders. The broad influence of 5-HT on brain function, is in part due to the vast connectivity pattern of 5-HT-producing neurons throughout the CNS. 5-HT neurons are born and terminally specified midway through embryogenesis, then enter a protracted period of maturation, where they functionally integrate into CNS circuitry and then are maintained throughout life. The transcriptional regulatory networks controlling progenitor cell generation and terminal specification of 5-HT neurons are relatively well-understood, yet the factors controlling 5-HT neuron maturation are only recently coming to light. In this review, we first provide an update on the regulatory network controlling 5-HT neuron development, then delve deeper into the properties and regulatory strategies governing 5-HT neuron maturation. In particular, we discuss the role of the 5-HT neuron terminal selector transcription factor (TF) Pet-1 as a key regulator of 5-HT neuron maturation. Pet-1 was originally shown to positively regulate genes needed for 5-HT synthesis, reuptake and vesicular transport, hence 5-HT neuron-type transmitter identity. It has now been shown to regulate, both positively and negatively, many other categories of genes in 5-HT neurons including ion channels, GPCRs, transporters, neuropeptides, and other transcription factors. Its function as a terminal selector results in the maturation of 5-HT neuron excitability, firing characteristics, and synaptic modulation by several neurotransmitters. Furthermore, there is a temporal requirement for Pet-1 in the control of postmitotic gene expression trajectories thus indicating a direct role in 5-HT neuron maturation. Proper regulation of the maturation of cellular identity is critical for normal neuronal functioning and perturbations in the gene regulatory networks controlling

  5. Locomotor Sub-functions for Control of Assistive Wearable Robots

    OpenAIRE

    Sharbafi, Maziar A.; Seyfarth, Andre; Zhao, Guoping

    2017-01-01

    A primary goal of comparative biomechanics is to understand the fundamental physics of locomotion within an evolutionary context. Such an understanding of legged locomotion results in a transition from copying nature to borrowing strategies for interacting with the physical world regarding design and control of bio-inspired legged robots or robotic assistive devices. Inspired from nature, legged locomotion can be composed of three locomotor sub-functions, which are intrinsically interrelated:...

  6. Baduanjin Mind-Body Intervention Improves the Executive Control Function

    OpenAIRE

    Chen, Tingting; Yue, Guang H.; Tian, Yingxue; Jiang, Changhao

    2017-01-01

    This study aims at comparing the effects of the Baduanjin mind-body (BMB) intervention with a conventional relaxation training program on enhancing the executive function. The study also attempts to explore the neural substrates underlying the cognitive effect of BMB intervention using near-infrared spectroscopy (NIRS) technique. Forty-two healthy college students were randomly allocated into either the Baduanjin intervention group or relaxation training (control) group. Training lasted for 8...

  7. Accelerometer method and apparatus for integral display and control functions

    Science.gov (United States)

    Bozeman, Richard J., Jr.

    1992-06-01

    Vibration analysis has been used for years to provide a determination of the proper functioning of different types of machinery, including rotating machinery and rocket engines. A determination of a malfunction, if detected at a relatively early stage in its development, will allow changes in operating mode or a sequenced shutdown of the machinery prior to a total failure. Such preventative measures result in less extensive and/or less expensive repairs, and can also prevent a sometimes catastrophic failure of equipment. Standard vibration analyzers are generally rather complex, expensive, and of limited portability. They also usually result in displays and controls being located remotely from the machinery being monitored. Consequently, a need exists for improvements in accelerometer electronic display and control functions which are more suitable for operation directly on machines and which are not so expensive and complex. The invention includes methods and apparatus for detecting mechanical vibrations and outputting a signal in response thereto. The apparatus includes an accelerometer package having integral display and control functions. The accelerometer package is suitable for mounting upon the machinery to be monitored. Display circuitry provides signals to a bar graph display which may be used to monitor machine condition over a period of time. Control switches may be set which correspond to elements in the bar graph to provide an alert if vibration signals increase over the selected trip point. The circuitry is shock mounted within the accelerometer housing. The method provides for outputting a broadband analog accelerometer signal, integrating this signal to produce a velocity signal, integrating and calibrating the velocity signal before application to a display driver, and selecting a trip point at which a digitally compatible output signal is generated. The benefits of a vibration recording and monitoring system with controls and displays readily

  8. Melittin restores PTEN expression by down-regulating HDAC2 in human hepatocelluar carcinoma HepG2 cells.

    Directory of Open Access Journals (Sweden)

    Hui Zhang

    Full Text Available Melittin is a water-soluble toxic peptide derived from the venom of the bee. Although many studies show the anti-tumor activity of melittin in human cancer including glioma cells, the underlying mechanisms remain elusive. Here the effect of melittin on human hepatocelluar carcinoma HepG2 cell proliferation in vitro and further mechanisms was investigated. We found melittin could inhibit cell proliferation in vitro using Flow cytometry and MTT method. Besides, we discovered that melittin significantly downregulated the expressions of CyclinD1 and CDK4. Results of western Blot and Real-time PCR analysis indicated that melittin was capable to upregulate the expression of PTEN and attenuate histone deacetylase 2 (HDAC2 expression. Further studies demonstrated that knockdown of HDAC2 completely mimicked the effects of melittin on PTEN gene expression. Conversely, it was that the potential utility of melittin on PTEN expression was reversed in cells treated with a recombinant pEGFP-C2-HDAC2 plasmid. In addition, treatment with melittin caused a downregulation of Akt phosphorylation, while overexpression of HDAC2 promoted Akt phosphorylation. These findings suggested that the inhibitory of cell growth by melittin might be led by HDAC2-mediated PTEN upregulation, Akt inactivation, and inhibition of the PI3K/Akt signaling pathways.

  9. Assessing PIK3CA and PTEN in Early-Phase Trials with PI3K/AKT/mTOR Inhibitors

    Directory of Open Access Journals (Sweden)

    Filip Janku

    2014-01-01

    Full Text Available Despite a wealth of preclinical studies, it is unclear whether PIK3CA or phosphatase and tensin homolog (PTEN gene aberrations are actionable in the clinical setting. Of 1,656 patients with advanced, refractory cancers tested for PIK3CA or PTEN abnormalities, PIK3CA mutations were found in 9% (146/1,589, and PTEN loss and/or mutation was found in 13% (149/1,157. In multicovariable analysis, treatment with a phosphatidylinositol 3-kinase (PI3K/AKT/mammalian target of rapamycin (mTOR inhibitor was the only independent factor predicting response to therapy in individuals harboring a PIK3CA or PTEN aberration. The rate of stable disease ≥6 months/partial response reached 45% in a subgroup of individuals with H1047R PIK3CA mutations. Aberrations in the PI3K/AKT/mTOR pathway are common and potentially actionable in patients with diverse advanced cancers. This work provides further important clinical validation for continued and accelerated use of biomarker-driven trials incorporating rational drug combinations.

  10. Association of germline mutation in the PTEN tumour suppressor gene and Proteus and Proteus-like syndromes

    NARCIS (Netherlands)

    Zhou, X.; Hampel, H.; Thiele, H.; Gorlin, R. J.; Hennekam, R. C.; Parisi, M.; Winter, R. M.; Eng, C.

    2001-01-01

    The molecular aetiology of Proteus syndrome (PS) remains elusive. Germline mutations in PTEN cause Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome, which are hereditary hamartoma syndromes. Some features-eg, macrocephaly, lipomatosis, and vascular malformations-can be seen in all three

  11. TGF-β1 stimulates migration of type II endometrial cancer cells by down-regulating PTEN via activation of SMAD and ERK1/2 signaling pathways.

    Science.gov (United States)

    Xiong, Siyuan; Cheng, Jung-Chien; Klausen, Christian; Zhao, Jianfang; Leung, Peter C K

    2016-09-20

    PTEN acts as a tumor suppressor primarily by antagonizing the PI3K/AKT signaling pathway. PTEN is frequently mutated in human cancers; however, in type II endometrial cancers its mutation rate is very low. Overexpression of TGF-β1 and its receptors has been reported to correlate with metastasis of human cancers and reduced survival rates. Although TGF-β1 has been shown to regulate PTEN expression through various mechanisms, it is not yet known if the same is true in type II endometrial cancer. In the present study, we show that treatment with TGF-β1 stimulates the migration of two type II endometrial cancer cell lines, KLE and HEC-50. In addition, TGF-β1 treatment down-regulates both mRNA and protein levels of PTEN. Overexpression of PTEN or inhibition of PI3K abolishes TGF-β1-stimulated cell migration. TGF-β1 induces SMAD2/3 phosphorylation and knockdown of common SMAD4 inhibits the suppressive effects of TGF-β1 on PTEN mRNA and protein. Interestingly, TGF-β1 induces ERK1/2 phosphorylation and pre-treatment with a MEK inhibitor attenuates the suppression of PTEN protein, but not mRNA, by TGF-β1. This study provides important insights into the molecular mechanisms mediating TGF-β1-induced down-regulation of PTEN and demonstrates an important role of PTEN in the regulation of type II endometrial cancer cell migration.

  12. PTEN loss promotes intratumoral androgen synthesis and tumor microenvironment remodeling via aberrant activation of RUNX2 in castration-resistant prostate cancer

    Science.gov (United States)

    Yang, Yinhui; Bai, Yang; He, Yundong; Zhao, Yu; Chen, Jiaxiang; Ma, Linlin; Pan, Yunqian; Hinten, Michael; Zhang, Jun; Karnes, R. Jeffrey; Kohli, Manish; Westendorf, Jennifer J.; Li, Benyi; Zhu, Runzhi; Huang, Haojie; Xu, Wanhai

    2018-01-01

    Purpose Intratumoral androgen synthesis (IAS) is a key mechanism promoting androgen receptor (AR)reactivation and anti-androgen resistance in castration-resistant prostate cancer (CRPC). However, signaling pathways driving aberrant IAS remain poorly understood. Experimental Design The effect of components of the AKT-RUNX2-osteocalcin (OCN)-GPRC6A-CREB signaling axis on expression of steroidogenesis genes CYP11A1 and CYP17A1 and testosterone level were examined in PTEN-null human PCa cell lines. Pten knockout mice were employed to examine the effect of Runx2 heterozygous deletion or abiraterone acetate (ABA), a prodrug of the CYP17A1 inhibitor abiraterone on Cyp11a1 and Cyp17a1 expression, testosterone level and tumor microenvironment (TME) remodeling in vivo. Results We uncovered that activation of the AKT-RUNX2-OCN-GPRC6A-CREB signaling axis induced expression of CYP11A1 and CYP17A1 and testosterone production in PTEN-null PCa cell lines in culture. Deletion of Runx2 in Pten homozygous knockout prostate tumors decreased Cyp11a1 and Cyp17a1 expression, testosterone level and tumor growth in castrated mice. ABA treatment also inhibited testosterone synthesis and alleviated Pten loss-induced tumorigenesis in vivo. Pten deletion induced TME remodeling, but Runx2 heterozygous deletion or ABA treatment reversed the effect of Pten loss by decreasing expression of the collagenase Mmp9. Conclusions Abnormal RUNX2 activation plays a pivotal role in PTEN loss-induced IAS and TME remodeling, suggesting that the identified signaling cascade represents a viable target for effective treatment of PTEN-null PCa including CRPC. PMID:29167276

  13. Functional fractional calculus for system identification and controls

    CERN Document Server

    Das, Shantanu

    2008-01-01

    This work is inspired by thought to have an overall fuel-ef?cient nuclear plant control system. I picked up the topic in 2002 while deriving the reactor control laws, which aimed at fuel ef?ciency. Controlling the nuclear reactor close to its natural behavior by concept of exponent shape governor, ratio control and use of logarithmic logic, aims at the fuel ef?ciency. The power-maneuvering trajectory is obtained by shaped-normalized-period function, and this de?nes the road map on which the reactor should be governed. The experience of this concept governing the Atomic Power Plant of Tarapur Atomic Power Station gives lesser overall gains compared to the older plants, where conventional proportional integral and deri- tive type (PID) scheme is employed. Therefore, this motivation led to design the scheme for control system than the conventional schemes to aim at overall plant ef?ciency. Thus, I felt the need to look beyondPID and obtained the answer in fr- tional order control system, requiring fractional cal...

  14. Integrated Control Strategies Supporting Autonomous Functionalities in Mobile Robots

    Directory of Open Access Journals (Sweden)

    Brandon Sights

    2006-10-01

    Full Text Available High-level intelligence allows a mobile robot to create and interpret complex world models, but without a precise control system, the accuracy of the world model and the robot's ability to interact with its surroundings are greatly diminished. This problem is amplified when the environment is hostile, such as in a battlefield situation where an error in movement or a slow response may lead to destruction of the robot. As the presence of robots on the battlefield continues to escalate and the trend toward relieving the human of the low-level control burden advances, the ability to combine the functionalities of several critical control systems on a single platform becomes imperative.

  15. Orthogonal functionalization of nanoporous substrates: control of 3D surface functionality.

    Science.gov (United States)

    Lazzara, Thomas D; Kliesch, Torben-Tobias; Janshoff, Andreas; Steinem, Claudia

    2011-04-01

    Anodic aluminum oxide (AAO) membranes with aligned, cylindrical, nonintersecting pores were selectively functionalized in order to create dual-functionality substrates with different pore-rim and pore-interior surface functionalities, using silane chemistry. We used a two-step process involving an evaporated thin gold film to protect the underlying surface functionality of the pore rims. Subsequent treatment with oxygen plasma of the modified AAO membrane removed the unprotected organic functional groups, i.e., the pore-interior surface. After gold removal, the substrate became optically transparent, and displayed two distinct surface functionalities, one at the pore-rim surface and another at the pore-interior surface. We achieved a selective hydrophobic functionalization with dodecyl-trichlorosilane of either the pore rims or the pore interiors. The deposition of planar lipid membranes on the functionalized areas by addition of small unilamellar vesicles occurred in a predetermined fashion. Small unilamellar vesicles only ruptured upon contact with the hydrophobic substrate regions forming solid supported hybrid bilayers. In addition, pore-rim functionalization with dodecyl-trichlorosilane allowed the formation of pore-spanning hybrid lipid membranes as a result of giant unilamellar vesicle rupture. Confocal laser scanning microscopy was employed to identify the selective spatial localization of the adsorbed fluorescently labeled lipids. The corresponding increase in the AAO refractive index due to lipid adsorption on the hydrophobic regions was monitored by optical waveguide spectroscopy. This simple orthogonal functionalization route is a promising method to control the three-dimensional surface functionality of nanoporous films. © 2011 American Chemical Society

  16. Mindfulness Meditation Training and Executive Control Network Resting State Functional Connectivity: A Randomized Controlled Trial.

    Science.gov (United States)

    Taren, Adrienne A; Gianaros, Peter J; Greco, Carol M; Lindsay, Emily K; Fairgrieve, April; Brown, Kirk Warren; Rosen, Rhonda K; Ferris, Jennifer L; Julson, Erica; Marsland, Anna L; Creswell, J David

    Mindfulness meditation training has been previously shown to enhance behavioral measures of executive control (e.g., attention, working memory, cognitive control), but the neural mechanisms underlying these improvements are largely unknown. Here, we test whether mindfulness training interventions foster executive control by strengthening functional connections between dorsolateral prefrontal cortex (dlPFC)-a hub of the executive control network-and frontoparietal regions that coordinate executive function. Thirty-five adults with elevated levels of psychological distress participated in a 3-day randomized controlled trial of intensive mindfulness meditation or relaxation training. Participants completed a resting state functional magnetic resonance imaging scan before and after the intervention. We tested whether mindfulness meditation training increased resting state functional connectivity (rsFC) between dlPFC and frontoparietal control network regions. Left dlPFC showed increased connectivity to the right inferior frontal gyrus (T = 3.74), right middle frontal gyrus (MFG) (T = 3.98), right supplementary eye field (T = 4.29), right parietal cortex (T = 4.44), and left middle temporal gyrus (T = 3.97, all p < .05) after mindfulness training relative to the relaxation control. Right dlPFC showed increased connectivity to right MFG (T = 4.97, p < .05). We report that mindfulness training increases rsFC between dlPFC and dorsal network (superior parietal lobule, supplementary eye field, MFG) and ventral network (right IFG, middle temporal/angular gyrus) regions. These findings extend previous work showing increased functional connectivity among brain regions associated with executive function during active meditation by identifying specific neural circuits in which rsFC is enhanced by a mindfulness intervention in individuals with high levels of psychological distress. Clinicaltrials.gov,NCT01628809.

  17. Apc inactivation, but not obesity, synergizes with Pten deficiency to drive intestinal stem cell-derived tumorigenesis.

    Science.gov (United States)

    Tabrizian, Tahmineh; Wang, Donghai; Guan, Fangxia; Hu, Zunju; Beck, Amanda P; Delahaye, Fabien; Huffman, Derek M

    2017-06-01

    Obesity is a major risk factor for colorectal cancer and can accelerate Lgr5+ intestinal stem cell (ISC)-derived tumorigenesis after the inactivation of Apc However, whether non-canonical pathways involving PI3K-Akt signaling in ISCs can lead to tumor formation, and if this can be further exacerbated by obesity is unknown. Despite the synergy between Pten and Apc inactivation in epithelial cells on intestinal tumor formation, their combined role in Lgr5+-ISCs, which are the most rapidly dividing ISC population in the intestine, is unknown. Lgr5+-GFP mice were provided low-fat diet (LFD) or high-fat diet (HFD) for 8 months, and the transcriptome was evaluated in Lgr5+-ISCs. For tumor studies, Lgr5+-GFP and Lgr5+-GFP- Pten flox/flox mice were tamoxifen treated to inactivate Pten in ISCs and provided LFD or HFD until 14-15 months of age. Finally, various combinations of Lgr5+-ISC-specific, Apc- and Pten -deleted mice were generated and evaluated for histopathology and survival. HFD did not overtly alter Akt signaling in ISCs, but did increase other metabolic pathways. Pten deficiency, but not HFD, increased BrdU-positive cells in the small intestine ( P  Apc deficiency synergistically increased proliferative markers, tumor pathology and mortality, in a dose-dependent fashion ( P  Apc deficiency in ISCs synergistically increases proliferation, tumor formation and mortality. Thus, aberrant Wnt/β-catenin, rather than PI3K-Akt signaling, is requisite for obesity to drive Lgr5+ ISC-derived tumorigenesis. © 2017 Society for Endocrinology.

  18. Baduanjin Mind-Body Intervention Improves the Executive Control Function.

    Science.gov (United States)

    Chen, Tingting; Yue, Guang H; Tian, Yingxue; Jiang, Changhao

    2016-01-01

    This study aims at comparing the effects of the Baduanjin mind-body (BMB) intervention with a conventional relaxation training program on enhancing the executive function. The study also attempts to explore the neural substrates underlying the cognitive effect of BMB intervention using near-infrared spectroscopy (NIRS) technique. Forty-two healthy college students were randomly allocated into either the Baduanjin intervention group or relaxation training (control) group. Training lasted for 8 weeks (90 min/day, 5 days/week). Each participant was administered the shortened Profile of Mood States to evaluate their mood status and the flanker task to evaluate executive function before and after training. While performing the flanker task, the NIRS data were collected from each participant. After training, individuals who have participated in BMB exercise showed a significant reduction in depressive mood compared with the same measure before the intervention. However, participants in the control group showed no such reduction. The before vs. after measurement difference in the flanker task incongruent trails was significant only for the Baduanjin intervention group. Interestingly, an increase in oxygenated hemoglobin in the left prefrontal cortex was observed during the Incongruent Trails test only after the BMB exercise intervention. These findings implicate that Baduanjin is an effective and easy-to-administering mind-body exercise for improving executive function and perhaps brain self-regulation in a young and healthy population.

  19. Temperature measurement and control system for transtibial prostheses: Functional evaluation.

    Science.gov (United States)

    Ghoseiri, Kamiar; Zheng, Yong Ping; Leung, Aaron K L; Rahgozar, Mehdi; Aminian, Gholamreza; Lee, Tat Hing; Safari, Mohammad Reza

    2018-01-01

    The accumulation of heat inside the prosthetic socket increases skin temperature and fosters perspiration, which consequently leads to high tissue stress, friction blister, discomfort, unpleasant odor, and decreased prosthesis suspension and use. In the present study, the prototype of a temperature measurement and control (TM&C) system was designed, fabricated, and functionally evaluated in a phantom model of the transtibial prosthetic socket. The TM&C system was comprised of 12 thermistors divided equally into two groups that arranged internal and external to a prosthetic silicone liner. Its control system was programmed to select the required heating or cooling function of a thermal pump to provide thermal equilibrium based on the amount of temperature difference from a defined set temperature, or the amount of difference between the mean temperature recorded by inside and outside thermistors. A thin layer of aluminum was used for thermal conduction between the thermal pump and different sites around the silicone liner. The results showed functionality of the TM&C system for thermoregulation inside the prosthetic socket. However, enhancing the structure of this TM&C system, increasing its thermal power, and decreasing its weight and cost are main priorities before further development.

  20. Control of Polymer Nanostructure and Functionality via Radiation Grafting

    International Nuclear Information System (INIS)

    Palmese, G.R.

    2006-01-01

    Radiation grafting provides a useful means for controlling polymer structure and performance. Particularly, it is appropriate for combining materials with distinct thermodynamic characteristics chemically at interfaces. Therefore polymeric materials that generally will not mix - i.e hydrophilic and hydrophobic polymers - can be combined efficiently using radiation based methods. This is of particular importance when attempting to form polymer-polymer nanocomposites where the thermodynamic penalty associated with high specific interfacial surface area is very large. Generally, the combination at small scales of such distinct materials is appropriate when specific functionality is desired while maintaining structural performance characteristics. In such cases the hydrophilic polymer lends functional characteristics such as ionic conductivity, self-healing, and actuation, while the hydrophobic polymer component provides structural stability. In this communication a summary of our recent work concerning the use of radiation grafting for the synthesis of nanostructured functional materials is given. Examples to be discussed include toughing of polymeric systems, the synthesis polymeric and inorganic nanotubes, and the design of permeation selective membranes. These examples will be used to demonstrate the effectiveness of radiation grafting techniques for controlling polymer properties and small-scale structure

  1. A Tiered Control Plane Model for Service Function Chaining Isolation

    Directory of Open Access Journals (Sweden)

    Håkon Gunleifsen

    2018-06-01

    Full Text Available This article presents an architecture for encryption automation in interconnected Network Function Virtualization (NFV domains. Current NFV implementations are designed for deployment within trusted domains, where overlay networks with static trusted links are utilized for enabling network security. Nevertheless, within a Service Function Chain (SFC, Virtual Network Function (VNF flows cannot be isolated and end-to-end encrypted because each VNF requires direct access to the overall SFC data-flow. This restricts both end-users and Service Providers from enabling end-to-end security, and in extended VNF isolation within the SFC data traffic. Encrypting data flows on a per-flow basis results in an extensive amount of secure tunnels, which cannot scale efficiently in manual configurations. Additionally, creating secure data plane tunnels between NFV providers requires secure exchange of key parameters, and the establishment of an east–west control plane protocol. In this article, we present an architecture focusing on these two problems, investigating how overlay networks can be created, isolated, and secured dynamically. Accordingly, we propose an architecture for automated establishment of encrypted tunnels in NFV, which introduces a novel, tiered east–west communication channel between network controllers in a multi-domain environment.

  2. Functional hypothalamic amenorrhea and its psychological correlates: a controlled comparison.

    Science.gov (United States)

    Pentz, Ivana; Nakić Radoš, Sandra

    2017-04-01

    The goal of the study was to examine differences between adolescents and young women with functional hypothalamic amenorrhea (FHA) and control groups in personality traits, eating attitudes and behaviours, and perception of parental behaviour. The FHA is stress-induced anovulation, both related to metabolic challenges, such as excessive exercise and malnutrition, and psychogenic challenges, such as perfectionism and poor coping strategies. Three groups of adolescents and young women participated in the study: the FHA group (N = 25), the organic anovulation group (N = 21) and the eumenorrheic group with regular menstrual cycle (N = 20). Questionnaires on multidimensional perfectionism, self-control methods, eating attitudes and behaviours and perception of parental behaviour were administered. A clinical interview (SCID) was conducted with each participant. The FHA group had higher levels of perfectionism traits, i.e. higher levels of concerns over mistakes and personal standards, compared to control groups. The FHA group did not engage in disordered eating behaviours more often in comparison with control groups, but reported more prevalent history of anorexia nervosa. The FHA group did not differ from controls in perception of parental rejection, emotional warmth or overprotection. The findings suggest that FHA can be characterised by the subtle psychological differences in personality traits, so the patients need to be diagnosed carefully.

  3. The Subthalamic Nucleus, Limbic Function, and Impulse Control.

    Science.gov (United States)

    Rossi, P Justin; Gunduz, Aysegul; Okun, Michael S

    2015-12-01

    It has been well documented that deep brain stimulation (DBS) of the subthalamic nucleus (STN) to address some of the disabling motor symptoms of Parkinson's disease (PD) can evoke unintended effects, especially on non-motor behavior. This observation has catalyzed more than a decade of research concentrated on establishing trends and identifying potential mechanisms for these non-motor effects. While many issues remain unresolved, the collective result of many research studies and clinical observations has been a general recognition of the role of the STN in mediating limbic function. In particular, the STN has been implicated in impulse control and the related construct of valence processing. A better understanding of STN involvement in these phenomena could have important implications for treating impulse control disorders (ICDs). ICDs affect up to 40% of PD patients on dopamine agonist therapy and approximately 15% of PD patients overall. ICDs have been reported to be associated with STN DBS. In this paper we will focus on impulse control and review pre-clinical, clinical, behavioral, imaging, and electrophysiological studies pertaining to the limbic function of the STN.

  4. Developmental and Functional Control of Natural Killer Cells by Cytokines

    Directory of Open Access Journals (Sweden)

    Yang Wu

    2017-08-01

    Full Text Available Natural killer (NK cells are effective in combating infections and tumors and as such are tempting for adoptive transfer therapy. However, they are not homogeneous but can be divided into three main subsets, including cytotoxic, tolerant, and regulatory NK cells, with disparate phenotypes and functions in diverse tissues. The development and functions of such NK cells are controlled by various cytokines, such as fms-like tyrosine kinase 3 ligand (FL, kit ligand (KL, interleukin (IL-3, IL-10, IL-12, IL-18, transforming growth factor-β, and common-γ chain family cytokines, which operate at different stages by regulating distinct signaling pathways. Nevertheless, the specific roles of each cytokine that regulates NK cell development or that shapes different NK cell functions remain unclear. In this review, we attempt to describe the characteristics of each cytokine and the existing protocols to expand NK cells using different combinations of cytokines and feeder cells. A comprehensive understanding of the role of cytokines in NK cell development and function will aid the generation of better efficacy for adoptive NK cell treatment.

  5. Compositional control of continuously graded anode functional layer

    Science.gov (United States)

    McCoppin, J.; Barney, I.; Mukhopadhyay, S.; Miller, R.; Reitz, T.; Young, D.

    2012-10-01

    In this work, solid oxide fuel cells (SOFC's) are fabricated with linear-compositionally graded anode functional layers (CGAFL) using a computer-controlled compound aerosol deposition (CCAD) system. Cells with different CGAFL thicknesses (30 um and 50 um) are prepared with a continuous compositionally graded interface deposited between the electrolyte and anode support current collecting regions. The compositional profile was characterized using energy dispersive X-ray spectroscopic mapping. An analytical model of the compound aerosol deposition was developed. The model predicted compositional profiles for both samples that closely matched the measured profiles, suggesting that aerosol-based deposition methods are capable of creating functional gradation on length scales suitable for solid oxide fuel cell structures. The electrochemical performances of the two cells are analyzed using electrochemical impedance spectroscopy (EIS).

  6. Structure, function, and control of the human musculoskeletal network.

    Directory of Open Access Journals (Sweden)

    Andrew C Murphy

    2018-01-01

    Full Text Available The human body is a complex organism, the gross mechanical properties of which are enabled by an interconnected musculoskeletal network controlled by the nervous system. The nature of musculoskeletal interconnection facilitates stability, voluntary movement, and robustness to injury. However, a fundamental understanding of this network and its control by neural systems has remained elusive. Here we address this gap in knowledge by utilizing medical databases and mathematical modeling to reveal the organizational structure, predicted function, and neural control of the musculoskeletal system. We constructed a highly simplified whole-body musculoskeletal network in which single muscles connect to multiple bones via both origin and insertion points. We demonstrated that, using this simplified model, a muscle's role in this network could offer a theoretical prediction of the susceptibility of surrounding components to secondary injury. Finally, we illustrated that sets of muscles cluster into network communities that mimic the organization of control modules in primary motor cortex. This novel formalism for describing interactions between the muscular and skeletal systems serves as a foundation to develop and test therapeutic responses to injury, inspiring future advances in clinical treatments.

  7. Interaction between functional health literacy, patient activation, and glycemic control

    Directory of Open Access Journals (Sweden)

    Woodard LD

    2014-07-01

    Full Text Available LeChauncy D Woodard, Cassie R Landrum, Amber B Amspoker, David Ramsey, Aanand D Naik Veterans Affairs Health Services Research and Development Center for Innovations in Quality, Effectiveness and Safety, Michael E DeBakey Veterans Affairs Medical Center, and Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA Background: Functional health literacy (FHL and patient activation can impact diabetes control through enhanced diabetes self-management. Less is known about the combined effect of these characteristics on diabetes outcomes. Using brief, validated measures, we examined the interaction between FHL and patient activation in predicting glycosylated hemoglobin (HbA1c control among a cohort of multimorbid diabetic patients.Methods: We administered a survey via mail to 387 diabetic patients with coexisting ­hypertension and ischemic heart disease who received outpatient care at one regional VA medical center between November 2010 and December 2010. We identified patients with the study conditions using the International Classification of Diseases-Ninth Revision-Clinical ­Modification (ICD-9-CM diagnoses codes and Current Procedure Terminology (CPT ­procedures codes. Surveys were returned by 195 (50.4% patients. We determined patient activation levels based on participant responses to the 13-item Patient Activation Measure and FHL levels using the single-item screening question, “How confident are you filling out medical forms by yourself?” We reviewed patient medical records to assess glycemic control. We used multiple logistic regression to examine whether activation and FHL were individually or jointly related to HbA1c control.Results: Neither patient activation nor FHL was independently related to glycemic control in the unadjusted main effects model; however, the interaction between the two was significantly associated with glycemic control (odds ratio 1.05 [95% confidence

  8. The construction of control chart for PM10 functional data

    Science.gov (United States)

    Shaadan, Norshahida; Jemain, Abdul Aziz; Deni, Sayang Mohd

    2014-06-01

    In this paper, a statistical procedure to construct a control chart for monitoring air quality (PM10) using functional data is proposed. A set of daily indices that represent the daily PM10 curves were obtained using Functional Principal Component Analysis (FPCA). By means of an iterative charting procedure, a reference data set that represented a stable PM10 process was obtained. The data were then used as a reference for monitoring future data. The application of the procedure was conducted using seven-year (2004-2010) period of recorded data from the Klang air quality monitoring station located in the Klang Valley region of Peninsular Malaysia. The study showed that the control chart provided a useful visualization tool for monitoring air quality and was capable in detecting abnormality in the process system. As in the case of Klang station, the results showed that with reference to 2004-2008, the air quality (PM10) in 2010 was better than that in 2009.

