Science.gov

Sample records for protein-2 drives apoptosis

  1. Amphiregulin impairs apoptosis-stimulating protein 2 of p53 overexpression-induced apoptosis in hepatoma cells.

    PubMed

    Liu, Kai; Lin, Dongdong; Ouyang, Yabo; Pang, Lijun; Guo, Xianghua; Wang, Shanshan; Zang, Yunjin; Chen, Dexi

    2017-03-01

    Overexpression of apoptosis-stimulating protein 2 of p53 (ASPP2) induces apoptotic cell death in hepatoma cells (e.g. HepG2 cells) by enhancing the transactivation activity of p53, but long-term ASPP2 overexpression fails to induce more apoptosis since activation of the epidermal growth factor/epidermal growth factor receptor/SOS1 pathway impairs the pro-apoptotic role of ASPP2. In this study, in recombinant adenovirus-ASPP2-infected HepG2 cells, ASPP2 overexpression induces amphiregulin expression in a p53-dependent manner. Although amphiregulin initially contributes to ASPP2-induced apoptosis, it eventually impairs the pro-apoptotic function of ASPP2 by activating the epidermal growth factor/epidermal growth factor receptor/SOS1 pathway, leading to apoptosis resistance. Moreover, blocking soluble amphiregulin with a neutralizing antibody also significantly increased apoptotic cell death of HepG2 cells due to treatment with methyl methanesulfonate, cisplatin, or a recombinant p53 adenovirus, suggesting that the function of amphiregulin involved in inhibiting apoptosis may be a common mechanism by which hepatoma cells escape from stimulus-induced apoptosis. Thus, our data elucidate an apoptosis-evasion mechanism in hepatocellular carcinoma and have potential implications for hepatocellular carcinoma therapy.

  2. Calpain-mediated cleavage of collapsin response mediator protein-2 drives acute axonal degeneration

    PubMed Central

    Zhang, Jian-Nan; Michel, Uwe; Lenz, Christof; Friedel, Caroline C.; Köster, Sarah; d’Hedouville, Zara; Tönges, Lars; Urlaub, Henning; Bähr, Mathias; Lingor, Paul; Koch, Jan C.

    2016-01-01

    Axonal degeneration is a key initiating event in many neurological diseases. Focal lesions to axons result in a rapid disintegration of the perilesional axon by acute axonal degeneration (AAD) within several hours. However, the underlying molecular mechanisms of AAD are only incompletely understood. Here, we studied AAD in vivo through live-imaging of the rat optic nerve and in vitro in primary rat cortical neurons in microfluidic chambers. We found that calpain is activated early during AAD of the optic nerve and that calpain inhibition completely inhibits axonal fragmentation on the proximal side of the crush while it attenuates AAD on the distal side. A screening of calpain targets revealed that collapsin response mediator protein-2 (CRMP2) is a main downstream target of calpain activation in AAD. CRMP2-overexpression delayed bulb formation and rescued impairment of axonal mitochondrial transport after axotomy in vitro. In vivo, CRMP2-overexpression effectively protected the proximal axon from fragmentation within 6 hours after crush. Finally, a proteomic analysis of the optic nerve was performed at 6 hours after crush, which identified further proteins regulated during AAD, including several interactors of CRMP2. These findings reveal CRMP2 as an important mediator of AAD and define it as a putative therapeutic target. PMID:27845394

  3. The microRNA-302b-inhibited insulin-like growth factor-binding protein 2 signaling pathway induces glioma cell apoptosis by targeting nuclear factor IA

    PubMed Central

    Lee, Chin-Cheng; Chen, Peng-Hsu; Ho, Kuo-Hao; Shih, Chwen-Ming; Cheng, Chia-Hsiung; Lin, Cheng-Wei; Cheng, Kur-Ta; Liu, Ann-Jeng

    2017-01-01

    MicroRNAs are small noncoding RNAs that post-transcriptionally control the expression of genes involved in glioblastoma multiforme (GBM) development. Although miR-302b functions as a tumor suppressor, its role in GBM is still unclear. Therefore, this study comprehensively explored the roles of miR-302b-mediated gene networks in GBM cell death. We found that miR-302b levels were significantly higher in primary astrocytes than in GBM cell lines. miR-302b overexpression dose dependently reduced U87-MG cell viability and induced apoptosis through caspase-3 activation and poly(ADP ribose) polymerase degradation. A transcriptome microarray revealed 150 downregulated genes and 380 upregulated genes in miR-302b-overexpressing cells. Nuclear factor IA (NFIA), higher levels of which were significantly related to poor survival, was identified as a direct target gene of miR-302b and was involved in miR-302b-induced glioma cell death. Higher NFIA levels were observed in GBM cell lines and human tumor sections compared with astrocytes and non-tumor tissues, respectively. NFIA knockdown significantly enhanced apoptosis. We found high levels of insulin-like growth factor-binding protein 2 (IGFBP2), another miR-302b-downregulated gene, in patients with poor survival. We verified that NFIA binds to the IGFBP2 promoter and transcriptionally enhances IGFBP2 expression levels. We identified that NFIA-mediated IGFBP2 signaling pathways are involved in miR-302b-induced glioma cell death. The identification of a regulatory loop whereby miR-302b inhibits NFIA, leading to a decrease in expression of IGFBP-2, may provide novel directions for developing therapies to target glioblastoma tumorigenesis. PMID:28323865

  4. Poly (C)-binding protein 2 (PCBP2) promotes the progression of esophageal squamous cell carcinoma (ESCC) through regulating cellular proliferation and apoptosis.

    PubMed

    Ye, Jinjun; Zhou, Guoren; Zhang, Zhi; Sun, Lei; He, Xia; Zhou, Jianwei

    2016-08-01

    PCBP2 (Poly(C)-binding protein 2) is a member of PCBP family, which has many functions including mRNA stabilization, translational silence and translational enhancement performed by their poly(C)-binding ability. The abnormal expression of PCBP2 was correlated with various carcinomas. However, the significance and mechanism of PCBP2 in esophageal squamous cell carcinoma (ESCC) progression remain unclear. In this study, Western Blot and immunohistochemistry (IHC) analysis revealed that PCBP2 was overexpressed in ESCC tissues and cell lines. Statistical results also indicated that PCBP2 expression level was significantly positively correlated with ESCC clinicopathological parameters such as tumor grade and tumor size. Furthermore, PCBP2 expression level could also be recognized as an independent prognostic factor for ESCC patients' overall survival. Serum starvation and refeeding assay along with PCBP2-shRNA transfection demonstrated that PCBP2 expression promoted proliferation of ESCC cells. The results above are partly due to growth arrest of cell cycle at G1/S phase. We also found that reduced PCBP2 expression might induce ESCC cell apoptosis with increased cleaved caspase3 expression. Overall, our findings indicated that PCBP2 might be involved in the ESCC progression and be considered as a new treatment target in ESCC.

  5. PUMA promotes apoptosis of hematopoietic progenitors driving leukemic progression in a mouse model of myelodysplasia.

    PubMed

    Guirguis, A A; Slape, C I; Failla, L M; Saw, J; Tremblay, C S; Powell, D R; Rossello, F; Wei, A; Strasser, A; Curtis, D J

    2016-06-01

    Myelodysplastic syndrome (MDS) is characterized by ineffective hematopoiesis with resultant cytopenias. Increased apoptosis and aberrantly functioning progenitors are thought to contribute to this phenotype. As is the case for other malignancies, overcoming apoptosis is believed to be important in progression toward acute myeloid leukemia (AML). Using the NUP98-HOXD13 (NHD13) transgenic mouse model of MDS, we previously reported that overexpression of the anti-apoptotic protein BCL2, blocked apoptosis and improved cytopenias, paradoxically, delaying leukemic progression. To further understand this surprising result, we examined the role of p53 and its pro-apoptotic effectors, PUMA and NOXA in NHD13 mice. The absence of p53 or PUMA but not NOXA reduced apoptosis and expanded the numbers of MDS-repopulating cells. Despite a similar effect on apoptosis and cell numbers, the absence of p53 and PUMA had diametrically opposed effects on progression to AML: absence of p53 accelerated leukemic progression, while absence of PUMA significantly delayed progression. This may be explained in part by differences in cellular responses to DNA damage. The absence of p53 led to higher levels of γ-H2AX (indicative of persistent DNA lesions) while PUMA-deficient NHD13 progenitors resolved DNA lesions in a manner comparable to wild-type cells. These results suggest that targeting PUMA may improve the cytopenias of MDS without a detrimental effect on leukemic progression thus warranting further investigation.

  6. Lutzomyia longipalpis saliva drives apoptosis and enhances parasite burden in neutrophils.

    PubMed

    Prates, Deboraci Brito; Araújo-Santos, Théo; Luz, Nívea Farias; Andrade, Bruno B; França-Costa, Jaqueline; Afonso, Lilian; Clarêncio, Jorge; Miranda, José Carlos; Bozza, Patrícia T; Dosreis, George A; Brodskyn, Cláudia; Barral-Netto, Manoel; Borges, Valéria Matos; Borges, Valéria de Matos; Barral, Aldina

    2011-09-01

    Neutrophils are considered the host's first line of defense against infections and have been implicated in the immunopathogenesis of Leishmaniasis. Leishmania parasites are inoculated alongside vectors' saliva, which is a rich source of pharmacologically active substances that interfere with host immune response. In the present study, we tested the hypothesis that salivary components from Lutzomyia longipalpis, an important vector of visceral Leishmaniasis, enhance neutrophil apoptosis. Murine inflammatory peritoneal neutrophils cultured in the presence of SGS presented increased surface expression of FasL and underwent caspase-dependent and FasL-mediated apoptosis. This proapoptosis effect of SGS on neutrophils was abrogated by pretreatment with protease as well as preincubation with antisaliva antibodies. Furthermore, in the presence of Leishmania chagasi, SGS also increased apoptosis on neutrophils and increased PGE(2) release and decreased ROS production by neutrophils, while enhancing parasite viability inside these cells. The increased parasite burden was abrogated by treatment with z-VAD, a pan caspase inhibitor, and NS-398, a COX-2 inhibitor. In the presence of SGS, Leishmania-infected neutrophils produced higher levels of MCP-1 and attracted a high number of macrophages by chemotaxis in vitro assays. Both of these events were abrogated by pretreatment of neutrophils with bindarit, an inhibitor of CCL2/MCP-1 expression. Taken together, our data support the hypothesis that vector salivary proteins trigger caspase-dependent and FasL-mediated apoptosis, thereby favoring Leishmania survival inside neutrophils, which may represent an important mechanism for the establishment of Leishmania infection.

  7. On How Fas Apoptosis-Independent Pathways Drive T Cell Hyperproliferation and Lymphadenopathy in lpr Mice

    PubMed Central

    Balomenos, Dimitrios; Shokri, Rahman; Daszkiewicz, Lidia; Vázquez-Mateo, Cristina; Martínez-A, Carlos

    2017-01-01

    Fas induces massive apoptosis in T cells after repeated in vitro T cell receptor (TCR) stimulation and is critical for lymphocyte homeostasis in Fas-deficient (lpr) mice. Although the in vitro Fas apoptotic mechanism has been defined, there is a large conceptual gap between this in vitro phenomenon and the pathway that leads to in vivo development of lymphadenopathy and autoimmunity. A striking abnormality in lpr mice is the excessive proliferation of CD4+ and CD8+ T cells, and more so of the double-negative TCR+CD4−CD8−B220+ T cells. The basis of lpr T cell hyperproliferation remains elusive, as it cannot be explained by Fas-deficient apoptosis. T cell-directed p21 overexpression reduces hyperactivation/hyperproliferation of all lpr T cell subtypes and lymphadenopathy in lpr mice. p21 controls expansion of repeatedly stimulated T cells without affecting apoptosis. These results confirm a direct link between hyperactivation/hyperproliferation, autoreactivity, and lymphadenopathy in lpr mice and, with earlier studies, suggest that Fas apoptosis-independent pathways control lpr T cell hyperproliferation. lpr T cell hyperproliferation could be an indirect result of the defective apoptosis of repeatedly stimulated lpr T cells. Nonetheless, in this perspective, we argue for an alternative setting, in which lack of Fas would directly cause lpr T cell hyperactivation/hyperproliferation in vivo. We propose that Fas/Fas ligand (FasL) acts as an activation inhibitor of recurrently stimulated T cells, and that its disruption causes overexpansion of T cells in lpr mice. Research to define the underlying mechanism of this Fas/FasL effect could resolve the phenotype of lpr mice and lead to therapeutics for related human syndromes. PMID:28344578

  8. On How Fas Apoptosis-Independent Pathways Drive T Cell Hyperproliferation and Lymphadenopathy in lpr Mice.

    PubMed

    Balomenos, Dimitrios; Shokri, Rahman; Daszkiewicz, Lidia; Vázquez-Mateo, Cristina; Martínez-A, Carlos

    2017-01-01

    Fas induces massive apoptosis in T cells after repeated in vitro T cell receptor (TCR) stimulation and is critical for lymphocyte homeostasis in Fas-deficient (lpr) mice. Although the in vitro Fas apoptotic mechanism has been defined, there is a large conceptual gap between this in vitro phenomenon and the pathway that leads to in vivo development of lymphadenopathy and autoimmunity. A striking abnormality in lpr mice is the excessive proliferation of CD4(+) and CD8(+) T cells, and more so of the double-negative TCR(+)CD4(-)CD8(-)B220(+) T cells. The basis of lpr T cell hyperproliferation remains elusive, as it cannot be explained by Fas-deficient apoptosis. T cell-directed p21 overexpression reduces hyperactivation/hyperproliferation of all lpr T cell subtypes and lymphadenopathy in lpr mice. p21 controls expansion of repeatedly stimulated T cells without affecting apoptosis. These results confirm a direct link between hyperactivation/hyperproliferation, autoreactivity, and lymphadenopathy in lpr mice and, with earlier studies, suggest that Fas apoptosis-independent pathways control lpr T cell hyperproliferation. lpr T cell hyperproliferation could be an indirect result of the defective apoptosis of repeatedly stimulated lpr T cells. Nonetheless, in this perspective, we argue for an alternative setting, in which lack of Fas would directly cause lpr T cell hyperactivation/hyperproliferation in vivo. We propose that Fas/Fas ligand (FasL) acts as an activation inhibitor of recurrently stimulated T cells, and that its disruption causes overexpansion of T cells in lpr mice. Research to define the underlying mechanism of this Fas/FasL effect could resolve the phenotype of lpr mice and lead to therapeutics for related human syndromes.

  9. Coagulation factor Xa drives tumor cells into apoptosis through BH3-only protein Bim up-regulation

    SciTech Connect

    Borensztajn, Keren S. . E-mail: K.S.Borensztajn@amc.uva.nl; Bijlsma, Maarten F.; Groot, Angelique P.; Brueggemann, Lois W.; Versteeg, Henri H.; Reitsma, Pieter H.; Peppelenbosch, Maikel P.; Spek, C. Arnold

    2007-07-15

    Coagulation Factor (F)Xa is a serine protease that plays a crucial role during blood coagulation by converting prothrombin into active thrombin. Recently, however, it emerged that besides this role in coagulation, FXa induces intracellular signaling leading to different cellular effects. Here, we show that coagulation factor (F)Xa drives tumor cells of epithelial origin, but not endothelial cells or monocytes, into apoptosis, whereas it even enhances fibroblast survival. FXa signals through the protease activated receptor (PAR)-1 to activate extracellular-signal regulated kinase (ERK) 1/2 and p38. This activation is associated with phosphorylation of the transcription factor CREB, and in tumor cells with up-regulation of the BH3-only pro-apoptotic protein Bim, leading to caspase-3 cleavage, the main hallmark of apoptosis. Transfection of tumor cells with dominant negative forms of CREB or siRNA for either PAR-1, Bim, ERK1 and/or p38 inhibited the pro-apoptotic effect of FXa. In fibroblasts, FXa-induced PAR-1 activation leads to down-regulation of Bim and pre-treatment with PAR-1 or Bim siRNA abolishes proliferation. We thus provide evidence that beyond its role in blood coagulation, FXa plays a key role in cellular processes in which Bim is the central player in determining cell survival.

  10. The Alternative Splicing of Cytoplasmic Polyadenylation Element Binding Protein 2 Drives Anoikis Resistance and the Metastasis of Triple Negative Breast Cancer.

    PubMed

    Johnson, Ryan M; Vu, Ngoc T; Griffin, Brian P; Gentry, Amanda E; Archer, Kellie J; Chalfant, Charles E; Park, Margaret A

    2015-10-16

    Triple negative breast cancer (TNBC) represents an anomalous subset of breast cancer with a greatly reduced (30%) 5-year survival rate. The enhanced mortality and morbidity of TNBC arises from the high metastatic rate, which requires the acquisition of AnR, a process whereby anchorage-dependent cells become resistant to cell death induced by detachment. In this study TNBC cell lines were selected for AnR, and these cell lines demonstrated dramatic enhancement in the formation of lung metastases as compared with parental cells. Genetic analysis of the AnR subclones versus parental cells via next generation sequencing and analysis of global alternative RNA splicing identified that the mRNA splicing of cytoplasmic polyadenylation element binding 2 (CPEB2), a translational regulator, was altered in AnR TNBC cells. Specifically, increased inclusion of exon 4 into the mature mRNA to produce the CPEB2B isoform was observed in AnR cell lines. Molecular manipulations of CPEB2 splice variants demonstrated a key role for this RNA splicing event in the resistance of cells to anoikis. Specifically, down-regulation of the CPEB2B isoform using siRNA re-sensitized the AnR cell lines to detachment-induced cell death. The ectopic expression of CPEB2B in parental TNBC cell lines induced AnR and dramatically increased metastatic potential. Importantly, alterations in the alternative splicing of CPEB2 were also observed in human TNBC and additional subtypes of human breast cancer tumors linked to a high metastatic rate. Our findings demonstrate that the regulation of CPEB2 mRNA splicing is a key mechanism in AnR and a driving force in TNBC metastasis.