  9. Working Memory in the Service of Executive Control Functions.

    Science.gov (United States)

    Mansouri, Farshad A; Rosa, Marcello G P; Atapour, Nafiseh

    2015-01-01

    Working memory is a type of short-term memory which has a crucial cognitive function that supports ongoing and upcoming behaviors, allowing storage of information across delay periods. The content of this memory may typically include tangible information about features such as the shape, color or texture of an object, and its location and motion relative to the body, as well as phonological information. The neural correlate of working memory has been found in different brain areas that are involved in organizing perceptual or motor functions. In particular, neuronal activity in prefrontal areas encodes task-related information corresponding to working memory across delay periods, and lesions in the prefrontal cortex severely affect the ability to retain this type of memory. Recent studies have further expanded the scope and possible role of working memory by showing that information of a more abstract nature (including a behavior-guiding rule, or the occurrence of a conflict in information processing) can also be maintained in short-term memory, and used for adjusting the allocation of executive control in dynamic environments. It has also been shown that neuronal activity in the prefrontal cortex encodes and maintains information about such abstract entities. These findings suggest that the prefrontal cortex plays crucial roles in the organization of goal-directed behavior by supporting many different mnemonic processes, which maintain a wide range of information required for the executive control of ongoing and upcoming behaviors.

  10. Targeting of the tumor suppressor GRHL3 by a miR-21-dependent proto-oncogenic network results in PTEN loss and tumorigenesis.

    Science.gov (United States)

    Darido, Charbel; Georgy, Smitha R; Wilanowski, Tomasz; Dworkin, Sebastian; Auden, Alana; Zhao, Quan; Rank, Gerhard; Srivastava, Seema; Finlay, Moira J; Papenfuss, Anthony T; Pandolfi, Pier Paolo; Pearson, Richard B; Jane, Stephen M

    2011-11-15

    Despite its prevalence, the molecular basis of squamous cell carcinoma (SCC) remains poorly understood. Here, we identify the developmental transcription factor Grhl3 as a potent tumor suppressor of SCC in mice, and demonstrate that targeting of Grhl3 by a miR-21-dependent proto-oncogenic network underpins SCC in humans. Deletion of Grhl3 in adult epidermis evokes loss of expression of PTEN, a direct GRHL3 target, resulting in aggressive SCC induced by activation of PI3K/AKT/mTOR signaling. Restoration of Pten expression completely abrogates SCC formation. Reduced levels of GRHL3 and PTEN are evident in human skin, and head and neck SCC, associated with increased expression of miR-21, which targets both tumor suppressors. Our data define the GRHL3-PTEN axis as a critical tumor suppressor pathway in SCC. 2011 Elsevier Inc. All rights reserved.

  11. The Role of Control Functions in Mentalizing: Dual-Task Studies of Theory of Mind and Executive Function

    Science.gov (United States)

    Bull, Rebecca; Phillips, Louise H.; Conway, Claire A.

    2008-01-01

    Conflicting evidence has arisen from correlational studies regarding the role of executive control functions in Theory of Mind. The current study used dual-task manipulations of executive functions (inhibition, updating and switching) to investigate the role of these control functions in mental state and non-mental state tasks. The "Eyes"…

  12. Functionally-interdependent shape-switching nanoparticles with controllable properties

    Science.gov (United States)

    Halman, Justin R.; Satterwhite, Emily; Roark, Brandon; Chandler, Morgan; Viard, Mathias; Ivanina, Anna; Bindewald, Eckart; Kasprzak, Wojciech K.; Panigaj, Martin; Bui, My N.; Lu, Jacob S.; Miller, Johann; Khisamutdinov, Emil F.; Shapiro, Bruce A.; Dobrovolskaia, Marina A.

    2017-01-01

    Abstract We introduce a new concept that utilizes cognate nucleic acid nanoparticles which are fully complementary and functionally-interdependent to each other. In the described approach, the physical interaction between sets of designed nanoparticles initiates a rapid isothermal shape change which triggers the activation of multiple functionalities and biological pathways including transcription, energy transfer, functional aptamers and RNA interference. The individual nanoparticles are not active and have controllable kinetics of re-association and fine-tunable chemical and thermodynamic stabilities. Computational algorithms were developed to accurately predict melting temperatures of nanoparticles of various compositions and trace the process of their re-association in silico. Additionally, tunable immunostimulatory properties of described nanoparticles suggest that the particles that do not induce pro-inflammatory cytokines and high levels of interferons can be used as scaffolds to carry therapeutic oligonucleotides, while particles with strong interferon and mild pro-inflammatory cytokine induction may qualify as vaccine adjuvants. The presented concept provides a simple, cost-effective and straightforward model for the development of combinatorial regulation of biological processes in nucleic acid nanotechnology. PMID:28108656

  13. Variable laterality of corticospinal tract axons that regenerate after spinal cord injury as a result of PTEN deletion or knock-down

    Science.gov (United States)

    Willenberg, Rafer; Zukor, Katherine; Liu, Kai; He, Zhigang; Steward, Oswald

    2016-01-01

    Corticospinal tract (CST) axons from one hemisphere normally extend and terminate predominantly in the contralateral spinal cord. We previously showed that deleting PTEN in the sensorimotor cortex enables CST axons to regenerate after spinal cord injury and that some regenerating axons extend along the “wrong” side. Here, we characterize the degree of specificity of regrowth in terms of laterality. PTEN was selectively deleted via cortical AAV-Cre injections in neonatal PTEN-floxed mice. As adults, mice received dorsal hemisection injuries at T12 or complete crush injuries at T9. CST axons from one hemisphere were traced by unilateral BDA injections in PTEN-deleted mice with spinal cord injury and in non-injured PTEN-floxed mice that had not received AAV-Cre. In non-injured mice, 97.9 ± 0.7% of BDA-labeled axons in white matter and 88.5 ± 1.0% of BDA-labeled axons in grey matter were contralateral to the cortex of origin. In contrast, laterality of CST axons that extended past a lesion due to PTEN deletion varied across animals. In some cases, regenerated axons extended predominantly on the ipsilateral side, in other cases, axons extended predominantly contralaterally, and in others, axons were similar in numbers on both sides. Similar results were seen in analyses of cases from previous studies using shRNA-mediated PTEN knock-down. These results indicate that CST axons that extend past a lesion due to PTEN deletion or knock-down do not maintain the contralateral rule of the non-injured CST, highlighting one aspect for how resultant circuitry from regenerating axons may differ from that of the uninjured CST. PMID:26878190

  14. Loss of mTOR repressors Tsc1 or Pten has divergent effects on excitatory and inhibitory synaptic transmission in single hippocampal neuron cultures.

    Science.gov (United States)

    Weston, Matthew C; Chen, Hongmei; Swann, John W

    2014-01-01

    The Pten and Tsc1 genes both encode proteins that repress mechanistic target of rapamycin (mTOR) signaling. Disruption of either gene in the brain results in epilepsy and autism-like symptoms in humans and mouse models, therefore it is important to understand the molecular and physiological events that lead from gene disruption to disease phenotypes. Given the similar roles these two molecules play in the regulation of cellular growth and the overlap in the phenotypes that result from their loss, we predicted that the deletion of either the Pten or Tsc1 gene from autaptic hippocampal neurons would have similar effects on neuronal morphology and synaptic transmission. Accordingly, we found that loss of either Pten or Tsc1 caused comparable increases in soma size, dendrite length and action potential properties. However, the effects of Pten and Tsc1 loss on synaptic transmission were different. Loss of Pten lead to an increase in both excitatory and inhibitory neurotransmission, while loss of Tsc1 did not affect excitatory neurotransmission and reduced inhibitory transmission by decreasing mIPSC amplitude. Although the loss of Pten or Tsc1 both increased downstream mTORC1 signaling, phosphorylation of Akt was increased in Pten-ko and decreased in Tsc1-ko neurons, potentially accounting for the different effects on synaptic transmission. Despite the different effects at the synaptic level, our data suggest that loss of Pten or Tsc1 may both lead to an increase in the ratio of excitation to inhibition at the network level, an effect that has been proposed to underlie both epilepsy and autism.

  15. Controllable synthesis of functional nanocomposites: Covalently functionalize graphene sheets with biocompatible L-lysine

    International Nuclear Information System (INIS)

    Mo, Zunli; Gou, Hao; He, Jingxian; Yang, Peipei; Feng, Chao; Guo, Ruibin

    2012-01-01

    Highlights: ► The biocompatible L-lysine functionalized graphene sheets (Gs/Lys) were synthesized controllably using a novel method. ► The Gs/Lys nanocomposites are water-soluble, biocompatible and chiral. ► A chiral graphene derivative was proposed. - Abstract: In this paper a novel method to synthesize functionalize graphene sheets (Gs) by biocompatible L-lysine (Gs/Lys) is reported. The method was composed of two steps: (1) we controllably synthesized self-assembly Gs/Lys-Cu-Lys through the terminal amino of copper L-lysine (Lys-Cu-Lys) attaching to graphite oxide (GO) and then reducing. (2) Obtained the Gs/Lys by eliminating the copper ion. This method could also be used to functionalize other nanomaterials by L-lysine. The Gs/Lys nanocomposites are water-soluble, biocompatible, and above all, it is a chiral material of graphene, which is proposed by us. This novel material will be promising for more applications of graphene. The formation of Gs/Lys nanocomposites were confirmed by scanning electron microscopy (SEM), Fourier-transform infrared spectra (FT-IR), X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), and thermal gravimetric (TG) analysis.

  16. PTENp1, a natural sponge of miR-21, mediates PTEN expression to inhibit the proliferation of oral squamous cell carcinoma.

    Science.gov (United States)

    Gao, Ling; Ren, Wenhao; Zhang, Linmei; Li, Shaoming; Kong, Xinjuan; Zhang, Hao; Dong, Jianwei; Cai, Guangfeng; Jin, Changxiong; Zheng, Danqing; Zhi, Keqian

    2017-04-01

    PTENp1, non-coding RNA (ncRNA) pseudogene, is involved in oral squamous cell carcinoma (OSCC). The precise effects mediated by PTENp1 transcripts within intricate regulatory networks involving molecular interactions with ancestral gene PTEN and tumorigenicity in OSCC remain unclear. Here, we found that PTENp1 was aberrantly expressed in OSCC. There was a positive correlation between the expression levels of PTENp1 and PTEN. Further, we showed that PTENp1 acted as a competing endogenous RNA that protects PTEN transcripts from being inhibited by miR-21, and consequently inhibited proliferation and colony formation and triggered S-G2/M cell cycle arrest through the AKT pathway. Also, the homogeneous relationship between expression of PTENp1 and PTEN was confirmed in OSCC tumor xenografts. Finally, low expression of PTENp1 and PTEN was negatively associated with histological differentiation and OSCC prognosis. The present work provided the first evidence for the extraordinary crosstalk among PTENp1, PTEN, and miR-21, and rendered a new light on the treatment of OSCC. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  17. Electron energy distribution function control in gas discharge plasmas

    International Nuclear Information System (INIS)

    Godyak, V. A.

    2013-01-01

    The formation of the electron energy distribution function (EEDF) and electron temperature in low temperature gas discharge plasmas is analyzed in frames of local and non-local electron kinetics. It is shown, that contrary to the local case, typical for plasma in uniform electric field, there is the possibility for EEDF modification, at the condition of non-local electron kinetics in strongly non-uniform electric fields. Such conditions “naturally” occur in some self-organized steady state dc and rf discharge plasmas, and they suggest the variety of artificial methods for EEDF modification. EEDF modification and electron temperature control in non-equilibrium conditions occurring naturally and those stimulated by different kinds of plasma disturbances are illustrated with numerous experiments. The necessary conditions for EEDF modification in gas discharge plasmas are formulated

  18. Computing exact bundle compliance control charts via probability generating functions.

    Science.gov (United States)

    Chen, Binchao; Matis, Timothy; Benneyan, James

    2016-06-01

    Compliance to evidenced-base practices, individually and in 'bundles', remains an important focus of healthcare quality improvement for many clinical conditions. The exact probability distribution of composite bundle compliance measures used to develop corresponding control charts and other statistical tests is based on a fairly large convolution whose direct calculation can be computationally prohibitive. Various series expansions and other approximation approaches have been proposed, each with computational and accuracy tradeoffs, especially in the tails. This same probability distribution also arises in other important healthcare applications, such as for risk-adjusted outcomes and bed demand prediction, with the same computational difficulties. As an alternative, we use probability generating functions to rapidly obtain exact results and illustrate the improved accuracy and detection over other methods. Numerical testing across a wide range of applications demonstrates the computational efficiency and accuracy of this approach.

  19. Research on control function switch of nuclear power plant control room

    International Nuclear Information System (INIS)

    Mei Shibo; Mao Ting; Cheng Bo; Zhang Gang

    2014-01-01

    The nuclear power plant provides main control room (MCR) to the unit operators for the plant monitoring and control, and provides the remote shutdown station (RSS) as the back-up control room, which is used only when MCR is unavailable. The RSS could be used to monitor and control the plant, bring the plant into shutdown state and remove the residual heat. The command from MCR and RSS is blocked by each other and can not be executed at the same time. The operation mode switch function between MCR and RSS is carried out by MCR/RSS mode switches. The operation mode switch scheme of CPR1000, ERP and AP1000 were compared and researched, and some design bases for new nuclear power plant were submitted in this paper. These design bases could be referred during the design of control function switch for the new nuclear power plants, in order to put forward a more practical, simple, safe and convenient scheme. (authors)

  20. Functionalized scaffolds to control dental pulp stem cell fate

    Science.gov (United States)

    Piva, Evandro; Silva, Adriana F.; Nör, Jacques E.

    2014-01-01

    Emerging understanding about interactions between stem cells, scaffolds and morphogenic factors has accelerated translational research in the field of dental pulp tissue engineering. Dental pulp stem cells constitute a sub-population of cells endowed with self-renewal and multipotency. Dental pulp stem cells seeded in biodegradable scaffolds and exposed to dentin-derived morphogenic signals give rise to a pulp-like tissue capable of generating new dentin. Notably, dentin-derived proteins are sufficient to induce dental pulp stem cell differentiation into odontoblasts. Ongoing work is focused on developing ways of mobilizing dentin-derived proteins and disinfecting the root canal of necrotic teeth without compromising the morphogenic potential of these signaling molecules. On the other hand, dentin by itself does not appear to be capable of inducing endothelial differentiation of dental pulp stem cells, despite the well known presence of angiogenic factors in dentin. This is particularly relevant in the context of dental pulp tissue engineering in full root canals, where access to blood supply is limited to the apical foramina. To address this challenge, scientists are looking at ways to use the scaffold as a controlled release device for angiogenic factors. The aim of this manuscript is to present and discuss current strategies to functionalize injectable scaffolds and customize them for dental pulp tissue engineering. The long-term goal of this work is to develop stem cell-based therapies that enable the engineering of functional dental pulps capable of generating new tubular dentin in humans. PMID:24698691

  1. Functional MRI in human motor control studies and clinical applications

    International Nuclear Information System (INIS)

    Toma, Keiichiro

    2002-01-01

    Functional magnetic resonance imaging (fMRI) has been a useful tool for the noninvasive mapping of brain function associated with various motor and cognitive tasks. Because fMRI is based on the blood oxygenation level dependent (BOLD) effect, it does not directly record neural activity. With the fMRI technique, distinguishing BOLD signals creased by cortical projection neurons from those created by intracortical neurons appears to be difficult. Two major experimental designs are used in fMRI studies: block designs and event-related designs. Block-designed fMRI presupposes the steady state of regional cerebral blood flow and has been applied to examinations of brain activation caused by tasks requiring sustained or repetitive movements. By contrast, the more recently developed event-related fMRI with time resolution of a few seconds allows the mapping of brain activation associated with a single movement according to the transient aspects of the hemodynamic response. Increasing evidence suggests that multiple motor areas are engaged in a networked manner to execute various motor acts. In order to understand functional brain maps, it is important that one understands sequential and parallel organizations of anatomical connections between multiple motor areas. In fMRI studies of complex motor tasks, elementary parameters such as movement length, force, velocity, acceleration and frequency should be controlled, because inconsistency in those parameters may alter the extent and intensity of motor cortical activation, confounding interpretation of the findings obtained. In addition to initiation of movements, termination of movements plays an important role in the successful achievement of complex movements. Brain areas exclusively related to the termination of movements have been, for the first time, uncovered with an event-related fMRI technique. We propose the application of fMRI to the elucidation of the pathophysiology of movement disorders, particularly dystonia

  2. Functional MRI in human motor control studies and clinical applications

    Energy Technology Data Exchange (ETDEWEB)

    Toma, Keiichiro [Kyoto Univ. (Japan). Graduate School of Medicine; Nakai, Toshiharu [Inst. of Biomedical Research and Innovation, Kobe (Japan)

    2002-07-01

    Functional magnetic resonance imaging (fMRI) has been a useful tool for the noninvasive mapping of brain function associated with various motor and cognitive tasks. Because fMRI is based on the blood oxygenation level dependent (BOLD) effect, it does not directly record neural activity. With the fMRI technique, distinguishing BOLD signals creased by cortical projection neurons from those created by intracortical neurons appears to be difficult. Two major experimental designs are used in fMRI studies: block designs and event-related designs. Block-designed fMRI presupposes the steady state of regional cerebral blood flow and has been applied to examinations of brain activation caused by tasks requiring sustained or repetitive movements. By contrast, the more recently developed event-related fMRI with time resolution of a few seconds allows the mapping of brain activation associated with a single movement according to the transient aspects of the hemodynamic response. Increasing evidence suggests that multiple motor areas are engaged in a networked manner to execute various motor acts. In order to understand functional brain maps, it is important that one understands sequential and parallel organizations of anatomical connections between multiple motor areas. In fMRI studies of complex motor tasks, elementary parameters such as movement length, force, velocity, acceleration and frequency should be controlled, because inconsistency in those parameters may alter the extent and intensity of motor cortical activation, confounding interpretation of the findings obtained. In addition to initiation of movements, termination of movements plays an important role in the successful achievement of complex movements. Brain areas exclusively related to the termination of movements have been, for the first time, uncovered with an event-related fMRI technique. We propose the application of fMRI to the elucidation of the pathophysiology of movement disorders, particularly dystonia

  3. The 5-lipoxygenase inhibitor tepoxalin induces oxidative damage and altered PTEN status prior to apoptosis in canine osteosarcoma cell lines.

    Science.gov (United States)

    Loftus, J P; Cavatorta, D; Bushey, J J; Levine, C B; Sevier, C S; Wakshlag, J J

    2016-06-01

    The 5-lipoxygenase (5-LOX) inhibitor tepoxalin has been shown to slow canine osteosarcoma (OSA) tumour xenografts growth, yet the mechanisms are poorly elucidated. Further examination of tepoxalin in canine OSA cell lines shows that tepoxalin treated cells undergo apoptosis through caspase-3 activation and annexin staining. Interestingly, apoptosis is superseded by an increase in reactive oxygen species (ROS), as measured by activation of dihydrorhodamine 123 and mitosox. This increase in ROS appears to be related to the 5-LOX inhibitor regardless of cellular 5-LOX status, and was not observed after treatment with the tepoxalin metabolite RWJ20142. Additionally, 5-LOX inhibition by tepoxalin appears to increase phosphatase and tensin (PTEN) homolog activity by preventing its alkylation or oxidation. PTEN modification or inhibition allows phosphoinositide-3 (PI3) kinase activity thereby heightening activation of protein kinase B (AKT) phosphorylation. Our data suggest that off target oxidation and LOX inhibition play roles in the apoptotic response. © 2014 John Wiley & Sons Ltd.

  4. Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer.

    Science.gov (United States)

    Carver, Brett S; Chapinski, Caren; Wongvipat, John; Hieronymus, Haley; Chen, Yu; Chandarlapaty, Sarat; Arora, Vivek K; Le, Carl; Koutcher, Jason; Scher, Howard; Scardino, Peter T; Rosen, Neal; Sawyers, Charles L

    2011-05-17

    Prostate cancer is characterized by its dependence on androgen receptor (AR) and frequent activation of PI3K signaling. We find that AR transcriptional output is decreased in human and murine tumors with PTEN deletion and that PI3K pathway inhibition activates AR signaling by relieving feedback inhibition of HER kinases. Similarly, AR inhibition activates AKT signaling by reducing levels of the AKT phosphatase PHLPP. Thus, these two oncogenic pathways cross-regulate each other by reciprocal feedback. Inhibition of one activates the other, thereby maintaining tumor cell survival. However, combined pharmacologic inhibition of PI3K and AR signaling caused near-complete prostate cancer regressions in a Pten-deficient murine prostate cancer model and in human prostate cancer xenografts, indicating that both pathways coordinately support survival. Copyright © 2011 Elsevier Inc. All rights reserved.

  5. Review of selected dynamic material control functions for international safeguards

    International Nuclear Information System (INIS)

    Lowry, L.L.

    1980-09-01

    With the development of Dynamic Special Nuclear Material Accounting and Control systems used in nuclear manufacturing and reprocessing plants, there arises the question as to how these systems affect the IAEA inspection capabilities. The systems in being and under development provide information and control for a variety of purposes important to the plant operator, the safeguards purpose being one of them. This report attempts to judge the usefulness of these dynamic systems to the IAEA and have defined 12 functions that provide essential information to it. If the information acquired by these dynamic systems is to be useful to the IAEA, the inspectors must be able to independently verify it. Some suggestions are made as to how this might be done. But, even if it should not be possible to verify all the data, the availability to the IAEA of detailed, simultaneous, and plant-wide information would tend to inhibit a plant operator from attempting to generate a floating or fictitious inventory. Suggestions are made that might be helpful in the design of future software systems, an area which has proved to be fatally deficient in some systems and difficult in all

  6. Multi-function magnetic jack control drive mechanism

    International Nuclear Information System (INIS)

    Bollinger, L.R.; Crawford, D.C.

    1986-01-01

    A multi-function magnetic jack control drive mechanism is described for controlling a nuclear reactor comprising: an elongate pressure housing; closely-spaced drive rods located in the pressure housing, the drive rod being connected to a reactor rod which is insertable in a reactor core; electrochemical stationary latch means which are selectively actuatable for holding a respective one of the drive rods stationary with respect to the pressure housing, the plurality of stationary latch means including at least one coil located about the pressure housing; longitudinally spaced electromechanical movable latch means, individually associated with one of the drive rods and each including a base for the drive rod associated therewith, for, when actuated, holding the associated drive rod stationary with respect to the base associated therewith, the movable latch means including an associated coil located about the pressure housing; and longitudinally spaced electromechanical lift means, individually associated with the base, for, when actuated, moving an associated base longitudinally along the pressure housing from a first position to a second position to thereby enable movement of one or more of the other drive rods longitudinally independently of the other drive rods in response to sequential and repeated operation of the electromechanical means, the lift means including an associated coil located about the pressure housing

  7. Towards functional specification independent of control system suppliers

    International Nuclear Information System (INIS)

    Galara, D.; Leret, E.

    1997-01-01

    For the next nuclear power plant generation, REP 2000, the Engineering and construction Division (ED) and the Research and development Division (R and D) of Electricite de France are working together in the field of Instrumentation and Control (I and C) to improve its engineering method and tools. This method and these tools are defined on the basis of the experience feedback from the N4 nuclear power plant generation and the current information technology, to improve engineering competitiveness and quality of control applications. We intend to decouple the I and C processing from the I and C Human Machine Interface (HMI), because methods and tools are different. In this paper, we only focus on method and tools for I and C processing. We define the I and C processing life cycle into three phases. The first phase is the specification of the control application processing, the product of which is called Functional Requirement Diagrams (FRDs). The second phase is the design of the I and C system. This phase is subdivided into two steps. The step 1 is the distribution of the FRDs into an I and C architecture. The step 2 is the allocation of resources of the I and C system, to support the distributed FRDs. The third phase is the implementation of the distributed FRDs into I and C equipment. The aim of the Engineering Division is to achieve formal FRDs, independent of I and C suppliers. This allows a large improvement for the quality of the specification and the dimensioning of the I and C system before calls for tenders. For the specification phase, studies are almost completed. For the design and the implementation phases, studies and experiments are in progress with European I and C system suppliers. As a conclusion, we present the interest of EDF for standards and especially IEC 1131 improvements. (author). 5 figs

  8. PWR primary system chemistry control during hot functional testing

    International Nuclear Information System (INIS)

    Reid, Richard D.; Little, Michael J.

    2014-01-01

    Hot Functional Testing (HFT) involves a number of pre-operational exercises performed to confirm the operability of plant systems at conditions expected during both normal and off-normal operation of a pressurized water reactor (PWR), including operability of safety systems. While the primary purposes of HFT are to demonstrate operability of plant systems and satisfy regulatory requirements, chemistry control during HFT is important to long-term integrity and performance of plant systems. Specifically, HFT is the first time plant equipment is exposed to high temperature water and the chemistry maintained during HFT can impact the passivation layers that form on wetted surfaces and long-term release of metals from these surfaces. Metals released from the inner surfaces of steam generator tubing and reactor coolant loop piping become activated in the core and can redeposit on ex-core surfaces. Because HFT is performed before fuel is loaded in the core, HFT provides an opportunity to produce a passive layer on primary surfaces that is free of activated corrosion products, resistant to metals release during subsequent plant operation, and also resistant to incorporation of activated corrosion products (once fuel is loaded in the core). Thus, maintaining desirable primary chemistry control during HFT is important for source term management, minimization of future shutdown activity releases, minimization of dose rates, and asset preservation. This paper presents an overview of passive film formation in the austenitic stainless steel and high nickel alloys that make up the majority of the primary circuit in advanced PWR designs. Based on this information, a summary is provided of the effects on passive film formation of key chemistry parameters that may be controlled during HFT. (author)

  9. Towards functional specification independent of control system suppliers

    Energy Technology Data Exchange (ETDEWEB)

    Galara, D; Leret, E [Electricite de France, Research and Development Div., Power Plant Control Branch, Chatou (France)

    1997-07-01

    For the next nuclear power plant generation, REP 2000, the Engineering and construction Division (ED) and the Research and development Division (R and D) of Electricite de France are working together in the field of Instrumentation and Control (I and C) to improve its engineering method and tools. This method and these tools are defined on the basis of the experience feedback from the N4 nuclear power plant generation and the current information technology, to improve engineering competitiveness and quality of control applications. We intend to decouple the I and C processing from the I and C Human Machine Interface (HMI), because methods and tools are different. In this paper, we only focus on method and tools for I and C processing. We define the I and C processing life cycle into three phases. The first phase is the specification of the control application processing, the product of which is called Functional Requirement Diagrams (FRDs). The second phase is the design of the I and C system. This phase is subdivided into two steps. The step 1 is the distribution of the FRDs into an I and C architecture. The step 2 is the allocation of resources of the I and C system, to support the distributed FRDs. The third phase is the implementation of the distributed FRDs into I and C equipment. The aim of the Engineering Division is to achieve formal FRDs, independent of I and C suppliers. This allows a large improvement for the quality of the specification and the dimensioning of the I and C system before calls for tenders. For the specification phase, studies are almost completed. For the design and the implementation phases, studies and experiments are in progress with European I and C system suppliers. As a conclusion, we present the interest of EDF for standards and especially IEC 1131 improvements. (author). 5 figs.

  10. Cancer cell-oriented migration of mesenchymal stem cells engineered with an anticancer gene (PTEN: an imaging demonstration

    Directory of Open Access Journals (Sweden)

    Yang ZS

    2014-03-01

    Full Text Available Zhuo-Shun Yang,1,* Xiang-Jun Tang,2,* Xing-Rong Guo,1 Dan-Dan Zou,1 Xu-Yong Sun,3 Jing-Bo Feng,1 Jie Luo,1 Long-Jun Dai,1,4 Garth L Warnock4 1Hubei Key Laboratory of Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, People’s Republic of China; 2Department of Neurosurgery, Taihe Hospital, Hubei University of Medicine, Shiyan, People’s Republic of China; 3Guangxi Key Laboratory for Transplant Medicine, 303 Hospital of PLA, Nanning, People’s Republic of China; 4Department of Surgery, University of British Columbia, Vancouver, BC, Canada *These authors contributed equally to this work Background: Mesenchymal stem cells (MSCs have been considered to hold great potential as ideal carriers for the delivery of anticancer agents since the discovery of their tumor tropism. This study was performed to demonstrate the effects of phosphatase and tensin homolog (PTEN engineering on MSCs’ capacity for cancer cell-oriented migration. Methods: MSCs were engineered with a PTEN-bearing plasmid and the expression was confirmed with Western blotting. A human glioma cell line (DBTRG was used as the target cell; DBTRG cell-oriented migration of MSCs was monitored with a micro speed photographic system. Results: The expression of transfected PTEN in MSCs was identified by immunoblotting analysis and confirmed with cell viability assessment of target cells. The DBTRG cell-oriented migration of PTEN-engineered MSCs was demonstrated by a real-time dynamic monitoring system, and a phagocytosis-like action of MSCs was also observed. Conclusion: MSCs maintained their capacity for cancer cell-directed migration after they were engineered with anticancer genes. This study provides the first direct evidence of MSCs’ tropism post-anticancer gene engineering. Keywords: gene therapy, mesenchymal stem cells, phosphatase and tensin homolog, cancer

  11. MicroRNA-21 induces 5-fluorouracil resistance in human pancreatic cancer cells by regulating PTEN and PDCD4

    International Nuclear Information System (INIS)

    Wei, Xueju; Wang, Weibin; Wang, Lanlan; Zhang, Yuanyuan; Zhang, Xian; Chen, Mingtai; Wang, Fang; Yu, Jia; Ma, Yanni; Sun, Guotao

    2016-01-01

    Pancreatic cancer patients are often resistant to chemotherapy treatment, which results in poor prognosis. The objective of this study was to delineate the mechanism by which miR-21 induces drug resistance to 5-fluorouracil (5-FU) in human pancreatic cancer cells (PATU8988 and PANC-1). We report that PATU8988 cells resistant to 5-FU express high levels of miR-21 in comparison to sensitive primary PATU8988 cells. Suppression of miR-21 expression in 5-Fu-resistant PATU8988 cells can alleviate its 5-FU resistance. Meanwhile, lentiviral vector-mediated overexpression of miR-21 not only conferred resistance to 5-FU but also promoted proliferation, migration, and invasion of PATU8988 and PANC-1 cells. The proresistance effects of miR-21 were attributed to the attenuated expression of tumor suppressor genes, including PTEN and PDCD4. Overexpression of PTEN and PDCD4 antagonized miR-21-induced resistance to 5-FU and migration activity. Our work demonstrates that miR-21 can confer drug resistance to 5-FU in pancreatic cancer cells by regulating the expression of tumor suppressor genes, as the target genes of miR-21, PTEN and PDCD4 can rescue 5-FU sensitivity and the phenotypic characteristics disrupted by miR-21

  12. Resistance to EGF receptor inhibitors in glioblastoma mediated by phosphorylation of the PTEN tumor suppressor at tyrosine 240.