  11. Hyaluronic acid-fabricated nanogold delivery of the inhibitor of apoptosis protein-2 siRNAs inhibits benzo[a]pyrene-induced oncogenic properties of lung cancer A549 cells

    NASA Astrophysics Data System (ADS)

    Lin, Chung-Ming; Kao, Wei-Chien; Yeh, Chun-An; Chen, Hui-Jye; Lin, Shinn-Zong; Hsieh, Hsien-Hsu; Sun, Wei-Shen; Chang, Chih-Hsuan; Hung, Huey-Shan

    2015-03-01

    Benzo[a]pyrene (BaP), a component of cooking oil fumes (COF), promotes lung cancer cell proliferation and survival via the induction of inhibitor of apoptosis protein-2 (IAP-2) proteins. Thus knockdown of IAP-2 would be a promising way to battle against lung cancer caused by COF. Functionalized gold nanoparticle (AuNP) is an effective delivery system for bio-active materials. Here, biocompatible hyaluronic acid (HA) was fabricated into nanoparticles to increase the target specificity by binding to CD44-over-expressed cancer cells. IAP-2-specific small-interfering RNA (siRNAs) or fluorescein isothiocyanate (FITC) were then incorporated into AuNP-HA. Conjugation of IAP-2 siRNA into AuNPs-HA was verified by the UV-vis spectrometer and Fourier transform infrared spectrometer. Further studies showed that AuNP-HA/FITC were effectively taken up by A549 cells through CD44-mediated endocytosis. Incubation of BaP-challenged cells with AuNP-HA-IAP-2 siRNAs silenced the expression of IAP-2, decreased cell proliferation and triggered pronounced cell apoptosis by the decrease in Bcl-2 protein and the increase in Bax protein as well as the active form of caspases-3. The BaP-elicited cell migration and enzymatic activity of the secreted matrix metalloproteinase-2 were also substantially suppressed by treatment with AuNP-HA-IAP-2 siRNAs. These results indicated that IAP-2 siRNAs can be efficiently delivered into A549 cells by functionalized AuNP-HA to repress the IAP-2 expression and BaP-induced oncogenic events, suggesting the potential therapeutic application of IAP-2 siRNA or other siRNA-conjugated AuNP-HA composites to COF-induced lung cancer and other gene-caused diseases in the future.

  12. Hypoxia drives apoptosis independently of p53 and metallothionein transcript levels in hemocytes of the whiteleg shrimp Litopenaeus vannamei.

    PubMed

    Felix-Portillo, Monserrath; Martínez-Quintana, José A; Arenas-Padilla, Marina; Mata-Haro, Verónica; Gómez-Jiménez, Silvia; Yepiz-Plascencia, Gloria

    2016-10-01

    The cellular mechanisms used by the shrimp Litopenaeus vannamei to respond to hypoxia have been studied from the energetic metabolism and antioxidant angles. We herein investigated the participation of p53 and metallothionein (MT) in the apoptotic process in response to hypoxia in shrimp hemocytes. The Lvp53 or LvMT genes were efficiently silenced by injection of double stranded RNA for p53 or MT. The effects of silencing on apoptosis were measured as caspase-3 activity and flow cytometry in hemocytes after 24 and 48 h of hypoxia (1.5 mg DO L(-1)). Hemocytes from unsilenced animals had significantly higher apoptosis levels upon both times of hypoxia. The apoptotic levels were diminished but not suppressed in dsp53-silenced but not dsMT-silenced hemocytes after 24 h of hypoxia, indicating a contribution of Lvp53 to apoptosis. Apoptosis in normoxia was significantly higher in dsp53-and dsMT-silenced animals compared to the unsilenced controls, pointing to a possible cytoprotective role of LvMT and Lvp53 during the basal apoptotic program in normoxia. Overall, these results indicate that hypoxia augments apoptosis in shrimp hemocytes and high mRNA levels of Lvp53 and LvMT are not necessary for this response.

  13. Genetic and pharmacological inhibition of CDK9 drives neutrophil apoptosis to resolve inflammation in zebrafish in vivo

    PubMed Central

    Hoodless, Laura J.; Lucas, Christopher D.; Duffin, Rodger; Denvir, Martin A.; Haslett, Christopher; Tucker, Carl S.; Rossi, Adriano G.

    2016-01-01

    Neutrophilic inflammation is tightly regulated and subsequently resolves to limit tissue damage and promote repair. When the timely resolution of inflammation is dysregulated, tissue damage and disease results. One key control mechanism is neutrophil apoptosis, followed by apoptotic cell clearance by phagocytes such as macrophages. Cyclin-dependent kinase (CDK) inhibitor drugs induce neutrophil apoptosis in vitro and promote resolution of inflammation in rodent models. Here we present the first in vivo evidence, using pharmacological and genetic approaches, that CDK9 is involved in the resolution of neutrophil-dependent inflammation. Using live cell imaging in zebrafish with labelled neutrophils and macrophages, we show that pharmacological inhibition, morpholino-mediated knockdown and CRISPR/cas9-mediated knockout of CDK9 enhances inflammation resolution by reducing neutrophil numbers via induction of apoptosis after tailfin injury. Importantly, knockdown of the negative regulator La-related protein 7 (LaRP7) increased neutrophilic inflammation. Our data show that CDK9 is a possible target for controlling resolution of inflammation. PMID:27833165

  14. Biomechanics drive histological wall remodeling of neoaortic root: A mathematical model to study the expression levels of ki 67, metalloprotease, and apoptosis transition.

    PubMed

    Nappi, Francesco; Fraldi, Massimiliano; Spadaccio, Cristiano; Carotenuto, Angelo Rosario; Montagnani, Stefania; Castaldo, Clotilde; Chachques, Juan Carlos; Acar, Christophe

    2016-11-01

    The pulmonary artery autograft (PA) is the ideal substitute for aortic valve disease in children and young adult. However, it is harnessed by the issue of long-term dilation and regurgitation, often requiring surgery. PA implanted in aortic position during the growth phase in children undergoes a process of mechanical remodeling. We previously developed a semiresorbable armored prosthesis able to mechanically sustain the neoaorta preventing dilation and to gradually integrate with the PA wall inducing a progressive arterial-like tissue positive remodeling. We also described the mechanisms of growth, remodeling and stress shielding of the reinforced PA through a mathematical model. We sought to demonstrate the biological counterpart and the potential molecular mechanisms underlying this histological and mechanical remodeling. A specific mathematical model was developed to describe mechanical behavior of the PA. Mallory trichrome red staining and immunohistochemistry for MMP-9 were performed to elucidate extracellular matrix remodeling phenomena. Apoptosis and cell proliferation were determined by TUNEL assay and immunohistochemistry for Ki67, respectively. An histological remodeling phenomenon sustained by increased level of MMP-9, augmented cell proliferation and reduced apoptosis in the reinforced PA was demonstrated. The mathematical model predicted the biomechanical behavior subtended by the histological changes of the PA in these settings. Changes in metalloproteinases (MMP-9), cell proliferation and apoptosis are the main actors in the remodeling process occurring after transposition of the PA into systemic regimens. Use of semiresorbable reinforcements might induce a positive remodeling of the PA in the context of Ross operation. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2785-2793, 2016.

  15. Perturbation of neddylation-dependent NF-κB responses in the intestinal epithelium drives apoptosis and inhibits resolution of mucosal inflammation.

    PubMed

    Ehrentraut, Stefan F; Curtis, Valerie F; Wang, Ruth X; Saeedi, Bejan J; Ehrentraut, Heidi; Onyiah, Joseph C; Kelly, Caleb J; Campbell, Eric L; Glover, Louise E; Kominsky, Douglas J; Colgan, Sean P

    2016-09-28

    Recent work has revealed a central role for neddylation (the conjugation of a Nedd8-moiety to Cullin proteins) in the fine tuning of the NF-κB response (via Cullin-1). In the present study, we investigated the contribution of Cullin-1 neddylation and NF-κB signaling to mucosal inflammatory responses in vitro and in vivo. Initial in vitro studies using cultured intestinal epithelial cells revealed that the neddylation inhibitor MLN4924 prominently induces the deneddylation of Cullin-1. Parallel western blot, luciferase reporter and gene target assays identified MLN4924 as a potent inhibitor of intestinal epithelial NF-κB. Subsequent studies revealed that MLN4924 potently induces epithelial apoptosis but only in the presence of additional inflammatory stimuli. In vivo administration of MLN4924 (3 mg/kg/d) in a TNBS-induce colitis model significantly accentuated disease severity. Indeed, MLN4924 resulted in worsened clinical scores and increased mortality early in the inflammatory response. Histologic analysis of the colon revealed that neddylation inhibition results in increased tissue damage and significantly increased mucosal apoptosis as determined by TUNEL and cleaved caspase-3 staining, particularly prominent within the epithelium. Extensions of these studies revealed that ongoing inflammation is associated with significant loss of deneddylase-1 (SENP8) expresssion. These studies reveal that intact Cullin-1 neddylation is central to resolution of acute inflammation.

  16. Perturbation of neddylation-dependent NF-κB responses in the intestinal epithelium drives apoptosis and inhibits resolution of mucosal inflammation

    PubMed Central

    Ehrentraut, Stefan F.; Curtis, Valerie F.; Wang, Ruth X.; Saeedi, Bejan J.; Ehrentraut, Heidi; Onyiah, Joseph C.; Kelly, Caleb J.; Campbell, Eric L.; Glover, Louise E.; Kominsky, Douglas J.; Colgan, Sean P.

    2016-01-01

    Recent work has revealed a central role for neddylation (the conjugation of a Nedd8 moiety to Cullin proteins) in the fine-tuning of the NF-κB response (via Cullin-1). In the present study, we investigated the contribution of Cullin-1 neddylation and NF-κB signaling to mucosal inflammatory responses in vitro and in vivo. Initial in vitro studies using cultured intestinal epithelial cells revealed that the neddylation inhibitor MLN4924 prominently induces the deneddylation of Cullin-1. Parallel Western blot, luciferase reporter, and gene target assays identified MLN4924 as a potent inhibitor of intestinal epithelial NF-κB. Subsequent studies revealed that MLN4924 potently induces epithelial apoptosis but only in the presence of additional inflammatory stimuli. In vivo administration of MLN4924 (3 mg/kg per day) in a TNBS-induced colitis model significantly accentuated disease severity. Indeed, MLN4924 resulted in worsened clinical scores and increased mortality early in the inflammatory response. Histologic analysis of the colon revealed that neddylation inhibition results in increased tissue damage and significantly increased mucosal apoptosis as determined by TUNEL and cleaved caspase-3 staining, which was particularly prominent within the epithelium. Extensions of these studies revealed that ongoing inflammation is associated with significant loss of deneddylase-1 (SENP8) expression. These studies reveal that intact Cullin-1 neddylation is central to resolution of acute inflammation. PMID:27682585

  17. Bromelain inhibits nuclear factor kappa-B translocation, driving human epidermoid carcinoma A431 and melanoma A375 cells through G(2)/M arrest to apoptosis.

    PubMed

    Bhui, Kulpreet; Tyagi, Shilpa; Srivastava, Amit Kumar; Singh, Madhulika; Roy, Preeti; Singh, Richa; Shukla, Yogeshwer

    2012-03-01

    Bromelain, obtained from pineapple, is already in use clinically as adjunct in chemotherapy. Our objective was to test its ability to act as a sole anti-cancer agent. Therefore, we describe its anti-proliferative, anti-inflammatory and subsequent anti-cancer effects in vitro, against human epidermoid carcinoma-A431 and melanoma-A375 cells. Bromelain exhibited reduction in proliferation of both these cell-lines and suppressed their potential for anchorage-independent growth. Further, suppression of inflammatory signaling by bromelain was evident by inhibition of Akt regulated-nuclear factor-kappaB activation via suppression of inhibitory-kappaBα phosphorylation and concomitant reduction in cyclooxygenase-2. Since, the inflammatory cascade is well-known to be closely allied to cancer; we studied the effect of bromelain on events/molecules central to it. Bromelain caused depletion of intracellular glutathione and generation of reactive oxygen-species followed by mitochondrial membrane depolarization. This led to bromelain-induced cell-cycle arrest at G(2)/M phase which was mediated by modulation of cyclin B1, phospho-cdc25C, Plk1, phospho-cdc2, and myt1. This was subsequently followed by induction of apoptosis, indicated by membrane-blebbing, modulation of Bax-Bcl-2 ratio, Apaf-1, caspase-9, and caspase-3; chromatin-condensation, increase in caspase-activity and DNA-fragmentation. Bromelain afforded substantial anti-cancer potential in these settings; hence we suggest it as a potential prospect for anti-cancer agent besides only an additive in chemotherapy.

  18. Maternal and Fetal Mechanisms of B Cell Regulation during Pregnancy: Human Chorionic Gonadotropin Stimulates B Cells to Produce IL-10 While Alpha-Fetoprotein Drives Them into Apoptosis

    PubMed Central

    Fettke, Franziska; Schumacher, Anne; Canellada, Andrea; Toledo, Natalia; Bekeredjian-Ding, Isabelle; Bondt, Albert; Wuhrer, Manfred; Costa, Serban-Dan; Zenclussen, Ana Claudia

    2016-01-01

    Maternal immune tolerance toward the fetus is an essential requisite for pregnancy. While T cell functions are well documented, little is known about the participation of B cells. We have previously suggested that IL-10-producing B cells are involved in pregnancy tolerance in mice and humans. By employing murine and human systems, we report now that fetal trophoblasts positively regulate the generation of IL-10-producing B cells. We next studied the participation of hormones produced by the placenta as well as the fetal protein alpha-fetoprotein (AFP) in B cell modulation. Human chorionic gonadotropin (hCG), but not progesterone, estrogen, or a combination of both, was able to promote changes in B cell phenotype and boost their IL-10 production, which was abolished after blocking hCG. The hCG-induced B cell phenotype was not associated with augmented galactosylation, sialylation, or fucosylation of IgG subclasses in their Fc. In vitro, hCG induced the synthesis of asymmetrically glycosylated antibodies in their Fab region. Interestingly, AFP had dual effects depending on the concentration. At concentrations corresponding to maternal serum levels, it did not modify the phenotype or IL-10 secretion of B cells. At fetal concentrations, however, AFP was able to drive B cells into apoptosis, which may indicate a protective mechanism to avoid maternal B cells to reach the fetus. Our data suggest that the fetus secrete factors that promote a pregnancy-friendly B cell phenotype, unraveling interesting aspects of B cell function, and modulation by pregnancy hormones and fetal proteins. PMID:28008329

  19. iDriving (Intelligent Driving)

    SciTech Connect

    Malikopoulos, Andreas

    2012-09-17

    iDriving identifies the driving style factors that have a major impact on fuel economy. An optimization framework is used with the aim of optimizing a driving style with respect to these driving factors. A set of polynomial metamodels is constructed to reflect the responses produced in fuel economy by changing the driving factors. The optimization framework is used to develop a real-time feedback system, including visual instructions, to enable drivers to alter their driving styles in responses to actual driving conditions to improve fuel efficiency.

  20. A hallmark of immunoreceptor, the tyrosine-based inhibitory motif ITIM, is present in the G protein-coupled receptor OX1R for orexins and drives apoptosis: a novel mechanism.

    PubMed

    Voisin, Thierry; El Firar, Aadil; Rouyer-Fessard, Christiane; Gratio, Valérie; Laburthe, Marc

    2008-06-01

    Orexins acting at the G protein-coupled receptor (GPCR) OX1R have recently been shown to promote dramatic apoptosis in cancer cells. We report here that orexin-induced apoptosis is driven by an immunoreceptor tyrosine-based inhibitory motif (ITIM) (IIY(358)NFL) present in the OX1R. This effect is mediated by SHP-2 phosphatase recruitment via a mechanism that requires Gq protein but is independent of phospholipase C activation. This is based on the following observations: 1) mutation of Y(358) into F abolished orexin-induced tyrosine phosphorylation in ITIM, orexin-induced apoptosis, and uncoupled OX1R from Gq protein in transfected Chinese hamster ovary (CHO) cells; 2) orexin-induced apoptosis in CHO cells expressing recombinant OX1R and in colon cancer cells expressing the native receptor was abolished by treatment with the tyrosine phosphatase inhibitor PAO and by transfection with a dominant-negative mutant of SHP-2; 3) orexins were unable to promote apoptosis in fibroblast cells invalidated for the G alpha q subunit and transfected with OX1R cDNA, whereas they promoted apoptosis in cells equipped with G alpha q and OX1R; and 4) the phospholipase C inhibitor U-73122 blocked orexin-stimulated inositol phosphate formation, whereas it had no effect on orexin-induced apoptosis in CHO cells expressing OX1R. These data unravel a novel mechanism, whereby ITIM-expressing GPCRs may trigger apoptosis.

  1. Drugged Driving

    MedlinePlus

    ... Alerts Alcohol Club Drugs Cocaine Hallucinogens Heroin Inhalants Marijuana MDMA (Ecstasy/Molly) Methamphetamine Opioids Prescription Drugs & Cold ... in the past year. Middle Figure: Driving after marijuana use is more common than driving after alcohol ...

  2. Impaired Driving

    MedlinePlus

    Impaired driving is dangerous. It's the cause of more than half of all car crashes. It means operating a ... texting Having a medical condition which affects your driving For your safety and the safety of others, ...

  3. Pile Driving

    NASA Technical Reports Server (NTRS)

    1987-01-01

    Machine-oriented structural engineering firm TERA, Inc. is engaged in a project to evaluate the reliability of offshore pile driving prediction methods to eventually predict the best pile driving technique for each new offshore oil platform. Phase I Pile driving records of 48 offshore platforms including such information as blow counts, soil composition and pertinent construction details were digitized. In Phase II, pile driving records were statistically compared with current methods of prediction. Result was development of modular software, the CRIPS80 Software Design Analyzer System, that companies can use to evaluate other prediction procedures or other data bases.

  4. Distracted driving

    MedlinePlus

    ... the road Your hands on the wheel Your mind on driving Distracted driving occurs when something gets in the way of you doing all 3 things. Examples include: Talking on a cell phone Reading or sending text messages Eating and drinking Grooming ( ...

  5. Dementia & Driving

    MedlinePlus

    ... Caregiver Resource Center Family Care Navigator Research Registry Support Groups Caregiver Stories Connections e-Newsletter FCA+(plus) Services ... be like if you could no longer drive. Support groups provide a good venue for both the caregivers ...

  6. Disk Drives

    NASA Technical Reports Server (NTRS)

    1994-01-01

    A new material known as AlBeMet, developed by Brush Wellman for research applications in the National Aero-Space Plane (NASP) program, is now used for high performance disk drives. AlBeMet is a compression of aluminum, beryllium metal matrix composite. It reduces system weight and its high thermal conductivity can effectively remove heat and increase an electrical system's lifetime. The lighter, stiffer AlBeMet (AlBeMet 160) used in the disk drive means heads can be moved faster, improving disk performance.

  7. Cl(-) channels in apoptosis.

    PubMed

    Wanitchakool, Podchanart; Ousingsawat, Jiraporn; Sirianant, Lalida; MacAulay, Nanna; Schreiber, Rainer; Kunzelmann, Karl

    2016-10-01

    A remarkable feature of apoptosis is the initial massive cell shrinkage, which requires opening of ion channels to allow release of K(+), Cl(-), and organic osmolytes to drive osmotic water movement and cell shrinkage. This article focuses on the role of the Cl(-) channels LRRC8, TMEM16/anoctamin, and cystic fibrosis transmembrane conductance regulator (CFTR) in cellular apoptosis. LRRC8A-E has been identified as a volume-regulated anion channel expressed in many cell types. It was shown to be required for regulatory and apoptotic volume decrease (RVD, AVD) in cultured cell lines. Its presence also determines sensitivity towards cytostatic drugs such as cisplatin. Recent data point to a molecular and functional relationship of LRRC8A and anoctamins (ANOs). ANO6, 9, and 10 (TMEM16F, J, and K) augment apoptotic Cl(-) currents and AVD, but it remains unclear whether these anoctamins operate as Cl(-) channels or as regulators of other apoptotic Cl(-) channels, such as LRRC8. CFTR has been known for its proapoptotic effects for some time, and this effect may be based on glutathione release from the cell and increase in cytosolic reactive oxygen species (ROS). Although we find that CFTR is activated by cell swelling, it is possible that CFTR serves RVD/AVD through accumulation of ROS and activation of independent membrane channels such as ANO6. Thus activation of ANO6 will support cell shrinkage and induce additional apoptotic events, such as membrane phospholipid scrambling.

  8. Uncoupling protein 2 regulates palmitic acid-induced hepatoma cell autophagy.

    PubMed

    Lou, Jiaxin; Wang, Yunjiao; Wang, Xuejiang; Jiang, Ying

    2014-01-01

    Mitochondrial uncoupling protein 2 (UCP2) is suggested to have a role in the development of nonalcoholic steatohepatitis (NASH). However, the mechanism remains unclear. Autophagy is an important mediator of many pathological responses. This study aims to investigate the relationship between UCP2 and hepatoma cells autophagy in palmitic acid- (PA-) induced lipotoxicity. H4IIE cells were treated with palmitic acid (PA), and cell autophagy and apoptosis were examined. UCP2 expression, in association with LC3-II and caspase-3, which are indicators of cell autophagy and apoptosis, respectively,was measured. Results demonstrated that UCP2 was associated with autophagy during PA-induced hepatic carcinoma cells injury. Tests on reactive oxygen species (ROS) showed that UCP2 overexpression strongly decreases PA-induced ROS production and apoptosis. Conversely, UCP2 inhibition by genipin or UCP2 mRNA silencing enhances PA-induced ROS production and apoptosis. Autophagy partially participates in this progress. Moreover, UCP2 was associated with ATP synthesis during PA-induced autophagy. In conclusion, increasing UCP2 expression in hepatoma cells may contribute to cell autophagy and antiapoptotic as result of fatty acid injury. Our results may bring new insights for potential NASH therapies.

  9. Mechanism of Hepatocyte Apoptosis

    PubMed Central

    Cao, Lei; Quan, Xi-Bing; Zeng, Wen-Jiao; Yang, Xiao-Ou; Wang, Ming-Jie

    2016-01-01

    Hepatocyte apoptosis plays important roles in both the removal of external microorganisms and the occurrence and development of liver diseases. Different conditions, such as virus infection, fatty liver disease, hepatic ischemia reperfusion, and drug-induced liver injury, are accompanied by hepatocyte apoptosis. This review summarizes recent research on the mechanism of hepatocyte apoptosis involving the classical extrinsic and intrinsic apoptotic pathways, endoplasmic reticulum stress, and oxidative stress-induced apoptosis. We emphasized the major causes of apoptosis according to the characteristics of different liver diseases. Several concerns regarding future research and clinical application are also raised. PMID:28058033

  10. Coaxial Redundant Drives

    NASA Technical Reports Server (NTRS)

    Brissette, R.

    1983-01-01

    Harmonic drives allow redundancy and high out put torque in small package. If main drive fails, standby drive takes over and produces torque along same axis as main drive. Uses include power units in robot for internal pipeline inspection, manipulators in deep submersible probes or other applications in which redundancy protects against costly failures.

  11. [Apoptosis in allergic disease].

    PubMed

    Rojas Ramos, E; Martínez Jiménez, N E; Martínez Aguilar, N E; Garfias Becerra, J

    2000-01-01

    Apoptosis (cell programmed death) it is a mechanism that implicate a physiological suicide, to keep the cellular homeostasis in big amount of tissues. Fas (APO-1; CD95) system is one of the most important cellular responsible via to induce apoptosis on different tissues. Eosinophillia on peripheral blood and tissues are the main characteristics on allergic like asthma. Eosinophil apoptosis is upper regulated in those diseases by IL-5 y GM-CSF. Corticoids, teophyllin and some macrolids have been used like apoptosis inductors on eosinophills, these could be a novel mechanism to promote a better solution on inflammatory allergic diseases.

  12. Uncoupling Protein 2 Increases Susceptibility to Lipopolysaccharide-Induced Acute Lung Injury in Mice

    PubMed Central

    Wang, Qin; Wang, Jianchun; Hu, Mingdong; Yang, Yu; Guo, Liang; Xu, Jing; Lei, Chuanjiang; Jiao, Yan; Xu, JianCheng

    2016-01-01

    Uncoupling protein 2 (UCP2) is upregulated in patients with systemic inflammation and infection, but its functional role is unclear. We up- or downregulated UCP2 expression using UCP2 recombinant adenovirus or the UCP2 inhibitor, genipin, in lungs of mice, and investigated the mechanisms of UCP2 in ALI. UCP2 overexpression in mouse lungs increased LPS-induced pathological changes, lung permeability, lung inflammation, and lowered survival rates. Furthermore, ATP levels and mitochondrial membrane potential were decreased, while reactive oxygen species production was increased. Additionally, mitogen-activated protein kinases (MAPKs) activity was elevated, which increased the sensitivity to LPS-induced apoptosis and inflammation. LPS-induced apoptosis and release of inflammatory factors were alleviated by pretreatment of the Jun N-terminal kinase (JNK) inhibitor SP600125 or the p38 MAPK inhibitor SB203580, but not by the extracellular signal-regulated kinase (ERK) inhibitor PD98059 in UCP2-overexpressing mice. On the other hand, LPS-induced alveolar epithelial cell death and inflammation were attenuated by genipin. In conclusion, UCP2 increased susceptibility to LPS-induced cell death and pulmonary inflammation, most likely via ATP depletion and activation of MAPK signaling following ALI in mice. PMID:27057102

  13. Power semiconductor controlled drives

    NASA Astrophysics Data System (ADS)

    Dubey, Gopal K.

    This book presents power semiconductor controlled drives employing dc motors, induction motors, and synchronous motors. The dynamics of motor and load systems are covered. Open-loop and closed-loop drives are considered, and thyristor, power transistor, and GTO converters are discussed. In-depth coverage is given to ac drives, particularly those fed by voltage and current source inverters and cycloconverters. Full coverage is given to brushless and commutatorless dc drives, including load-commuted synchronous motor drives. Rectifier-controlled dc drives are presented in detail.

  14. Ocular disease and driving.

    PubMed

    Wood, Joanne M; Black, Alex A

    2016-09-01

    As the driving population ages, the number of drivers with visual impairment resulting from ocular disease will increase given the age-related prevalence of ocular disease. The increase in visual impairment in the driving population has a number of implications for driving outcomes. This review summarises current research regarding the impact of common ocular diseases on driving ability and safety, with particular focus on cataract, glaucoma, age-related macular degeneration, hemianopia and diabetic retinopathy. The evidence considered includes self-reported driving outcomes, driving performance (on-road and simulator-based) and various motor vehicle crash indices. Collectively, this review demonstrates that driving ability and safety are negatively affected by ocular disease; however, further research is needed in this area. Older drivers with ocular disease need to be aware of the negative consequences of their ocular condition and in the case where treatment options are available, encouraged to seek these earlier for optimum driving safety and quality of life benefits.

  15. Dementia and driving

    MedlinePlus

    ... medlineplus.gov/ency/patientinstructions/000028.htm Dementia and driving To use the sharing features on this page, ... their independence is being taken away. Signs That Driving May No Longer be Safe People with signs ...

  16. Safe driving for teens

    MedlinePlus

    ... gov/pubmed/25837240 . Simons-Morton B, Ouimet MC. Parent involvement in novice teen driving: a review of the ... nlm.nih.gov/pubmed/16788109 . Simons-Morton B. Parent involvement in novice teen driving: rationale, evidence of effects, ...

  17. Gear bearing drive

    NASA Technical Reports Server (NTRS)

    Weinberg, Brian (Inventor); Mavroidis, Constantinos (Inventor); Vranish, John M. (Inventor)

    2011-01-01

    A gear bearing drive provides a compact mechanism that operates as an actuator providing torque and as a joint providing support. The drive includes a gear arrangement integrating an external rotor DC motor within a sun gear. Locking surfaces maintain the components of the drive in alignment and provide support for axial loads and moments. The gear bearing drive has a variety of applications, including as a joint in robotic arms and prosthetic limbs.

  18. Sequential Dependencies in Driving

    ERIC Educational Resources Information Center

    Doshi, Anup; Tran, Cuong; Wilder, Matthew H.; Mozer, Michael C.; Trivedi, Mohan M.

    2012-01-01

    The effect of recent experience on current behavior has been studied extensively in simple laboratory tasks. We explore the nature of sequential effects in the more naturalistic setting of automobile driving. Driving is a safety-critical task in which delayed response times may have severe consequences. Using a realistic driving simulator, we find…

  19. Magnetic drive coupling

    NASA Technical Reports Server (NTRS)

    Carter, Edward L. (Inventor)

    1987-01-01

    The driving and driven members of a magnetic drive are separated by en enlarged gap to provide clearance for a conduit or other member. Flux pins in the gap maintain the torque transmitting capability of the drive. The spacing between two of the flux pins is increased to provide space for the conduit.

  20. Grieving while Driving

    ERIC Educational Resources Information Center

    Rosenblatt, Paul C.

    2004-01-01

    Secondary analysis of data from 84 people in 2 interview studies shows that some bereaved people grieve actively while driving. The grief can be intense, even years after a death. Grief while driving may erupt spontaneously or be set off by a wide range of reminders. Some bereaved people seem to save their grieving for times when they drive,…

  1. Syncope and Driving.

    PubMed

    Guzman, Juan C; Morillo, Carlos A

    2015-08-01

    The occurrence of syncope while driving has obvious implications for personal and public safety. Neurally mediated syncope is the most common type of syncope in general and, thereby, also while driving. The presence of structural heart disease (reduced ejection fraction, previous myocardial infarction, significant congenital heart disease) potentially leads to high risk and should determine driving restrictions pending clarification of underlying heart disease and etiology of syncope. The clinical approach to syncope evaluation and recommendations for driving should not differ, whether or not the syncopal spell occurred while driving.

  2. Drill drive mechanism

    DOEpatents

    Dressel, Michael O.

    1979-01-01

    A drill drive mechanism is especially adapted to provide both rotational drive and axial feed for a drill of substantial diameter such as may be used for drilling holes for roof bolts in mine shafts. The drill shaft is made with a helical pattern of scroll-like projections on its surface for removal of cuttings. The drill drive mechanism includes a plurality of sprockets carrying two chains of drive links which are arranged to interlock around the drill shaft with each drive link having depressions which mate with the scroll-like projections. As the chain links move upwardly or downwardly the surfaces of the depressions in the links mate with the scroll projections to move the shaft axially. Tangs on the drive links mate with notch surfaces between scroll projections to provide a means for rotating the shaft. Projections on the drive links mate together at the center to hold the drive links tightly around the drill shaft. The entire chain drive mechanism is rotated around the drill shaft axis by means of a hydraulic motor and gear drive to cause rotation of the drill shaft. This gear drive also connects with a differential gearset which is interconnected with a second gear. A second motor is connected to the spider shaft of the differential gearset to produce differential movement (speeds) at the output gears of the differential gearset. This differential in speed is utilized to drive said second gear at a speed different from the speed of said gear drive, this speed differential being utilized to drive said sprockets for axial movement of said drill shaft.

  3. Poliovirus protein 2BC increases cytosolic free calcium concentrations.

    PubMed Central

    Aldabe, R; Irurzun, A; Carrasco, L

    1997-01-01

    Poliovirus-infected cells undergo an increase in cytoplasmic calcium concentrations from the 4th h postinfection. The protein responsible for this effect was identified by the expression of different poliovirus nonstructural proteins in HeLa cells by using a recombinant vaccinia virus system. Synthesis of protein 2BC enhances cytoplasmic calcium concentrations in a manner similar to that observed in poliovirus-infected cells. To identify the regions in 2BC involved in modifying cytoplasmic calcium levels, several 2BC variants were generated. Regions present in both 2B and 2C are necessary to augment cellular free calcium levels. Therefore, in addition to inducing proliferation of membranous vesicles, poliovirus protein 2BC also alters cellular calcium homeostasis. PMID:9223520

  4. Marihuana and driving.

    PubMed

    Moskowitz, H

    1985-08-01

    A review was performed of the marihuana and driving literature, both epidemiological and experimental. It was noted that epidemiological studies face considerable difficulties in obtaining estimates of risks involved for drivers utilizing marihuana due to the rapid decline in blood levels of tetrahydrocannabinol. On the other hand, experimental studies examining the relationship between administered marihuana dose and performance have identified many driving-related areas as exhibiting impairment. Areas impaired include coordination, tracking, perception, vigilance and performance in both driving simulators and on the road. Other behavioral areas of lesser importance for driving also exhibited evidence of impairment by marihuana. Areas for further research are suggested.

  5. Apoptosis in metanephric development

    PubMed Central

    1992-01-01

    During metanephric development, non-polarized mesenchymal cells are induced to form the epithelial structures of the nephron following interaction with extracellular matrix proteins and factors produced by the inducing tissue, ureteric bud. This induction can occur in a transfilter organ culture system where it can also be produced by heterologous cells such as the embryonic spinal cord. We found that when embryonic mesenchyme was induced in vitro and in vivo, many of the cells surrounding the new epithelium showed morphological evidence of programmed cell death (apoptosis) such as condensed nuclei, fragmented cytoplasm, and cell shrinking. A biochemical correlate of apoptosis is the transcriptional activation of a calcium-sensitive endonuclease. Indeed, DNA isolated from uninduced mesenchyme showed progressive degradation, a process that was prevented by treatment with actinomycin- D or cycloheximide and by buffering intracellular calcium. These results demonstrate that the metanephric mesenchyme is programmed for apoptosis. Incubation of mesenchyme with a heterologous inducer, embryonic spinal cord prevented this DNA degradation. To investigate the mechanism by which inducers prevented apoptosis we tested the effects of protein kinase C modulators on this process. Phorbol esters mimicked the effects of the inducer and staurosporine, an inhibitor of this protein kinase, prevented the effect of the inducer. EGF also prevented DNA degradation but did not lead to differentiation. These results demonstrate that conversion of mesenchyme to epithelial requires at least two steps, rescue of the mesenchyme from apoptosis and induction of differentiation. PMID:1447305

  6. Spaceflight Associated Apoptosis

    NASA Technical Reports Server (NTRS)

    Ichiki, Albert T.; Gibson, Linda A.; Allebban, Zuhair

    1996-01-01

    Lymphoid tissues have been shown to atrophy in rats flown on Russian spaceflights. Histological examination indicated evidence for cell degradation. Lymphoid tissues from rats flown on Spacelab Life Sciences-2 mission were analyzed for apoptosis by evidence of fragmented lymphocytes, which could be engulfed by macrophages, or DNA strand breaks using the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay. Apoptosis was not detected in the thymus and spleen collected inflight or from the synchronous ground rats but was detected in the thymus, spleen and inguinal lymph node of the flight animals on recovery. These results indicate that the apoptosis observed in the lymphatic tissues of the rats on recovery could have been induced by the gravitational stress of reentry, corroborating the findings from the early space-flight observations.

  7. Glutathione and apoptosis

    PubMed Central

    Circu, Magdalena L.; Yee Aw, Tak

    2011-01-01

    Apoptosis or programmed cell death represents a physiologically conserved mechanism of cell death that is pivotal in normal development and tissue homeostasis in all organisms. As a key modulator of cell functions, the most abundant non-protein thiol, glutathione (GSH), has important roles in cellular defense against oxidant aggression, redox regulation of proteins thiols and maintaining redox homeostasis that is critical for proper function of cellular processes, including apoptosis. Thus, a shift in the cellular GSH-to-GSSG redox balance in favour of the oxidized species, GSSG, constitutes an important signal that could decide the fate of a cell. The current review will focus on three main areas: (1) general description of cellular apoptotic pathways, (2) cellular compartmentation of GSH and the contribution of mitochondrial GSH and redox proteins to apoptotic signalling and (3) role of redox mechanisms in the initiation and execution phases of apoptosis. PMID:18671159

  8. Piezoelectric drive circuit

    DOEpatents

    Treu, C.A. Jr.

    1999-08-31

    A piezoelectric motor drive circuit is provided which utilizes the piezoelectric elements as oscillators and a Meacham half-bridge approach to develop feedback from the motor ground circuit to produce a signal to drive amplifiers to power the motor. The circuit automatically compensates for shifts in harmonic frequency of the piezoelectric elements due to pressure and temperature changes. 7 figs.

  9. Piezoelectric drive circuit

    DOEpatents

    Treu, Jr., Charles A.

    1999-08-31

    A piezoelectric motor drive circuit is provided which utilizes the piezoelectric elements as oscillators and a Meacham half-bridge approach to develop feedback from the motor ground circuit to produce a signal to drive amplifiers to power the motor. The circuit automatically compensates for shifts in harmonic frequency of the piezoelectric elements due to pressure and temperature changes.

  10. Electric vehicles: Driving range

    NASA Astrophysics Data System (ADS)

    Kempton, Willett

    2016-09-01

    For uptake of electric vehicles to increase, consumers' driving-range needs must be fulfilled. Analysis of the driving patterns of personal vehicles in the US now shows that today's electric vehicles can meet all travel needs on almost 90% of days from a single overnight charge.

  11. The biochemistry of apoptosis.

    PubMed

    Hengartner, M O

    2000-10-12

    Apoptosis--the regulated destruction of a cell--is a complicated process. The decision to die cannot be taken lightly, and the activity of many genes influence a cell's likelihood of activating its self-destruction programme. Once the decision is taken, proper execution of the apoptotic programme requires the coordinated activation and execution of multiple subprogrammes. Here I review the basic components of the death machinery, describe how they interact to regulate apoptosis in a coordinated manner, and discuss the main pathways that are used to activate cell death.