    Science.gov (United States)

    Fenton, Tim R; Nathanson, David; Ponte de Albuquerque, Claudio; Kuga, Daisuke; Iwanami, Akio; Dang, Julie; Yang, Huijun; Tanaka, Kazuhiro; Oba-Shinjo, Sueli Mieko; Uno, Miyuki; Inda, Maria del Mar; Wykosky, Jill; Bachoo, Robert M; James, C David; DePinho, Ronald A; Vandenberg, Scott R; Zhou, Huilin; Marie, Suely K N; Mischel, Paul S; Cavenee, Webster K; Furnari, Frank B

    2012-08-28

    Glioblastoma multiforme (GBM) is the most aggressive of the astrocytic malignancies and the most common intracranial tumor in adults. Although the epidermal growth factor receptor (EGFR) is overexpressed and/or mutated in at least 50% of GBM cases and is required for tumor maintenance in animal models, EGFR inhibitors have thus far failed to deliver significant responses in GBM patients. One inherent resistance mechanism in GBM is the coactivation of multiple receptor tyrosine kinases, which generates redundancy in activation of phosphoinositide-3'-kinase (PI3K) signaling. Here we demonstrate that the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor is frequently phosphorylated at a conserved tyrosine residue, Y240, in GBM clinical samples. Phosphorylation of Y240 is associated with shortened overall survival and resistance to EGFR inhibitor therapy in GBM patients and plays an active role in mediating resistance to EGFR inhibition in vitro. Y240 phosphorylation can be mediated by both fibroblast growth factor receptors and SRC family kinases (SFKs) but does not affect the ability of PTEN to antagonize PI3K signaling. These findings show that, in addition to genetic loss and mutation of PTEN, its modulation by tyrosine phosphorylation has important implications for the development and treatment of GBM.

  13. No direct association among respiratory function, disease control and family functioning in a sample of Mexican children with intermittent asthma.

    Science.gov (United States)

    Rodriguez-Orozco, Alain Raimundo; Núñez-Tapia, Rosa María; Ramírez-Silva, Armando; Gómez-Alonso, Carlos

    2013-05-15

    Asthma has been linked to family disfunctioning and poor control of the disease.This study was conducted to analyze the interactions between the level of intermittent asthma control, family functioning and respiratory function and between quality of life of asthmatic patients and their caregivers.7 to 15 years old children with intermittent asthma were included. Asthma Control Test Questionnaire, Pediatric Asthma Quality of Life Questionnaire (PAQLQ) test, and flowmetry were applied to children and Pediatric Asthma Caregiver´s Quatily of Life Questionnaire (PAQCLQ) and the Family Functioning Perception Test (FF-SIL) were applied to their parents.The most affected areas of family functioning in dysfunctional families were adaptability and permeability. A medium to high strength of association was founded between the emotional function of parents and the emotional function of children, R2=0.552. The most remarkable associations were among parents' limitation of activities and parents' emotional function (r=0.837), parents' limitation of activities and child's emotional function (r=0.722), parents' emotional role and limitation of activities (r=0.837), parents' emotional role and emotional functioning of children with asthma (r=0.743) and the limitation of activities of children with asthma and the emotional function of children with asthma (r=0.870).No direct associations were founded among respiratory function, disease control and family functioning in Mexican children with intermittent asthma and emotional function of parents and children were associated in both groups.

  14. Tools for functional analysis of faults and methods of fault-stable motion control

    International Nuclear Information System (INIS)

    Timofeev, A.V.

    2003-01-01

    In this article a big attention is given to the problems of functional diagnostics, when control and faults diagnostics are made in real time simultaneously in the process of functioning of controlled dynamical systems

  15. Controlled short-linkage assembly of functional nano-objects

    Energy Technology Data Exchange (ETDEWEB)

    Chaudhary, Shilpi; Kamra, Tripta [Division of Pure and Applied Biochemistry, Lund University, Box 124, 221 00 Lund (Sweden); ENI AB, Malmö (Sweden); Division of Synchrotron Radiation Research, Lund University, Box 118, 221 00 Lund (Sweden); Uddin, Khan Mohammad Ahsan [Division of Pure and Applied Biochemistry, Lund University, Box 124, 221 00 Lund (Sweden); Snezhkova, Olesia [Division of Synchrotron Radiation Research, Lund University, Box 118, 221 00 Lund (Sweden); Jayawardena, H. Surangi N. [Department of Chemistry, University of Massachusetts Lowell, 1 University Ave., Lowell, MA 01854 (United States); Yan, Mingdi [Department of Chemistry, University of Massachusetts Lowell, 1 University Ave., Lowell, MA 01854 (United States); Department of Chemistry, KTH – Royal Institute of Technology, Teknikringen 30, S-10044 Stockholm (Sweden); Montelius, Lars [ENI AB, Malmö (Sweden); Schnadt, Joachim, E-mail: joachim.schnadt@sljus.lu.se [Division of Synchrotron Radiation Research, Lund University, Box 118, 221 00 Lund (Sweden); Ye, Lei, E-mail: lei.ye@tbiokem.lth.se [Division of Pure and Applied Biochemistry, Lund University, Box 124, 221 00 Lund (Sweden)

    2014-05-01

    Graphical abstract: - Highlights: • Fast photoconjugation of nanoparticles on surface. • Non-destructive feature guarantees intact function of nanoparticles. • Direct contact between nano-objects allows efficient photon and electron transfer. • Possibility of generating patterned nanoparticle assemblies on surface. • Open new opportunities for assembling chemical sensors. - Abstract: In this work, we report a method that allows the deterministic, photo-controlled covalent assembly of nanoparticles directly on surface. As a model system, we study the conjugation of molecularly imprinted polymer (MIP) nanoparticles on a glass surface and confirm that the immobilized nanoparticles maintain their molecular recognition functionality. The glass slide was first modified with perfluorophenylazide and then used to bind MIP nanoparticles under UV irradiation. After each step the surface was analyzed by water contact angle measurement, fluorescence microscopy, scanning electron microscopy, and/or synchrotron-based X-ray photoelectron spectroscopy. The MIP nanoparticles immobilized on the glass surface remained stable and maintained specific binding for the template molecule, propranolol. The method developed in this work allows MIP nanoparticles to be directly coupled to a flat surface, offering a straightforward means to construct robust chemical sensors. Using the reported photo conjugation method, it is possible to generate patterned assembly of nanoparticles using a photomask. Since perfluorophenylazide-based photochemistry works with all kinds of organic material, the method developed in this work is expected to enable immobilization of not only MIPs but also other kinds of organic and inorganic–organic core–shell particles for various applications involving photon or electron transfer.

  16. Rac1 Regulates Endometrial Secretory Function to Control Placental Development.

    Directory of Open Access Journals (Sweden)

    Juanmahel Davila

    2015-08-01

    Full Text Available During placenta development, a succession of complex molecular and cellular interactions between the maternal endometrium and the developing embryo ensures reproductive success. The precise mechanisms regulating this maternal-fetal crosstalk remain unknown. Our study revealed that the expression of Rac1, a member of the Rho family of GTPases, is markedly elevated in mouse decidua on days 7 and 8 of gestation. To investigate its function in the uterus, we created mice bearing a conditional deletion of the Rac1 gene in uterine stromal cells. Ablation of Rac1 did not affect the formation of the decidua but led to fetal loss in mid gestation accompanied by extensive hemorrhage. To gain insights into the molecular pathways affected by the loss of Rac1, we performed gene expression profiling which revealed that Rac1 signaling regulates the expression of Rab27b, another GTPase that plays a key role in targeting vesicular trafficking. Consequently, the Rac1-null decidual cells failed to secrete vascular endothelial growth factor A, which is a critical regulator of decidual angiogenesis, and insulin-like growth factor binding protein 4, which regulates the bioavailability of insulin-like growth factors that promote proliferation and differentiation of trophoblast cell lineages in the ectoplacental cone. The lack of secretion of these key factors by Rac1-null decidua gave rise to impaired angiogenesis and dysregulated proliferation of trophoblast cells, which in turn results in overexpansion of the trophoblast giant cell lineage and disorganized placenta development. Further experiments revealed that RAC1, the human ortholog of Rac1, regulates the secretory activity of human endometrial stromal cells during decidualization, supporting the concept that this signaling G protein plays a central and conserved role in controlling endometrial secretory function. This study provides unique insights into the molecular mechanisms regulating endometrial secretions

  17. Rac1 Regulates Endometrial Secretory Function to Control Placental Development

    Science.gov (United States)

    Davila, Juanmahel; Laws, Mary J.; Kannan, Athilakshmi; Li, Quanxi; Taylor, Robert N.; Bagchi, Milan K.; Bagchi, Indrani C.

    2015-01-01

    During placenta development, a succession of complex molecular and cellular interactions between the maternal endometrium and the developing embryo ensures reproductive success. The precise mechanisms regulating this maternal-fetal crosstalk remain unknown. Our study revealed that the expression of Rac1, a member of the Rho family of GTPases, is markedly elevated in mouse decidua on days 7 and 8 of gestation. To investigate its function in the uterus, we created mice bearing a conditional deletion of the Rac1 gene in uterine stromal cells. Ablation of Rac1 did not affect the formation of the decidua but led to fetal loss in mid gestation accompanied by extensive hemorrhage. To gain insights into the molecular pathways affected by the loss of Rac1, we performed gene expression profiling which revealed that Rac1 signaling regulates the expression of Rab27b, another GTPase that plays a key role in targeting vesicular trafficking. Consequently, the Rac1-null decidual cells failed to secrete vascular endothelial growth factor A, which is a critical regulator of decidual angiogenesis, and insulin-like growth factor binding protein 4, which regulates the bioavailability of insulin-like growth factors that promote proliferation and differentiation of trophoblast cell lineages in the ectoplacental cone. The lack of secretion of these key factors by Rac1-null decidua gave rise to impaired angiogenesis and dysregulated proliferation of trophoblast cells, which in turn results in overexpansion of the trophoblast giant cell lineage and disorganized placenta development. Further experiments revealed that RAC1, the human ortholog of Rac1, regulates the secretory activity of human endometrial stromal cells during decidualization, supporting the concept that this signaling G protein plays a central and conserved role in controlling endometrial secretory function. This study provides unique insights into the molecular mechanisms regulating endometrial secretions that mediate stromal

  18. Controlled short-linkage assembly of functional nano-objects

    International Nuclear Information System (INIS)

    Chaudhary, Shilpi; Kamra, Tripta; Uddin, Khan Mohammad Ahsan; Snezhkova, Olesia; Jayawardena, H. Surangi N.; Yan, Mingdi; Montelius, Lars; Schnadt, Joachim; Ye, Lei

    2014-01-01

    Graphical abstract: - Highlights: • Fast photoconjugation of nanoparticles on surface. • Non-destructive feature guarantees intact function of nanoparticles. • Direct contact between nano-objects allows efficient photon and electron transfer. • Possibility of generating patterned nanoparticle assemblies on surface. • Open new opportunities for assembling chemical sensors. - Abstract: In this work, we report a method that allows the deterministic, photo-controlled covalent assembly of nanoparticles directly on surface. As a model system, we study the conjugation of molecularly imprinted polymer (MIP) nanoparticles on a glass surface and confirm that the immobilized nanoparticles maintain their molecular recognition functionality. The glass slide was first modified with perfluorophenylazide and then used to bind MIP nanoparticles under UV irradiation. After each step the surface was analyzed by water contact angle measurement, fluorescence microscopy, scanning electron microscopy, and/or synchrotron-based X-ray photoelectron spectroscopy. The MIP nanoparticles immobilized on the glass surface remained stable and maintained specific binding for the template molecule, propranolol. The method developed in this work allows MIP nanoparticles to be directly coupled to a flat surface, offering a straightforward means to construct robust chemical sensors. Using the reported photo conjugation method, it is possible to generate patterned assembly of nanoparticles using a photomask. Since perfluorophenylazide-based photochemistry works with all kinds of organic material, the method developed in this work is expected to enable immobilization of not only MIPs but also other kinds of organic and inorganic–organic core–shell particles for various applications involving photon or electron transfer

  19. Adaptive Functional-Based Neuro-Fuzzy-PID Incremental Controller Structure

    Directory of Open Access Journals (Sweden)

    Ashraf Ahmed Fahmy

    2014-03-01

    Full Text Available This paper presents an adaptive functional-based Neuro-fuzzy-PID incremental (NFPID controller structure that can be tuned either offline or online according to required controller performance. First, differential membership functions are used to represent the fuzzy membership functions of the input-output space of the three term controller. Second, controller rules are generated based on the discrete proportional, derivative, and integral function for the fuzzy space. Finally, a fully differentiable fuzzy neural network is constructed to represent the developed controller for either offline or online controller parameter adaptation.  Two different adaptation methods are used for controller tuning, offline method based on controller transient performance cost function optimization using Bees Algorithm, and online method based on tracking error minimization using back-propagation with momentum algorithm. The proposed control system was tested to show the validity of the controller structure over a fixed PID controller gains to control SCARA type robot arm.

  20. FIT for FUNCTION: study protocol for a randomized controlled trial.

    Science.gov (United States)

    Richardson, Julie; Tang, Ada; Guyatt, Gordon; Thabane, Lehana; Xie, Feng; Sahlas, Demetrios; Hart, Robert; Fleck, Rebecca; Hladysh, Genevieve; Macrae, Louise

    2018-01-15

    The current state of evidence suggests that community-based exercise programs are beneficial in improving impairment, function, and health status, and are greatly needed for persons with stroke. However, limitations of these studies include risk of bias, feasibility, and cost issues. This single-blinded, randomized controlled trial (RCT) of 216 participants with stroke will compare the effectiveness of a 12-week YMCA community-based wellness program (FIT for FUNCTION) specifically designed for community-dwelling persons with stroke to persons who receive a standard YMCA membership. The primary outcome will be community reintegration using the Reintegration to Normal Living Index at 12 and 24 weeks. Secondary outcomes include measurement of physical activity level using the Rapid Assessment of Physical Activity and accelerometry; balance using the Berg Balance Scale; lower extremity function using the Short Physical Performance Battery; exercise capacity using the 6-min walk test; grip strength and isometric knee extension strength using hand held dynamometry; and health-related quality of life using the European Quality of Life 5-Dimension Questionnaire. We are also assessing cardiovascular health and lipids; glucose and inflammatory markers will be collected following 12-h fast for total cholesterol, insulin, glucose, and glycated hemoglobin. Self-efficacy for physical activity will be assessed with a single question and self-efficacy for managing chronic disease will be assessed using the Stanford 6-item Scale. The Patient Activation Measure will be used to assess the patient's level of knowledge, skill, and confidence for self-management. Healthcare utilization and costs will be evaluated. Group, time, and group × time interaction effects will be estimated using generalized linear models for continuous variables, including relevant baseline variables as covariates in the analysis that differ appreciably between groups at baseline. Cost data will be treated

  1. Cell surface area and membrane folding in glioblastoma cell lines differing in PTEN and p53 status.

    Directory of Open Access Journals (Sweden)

    Simon Memmel

    Full Text Available Glioblastoma multiforme (GBM is characterized by rapid growth, invasion and resistance to chemo-/radiotherapy. The complex cell surface morphology with abundant membrane folds, microvilli, filopodia and other membrane extensions is believed to contribute to the highly invasive behavior and therapy resistance of GBM cells. The present study addresses the mechanisms leading to the excessive cell membrane area in five GBM lines differing in mutational status for PTEN and p53. In addition to scanning electron microscopy (SEM, the membrane area and folding were quantified by dielectric measurements of membrane capacitance using the single-cell electrorotation (ROT technique. The osmotic stability and volume regulation of GBM cells were analyzed by video microscopy. The expression of PTEN, p53, mTOR and several other marker proteins involved in cell growth and membrane synthesis were examined by Western blotting. The combined SEM, ROT and osmotic data provided independent lines of evidence for a large variability in membrane area and folding among tested GBM lines. Thus, DK-MG cells (wild type p53 and wild type PTEN exhibited the lowest degree of membrane folding, probed by the area-specific capacitance C m = 1.9 µF/cm(2. In contrast, cell lines carrying mutations in both p53 and PTEN (U373-MG and SNB19 showed the highest C m values of 3.7-4.0 µF/cm(2, which corroborate well with their heavily villated cell surface revealed by SEM. Since PTEN and p53 are well-known inhibitors of mTOR, the increased membrane area/folding in mutant GBM lines may be related to the enhanced protein and lipid synthesis due to a deregulation of the mTOR-dependent downstream signaling pathway. Given that membrane folds and extensions are implicated in tumor cell motility and metastasis, the dielectric approach presented here provides a rapid and simple tool for screening the biophysical cell properties in studies on targeting chemo- or radiotherapeutically the

  2. Odontogenic ameloblast-associated protein (ODAM) inhibits growth and migration of human melanoma cells and elicits PTEN elevation and inactivation of PI3K/AKT signaling

    International Nuclear Information System (INIS)

    Foster, James S; Fish, Lindsay M; Phipps, Jonathan E; Bruker, Charles T; Lewis, James M; Bell, John L; Solomon, Alan; Kestler, Daniel P

    2013-01-01

    The Odontogenic Ameloblast-associated Protein (ODAM) is expressed in a wide range of normal epithelial, and neoplastic tissues, and we have posited that ODAM serves as a novel prognostic biomarker for breast cancer and melanoma. Transfection of ODAM into breast cancer cells yields suppression of cellular growth, motility, and in vivo tumorigenicity. Herein we have extended these studies to the effects of ODAM on cultured melanoma cell lines. The A375 and C8161 melanoma cell lines were stably transfected with ODAM and assayed for properties associated with tumorigenicity including cell growth, motility, and extracellular matrix adhesion. In addition, ODAM–transfected cells were assayed for signal transduction via AKT which promotes cell proliferation and survival in many neoplasms. ODAM expression in A375 and C8161 cells strongly inhibited cell growth and motility in vitro, increased cell adhesion to extracellular matrix, and yielded significant cytoskeletal/morphologic rearrangement. Furthermore, AKT activity was downregulated by ODAM expression while an increase was noted in expression of the PTEN (phosphatase and tensin homolog on chromosome 10) tumor suppressor gene, an antagonist of AKT activation. Increased PTEN in ODAM-expressing cells was associated with increases in PTEN mRNA levels and de novo protein synthesis. Silencing of PTEN expression yielded recovery of AKT activity in ODAM-expressing melanoma cells. Similar PTEN elevation and inhibition of AKT by ODAM was observed in MDA-MB-231 breast cancer cells while ODAM expression had no effect in PTEN-deficient BT-549 breast cancer cells. The apparent anti-neoplastic effects of ODAM in cultured melanoma and breast cancer cells are associated with increased PTEN expression, and suppression of AKT activity. This association should serve to clarify the clinical import of ODAM expression and any role it may serve as an indicator of tumor behavior

  3. Navigation control of a multi-functional eye robot

    International Nuclear Information System (INIS)

    Ali, F.A.M.; Hashmi, B.; Younas, A.; Abid, B.

    2016-01-01

    The advancement in robotic field is enhanced rigorously in the past Few decades. Robots are being used in different fields of science as well as warfare. The research shows that in the near future, robots would be able to serve in fighting wars. Different countries and their armies have already deployed several military robots. However, there exist some drawbacks of robots like their inefficiency and inability to work under abnormal conditions. Ascent of artificial intelligence may resolve this issue in the coming future. The main focus of this paper is to provide a low cost and long range most efficient mechanical as well as software design of an Eye Robot. Using a blend of robotics and image processing with an addition of artificial intelligence path navigation techniques, this project is designed and implemented by controlling the robot (including robotic arm and camera) through a 2.4 GHz RF module manually. Autonomous function of the robot includes navigation based on the path assigned to the robot. The path is drawn on a VB based application and then transferred to the robot wirelessly or through serial port. A Wi-Fi based Optical Character Recognition (OCR) implemented video streaming can also be observed at remote devices like laptops. (author)

  4. Kinetic modelling of in vitro data of PI3K, mTOR1, PTEN enzymes and on-target inhibitors Rapamycin, BEZ235, and LY294002.

    Science.gov (United States)

    Goltsov, Alexey; Tashkandi, Ghassan; Langdon, Simon P; Harrison, David J; Bown, James L

    2017-01-15

    The phosphatidylinositide 3-kinases (PI3K) and mammalian target of rapamycin-1 (mTOR1) are two key targets for anti-cancer therapy. Predicting the response of the PI3K/AKT/mTOR1 signalling pathway to targeted therapy is made difficult because of network complexities. Systems biology models can help explore those complexities but the value of such models is dependent on accurate parameterisation. Motivated by a need to increase accuracy in kinetic parameter estimation, and therefore the predictive power of the model, we present a framework to integrate kinetic data from enzyme assays into a unified enzyme kinetic model. We present exemplar kinetic models of PI3K and mTOR1, calibrated on in vitro enzyme data and founded on Michaelis-Menten (MM) approximation. We describe the effects of an allosteric mTOR1 inhibitor (Rapamycin) and ATP-competitive inhibitors (BEZ235 and LY294002) that show dual inhibition of mTOR1 and PI3K. We also model the kinetics of phosphatase and tensin homolog (PTEN), which modulates sensitivity of the PI3K/AKT/mTOR1 pathway to these drugs. Model validation with independent data sets allows investigation of enzyme function and drug dose dependencies in a wide range of experimental conditions. Modelling of the mTOR1 kinetics showed that Rapamycin has an IC 50 independent of ATP concentration and that it is a selective inhibitor of mTOR1 substrates S6K1 and 4EBP1: it retains 40% of mTOR1 activity relative to 4EBP1 phosphorylation and inhibits completely S6K1 activity. For the dual ATP-competitive inhibitors of mTOR1 and PI3K, LY294002 and BEZ235, we derived the dependence of the IC 50 on ATP concentration that allows prediction of the IC 50 at different ATP concentrations in enzyme and cellular assays. Comparison of drug effectiveness in enzyme and cellular assays showed that some features of these drugs arise from signalling modulation beyond the on-target action and MM approximation and require a systems-level consideration of the whole PI3K/PTEN

  5. Doxycyclin ameliorates a starvation-induced germline tumor in C. elegans daf-18/PTEN mutant background.

    Science.gov (United States)

    Wolf, Tim; Qi, Wenjing; Schindler, Verena; Runkel, Eva Diana; Baumeister, Ralf

    2014-08-01

    Managing available resources is a key necessity of each organism to cope with the environment. The nematode C. elegans responds to nutritional deprivation or harsh environmental conditions with a multitude of developmental adaptations, among them a starvation-induced quiescence at early larval development (L1). daf-18, the C. elegans homolog of the human tumor suppressor gene PTEN, is essential for the maintenance of survival and germline stem cell arrest during the L1 diapause. We show here that daf-18 mutants, independently to their failure to maintain G2 arrest of the primordial germ cells, develop a gonad phenotype after refeeding. This highly penetrant gonadal phenotype is further enhanced by a mutation in shc-1, encoding a protein homologous to the human adaptor ShcA. Features of this phenotype are a tumor-like phenotype encompassing hyper-proliferation of germ cell nuclei and disruption/invasion of the basement membrane surrounding the gonad. The penetrance of this phenotype is reduced by decreasing starvation temperature. In addition, it is also ameliorated in a dose-dependent way by exposure to the antibiotic doxycyclin either during starvation or during subsequent refeeding. Since, in eukaryotic cells, doxycyclin specifically blocks mitochondrial translation, our results suggest that daf-18 and shc-1;daf-18 mutants fail to adapt mitochondrial activity to reduced nutritional availability during early larval developing. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. Mitochondrial respiration controls lysosomal function during inflammatory T cell responses

    Science.gov (United States)

    Baixauli, Francesc; Acín-Pérez, Rebeca; Villarroya-Beltrí, Carolina; Mazzeo, Carla; Nuñez-Andrade, Norman; Gabandé-Rodriguez, Enrique; Dolores Ledesma, Maria; Blázquez, Alberto; Martin, Miguel Angel; Falcón-Pérez, Juan Manuel; Redondo, Juan Miguel; Enríquez, Jose Antonio; Mittelbrunn, Maria

    2016-01-01

    Summary The endolysosomal system is critical for the maintenance of cellular homeostasis. However, how endolysosomal compartment is regulated by mitochondrial function is largely unknown. We have generated a mouse model with defective mitochondrial function in CD4+ T lymphocytes by genetic deletion of the mitochondrial transcription factor A (Tfam). Mitochondrial respiration-deficiency impairs lysosome function, promotes p62 and sphingomyelin accumulation and disrupts endolysosomal trafficking pathways and autophagy, thus linking a primary mitochondrial dysfunction to a lysosomal storage disorder. The impaired lysosome function in Tfam-deficient cells subverts T cell differentiation toward pro-inflammatory subsets and exacerbates the in vivo inflammatory response. Restoration of NAD+ levels improves lysosome function and corrects the inflammatory defects in Tfam-deficient T cells. Our results uncover a mechanism by which mitochondria regulate lysosome function to preserve T cell differentiation and effector functions, and identify novel strategies for intervention in mitochondrial-related diseases. PMID:26299452

  7. A Transition Zone Showing Highly Discontinuous or Alternating Levels of Stem Cell and Proliferation Markers Characterizes the Development of PTEN-Haploinsufficient Colorectal Cancer.

    Science.gov (United States)

    Arvai, Kevin J; Hsu, Ya-Hsuan; Lee, Lobin A; Jones, Dan

    2015-01-01

    Stepwise acquisition of oncogene mutations and deletion/inactivation of tumor suppressor genes characterize the development of colorectal cancer (CRC). These genetic events interact with discrete morphologic transitions from hyperplastic mucosa to adenomatous areas, followed by in situ malignant transformation and finally invasive carcinoma. The goal of this study was to identify tissue markers of the adenoma-carcinoma morphogenetic transitions in CRC. We analyzed the patterns of expression of growth regulatory and stem cell markers across these distinct morphologic transition zones in 735 primary CRC tumors. In 202 cases with preserved adenoma-adenocarcinoma transition, we identified, in 37.1% of cases, a zone of adenomatous epithelium, located immediately adjacent to the invasive component, that showed rapidly alternating intraglandular stretches of PTEN+ and PTEN- epithelium. This zone exactly overlapped with similar alternating expression of Ki-67 and inversely with the transforming growth factor-beta (TGF-β) growth regulator SMAD4. These zones also show parallel alternating levels and/or subcellular localization of multiple cancer stem/progenitor cell (CSC) markers, including β-catenin/CTNNB1, ALDH1, and CD44. PTEN was always re-expressed in the invasive tumor in these cases, unlike those with complete loss of PTEN expression. Genomic microarray analysis of CRC with prominent CSC-like expansions demonstrated a high frequency of PTEN genomic deletion/haploinsufficiency in tumors with CSC-like transition zones (62.5%) but not in tumors with downregulated but non-alternating PTEN expression (14.3%). There were no significant differences in the levels of KRAS mutation or CTNNB1 mutation in CSC-like tumors as compared to unselected CRC cases. In conclusion, we have identified a distinctive CSC-like pre-invasive transition zone in PTEN-haploinsufficient CRC that shows convergent on-off regulation of the PTEN/AKT, TGF-β/SMAD and Wnt/β-catenin pathways. This

  8. A Transition Zone Showing Highly Discontinuous or Alternating Levels of Stem Cell and Proliferation Markers Characterizes the Development of PTEN-Haploinsufficient Colorectal Cancer.

    Directory of Open Access Journals (Sweden)

    Kevin J Arvai

    Full Text Available Stepwise acquisition of oncogene mutations and deletion/inactivation of tumor suppressor genes characterize the development of colorectal cancer (CRC. These genetic events interact with discrete morphologic transitions from hyperplastic mucosa to adenomatous areas, followed by in situ malignant transformation and finally invasive carcinoma. The goal of this study was to identify tissue markers of the adenoma-carcinoma morphogenetic transitions in CRC.We analyzed the patterns of expression of growth regulatory and stem cell markers across these distinct morphologic transition zones in 735 primary CRC tumors. In 202 cases with preserved adenoma-adenocarcinoma transition, we identified, in 37.1% of cases, a zone of adenomatous epithelium, located immediately adjacent to the invasive component, that showed rapidly alternating intraglandular stretches of PTEN+ and PTEN- epithelium. This zone exactly overlapped with similar alternating expression of Ki-67 and inversely with the transforming growth factor-beta (TGF-β growth regulator SMAD4. These zones also show parallel alternating levels and/or subcellular localization of multiple cancer stem/progenitor cell (CSC markers, including β-catenin/CTNNB1, ALDH1, and CD44. PTEN was always re-expressed in the invasive tumor in these cases, unlike those with complete loss of PTEN expression. Genomic microarray analysis of CRC with prominent CSC-like expansions demonstrated a high frequency of PTEN genomic deletion/haploinsufficiency in tumors with CSC-like transition zones (62.5% but not in tumors with downregulated but non-alternating PTEN expression (14.3%. There were no significant differences in the levels of KRAS mutation or CTNNB1 mutation in CSC-like tumors as compared to unselected CRC cases.In conclusion, we have identified a distinctive CSC-like pre-invasive transition zone in PTEN-haploinsufficient CRC that shows convergent on-off regulation of the PTEN/AKT, TGF-β/SMAD and Wnt

  9. Effect of 17-allylamino-17-demethoxygeldanamycin (17-AAG) on Akt protein expression is more effective in head and neck cancer cell lineages that retain PTEN protein expression.

    Science.gov (United States)

    Pontes, Flávia Sirotheau C; Pontes, Hélder A R; de Souza, Lucas L; de Jesus, Adriana S; Joaquim, Andrea M C; Miyahara, Ligia A N; Fonseca, Felipe P; Pinto Junior, Décio S

    2018-03-01

    The aim of this study was to evaluate the expression of Akt, PTEN, Mdm2 and p53 proteins in three different head and neck squamous cell carcinoma (HNSCC) cell lines (HN6, HN19 and HN30), all of them treated with epidermal growth factor (EGF) and 17-allylamino-17-demethoxygeldanamycin (17-AAG), an inhibitor of Hsp90 protein. Immunofluorescence and western blot were performed in order to analyze the location and quantification, respectively, of proteins under the action 17-AAG and EGF. Treatment with EGF resulted in increased levels of Akt, PTEN and p53 in all cell lineages. The expression of Mdm2 was constant in HN30 and HN6 lineages, while in HN19 showed slightly decreased expression. Under the action 17-AAG, in HN6 and HN19, the expression of PTEN and p53 proteins was suppressed, while Akt and Mdm2 expression was reduced. Finally, in the HN30 cell lineage were absolute absence of expression of Akt, Mdm2 and p53 and decreased expression of PTEN. These data allow us to speculate on the particular utility of 17-AAG for HNSCC treatment through the inhibition of Akt protein expression, especially in the cases that retain the expression of PTEN protein. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  10. Design of Connectivity Preserving Flocking Using Control Lyapunov Function

    OpenAIRE

    Erfianto, Bayu; Bambang, Riyanto T.; Hindersah, Hilwadi; Muchtadi-Alamsyah, Intan

    2016-01-01

    This paper investigates cooperative flocking control design with connectivity preserving mechanism. During flocking, interagent distance is measured to determine communication topology of the flocks. Then, cooperative flocking motion is built based on cooperative artificial potential field with connectivity preserving mechanism to achieve the common flocking objective. The flocking control input is then obtained by deriving cooperative artificial potential field using control Lyapunov functio...

  11. Functional Neuroimaging of Motor Control inParkinson’s Disease

    DEFF Research Database (Denmark)

    Herz, Damian M; Eickhoff, Simon B; Løkkegaard, Annemette

    2014-01-01

    Functional neuroimaging has been widely used to study the activation patterns of the motor network in patients with Parkinson's disease (PD), but these studies have yielded conflicting results. This meta-analysis of previous neuroimaging studies was performed to identify patterns of abnormal...... movement-related activation in PD that were consistent across studies. We applied activation likelihood estimation (ALE) of functional neuroimaging studies probing motor function in patients with PD. The meta-analysis encompassed data from 283 patients with PD reported in 24 functional neuroimaging studies...

  12. Adaptive Control and Function Projective Synchronization in 2D Discrete-Time Chaotic Systems

    International Nuclear Information System (INIS)

    Li Yin; Chen Yong; Li Biao

    2009-01-01

    This study addresses the adaptive control and function projective synchronization problems between 2D Rulkov discrete-time system and Network discrete-time system. Based on backstepping design with three controllers, a systematic, concrete and automatic scheme is developed to investigate the function projective synchronization of discrete-time chaotic systems. In addition, the adaptive control function is applied to achieve the state synchronization of two discrete-time systems. Numerical results demonstrate the effectiveness of the proposed control scheme.

  13. Conditions for the existence of control functions in nonseparable simultaneous equations models

    OpenAIRE

    Blundell, Richard; Matzkin, Rosa L.

    2010-01-01

    The control function approach (Heckman and Robb (1985)) in a system of linear simultaneous equations provides a convenient procedure to estimate one of the functions in the system using reduced form residuals from the other functions as additional regressors. The conditions on the structural system under which this procedure can be used in nonlinear and nonparametric simultaneous equations has thus far been unknown. In this note, we define a new property of functions called control function s...

  14. Computer Simulation Tests of Feedback Error Learning Controller with IDM and ISM for Functional Electrical Stimulation in Wrist Joint Control

    OpenAIRE

    Watanabe, Takashi; Sugi, Yoshihiro

    2010-01-01

    Feedforward controller would be useful for hybrid Functional Electrical Stimulation (FES) system using powered orthotic devices. In this paper, Feedback Error Learning (FEL) controller for FES (FEL-FES controller) was examined using an inverse statics model (ISM) with an inverse dynamics model (IDM) to realize a feedforward FES controller. For FES application, the ISM was tested in learning off line using training data obtained by PID control of very slow movements. Computer simulation tests ...

  15. Control-flow analysis of function calls and returns by abstract interpretation

    DEFF Research Database (Denmark)

    Midtgaard, Jan; Jensen, Thomas P.

    2012-01-01

    Abstract interpretation techniques are used to derive a control-flow analysis for a simple higher-order functional language. The analysis approximates the interprocedural control-flow of both function calls and returns in the presence of first-class functions and tail-call optimization. In additi...... a rational reconstruction of a constraint-based CFA from abstract interpretation principles....

  16. Bi-phasic regulation of glycogen content in astrocytes via Cav-1/PTEN/PI3K/AKT/GSK-3β pathway by fluoxetine.

    Science.gov (United States)

    Bai, Qiufang; Song, Dan; Gu, Li; Verkhratsky, Alexei; Peng, Liang

    2017-04-01

    Here, we present the data indicating that chronic treatment with fluoxetine regulates Cav-1/PTEN/PI3K/AKT/GSK-3β signalling pathway and glycogen content in primary cultures of astrocytes with bi-phasic concentration dependence. At lower concentrations, fluoxetine downregulates gene expression of Cav-1, decreases membrane content of PTEN, increases activity of PI3K/AKT, and elevates GSK-3β phosphorylation thus suppressing its activity. At higher concentrations, fluoxetine acts in an inverse fashion. As expected, fluoxetine at lower concentrations increased while at higher concentrations decreased glycogen content in astrocytes. Our findings indicate that bi-phasic regulation of glycogen content via Cav-1/PTEN/PI3K/AKT/GSK-3β pathway by fluoxetine may be responsible for both therapeutic and side effects of the drug.

  17. New control system: distribution of the GANICIEL functions

    International Nuclear Information System (INIS)

    David, L.; Lecorche, E.

    1992-01-01

    This report describes the material configurations of the various processors, and of the distribution between them of the different software functions which constitute the GANICIEL. (A.B.). 9 refs., 4 figs

  18. Decomposing Objectives and Functions in Power System Operation and Control

    DEFF Research Database (Denmark)

    Heussen, Kai; Lind, Morten

    2009-01-01

    mix of challenges posed by renewable energy sources, demand response technologies and smartgrid concepts, affecting all areas of power system operation. Both, new control modes and changes in market design are required. This paper presents a mean-ends perspective to the analysis of the control......The introduction of many new energy solutions requires the adaptation of classical operation paradigms in power systems. In the standard paradigm, a power system is some equivalent of a synchronous generators, a power line and an uncontrollable load. This paradigm has been challenged by a diverse...... structures and operation paradigms in present power systems. In a top-down approach, traditional frequency- and area-control mechanisms are formalized. It is demonstrated that future power system operation paradigms with different generation control modes and controllable demand can be modeled in a coherent...

  19. SPINK1 Overexpression in Localized Prostate Cancer: a Rare Event Inversely Associated with ERG Expression and Exclusive of Homozygous PTEN Deletion.

    Science.gov (United States)

    Huang, Kuo-Cheng; Evans, Andrew; Donnelly, Bryan; Bismar, Tarek A

    2017-04-01

    SPINK1 is proposed as potential prognostic marker in prostate cancer (PCA). However, its relation to PTEN and ERG in localized PCA remains unclear. The study population consisted of two independent cohorts of men treated by radical prostatectomy for localized PCA (discovery n = 218 and validation n = 129). Patterns of association between SPINK1 and each of ERG and PTEN were evaluated by immunohistochemistry and fluorescence in situ hybridization. Associations between SPINK1 expression and various pathologic parameters and clinical outcome were also investigated. SPINK1 was expressed in 15.3 % and 10.9 % of cases in the discovery and validation cohort, respectively. SPINK expression was observed in 5.56 % of high-grade prostatic intraepithelial neoplasia and 1.1 % of adjacent morphologically benign prostatic glands. SPINK1 and ERG expression were almost exclusive, with only 1.0 % of the cases co-expressing both in the same core sample. SPINK1 interfocal and within-core heterogeneity was noted in 29.2 % and 64.6 % of cases, respectively. SPINK1 expression was not significantly associated with PTEN deletion in the two cohorts (p = 0.871 for discovery cohort and p = 0.293 for validation cohort). While SPINK1 expression did occur with hemizygous PTEN deletion, there was a complete absence of SPINK1 expression in PCA showing homozygous PTEN deletion, which was confirmed in the validation cohort (p = 0.02). Despite SPINK1's association with higher Gleason score (>7) (p = 0.02), it was not associated with other pathological parameters or biochemical recurrence post-radical prostatectomy. We documented absolute exclusivity between SPINK1 overexpression and homozygous PTEN deletion in localized PCA. SPINK1 and ERG expressions are exclusive events in PCA. SPINK1 is not of added prognostic value in localized PCA.

  20. Adaptive Incentive Controls for Stackelberg Games with Unknown Cost Functionals.

    Science.gov (United States)

    1984-01-01

    APR EZT:: F I AN 73S e OsL:-: UNCLASSI?:-- Q4~.’~- .A.., 6, *~*i i~~*~~*.- U ADAPTIVE INCENTIVE CONTROLS FOR STACKELBERG GAMES WITH UNKNOWN COST...AD-A161 885 ADAPTIVE INCENTIVE CONTROLS FOR STACKELBERG GAMES WITH i/1 UNKNOWN COST FUNCTIONALSCU) ILLINOIS UNIV AT URBANA DECISION AND CONTROL LAB T...ORGANIZATION 6b. OFFICE SYMBOL 7.. NAME OF MONITORING ORGANIZATION CoriaeLcenef~pda~ Joint Services Electronics Program Laboratory, Univ. of Illinois N/A

  1. PTEN differentially regulates expressions of ICAM-1 and VCAM-1 through PI3K/Akt/GSK-3β/GATA-6 signaling pathways in TNF-α-activated human endothelial cells.

    Science.gov (United States)

    Tsoyi, Konstantin; Jang, Hwa Jin; Nizamutdinova, Irina Tsoy; Park, Kyungok; Kim, Young Min; Kim, Hye Jung; Seo, Han Geuk; Lee, Jae Heun; Chang, Ki Churl

    2010-11-01

    Phosphotase and tensin homolog deleted on chromosome 10 (PTEN) is a potent negative regulator of PI3K/Akt pathway. Here, we tried to elucidate the role of PTEN in the regulation of endothelial adhesion molecules, vascular cell adhesion molecule (VCAM)-1 and intracellular adhesion molecule (ICAM)-1, induced by TNF-α in human endothelial cells (ECs). Transfection with PTEN overexpressing vector resulted in the significant decrease in phosphorylation of Akt in TNF-α-treated ECs. PTEN strongly inhibited VCAM-1 but not ICAM-1, however this inhibitory effect was reversed by co-transfection with constitutively active-Akt (CA-Akt-HA) in TNF-α-stimulated ECs. Additionally, silencing of PTEN with specific siRNA showed significant increase of phosphor-Akt compared with TNF-α alone treated ECs. siPTEN significantly upregulated VCAM-1 but was indifferent to ICAM-1 in TNF-α-treated cells. Further, chromatin immunoprecipitation (ChIP) assay showed that PTEN targets GATA-6 but not IRF-1 binding to VCAM-1 promoter. In addition, GATA-6 is associated with glycogen synthesis kinase-3beta (GSK-3β) which is in turn regulated by PTEN-dependent Akt activity. Finally, PTEN significantly prevented monocyte adhesion to TNF-α-induced ECs probably through VCAM-1 regulation. It is concluded that PTEN selectively inhibits expression of VCAM-1 but not ICAM-1 through modulation of PI3K/Akt/GSK-3β/GATA-6 signaling cascade in TNF-α-treated ECs. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  2. Combinatorial therapy with adenoviral-mediated PTEN and a PI3K inhibitor suppresses malignant glioma cell growth in vitro and in vivo by regulating the PI3K/AKT signaling pathway.

    Science.gov (United States)

    Nan, Yang; Guo, Liyun; Song, Yunpeng; Wang, Le; Yu, Kai; Huang, Qiang; Zhong, Yue

    2017-08-01

    Glioblastoma is a highly invasive and challenging tumor of the central nervous system. The mutation/deletion of the tumor suppressor phosphatase and tensin homolog (PTEN) gene is the main genetic change identified in glioblastomas. PTEN plays a critical role in tumorigenesis and has been shown to be an important therapeutic target. The phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 is commonly used to inhibit glioma cell growth via regulation of the PI3K/AKT signaling pathway. In this study, we examined the growth inhibitory effects of a combinatorial therapy of adenoviral-mediated PTEN (Ad-PTEN) and LY294002 on LN229 and U251 glioma cells in vitro and on tumor xenografts in vivo. In vitro, LN229 and U251 glioma cells were treated by combinatorial therapy with Ad-PTEN and LY294002. The growth ability was determined by MTT assay. The cell cycle distribution was analyzed by flow cytometry. Cell invasive ability was analyzed by transwell invasion assay and cell apoptosis analysis via FITC-Annexin V analysis. In vivo, U251 subcutaneous glioblastoma xenograft was used to assay anti-tumor effect of combinatorial therapy with Ad-PTEN and LY294002 by mean volume of tumors, immunohistochemistry and TUNEL method. The combinatorial treatment clearly suppressed cell proliferation, arrested the cell cycle, reduced cell invasion and promoted cell apoptosis compared with the Ad-PTEN or LY294002 treatment alone. The treatment worked by inhibiting the PI3K/AKT pathway. In addition, the growth of U251 glioma xenografts treated with the combination of Ad-PTEN and LY294002 was significantly inhibited compared with those treated with Ad-PTEN or LY294002 alone. Our data indicated that the combination of Ad-PTEN and LY294002 effectively suppressed the malignant growth of human glioma cells in vitro and in tumor xenografts, suggesting a promising new approach for glioma gene therapy that warrants further investigation.

  3. Integrated Control Strategies Supporting Autonomous Functionalities in Mobile Robots

    National Research Council Canada - National Science Library

    Sights, B; Everett, H. R; Pacis, E. B; Kogut, G; Thompson, M

    2005-01-01

    High-level intelligence allows a mobile robot to create and interpret complex world models, but without a precise control system, the accuracy of the world model and the robot's ability to interact...

  4. Effective control of complex turbulent dynamical systems through statistical functionals.

    Science.gov (United States)

    Majda, Andrew J; Qi, Di

    2017-05-30

    Turbulent dynamical systems characterized by both a high-dimensional phase space and a large number of instabilities are ubiquitous among complex systems in science and engineering, including climate, material, and neural science. Control of these complex systems is a grand challenge, for example, in mitigating the effects of climate change or safe design of technology with fully developed shear turbulence. Control of flows in the transition to turbulence, where there is a small dimension of instabilities about a basic mean state, is an important and successful discipline. In complex turbulent dynamical systems, it is impossible to track and control the large dimension of instabilities, which strongly interact and exchange energy, and new control strategies are needed. The goal of this paper is to propose an effective statistical control strategy for complex turbulent dynamical systems based on a recent statistical energy principle and statistical linear response theory. We illustrate the potential practical efficiency and verify this effective statistical control strategy on the 40D Lorenz 1996 model in forcing regimes with various types of fully turbulent dynamics with nearly one-half of the phase space unstable.

  5. Design of a new PID controller using predictive functional control optimization for chamber pressure in a coke furnace.

    Science.gov (United States)

    Zhang, Jianming

    2017-03-01

    An improved proportional-integral-derivative (PID) controller based on predictive functional control (PFC) is proposed and tested on the chamber pressure in an industrial coke furnace. The proposed design is motivated by the fact that PID controllers for industrial processes with time delay may not achieve the desired control performance because of the unavoidable model/plant mismatches, while model predictive control (MPC) is suitable for such situations. In this paper, PID control and PFC algorithm are combined to form a new PID controller that has the basic characteristic of PFC algorithm and at the same time, the simple structure of traditional PID controller. The proposed controller was tested in terms of set-point tracking and disturbance rejection, where the obtained results showed that the proposed controller had the better ensemble performance compared with traditional PID controllers. Copyright © 2016 ISA. Published by Elsevier Ltd. All rights reserved.

  6. Top Management Control Functions for Information Systems in Small and Medium Enterprises

    OpenAIRE

    Uma VIJAYAKUMAR

    2009-01-01

    This paper analyzes the Top Management Control functions for Information Systems (IS) in Small and Medium Enterprises (SMEs). SMEs extensively rely on information technology resources to enhance their competence in today’s global economy. They should have adequate top management control mechanisms in place for their efficient functioning. Top Management Controls determine how effectively the senior management manages the IS functions in a SME. The major tasks at this level consist of Planni...

  7. Cognitive performance and psychosocial functioning in patients with bipolar disorder, unaffected siblings, and healthy controls

    OpenAIRE

    Vasconcelos-Moreno, Mirela P.; Bücker, Joana; Bürke, Kelen P.; Czepielewski, Leticia; Santos, Barbara T.; Fijtman, Adam; Passos, Ives C.; Kunz, Mauricio; Bonnín, Caterina del Mar; Vieta i Pascual, Eduard, 1963-; Kapczinski, Flávio; Rosa, Adriane R.; Kauer-Sant'Anna, Marcia

    2016-01-01

    Objective: To assess cognitive performance and psychosocial functioning in patients with bipolar disorder (BD), in unaffected siblings, and in healthy controls. Methods: Subjects were patients with BD (n=36), unaffected siblings (n=35), and healthy controls (n=44). Psychosocial functioning was accessed using the Functioning Assessment Short Test (FAST). A sub-group of patients with BD (n=21), unaffected siblings (n=14), and healthy controls (n=22) also underwent a battery of neuropsychologic...

  8. Development of fuzzy algorithm with learning function for nuclear steam generator level control

    International Nuclear Information System (INIS)

    Park, Gee Yong; Seong, Poong Hyun

    1993-01-01

    A fuzzy algorithm with learning function is applied to the steam generator level control of nuclear power plant. This algorithm can make its rule base and membership functions suited for steam generator level control by use of the data obtained from the control actions of a skilled operator or of other controllers (i.e., PID controller). The rule base of fuzzy controller with learning function is divided into two parts. One part of the rule base is provided to level control of steam generator at low power level (0 % - 30 % of full power) and the other to level control at high power level (30 % - 100 % of full power). Response time of steam generator level control at low power range with this rule base is shown to be shorter than that of fuzzy controller with direct inference. (Author)

  9. Identification of hidden failures in control systems: a functional modelling approach

    International Nuclear Information System (INIS)

    Jalashgar, A.; Modarres, M.

    1996-01-01

    This paper presents a model which encompasses knowledge about a process control system's functionalities in a function-oriented failure analysis task. The technique called Hybrid MFM-GTST, mainly utilizes two different function - oriented methods (MFM and GTST) to identify all functions of the system components, and hence possible sources of hidden failures in process control systems. Hidden failures are referred to incipient failures within the system that in long term may lead to loss of major functions. The features of the method are described and demonstrated by using an example of a process control system

  10. FAB (Functionally Alert Behavior Strategies) to Improve Self-Control

    Science.gov (United States)

    Pagano, John

    2015-01-01

    This paper describes the FAB (Functionally Alert Behavior) Strategies approach to improve behavior in children and adolescents with complex behavioral challenges. FAB Strategies include evidence-based environmental adaptations, sensory modulation, positive behavioral support, and physical self-regulation strategies. FAB Strategies can be used by…

  11. Platelet function and HIV: a case-control study.

    LENUS (Irish Health Repository)

    Satchell, Claudette S

    2010-03-13

    Cardiovascular disease and myocardial infarction are of increasing concern in HIV-infected populations. Although platelets mediate arterial thrombosis, central to myocardial infarction, data on platelet function in HIV infection are lacking. We hypothesized that HIV-infected patients would have altered platelet reactivity.

  12. Bilingualism Alters Children's Frontal Lobe Functioning for Attentional Control

    Science.gov (United States)

    Arredondo, Maria M.; Hu, Xiao-Su; Satterfield, Teresa; Kovelman, Ioulia

    2017-01-01

    Bilingualism is a typical linguistic experience, yet relatively little is known about its impact on children's cognitive and brain development. Theories of bilingualism suggest that early dual-language acquisition can improve children's cognitive abilities, specifically those relying on frontal lobe functioning. While behavioral findings present…

  13. A placebo-controlled trial of itopride in functional dyspepsia.

    Science.gov (United States)

    Holtmann, Gerald; Talley, Nicholas J; Liebregts, Tobias; Adam, Birgit; Parow, Christopher

    2006-02-23

    The treatment of patients with functional dyspepsia remains unsatisfactory. We assessed the efficacy of itopride, a dopamine D2 antagonist with anti-acetylcholinesterase [corrected] effects, in patients with functional dyspepsia. Patients with functional dyspepsia were randomly assigned to receive either itopride (50, 100, or 200 mg three times daily) or placebo. After eight weeks of treatment, three primary efficacy end points were analyzed: the change from baseline in the severity of symptoms of functional dyspepsia (as assessed by the Leeds Dyspepsia Questionnaire), patients' global assessment of efficacy (the proportion of patients without symptoms or with marked improvement), and the severity of pain or fullness as rated on a five-grade scale. We randomly assigned 554 patients; 523 had outcome data and could be included in the analyses. After eight weeks, 41 percent of the patients receiving placebo were symptom-free or had marked improvement, as compared with 57 percent, 59 percent, and 64 percent receiving itopride at a dose of 50, 100, or 200 mg three times daily, respectively (Pitopride). Although the symptom score improved significantly in all four groups, an overall analysis revealed that itopride was significantly superior to placebo, with the greatest symptom-score improvement in the 100- and 200-mg groups (-6.24 and -6.27, vs. -4.50 in the placebo group; P=0.05). Analysis of the combined end point of pain and fullness showed that itopride yielded a greater rate of response than placebo (73 percent vs. 63 percent, P=0.04). Itopride significantly improves symptoms in patients with functional dyspepsia. (ClinicalTrials.gov number, NCT00272103.). Copyright 2006 Massachusetts Medical Society.

  14. p53 and PTEN/MMAC1/TEP1 gene therapy of human prostate PC-3 carcinoma xenograft, using transferrin-facilitated lipofection gene delivery strategy.

    Science.gov (United States)

    Seki, Masafumi; Iwakawa, Jun; Cheng, Helen; Cheng, Pi-Wan

    2002-04-10

    We previously reported that supplementation of a cationic liposome with transferrin (Tf) greatly enhanced lipofection efficiency (P.-W. Cheng, Hum. Gene Ther. 1996;7:275-282). In this study, we examined the efficacy of p53 and PTEN tumor suppressor gene therapy in a mouse xenograft model of human prostate PC-3 carcinoma cells, using a vector consisting of dimyristoyloxypropyl-3-dimethylhydroxyethyl ammonium bromide (DMRIE)-cholesterol (DC) and Tf. When the volume of the tumors grown subcutaneously in athymic nude mice reached 50-60 mm(3), three intratumoral injections of the following four formulations were performed during week 1 and then during week 3: (1) saline, (2) DC + Tf + pCMVlacZ, (3) DC + Tf + pCMVPTEN, and (4) DC + Tf + pCMVp53 (standard formulation). There was no significant difference in tumor volume and survival between group 1 and group 2 animals. As compared with group 1 controls, group 3 animals had slower tumor growth during the first 3 weeks but thereafter their tumor growth rate was similar to that of the controls. By day 2 posttreatment, group 4 animals had significantly lower tumor volume relative to initial tumor volume as well as controls at the comparable time point. Also, animals treated with p53 survived longer. Treatment with DC, Tf, pCMVp53, DC + pCMVp53, or Tf + pCMVp53 had no effect on tumor volume or survival. Expression of p53 protein and apoptosis were detected in tumors treated with the standard formulation, thus associating p53 protein expression and apoptosis with efficacy. However, p53 protein was expressed in only a fraction of the tumor cells, suggesting a role for bystander effects in the efficacy of p53 gene therapy. We conclude that intratumoral gene delivery by a nonviral vector consisting of a cationic liposome and Tf can achieve efficacious p53 gene therapy of prostate cancer.

  15. Controlling striatal function via anterior frontal cortex stimulation

    NARCIS (Netherlands)

    Holstein, M.G.A. van; Froböse, M.I.; O'Shea, J.; Aarts, E.; Cools, R.

    2018-01-01

    Motivational, cognitive and action goals are processed by distinct, topographically organized, corticostriatal circuits. We aimed to test whether processing in the striatum is under causal control by cortical regions in the human brain by investigating the effects of offline transcranial magnetic

  16. Controlled torque on superparamagnetic beads for functional biosensors

    NARCIS (Netherlands)

    Janssen, X.J.A.; Schellekens, A.J.; van Ommering, K.; IJzendoorn, van L.J.; Prins, M.W.J.

    2009-01-01

    We demonstrate that a rotating magnetic field can be used to apply a controlled torque on superparamagnetic beads which leads to a tunable bead rotation frequency in fluid. Smooth rotation is obtained for field rotation frequencies many orders of magnitude higher than the bead rotation frequency. A

  17. Function and control of the ssg genes in streptomyces

    NARCIS (Netherlands)

    Traag, Bjørn Alwin

    2008-01-01

    Streptomycetes are Gram-positive soil-dwelling bacteria, in appearance similar to filamentous fungi. The SsgA-like proteins or SALPs, of which streptomycetes typically have at least five paralogues, control specific steps of sporulation-specific cell division in streptomycetes. The expression level

  18. Topological estimation of aerodynamic controlled airplane system functionality of quality

    Directory of Open Access Journals (Sweden)

    С.В. Павлова

    2005-01-01

    Full Text Available  It is suggested to use topological methods for stage estimation of aerodynamic airplane control in widespread range of its conditions The estimation is based on normalized stage virtual non-isotropy of configurational airplane systems calculation.

  19. Prospective associations between bilingualism and executive function in Latino children: sustained effects while controlling for biculturalism.

    Science.gov (United States)

    Riggs, Nathaniel R; Shin, Hee-Sung; Unger, Jennifer B; Spruijt-Metz, Donna; Pentz, Mary Ann

    2014-10-01

    The study purpose was to test 1-year prospective associations between English-Spanish bilingualism and executive function in 5th to 6th grade students while controlling for biculturalism. Participants included 182 US Latino students (50 % female). Self-report surveys assessed biculturalism, bilingualism, and executive function (i.e., working memory, organizational skills, inhibitory control, and emotional control, as well as a summary executive function score). General linear model regressions demonstrated that bilingualism significantly predicted the summary executive function score as well as working memory such that bilingual proficiency was positively related to executive function. Results are the first to demonstrate (a) prospective associations between bilingualism to executive function while controlling for the potential third variable of biculturalism, and (b) a principal role for working memory in this relationship. Since executive function is associated with a host of health outcomes, one implication of study findings is that bilingualism may have an indirect protective influence on youth development.

  20. Controlling for quality in the hospital cost function.

    Science.gov (United States)

    Carey, Kathleen; Stefos, Theodore

    2011-06-01

    This paper explores the relationship between the cost and quality of hospital care from the perspective of applied microeconomics. It addresses both theoretical and practical complexities entailed in incorporating hospital quality into the estimation of hospital cost functions. That literature is extended with an empirical analysis that examines the use of 15 Patient Safety Indicators (PSIs) as measures of hospital quality. A total operating cost function is estimated on 2,848 observations from five states drawn from the period 2001 to 2007. In general, findings indicate that the PSIs are successful in capturing variation in hospital cost due to adverse patient safety events. Measures that rely on the aggregate number of adverse events summed over PSIs are found to be superior to risk-adjusted rates for individual PSIs. The marginal cost of an adverse event is estimated to be $22,413. The results contribute to a growing business case for inpatient safety in hospital services.

  1. Biphasic Estradiol-induced AKT Phosphorylation Is Modulated by PTEN via MAP Kinase in HepG2 Cells

    Science.gov (United States)

    Marino, Maria; Acconcia, Filippo; Trentalance, Anna

    2003-01-01

    We reported previously in HepG2 cells that estradiol induces cell cycle progression throughout the G1–S transition by the parallel stimulation of both PKC-α and ERK signaling molecules. The analysis of the cyclin D1 gene expression showed that only the MAP kinase pathway was involved. Here, the presence of rapid/nongenomic, estradiol-regulated, PI3K/AKT signal transduction pathway, its modulation by the levels of the tumor suppressor PTEN, its cross-talk with the ERK pathway, and its involvement in DNA synthesis and cyclin D1 gene promoter activity have all been studied in HepG2 cells. 17β-Estradiol induced the rapid and biphasic phosphorylation of AKT. These phosphorylations were independent of each other, being the first wave of activation independent of the estrogen receptor (ER), whereas the second was dependent on ER. Both activations were dependent on PI3K activity; furthermore, the ERK pathway modulated AKT phosphorylation by acting on the PTEN levels. The results showed that the PI3K pathway, as well as ER, were strongly involved in both G1–S progression and cyclin D1 promoter activity by acting on its proximal region (-254 base pairs). These data indicate that in HepG2 cells, different rapid/nongenomic estradiol-induced signal transduction pathways modulate the multiple steps of G1–S phase transition. PMID:12808053

  2. Reliability analysis and component functional allocations for the ESF multi-loop controller design

    International Nuclear Information System (INIS)

    Hur, Seop; Kim, D.H.; Choi, J.K.; Park, J.C.; Seong, S.H.; Lee, D.Y.

    2006-01-01

    This paper deals with the reliability analysis and component functional allocations to ensure the enhanced system reliability and availability. In the Engineered Safety Features, functionally dependent components are controlled by a multi-loop controller. The system reliability of the Engineered Safety Features-Component Control System, especially, the multi-loop controller which is changed comparing to the conventional controllers is an important factor for the Probability Safety Assessment in the nuclear field. To evaluate the multi-loop controller's failure rate of the k-out-of-m redundant system, the binomial process is used. In addition, the component functional allocation is performed to tolerate a single multi-loop controller failure without the loss of vital operation within the constraints of the piping and component configuration, and ensure that mechanically redundant components remain functional. (author)

  3. Preservation of renal function by intensive glycemic control

    Directory of Open Access Journals (Sweden)

    Naoya Toriu

    2018-01-01

    Full Text Available We report the case of a 67-year-old Japanese woman with type 1 diabetes mellitus. At 47 years of age, her hemoglobin A1c (HbA1c was 10.0%, and she had overt nephropathy. The first renal biopsy yielded a diagnosis of diabetic nephropathy. Intensive glycemic control was initiated and her HbA1c improved to 6.0%. Renal dysfunction showed no progression for 15 years. At 62 years of age, a second renal biopsy was performed. Glomerular lesions did not show progression but tubulointerstitial fibrosis and vascular lesions showed progression compared with the first biopsy. Intensive glycemic control can prevent the progression of glomerular lesions, but might not be effective for interstitial and vascular lesions.

  4. Hepatitis B virus induces cell proliferation via HBx-induced microRNA-21 in hepatocellular carcinoma by targeting programmed cell death protein4 (PDCD4 and phosphatase and tensin homologue (PTEN.

    Directory of Open Access Journals (Sweden)

    Preeti Damania

    Full Text Available Hepatitis B viral infection-induced hepatocellular carcinoma is one of the major problems in the developing countries. One of the HBV proteins, HBx, modulates the host cell machinery via several mechanisms. In this study we hypothesized that HBV enhances cell proliferation via HBx-induced microRNA-21 in hepatocellular carcinoma. HBx gene was over-expressed, and miRNA-21 expression and cell proliferation were measured in Huh 7 and Hep G2 cells. miRNA-21 was over-expressed in these cells, cell proliferation and the target proteins were analyzed. To confirm the role of miRNA-21 in HBx-induced proliferation, Hep G 2.2.1.5 cells (a cell line that expresses HBV stably were used for miRNA-21 inhibition studies. HBx over-expression enhanced proliferation (3.7- and 4.5-fold increase; n = 3; p<0.01 and miRNA-21 expression (24- and 36-fold increase, normalized with 5S rRNA; p<0.001 in Huh 7 and Hep G2 cells respectively. HBx also resulted in the inhibition of miRNA-21 target proteins, PDCD4 and PTEN. miRNA-21 resulted in a significant increase in proliferation (2- and 2.3-fold increase over control cells; p<0.05 in Huh 7 and Hep G2 cells respectively and decreased target proteins, PDCD4 and PTEN expression. Anti-miR-21 resulted in a significant decrease in proliferation (p<0.05 and increased miRNA-21 target protein expression. We conclude that HBV infection enhances cell proliferation, at least in part, via HBx-induced miRNA-21 expression during hepatocellular carcinoma progression.