  12. Epstein-Barr virus latent membrane protein 2A contributes to anoikis resistance through ERK activation.

    PubMed

    Iwakiri, Dai; Minamitani, Takeharu; Samanta, Mrinal

    2013-07-01

    Epstein-Barr virus (EBV) is associated with various malignancies, including epithelial cancers. In this study, we analyzed the effect of EBV infection on epithelial cells by using EBV-converted epithelial cells. In EBV-positive cells, the extracellular signal-regulated kinase (ERK) pathway is constitutively activated. Inhibition of ERK activity leads to reduced anoikis resistance; therefore, EBV-positive cells are more resistant to anoikis, a type of apoptosis induced by cell detachment, than are EBV-negative cells. Among the viral genes expressed in EBV-positive cells, the latent membrane protein 2A (LMP2A) is responsible for induction of ERK-mediated anoikis resistance, although the expression level of LMP2A is much lower in EBV-positive cells than in EBV-transformed B cells. Further analysis demonstrated that LMP2A downregulation of the proanoikis mediator Bim through proteasomal degradation is dependent on the immunoreceptor tyrosine-based activation motif (ITAM). These findings suggest that LMP2A-mediated ERK activation is involved in the generation of EBV-associated epithelial malignancies.

  13. Role of nuclear bodies in apoptosis signalling.

    PubMed

    Krieghoff-Henning, Eva; Hofmann, Thomas G

    2008-11-01

    Promyelocytic leukemia nuclear bodies (PML NBs) are dynamic macromolecular multiprotein complexes that recruit and release a plethora of proteins. A considerable number of PML NB components play vital roles in apoptosis, senescence regulation and tumour suppression. The molecular basis by which PML NBs control these cellular responses is still just beginning to be understood. In addition to PML itself, numerous further tumour suppressors including transcriptional regulator p53, acetyl transferase CBP (CREB binding protein) and protein kinase HIPK2 (homeodomain interacting protein kinase 2) are recruited to PML NBs in response to genotoxic stress or oncogenic transformation and drive the senescence and apoptosis response by regulating p53 activity. Moreover, in response to death-receptor activation, PML NBs may act as nuclear depots that release apoptotic factors, such as the FLASH (FLICE-associated huge) protein, to amplify the death signal. PML NBs are also associated with other nuclear domains including Cajal bodies and nucleoli and share apoptotic regulators with these domains, implying crosstalk between NBs in apoptosis regulation. In conclusion, PML NBs appear to regulate cell death decisions through different, pathway-specific molecular mechanisms.

  14. Driving and dementia

    PubMed Central

    Lee, Linda; Molnar, Frank

    2017-01-01

    Abstract Objective To provide primary care physicians with an approach to driving safety concerns when older persons present with memory difficulties. Sources of information The approach is based on an accredited memory clinic training program developed by the Centre for Family Medicine Primary Care Collaborative Memory Clinic. Main message One of the most challenging aspects of dementia care is the assessment of driving safety. Drivers with dementia are at higher risk of motor vehicle collisions, yet many drivers with mild dementia might be safely able to continue driving for several years. Because safe driving is dependent on multiple cognitive and functional skills, clinicians should carefully consider many factors when determining if cognitive concerns affect driving safety. Specific findings on corroborated history and office-based cognitive testing might aid in the physician’s decisions to refer for comprehensive on-road driving evaluation and whether to notify transportation authorities in accordance with provincial reporting requirements. Sensitive communication and a person-centred approach are essential. Conclusion Primary care physicians must consider many factors when determining if cognitive concerns might affect driving safety in older drivers. PMID:28115437

  15. Drive System Research

    NASA Technical Reports Server (NTRS)

    Handschuh, Robert F.

    2007-01-01

    An overview of the NASA Glenn Research Center Drive Systems Research will be presented. The primary purpose of this research is to improve performance, reliability, and integrity of aerospace drive systems and space mechanisms. The research is conducted through a combination of in-house, academia, and through contractors. Research is conducted through computer code development and validated through component and system testing. The drive system activity currently has four major thrust areas including: thermal behavior of high speed gearing, health and usage monitoring, advanced components, and space mechanisms.

  16. Vision and Driving

    PubMed Central

    Owsley, Cynthia; McGwin, Gerald

    2010-01-01

    Driving is the primary means of personal travel in many countries and is relies heavily on vision for its successful execution. Research over the past few decades has addressed the role of vision in driver safety (motor vehicle collision involvement) and in driver performance (both on-road and using interactive simulators in the laboratory). Here we critically review what is currently known about the role of various aspects of visual function in driving. We also discuss translational research issues on vision screening for licensure and re-licensure and rehabilitation of visually impaired persons who want to drive. PMID:20580907

  17. The Test Drive

    NASA Technical Reports Server (NTRS)

    2004-01-01

    This image taken at NASA's Jet Propulsion Laboratory shows engineers rehearsing the sol 133 (June 8, 2004) drive into 'Endurance' crater by NASA's Mars Exploration Rover Opportunity. Engineers and scientists have recreated the martian surface and slope the rover will encounter using a combination of bare and thinly sand-coated rocks, simulated martian 'blueberries' and a platform tilted at a 25-degree angle. The results of this test convinced engineers that the rover was capable of driving up and down a straight slope before it attempted the actual drive on Mars.

  18. Fast wave current drive

    SciTech Connect

    Goree, J.; Ono, M.; Colestock, P.; Horton, R.; McNeill, D.; Park, H.

    1985-07-01

    Fast wave current drive is demonstrated in the Princeton ACT-I toroidal device. The fast Alfven wave, in the range of high ion-cyclotron harmonics, produced 40 A of current from 1 kW of rf power coupled into the plasma by fast wave loop antenna. This wave excites a steady current by damping on the energetic tail of the electron distribution function in the same way as lower-hybrid current drive, except that fast wave current drive is appropriate for higher plasma densities.

  19. [Driving and Alzheimer's disease].

    PubMed

    Roche, Jean

    2005-09-01

    Although most aged people remain safe drivers, a greater risk for crashes due to medical conditions is observed in the elderly. Impairment of important functions for safe driving such as visuospatial skills, attention, memory and judgement are observed in dementia, particularly in Alzheimer's disease. The accident rate increases from 9.4 accidents per million vehicle kilometers traveled for 80 to 85 year-old drivers, but raises to 163.6 for drivers with moderate AD. Patients and their families should be informed that patients with mild dementia related to Alzheimer's disease (stage 1 on the Clinical Dementia Rating, CDR), have a substantially increased rate of traffic accidents and therefore should not drive. But subjects in the pre-dementia phase (stage 0.5 at the CDR, mild cognitive impairment) also pose significant driving safety problems. In most States of the USA, and many European countries, but not in France, law requires regular investigating of driving performance in the elderly.

  20. [Driving and aging].

    PubMed

    Cantón-Cortés, David; Durán Segura, Mercedes; Castro Ramírez, Cándida

    2010-01-01

    The number of older people who continue to drive is constantly increasing. However, whether older people have more traffic accidents than other age groups is unclear. This age group has certain risk factors due to decreased motor, sensory and cognitive functions and also has greater frailty and vulnerability to injury. However, older drivers are aware of their heightened crash risk and employ certain compensatory actions, avoiding traveling under threatening conditions (dense traffic, bad weather or night driving), traveling by well-known routes and driving carefully. In view of these apparent contradictions, the present study attempts to discern the real crash risk and the driving and crash patterns characteristic of this population, which is continually increasing in industrialized countries.

  1. Control rod drive

    SciTech Connect

    Hawke, Basil C.

    1986-01-01

    A control rod drive uses gravitational forces to insert one or more control rods upwardly into a reactor core from beneath the reactor core under emergency conditions. The preferred control rod drive includes a vertically movable weight and a mechanism operatively associating the weight with the control rod so that downward movement of the weight is translated into upward movement of the control rod. The preferred control rod drive further includes an electric motor for driving the control rods under normal conditions, an electrically actuated clutch which automatically disengages the motor during a power failure and a decelerator for bringing the control rod to a controlled stop when it is inserted under emergency conditions into a reactor core.

  2. Assessment: A Driving Force.

    ERIC Educational Resources Information Center

    Rakow, Steven J.

    1992-01-01

    Asserts that educational assessment drives the curriculum. Thus, assessment is very important in contemplating reform in science education. Assessment should be an integral part of the instructional process, utilizing diagnostic testing, monitoring, and summative evaluations. (PR)

  3. CONTROL ROD DRIVE

    DOEpatents

    Chapellier, R.A.

    1960-05-24

    BS>A drive mechanism was invented for the control rod of a nuclear reactor. Power is provided by an electric motor and an outside source of fluid pressure is utilized in conjunction with the fluid pressure within the reactor to balance the loadings on the motor. The force exerted on the drive mechanism in the direction of scramming the rod is derived from the reactor fluid pressure so that failure of the outside pressure source will cause prompt scramming of the rod.

  4. Common drive unit

    NASA Technical Reports Server (NTRS)

    Ellis, R. C.; Fink, R. A.; Moore, E. A.

    1987-01-01

    The Common Drive Unit (CDU) is a high reliability rotary actuator with many versatile applications in mechanism designs. The CDU incorporates a set of redundant motor-brake assemblies driving a single output shaft through differential. Tachometers provide speed information in the AC version. Operation of both motors, as compared to the operation of one motor, will yield the same output torque with twice the output speed.

  5. Direct drive wind turbine

    DOEpatents

    Bywaters, Garrett; Danforth, William; Bevington, Christopher; Stowell, Jesse; Costin, Daniel

    2006-07-11

    A wind turbine is provided that minimizes the size of the drive train and nacelle while maintaining the power electronics and transformer at the top of the tower. The turbine includes a direct drive generator having an integrated disk brake positioned radially inside the stator while minimizing the potential for contamination. The turbine further includes a means for mounting a transformer below the nacelle within the tower.

  6. Direct drive wind turbine

    DOEpatents

    Bywaters, Garrett; Danforth, William; Bevington, Christopher; Jesse, Stowell; Costin, Daniel

    2007-02-27

    A wind turbine is provided that minimizes the size of the drive train and nacelle while maintaining the power electronics and transformer at the top of the tower. The turbine includes a direct drive generator having an integrated disk brake positioned radially inside the stator while minimizing the potential for contamination. The turbine further includes a means for mounting a transformer below the nacelle within the tower.

  7. Direct drive wind turbine

    DOEpatents

    Bywaters, Garrett Lee; Danforth, William; Bevington, Christopher; Stowell, Jesse; Costin, Daniel

    2006-09-19

    A wind turbine is provided that minimizes the size of the drive train and nacelle while maintaining the power electronics and transformer at the top of the tower. The turbine includes a direct drive generator having an integrated disk brake positioned radially inside the stator while minimizing the potential for contamination. The turbine further includes a means for mounting a transformer below the nacelle within the tower.

  8. Direct drive wind turbine

    DOEpatents

    Bywaters, Garrett; Danforth, William; Bevington, Christopher; Jesse, Stowell; Costin, Daniel

    2006-10-10

    A wind turbine is provided that minimizes the size of the drive train and nacelle while maintaining the power electronics and transformer at the top of the tower. The turbine includes a direct drive generator having an integrated disk brake positioned radially inside the stator while minimizing the potential for contamination. The turbine further includes a means for mounting a transformer below the nacelle within the tower.

  9. Electric Drive Study

    DTIC Science & Technology

    1987-03-01

    Track-Laying Combat Vehicles , and (3) Parametric Study of Electric Drive Component Technologies. The technology survey results are given in a separate...and projections of future electric drive system improvements relative to combat vehicle applications. Unclassified SECURITY CLASSIFICATION OF THIS...273 5.7.2.3.1 DC Homopolar Drum Machine, Design and Performance 5-278 APPENDIX A 19.5 TON AND 40.0 TON VEHICLE SPECIFICATION APPENDIX B ELECTRIC

  10. Self-driving carsickness.

    PubMed

    Diels, Cyriel; Bos, Jelte E

    2016-03-01

    This paper discusses the predicted increase in the occurrence and severity of motion sickness in self-driving cars. Self-driving cars have the potential to lead to significant benefits. From the driver's perspective, the direct benefits of this technology are considered increased comfort and productivity. However, we here show that the envisaged scenarios all lead to an increased risk of motion sickness. As such, the benefits this technology is assumed to bring may not be capitalised on, in particular by those already susceptible to motion sickness. This can negatively affect user acceptance and uptake and, in turn, limit the potential socioeconomic benefits that this emerging technology may provide. Following a discussion on the causes of motion sickness in the context of self-driving cars, we present guidelines to steer the design and development of automated vehicle technologies. The aim is to limit or avoid the impact of motion sickness and ultimately promote the uptake of self-driving cars. Attention is also given to less well known consequences of motion sickness, in particular negative aftereffects such as postural instability, and detrimental effects on task performance and how this may impact the use and design of self-driving cars. We conclude that basic perceptual mechanisms need to be considered in the design process whereby self-driving cars cannot simply be thought of as living rooms, offices, or entertainment venues on wheels.

  11. Dementia and driving.

    PubMed

    O'Neill, D; Neubauer, K; Boyle, M; Gerrard, J; Surmon, D; Wilcock, G K

    1992-04-01

    Many European countries test cars, but not their drivers, as they age. There is evidence to suggest that human factors are more important than vehicular factors as causes of motor crashes. The elderly also are involved in more accidents per distance travelled than middle-aged drivers. As the UK relies on self-certification of health by drivers over the age of 70 years, we examined the driving practices of patients with dementia attending a Memory Clinic. Nearly one-fifth of 329 patients with documented dementia continued to drive after the onset of dementia, and impaired driving ability was noted in two-thirds of these. Their families experienced great difficulty in persuading patients to stop driving, and had to invoke outside help in many cases. Neuropsychological tests did not help to identify those who drove badly while activity of daily living scores were related to driving ability. These findings suggest that many patients with dementia drive in an unsafe fashion after the onset of the illness. The present system of self-certification of health by the elderly for driver-licensing purposes needs to be reassessed.

  12. Hydraulic drive system prevents backlash

    NASA Technical Reports Server (NTRS)

    Acord, J. D.

    1965-01-01

    Hydraulic drive system uses a second drive motor operating at reduced torque. This exerts a relative braking action which eliminates the normal gear train backlash that is intolerable when driving certain heavy loads.

  13. Mortalin, Apoptosis, and Neurodegeneration

    PubMed Central

    Londono, Carolina; Osorio, Cristina; Gama, Vivian; Alzate, Oscar

    2012-01-01

    Mortalin is a highly conserved heat-shock chaperone usually found in multiple subcellular locations. It has several binding partners and has been implicated in various functions ranging from stress response, control of cell proliferation, and inhibition/prevention of apoptosis. The activity of this protein involves different structural and functional mechanisms, and minor alterations in its expression level may lead to serious biological consequences, including neurodegeneration. In this article we review the most current data associated with mortalin’s binding partners and how these protein-protein interactions may be implicated in apoptosis and neurodegeneration. A complete understanding of the molecular pathways in which mortalin is involved is important for the development of therapeutic strategies for cancer and neurodegenerative diseases. PMID:24970131

  14. Mental workload and driving

    PubMed Central

    Paxion, Julie; Galy, Edith; Berthelon, Catherine

    2014-01-01

    The aim of this review is to identify the most representative measures of subjective and objective mental workload in driving, and to understand how the subjective and objective levels of mental workload influence the performance as a function of situation complexity and driving experience, i.e., to verify whether the increase of situation complexity and the lack of experience increase the subjective and physiological levels of mental workload and lead to driving performance impairments. This review will be useful to both researchers designing an experimental study of mental workload and to designers of drivers’ training content. In the first part, we will broach the theoretical approach with two factors of mental workload and performance, i.e., situation complexity and driving experience. Indeed, a low complex situation (e.g., highways), or conversely a high complex situation (e.g., town) can provoke an overload. Additionally, performing the driving tasks implies producing a high effort for novice drivers who have not totally automated the driving activity. In the second part, we will focus on subjective measures of mental workload. A comparison of questionnaires usually used in driving will allow identifying the most appropriate ones as a function of different criteria. Moreover, we will review the empirical studies to verify if the subjective level of mental workload is high in simple and very complex situations, especially for novice drivers compared to the experienced ones. In the third part, we will focus on physiological measures. A comparison of physiological indicators will be realized in order to identify the most correlated to mental workload. An empirical review will also take the effect of situation complexity and experience on these physiological indicators into consideration. Finally, a more nuanced comparison between subjective and physiological measures will be established from the impact on situation complexity and experience. PMID:25520678

  15. Apoptosis in canine distemper.

    PubMed

    Moro, L; de Sousa Martins, A; de Moraes Alves, C; de Araújo Santos, F G; dos Santos Nunes, J E; Carneiro, R A; Carvalho, R; Vasconcelos, A C

    2003-01-01

    Canine distemper is a systemic viral disease characterized by immunosuppression followed by secondary infections. Apoptosis is observed in several immunosuppressive diseases and its occurrence on canine distemper in vivo has not been published. In this study, the occurrence of apoptosis was determined in lymphoid tissues of thirteen naturally infected dogs and nine experimentally inoculated puppies. Healthy dogs were used as negative controls. Samples of lymph nodes, thymus, spleen and brain were collected for histopathological purposes. Sections, 5 microm thick, of retropharingeal lymph nodes were stained by HE, Shorr, Methyl Green-Pyronin and TUNEL reaction. Shorr stained sections were further evaluated by morphometry. Canine distemper virus nucleoprotein was detected by immunohistochemistry. Retropharingeal lymph nodes of naturally and experimentally infected dogs had more apoptotic cells per field than controls. In addition, DNA from thymus of infected dogs were more fragmented than controls. Therefore, apoptosis is increased in lymphoid depletion induced by canine distemper virus and consequently play a role in the immunosuppression seen in this disease.