  5. Computer Simulation Tests of Feedback Error Learning Controller with IDM and ISM for Functional Electrical Stimulation in Wrist Joint Control

    Directory of Open Access Journals (Sweden)

    Takashi Watanabe

    2010-01-01

    Full Text Available Feedforward controller would be useful for hybrid Functional Electrical Stimulation (FES system using powered orthotic devices. In this paper, Feedback Error Learning (FEL controller for FES (FEL-FES controller was examined using an inverse statics model (ISM with an inverse dynamics model (IDM to realize a feedforward FES controller. For FES application, the ISM was tested in learning off line using training data obtained by PID control of very slow movements. Computer simulation tests in controlling wrist joint movements showed that the ISM performed properly in positioning task and that IDM learning was improved by using the ISM showing increase of output power ratio of the feedforward controller. The simple ISM learning method and the FEL-FES controller using the ISM would be useful in controlling the musculoskeletal system that has nonlinear characteristics to electrical stimulation and therefore is expected to be useful in applying to hybrid FES system using powered orthotic device.

  6. A functional approach for research on cognitive control: Analysing cognitive control tasks and their effects in terms of operant conditioning.

    Science.gov (United States)

    Liefooghe, Baptist; De Houwer, Jan

    2016-02-01

    Cognitive control is an important mental ability that is examined using a multitude of cognitive control tasks and effects. The present paper presents the first steps in the elaboration of a functional approach, which aims to uncover the communalities and differences between different cognitive control tasks and their effects. Based on the idea that responses in cognitive control tasks qualify as operant behaviour, we propose to reinterpret cognitive control tasks in terms of operant contingencies and cognitive control effects as instances of moderated stimulus control. We illustrate how our approach can be used to uncover communalities between topographically different cognitive control tasks and can lead to novel questions about the processes underlying cognitive control. © 2015 International Union of Psychological Science.

  7. Consumers control diversity and functioning of a natural marine ecosystem.

    Directory of Open Access Journals (Sweden)

    Andrew H Altieri

    Full Text Available BACKGROUND: Our understanding of the functional consequences of changes in biodiversity has been hampered by several limitations of previous work, including limited attention to trophic interactions, a focus on species richness rather than evenness, and the use of artificially assembled communities. METHODOLOGY AND PRINCIPAL FINDINGS: In this study, we manipulated the density of an herbivorous snail in natural tide pools and allowed seaweed communities to assemble in an ecologically relevant and non-random manner. Seaweed species evenness and biomass-specific primary productivity (mg O(2 h(-1 g(-1 were higher in tide pools with snails because snails preferentially consumed an otherwise dominant seaweed species that can reduce biomass-specific productivity rates of algal assemblages. Although snails reduced overall seaweed biomass in tide pools, they did not affect gross primary productivity at the scale of tide pools (mg O(2 h(-1 pool(-1 or mg O(2 h(-1 m(-2 because of the enhanced biomass-specific productivity associated with grazer-mediated increases in algal evenness. SIGNIFICANCE: Our results suggest that increased attention to trophic interactions, diversity measures other than richness, and particularly the effects of consumers on evenness and primary productivity, will improve our understanding of the relationship between diversity and ecosystem functioning and allow more effective links between experimental results and real-world changes in biodiversity.

  8. Cost and Benefit of Control Strategies - Estimation of Benefit functions, enforcement-probability function and enforcement-cost function

    DEFF Research Database (Denmark)

    Kronbak, Lone Grønbæk; Jensen, Frank

    of undersized lobsters and illegal bycactch of cod. The enforcement to avoid the illegal activities consists of physical control, such as dock side inspections and boarding, and administrative control with integration of different databases. This paper presents the first steps in the application of the theory...

  9. Supratentorial Ependymoma: Disease Control, Complications, and Functional Outcomes After Irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Landau, Efrat [Department of Radiation Oncology, Sheba Medical Center, Ramat Gan (Israel); Boop, Frederick A. [Department of Neurosurgery, St Jude Children' s Research Hospital, Memphis, Tennessee (United States); Conklin, Heather M. [Department of Psychology, St Jude Children' s Research Hospital, Memphis, Tennessee (United States); Wu, Shengjie; Xiong, Xiaoping [Department of Biostatistics, St Jude Children' s Research Hospital, Memphis, Tennessee (United States); Merchant, Thomas E., E-mail: thomas.merchant@stjude.org [Division of Radiation Oncology, St Jude Children' s Research Hospital, Memphis, Tennessee (United States)

    2013-03-15

    Purpose: Ependymoma is less commonly found in the supratentorial brain and has known clinical and molecular features that are unique. Our single-institution series provides valuable information about disease control for supratentorial ependymoma and the complications of supratentorial irradiation in children. Methods and Materials: A total of 50 children with newly diagnosed supratentorial ependymoma were treated with adjuvant radiation therapy (RT); conformal methods were used in 36 after 1996. The median age at RT was 6.5 years (range, 1-18.9 years). The entire group was characterized according to sex (girls 27), race (white 43), extent of resection (gross-total 46), and tumor grade (anaplastic 28). The conformal RT group was prospectively evaluated for neurologic, endocrine, and cognitive effects. Results: With a median follow-up time of 9.1 years from the start of RT for survivors (range, 0.2-23.2 years), the 10-year progression-free and overall survival were 73% + 7% and 76% + 6%, respectively. None of the evaluated factors was prognostic for disease control. Local and distant failures were evenly divided among the 16 patients who experienced progression. Eleven patients died of disease, and 1 of central nervous system necrosis. Seizure disorders were present in 17 patients, and 4 were considered to be clinically disabled. Clinically significant cognitive effects were limited to children with difficult-to-control seizures. The average values for intelligence quotient and academic achievement (reading, spelling, and math) were within the range of normal through 10 years of follow-up. Central hypothyroidism was the most commonly treated endocrinopathy. Conclusion: RT may be administered with acceptable risks for complications in children with supratentorial ependymoma. These results suggest that outcomes for these children are improving and that complications may be limited by use of focal irradiation methods.

  10. Supratentorial Ependymoma: Disease Control, Complications, and Functional Outcomes After Irradiation

    International Nuclear Information System (INIS)

    Landau, Efrat; Boop, Frederick A.; Conklin, Heather M.; Wu, Shengjie; Xiong, Xiaoping; Merchant, Thomas E.

    2013-01-01

    Purpose: Ependymoma is less commonly found in the supratentorial brain and has known clinical and molecular features that are unique. Our single-institution series provides valuable information about disease control for supratentorial ependymoma and the complications of supratentorial irradiation in children. Methods and Materials: A total of 50 children with newly diagnosed supratentorial ependymoma were treated with adjuvant radiation therapy (RT); conformal methods were used in 36 after 1996. The median age at RT was 6.5 years (range, 1-18.9 years). The entire group was characterized according to sex (girls 27), race (white 43), extent of resection (gross-total 46), and tumor grade (anaplastic 28). The conformal RT group was prospectively evaluated for neurologic, endocrine, and cognitive effects. Results: With a median follow-up time of 9.1 years from the start of RT for survivors (range, 0.2-23.2 years), the 10-year progression-free and overall survival were 73% + 7% and 76% + 6%, respectively. None of the evaluated factors was prognostic for disease control. Local and distant failures were evenly divided among the 16 patients who experienced progression. Eleven patients died of disease, and 1 of central nervous system necrosis. Seizure disorders were present in 17 patients, and 4 were considered to be clinically disabled. Clinically significant cognitive effects were limited to children with difficult-to-control seizures. The average values for intelligence quotient and academic achievement (reading, spelling, and math) were within the range of normal through 10 years of follow-up. Central hypothyroidism was the most commonly treated endocrinopathy. Conclusion: RT may be administered with acceptable risks for complications in children with supratentorial ependymoma. These results suggest that outcomes for these children are improving and that complications may be limited by use of focal irradiation methods

  11. A transfer function model of the BEPO reactor for control studies

    Energy Technology Data Exchange (ETDEWEB)

    Cummins, J D [Dynamics Group, Control and Instrumentation Division, Atomic Energy Establishment, Winfrith, Dorchester, Dorset (United Kingdom)

    1962-09-15

    A spatially independent (one point) transfer function model of the BEPO reactor is presented. Perturbations in control rod reactivity and coolant flow are considered and transfer functions deduced for variations about four steady states namely zero power, one sixth full power and one sixth full flow, one sixth full power and full flow and also full power and full flow. The transfer functions are presented in pole-zero form. The use of the transfer functions in verifying experimental frequency responses, in automatic control studies and in multi-variable non-interacting control design are briefly considered. (author)

  12. PTEN Loss in E-Cadherin-Deficient Mouse Mammary Epithelial Cells Rescues Apoptosis and Results in Development of Classical Invasive Lobular Carcinoma

    Directory of Open Access Journals (Sweden)

    Mirjam C. Boelens

    2016-08-01

    Full Text Available Invasive lobular carcinoma (ILC is an aggressive breast cancer subtype with poor response to chemotherapy. Besides loss of E-cadherin, a hallmark of ILC, genetic inactivation of PTEN is frequently observed in patients. Through concomitant Cre-mediated inactivation of E-cadherin and PTEN in mammary epithelium, we generated a mouse model of classical ILC (CLC, the main histological ILC subtype. While loss of E-cadherin induced cell dissemination and apoptosis, additional PTEN inactivation promoted cell survival and rapid formation of invasive mammary tumors that recapitulate the histological and molecular features, estrogen receptor (ER status, growth kinetics, metastatic behavior, and tumor microenvironment of human CLC. Combined inactivation of E-cadherin and PTEN is sufficient to cause CLC development. These CLCs showed significant tumor regression upon BEZ235-mediated inhibition of PI3K signaling. In summary, this mouse model provides important insights into CLC development and suggests inhibition of phosphatidylinositol 3-kinase (PI3K signaling as a potential therapeutic strategy for targeting CLC.

  13. Tumour-associated neutrophils and loss of epithelial PTEN can promote corticosteroid-insensitive MMP-9 expression in the chronically inflamed lung microenvironment.

    Science.gov (United States)

    Vannitamby, Amanda; Seow, Huei Jiunn; Anderson, Gary; Vlahos, Ross; Thompson, Michelle; Steinfort, Daniel; Irving, Louis B; Bozinovski, Steven

    2017-12-01

    Matrix metalloproteinase-9 (MMP-9) is increased in a number of pathological lung conditions, where the proteinase contributes to deleterious remodelling of the airways. While both lung cancer and COPD are associated with increased MMP-9 expression, the cellular and molecular drivers of MMP-9 remain unresolved. In this study, MMP-9 transcript measured within the tumour region from patients with non-small-cell lung cancer (NSCLC) and coexisting COPD was found to be uniformly increased relative to adjacent tumour-free tissue. MMP-9 gene expression and immunohistochemistry identified tumour-associated neutrophils, but not macrophages, as a predominant source of this proteinase. In addition, PTEN gene expression was significantly reduced in tumour and there was evidence of epithelial MMP-9 expression. To explore whether PTEN can regulate epithelial MMP-9 expression, a small interfering (si)RNA knockdown strategy was used in Beas-2B bronchial epithelial cells. PTEN knockdown by siRNA selectively increased MMP-9 expression in response to lipopolysaccharide in a corticosteroid-insensitive manner. In summary, tumour-associated neutrophils represent an important source of MMP-9 in NSCLC, and loss of epithelial PTEN may further augment steroid-insensitive expression. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  14. Alkylation of the tumor suppressor PTEN activates Akt and β-catenin signaling: a mechanism linking inflammation and oxidative stress with cancer.

    Directory of Open Access Journals (Sweden)

    Tracy M Covey

    2010-10-01

    Full Text Available PTEN, a phosphoinositide-3-phosphatase, serves dual roles as a tumor suppressor and regulator of cellular anabolic/catabolic metabolism. Adaptation of a redox-sensitive cysteinyl thiol in PTEN for signal transduction by hydrogen peroxide may have superimposed a vulnerability to other mediators of oxidative stress and inflammation, especially reactive carbonyl species, which are commonly occurring by-products of arachidonic acid peroxidation. Using MCF7 and HEK-293 cells, we report that several reactive aldehydes and ketones, e.g. electrophilic α,β-enals (acrolein, 4-hydroxy-2-nonenal and α,β-enones (prostaglandin A(2, Δ12-prostaglandin J(2 and 15-deoxy-Δ-12,14-prostaglandin J(2 covalently modify and inactivate cellular PTEN, with ensuing activation of PKB/Akt kinase; phosphorylation of Akt substrates; increased cell proliferation; and increased nuclear β-catenin signaling. Alkylation of PTEN by α,β-enals/enones and interference with its restraint of cellular PKB/Akt signaling may accentuate hyperplastic and neoplastic disorders associated with chronic inflammation, oxidative stress, or aging.

  15. PTEN Loss in E-Cadherin-Deficient Mouse Mammary Epithelial Cells Rescues Apoptosis and Results in Development of Classical Invasive Lobular Carcinoma.

    Science.gov (United States)

    Boelens, Mirjam C; Nethe, Micha; Klarenbeek, Sjoerd; de Ruiter, Julian R; Schut, Eva; Bonzanni, Nicola; Zeeman, Amber L; Wientjens, Ellen; van der Burg, Eline; Wessels, Lodewyk; van Amerongen, Renée; Jonkers, Jos

    2016-08-23

    Invasive lobular carcinoma (ILC) is an aggressive breast cancer subtype with poor response to chemotherapy. Besides loss of E-cadherin, a hallmark of ILC, genetic inactivation of PTEN is frequently observed in patients. Through concomitant Cre-mediated inactivation of E-cadherin and PTEN in mammary epithelium, we generated a mouse model of classical ILC (CLC), the main histological ILC subtype. While loss of E-cadherin induced cell dissemination and apoptosis, additional PTEN inactivation promoted cell survival and rapid formation of invasive mammary tumors that recapitulate the histological and molecular features, estrogen receptor (ER) status, growth kinetics, metastatic behavior, and tumor microenvironment of human CLC. Combined inactivation of E-cadherin and PTEN is sufficient to cause CLC development. These CLCs showed significant tumor regression upon BEZ235-mediated inhibition of PI3K signaling. In summary, this mouse model provides important insights into CLC development and suggests inhibition of phosphatidylinositol 3-kinase (PI3K) signaling as a potential therapeutic strategy for targeting CLC. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  16. The Expansion of Criminal Control: A Critical to Feather Functions

    Directory of Open Access Journals (Sweden)

    Mariel Muraro

    2015-12-01

    Full Text Available This article aims to relate the theories of punishment, retributive and preventive, with the criminological discourse, and make brief notes about the negative theories and criticism of the sentence. The article begins by making a few notes on the mass incarceration of the phenomenon, then going to discuss and present the form of action of the police state. Then they present the theories of punishment under the critical perspective, and then work the two main critical theories of punishment, thus treating the position Prof. Eugenio Raúl Zaffaroni and Prof. Juarez Cirino dos Santos. These presentations and discussions have left the critical discourse, not taking our work as end revisit the theoretical construction of the functions of the pen, just to demonstrate how the discourse of shame built by criminal law legitimizes selective and violent actions of the penal system.

  17. Sexual function and hormone profile in young adult men with idiopathic gynecomastia: Comparison with healthy controls.

    Science.gov (United States)

    Sir, Emin; Üçer, Oktay; Aksoy, Alper; Güngör, Melike; Ceylan, Yasin

    2016-01-22

    To compare sexual function and hormone profile in male patients with gynecomastia with matched controls. Forty-seven male subjects with gynecomastia and thirty healthy controls were enrolled in this study. Serum free T3, free T4, TSH, FSH, prolactin, estradiol, total testosterone, free testosterone, DHEA-SO4, LH and total PSA were measured in the patients and controls. Sexual function of the patients and controls were evaluated using International Index of Erectile Function (IIEF). The hormone values and IIEF scores of the patients were statistically compared with the controls'. The mean of age, body mass index, right and left testicular volume in the patient and control group were similar. The mean FSH and free T3 values of the patients were significantly lower than the controls (p = 0.007 and p = 0.03, respectively). The mean of the other hormone values in the both groups were found to be statistically similar (p > 0.05). The mean ±SD of total IIEF scores in the patient and control group were 60.14 ± 8.78 and 65.24 ± 5.52, respectively (p = 0.007). Although the mean IIEF-erectile function, orgasmic function and intercourse satisfaction scores in the patient group were significantly lower than the control group (p gynecomastia were similar with the controls. However, gynecomastia adversely affected male sexual function.

  18. Functional Based Adaptive and Fuzzy Sliding Controller for Non-Autonomous Active Suspension System

    Science.gov (United States)

    Huang, Shiuh-Jer; Chen, Hung-Yi

    In this paper, an adaptive sliding controller is developed for controlling a vehicle active suspension system. The functional approximation technique is employed to substitute the unknown non-autonomous functions of the suspension system and release the model-based requirement of sliding mode control algorithm. In order to improve the control performance and reduce the implementation problem, a fuzzy strategy with online learning ability is added to compensate the functional approximation error. The update laws of the functional approximation coefficients and the fuzzy tuning parameters are derived from the Lyapunov theorem to guarantee the system stability. The proposed controller is implemented on a quarter-car hydraulic actuating active suspension system test-rig. The experimental results show that the proposed controller suppresses the oscillation amplitude of the suspension system effectively.

  19. Functionalized bimodal mesoporous silicas as carriers for controlled aspirin delivery

    Science.gov (United States)

    Gao, Lin; Sun, Jihong; Li, Yuzhen

    2011-08-01

    The bimodal mesoporous silica modified with 3-aminopropyltriethoxysilane was performed as the aspirin carrier. The samples' structure, drug loading and release profiles were characterized with X-ray diffraction, scanning electron microscopy, N 2 adsorption and desorption, Fourier transform infrared spectroscopy, TG analysis, elemental analysis and UV-spectrophotometer. For further exploring the effects of the bimodal mesopores on the drug delivery behavior, the unimodal mesoporous material MCM-41 was also modified as the aspirin carrier. Meantime, Korsmeyer-Peppas equation ft= ktn was employed to analyze the dissolution data in details. It is indicated that the bimodal mesopores are beneficial for unrestricted drug molecules diffusing and therefore lead to a higher loading and faster releasing than that of MCM-41. The results show that the aspirin delivery properties are influenced considerably by the mesoporous matrix, whereas the large pore of bimodal mesoporous silica is the key point for the improved controlled-release properties.

  20. Protective Controller against Cascade Outages with Selective Harmonic Compensation Function

    Science.gov (United States)

    Abramovich, B. N.; Kuznetsov, P. A.; Sychev, Yu A.

    2018-05-01

    The paper presents data on the power quality and development of protective devices for the power networks with distributed generation (DG).The research has shown that power quality requirements for DG networks differ from conventional ones. That is why main tendencies, protective equipment and filters should be modified. There isa developed algorithm for detection and prevention of cascade outages that can lead to the blackoutin DG networks and there was a proposed structural scheme for a new active power filter for selective harmonics compensation. Analysis of these theories and equipment led to the development of protective device that could monitor power balance and cut off non-important consumers. The last part of the article describes a microcontroller prototype developed for connection to the existing power station control center.

  1. Sensitivity of control times in function of core parameters and oscillations control in thermal nuclear systems

    International Nuclear Information System (INIS)

    Amorim, E.S. do; D'Oliveira, A.B.; Galvao, O.B.; Oyama, K.

    1981-03-01

    Sensitivity of control times to variation of a thermal reactor core parameters is defined by suitable changes in the power coefficient, core size and fuel enrichment. A control strategy is developed based on control theory concepts and on considerations of the physics of the problem. Digital diffusion theory simulation is described which tends to verify the control concepts considered, face dumped oscillations introduced in one thermal nuclear power system. The effectivity of the control actions, in terms of eliminating oscillations, provided guidelines for the working-group engaged in the analysis of the control rods and its optimal performance. (Author) [pt

  2. Polynomial fuzzy model-based control systems stability analysis and control synthesis using membership function dependent techniques

    CERN Document Server

    Lam, Hak-Keung

    2016-01-01

    This book presents recent research on the stability analysis of polynomial-fuzzy-model-based control systems where the concept of partially/imperfectly matched premises and membership-function dependent analysis are considered. The membership-function-dependent analysis offers a new research direction for fuzzy-model-based control systems by taking into account the characteristic and information of the membership functions in the stability analysis. The book presents on a research level the most recent and advanced research results, promotes the research of polynomial-fuzzy-model-based control systems, and provides theoretical support and point a research direction to postgraduate students and fellow researchers. Each chapter provides numerical examples to verify the analysis results, demonstrate the effectiveness of the proposed polynomial fuzzy control schemes, and explain the design procedure. The book is comprehensively written enclosing detailed derivation steps and mathematical derivations also for read...

  3. 21 CFR 1401.2 - The Office of National Drug Control Policy-organization and functions.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 9 2010-04-01 2010-04-01 false The Office of National Drug Control Policy-organization and functions. 1401.2 Section 1401.2 Food and Drugs OFFICE OF NATIONAL DRUG CONTROL POLICY PUBLIC AVAILABILITY OF INFORMATION § 1401.2 The Office of National Drug Control Policy—organization and functions. (a) The Office of National Drug...

  4. Functional Brain Networks Associated with Cognitive Control, Cocaine Dependence and Treatment Outcome

    OpenAIRE

    Worhunsky, Patrick D.; Stevens, Michael C.; Carroll, Kathleen M.; Rounsaville, Bruce J.; Calhoun, Vince D.; Pearlson, Godfrey D.; Potenza, Marc N.

    2012-01-01

    Individuals with cocaine dependence often evidence poor cognitive control. The purpose of this exploratory study was to investigate networks of functional connectivity underlying cognitive control in cocaine dependence and examine the relationship of the networks to the disorder and its treatment. Independent component analysis (ICA) was applied to fMRI data to investigate if regional activations underlying cognitive control processes operate in functional networks, and whether these networks...

  5. Allocation of functions to man and machine in the automated control room

    International Nuclear Information System (INIS)

    Pulliam, R.; Price, H.E.

    1983-01-01

    A practical framework and set of methodologic tools are discussed which could be used by a design team in allocating nuclear power plant control functions to either man or machine control. It is concluded that allocations of functions must eventually become a formal step in control system design, i.e., it will become increasingly necessary to invest in human factors analysis as an integral part of the design process

  6. Seizure Control and Memory Impairment Are Related to Disrupted Brain Functional Integration in Temporal Lobe Epilepsy.

    Science.gov (United States)

    Park, Chang-Hyun; Choi, Yun Seo; Jung, A-Reum; Chung, Hwa-Kyoung; Kim, Hyeon Jin; Yoo, Jeong Hyun; Lee, Hyang Woon

    2017-01-01

    Brain functional integration can be disrupted in patients with temporal lobe epilepsy (TLE), but the clinical relevance of this disruption is not completely understood. The authors hypothesized that disrupted functional integration over brain regions remote from, as well as adjacent to, the seizure focus could be related to clinical severity in terms of seizure control and memory impairment. Using resting-state functional MRI data acquired from 48 TLE patients and 45 healthy controls, the authors mapped functional brain networks and assessed changes in a network parameter of brain functional integration, efficiency, to examine the distribution of disrupted functional integration within and between brain regions. The authors assessed whether the extent of altered efficiency was influenced by seizure control status and whether the degree of altered efficiency was associated with the severity of memory impairment. Alterations in the efficiency were observed primarily near the subcortical region ipsilateral to the seizure focus in TLE patients. The extent of regional involvement was greater in patients with poor seizure control: it reached the frontal, temporal, occipital, and insular cortices in TLE patients with poor seizure control, whereas it was limited to the limbic and parietal cortices in TLE patients with good seizure control. Furthermore, TLE patients with poor seizure control experienced more severe memory impairment, and this was associated with lower efficiency in the brain regions with altered efficiency. These findings indicate that the distribution of disrupted brain functional integration is clinically relevant, as it is associated with seizure control status and comorbid memory impairment.

  7. DESCRIBING FUNCTION METHOD FOR PI-FUZZY CONTROLLED SYSTEMS STABILITY ANALYSIS

    Directory of Open Access Journals (Sweden)

    Stefan PREITL

    2004-12-01

    Full Text Available The paper proposes a global stability analysis method dedicated to fuzzy control systems containing Mamdani PI-fuzzy controllers with output integration to control SISO linear / linearized plants. The method is expressed in terms of relatively simple steps, and it is based on: the generalization of the describing function method for the considered fuzzy control systems to the MIMO case, the approximation of the describing functions by applying the least squares method. The method is applied to the stability analysis of a class of PI-fuzzy controlled servo-systems, and validated by considering a case study.

  8. Gain-Scheduled Model Predictive Control of Wind Turbines using Laguerre Functions

    DEFF Research Database (Denmark)

    Adegas, Fabiano Daher; Wisniewski, Rafal; Larsen, Lars Finn Sloth

    2014-01-01

    This paper presents a systematic approach to design gain-scheduled predictive controllers for wind turbines. The predictive control law is based on Laguerre functions to parameterize control signals and a parameter-dependent cost function that is analytically determined from turbine data....... These properties facilitate the design of speed controllers by placement of the closed-loop poles (when constraints are not active) and systematic adaptation towards changes in the operating point. Vibration control of undamped modes is achieved by imposing a certain degree of stability to the closed-loop system....... The approach can be utilized to the design of new controllers and to represent existing gain-scheduled controllers as predictive controllers. The numerical example and simulations illustrate the design of a speed controller augmented with active damping of the tower fore-aft displacement....

  9. KRAS and BRAF Mutations and PTEN Expression Do Not Predict Efficacy of Cetuximab-Based Chemoradiotherapy in Locally Advanced Rectal Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Erben, Philipp, E-mail: philipp.erben@medma.uni-heidelberg.de [III. Medizinische Klinik, Universitaetsmedizin Mannheim, Universitaet Heidelberg, Mannheim (Germany); Stroebel, Philipp [Pathologisches Institut, Universitaetsmedizin Mannheim, Universitaet Heidelberg, Mannheim (Germany); Horisberger, Karoline [Chirurgische Klinik, Universitaetsmedizin Mannheim, Universitaet Heidelberg, Mannheim (Germany); Popa, Juliana; Bohn, Beatrice; Hanfstein, Benjamin [III. Medizinische Klinik, Universitaetsmedizin Mannheim, Universitaet Heidelberg, Mannheim (Germany); Kaehler, Georg; Kienle, Peter; Post, Stefan [Chirurgische Klinik, Universitaetsmedizin Mannheim, Universitaet Heidelberg, Mannheim (Germany); Wenz, Frederik [Klinik fuer Strahlentherapie und Radioonkologie, Universitaetsmedizin Mannheim, Universitaet Heidelberg, Mannheim (Germany); Hochhaus, Andreas [III. Medizinische Klinik, Universitaetsmedizin Mannheim, Universitaet Heidelberg, Mannheim (Germany); Klinik fuer Innere Medizin II, Abteilung Haematologie/Onkologie, Universitaetsklinikum Jena, Jena (Germany); Hofheinz, Ralf-Dieter [III. Medizinische Klinik, Universitaetsmedizin Mannheim, Universitaet Heidelberg, Mannheim (Germany)

    2011-11-15

    Purpose: Mutations in KRAS and BRAF genes as well as the loss of expression of phosphatase and tensin homolog (PTEN) (deleted on chromosome 10) are associated with impaired activity of antibodies directed against epidermal growth factor receptor in patients with metastatic colorectal cancer. The predictive and prognostic value of the KRAS and BRAF point mutations as well as PTEN expression in patients with locally advanced rectal cancer (LARC) treated with cetuximab-based neoadjuvant chemoradiotherapy is unknown. Methods and Materials: We have conducted phase I and II trials of the combination of weekly administration of cetuximab and irinotecan and daily doses of capecitabine in conjunction with radiotherapy (45 Gy plus 5.4 Gy) in patients with LARC (stage uT3/4 or uN+). The status of KRAS and BRAF mutations was determined with direct sequencing, and PTEN expression status was determined with immunohistochemistry testing of diagnostic tumor biopsies. Tumor regression was evaluated by using standardized regression grading, and disease-free survival (DFS) was calculated according to the Kaplan-Meier method. Results: A total of 57 patients were available for analyses. A total of 31.6% of patients carried mutations in the KRAS genes. No BRAF mutations were found, while the loss of PTEN expression was observed in 9.6% of patients. Six patients achieved complete remission, and the 3-year DFS rate was 73%. No correlation was seen between tumor regression or DFS rate and a single marker or a combination of all markers. Conclusions: In the present series, no BRAF mutation was detected. The presence of KRAS mutations and loss of PTEN expression were not associated with impaired response to cetuximab-based chemoradiotherapy and 3-year DFS.

  10. KRAS and BRAF Mutations and PTEN Expression Do Not Predict Efficacy of Cetuximab-Based Chemoradiotherapy in Locally Advanced Rectal Cancer

    International Nuclear Information System (INIS)

    Erben, Philipp; Ströbel, Philipp; Horisberger, Karoline; Popa, Juliana; Bohn, Beatrice; Hanfstein, Benjamin; Kähler, Georg; Kienle, Peter; Post, Stefan; Wenz, Frederik; Hochhaus, Andreas; Hofheinz, Ralf-Dieter

    2011-01-01

    Purpose: Mutations in KRAS and BRAF genes as well as the loss of expression of phosphatase and tensin homolog (PTEN) (deleted on chromosome 10) are associated with impaired activity of antibodies directed against epidermal growth factor receptor in patients with metastatic colorectal cancer. The predictive and prognostic value of the KRAS and BRAF point mutations as well as PTEN expression in patients with locally advanced rectal cancer (LARC) treated with cetuximab-based neoadjuvant chemoradiotherapy is unknown. Methods and Materials: We have conducted phase I and II trials of the combination of weekly administration of cetuximab and irinotecan and daily doses of capecitabine in conjunction with radiotherapy (45 Gy plus 5.4 Gy) in patients with LARC (stage uT3/4 or uN+). The status of KRAS and BRAF mutations was determined with direct sequencing, and PTEN expression status was determined with immunohistochemistry testing of diagnostic tumor biopsies. Tumor regression was evaluated by using standardized regression grading, and disease-free survival (DFS) was calculated according to the Kaplan–Meier method. Results: A total of 57 patients were available for analyses. A total of 31.6% of patients carried mutations in the KRAS genes. No BRAF mutations were found, while the loss of PTEN expression was observed in 9.6% of patients. Six patients achieved complete remission, and the 3-year DFS rate was 73%. No correlation was seen between tumor regression or DFS rate and a single marker or a combination of all markers. Conclusions: In the present series, no BRAF mutation was detected. The presence of KRAS mutations and loss of PTEN expression were not associated with impaired response to cetuximab-based chemoradiotherapy and 3-year DFS.

  11. Actin cytoskeleton organization, cell surface modification and invasion rate of 5 glioblastoma cell lines differing in PTEN and p53 status

    International Nuclear Information System (INIS)

    Djuzenova, Cholpon S.; Fiedler, Vanessa; Memmel, Simon; Katzer, Astrid; Hartmann, Susanne; Krohne, Georg; Zimmermann, Heiko; Scholz, Claus-Jürgen; Polat, Bülent; Flentje, Michael

    2015-01-01

    Glioblastoma cells exhibit highly invasive behavior whose mechanisms are not yet fully understood. The present study explores the relationship between the invasion capacity of 5 glioblastoma cell lines differing in p53 and PTEN status, expression of mTOR and several other marker proteins involved in cell invasion, actin cytoskeleton organization and cell morphology. We found that two glioblastoma lines mutated in both p53 and PTEN genes (U373-MG and SNB19) exhibited the highest invasion rates through the Matrigel or collagen matrix. In DK-MG (p53wt/PTENwt) and GaMG (p53mut/PTENwt) cells, F-actin mainly occurred in the numerous stress fibers spanning the cytoplasm, whereas U87-MG (p53wt/PTENmut), U373-MG and SNB19 (both p53mut/PTENmut) cells preferentially expressed F-actin in filopodia and lamellipodia. Scanning electron microscopy confirmed the abundant filopodia and lamellipodia in the PTEN mutated cell lines. Interestingly, the gene profiling analysis revealed two clusters of cell lines, corresponding to the most (U373-MG and SNB19, i.e. p53 and PTEN mutated cells) and less invasive phenotypes. The results of this study might shed new light on the mechanisms of glioblastoma invasion. - Highlights: • We examine 5 glioblastoma lines on the invasion capacity and actin cytoskeleton. • Glioblastoma cell lines mutated in both p53 and PTEN were the most invasive. • Less invasive cells showed much less lamellipodia, but more actin stress fibers. • A mechanism for the differences in tumor cell invasion is proposed

  12. Actin cytoskeleton organization, cell surface modification and invasion rate of 5 glioblastoma cell lines differing in PTEN and p53 status

    Energy Technology Data Exchange (ETDEWEB)

    Djuzenova, Cholpon S., E-mail: djuzenova_t@ukw.de [Department of Radiation Oncology, University Hospital, Josef-Schneider-Strasse 11, D-97080 Würzburg (Germany); Fiedler, Vanessa [Department of Radiation Oncology, University Hospital, Josef-Schneider-Strasse 11, D-97080 Würzburg (Germany); Memmel, Simon [Lehrstuhl für Biotechnologie und Biophysik, Universität Würzburg, Biozentrum Am Hubland, 97070 Würzburg (Germany); Katzer, Astrid; Hartmann, Susanne [Department of Radiation Oncology, University Hospital, Josef-Schneider-Strasse 11, D-97080 Würzburg (Germany); Krohne, Georg [Elektronenmikroskopie, Biozentrum, Universität Würzburg, Am Hubland, 97070 Würzburg (Germany); Zimmermann, Heiko [Hauptabteilung Biophysik and Kryotechnologie, Fraunhofer-Institut für Biomedizinische Technik, Lehrstuhl für Molekulare und Zelluläre Biotechnologie/Nanotechnologie, Universität des Saarlandes, Ensheimer Strasse 48, 66386 St. Ingbert (Germany); Scholz, Claus-Jürgen [Interdisciplinary Center for Clinical Research, University Hospital, Versbacher Strasse 7, 97078 Würzburg (Germany); Polat, Bülent; Flentje, Michael [Department of Radiation Oncology, University Hospital, Josef-Schneider-Strasse 11, D-97080 Würzburg (Germany); and others

    2015-01-15

    Glioblastoma cells exhibit highly invasive behavior whose mechanisms are not yet fully understood. The present study explores the relationship between the invasion capacity of 5 glioblastoma cell lines differing in p53 and PTEN status, expression of mTOR and several other marker proteins involved in cell invasion, actin cytoskeleton organization and cell morphology. We found that two glioblastoma lines mutated in both p53 and PTEN genes (U373-MG and SNB19) exhibited the highest invasion rates through the Matrigel or collagen matrix. In DK-MG (p53wt/PTENwt) and GaMG (p53mut/PTENwt) cells, F-actin mainly occurred in the numerous stress fibers spanning the cytoplasm, whereas U87-MG (p53wt/PTENmut), U373-MG and SNB19 (both p53mut/PTENmut) cells preferentially expressed F-actin in filopodia and lamellipodia. Scanning electron microscopy confirmed the abundant filopodia and lamellipodia in the PTEN mutated cell lines. Interestingly, the gene profiling analysis revealed two clusters of cell lines, corresponding to the most (U373-MG and SNB19, i.e. p53 and PTEN mutated cells) and less invasive phenotypes. The results of this study might shed new light on the mechanisms of glioblastoma invasion. - Highlights: • We examine 5 glioblastoma lines on the invasion capacity and actin cytoskeleton. • Glioblastoma cell lines mutated in both p53 and PTEN were the most invasive. • Less invasive cells showed much less lamellipodia, but more actin stress fibers. • A mechanism for the differences in tumor cell invasion is proposed.

  13. Multi-functional surfaces with controllable wettability and water adhesion

    Science.gov (United States)

    Anastasiadis, Spiros H.; Frysali, Melani A.; Kenanakis, George; Kaklamani, Georgia; Papoutsakis, Lampros

    The design of multifunctional surfaces based on biomimetic structures has gained the interest of the scientific community. Novel multifunctional surfaces have been developed, able to alter their wetting properties in response to temperature and pH as well as light illumination, by combining proper chemistry and surface micro/nano-structuring using ultrafast (femtosecond) laser irradiation. The combination of the hierarchical surface with a ZnO and/or a responsive polymer coating results in efficient photo-active properties as well as reversible superhydrophobic / superhydrophilic surfaces in response to external stimuli. These surfaces can be optimized to exhibit high or zero water adhesion and/or controllable directionality as well. Moreover, they can be seeded with human fibroblasts to examine the cellular response on both surface roughness and surface chemistry. Acknowledgements: This research has been co-financed by the General Secretariat for Research and Technology (''ARISTEIA II'' Action, SMART-SURF) and the European Union (NFFA Europe -Grant agreement No. 654360).

  14. Functionalized bimodal mesoporous silicas as carriers for controlled aspirin delivery

    International Nuclear Information System (INIS)

    Gao Lin; Sun Jihong; Li Yuzhen

    2011-01-01

    The bimodal mesoporous silica modified with 3-aminopropyltriethoxysilane was performed as the aspirin carrier. The samples' structure, drug loading and release profiles were characterized with X-ray diffraction, scanning electron microscopy, N 2 adsorption and desorption, Fourier transform infrared spectroscopy, TG analysis, elemental analysis and UV-spectrophotometer. For further exploring the effects of the bimodal mesopores on the drug delivery behavior, the unimodal mesoporous material MCM-41 was also modified as the aspirin carrier. Meantime, Korsmeyer-Peppas equation f t =kt n was employed to analyze the dissolution data in details. It is indicated that the bimodal mesopores are beneficial for unrestricted drug molecules diffusing and therefore lead to a higher loading and faster releasing than that of MCM-41. The results show that the aspirin delivery properties are influenced considerably by the mesoporous matrix, whereas the large pore of bimodal mesoporous silica is the key point for the improved controlled-release properties. - Graphical abstract: Loading (A) and release profiles (B) of aspirin in N-BMMs and N-MCM-41 indicated that BMMs have more drug loading capacity and faster release rate than that MCM-41. Highlights: → Bimodal mesoporous silicas (BMMs) and MCM-41 modified with amino group via post-treatment procedure. → Loading and release profiles of aspirin in modified BMMs and MCM-41. → Modified BMMs have more drug loading capacity and faster release rate than that modified MCM-41.

  15. The role of function analysis in the ACR control centre design

    International Nuclear Information System (INIS)

    Leger, R.P.; Davey, E.C.

    2006-01-01

    An essential aspect of control centre design is the need to characterize: plant functions and their inter-relationships to support the achievement of operational goals, and roles for humans and automation in sharing and exchanging the execution of functions across all operational phases. Function analysis is a design activity that has been internationally accepted as an approach to satisfy this need. It is recognized as a fundamental and necessary component in the systematic approach to control centre design and is carried out early in the design process. A function analysis can provide a clear basis for: the control centre design for the purposes of design team communication, and customer or regulatory review, the control centre display and control systems, the staffing and layout requirements of the control centre, assessing the completeness of control centre displays and controls prior and supplementary to mock-up walkthroughs or simulator evaluations, and the design of operating procedures and training programs. This paper will explore the role for function analysis in supporting the design of the control centre. The development of the ACR control room will be used as an illustrative context for the discussion. The paper will also discuss the merits of using function analysis in a goal-or function-based approach resulting in a more robust, operationally compatible, and cost-effective design over the life of the plant. Two former papers have previously outlined, the evolution in AECL's application approach and lessons learned in applying function analysis in support of control room design. This paper provides the most recent update to this progression in application refinement. (author)

  16. Top Management Control Functions for Information Systems in Small and Medium Enterprises

    Directory of Open Access Journals (Sweden)

    Uma VIJAYAKUMAR

    2009-01-01

    Full Text Available This paper analyzes the Top Management Control functions for Information Systems (IS in Small and Medium Enterprises (SMEs. SMEs extensively rely on information technology resources to enhance their competence in today’s global economy. They should have adequate top management control mechanisms in place for their efficient functioning. Top Management Controls determine how effectively the senior management manages the IS functions in a SME. The major tasks at this level consist of Planning, Organizing, Leading and Controlling functions. A brief introduction to SMEs is given at the beginning followed by the different categories of Top Management Controls. The final section highlights on some good practices to be followed by Top Management to realize the vision for the IS project in SMEs.

  17. Expression of Versican 3′-Untranslated Region Modulates Endogenous MicroRNA Functions

    Science.gov (United States)

    Lee, Daniel Y.; Jeyapalan, Zina; Fang, Ling; Yang, Jennifer; Zhang, Yaou; Yee, Albert Y.; Li, Minhui; Du, William W.; Shatseva, Tatiana; Yang, Burton B.

    2010-01-01

    Background Mature microRNAs (miRNAs) are single-stranded RNAs that regulate post-transcriptional gene expression. In our previous study, we have shown that versican 3′UTR, a fragment of non-coding transcript, has the ability to antagonize miR-199a-3p function thereby regulating expression of the matrix proteins versican and fibronectin, and thus resulting in enhanced cell-cell adhesion and organ adhesion. However, the impact of this non-coding fragment on tumorigenesis is yet to be determined. Methods and Findings Using computational prediction confirmed with in vitro and in vivo experiments, we report that the expression of versican 3′UTR not only antagonizes miR-199a-3p but can also lower its steady state expression. We found that expression of versican 3′UTR in a mouse breast carcinoma cell line, 4T1, decreased miR-199a-3p levels. The decrease in miRNA activity consequently translated into differences in tumor growth. Computational analysis indicated that both miR-199a-3p and miR-144 targeted a cell cycle regulator, Rb1. In addition, miR-144 and miR-136, which have also been shown to interact with versican 3′UTR, was found to target PTEN. Expression of Rb1 and PTEN were up-regulated synergistically in vitro and in vivo, suggesting that the 3′UTR binds and modulates miRNA activities, freeing Rb1 and PTEN mRNAs for translation. In tumor formation assays, cells transfected with the 3′UTR formed smaller tumors compared with cells transfected with a control vector. Conclusion Our results demonstrated that a 3′UTR fragment can be used to modulate miRNA functions. Our study also suggests that miRNAs in the cancer cells are more susceptible to degradation, due to its interaction with a non-coding 3′UTR. This non-coding component of mRNA may be used retrospectively to modulate miRNA activities. PMID:21049042

  18. Expression of versican 3'-untranslated region modulates endogenous microRNA functions.

    Science.gov (United States)

    Lee, Daniel Y; Jeyapalan, Zina; Fang, Ling; Yang, Jennifer; Zhang, Yaou; Yee, Albert Y; Li, Minhui; Du, William W; Shatseva, Tatiana; Yang, Burton B

    2010-10-25

    Mature microRNAs (miRNAs) are single-stranded RNAs that regulate post-transcriptional gene expression. In our previous study, we have shown that versican 3'UTR, a fragment of non-coding transcript, has the ability to antagonize miR-199a-3p function thereby regulating expression of the matrix proteins versican and fibronectin, and thus resulting in enhanced cell-cell adhesion and organ adhesion. However, the impact of this non-coding fragment on tumorigenesis is yet to be determined. Using computational prediction confirmed with in vitro and in vivo experiments, we report that the expression of versican 3'UTR not only antagonizes miR-199a-3p but can also lower its steady state expression. We found that expression of versican 3'UTR in a mouse breast carcinoma cell line, 4T1, decreased miR-199a-3p levels. The decrease in miRNA activity consequently translated into differences in tumor growth. Computational analysis indicated that both miR-199a-3p and miR-144 targeted a cell cycle regulator, Rb1. In addition, miR-144 and miR-136, which have also been shown to interact with versican 3'UTR, was found to target PTEN. Expression of Rb1 and PTEN were up-regulated synergistically in vitro and in vivo, suggesting that the 3'UTR binds and modulates miRNA activities, freeing Rb1 and PTEN mRNAs for translation. In tumor formation assays, cells transfected with the 3'UTR formed smaller tumors compared with cells transfected with a control vector. Our results demonstrated that a 3'UTR fragment can be used to modulate miRNA functions. Our study also suggests that miRNAs in the cancer cells are more susceptible to degradation, due to its interaction with a non-coding 3'UTR. This non-coding component of mRNA may be used retrospectively to modulate miRNA activities.

  19. Expression of versican 3'-untranslated region modulates endogenous microRNA functions.

    Directory of Open Access Journals (Sweden)

    Daniel Y Lee

    Full Text Available BACKGROUND: Mature microRNAs (miRNAs are single-stranded RNAs that regulate post-transcriptional gene expression. In our previous study, we have shown that versican 3'UTR, a fragment of non-coding transcript, has the ability to antagonize miR-199a-3p function thereby regulating expression of the matrix proteins versican and fibronectin, and thus resulting in enhanced cell-cell adhesion and organ adhesion. However, the impact of this non-coding fragment on tumorigenesis is yet to be determined. METHODS AND FINDINGS: Using computational prediction confirmed with in vitro and in vivo experiments, we report that the expression of versican 3'UTR not only antagonizes miR-199a-3p but can also lower its steady state expression. We found that expression of versican 3'UTR in a mouse breast carcinoma cell line, 4T1, decreased miR-199a-3p levels. The decrease in miRNA activity consequently translated into differences in tumor growth. Computational analysis indicated that both miR-199a-3p and miR-144 targeted a cell cycle regulator, Rb1. In addition, miR-144 and miR-136, which have also been shown to interact with versican 3'UTR, was found to target PTEN. Expression of Rb1 and PTEN were up-regulated synergistically in vitro and in vivo, suggesting that the 3'UTR binds and modulates miRNA activities, freeing Rb1 and PTEN mRNAs for translation. In tumor formation assays, cells transfected with the 3'UTR formed smaller tumors compared with cells transfected with a control vector. CONCLUSION: Our results demonstrated that a 3'UTR fragment can be used to modulate miRNA functions. Our study also suggests that miRNAs in the cancer cells are more susceptible to degradation, due to its interaction with a non-coding 3'UTR. This non-coding component of mRNA may be used retrospectively to modulate miRNA activities.

  20. Functional integration of vertical flight path and speed control using energy principles

    Science.gov (United States)

    Lambregts, A. A.

    1984-01-01

    A generalized automatic flight control system was developed which integrates all longitudinal flight path and speed control functions previously provided by a pitch autopilot and autothrottle. In this design, a net thrust command is computed based on total energy demand arising from both flight path and speed targets. The elevator command is computed based on the energy distribution error between flight path and speed. The engine control is configured to produce the commanded net thrust. The design incorporates control strategies and hierarchy to deal systematically and effectively with all aircraft operational requirements, control nonlinearities, and performance limits. Consistent decoupled maneuver control is achieved for all modes and flight conditions without outer loop gain schedules, control law submodes, or control function duplication.

  1. Functioning strategy study on control systems of large physical installations used with a digital computer

    International Nuclear Information System (INIS)

    Bel'man, L.B.; Lavrikov, S.A.; Lenskij, O.D.

    1975-01-01

    A criterion to evaluate the efficiency of a control system functioning of large physical installations by means of a control computer. The criteria are the object utilization factor and computer load factor. Different strategies of control system functioning are described, and their comparative analysis is made. A choice of such important parameters as sampling time and parameter correction time is made. A single factor to evaluate the system functioning efficiency is introduced and its dependence on the sampling interval value is given. Using diagrams attached, it is easy to find the optimum value of the sampling interval and the corresponding maximum value of the single efficiency factor proposed

  2. Control-flow analysis of function calls and returns by abstract interpretation

    DEFF Research Database (Denmark)

    Midtgaard, Jan; Jensen, Thomas P.

    2009-01-01

    We derive a control-flow analysis that approximates the interprocedural control-flow of both function calls and returns in the presence of first-class functions and tail-call optimization. In addition to an abstract environment, our analysis computes for each expression an abstract control stack......, effectively approximating where function calls return across optimized tail calls. The analysis is systematically calculated by abstract interpretation of the stack-based CaEK abstract machine of Flanagan et al. using a series of Galois connections. Abstract interpretation provides a unifying setting in which...

  3. State feedback integral control for a rotary direct drive servo valve using a Lyapunov function approach.

    Science.gov (United States)

    Yu, Jue; Zhuang, Jian; Yu, Dehong

    2015-01-01

    This paper concerns a state feedback integral control using a Lyapunov function approach for a rotary direct drive servo valve (RDDV) while considering parameter uncertainties. Modeling of this RDDV servovalve reveals that its mechanical performance is deeply influenced by friction torques and flow torques; however, these torques are uncertain and mutable due to the nature of fluid flow. To eliminate load resistance and to achieve satisfactory position responses, this paper develops a state feedback control that integrates an integral action and a Lyapunov function. The integral action is introduced to address the nonzero steady-state error; in particular, the Lyapunov function is employed to improve control robustness by adjusting the varying parameters within their value ranges. This new controller also has the advantages of simple structure and ease of implementation. Simulation and experimental results demonstrate that the proposed controller can achieve higher control accuracy and stronger robustness. Copyright © 2014 ISA. Published by Elsevier Ltd. All rights reserved.

  4. Using block pulse functions for seismic vibration semi-active control of structures with MR dampers

    Science.gov (United States)

    Rahimi Gendeshmin, Saeed; Davarnia, Daniel

    2018-03-01

    This article applied the idea of block pulse functions in the semi-active control of structures. The BP functions give effective tools to approximate complex problems. The applied control algorithm has a major effect on the performance of the controlled system and the requirements of the control devices. In control problems, it is important to devise an accurate analytical technique with less computational cost. It is proved that the BP functions are fundamental tools in approximation problems which have been applied in disparate areas in last decades. This study focuses on the employment of BP functions in control algorithm concerning reduction the computational cost. Magneto-rheological (MR) dampers are one of the well-known semi-active tools that can be used to control the response of civil Structures during earthquake. For validation purposes, numerical simulations of a 5-story shear building frame with MR dampers are presented. The results of suggested method were compared with results obtained by controlling the frame by the optimal control method based on linear quadratic regulator theory. It can be seen from simulation results that the suggested method can be helpful in reducing seismic structural responses. Besides, this method has acceptable accuracy and is in agreement with optimal control method with less computational costs.

  5. The central role of trunk control in the gross motor function of children with cerebral palsy

    DEFF Research Database (Denmark)

    Curtis, Derek John; Butler, Penny; Saavedra, Sandy

    2015-01-01

    . The participants were tested using the Gross Motor Function Measure (GMFM), the Pediatric Evaluation of Disability Inventory (PEDI), and the Segmental Assessment of Trunk Control (SATCo). Results Linear regression analysis showed a positive relationship between the segmental level of trunk control and age......, with both gross motor function and mobility. Segmental trunk control measured using the SATCo could explain between 38% and 40% of variation in GMFM and between 32% and 37% of variation in PEDI. Interpretation This study suggests a strong association between segmental trunk postural control and gross motor...

  6. Integrative Genomic Analysis of Coincident Cancer Foci Implicates CTNNB1 and PTEN Alterations in Ductal Prostate Cancer.

    Science.gov (United States)

    Gillard, Marc; Lack, Justin; Pontier, Andrea; Gandla, Divya; Hatcher, David; Sowalsky, Adam G; Rodriguez-Nieves, Jose; Vander Griend, Donald; Paner, Gladell; VanderWeele, David

    2017-12-08

    Ductal adenocarcinoma of the prostate is an aggressive subtype, with high rates of biochemical recurrence and overall poor prognosis. It is frequently found coincident with conventional acinar adenocarcinoma. The genomic features driving evolution to its ductal histology and the biology associated with its poor prognosis remain unknown. To characterize genomic features distinguishing ductal adenocarcinoma from coincident acinar adenocarcinoma foci from the same patient. Ten patients with coincident acinar and ductal prostate cancer underwent prostatectomy. Laser microdissection was used to separately isolate acinar and ductal foci. DNA and RNA were extracted, and used for integrative genomic and transcriptomic analyses. Single nucleotide mutations, small indels, copy number estimates, and expression profiles were identified. Phylogenetic relationships between coincident foci were determined, and characteristics distinguishing ductal from acinar foci were identified. Exome sequencing, copy number estimates, and fusion genes demonstrated coincident ductal and acinar adenocarcinoma diverged from a common progenitor, yet they harbored distinct alterations unique to each focus. AR expression and activity were similar in both histologies. Nine of 10 cases had mutually exclusive CTNNB1 hotspot mutations or phosphatase and tensin homolog (PTEN) alterations in the ductal component, and these were absent in the acinar foci. These alterations were associated with changes in expression in WNT- and PI3K-pathway genes. Coincident ductal and acinar histologies typically are clonally related and thus arise from the same cell of origin. Ductal foci are enriched for cases with either a CTNNB1 hotspot mutation or a PTEN alteration, and are associated with WNT- or PI3K-pathway activation. These alterations are mutually exclusive and may represent distinct subtypes. The aggressive subtype ductal adenocarcinoma is closely related to conventional acinar prostate cancer. Ductal foci

  7. Self-tuning control of a nuclear reactor using a Gaussian function neural network

    International Nuclear Information System (INIS)

    Park, M.G.; Cho, N.Z.

    1995-01-01

    A self-tuning control method is described for a nuclear reactor system that requires only a set of input-output measurements. The use of an artificial neural network in nonlinear model-based adaptive control, both as a plant model and a controller, is investigated. A neural network called a Gaussian function network is used for one-step-ahead predictive control to track the desired plant output. The effectiveness of the controller is demonstrated by the application of the method to the power tracking control of the Korea Multipurpose Research Reactor

  8. INTEGRATION OF INFORMATIONAL COMPUTER TECHNOLOGIES SMK: AUTOMATION OF THE MAIN FUNCTIONS OF THE TECHNICAL CONTROL DEPARTMENT

    Directory of Open Access Journals (Sweden)

    S. A. Pavlenko

    2010-01-01

    Full Text Available It is shown that automation of some functions of control department allows to record defects, reclamations and failures of technology, to make the necessary reporting forms and quality certificates for production.

  9. Cognitive Functions, Personality Traits, and Social Values in Heavy Marihuana Smokers and Nonsmoker Controls

    Science.gov (United States)

    Weckowicz, Thaddeus E.; Janssen, Doug V.

    1973-01-01

    To determine the effect of chronic marihuana smoking on cognitive functions, personality traits, and social values, a group of heavy marihuana smokers was compared with a matched control group. (Author)

  10. Controllability of impulsive neutral functional differential inclusions with infinite delay in Banach spaces

    International Nuclear Information System (INIS)

    Chang, Y.-K.; Anguraj, A.; Mallika Arjunan, M.

    2009-01-01

    In this work, we establish a sufficient condition for the controllability of the first-order impulsive neutral functional differential inclusions with infinite delay in Banach spaces. The results are obtained by using the Dhage's fixed point theorem.

  11. Adaptive Neural Control of Nonaffine Nonlinear Systems without Differential Condition for Nonaffine Function

    Directory of Open Access Journals (Sweden)

    Chaojiao Sun

    2016-01-01

    Full Text Available An adaptive neural control scheme is proposed for nonaffine nonlinear system without using the implicit function theorem or mean value theorem. The differential conditions on nonaffine nonlinear functions are removed. The control-gain function is modeled with the nonaffine function probably being indifferentiable. Furthermore, only a semibounded condition for nonaffine nonlinear function is required in the proposed method, and the basic idea of invariant set theory is then constructively introduced to cope with the difficulty in the control design for nonaffine nonlinear systems. It is rigorously proved that all the closed-loop signals are bounded and the tracking error converges to a small residual set asymptotically. Finally, simulation examples are provided to demonstrate the effectiveness of the designed method.

  12. Hydrotherapy improves pain and function in older women with knee osteoarthritis: a randomized controlled trial

    OpenAIRE

    Dias, João Marcos; Cisneros, Lígia; Dias, Rosângela; Fritsch, Carolina; Gomes, Wellington; Pereira, Leani; Santos, Mary Luci; Ferreira, Paulo Henrique

    2017-01-01

    Background Currently, there is poor evidence of the effect of hydrotherapy alone on patients with hip or knee osteoarthritis. Objectives The study aimed to assess the impact of hydrotherapy on pain, function, and muscle function in older women with knee osteoarthritis. Methods A randomized controlled trial was conducted to evaluate the efficacy of hydrotherapy in women with knee osteoarthritis. Seventy-three women aged 65 and older were randomized to hydrotherapy (n = 36) or a control group (...

  13. Controlled growth of silica-titania hybrid functional nanoparticles through a multistep microfluidic approach.

    Science.gov (United States)

    Shiba, K; Sugiyama, T; Takei, T; Yoshikawa, G

    2015-11-11

    Silica/titania-based functional nanoparticles were prepared through controlled nucleation of titania and subsequent encapsulation by silica through a multistep microfluidic approach, which was successfully applied to obtaining aminopropyl-functionalized silica/titania nanoparticles for a highly sensitive humidity sensor.

  14. Computer-controlled mechanical lung model for application in pulmonary function studies

    NARCIS (Netherlands)

    A.F.M. Verbraak (Anton); J.E.W. Beneken; J.M. Bogaard (Jan); A. Versprille (Adrian)

    1995-01-01

    textabstractA computer controlled mechanical lung model has been developed for testing lung function equipment, validation of computer programs and simulation of impaired pulmonary mechanics. The construction, function and some applications are described. The physical model is constructed from two

  15. A new kind of data acquisition control system with multi-functions

    International Nuclear Information System (INIS)

    Zhang Songshou; Li Shuyuan; Li Runxin; Guo Dunjun

    1996-01-01

    The paper introduces a new kind of data acquisition control system with multi-functions. The system uses the single-chip microcomputer and the standard STD system. The text recounts its functions, principal, constitution, software and hardware designs, experiment outcome and the conclusions

  16. Computation of piecewise affine terminal cost functions for model predictive control

    NARCIS (Netherlands)

    Brunner, F.D.; Lazar, M.; Allgöwer, F.; Fränzle, Martin; Lygeros, John

    2014-01-01

    This paper proposes a method for the construction of piecewise affine terminal cost functions for model predictive control (MPC). The terminal cost function is constructed on a predefined partition by solving a linear program for a given piecewise affine system, a stabilizing piecewise affine

  17. Functional Group Analysis for Diesel-like Mixing-Controlled Compression Ignition Combustion Blendstocks

    Energy Technology Data Exchange (ETDEWEB)

    Gaspar, Daniel J.; McCormick, Robert L.; Polikarpov, Evgueni; Fioroni, Gina; George, Anthe; Albrecht, Karl O.

    2016-12-30

    This report addresses the suitability of hydrocarbon and oxygenate functional groups for use as a diesel-like fuel blending component in an advanced, mixing-controlled, compression ignition combustion engine. The functional groups are chosen from those that could be derived from a biomass feedstock, and represent a full range of chemistries. This first systematic analysis of functional groups will be of value to all who are pursuing new bio-blendstocks for diesel-like fuels.

  18. Family functioning in patients with obsessive compulsive disorder: A case - control study

    OpenAIRE

    Sateesh R Koujalgi; Raghavendra B Nayak; Adithya A Pandurangi; Nanasahed M Patil

    2015-01-01

    Background: Psychological disorders can have a direct impact on family functioning. Family dysfunction is an indirect factor leading to the relapse of psychological disorders. Literature on family dysfunction in anxiety disorder is limited. Role of family and its functioning in obsessive-compulsive disorder (OCD) may help in better understanding of the role of social factors in OCD. Aim: The aim was to compare family functions in patients with OCD and compare with controls. Materials and Meth...

  19. Modeling goals and functions of control and safety systems - theoretical foundations and extensions of MFM

    International Nuclear Information System (INIS)

    Lind, M.

    2005-10-01

    Multilevel Flow Modeling (MFM) has proven to be an effective modeling tool for reasoning about plant failure and control strategies and is currently exploited for operator support in diagnosis and on-line alarm analysis. Previous MFM research was focussed on representing goals and functions of process plants which generate, transform and distribute mass and energy. However, only a limited consideration has been given to the problems of modeling the control systems. Control functions are indispensable for operating any industrial plant. But modeling of control system functions has proven to be a more challenging problem than modeling functions of energy and mass processes. The problems were discussed by Lind and tentative solutions has been proposed but have not been investigated in depth until recently, partly due to the lack of an appropriate theoretical foundation. The purposes of the present report are to show that such a theoretical foundation for modeling goals and functions of control systems can be built from concepts and theories of action developed by Von Wright and to show how the theoretical foundation can be used to extend MFM with concepts for modeling control systems. The theoretical foundations has been presented in detail elsewhere by the present author without the particular focus on modeling control actions and MFM adopted here. (au)

  20. Modeling goals and functions of control and safety systems -theoretical foundations and extensions of MFM

    Energy Technology Data Exchange (ETDEWEB)

    Lind, M. [Oersted - DTU, Kgs. Lyngby (Denmark)

    2005-10-01

    Multilevel Flow Modeling (MFM) has proven to be an effective modeling tool for reasoning about plant failure and control strategies and is currently exploited for operator support in diagnosis and on-line alarm analysis. Previous MFM research was focussed on representing goals and functions of process plants which generate, transform and distribute mass and energy. However, only a limited consideration has been given to the problems of modeling the control systems. Control functions are indispensable for operating any industrial plant. But modeling of control system functions has proven to be a more challenging problem than modeling functions of energy and mass processes. The problems were discussed by Lind and tentative solutions has been proposed but have not been investigated in depth until recently, partly due to the lack of an appropriate theoretical foundation. The purposes of the present report are to show that such a theoretical foundation for modeling goals and functions of control systems can be built from concepts and theories of action developed by Von Wright and to show how the theoretical foundation can be used to extend MFM with concepts for modeling control systems. The theoretical foundations has been presented in detail elsewhere by the present author without the particular focus on modeling control actions and MFM adopted here. (au)

  1. Real-time and wearable functional electrical stimulation system for volitional hand motor function control using the electromyography bridge method

    Directory of Open Access Journals (Sweden)

    Hai-peng Wang

    2017-01-01

    Full Text Available Voluntary participation of hemiplegic patients is crucial for functional electrical stimulation therapy. A wearable functional electrical stimulation system has been proposed for real-time volitional hand motor function control using the electromyography bridge method. Through a series of novel design concepts, including the integration of a detecting circuit and an analog-to-digital converter, a miniaturized functional electrical stimulation circuit technique, a low-power super-regeneration chip for wireless receiving, and two wearable armbands, a prototype system has been established with reduced size, power, and overall cost. Based on wrist joint torque reproduction and classification experiments performed on six healthy subjects, the optimized surface electromyography thresholds and trained logistic regression classifier parameters were statistically chosen to establish wrist and hand motion control with high accuracy. Test results showed that wrist flexion/extension, hand grasp, and finger extension could be reproduced with high accuracy and low latency. This system can build a bridge of information transmission between healthy limbs and paralyzed limbs, effectively improve voluntary participation of hemiplegic patients, and elevate efficiency of rehabilitation training.