  16. DEDRICK DRIVE, LOOKING NORTH FROM SOUTH END OF DEDRICK DRIVE ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    DEDRICK DRIVE, LOOKING NORTH FROM SOUTH END OF DEDRICK DRIVE NEAR BUILDING 80 - Pacific Coast Torpedo Station, Keyport Industrial District, Both sides of Second Street, between Dedrick Drive and Liberty Bay and one building west of Dedrick Drive and south of Second Street, Keyport, Kitsap County, WA

  17. Driving Anger and Driving Behavior in Adults with ADHD

    ERIC Educational Resources Information Center

    Richards, Tracy L.; Deffenbacher, Jerry L.; Rosen, Lee A.; Barkley, Russell A.; Rodricks, Trisha

    2006-01-01

    Objective: This study assesses whether anger in the context of driving is associated with the negative driving outcomes experienced by individuals with ADHD. Method: ADHD adults (n = 56) complete measures of driving anger, driving anger expression, angry thoughts behind the wheel, and aggressive, risky, and crash-related behavior. Results are…

  18. Driving anger in Malaysia.

    PubMed

    Sullman, Mark J M; Stephens, Amanda N; Yong, Michelle

    2014-10-01

    The present study examined the types of situations that cause Malaysian drivers to become angry. The 33-item version of the driver anger scale (Deffenbacher et al., 1994) was used to investigate driver anger amongst a sample of 339 drivers. Confirmatory factor analysis showed that the fit of the original six-factor model (discourtesy, traffic obstructions, hostile gestures, slow driving, illegal driving and police presence), after removing one item and allowing three error pairs to covary, was satisfactory. Female drivers reported more anger, than males, caused by traffic obstruction and hostile gestures. Age was also negatively related to five (discourtesy, traffic obstructions, hostile gestures, slow driving and police presence) of the six factors and also to the total DAS score. Furthermore, although they were not directly related to crash involvement, several of the six forms of driving anger were significantly related to the crash-related conditions of: near misses, loss of concentration, having lost control of a vehicle and being ticketed. Overall the pattern of findings made in the present research were broadly similar to those from Western countries, indicating that the DAS is a valid measure of driving anger even among non-European based cultures.

  19. Stromal cell-derived factor-1 potentiates bone morphogenetic protein-2 induced bone formation.

    PubMed

    Higashino, Kosaku; Viggeswarapu, Manjula; Bargouti, Maggie; Liu, Hui; Titus, Louisa; Boden, Scott D

    2011-02-01

    The mechanisms driving bone marrow stem cell mobilization are poorly understood. A recent murine study found that circulating bone marrow-derived osteoprogenitor cells (MOPCs) were recruited to the site of recombinant human bone morphogenetic protein-2 (BMP-2)-induced bone formation. Stromal cell-derived factor-1α (SDF-1α) and its cellular receptor CXCR4 have been shown to mediate the homing of stem cells to injured tissues. We hypothesized that chemokines, such as SDF-1, are also involved with mobilization of bone marrow cells. The CD45(-) fraction is a major source of MOPCs. In this report we determined that the addition of BMP-2 or SDF-1 to collagen implants increased the number of MOPCs in the peripheral blood. BMP-2-induced mobilization was blocked by CXCR4 antibody, confirming the role of SDF-1 in mobilization. We determined for the first time that addition of SDF-1 to implants containing BMP-2 enhances mobilization, homing of MOPCs to the implant, and ectopic bone formation induced by suboptimal BMP-2 doses. These results suggest that SDF-1 increases the number of osteoprogenitor cells that are mobilized from the bone marrow and then home to the implant. Thus, addition of SDF-1 to BMP-2 may improve the efficiency of BMPs in vivo, making their routine use for orthopaedic applications more affordable and available to more patients.

  20. Broad targeting of resistance to apoptosis in cancer

    PubMed Central

    Mohammad, Ramzi M.; Muqbil, Irfana; Lowe, Leroy; Yedjou, Clement; Hsu, Hsue-Yin; Lin, Liang-Tzung; Siegelin, Markus David; Fimognari, Carmela; Kumar, Nagi B.; Dou, Q. Ping; Yang, Huanjie; Samadi, Abbas K.; Russo, Gian Luigi; Spagnuolo, Carmela; Ray, Swapan K.; Chakrabarti, Mrinmay; Morre, James D.; Coley, Helen M.; Honoki, Kanya; Fujii, Hiromasa; Georgakilas, Alexandros G.; Amedei, Amedeo; Niccolai, Elena; Amin, Amr; Ashraf, S. Salman; Helferich, William G.; Yang, Xujuan; Boosani, Chandra S.; Guha, Gunjan; Bhakta, Dipita; Ciriolo, Maria Rosa; Aquilano, Katia; Chen, Sophie; Mohammed, Sulma I.; Keith, W. Nicol; Bilsland, Alan; Halicka, Dorota; Nowsheen, Somaira; Azmi, Asfar S.

    2015-01-01

    Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer. PMID:25936818

  1. U.S. DRIVE

    SciTech Connect

    2012-03-16

    U.S. DRIVE, which stands for United States Driving Research and Innovation for Vehicle efficiency and Energy sustainability, is an expanded government-industry partnership among the U.S. Department of Energy; USCAR, representing Chrysler Group LLC, Ford Motor Company and General Motors; Tesla Motors; five energy companies – BP America, Chevron Corporation, ConocoPhillips, ExxonMobil Corporation, and Shell Oil Products US; two utilities – Southern California Edison and Michigan-based DTE Energy; and the Electric Power Research Institute (EPRI). The U.S. DRIVE mission is to accelerate the development of pre-competitive and innovative technologies to enable a full range of affordable and clean advanced light-duty vehicles, as well as related energy infrastructure.

  2. Ceramic vane drive joint

    DOEpatents

    Smale, Charles H.

    1981-01-01

    A variable geometry gas turbine has an array of ceramic composition vanes positioned by an actuating ring coupled through a plurality of circumferentially spaced turbine vane levers to the outer end of a metallic vane drive shaft at each of the ceramic vanes. Each of the ceramic vanes has an end slot of bow tie configuration including flared end segments and a center slot therebetween. Each of the vane drive shafts has a cross head with ends thereof spaced with respect to the sides of the end slot to define clearance for free expansion of the cross head with respect to the vane and the cross head being configured to uniformly distribute drive loads across bearing surfaces of the vane slot.

  3. Microlinear piezo drive experiments

    NASA Astrophysics Data System (ADS)

    Azin, A. V.; Bogdanov, E. P.; Rikkonen, S. V.; Ponomarev, S. V.; Khramtsov, A. M.

    2017-02-01

    The article embraces the experimental description of the micro linear piezo drive intended for the peripheral cord tensioner in the reflecting surface shape regulator system for large-sized transformable spacecraft antenna reflectors. The research target is the experimental investigation of the micro linear piezo drive to determine the stable oscillatory system operating modes which would include improved energy conversion parameters. The following points are briefly presented: test stand construction-design of the peripheral cord tensioner; the determined frequency characteristics and the identified resonant and actual frequencies of an oscillatory system under inertia load. A series of experiments has been conducted for both different preliminary voltages and inertia mass values.

  4. CONTROL ROD DRIVE

    DOEpatents

    Chapellier, R.A.; Rogers, I.

    1961-06-27

    Accurate and controlled drive for the control rod is from an electric motor. A hydraulic arrangement is provided to balance a piston against which a control rod is urged by the application of fluid pressure. The electric motor drive of the control rod for normal operation is made through the aforementioned piston. In the event scramming is required, the fluid pressure urging the control rod against the piston is relieved and an opposite fluid pressure is applied. The lack of mechanical connection between the electric motor and control rod facilitates the scramming operation.

  5. Pathophysiological Significance of Hepatic Apoptosis

    PubMed Central

    Wang, Kewei; Lin, Bingliang

    2013-01-01

    Apoptosis is a classical pathological feature in liver diseases caused by various etiological factors such as drugs, viruses, alcohol, and cholestasis. Hepatic apoptosis and its deleterious effects exacerbate liver function as well as involvement in fibrosis/cirrhosis and carcinogenesis. An imbalance between apoptotic and antiapoptotic capabilities is a prominent characteristic of liver injury. The regulation of apoptosis and antiapoptosis can be a pivotal step in the treatment of liver diseases. PMID:27335822

  6. Interaction of Approved Drugs with Synaptic Vesicle Protein 2A.

    PubMed

    Danish, Azeem; Namasivayam, Vigneshwaran; Schiedel, Anke C; Müller, Christa E

    2017-04-01

    Levetiracetam (LEV) and its recently approved derivative brivaracetam are anti-epileptic drugs with a unique mechanism of action. The synaptic vesicle protein 2A (SV2A) was previously identified as their main target. In the current study, we tested a collection of 500 approved drugs for interaction with the human SV2A protein expressed in Chinese hamster ovary cells. Competition binding studies were performed using cell lysates with high SV2A expression and [(3) H]brivaracetam as a radioligand. A hit rate of 3% was obtained, defined as compounds that inhibited radioligand binding by more than 90% at a screening concentration of 20 μM. Subsequent concentration-inhibition curves revealed the antihistaminic prodrug loratadine (Ki  = 1.16 μM) and the antimalarial drug quinine (Ki  = 2.03 μM) to be the most potent SV2A protein ligands of the investigated drug library. Both compounds were similarly potent as LEV (Ki  = 1.74 μM), providing structurally novel scaffolds for SV2A ligands. A pharmacophore model was established, which indicated steric and electronic conformities of brivaracetam with the new SV2A ligands, and preliminary structure-activity relationships were determined. The anti-convulsive effects of the natural product quinine may - at least in part - be explained by interaction with SV2A. Loratadine and quinine represent new lead structures for anti-epileptic drug development.

  7. A structural appraisal of sterol carrier protein 2.

    PubMed

    Burgardt, Noelia I; Gianotti, Alejo R; Ferreyra, Raúl G; Ermácora, Mario R

    2017-05-01

    Sterol Carrier Protein 2 (SCP2) has been associated with lipid binding and transfer activities. However, genomic, proteomic, and structural studies revealed that it is an ubiquitous domain of complex proteins with a variety functions in all forms of life. High-resolution structures of representative SCP2 domains are available, encouraging a comprehensive review of the structural basis for its success. Most SCP2 domains pertain to three major families and are frequently found as stand-alone or at the C-termini of lipid related peroxisomal enzymes, acetyltransferases causing bacterial resistance, and bacterial environmentally important sulfatases. We (1) analyzed the structural basis of the fold and the classification of SCP2 domains; (2) identified structure-determined sequence features; (3) compared the lipid binding cavity of SCP2 and other lipid binding proteins; (4) surveyed proposed mechanisms of SCP2 mediated lipid transfer between membranes; and (5) uncovered a possible new function of the SCP2 domain as a protein-protein recognition device.

  8. The effect of bone morphogenetic protein-2 on osteosarcoma metastasis

    PubMed Central

    Gill, Jonathan; Connolly, Patrick; Roth, Michael; Chung, So Hak; Zhang, Wendong; Piperdi, Sajida; Hoang, Bang; Yang, Rui; Guzik, Hillary; Gorlick, Richard; Geller, David S.

    2017-01-01

    Purpose Bone Morphogenetic Protein-2 (BMP-2) may offer the potential to enhance allograft-host osseous union in limb-salvage surgery following osteosarcoma resection. However, there is concern regarding the effect of locally applied BMP-2 on tumor recurrence and metastasis. The purpose of this project was to evaluate the effect of exogenous BMP-2 on osteosarcoma migration and invasion across a panel of tumor cell lines in vitro and to characterize the effect of BMP-2 on pulmonary osteosarcoma metastasis within a xenograft model. Experimental design The effect of BMP-2 on in vitro tumor growth and development was assessed across multiple standard and patient-derived xenograft osteosarcoma cell lines. Tumor migration capacity, invasion, and cell proliferation were characterized. In addition, the effect on metastasis was measured using a xenograft model following tail-vein injection. The effect of exogenous BMP-2 on the development of metastases was measured following both single and multiple BMP-2 administrations. Results There was no significant difference in migration capacity, invasion, or cell proliferation between the BMP-2 treated and the untreated osteosarcoma cell lines. There was no significant difference in pulmonary metastases between either the single-dose or multi-dose BMP-2 treated animals and the untreated control animals. Conclusions In the model systems tested, the addition of BMP-2 does not increase osteosarcoma proliferation, migration, invasion, or metastasis to the lungs. PMID:28264040

  9. Teachers with Drive

    ERIC Educational Resources Information Center

    Coggins, Celine; Diffenbaugh, P. K.

    2013-01-01

    For students in U.S. classrooms today, the odds of being assigned to an inexperienced teacher are higher than they have ever been because so many teachers, some in the top 20 percent of effectiveness are leaving the classroom in their first five years. Coggins and Diffenbaugh turn to Daniel Pink's work on drive to determine how to motivate…

  10. DrivePy

    SciTech Connect

    King, Ryan; Guo, Yi

    2014-08-30

    DrivePy is physics-based drivetrain model that sizes drivetrain components based on aerodynamic and operational loads for use in a systems engineering model. It also calculates costs based on empirical data collected by NREL's National Wind Technology Center.

  11. Magnetized drive fluids

    SciTech Connect

    Rosensweig, R.E.; Zahn, M.

    1986-04-01

    A process is described for recovering a first fluid from a porous subterranean formation which comprises injecting a displacement fluid in an effective amount to displace the first fluid, injecting a ferrofluid, applying a magnetic field containing a gradient of field intensity within the formation, driving the displacement fluid through the formation with the ferrofluid and recovering first fluid.

  12. Drive-Through Training

    ERIC Educational Resources Information Center

    Carter, Margie

    2010-01-01

    In this article, the author discusses how the early childhood field's approach to staff training reflects the drive-through, fast-food culture. Year after year directors send their teachers to workshops to get some quick refresher techniques. The author suggests that rather than focusing professional development on topics, focus on observing…

  13. Flywheel sickle drive mechanism

    SciTech Connect

    Guinn, R.K.

    1989-03-21

    A releasable, eccentric drive mechanism is described, comprising: a first shaft extending along a central axis and presenting a generally cylindrical portion; a second shaft extending along a reference axis substantially parallel to the central axis in offset relation to the latter and having a generally cylindrical portion; a drive member having structure defining an opening including a first, generally cylindrical region receiving over one half of the circumference of the first shaft portion and a second, generally cylindrical region receiving over one half of the circumference of the second shaft portion, the second region being in side-by-side relationship to the first region and in open communication with the latter, the first shaft portion and the second shaft portion each including a substantially flat wall section extending in a plane substantially perpendicular to a reference plane passing through the central axis and the reference axis, each of the wall sections being inclined relative to the central axis in complemental, flat engagement with each other; and means coupled to one of the drive member and the second shaft for urging the first shaft in a longitudinal direction generally toward the second shaft in order to bring the wall section of the first shaft into a position of flat, wedging contact with the wall section of the second shaft and in contact with the structure defining the opening in order to securely interconnect the first shaft, the second shaft and the drive member.

  14. Driving While Intoxicated.

    ERIC Educational Resources Information Center

    Brick, John

    Alcohol intoxication increases the risk of highway accidents, the relative risk of crash probability increasing as a function of blood alcohol content (BAC). Because alcohol use is more prevalent than use of other drugs, more is known about the relationship between alcohol use and driving. Most states presume a BAC of .10% to be evidence of drunk…

  15. The Drive to Influence

    ERIC Educational Resources Information Center

    Rodriguez, Diego

    2017-01-01

    At the heart of the educational vocation is a drive to influence, to meaningfully affect the learning and development of others. For adult educators working in higher education, daily activities--from teaching classes to supervising student research to attending faculty meetings to sitting on advisory boards--are full of opportunities to…

  16. CSI: Hard Drive

    ERIC Educational Resources Information Center

    Sturgeon, Julie

    2008-01-01

    Acting on information from students who reported seeing a classmate looking at inappropriate material on a school computer, school officials used forensics software to plunge the depths of the PC's hard drive, searching for evidence of improper activity. Images were found in a deleted Internet Explorer cache as well as deleted file space.…

  17. Apoptosis Resistance in Endometriosis

    PubMed Central

    Salmassi, Ali; Acar-Perk, Bengi; Schmutzler, Andreas G.; Koch, Kerstin; Püngel, Frank; Jonat, Walter; Mettler, Liselotte

    2011-01-01

    Introduction In a cytological analysis of endometriotic lesions neither granulocytes nor cytotoxic T-cells appear in an appreciable number. Based on this observation we aimed to know, whether programmed cell death plays an essential role in the destruction of dystopic endometrium. Disturbances of the physiological mechanisms of apoptosis, a persistence of endometrial tissue could explain the disease. Another aspect of this consideration is the proliferation competence of the dystopic mucous membrane. Methods Endometriotic lesions of 15 patients were examined through a combined measurement of apoptosis activity with the TUNEL technique (terminal deoxyribosyltransferase mediated dUTP Nick End Labeling) and the proliferation activity (with the help of the Ki-67-Antigens using the monoclonal antibody Ki-S5). Results Twelve out of 15 women studied showed a positive apoptotic activity of 3-47% with a proliferation activity of 2-25% of epithelial cells. Therefore we concluded that the persistence of dystopic endometrium requires proliferative epithelial cells from middle to lower endometrial layers. Conclusion A dystopia misalignment of the epithelia of the upper layers of the functionalism can be rapidly eliminated by apoptotic procedures. PMID:23678417

  18. Uncoupling protein 2 gene polymorphisms are associated with obesity

    PubMed Central

    2012-01-01

    Background Uncoupling protein 2 (UCP2) gene polymorphisms have been reported as genetic risk factors for obesity and type 2 diabetes mellitus (T2DM). We examined the association of commonly observed UCP2 G(−866)A (rs659366) and Ala55Val (C > T) (rs660339) single nucleotide polymorphisms (SNPs) with obesity, high fasting plasma glucose, and serum lipids in a Balinese population. Methods A total of 603 participants (278 urban and 325 rural subjects) were recruited from Bali Island, Indonesia. Fasting plasma glucose (FPG), triglyceride (TG), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) were measured. Obesity was determined based on WHO classifications for adult Asians. Participants were genotyped for G(−866)A and Ala55Val polymorphisms of the UCP2 gene. Results Obesity prevalence was higher in urban subjects (51%) as compared to rural subjects (23%). The genotype, minor allele (MAF), and heterozygosity frequencies were similar between urban and rural subjects for both SNPs. All genotype frequencies were in Hardy-Weinberg equilibrium. A combined analysis of genotypes and environment revealed that the urban subjects carrying the A/A genotype of the G(−866)A SNP have higher BMI than the rural subjects with the same genotype. Since the two SNPs showed strong linkage disequilibrium (D’ = 0.946, r2 = 0.657), a haplotype analysis was performed. We found that the AT haplotype was associated with high BMI only when the urban environment was taken into account. Conclusions We have demonstrated the importance of environmental settings in studying the influence of the common UCP2 gene polymorphisms in the development of obesity in a Balinese population. PMID:22533685

  19. BARC: A Novel Apoptosis Regulator

    DTIC Science & Technology

    2004-07-01

    turnover is normally achieved through programmed cell death , also known as apoptosis. Effects in apoptosis occur in breast cancers and other types of...malignancies, making tumor cells difficult to kill by chemotherapy, hormonal therapy, and radiation. Restoring function of cell death pathways is a strategy...These findings provide new insights into cell death regulation in breast cancer.