  2. Cognitive performance and psychosocial functioning in patients with bipolar disorder, unaffected siblings, and healthy controls.

    Science.gov (United States)

    Vasconcelos-Moreno, Mirela P; Bücker, Joana; Bürke, Kelen P; Czepielewski, Leticia; Santos, Barbara T; Fijtman, Adam; Passos, Ives C; Kunz, Mauricio; Bonnín, Caterina Del Mar; Vieta, Eduard; Kapczinski, Flavio; Rosa, Adriane R; Kauer-Sant'Anna, Marcia

    2016-01-01

    To assess cognitive performance and psychosocial functioning in patients with bipolar disorder (BD), in unaffected siblings, and in healthy controls. Subjects were patients with BD (n=36), unaffected siblings (n=35), and healthy controls (n=44). Psychosocial functioning was accessed using the Functioning Assessment Short Test (FAST). A sub-group of patients with BD (n=21), unaffected siblings (n=14), and healthy controls (n=22) also underwent a battery of neuropsychological tests: California Verbal Learning Test (CVLT), Stroop Color and Word Test, and Wisconsin Card Sorting Test (WCST). Clinical and sociodemographic characteristics were analyzed using one-way analysis of variance or the chi-square test; multivariate analysis of covariance was used to examine differences in neuropsychological variables. Patients with BD showed higher FAST total scores (23.90±11.35) than healthy controls (5.86±5.47; p siblings (12.60±11.83; p 0.001). Siblings and healthy controls also showed statistically significant differences in FAST total scores (p = 0.008). Patients performed worse than healthy controls on all CVLT sub-tests (p Siblings did not differ from healthy controls in cognitive tests. Unaffected siblings of patients with BD may show poorer functional performance compared to healthy controls. FAST scores may contribute to the development of markers of vulnerability and endophenotypic traits in at-risk populations.

  3. Interpolation of polytopic control Lyapunov functions for discrete–time linear systems

    NARCIS (Netherlands)

    Nguyen, T.T.; Lazar, M.; Spinu, V.; Boje, E.; Xia, X.

    2014-01-01

    This paper proposes a method for interpolating two (or more) polytopic control Lyapunov functions (CLFs) for discrete--time linear systems subject to polytopic constraints, thereby combining different control objectives. The corresponding interpolated CLF is used for synthesis of a stabilizing

  4. Unilateral versus bilateral robot-assisted rehabilitation on arm-trunk control and functions post stroke: a randomized controlled trial.

    Science.gov (United States)

    Wu, Ching-Yi; Yang, Chieh-Ling; Chen, Ming-de; Lin, Keh-Chung; Wu, Li-Ling

    2013-04-12

    Although the effects of robot-assisted arm training after stroke are promising, the relative effects of unilateral (URT) vs. bilateral (BRT) robot-assisted arm training remain uncertain. This study compared the effects of URT vs. BRT on upper extremity (UE) control, trunk compensation, and function in patients with chronic stroke. This was a single-blinded, randomized controlled trial. The intervention was implemented at 4 hospitals. Fifty-three patients with stroke were randomly assigned to URT, BRT, or control treatment (CT). Each group received UE training for 90 to 105 min/day, 5 days/week, for 4 weeks. The kinematic variables for arm motor control and trunk compensation included normalized movement time, normalized movement units, and the arm-trunk contribution slope in unilateral and bilateral tasks. Motor function and daily function were measured by the Wolf Motor Function Test (WMFT), Motor Activity Log (MAL), and ABILHAND Questionnaire. The BRT and CT groups elicited significantly larger slope values (i.e., less trunk compensation) at the start of bilateral reaching than the URT group. URT led to significantly better effects on WMFT-Time than BRT. Differences in arm control kinematics and performance on the MAL and ABILHAND among the 3 groups were not significant. BRT and URT resulted in differential improvements in specific UE/trunk performance in patients with stroke. BRT elicited larger benefits than URT on reducing compensatory trunk movements at the beginning of reaching. In contrast, URT produced better improvements in UE temporal efficiency. These relative effects on movement kinematics, however, did not translate into differential benefits in daily functions. ClinicalTrials.gov: NCT00917605.

  5. Nonlinear H∞ Optimal Control Scheme for an Underwater Vehicle with Regional Function Formulation

    Directory of Open Access Journals (Sweden)

    Zool H. Ismail

    2013-01-01

    Full Text Available A conventional region control technique cannot meet the demands for an accurate tracking performance in view of its inability to accommodate highly nonlinear system dynamics, imprecise hydrodynamic coefficients, and external disturbances. In this paper, a robust technique is presented for an Autonomous Underwater Vehicle (AUV with region tracking function. Within this control scheme, nonlinear H∞ and region based control schemes are used. A Lyapunov-like function is presented for stability analysis of the proposed control law. Numerical simulations are presented to demonstrate the performance of the proposed tracking control of the AUV. It is shown that the proposed control law is robust against parameter uncertainties, external disturbances, and nonlinearities and it leads to uniform ultimate boundedness of the region tracking error.

  6. Task control signals in pediatric Tourette syndrome show evidence of immature and anomalous functional activity

    Directory of Open Access Journals (Sweden)

    Jessica A Church

    2009-11-01

    Full Text Available Tourette Syndrome (TS is a pediatric movement disorder that may affect control signaling in the brain. Previous work has proposed a dual-networks architecture of control processing involving a task-maintenance network and an adaptive control network (Dosenbach et al., 2008. A prior resting-state functional connectivity MRI (rs-fcMRI analysis in TS has revealed functional immaturity in both putative control networks, with “anomalous” correlations (i.e. correlations outside the typical developmental range limited to the adaptive control network (Church et al., 2009. The present study used functional MRI (fMRI to study brain activity related to adaptive control (by studying start-cues signals, and to task-maintenance (by studying signals sustained across a task set. Two hypotheses from the previous rs-fcMRI results were tested. First, adaptive control (i.e., start-cue activity will be altered in TS, including activity inconsistent with typical development (“anomalous”. Second, group differences found in task maintenance (i.e., sustained activity will be consistent with functional immaturity in TS. We examined regions found through a direct comparison of adolescents with and without TS, as well as regions derived from a previous investigation that showed differences between unaffected children and adults. The TS group showed decreased start-cue signal magnitude in regions where start-cue activity is unchanged over typical development, consistent with anomalous adaptive control. The TS group also had higher magnitude sustained signals in frontal cortex regions that overlapped with regions showing differences over typical development, consistent with immature task maintenance in TS. The results demonstrate task-related fMRI signal differences anticipated by the atypical functional connectivity found previously in adolescents with TS, strengthening the evidence for functional immaturity and anomalous signaling in control networks in adolescents

  7. Patients suffering from restless legs syndrome have low internal locus of control and poor psychological functioning compared to healthy controls.

    Science.gov (United States)

    Brand, Serge; Beck, Johannes; Hatzinger, Martin; Holsboer-Trachsler, Edith

    2013-01-01

    Restless legs syndrome (RLS) is a disturbing sensorimotor disorder negatively influencing both sleep and psychological functioning. The aim of the present study was to assess RLS patients with respect to locus of control, sleep-related personality traits, quality of life, and sleep as compared to healthy controls. Thirty-eight patients (18 females and 20 males; mean age: 56.06 years) diagnosed with RLS and an age- and gender-matched control group (n = 42) were recruited. Participants completed a series of questionnaires related to locus of control, personality traits, quality of life, and sleep. Compared to healthy controls, RLS patients had a lower internal locus of control, unfavourable sleep-related personality traits such as low self-confidence and higher mental arousal, poorer quality of life, and more depressive symptoms. Sleep was also affected. Multiple regression analyses showed that a low internal and a high external locus of control were predicted by RLS. The pattern of results suggests that RLS is associated with a low locus of control, negative personality traits, and poor quality of life as compared to healthy controls. Copyright © 2013 S. Karger AG, Basel.

  8. Life event stress in duodenal ulcer compared with functional dyspepsia: A case-control study

    OpenAIRE

    Abdel Hafeiz Hassan; Al Quorain Abdulaziz; Karim Ahmed; Al-Mangoor Shuaa

    1997-01-01

    This is a prospective study of life event stress in 80 duodenal ulcer patients compared with 80 patients with functional dyspepsia and 80 healthy controls; matched for age, sex and marital status. A semi structured psychiatric interview was used in the psychiatric assessment of the dyspeptic patients and controls. A modified version of Life Events Scale by Tennant and Andrews was used in the assessment of life event stress. More dyspeptic patients reported life events than the controls, but, ...

  9. Regulation of brain insulin signaling: A new function for tau.

    Science.gov (United States)

    Gratuze, Maud; Planel, Emmanuel

    2017-08-07

    In this issue of JEM, Marciniak et al. (https://doi.org/10.1084/jem.20161731) identify a putative novel function of tau protein as a regulator of insulin signaling in the brain. They find that tau deletion impairs hippocampal response to insulin through IRS-1 and PTEN dysregulation and suggest that, in Alzheimer's disease, impairment of brain insulin signaling might occur via tau loss of function. © 2017 Gratuze and Planel.

  10. A comparison of the difference of requirements between functional safety and nuclear safety controllers

    Energy Technology Data Exchange (ETDEWEB)

    Chen, C.K.; Lee, C.L.; Shyu, S.S. [Inst. of Nuclear Energy Research, Taoyuan, Taiwan (China)

    2014-07-01

    In order to establish self-reliant capabilities of nuclear I&C systems in Taiwan, Taiwan's Nuclear I&C System (TNICS) project had been established by Institute of Nuclear Energy Research (INER). A Triple Modular Redundant (TMR) safety controller (SCS-2000) has been completed and gone through the IEC 61508 Safety Integrity Level 3 (SIL3) certification of Functional Safety for industries. Based on the certification processes, the difference of requirements between Functional Safety and Nuclear Safety controllers in term of hardware and software are addressed in this study. Besides, the measures used to determine and verify the reliability of the safety control system design are presented. (author)

  11. Sliding mode control-based linear functional observers for discrete-time stochastic systems

    Science.gov (United States)

    Singh, Satnesh; Janardhanan, Sivaramakrishnan

    2017-11-01

    Sliding mode control (SMC) is one of the most popular techniques to stabilise linear discrete-time stochastic systems. However, application of SMC becomes difficult when the system states are not available for feedback. This paper presents a new approach to design a SMC-based functional observer for discrete-time stochastic systems. The functional observer is based on the Kronecker product approach. Existence conditions and stability analysis of the proposed observer are given. The control input is estimated by a novel linear functional observer. This approach leads to a non-switching type of control, thereby eliminating the fundamental cause of chatter. Furthermore, the functional observer is designed in such a way that the effect of process and measurement noise is minimised. Simulation example is given to illustrate and validate the proposed design method.

  12. Functional-Strengthening: A Pilot Study on Balance Control Improvement in Community-Dwelling Older Adults

    Directory of Open Access Journals (Sweden)

    Micah D. Josephson

    2017-09-01

    Full Text Available Adults over the age of 65 have a 1 in 3 chance of falling; in 2012, more than $30 billion was spent on medical costs due to these falls. The division of resistance training and neuromotor training balance improvement interventions has shown to yield low to moderate results. Athletes combine both resistance training and skill development (function training to improve skilled performance. Older adults may not be performing high-level sports activities, but still require strength, power, and functional fitness levels to perform relatively high-level skills. The purpose of this study was to determine the effects of combining resistance and functional training into functional-strength training on dynamic balance control in moderately active older adults. Eighteen healthy older adults were divided into three groups; functional resistance, standard resistance, and control. All groups met for their intervention twice a week for six weeks. Dynamic balance was assessed using the Fullerton Advanced Balance Scale (0-40. Results of individual paired T-tests showed a significant improvement in balance control in the functional resistance group (t(5 =-3.492, p=.017 and a very large effect size (d=1.33 whereas neither the standard resistance nor control group had a significant reduction in the risk of falls. Manipulating multidimensional, neuromotor function during resistance training exercises is an effective method of applying the overload principle in order to reduce falls risk in moderately active seniors.

  13. Coherent molecular transistor: control through variation of the gate wave function.

    Science.gov (United States)

    Ernzerhof, Matthias

    2014-03-21

    In quantum interference transistors (QUITs), the current through the device is controlled by variation of the gate component of the wave function that interferes with the wave function component joining the source and the sink. Initially, mesoscopic QUITs have been studied and more recently, QUITs at the molecular scale have been proposed and implemented. Typically, in these devices the gate lead is subjected to externally adjustable physical parameters that permit interference control through modifications of the gate wave function. Here, we present an alternative model of a molecular QUIT in which the gate wave function is directly considered as a variable and the transistor operation is discussed in terms of this variable. This implies that we specify the gate current as well as the phase of the gate wave function component and calculate the resulting current through the source-sink channel. Thus, we extend on prior works that focus on the phase of the gate wave function component as a control parameter while having zero or certain discrete values of the current. We address a large class of systems, including finite graphene flakes, and obtain analytic solutions for how the gate wave function controls the transistor.

  14. Coherent molecular transistor: Control through variation of the gate wave function

    International Nuclear Information System (INIS)

    Ernzerhof, Matthias

    2014-01-01

    In quantum interference transistors (QUITs), the current through the device is controlled by variation of the gate component of the wave function that interferes with the wave function component joining the source and the sink. Initially, mesoscopic QUITs have been studied and more recently, QUITs at the molecular scale have been proposed and implemented. Typically, in these devices the gate lead is subjected to externally adjustable physical parameters that permit interference control through modifications of the gate wave function. Here, we present an alternative model of a molecular QUIT in which the gate wave function is directly considered as a variable and the transistor operation is discussed in terms of this variable. This implies that we specify the gate current as well as the phase of the gate wave function component and calculate the resulting current through the source-sink channel. Thus, we extend on prior works that focus on the phase of the gate wave function component as a control parameter while having zero or certain discrete values of the current. We address a large class of systems, including finite graphene flakes, and obtain analytic solutions for how the gate wave function controls the transistor

  15. Power probability density function control and performance assessment of a nuclear research reactor

    International Nuclear Information System (INIS)

    Abharian, Amir Esmaeili; Fadaei, Amir Hosein

    2014-01-01

    Highlights: • In this paper, the performance assessment of static PDF control system is discussed. • The reactor PDF model is set up based on the B-spline functions. • Acquaints of Nu, and Th-h. equations solve concurrently by reformed Hansen’s method. • A principle of performance assessment is put forward for the PDF of the NR control. - Abstract: One of the main issues in controlling a system is to keep track of the conditions of the system function. The performance condition of the system should be inspected continuously, to keep the system in reliable working condition. In this study, the nuclear reactor is considered as a complicated system and a principle of performance assessment is used for analyzing the performance of the power probability density function (PDF) of the nuclear research reactor control. First, the model of the power PDF is set up, then the controller is designed to make the power PDF for tracing the given shape, that make the reactor to be a closed-loop system. The operating data of the closed-loop reactor are used to assess the control performance with the performance assessment criteria. The modeling, controller design and the performance assessment of the power PDF are all applied to the control of Tehran Research Reactor (TRR) power in a nuclear process. In this paper, the performance assessment of the static PDF control system is discussed, the efficacy and efficiency of the proposed method are investigated, and finally its reliability is proven

  16. Effect of a Dynamic Seating Surface on Postural Control and Function in Children with Cerebral Palsy

    DEFF Research Database (Denmark)

    Meyer, Erna Rosenlund; Trew, Lisa

    Purpose: The purpose was to investigate if a seating system involving a dynamic material covering the seat back and base improves postural control, alignment and function in children with cerebral palsy and to investigate consequences of adapting The Seated Postural Control Measure to a target...... group with multifunctional disabilities. Relevance: Developing sitting systems for disabled persons is of great importance to avoid sitting problems, to increase the level of functioning and postural control which will have an impact on their daily living and activities. This project takes its starting...... Ethical Committee. Outcome measures were Seated Postural Control Measure (SPCM), which was modified to meet the children’s needs, was used to measure alignment and function. Force Sensitive Applications (FSA) on the seat surfaces was used to measure postural movements and interface pressure. All tests...

  17. Automatic transfer function generation using contour tree controlled residue flow model and color harmonics.

    Science.gov (United States)

    Zhou, Jianlong; Takatsuka, Masahiro

    2009-01-01

    Transfer functions facilitate the volumetric data visualization by assigning optical properties to various data features and scalar values. Automation of transfer function specifications still remains a challenge in volume rendering. This paper presents an approach for automating transfer function generations by utilizing topological attributes derived from the contour tree of a volume. The contour tree acts as a visual index to volume segments, and captures associated topological attributes involved in volumetric data. A residue flow model based on Darcy's Law is employed to control distributions of opacity between branches of the contour tree. Topological attributes are also used to control color selection in a perceptual color space and create harmonic color transfer functions. The generated transfer functions can depict inclusion relationship between structures and maximize opacity and color differences between them. The proposed approach allows efficient automation of transfer function generations, and exploration on the data to be carried out based on controlling of opacity residue flow rate instead of complex low-level transfer function parameter adjustments. Experiments on various data sets demonstrate the practical use of our approach in transfer function generations.

  18. Organosilane functionalization of halloysite nanotubes for enhanced loading and controlled release

    International Nuclear Information System (INIS)

    Yuan Peng; Southon, Peter D; Kepert, Cameron J; Liu Zongwen

    2012-01-01

    The surfaces of naturally occurring halloysite nanotubes were functionalized with γ-aminopropyltriethoxysilane (APTES), which was found to have a substantial effect on the loading and subsequent release of a model dye molecule. APTES was mostly anchored at the internal lumen surface of halloysite through covalent grafting, forming a functionalized surface covered by aminopropyl groups. The dye loading of the functionalized halloysite was 32% greater than that of the unmodified sample, and the release from the functionalized halloysite was dramatically prolonged as compared to that from the unmodified one. Dye release was prolonged at low pH and the release at pH 3.5 was approximately three times slower than that at pH 10.0. These results demonstrate that organosilane functionalization makes pH an external trigger for controlling the loading of guest on halloysite and the subsequent controlled release. (paper)

  19. Organosilane functionalization of halloysite nanotubes for enhanced loading and controlled release.

    Science.gov (United States)

    Yuan, Peng; Southon, Peter D; Liu, Zongwen; Kepert, Cameron J

    2012-09-21

    The surfaces of naturally occurring halloysite nanotubes were functionalized with γ-aminopropyltriethoxysilane (APTES), which was found to have a substantial effect on the loading and subsequent release of a model dye molecule. APTES was mostly anchored at the internal lumen surface of halloysite through covalent grafting, forming a functionalized surface covered by aminopropyl groups. The dye loading of the functionalized halloysite was 32% greater than that of the unmodified sample, and the release from the functionalized halloysite was dramatically prolonged as compared to that from the unmodified one. Dye release was prolonged at low pH and the release at pH 3.5 was approximately three times slower than that at pH 10.0. These results demonstrate that organosilane functionalization makes pH an external trigger for controlling the loading of guest on halloysite and the subsequent controlled release.

  20. Functional Basis for Efficient Physical Layer Classical Control in Quantum Processors

    Science.gov (United States)

    Ball, Harrison; Nguyen, Trung; Leong, Philip H. W.; Biercuk, Michael J.

    2016-12-01

    The rapid progress seen in the development of quantum-coherent devices for information processing has motivated serious consideration of quantum computer architecture and organization. One topic which remains open for investigation and optimization relates to the design of the classical-quantum interface, where control operations on individual qubits are applied according to higher-level algorithms; accommodating competing demands on performance and scalability remains a major outstanding challenge. In this work, we present a resource-efficient, scalable framework for the implementation of embedded physical layer classical controllers for quantum-information systems. Design drivers and key functionalities are introduced, leading to the selection of Walsh functions as an effective functional basis for both programing and controller hardware implementation. This approach leverages the simplicity of real-time Walsh-function generation in classical digital hardware, and the fact that a wide variety of physical layer controls, such as dynamic error suppression, are known to fall within the Walsh family. We experimentally implement a real-time field-programmable-gate-array-based Walsh controller producing Walsh timing signals and Walsh-synthesized analog waveforms appropriate for critical tasks in error-resistant quantum control and noise characterization. These demonstrations represent the first step towards a unified framework for the realization of physical layer controls compatible with large-scale quantum-information processing.

  1. Cytotoxic activities of amentoflavone against human breast and cervical cancers are mediated by increasing of PTEN expression levels due to peroxisomes proliferate-activated receptor {gamma} activation

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Eunjung; Shin, Soyoung; Lee, Jeeyoung; Lee, So Jung; Kim, Jinkyoung; Yoon, Doyoung; Kim, Yangmee [Konkuk Univ., Seoul (Korea, Republic of); Woo, Eunrhan [Chosun Univ., Gwangju (Korea, Republic of)

    2012-07-15

    Human peroxisomes proliferate-activated receptor gamma (hPPAR{gamma}) has been implicated in numerous pathologies, including obesity, diabetes, and cancer. Previously, we verified that amentoflavone is an activator of hPPAR{gamma} and probed the molecular basis of its action. In this study, we investigated the mechanism of action of amentoflavone in cancer cells and demonstrated that amentoflavone showed strong cytotoxicity against MCF-7 and HeLa cancer cell lines. We showed that hPPAR{gamma} expression in MCF-7 and HeLa cells is specifically stimulated by amentoflavone, and suggested that amentoflavone-induced cytotoxic activities are mediated by activation of hPPAR{gamma} in these two cancer cell lines. Moreover, amentoflavone increased PTEN levels in these two cancer cell lines, indicating that the cytotoxic activities of amentoflavone are mediated by increasing of PTEN expression levels due to hPPAR{gamma} activation.

  2. Road load simulator tests of the Gould phase 1 functional model silicon controlled rectifier ac motor controller for electric vehicles

    Science.gov (United States)

    Gourash, F.

    1984-01-01

    The test results for a functional model ac motor controller for electric vehicles and a three-phase induction motor which were dynamically tested on the Lewis Research Center road load simulator are presented. Results show that the controller has the capability to meet the SAE-J227a D cycle test schedule and to accelerate a 1576-kg (3456-lb) simulated vehicle to a cruise speed of 88.5 km/hr (55 mph). Combined motor controller efficiency is 72 percent and the power inverter efficiency alone is 89 percent for the cruise region of the D cycle. Steady state test results for motoring, regeneration, and thermal data obtained by operating the simulator as a conventional dynamometer are in agreement with the contractor's previously reported data. The regeneration test results indicate that a reduction in energy requirements for urban driving cycles is attainable with regenerative braking. Test results and data in this report serve as a data base for further development of ac motor controllers and propulsion systems for electric vehicles. The controller uses state-of-the-art silicon controlled rectifier (SCR) power semiconductors and microprocessor-based logic and control circuitry. The controller was developed by Gould Laboratories under a Lewis contract for the Department of Energy's Electric and Hybrid Vehicle program.

  3. Road load simulator tests of the Gould phase 1 functional model silicon controlled rectifier ac motor controller for electric vehicles

    Science.gov (United States)

    Gourash, F.

    1984-02-01

    The test results for a functional model ac motor controller for electric vehicles and a three-phase induction motor which were dynamically tested on the Lewis Research Center road load simulator are presented. Results show that the controller has the capability to meet the SAE-J227a D cycle test schedule and to accelerate a 1576-kg (3456-lb) simulated vehicle to a cruise speed of 88.5 km/hr (55 mph). Combined motor controller efficiency is 72 percent and the power inverter efficiency alone is 89 percent for the cruise region of the D cycle. Steady state test results for motoring, regeneration, and thermal data obtained by operating the simulator as a conventional dynamometer are in agreement with the contractor's previously reported data. The regeneration test results indicate that a reduction in energy requirements for urban driving cycles is attainable with regenerative braking. Test results and data in this report serve as a data base for further development of ac motor controllers and propulsion systems for electric vehicles. The controller uses state-of-the-art silicon controlled rectifier (SCR) power semiconductors and microprocessor-based logic and control circuitry. The controller was developed by Gould Laboratories under a Lewis contract for the Department of Energy's Electric and Hybrid Vehicle program.

  4. The effects of physical activity on functional MRI activation associated with cognitive control in children: a randomized controlled intervention

    Directory of Open Access Journals (Sweden)

    Laura eChaddock-Heyman

    2013-03-01

    Full Text Available This study used functional magnetic resonance imaging (fMRI to examine the influence of a 9-month physical activity program on task-evoked brain activation during childhood. The results demonstrated that 8- to 9-year-old children who participated in 60+ minutes of physical activity, 5 days per week, for 9 months, showed decreases in fMRI brain activation in the right anterior prefrontal cortex coupled with within-group improvements in performance on a task of attentional and interference control. Children assigned to a wait list control group did not show changes in brain function. Furthermore, at post-test, children in the physical activity group showed similar anterior frontal brain patterns and incongruent accuracy rates to a group of college-aged young adults. Children in the wait list control group still differed from the young adults in terms of anterior prefrontal activation and performance at post-test. There were no significant changes in fMRI activation in the anterior cingulate cortex for either group. These results suggest that physical activity during childhood may enhance specific elements of prefrontal cortex function involved in cognitive control.

  5. Dexterous Control of Seven Functional Hand Movements Using Cortically-Controlled Transcutaneous Muscle Stimulation in a Person With Tetraplegia

    Directory of Open Access Journals (Sweden)

    Samuel C. Colachis

    2018-04-01

    Full Text Available Individuals with tetraplegia identify restoration of hand function as a critical, unmet need to regain their independence and improve quality of life. Brain-Computer Interface (BCI-controlled Functional Electrical Stimulation (FES technology addresses this need by reconnecting the brain with paralyzed limbs to restore function. In this study, we quantified performance of an intuitive, cortically-controlled, transcutaneous FES system on standardized object manipulation tasks from the Grasp and Release Test (GRT. We found that a tetraplegic individual could use the system to control up to seven functional hand movements, each with >95% individual accuracy. He was able to select one movement from the possible seven movements available to him and use it to appropriately manipulate all GRT objects in real-time using naturalistic grasps. With the use of the system, the participant not only improved his GRT performance over his baseline, demonstrating an increase in number of transfers for all objects except the Block, but also significantly improved transfer times for the heaviest objects (videocassette (VHS, Can. Analysis of underlying motor cortex neural representations associated with the hand grasp states revealed an overlap or non-separability in neural activation patterns for similarly shaped objects that affected BCI-FES performance. These results suggest that motor cortex neural representations for functional grips are likely more related to hand shape and force required to hold objects, rather than to the objects themselves. These results, demonstrating multiple, naturalistic functional hand movements with the BCI-FES, constitute a further step toward translating BCI-FES technologies from research devices to clinical neuroprosthetics.

  6. Balancing Automatic-Controlled Behaviors and Emotional-Salience States: A Dynamic Executive Functioning Hypothesis.

    Science.gov (United States)

    Kluwe-Schiavon, Bruno; Viola, Thiago W; Sanvicente-Vieira, Breno; Malloy-Diniz, Leandro F; Grassi-Oliveira, Rodrigo

    2016-01-01

    Recently, there has been growing interest in understanding how executive functions are conceptualized in psychopathology. Since several models have been proposed, the major issue lies within the definition of executive functioning itself. Theoretical discussions have emerged, narrowing the boundaries between "hot" and "cold" executive functions or between self-regulation and cognitive control. Nevertheless, the definition of executive functions is far from a consensual proposition and it has been suggested that these models might be outdated. Current efforts indicate that human behavior and cognition are by-products of many brain systems operating and interacting at different levels, and therefore, it is very simplistic to assume a dualistic perspective of information processing. Based upon an adaptive perspective, we discuss how executive functions could emerge from the ability to solve immediate problems and to generalize successful strategies, as well as from the ability to synthesize and to classify environmental information in order to predict context and future. We present an executive functioning perspective that emerges from the dynamic balance between automatic-controlled behaviors and an emotional-salience state. According to our perspective, the adaptive role of executive functioning is to automatize efficient solutions simultaneously with cognitive demand, enabling individuals to engage such processes with increasingly complex problems. Understanding executive functioning as a mediator of stress and cognitive engagement not only fosters discussions concerning individual differences, but also offers an important paradigm to understand executive functioning as a continuum process rather than a categorical and multicomponent structure.

  7. Power control flexibilities for grid-connected multi-functional photovoltaic inverters

    DEFF Research Database (Denmark)

    Yang, Yongheng; Blaabjerg, Frede; Wang, Huai

    2014-01-01

    to reduced cost of energy. To implement the advanced features, a flexible power controller is developed in this paper, which can be configured in the PV inverter and flexibly be changed from one to another. This power control strategy is based on the single-phase PQ theory, and it offers the possibilities...... of ancillary and intelligent services, like Low Voltage Ride-Through (LVRT), reactive power compensation, and reliability-oriented thermal management/control by PV systems is a key to attain higher utilization of solar energy. Those essential functionalities for the future PV inverters can contribute...... to generate appropriate references for the inner current control loop. The references depend on the system conditions and also specific demands from both system operators and customers. Besides, this power control strategy can be implemented in a commercial PV inverter as standardized functions, and also...

  8. Effects of multicomponent training of cognitive control on cognitive function and brain activation in older adults.

    Science.gov (United States)

    Kim, Hoyoung; Chey, Jeanyung; Lee, Sanghun

    2017-11-01

    The aim of this study was to investigate the changes in cognitive functions and brain activation after multicomponent training of cognitive control in non-demented older adults, utilizing neuropsychological tests and fMRI. We developed and implemented a computerized Multicomponent Training of Cognitive Control (MTCC), characterized by task variability and adaptive procedures, in order to maximize training effects in cognitive control and transfer to other cognitive domains. Twenty-seven community-dwelling adults, aged 64-77 years, without any history of neurological or psychiatric problems, participated in this study (14 in the training group and 13 in the control group). The MTCC was administered to the participants assigned to the training group for 8 weeks, while those in the control group received no training. Neuropsychological tests and fMRI were administered prior to and after the training. Trained participants showed improvements in cognitive control, recognition memory and general cognitive functioning. Furthermore, the MTCC led to an increased brain activation of the regions adjacent to the baseline cognitive control-related areas in the frontoparietal network. Future studies are necessary to confirm our hypothesis that MTCC improves cognitive functioning of healthy elderly individuals by expanding their frontoparietal network that is involved in cognitive control. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  9. Bilingualism alters brain functional connectivity between "control" regions and "language" regions: Evidence from bimodal bilinguals.

    Science.gov (United States)

    Li, Le; Abutalebi, Jubin; Zou, Lijuan; Yan, Xin; Liu, Lanfang; Feng, Xiaoxia; Wang, Ruiming; Guo, Taomei; Ding, Guosheng

    2015-05-01

    Previous neuroimaging studies have revealed that bilingualism induces both structural and functional neuroplasticity in the dorsal anterior cingulate cortex (dACC) and the left caudate nucleus (LCN), both of which are associated with cognitive control. Since these "control" regions should work together with other language regions during language processing, we hypothesized that bilingualism may also alter the functional interaction between the dACC/LCN and language regions. Here we tested this hypothesis by exploring the functional connectivity (FC) in bimodal bilinguals and monolinguals using functional MRI when they either performed a picture naming task with spoken language or were in resting state. We found that for bimodal bilinguals who use spoken and sign languages, the FC of the dACC with regions involved in spoken language (e.g. the left superior temporal gyrus) was stronger in performing the task, but weaker in the resting state as compared to monolinguals. For the LCN, its intrinsic FC with sign language regions including the left inferior temporo-occipital part and right inferior and superior parietal lobules was increased in the bilinguals. These results demonstrate that bilingual experience may alter the brain functional interaction between "control" regions and "language" regions. For different control regions, the FC alters in different ways. The findings also deepen our understanding of the functional roles of the dACC and LCN in language processing. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. A Randomized Controlled Trial Examining the Effects of Reflexology on Children With Functional Constipation.