  20. [Driving ability with multiple sclerosis].

    PubMed

    Küst, J; Dettmers, C

    2014-07-01

    Driving is an important issue for young patients, especially for those whose walking capacity is impaired. Driving might support the patient's social and vocational participation. The question as to whether a patient with multiple sclerosis (MS) is restricted in the ability to drive a car depends on neurological and neuropsychological deficits, self-awareness, insight into deficits and ability to compensate for loss of function. Because of the enormous variability of symptoms in MS the question is highly individualized. A practical driving test under supervision of a driving instructor (possibly accompanied by a neuropsychologist) might be helpful in providing both patient and relatives adequate feedback on driving abilities.

  1. Apoptosis and the Airway Epithelium

    PubMed Central

    White, Steven R.

    2011-01-01

    The airway epithelium functions as a barrier and front line of host defense in the lung. Apoptosis or programmed cell death can be elicited in the epithelium as a response to viral infection, exposure to allergen or to environmental toxins, or to drugs. While apoptosis can be induced via activation of death receptors on the cell surface or by disruption of mitochondrial polarity, epithelial cells compared to inflammatory cells are more resistant to apoptotic stimuli. This paper focuses on the response of airway epithelium to apoptosis in the normal state, apoptosis as a potential regulator of the number and types of epithelial cells in the airway, and the contribution of epithelial cell apoptosis in important airways diseases. PMID:22203854

  2. Apoptosis Evaluation by Electrochemical Techniques.

    PubMed

    Yin, Jian; Miao, Peng

    2016-03-04

    Apoptosis has close relevance to pathology, pharmacology, and toxicology. Accurate and convenient detection of apoptosis would be beneficial for biological study, clinical diagnosis, and drug development. Based on distinct features of apoptotic cells, a diversity of analytical techniques have been exploited for sensitive analysis of apoptosis, such as surface plasmon resonance, electrochemical methods, flow cytometry, and some imaging assays. Among them, the features of simplicity, easy operation, low cost, and high sensitivity make electrochemical techniques powerful tools to investigate electron-transfer processes of in vitro biological systems. In this contribution, a general overview of current knowledge on various technical approaches for apoptosis evaluation is provided. Furthermore, recently developed electrochemical biosensors for detecting apoptotic cells and their advantages over traditional methods are summarized. One of the main considerations focuses on designing the recognition elements based on various biochemical events during apoptosis.

  3. Sex Chromosome Drive

    PubMed Central

    Helleu, Quentin; Gérard, Pierre R.; Montchamp-Moreau, Catherine

    2015-01-01

    Sex chromosome drivers are selfish elements that subvert Mendel's first law of segregation and therefore are overrepresented among the products of meiosis. The sex-biased progeny produced then fuels an extended genetic conflict between the driver and the rest of the genome. Many examples of sex chromosome drive are known, but the occurrence of this phenomenon is probably largely underestimated because of the difficulty to detect it. Remarkably, nearly all sex chromosome drivers are found in two clades, Rodentia and Diptera. Although very little is known about the molecular and cellular mechanisms of drive, epigenetic processes such as chromatin regulation could be involved in many instances. Yet, its evolutionary consequences are far-reaching, from the evolution of mating systems and sex determination to the emergence of new species. PMID:25524548

  4. [Cannabis affects driving skills].

    PubMed

    Khiabani, Hassan Z; Christophersen, Asbjørg S; Mørland, Jørg

    2007-03-01

    Delta (9)-tetrahydrocannabinol (THC), the most important psychoactive substance in cannabis, is frequently detected in blood from apprehended drivers suspected for drugged driving. Both experimental and epidemiological studies have demonstrated the negative effects of THC upon cognitive functions and psychomotor skills. These effects could last longer than a measurable concentration of THC in blood. Culpability studies have recently demonstrated an increased risk of becoming responsible in fatal or injurious traffic accidents, even with low blood concentrations of THC. It has also been demonstrated that there is a correlation between the degree of impairment, the drug dose and the THC blood concentration. It is very important to focus on the negative effect of cannabis on fitness to drive in order to prevent injuries and loss of human life and to avoid large economic consequences to the society.

  5. Magnetostrictive direct drive motors

    NASA Technical Reports Server (NTRS)

    Naik, Dipak; Dehoff, P. H.

    1990-01-01

    Developing magnetostrictive direct drive research motors to power robot joints is discussed. These type motors are expected to produce extraordinary torque density, to be able to perform microradian incremental steps and to be self-braking and safe with the power off. Several types of motor designs have been attempted using magnetostrictive materials. One of the candidate approaches (the magnetostrictive roller drive) is described. The method in which the design will function is described as is the reason why this approach is inherently superior to the other approaches. Following this, the design will be modelled and its expected performance predicted. This particular candidate design is currently undergoing detailed engineering with prototype construction and testing scheduled for mid 1991.

  6. Advanced Motor Drives Studies

    NASA Technical Reports Server (NTRS)

    Ehsani, M.; Tchamdjou, A.

    1997-01-01

    This report presents an evaluation of advanced motor drive systems as a replacement for the hydrazine fueled APU units. The replacement technology must meet several requirements which are particular to the space applications and the Orbiter in general. Some of these requirements are high efficiency, small size, high power density. In the first part of the study several motors are compared, based on their characteristics and in light of the Orbiter requirements. The best candidate, the brushless DC is chosen because of its particularly good performance with regards to efficiency. Several power electronics drive technologies including the conventional three-phase hard switched and several soft-switched inverters are then presented. In the last part of the study, a soft-switched inverter is analyzed and compared to its conventional hard-switched counterpart. Optimal efficiency is a basic requirement for space applications and the soft-switched technology represents an unavoidable trend for the future.

  7. Fas ligand-expressing lymphocytes enhance alveolar macrophage apoptosis in the resolution of acute pulmonary inflammation

    PubMed Central

    Barthel, Lea; Bednarek, Joseph M.; Yunt, Zulma X.; Henson, Peter M.; Janssen, William J.

    2014-01-01

    Apoptosis of alveolar macrophages and their subsequent clearance by neighboring phagocytes are necessary steps in the resolution of acute pulmonary inflammation. We have recently identified that activation of the Fas death receptor on the cell surface of macrophages drives macrophage apoptosis. However, the source of the cognate ligand for Fas (FasL) responsible for induction of alveolar macrophage apoptosis is not defined. Given their known role in the resolution of inflammation and ability to induce macrophage apoptosis ex vivo, we hypothesized that T lymphocytes represented a critical source of FasL. To address this hypothesis, C57BL/6J and lymphocyte-deficient (Rag-1−/−) mice were exposed to intratracheal lipopolysaccharide to induce pulmonary inflammation. Furthermore, utilizing mice expressing nonfunctional FasL, we adoptively transferred donor lymphocytes into inflamed lymphocyte-deficient mice to characterize the effect of lymphocyte-derived FasL on alveolar macrophage apoptosis in the resolution of inflammation. Herein, evidence is presented that lymphocytes expressing FasL enhance alveolar macrophage apoptosis during the resolution of LPS-induced inflammation. Moreover, lymphocyte induction of alveolar macrophage apoptosis results in contraction of the alveolar macrophage pool, which occurs in a FasL-dependent manner. Specifically, FasL-expressing CD8+ T lymphocytes potently induce alveolar macrophage apoptosis and contraction of the alveolar macrophage pool. Together, these studies identify a novel role for CD8+ T lymphocytes in the resolution of acute pulmonary inflammation. PMID:24838751

  8. Driving on the Descartes

    NASA Technical Reports Server (NTRS)

    1972-01-01

    Astronaut John W. Young, Apollo 16 mission commander, drives the 'Rover', Lunar Roving Vehicle (LRV) to its final parking place near the end of the third extravehicular activity (EVA-3) at the Descartes landing site. Astronaut Charles M. Duke Jr., Lunar Module pilot, took this photograph looking southward. The flank of Stone Mountain can be seen on the horizon at left. The shadow of the Lunar Module 'Orion' is visible in the foreground.

  9. Gear Drive Testing

    NASA Technical Reports Server (NTRS)

    1982-01-01

    Philadelphia Gear Corporation used two COSMIC computer programs; one dealing with shrink fit analysis and the other with rotor dynamics problems in computerized design and test work. The programs were used to verify existing in-house programs to insure design accuracy by checking its company-developed computer methods against procedures developed by other organizations. Its specialty is in custom units for unique applications, such as Coast Guard ice breaking ships, steel mill drives, coal crusher, sewage treatment equipment and electricity.

  10. Variable reluctance drive system

    SciTech Connect

    Lipo, T.A.; Liang, F.

    1995-10-17

    A variable reluctance drive system including a motor and corresponding converter for improved current commutation is described. The motor incorporates a salient pole rotor and a salient pole stator having one or more full pitch windings which operate by mutual inductance to transfer the current from the active short pitch winding following phase alignment. This increases output torque and/or speed and permits a number of simple and economical converter circuits. 17 figs.

  11. Butalbital and driving impairment.

    PubMed

    Yeakel, Jillian K; Logan, Barry K

    2013-07-01

    Butalbital (Fiorinal(®)), used in the treatment of migraines and muscle pain, is the most commonly encountered barbiturate in impaired driving cases. It has central nervous system (CNS) depressant properties, including sedation, drowsiness, and feelings of intoxication, which can contribute to driving impairment. Twenty-six driving under the influence cases are reviewed including results from field sobriety tests and toxicology testing. Blood samples were screened using enzyme multiplied immunoassay technique immunoassay, and the presence of butalbital was confirmed and quantified using gas chromatography/mass spectrometry, gas chromatography with flame ionization detection, or gas chromatography nitrogen/phosphorus detection. Butalbital concentrations ranged from 1.0 to 30.2 mg/L, with a mean and median of 16.0 mg/L. General impairment indicators in these cases included horizontal and vertical nystagmus, lack of convergence, poor motor coordination, and balance and speech problems, which are common to CNS depressant intoxication, similar to that associated with alcohol. These findings indicate the importance of toxicological testing for butalbital in cases where CNS depressants are indicated.

  12. [Automobile driving capacity in dementia].

    PubMed

    Seeger, Rolf

    2015-04-01

    Dementia influences at an early stage the driving aptitude of motor vehicle steering persons. Every year in Switzerland, around 16'000 driving permit holders suffer newly from dementia; therefore the driving aptitude is questioned, especially because of possibly limited executive functions. Individuals with early-stage dementia often may show a dangerous driving stile. However, a mild dementia does not a priori exclude the driving aptitude, and less than half of these drivers can continue driving for another 1 - 3 years. In contrast, there is no further driving aptitude in presence of moderate dementia. In the assessment of driving aptitude, the underlying cause of dementia is always taken into account. Cognitive short tests such as the Mini-Mental Status Exam, Clock Drawing Test and Trail-Making Test are not suitable to make reliable statements about the aptitude to drive, but these tests are very important for the initial diagnosis of dementia in primary care practice and can lead the way for further examination concerning driving aptitude. The legally prescribed regular check-up for motorists aged over 70 years in Switzerland provides an ideal opportunity for early detection of incipient dementia. The practical procedure for the assessment of aptitude to drive in the primary care practice is presented. The physician-guided on-road driving test represents a meaningful, practical and relatively cost-effective tool for the evaluation of driving aptitude in cases of doubt.

  13. Apoptosis in Primary Hyperparathyroidism.

    PubMed

    Segiet, Oliwia Anna; Mielańczyk, Łukasz; Piecuch, Adam; Michalski, Marek; Tyczyński, Szczepan; Brzozowa-Zasada, Marlena; Deska, Mariusz; Wojnicz, Romuald

    2017-03-31

    Primary hyperparathyroidism (PHPT) is defined by inappropriate elevation of parathormone, caused by parathyroid hyperplasia, also known as multi-gland disease (MGD), parathyroid adenoma (PA), or parathyroid carcinoma (PC). Although several studies have already been conducted, there is a lack of a definite diagnostic marker, which could unambiguously distinguish MGD from PA or PC. The accurate and prompt diagnosis has the key meaning for effective treatment and follow-up. This review paper presents the role of apoptosis in PHPT. The comparison of the expression of Fas, TRAIL, BCL-2 family members, p53 in MGD, PA, and PC, among others, was described. The expression of described factors varies among proliferative lesions of parathyroid gland; therefore, these could serve as additional markers to assist in the diagnosis.

  14. Drive Diagnostic Filter Wheel Control

    SciTech Connect

    Uhlich, D.

    2007-07-17

    DrD Filter Wheel Control is National Instrument's Labview software that drives a Drive Diagnostic filter wheel. The software can drive the filter wheel between each end limit, detect the positive and negative limit and each home position and post the stepper motot values to an Excel spreadsheet. The software can also be used to cycle the assembly between the end limits.

  15. Drive alignment pays maintenance dividends

    SciTech Connect

    Fedder, R.

    2008-12-15

    Proper alignment of the motor and gear drive on conveying and processing equipment will result in longer bearing and coupling life, along with lower maintenance costs. Selecting an alignment free drive package instead of a traditional foot mounted drive and motor is a major advancement toward these goals. 4 photos.

  16. Regulation of Apoptosis by Inhibitors of Apoptosis (IAPs)

    PubMed Central

    Berthelet, Jean; Dubrez, Laurence

    2013-01-01

    Abstract Inhibitors of Apoptosis (IAPs) are a family of proteins with various biological functions including regulation of innate immunity and inflammation, cell proliferation, cell migration and apoptosis. They are characterized by the presence of at least one N-terminal baculoviral IAP repeat (BIR) domain involved in protein-protein interaction. Most of them also contain a C-terminal RING domain conferring an E3-ubiquitin ligase activity. In drosophila, IAPs are essential to ensure cell survival, preventing the uncontrolled activation of the apoptotic protease caspases. In mammals, IAPs can also regulate apoptosis through controlling caspase activity and caspase-activating platform formation. Mammalian IAPs, mainly X-linked IAP (XIAP) and cellular IAPs (cIAPs) appeared to be important determinants of the response of cells to endogenous or exogenous cellular injuries, able to convert the survival signal into a cell death-inducing signal. This review highlights the role of IAP in regulating apoptosis in Drosophila and Mammals. PMID:24709650

  17. Offset Compound Gear Drive

    NASA Technical Reports Server (NTRS)

    Stevens, Mark A.; Handschuh, Robert F.; Lewicki, David G.

    2010-01-01

    The Offset Compound Gear Drive is an in-line, discrete, two-speed device utilizing a special offset compound gear that has both an internal tooth configuration on the input end and external tooth configuration on the output end, thus allowing it to mesh in series, simultaneously, with both a smaller external tooth input gear and a larger internal tooth output gear. This unique geometry and offset axis permits the compound gear to mesh with the smaller diameter input gear and the larger diameter output gear, both of which are on the same central, or primary, centerline. This configuration results in a compact in-line reduction gear set consisting of fewer gears and bearings than a conventional planetary gear train. Switching between the two output ratios is accomplished through a main control clutch and sprag. Power flow to the above is transmitted through concentric power paths. Low-speed operation is accomplished in two meshes. For the purpose of illustrating the low-speed output operation, the following example pitch diameters are given. A 5.0 pitch diameter (PD) input gear to 7.50 PD (internal tooth) intermediate gear (0.667 reduction mesh), and a 7.50 PD (external tooth) intermediate gear to a 10.00 PD output gear (0.750 reduction mesh). Note that it is not required that the intermediate gears on the offset axis be of the same diameter. For this example, the resultant low-speed ratio is 2:1 (output speed = 0.500; product of stage one 0.667 reduction and stage two 0.750 stage reduction). The design is not restricted to the example pitch diameters, or output ratio. From the output gear, power is transmitted through a hollow drive shaft, which, in turn, drives a sprag during which time the main clutch is disengaged.

  18. Base drive circuit

    DOEpatents

    Lange, Arnold C.

    1995-01-01

    An improved base drive circuit (10) having a level shifter (24) for providing bistable input signals to a pair of non-linear delays (30, 32). The non-linear delays (30, 32) provide gate control to a corresponding pair of field effect transistors (100, 106) through a corresponding pair of buffer components (88, 94). The non-linear delays (30, 32) provide delayed turn-on for each of the field effect transistors (100, 106) while an associated pair of transistors (72, 80) shunt the non-linear delays (30, 32) during turn-off of the associated field effect transistor (100, 106).

  19. Generative design drives manufacturing

    NASA Astrophysics Data System (ADS)

    Logan, Frank A.

    1989-04-01

    This paper reviews the collaboration that is being forced on Engineering and Manufacturing as they move from the manual translation of Engineering drawings toward automatic decoding of Product Data Definitions (PDDs), a pre-requisite to integrated manufacture. Based on case studies and implementation experience gained over the last decade, it defines the step-by-step evolution of a generative design capability that will drive manufacturing logic. It reviews the changing relationship of Engineering to Manufacturing and Industrial Engineering and the challenge this presents to manufacturing management in its struggle to remain competitive in both domestic and international markets.

  20. Engine valve driving apparatus

    SciTech Connect

    Masuda, S.; Uesugi, T.; Oda, H.

    1989-01-03

    An engine valve driving apparatus for an internal combustion engine having a cam driven engine valve is described. It consists of a camshaft rotatable in synchronism with rotation of a crankshaft of an engine and a movable cam member supported by the camshaft for axial movement and prevented from turning relative to the camshaft. The movable cam member can be axially shifted between an operative position wherein the cam member is cooperative with a member of the engine valve so as to cause an operation of the engine valve and an inoperative position wherein the cam member is out of cooperation with the member.

  1. Modular droplet actuator drive

    NASA Technical Reports Server (NTRS)

    Pollack, Michael G. (Inventor); Paik, Philip (Inventor)

    2011-01-01

    A droplet actuator drive including a detection apparatus for sensing a property of a droplet on a droplet actuator; circuitry for controlling the detection apparatus electronically coupled to the detection apparatus; a droplet actuator cartridge connector arranged so that when a droplet actuator cartridge electronically is coupled thereto: the droplet actuator cartridge is aligned with the detection apparatus; and the detection apparatus can sense the property of the droplet on a droplet actuator; circuitry for controlling a droplet actuator coupled to the droplet actuator connector; and the droplet actuator circuitry may be coupled to a processor.

  2. HLH Drive System

    DTIC Science & Technology

    1977-09-01

    M4 1" 4 C. C, 4 10 rYV .104 14144 \\- // S/ / " I 3.025 DPII 36 TEETH 2 n )r lj < ~( NEW ) _ _ _ 7986 RPM Figure 40. Combiner Configuration 6, Reference...based on testing of th le CH- 4 ` -7 •-• ’’• stage p lanet bearing , primarily from fa ilures in the • : , - gram of Reference 19. The test results are...USAAMRDL-TR-77-38 r, . . HLH DRIVE SYSTEM -I Boeing Vertol Company P.O. Box 16858 4 • Philadelphia, Pa. 19142 0 September 1977 4Q Final Report

  3. Base drive circuit

    DOEpatents

    Lange, A.C.

    1995-04-04

    An improved base drive circuit having a level shifter for providing bistable input signals to a pair of non-linear delays. The non-linear delays provide gate control to a corresponding pair of field effect transistors through a corresponding pair of buffer components. The non-linear delays provide delayed turn-on for each of the field effect transistors while an associated pair of transistors shunt the non-linear delays during turn-off of the associated field effect transistor. 2 figures.

  4. ASC directs NF-kappaB activation by regulating receptor interacting protein-2 (RIP2) caspase-1 interactions.

    PubMed

    Sarkar, Anasuya; Duncan, Michelle; Hart, Judy; Hertlein, Erin; Guttridge, Denis C; Wewers, Mark D

    2006-04-15

    Receptor interacting protein-2 (RIP2) is a caspase recruitment domain (CARD)-containing kinase that interacts with caspase-1 and plays an important role in NF-kappaB activation. Apoptosis-associated speck-like protein containing a CARD (ASC) is a PYRIN and CARD-containing molecule, important in the induction of apoptosis and caspase-1 activation. Although RIP2 has also been linked to caspase-1 activation, RIP2 knockout animals fail to show a defect in caspase-1-mediated processing of proIL-1beta to its active form. Therefore, RIP2 function in binding to caspase-1 remains poorly understood. We hypothesized that caspase-1 may serve as a scaffolding molecule that promotes RIP2 interaction with IkappaB kinase-gamma thus inducing NF-kappaB activation. We further hypothesized that ASC, which also interacts with caspase-1 via its CARD, may interfere with the caspase-1 RIP2 interaction. In HEK293 cells, ASC induced prominent activation of caspase-1 and proIL-1beta processing. RIP2 transient transfection induced transcription of an NF-kappaB reporter gene. This RIP2-induced NF-kappaB activity and caspase-1 binding was inhibited in a dose-dependent fashion by ASC. Consistent with a role for caspase-1 as a scaffold for RIP2, caspase-1 knockout macrophages were suppressed in their ability to activate NF-kappaB, and septic caspase-1 knockout animals produced less IL-6, a functional marker of NF-kappaB activity. Lastly, THP-1 cells treated with small interfering RNA for ASC decreased their caspase-1 activity while enhancing their NF-kappaB signal. These data suggest that ASC may direct caspase-1 away from RIP2-mediated NF-kappaB activation, toward caspase-1-mediated processing of proIL-1beta by interfering with the RIP2 caspase-1 interaction.

  5. Marked over expression of uncoupling protein-2 in beta cells exerts minor effects on mitochondrial metabolism

    SciTech Connect

    Hals, Ingrid K.; Ogata, Hirotaka; Pettersen, Elin; Ma, Zuheng; Bjoerklund, Anneli; Skorpen, Frank; Egeberg, Kjartan Wollo; Grill, Valdemar

    2012-06-29

    Highlights: Black-Right-Pointing-Pointer The impact of UCP-2 over expression on mitochondrial function is controversial. Black-Right-Pointing-Pointer We tested mitochondrial functions at defined levels of overexpression. Black-Right-Pointing-Pointer We find minor increases of fatty acid oxidation and uncoupling. Black-Right-Pointing-Pointer Effects were seen only at high level (fourfold) of over expression. Black-Right-Pointing-Pointer Hence it is doubtful whether these effects are of importance in diabetes. -- Abstract: Evidence is conflicting as to the impact of elevated levels of uncoupling protein-2 (UCP-2) on insulin-producing beta cells. Here we investigated effects of a fourfold induction of UCP-2 protein primarily on mitochondrial parameters and tested for replication of positive findings at a lower level of induction. We transfected INS-1 cells to obtain a tet-on inducible cell line. A 48 h exposure to 1 {mu}g/ml of doxycycline (dox) induced UCP-2 fourfold (424 {+-} 113%, mean {+-} SEM) and 0.1 {mu}g/ml twofold (178 {+-} 29%, n = 3). Fourfold induced cells displayed normal viability (MTT, apoptosis), normal cellular insulin contents and, glucose-induced insulin secretion (+27 {+-} 11%) as well as D-[U-{sup 14}C]-glucose oxidation (+5 {+-} 9% at 11 mM glucose). Oxidation of [1-{sup 14}C]-oleate was increased from 4088 to 5797 fmol/{mu}g prot/2 h at 3.3 mM glucose, p < 0.03. Oxidation of L-[{sup 14}C(U)]-glutamine was unaffected. Induction of UCP-2 did not significantly affect measures of mitochondrial membrane potential (Rhodamine 123) or mitochondrial mass (Mitotracker Green) and did not affect ATP levels. Oligomycin-inhibited oxygen consumption (a measure of mitochondrial uncoupling) was marginally increased, the effect being significant in comparison with dox-only treated cells, p < 0.05. Oxygen radicals, assessed by dichlorofluorescin diacetate, were decreased by 30%, p < 0.025. Testing for the lower level of UCP-2 induction did not reproduce any of the

  6. Advances in traction drive technology

    NASA Technical Reports Server (NTRS)

    Loewenthal, S. H.; Anderson, N. E.; Rohn, D. A.

    1983-01-01

    Traction drives are traced from early uses as main transmissions in automobiles at the turn of the century to modern, high-powered traction drives capable of transmitting hundreds of horsepower. Recent advances in technology are described which enable today's traction drive to be a serious candidate for off-highway vehicles and helicopter applications. Improvements in materials, traction fluids, design techniques, power loss and life prediction methods will be highlighted. Performance characteristics of the Nasvytis fixed-ratio drive are given. Promising future drive applications, such as helicopter main transmissions and servo-control positioning mechanisms are also addressed.

  7. Fast wave current drive

    NASA Astrophysics Data System (ADS)

    Goree, J.; Ono, M.; Colestock, P.; Horton, R.; McNeill, D.; Park, H.

    1985-07-01

    Experiments on the fast wave in the range of high ion cyclotron harmonics in the ACT-1 device show that current drive is possible with the fast wave just as it is for the lower hybrid wave, except that it is suitable for higher plasma densities. A 140° loop antenna launched the high ion cyclotron harmonic fast wave [ω/Ω=O(10)] into a He+ plasma with ne≂4×1012 cm-3 and B=4.5 kG. Probe and magnetic loop diagnostics and FIR laser scattering confirmed the presence of the fast wave, and the Rogowski loop indicated that the circulating plasma current increased by up to 40A with 1 kW of coupled power, which is comparable to lower hybrid current drive in the same device with the same unidirectional fast electron beam used as the target for the rf. A phased antenna array would be used for FWCD in a tokamak without the E-beam.

  8. Glaucoma and Driving: On-Road Driving Characteristics

    PubMed Central

    Wood, Joanne M.; Black, Alex A.; Mallon, Kerry; Thomas, Ravi; Owsley, Cynthia

    2016-01-01

    Purpose To comprehensively investigate the types of driving errors and locations that are most problematic for older drivers with glaucoma compared to those without glaucoma using a standardized on-road assessment. Methods Participants included 75 drivers with glaucoma (mean = 73.2±6.0 years) with mild to moderate field loss (better-eye MD = -1.21 dB; worse-eye MD = -7.75 dB) and 70 age-matched controls without glaucoma (mean = 72.6 ± 5.0 years). On-road driving performance was assessed in a dual-brake vehicle by an occupational therapist using a standardized scoring system which assessed the types of driving errors and the locations where they were made and the number of critical errors that required an instructor intervention. Driving safety was rated on a 10-point scale. Self-reported driving ability and difficulties were recorded using the Driving Habits Questionnaire. Results Drivers with glaucoma were rated as significantly less safe, made more driving errors, and had almost double the rate of critical errors than those without glaucoma. Driving errors involved lane positioning and planning/approach, and were significantly more likely to occur at traffic lights and yield/give-way intersections. There were few between group differences in self-reported driving ability. Conclusions Older drivers with glaucoma with even mild to moderate field loss exhibit impairments in driving ability, particularly during complex driving situations that involve tactical problems with lane-position, planning ahead and observation. These results, together with the fact that these drivers self-report their driving to be relatively good, reinforce the need for evidence-based on-road assessments for evaluating driving fitness. PMID:27472221

  9. Flavones induce neutrophil apoptosis by down-regulation of Mcl-1 via a proteasomal-dependent pathway.

    PubMed

    Lucas, Christopher D; Allen, Keith C; Dorward, David A; Hoodless, Laura J; Melrose, Lauren A; Marwick, John A; Tucker, Carl S; Haslett, Christopher; Duffin, Rodger; Rossi, Adriano G

    2013-03-01

    Neutrophil apoptosis and subsequent nonphlogistic clearance by surrounding phagocytes are key to the successful resolution of neutrophilic inflammation, with dysregulated apoptosis reported in multiple human inflammatory diseases. Enhancing neutrophil apoptosis has proresolution and anti-inflammatory effects in preclinical models of inflammation. Here we investigate the ability of the flavones apigenin, luteolin, and wogonin to induce neutrophil apoptosis in vitro and resolve neutrophilic inflammation in vivo. Human neutrophil apoptosis was assessed morphologically and by flow cytometry following incubation with apigenin, luteolin, and wogonin. All three flavones induced time- and concentration-dependent neutrophil apoptosis (apigenin, EC=12.2 μM; luteolin, EC=14.6 μM; and wogonin, EC=28.9 μM). Induction of apoptosis was caspase dependent, as it was blocked by the broad-spectrum caspase inhibitor Q-VD-OPh and was associated with both caspase-3 and caspase-9 activation. Flavone-induced apoptosis was preceded by down-regulation of the prosurvival protein Mcl-1, with proteasomal inhibition preventing flavone-induced Mcl-1 down-regulation and apoptosis. The flavones abrogated the survival effects of mediators that prolong neutrophil life span, including lipoteichoic acid, peptidoglycan, dexamethasone, and granulocyte-macrophage colony stimulating factor, by driving apoptosis. Furthermore, wogonin enhanced resolution of established neutrophilic inflammation in a zebrafish model of sterile tissue injury. Wogonin-induced resolution was dependent on apoptosis in vivo as it was blocked by caspase inhibition. Our data show that the flavones induce neutrophil apoptosis and have potential as neutrophil apoptosis-inducing anti-inflammatory, proresolution agents.

  10. [Apoptosis: cellular and clinical aspects].

    PubMed

    Løvschall, H; Mosekilde, L

    1997-04-01

    Removal of damaged cells is essential for the maintenance of life in multicellular organisms. The process of self destruction, apoptosis, eliminates surplus or damaged cells as part of the pathophysiological defence system. Apoptosis is essential in structural and functional organogenesis during embryological development. The physiological regulation of tissue kinetics is a product of both cell proliferation and cell death. Internal and external regulatory stimuli regulate the balance between apoptosis and mitosis by genetic interaction. Apoptosis is characterized by condensation of chromatine as a result of DNA degradation, formation of blebs in the plasma and nuclear membranes, condensation of cytoplasma, formation of vesicular apoptotic bodies, and phagocytosis by neighbouring cells without inflammatory response. A number of observations indicate that programmed cell death plays an important role in the regulation of cytofunctional homeostasis and defense against accumulation of damaged cells, eg with DNA alterations. Dysregulation of the apoptotic gene program, eg by mutations, may not only lead to loss or degeneration of tissue, but also to hyperproliferative and tumorigenic disorders. New evidence indicates that apoptosis regulation is important both in aging processes and diseases such as: neuropathies, immunopathies, viral infections, cancer, etc. Pharmacological intervention designed to modulate apoptosis seems to raise new possibilities in the treatment of disease.

  11. [Car driving and psychiatry].

    PubMed

    Jonas, Carol

    2015-10-01

    Among the specialties involved in the order of 31 August 2010, psychiatry is in Chapter IV alongside addictive behavior and drug use may impair the ability of the driver. As well as for personal vehicles for professional vehicles the incompatibility of health with driving exists when clinical factors can interfere with the skills required of the driver. There would simply absolute incompatibility for psychoses in active phase. In the other phases of psychosis is at the discretion of specialist as for illiteracy or social maladjustment. The role of the authorized psychiatrist is therefore always subjective. This article also makes room for attention-deficit disorder with hyperactivity (ADHD), not listed, but the subject of numerous articles in the English literature.

  12. Rotary drive mechanism

    DOEpatents

    Kenderdine, Eugene W.

    1991-01-01

    A rotary drive mechanism includes a rotary solenoid having a stator and multi-poled rotor. A moving member rotates with the rotor and is biased by a biasing device. The biasing device causes a further rotational movement after rotation by the rotary solenoid. Thus, energization of the rotary solenoid moves the member in one direction to one position and biases the biasing device against the member. Subsequently, de-energization of the rotary solenoid causes the biasing device to move the member in the same direction to another position from where the moving member is again movable by energization and de-energization of the rotary solenoid. Preferably, the moving member is a multi-lobed cam having the same number of lobes as the rotor has poles. An anti-overdrive device is also preferably provided for preventing overdrive in the forward direction or a reverse rotation of the moving member and for precisely aligning the moving member.

  13. Magnetostrictive direct drive motors

    NASA Technical Reports Server (NTRS)

    Naik, Dipak; Dehoff, P. H.

    1992-01-01

    A new rare earth alloy, Terfenol-D, combines low frequency operation and extremely high energy density with high magnetostriction. Its material properties make it suitable as a drive element for actuators requiring high output torque. The high strains, the high forces and the high controllability of Terfenol alloys provide a powerful and challenging basis for new ways to generate motion in actuators. Two prototypes of motors using Terfenol-D rods were developed at NASA Goddard. The basic principles of operation are provided of the motor along with other relevant details. A conceptual design of a torque limiting safety clutch/brake under development is illustrated. Also, preliminary design drawings of a linear actuator using Terfenol-D is shown.

  14. What Drives Blend Miscibility?

    NASA Astrophysics Data System (ADS)

    White, Ronald; Lipson, Jane

    2014-03-01

    With no mixture data available, can one predict phase behavior in polymeric systems based on pure component information only? Due to the very weak entropic drive for large molecules to mix, predicting and understanding miscibility behavior is indeed very difficult. However, while not perfect, some a priori insight is attainable when pure component properties are analyzed within the framework of a theoretical model. A theory provides a platform, allowing one to define quantities and other measures that may not always be directly measurable, but, are physically appealing and insightful none-the-less. Are there properties that can explain for example, why a polymer like polyisobutylene (PIB) exhibits such different phase behavior compared to other polyolefins? Applying our simple lattice-based equation of state, we have recently analyzed a large number of different polymers. In this talk we will present insights from trends and patterns we have observed. Work supported by the National Science Foundation.

  15. QUICK RELEASABLE DRIVE

    DOEpatents

    Dickson, J.J.

    1958-07-01

    A quick releasable mechanical drive system suitable for use in a nuclear reactor is described. A small reversible motor positions a control rod by means of a worm and gear speed reducer, a magnetic torque clutch, and a bell crank. As the control rod is raised to the operating position, a heavy coil spring is compressed. In the event of an emergency indicated by either a''scram'' signal or a power failure, the current to the magnetic clutch is cut off, thereby freeing the coil spring and the bell crank positioner from the motor and speed reduction gearing. The coil spring will immediately act upon the bell crank to cause the insertion of the control rod. This arrangement will allow the slow, accurate positioning of the control rod during reactor operation, while providing an independent force to rapidly insert the rod in the event of an emergency.

  16. Rottlerin exhibits anti-cancer effect through inactivation of S phase kinase-associated protein 2 in pancreatic cancer cells

    PubMed Central

    Su, Jingna; Wang, Lixia; Yin, Xuyuan; Zhao, Zhe; Hou, Yingying; Ye, Xiantao; Zhou, Xiuxia; Wang, Zhiwei

    2016-01-01

    Rottlerin, a natural product isolated from Mallotus philippinensis, has been characterized as an effective chemoprevention agent in inhibiting tumor cell growth. Although multiple studies have revealed the role of rottlerin in tumorigenesis, the molecular mechanism of rottlerin-mediated anti-tumor activity has not been fully elucidated. It has been reported that Skp2 (S-phase kinase associated protein 2) plays an oncogenic role in human malignancies, indicating that inactivation of Skp2 could be a promising approach for the treatment of cancers. Therefore, in this study, we aim to investigate whether rottlerin exhibits its anti-tumor activities via targeting Skp2 pathway in pancreatic cancer. We found that rottlerin inhibited cell growth, induced apoptosis, arrested cell cycle, and retarded cell invasion and migration. Notably, we observed that the expression of Skp2 was significantly decreased in rottlerin-treated pancreatic cancer cells. Importantly, overexpression of Skp2 abrogated the anti-tumor function induced by rottlerin in pancreatic cancer cells. Consistently, depletion of Skp2 promoted rottlerin-mediated inhibition of cell growth and invasion. Collectively, our study demonstrated that rottlerin could suppress Skp2 expression and subsequently exert its tumor suppressive function in pancreatic cancer cells, suggesting that rottlerin might be a potential therapeutic compound for treating pancreatic cancer. PMID:27822410

  17. Vesicle-associated membrane protein 2 mediates trafficking of {alpha}5{beta}1 integrin to the plasma membrane

    SciTech Connect

    Hasan, Nazarul; Hu, Chuan

    2010-01-01

    Integrins are major receptors for cell adhesion to the extracellular matrix (ECM). As transmembrane proteins, the levels of integrins at the plasma membrane or the cell surface are ultimately determined by the balance between two vesicle trafficking events: endocytosis of integrins at the plasma membrane and exocytosis of the vesicles that transport integrins. Here, we report that vesicle-associated membrane protein 2 (VAMP2), a SNARE protein that mediates vesicle fusion with the plasma membrane, is involved in the trafficking of {alpha}5{beta}1 integrin. VAMP2 was present on vesicles containing endocytosed {beta}1 integrin. Small interfering RNA (siRNA) silencing of VAMP2 markedly reduced cell surface {alpha}5{beta}1 and inhibited cell adhesion and chemotactic migration to fibronectin, the ECM ligand of {alpha}5{beta}1, without altering cell surface expression of {alpha}2{beta}1 integrin or {alpha}3{beta}1 integrin. By contrast, silencing of VAMP8, another SNARE protein, had no effect on cell surface expression of the integrins or cell adhesion to fibronectin. In addition, VAMP2-mediated trafficking is involved in cell adhesion to collagen but not to laminin. Consistent with disruption of integrin functions in cell proliferation and survival, VAMP2 silencing diminished proliferation and triggered apoptosis. Collectively, these data indicate that VAMP2 mediates the trafficking of {alpha}5{beta}1 integrin to the plasma membrane and VAMP2-dependent integrin trafficking is critical in cell adhesion, migration and survival.