    Science.gov (United States)

    Canbulat Sahiner, Nejla; Demirgoz Bal, Meltem

    Functional constipation is a common problem in Turkey that affects up to 10% of children. Reflexologists claim that reflexology can be beneficial in the treatment of constipation. The aim of this randomized controlled study was to determine the effectiveness of reflexology in treating functional constipation in children. Thirty-seven children who were referred to a pediatrician with functional constipation as defined by the Rome III criteria were recruited to the study. After the physician's diagnosis, two groups (intervention/control) were created. The intervention and control groups comprised 17 and 20 children, respectively. Each child in the intervention group was given a foot massage for 10 minutes five times a week, and toilet/diet/motivation training was given to their parents. The test period lasted for 4 weeks. Toilet/diet/motivation training was undertaken for 30 minutes once per week (for a total of 4 weeks) in an interactive manner. The parents of children in the control group received equivalent toilet/diet/motivation training only. No significant differences in terms of feces frequency and feces consistency were noted between the intervention and control groups (p > .05). This study sample showed that only toilet/diet/motivation training had potential benefit for treating functional constipation in children. Further larger randomized trials are required to establish whether there are benefits to foot message in the treatment of functional constipation in children.

  11. Brain functional plasticity associated with the emergence of expertise in extreme language control.

    Science.gov (United States)

    Hervais-Adelman, Alexis; Moser-Mercer, Barbara; Golestani, Narly

    2015-07-01

    We used functional magnetic resonance imaging (fMRI) to longitudinally examine brain plasticity arising from long-term, intensive simultaneous interpretation training. Simultaneous interpretation is a bilingual task with heavy executive control demands. We compared brain responses observed during simultaneous interpretation with those observed during simultaneous speech repetition (shadowing) in a group of trainee simultaneous interpreters, at the beginning and at the end of their professional training program. Age, sex and language-proficiency matched controls were scanned at similar intervals. Using multivariate pattern classification, we found distributed patterns of changes in functional responses from the first to second scan that distinguished the interpreters from the controls. We also found reduced recruitment of the right caudate nucleus during simultaneous interpretation as a result of training. Such practice-related change is consistent with decreased demands on multilingual language control as the task becomes more automatized with practice. These results demonstrate the impact of simultaneous interpretation training on the brain functional response in a cerebral structure that is not specifically linguistic, but that is known to be involved in learning, in motor control, and in a variety of domain-general executive functions. Along with results of recent studies showing functional and structural adaptations in the caudate nuclei of experts in a broad range of domains, our results underline the importance of this structure as a central node in expertise-related networks. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Radial basis function (RBF) neural network control for mechanical systems design, analysis and Matlab simulation

    CERN Document Server

    Liu, Jinkun

    2013-01-01

    Radial Basis Function (RBF) Neural Network Control for Mechanical Systems is motivated by the need for systematic design approaches to stable adaptive control system design using neural network approximation-based techniques. The main objectives of the book are to introduce the concrete design methods and MATLAB simulation of stable adaptive RBF neural control strategies. In this book, a broad range of implementable neural network control design methods for mechanical systems are presented, such as robot manipulators, inverted pendulums, single link flexible joint robots, motors, etc. Advanced neural network controller design methods and their stability analysis are explored. The book provides readers with the fundamentals of neural network control system design.   This book is intended for the researchers in the fields of neural adaptive control, mechanical systems, Matlab simulation, engineering design, robotics and automation. Jinkun Liu is a professor at Beijing University of Aeronautics and Astronauti...

  13. Longitudinal wave function control in single quantum dots with an applied magnetic field

    Science.gov (United States)

    Cao, Shuo; Tang, Jing; Gao, Yunan; Sun, Yue; Qiu, Kangsheng; Zhao, Yanhui; He, Min; Shi, Jin-An; Gu, Lin; Williams, David A.; Sheng, Weidong; Jin, Kuijuan; Xu, Xiulai

    2015-01-01

    Controlling single-particle wave functions in single semiconductor quantum dots is in demand to implement solid-state quantum information processing and spintronics. Normally, particle wave functions can be tuned transversely by an perpendicular magnetic field. We report a longitudinal wave function control in single quantum dots with a magnetic field. For a pure InAs quantum dot with a shape of pyramid or truncated pyramid, the hole wave function always occupies the base because of the less confinement at base, which induces a permanent dipole oriented from base to apex. With applying magnetic field along the base-apex direction, the hole wave function shrinks in the base plane. Because of the linear changing of the confinement for hole wave function from base to apex, the center of effective mass moves up during shrinking process. Due to the uniform confine potential for electrons, the center of effective mass of electrons does not move much, which results in a permanent dipole moment change and an inverted electron-hole alignment along the magnetic field direction. Manipulating the wave function longitudinally not only provides an alternative way to control the charge distribution with magnetic field but also a new method to tune electron-hole interaction in single quantum dots. PMID:25624018

  14. Longitudinal wave function control in single quantum dots with an applied magnetic field.

    Science.gov (United States)

    Cao, Shuo; Tang, Jing; Gao, Yunan; Sun, Yue; Qiu, Kangsheng; Zhao, Yanhui; He, Min; Shi, Jin-An; Gu, Lin; Williams, David A; Sheng, Weidong; Jin, Kuijuan; Xu, Xiulai

    2015-01-27

    Controlling single-particle wave functions in single semiconductor quantum dots is in demand to implement solid-state quantum information processing and spintronics. Normally, particle wave functions can be tuned transversely by an perpendicular magnetic field. We report a longitudinal wave function control in single quantum dots with a magnetic field. For a pure InAs quantum dot with a shape of pyramid or truncated pyramid, the hole wave function always occupies the base because of the less confinement at base, which induces a permanent dipole oriented from base to apex. With applying magnetic field along the base-apex direction, the hole wave function shrinks in the base plane. Because of the linear changing of the confinement for hole wave function from base to apex, the center of effective mass moves up during shrinking process. Due to the uniform confine potential for electrons, the center of effective mass of electrons does not move much, which results in a permanent dipole moment change and an inverted electron-hole alignment along the magnetic field direction. Manipulating the wave function longitudinally not only provides an alternative way to control the charge distribution with magnetic field but also a new method to tune electron-hole interaction in single quantum dots.

  15. The Method of a Standalone Functional Verifying Operability of Sonar Control Systems

    Directory of Open Access Journals (Sweden)

    A. A. Sotnikov

    2014-01-01

    Full Text Available This article describes a method of standalone verifying sonar control system, which is based on functional checking of control system operability.The main features of realized method are a development of the valid mathematic model for simulation of sonar signals at the point of hydroacoustic antenna, a valid representation of the sonar control system modes as a discrete Markov model, providing functional object verification in real time mode.Some ways are proposed to control computational complexity in case of insufficient computing resources of the simulation equipment, namely the way of model functionality reduction and the way of adequacy reduction.Experiments were made using testing equipment, which was developed by department of Research Institute of Information Control System at Bauman Moscow State Technical University to verify technical validity of industrial sonar complexes.On-board software was artificially changed to create malfunctions in functionality of sonar control systems during the verifying process in order to estimate verifying system performances.The method efficiency was proved by the theory and experiment results in comparison with the basic methodology of verifying technical systems.This method could be also used in debugging of on-board software of sonar complexes and in development of new promising algorithms of sonar signal processing.

  16. Interactions between default mode and control networks as a function of increasing cognitive reasoning complexity.

    Science.gov (United States)

    Hearne, Luke; Cocchi, Luca; Zalesky, Andrew; Mattingley, Jason B

    2015-07-01

    Successful performance of challenging cognitive tasks depends on a consistent functional segregation of activity within the default-mode network, on the one hand, and control networks encompassing frontoparietal and cingulo-opercular areas on the other. Recent work, however, has suggested that in some cognitive control contexts nodes within the default-mode and control networks may actually cooperate to achieve optimal task performance. Here, we used functional magnetic resonance imaging to examine whether the ability to relate variables while solving a cognitive reasoning problem involves transient increases in connectivity between default-mode and control regions. Participants performed a modified version of the classic Wason selection task, in which the number of variables to be related is systematically varied across trials. As expected, areas within the default-mode network showed a parametric deactivation with increases in relational complexity, compared with neural activity in null trials. Critically, some of these areas also showed enhanced connectivity with task-positive control regions. Specifically, task-based connectivity between the striatum and the angular gyri, and between the thalamus and right temporal pole, increased as a function of relational complexity. These findings challenge the notion that functional segregation between regions within default-mode and control networks invariably support cognitive task performance, and reveal previously unknown roles for the striatum and thalamus in managing network dynamics during cognitive reasoning. © 2015 Wiley Periodicals, Inc.

  17. Robust Predictive Functional Control for Flight Vehicles Based on Nonlinear Disturbance Observer

    Directory of Open Access Journals (Sweden)

    Yinhui Zhang

    2015-01-01

    Full Text Available A novel robust predictive functional control based on nonlinear disturbance observer is investigated in order to address the control system design for flight vehicles with significant uncertainties, external disturbances, and measurement noise. Firstly, the nonlinear longitudinal dynamics of the flight vehicle are transformed into linear-like state-space equations with state-dependent coefficient matrices. And then the lumped disturbances are considered in the linear structure predictive model of the predictive functional control to increase the precision of the predictive output and resolve the intractable mismatched disturbance problem. As the lumped disturbances cannot be derived or measured directly, the nonlinear disturbance observer is applied to estimate the lumped disturbances, which are then introduced to the predictive functional control to replace the unknown actual lumped disturbances. Consequently, the robust predictive functional control for the flight vehicle is proposed. Compared with the existing designs, the effectiveness and robustness of the proposed flight control are illustrated and validated in various simulation conditions.

  18. A PTEN-COL17A1 fusion gene and its novel regulatory role in Collagen XVII expression and GBM malignance.

    Science.gov (United States)

    Yan, Xiaoyan; Zhang, Chuanbao; Liang, Tingyu; Yang, Fan; Wang, Haoyuan; Wu, Fan; Wang, Wen; Wang, Zheng; Cheng, Wen; Xu, Jiangnan; Jiang, Tao; Chen, Jing; Ding, Yaozhong

    2017-10-17

    Collagen XVII expression has recently been demonstrated to be correlated with the tumor malignance. While Collagen XVII is known to be widely distributed in neurons of the human brain, its precise role in pathogenesis of glioblastoma multiforme (GBM) is unknown. In this study, we identified and characterized a new PTEN-COL17A1 fusion gene in GMB using transcriptome sequencing. Although fusion gene did not result in measurable fusion protein production, its presence is accompanied with high levels of COL17A1 expression, revealed a novel regulatory mechanism of Collagen XVII expression by PTEN-COL17A1 gene fusion. Knocked down Collagen XVII expression in glioma cell lines resulted in decreased tumor invasiveness, along with significant reduction of MMP9 expression, while increased Collagen XVII expression promotes invasive activities of glioma cells and associated with GBM recurrences. Together, our results uncovered a new PTEN-COL17A1 fusion gene and its novel regulatory role in Collagen XVII expression and GBM malignance, and demonstrated that COL17A1 could serve as a useful prognostic biomarker and therapeutic targets for GBM.

  19. PTP1B Deficiency Enables the Ability of a High-Fat Diet to Drive the Invasive Character of PTEN-Deficient Prostate Cancers.

    Science.gov (United States)

    Labbé, David P; Uetani, Noriko; Vinette, Valérie; Lessard, Laurent; Aubry, Isabelle; Migon, Eva; Sirois, Jacinthe; Haigh, Jody J; Bégin, Louis R; Trotman, Lloyd C; Paquet, Marilène; Tremblay, Michel L

    2016-06-01

    Diet affects the risk and progression of prostate cancer, but the interplay between diet and genetic alterations in this disease is not understood. Here we present genetic evidence in the mouse showing that prostate cancer progression driven by loss of the tumor suppressor Pten is mainly unresponsive to a high-fat diet (HFD), but that coordinate loss of the protein tyrosine phosphatase Ptpn1 (encoding PTP1B) enables a highly invasive disease. Prostate cancer in Pten(-/-)Ptpn1(-/-) mice was characterized by increased cell proliferation and Akt activation, interpreted to reflect a heightened sensitivity to IGF-1 stimulation upon HFD feeding. Prostate-specific overexpression of PTP1B was not sufficient to initiate prostate cancer, arguing that it acted as a diet-dependent modifier of prostate cancer development in Pten(-/-) mice. Our findings offer a preclinical rationale to investigate the anticancer effects of PTP1B inhibitors currently being studied clinically for diabetes treatment as a new modality for management of prostate cancer. Cancer Res; 76(11); 3130-5. ©2016 AACR. ©2016 American Association for Cancer Research.

  20. MicroRNA-486–dependent modulation of DOCK3/PTEN/AKT signaling pathways improves muscular dystrophy–associated symptoms

    Science.gov (United States)

    Alexander, Matthew S.; Casar, Juan Carlos; Motohashi, Norio; Vieira, Natássia M.; Eisenberg, Iris; Marshall, Jamie L.; Gasperini, Molly J.; Lek, Angela; Myers, Jennifer A.; Estrella, Elicia A.; Kang, Peter B.; Shapiro, Frederic; Rahimov, Fedik; Kawahara, Genri; Widrick, Jeffrey J.; Kunkel, Louis M.

    2014-01-01

    Duchenne muscular dystrophy (DMD) is caused by mutations in the gene encoding dystrophin, which results in dysfunctional signaling pathways within muscle. Previously, we identified microRNA-486 (miR-486) as a muscle-enriched microRNA that is markedly reduced in the muscles of dystrophin-deficient mice (Dmdmdx-5Cv mice) and in DMD patient muscles. Here, we determined that muscle-specific transgenic overexpression of miR-486 in muscle of Dmdmdx-5Cv mice results in reduced serum creatine kinase levels, improved sarcolemmal integrity, fewer centralized myonuclei, increased myofiber size, and improved muscle physiology and performance. Additionally, we identified dedicator of cytokinesis 3 (DOCK3) as a miR-486 target in skeletal muscle and determined that DOCK3 expression is induced in dystrophic muscles. DOCK3 overexpression in human myotubes modulated PTEN/AKT signaling, which regulates muscle hypertrophy and growth, and induced apoptosis. Furthermore, several components of the PTEN/AKT pathway were markedly modulated by miR-486 in dystrophin-deficient muscle. Skeletal muscle–specific miR-486 overexpression in Dmdmdx-5Cv animals decreased levels of DOCK3, reduced PTEN expression, and subsequently increased levels of phosphorylated AKT, which resulted in an overall beneficial effect. Together, these studies demonstrate that stable overexpression of miR-486 ameliorates the disease progression of dystrophin-deficient skeletal muscle. PMID:24789910

  1. Pollution control activities for waste-water treatment plants: planning, integrated approach, functionality controls and small plants

    International Nuclear Information System (INIS)

    Serena, F.; Tomiato, L.; Ostoich, M.; Falletti, L.

    2009-01-01

    The work presents the problem of the Wastewater Treatment Plants' (WWTPs) controls and the organization of the consequential activities with reference to the priorities of the Environmental Agencies through a hierarchy assessment according to the environmental importance of the pressure sources. The European Recommendation 2001/331/EC bases the environmental controls of industrial sites and also of WWTPs on an integrated approach overtaking the simple analytic control; the integrated approach requires documentary, technical, management and analytic controls. The Veneto Regional Environmental Prevention and Protection Agency (ARPAV) has recently developed and applied a check-list for the implementation of the European Recommendation for WWTPs. The check-list includes the functionality assessment of the WWTP in case of discharge control delegation to the plant manager as consented with Annex 5 third part Italian Decree 3/04/2006 n. 152. In the paper the general framework of environmental controls on public WWTPs in the Veneto region is described. Particular importance for the numerousness and for the required control typology is referred to the small WWTP ( [it

  2. Nonlinear Control of an Active Magnetic Bearing System Achieved Using a Fuzzy Control with Radial Basis Function Neural Network

    Directory of Open Access Journals (Sweden)

    Seng-Chi Chen

    2014-01-01

    Full Text Available Studies on active magnetic bearing (AMB systems are increasing in popularity and practical applications. Magnetic bearings cause less noise, friction, and vibration than the conventional mechanical bearings; however, the control of AMB systems requires further investigation. The magnetic force has a highly nonlinear relation to the control current and the air gap. This paper proposes an intelligent control method for positioning an AMB system that uses a neural fuzzy controller (NFC. The mathematical model of an AMB system comprises identification followed by collection of information from this system. A fuzzy logic controller (FLC, the parameters of which are adjusted using a radial basis function neural network (RBFNN, is applied to the unbalanced vibration in an AMB system. The AMB system exhibited a satisfactory control performance, with low overshoot, and produced improved transient and steady-state responses under various operating conditions. The NFC has been verified on a prototype AMB system. The proposed controller can be feasibly applied to AMB systems exposed to various external disturbances; demonstrating the effectiveness of the NFC with self-learning and self-improving capacities is proven.

  3. Investigation of a frequency dependent transfer function and its application to control rod localization

    International Nuclear Information System (INIS)

    Garis, N.S.; Pazsit, I.

    1997-02-01

    Control rod vibrations can be detected via the fluctuations they generate in the neutron flux, i.e. the neutron noise. In a previous paper, a neural network-based algorithm for locating a vibrating control rod from the measured neutron noise was developed. The transfer function used for the core model was based on the so called power-reactor approximation resulting in a simple, real-valued solution which means that the phase delay of the signal propagation is neglected. In the present work a more realistic transfer function is used, without the approximations of the previous model. The transfer function is calculated from the Fourier transformed diffusion equation with a complex, frequency dependent buckling leading to a complex solution. In physical terms, this means that the phase delay of the signal propagation is accounted for. Using such a complex core model, the present paper investigates the effectiveness of applying neural networks for control rod localisation. 7 refs, 4 figs

  4. Design of a structural and functional hierarchy for planning and control of telerobotic systems

    Science.gov (United States)

    Acar, Levent; Ozguner, Umit

    1989-01-01

    Hierarchical structures offer numerous advantages over conventional structures for the control of telerobotic systems. A hierarchically organized system can be controlled via undetailed task assignments and can easily adapt to changing circumstances. The distributed and modular structure of these systems also enables fast response needed in most telerobotic applications. On the other hand, most of the hierarchical structures proposed in the literature are based on functional properties of a system. These structures work best for a few given functions of a large class of systems. In telerobotic applications, all functions of a single system needed to be explored. This approach requires a hierarchical organization based on physical properties of a system and such a hierarchical organization is introduced. The decomposition, organization, and control of the hierarchical structure are considered, and a system with two robot arms and a camera is presented.

  5. Mapping of control functions of critical systems by reachability analysis in a network of communicating automata

    International Nuclear Information System (INIS)

    Lemattre, Thibault

    2013-01-01

    The design of operational control architectures is a very important step of the design of energy production systems. This step consists in mapping the functional architecture of the system onto its hardware architecture while respecting capacity and safety constraints, i.e. in allocating control functions to a set of controllers while respecting these constraints. The work presented in this thesis presents: i) a formalization of the data and constraints of the function allocation problem; ii) a mapping method, by reachability analysis, based on a request/response mechanism in a network of communicating automata with integer variables; iii) a comparison between this method and a resolution method by integer linear programming. The results of this work have been validated on examples of actual size and open the way to the coupling between reachability analysis and integer linear programming for the resolution of satisfaction problems for non-linear constraint systems. (author)

  6. The hierarchy of essential CANDU reactor control functions in a distributed system

    International Nuclear Information System (INIS)

    Mercier, P.

    1980-01-01

    Control functions in CANDU nuclear generating stations are programmed within two centralized and redundant minicomputers while safety functions are covered by conventional analog systems. This set-up is a product of standards, economic and technical considerations which are now being modified by the maturing of microprocessors, the progress in digital communications and the development of mathematical process models. Starting from the control and safety systems installed in Gentilly-2, this paper analyses trends that will affect the implementation of essential control functions within a distributed system. In particular, it emphasizes the characteristics of future software systems that must be built-in in order to comply with important operational requirements of nuclear generating stations. (auth) [fr

  7. Effect of Taichi Softball on Function-Related Outcomes in Older Adults: A Randomized Control Trial

    Directory of Open Access Journals (Sweden)

    Lin Lou

    2017-01-01

    Full Text Available The purpose of this present study was to examine the effect of Taichi softball (TCSB on physical function in Chinese older adults. Eighty Chinese older adults were randomly assigned into either an experimental group experiencing four 90-minute TCSB sessions weekly for seven consecutive weeks or a control group. At baseline and 7 weeks later, all participants were asked to perform physical functional tests for both lower and upper limbs. Multiple separate Analyses of Variance (ANOVA with repeated measures were applied to evaluate the effects of TCSB on function-related outcomes between baseline and postintervention in the two groups. The findings indicate that a short-term and intensive TCSB training program does not only improve low limb-related physical function such as dynamic balance and leg strength, but also strengthen upper limb-related physical function (e.g., arm and forearm strength, shoulder mobility, fine motor control, handgrip strength, and fine motor function. Health professionals could take into account TCSB exercise as an alternative method to help maintain or alleviate the inevitable age-related physical function degeneration in healthy older adults. In addition, researchers could investigate the effect of TCSB exercise on physical function in special populations such as patients with different chronic diseases or neurological disorder (e.g., Parkinson’s disease.

  8. Seeing conflict and engaging control: Experience with contrastive language benefits executive function in preschoolers.

    Science.gov (United States)

    Doebel, Sabine; Zelazo, Philip David

    2016-12-01

    Engaging executive function often requires overriding a prepotent response in favor of a conflicting but adaptive one. Language may play a key role in this ability by supporting integrated representations of conflicting rules. We tested whether experience with contrastive language that could support such representations benefits executive function in 3-year-old children. Children who received brief experience with language highlighting contrast between objects, attributes, and actions showed greater executive function on two of three 'conflict' executive function tasks than children who received experience with contrasting stimuli only and children who read storybooks with the experimenter, controlling for baseline executive function. Experience with contrasting stimuli did not benefit executive function relative to reading books with the experimenter, indicating experience with contrastive language, rather than experience with contrast generally, was key. Experience with contrastive language also boosted spontaneous attention to contrast, consistent with improvements in representing contrast. These findings indicate a role for language in executive function that is consistent with the Cognitive Complexity and Control theory's key claim that coordinating conflicting rules is critical to overcoming perseveration, and suggest new ideas for testing theories of executive function. Copyright © 2016 Elsevier B.V. All rights reserved.

  9. Comparing health locus of control in patients with Spasmodic Dysphonia, Functional Dysphonia and Nonlaryngeal Dystonia.

    Science.gov (United States)

    Haselden, Karen; Powell, Theresa; Drinnan, Mike; Carding, Paul

    2009-11-01

    Locus of Control (LoC) refers to an individuals' perception of whether they are in control of life events. Health Locus of Control refers to whether someone feels they have influence over their health. Health Locus of Control has not been studied in any depth in voice-disordered patients. The objective of this study was to examine Health Locus of Control in three patient groups: (1) Spasmodic Dysphonia, (2) Functional Dysphonia and (3) a nondysphonic group with Nonlaryngeal Dystonia. LoC was measured and compared in a total of 57 patients using the Multidimensional Health Locus of Control Scales (diagnostic specific) Form C. Internal, Chance, and Powerful others LoC were measured and comparisons were made using one-way analysis of variance. Contrary to expectations Internal LoC was found to be significantly higher in the Functional Dysphonia group when compared to the other two groups. There was no significant difference between the groups in Chance or Powerful others LoC. The two organic groups, Spasmodic Dysphonia and Nonlaryngeal Dystonia, were more alike in Internal Health Locus of Control than the Functional Dysphonia group. The diagnostic nature of the groups was reflected in their LoC scores rather than their voice loss. These results contribute to the debate about the etiology of Spasmodic Dysphonia and will be of interest to those involved in the psychology of voice and those managing voice-disordered patients.

  10. Episodic memory and executive functioning in currently depressed patients compared to healthy controls.

    Science.gov (United States)

    Pauls, Franz; Petermann, Franz; Lepach, Anja Christina

    2015-01-01

    At present, little is still known about the link between depression, memory and executive functioning. This study examined whether there are memory-related impairments in depressed patients and whether the size of such deficits depends on the age group and on specific types of cognitive measures. Memory performances of 215 clinically depressed patients were compared to the data of a matched control sample. Regression analyses were performed to determine the extent to which executive dysfunctions contributed to episodic memory impairments. When compared with healthy controls, significantly lower episodic memory and executive functioning performances were found for depressed patients of all age groups. Effect sizes appeared to vary across different memory and executive functioning measures. The extent to which executive dysfunctions could explain episodic memory impairments varied depending on the type of measure examined. These findings emphasise the need to consider memory-related functioning of depressed patients in the context of therapeutic treatments.

  11. Postural control and functional balance in individuals with diabetic peripheral neuropathy

    Directory of Open Access Journals (Sweden)

    Ana Claudia de Souza Fortaleza

    2013-04-01

    Full Text Available Diabetic Peripheral Neuropathy (DPN brings on reduced somatosensation, which can lead to changes in postural control. The objective of this study was to evaluate postural control in a standing position and in different conditions, as well as functional balance in individuals with DPN, make the correlation between the results obtained from the postural control assessment with the values from the functional balance test and compare the results obtained in the neuropathy group with those of the control group, checking for possible differences between the evaluation conditions of both groups. The study included 13 women with DPN (NG and 17 non-diabetic women (CG. Postural control assessment was performed by kinemetry in the following conditions: eyes opened (EO, eyes closed (EC, and semi-tandem (ST. The data was processed in MATLAB and the following variables were generated: mean amplitude of oscillation (MAO in the anterior-posterior (AP and medial-lateral (ML direction; and average speed of oscillation (ASO in AP and ML direction. Functional balance was assessed by the Timed Up and Go Test. There was significant difference between the groups (p≤0.005 in MAO-AP EO and EC, MAO-ML EC and ST, and ASO-ML ST. There were differences between the conditions EO and ST (p≤0.005 and EC and ST (p≤0.005 for the variables MAO-ML and ASO-ML with greater damage to the NG, which also had a lower functional balance (p=0.001. ML instability was positively correlated with functional imbalance. The results show a change in the postural control system in the DPN, which could lead these individuals to a higher risk for falls and functional impairment.

  12. Postural control and functional balance in individuals with diabetic peripheral neuropathy

    Directory of Open Access Journals (Sweden)

    Ana Claudia de Souza Fortaleza

    2013-03-01

    Full Text Available DOI: http://dx.doi.org/10.5007/1980-0037.2013v15n3p305 Diabetic Peripheral Neuropathy (DPN brings on reduced somatosensation, which can lead to changes in postural control. The objective of this study was to evaluate postural control in a standing position and in different conditions, as well as functional balance in individuals with DPN, make the correlation between the results obtained from the postural control assessment with the values from the functional balance test and compare the results obtained in the neuropathy group with those of the control group, checking for possible differences between the evaluation conditions of both groups. The study included 13 women with DPN (NG and 17 non-diabetic women (CG. Postural control assessment was performed by kinemetry in the following conditions: eyes opened (EO, eyes closed (EC, and semi-tandem (ST. The data was processed in MATLAB and the following variables were generated: mean amplitude of oscillation (MAO in the anterior-posterior (AP and medial-lateral (ML direction; and average speed of oscillation (ASO in AP and ML direction. Functional balance was assessed by the Timed Up and Go Test. There was significant difference between the groups (p≤0.005 in MAO-AP EO and EC, MAO-ML EC and ST, and ASO-ML ST. There were differences between the conditions EO and ST (p≤0.005 and EC and ST (p≤0.005 for the variables MAO-ML and ASO-ML with greater damage to the NG, which also had a lower functional balance (p=0.001. ML instability was positively correlated with functional imbalance. The results show a change in the postural control system in the DPN, which could lead these individuals to a higher risk for falls and functional impairment.

  13. Vibration control of uncertain multiple launch rocket system using radial basis function neural network

    Science.gov (United States)

    Li, Bo; Rui, Xiaoting

    2018-01-01

    Poor dispersion characteristics of rockets due to the vibration of Multiple Launch Rocket System (MLRS) have always restricted the MLRS development for several decades. Vibration control is a key technique to improve the dispersion characteristics of rockets. For a mechanical system such as MLRS, the major difficulty in designing an appropriate control strategy that can achieve the desired vibration control performance is to guarantee the robustness and stability of the control system under the occurrence of uncertainties and nonlinearities. To approach this problem, a computed torque controller integrated with a radial basis function neural network is proposed to achieve the high-precision vibration control for MLRS. In this paper, the vibration response of a computed torque controlled MLRS is described. The azimuth and elevation mechanisms of the MLRS are driven by permanent magnet synchronous motors and supposed to be rigid. First, the dynamic model of motor-mechanism coupling system is established using Lagrange method and field-oriented control theory. Then, in order to deal with the nonlinearities, a computed torque controller is designed to control the vibration of the MLRS when it is firing a salvo of rockets. Furthermore, to compensate for the lumped uncertainty due to parametric variations and un-modeled dynamics in the design of the computed torque controller, a radial basis function neural network estimator is developed to adapt the uncertainty based on Lyapunov stability theory. Finally, the simulated results demonstrate the effectiveness of the proposed control system and show that the proposed controller is robust with regard to the uncertainty.

  14. Improving gross motor function and postural control with hippotherapy in children with Down syndrome: case reports.

    Science.gov (United States)

    Champagne, Danielle; Dugas, Claude

    2010-11-01

    The purpose of this case report is to describe the impact of an 11-week hippotherapy program on the gross motor functions of two children (respectively 28 and 37 months old) diagnosed with Down syndrome. Hippotherapy is a strategy that uses the horse's motion to stimulate and enhance muscle contraction and postural control. The children were assessed by the Gross Motor Function Measure (GMFM) and accelerometry. The results indicate that both children improved on many dimensions of the GMFM. Power spectral analysis of the acceleration signals showed improvement in postural control of either the head or trunk, because the children adopted two different adaptative strategies to perturbation induced by the moving horse.

  15. Inflammatory Profile of Awake Function-Controlled Craniotomy and Craniotomy under General Anesthesia

    Directory of Open Access Journals (Sweden)

    Markus Klimek

    2009-01-01

    Results. Plasma IL-6 level significantly increased with time similarly in both groups. No significant plasma IL-8 and IL-10 change was observed in both experimental groups. The VAS pain score was significantly lower in the awake group compared to the anesthesia group at 12 hours postoperative. Postoperative anxiety and stress declined similarly in both groups. Conclusion. This study suggests that awake function-controlled craniotomy does not cause a significantly different inflammatory response than craniotomy performed under general anesthesia. It is also likely that function-controlled craniotomy does not cause a greater emotional challenge than tumor resection under general anesthesia.

  16. TS Fuzzy Model-Based Controller Design for a Class of Nonlinear Systems Including Nonsm