  18. Signaling pathway for apoptosis: a racetrack for life or death.

    PubMed

    Wang, E; Marcotte, R; Petroulakis, E

    1999-01-01

    Apoptosis, or programmed cell death, is a gene-directed mechanism activated as a suicidal event to get rid of excess, damaged, or infected cells. The recent astounding pace of research in this area has expanded our horizon of understanding that this mechanism is regulated largely by pro- and anti-apoptosis factors acting for or against the final death event. The driving force behind these factors, either pro-apoptosis or pro-survival, is largely determined by signal transduction pathways, starting with the initiation of a death signal at the plasma membrane, and following through a complex cytoplasmic network before reaching the end point of cell demise. Enmeshed in this intricate cytoplasmic network are many checkpoints, where complexes of pro- and anti-apoptosis factors function to facilitate or deter the death signals. The culmination of the balancing act between these two camps of factors at these signal transduction checkpoints may then result in the final decision to die or to live. Thus, the eventual death of a cell may require successful passage through all the checkpoints, a mechanism Nature has provided as a safeguard to prevent erroneous triggering of death. With the advent of a new biotechnology revolution at the dawn of the new millenium, we look forward to an exciting era when we can gain fuller understanding of the operation of all these checkpoints. Ultimately, this gain will pave the way to control the apoptosis event at the checkpoints, and to support the organism's functionality as long as possible. J. Cell. Biochem. Suppls. 32/33:95-102, 1999.

  19. Sequenced drive for rotary valves

    DOEpatents

    Mittell, Larry C.

    1981-01-01

    A sequenced drive for rotary valves which provides the benefits of applying rotary and linear motions to the movable sealing element of the valve. The sequenced drive provides a close approximation of linear motion while engaging or disengaging the movable element with the seat minimizing wear and damage due to scrubbing action. The rotary motion of the drive swings the movable element out of the flowpath thus eliminating obstruction to flow through the valve.

  20. Driving anger in Ukraine: Appraisals, not trait driving anger, predict anger intensity while driving.

    PubMed

    Stephens, A N; Hill, T; Sullman, M J M

    2016-03-01

    Trait driving anger is often, but not always, found to predict both the intensity of anger while driving and subsequent crash-related behaviours. However, a number of studies have not found support for a direct relationship between one's tendency to become angry and anger reported while driving, suggesting that other factors may mediate this relationship. The present self-report study investigated whether, in anger provoking driving situations, the appraisals made by drivers influence the relationship between trait and state anger. A sample of 339 drivers from Ukraine completed the 33-item version of the Driver Anger Scale (DAS; Deffenbacher et al., 1994) and eight questions about their most recent experience of driving anger. A structural equation model found that the intensity of anger experienced was predicted by the negative evaluations of the situation, which was in turn predicted by trait driving anger. However, trait driving anger itself did not predict anger intensity; supporting the hypothesis that evaluations of the driving situation mediate the relationship between trait and state anger. Further, the unique structure of the DAS required to fit the data from the Ukrainian sample, may indicate that the anger inducing situations in Ukraine are different to those of a more developed country. Future research is needed to investigate driving anger in Ukraine in a broader sample and also to confirm the role of the appraisal process in the development of driving anger in both developed and undeveloped countries.

  1. The drive-wise project: driving simulator training increases real driving performance in healthy older drivers

    PubMed Central

    Casutt, Gianclaudio; Theill, Nathan; Martin, Mike; Keller, Martin; Jäncke, Lutz

    2014-01-01

    Background: Age-related cognitive decline is often associated with unsafe driving behavior. We hypothesized that 10 active training sessions in a driving simulator increase cognitive and on-road driving performance. In addition, driving simulator training should outperform cognitive training. Methods: Ninety-one healthy active drivers (62–87 years) were randomly assigned to one of three groups: (1) a driving simulator training group, (2) an attention training group (vigilance and selective attention), or (3) a control group. The main outcome variables were on-road driving and cognitive performance. Seventy-seven participants (85%) completed the training and were included in the analyses. Training gains were analyzed using a multiple regression analysis with planned orthogonal comparisons. Results: The driving simulator-training group showed an improvement in on-road driving performance compared to the attention-training group. In addition, both training groups increased cognitive performance compared to the control group. Conclusion: Driving simulator training offers the potential to enhance driving skills in older drivers. Compared to the attention training, the simulator training seems to be a more powerful program for increasing older drivers' safety on the road. PMID:24860497

  2. Noninductive current drive in tokamaks

    SciTech Connect

    Uckan, N.A.

    1985-01-01

    Various current drive mechanisms may be grouped into four classes: (1) injection of energetic particle beams; (2) launching of rf waves; (3) hybrid schemes, which are combinations of various rf schemes (rf plus beams, rf and/or beam plus ohmic heating, etc.); and (4) other schemes, some of which are specific to reactor plasma conditions requiring the presence of alpha particle or intense synchrotron radiation. Particle injection schemes include current drive by neutral beams and relativistic electron beams. The rf schemes include current drive by the lower hybrid (LH) waves, the electron waves, the waves in the ion cyclotron range of frequencies, etc. Only a few of these approaches, however, have been tested experimentally, with the broadest data base available for LH waves. Included in this report are (1) efficiency criteria for current drive, (2) current drive by neutral beam injection, (3) LH current drive, (4) electron cyclotron current drive, (5) current drive by ion cyclotron waves - minority species heating, and (6) current drive by other schemes (such as hybrids and low frequency waves).

  3. 26. CAN CONVEYOR DRIVE MECHANISM Empty can conveyor driving mechanism, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    26. CAN CONVEYOR DRIVE MECHANISM Empty can conveyor driving mechanism, second floor above canning area. The belt has been removed from the conveyor, but sections of can conveyor tracks are visible on the floor. - Hovden Cannery, 886 Cannery Row, Monterey, Monterey County, CA

  4. Driving for All Seasons and Reasons. Book Four. Project Drive.

    ERIC Educational Resources Information Center

    Zook, Doris; And Others

    This Project Drive booklet titled Driving for All Seasons and Reasons is one of eight booklets designed for intermediate-level English-as-a-second-language students and low-level adult basic education/basic reading students. The goal of the booklet is to aid the student in developing the oral and sight vocabulary necessary for a basic driver…

  5. VIEW OF BEND IN CEDAR DRIVE WITH 603 CEDAR DRIVE ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    VIEW OF BEND IN CEDAR DRIVE WITH 603 CEDAR DRIVE ON RIGHT. VIEW FACING NORTHEAST - Camp H.M. Smith and Navy Public Works Center Manana Title VII (Capehart) Housing, Intersection of Acacia Road and Brich Circle, Pearl City, Honolulu County, HI

  6. The "genetics" of driving behavior: parents' driving style predicts their children's driving style.

    PubMed

    Bianchi, Alessandra; Summala, Heikki

    2004-07-01

    It can be hypothesized that children inherit their parents' driving habits both through genetic disposition and model learning. A few studies have shown indeed that parents' and their children's traffic convictions and accidents correlate which, however, may be due to life style and other exposure factors. This study aimed at investigating the relationships between parents' and their children's self-reported driving behavior. The subjects were 174 parent-child pairs who independently completed a questionnaire. Driving behavior-driving style-was evaluated by means of Manchester driver behavior questionnaire (DBQ), while data about driving exposure, life style, accidents, and traffic tickets were also collected. A series of regression models indicated that parents' self-reported driving behavior explains their children's respective self-reported behavior, even when exposure and demographic and life-style factors are controlled.

  7. Drive-By Pharming

    NASA Astrophysics Data System (ADS)

    Stamm, Sid; Ramzan, Zulfikar; Jakobsson, Markus

    This paper describes an attack concept termed Drive-by Pharming where an attacker sets up a web page that, when simply viewed by the victim (on a JavaScript-enabled browser), attempts to change the DNS server settings on the victim's home broadband router. As a result, future DNS queries are resolved by a DNS server of the attacker's choice. The attacker can direct the victim's Internet traffic and point the victim to the attacker's own web sites regardless of what domain the victim thinks he is actually going to, potentially leading to the compromise of the victim's credentials. The same attack methodology can be used to make other changes to the router, like replacing its firmware. Routers could then host malicious web pages or engage in click fraud. Since the attack is mounted through viewing a web page, it does not require the attacker to have any physical proximity to the victim nor does it require the explicit download of traditional malicious software. The attack works under the reasonable assumption that the victim has not changed the default management password on their broadband router.

  8. Handbook for Driving Knowledge Testing.

    ERIC Educational Resources Information Center

    Pollock, William T.; McDole, Thomas L.

    Materials intended for driving knowledge test development for use by operational licensing and education agencies are presented. A pool of 1,313 multiple choice test items is included, consisting of sets of specially developed and tested items covering principles of safe driving, legal regulations, and traffic control device knowledge pertinent to…

  9. Bidirectional drive and brake mechanism

    NASA Technical Reports Server (NTRS)

    Swan, Scott A. (Inventor)

    1991-01-01

    A space transport vehicle is disclosed as including a body which is arranged to be movably mounted on an elongated guide member disposed in outer space and driven therealong. A drive wheel is mounted on a drive shaft and arranged to be positioned in rolling engagement with the elongated guide carrying the vehicle. A brake member is arranged on the drive shaft for movement into and out of engagement with an adjacent surface of the drive wheel. An actuator is mounted on the body to be manually moved back and forth between spaced positions in an arc of movement. A ratchet-and-pawl mechanism is arranged to operate upon movements of the actuator in one direction between first and second positions for coupling the actuator to the drive wheel to incrementally rotate the wheel in one rotational direction and to operate upon movements of the actuator in the opposite direction for uncoupling the actuator from the wheel. The brake member is threadedly coupled to the drive shaft in order that the brake member will be operated only when the actuator is moved on beyond its first and second positions for shifting the brake member along the drive shaft and into frictional engagement with the adjacent surface on the drive wheel.

  10. Quantum gates by periodic driving

    PubMed Central

    Shi, Z. C.; Wang, W.; Yi, X. X.

    2016-01-01

    Topological quantum computation has been extensively studied in the past decades due to its robustness against decoherence. One way to realize the topological quantum computation is by adiabatic evolutions—it requires relatively long time to complete a gate, so the speed of quantum computation slows down. In this work, we present a method to realize single qubit quantum gates by periodic driving. Compared to adiabatic evolution, the single qubit gates can be realized at a fixed time much shorter than that by adiabatic evolution. The driving fields can be sinusoidal or square-well field. With the sinusoidal driving field, we derive an expression for the total operation time in the high-frequency limit, and an exact analytical expression for the evolution operator without any approximations is given for the square well driving. This study suggests that the period driving could provide us with a new direction in regulations of the operation time in topological quantum computation. PMID:26911900

  11. Driving the Landscape

    NASA Astrophysics Data System (ADS)

    Haff, P. K.

    2012-12-01

    Technological modification of the earth's surface (e.g., agriculture, urbanization) is an old story in human history, but what about the future? The future of landscape in an accelerating technological world, beyond a relatively short time horizon, lies hidden behind an impenetrable veil of complexity. Sufficiently complex dynamics generates not only the trajectory of a variable of interest (e.g., vegetation cover) but also the environment in which that variable evolves (e.g., background climate). There is no way to anticipate what variables will define that environment—the dynamics creates its own variables. We are always open to surprise by a change of conditions we thought or assumed were fixed or by the appearance of new phenomena of whose possible existence we had been unaware or thought unlikely. This is especially true under the influence of technology, where novelty is the rule. Lack of direct long-term predictability of landscape change does not, however, mean we cannot say anything about its future. The presence of persistence (finite time scales) in a system means that prediction by a calibrated numerical model should be good for a limited period of time barring bad luck or faulty implementation. Short-term prediction, despite its limitations, provides an option for dealing with the longer-term future. If a computer-controlled car tries to drive itself from New York to Los Angeles, no conceivable (or possible) stand-alone software can be constructed to predict a priori the space-time trajectory of the vehicle. Yet the drive is normally completed easily by most drivers. The trip is successfully completed because each in a series of very short (linear) steps can be "corrected" on the fly by the driver, who takes her cues from the environment to keep the car on the road and headed toward its destination. This metaphor differs in a fundamental way from the usual notion of predicting geomorphic change, because it involves a goal—to reach a desired

  12. Electric vehicle drive systems

    NASA Astrophysics Data System (ADS)

    Appleyard, M.

    1992-01-01

    New legislation in the State of California requires that 2% of vehicles sold there from 1998 will be 'zero-emitting'. This provides a unique market opportunity for developers of electric vehicles but substantial improvements in the technology are probably required if it is to be successfully exploited. There are around a dozen types of battery that are potentially relevant to road vehicles but, at the present, lead/acid and sodium—sulphur come closest to combining acceptable performance, life and cost. To develop an efficient, lightweight electric motor system requires up-to-date techniques of magnetics design, and the latest power-electronic and microprocessor control methods. Brushless machines, coupled with solid-state inverters, offer the most economical solution for mass production, even though their development costs are higher than for direct-current commutator machines. Fitted to a small car, even the highest energy-density batteries will only provide around 200 km average range before recharging. Therefore, some form of supplementary on-board power generation will probably be needed to secure widespread acceptance by the driving public. Engine-driven generators of quite low power can achieve useful increases in urban range but will fail to qualify as 'zero-emitting'. On the other hand, if the same function could be economically performed by a small fuel-cell using hydrogen derived from a methanol reformer, then most of the flexibility provided by conventional vehicles would be retained. The market prospects for electric cars would then be greatly enhanced and their dependence on very advanced battery technology would be reduced.

  13. The mechanism of PDT-induced apoptosis

    NASA Astrophysics Data System (ADS)

    Cai, Xiongwei; Liu, Timon C.; Ding, Xin-Min; Gu, Ying; Liu, Fan-Guang; Liu, Song-Hao

    2003-12-01

    Photodynamic therapy (PDT) can induce apoptosis in many cancer cells in vitro and in tumors in vivo. Cells become more oxidation with PDT, and maintain differentiation and proliferation, go apoptosis and necrosis with the increase of reactive oxygen species (ROS) concentration. ROS can induce apoptosis through mitochondria by inhibiting respiration chain or oxidative phosphorylation or damaging mitochondrial membrane. ROS can initiate apoptosis through endoplamic reticulum(ER) by opening Ca2+ channel or starting unfold protein response (UPR). ROS can also induce apoptosis through Golgi by producing ganglioside GD3 by use of ceramide, which induces apoptosis by activating caspase-3, JNK and p38 MAPK. It can also induce apoptosis by activating Bip (mitochondria-dependant) or preocaspase-12 (mitochondria- independent) or inhibiting protein synthesizing. There are so complicated cross-talking among different signal pathways or organnells that we think PDT-induced apoptosis is mediated by multiplex pathways and excessive levels in a refined network.

  14. Epigenetic inactivation of secreted frizzled-related protein 2 in esophageal squamous cell carcinoma

    PubMed Central

    Hao, Xiao-Wen; Zhu, Sheng-Tao; He, Yuan-Long; Li, Peng; Wang, Yong-Jun; Zhang, Shu-Tian

    2012-01-01

    AIM: To investigate the expression and methylation status of the secreted frizzled-related protein 2 (SFRP2) in esophageal squamous cell carcinoma (ESCC) and explore its role in ESCC carcinogenesis. METHODS: Seven ESCC cell lines (KYSE 30, KYSE150, KYSE410, KYSE510, EC109, EC9706 and TE-1) and one immortalized human esophageal epithelial cell line (Het-1A), 20 ESCC tissue samples and 20 paired adjacent non-tumor esophageal epithelial tissues were analyzed in this study. Reverse-transcription polymerase chain reaction (RT-PCR) was employed to investigate the expression of SFRP2 in cell lines, primary ESCC tumor tissue, and paired adjacent normal tissue. Methylation status was evaluated by methylation-specific PCR and bisulfite sequencing. The correlation between expression and promoter methylation of the SFRP2 gene was confirmed with treatment of 5-aza-2’-deoxycytidine. To assess the potential role of SFRP2 in ESCC, we established stable SFRP2-transfected cells and examined them with regard to cell proliferation, colony formation, apoptosis and cell cycle in vivo and in vitro. RESULTS: SFRP2 mRNA was expressed in the immortalized normal esophageal epithelial cell line but not in seven ESCC cell lines. By methylation-specific PCR, complete methylation was detected in three cell lines with silenced SFRP2 expression, and extensive methylation was observed in the other four ESCC cell lines. 5-aza-2’-deoxycytidine could restore the expression of SFRP2 mRNA in the three ESCC cell lines lacking SFRP2 expression. SFRP2 mRNA expression was obviously lower in primary ESCC tissue than in adjacent normal tissue (0.939 ± 0.398 vs 1.51 ± 0.399, P < 0.01). SFRP2 methylation was higher in tumor tissue than in paired normal tissue (95% vs 65%, P < 0.05). The DNA methylation status of the SFRP2 correlated inversely with the SFRP2 expression. To assess the potential role of SFRP2 in ESCC, we established stable SFRP2 transfectants and control counterparts by introducing pcDNA3

  15. Linear Back-Drive Differentials

    NASA Technical Reports Server (NTRS)

    Waydo, Peter

    2003-01-01

    Linear back-drive differentials have been proposed as alternatives to conventional gear differentials for applications in which there is only limited rotational motion (e.g., oscillation). The finite nature of the rotation makes it possible to optimize a linear back-drive differential in ways that would not be possible for gear differentials or other differentials that are required to be capable of unlimited rotation. As a result, relative to gear differentials, linear back-drive differentials could be more compact and less massive, could contain fewer complex parts, and could be less sensitive to variations in the viscosities of lubricants. Linear back-drive differentials would operate according to established principles of power ball screws and linear-motion drives, but would utilize these principles in an innovative way. One major characteristic of such mechanisms that would be exploited in linear back-drive differentials is the possibility of designing them to drive or back-drive with similar efficiency and energy input: in other words, such a mechanism can be designed so that a rotating screw can drive a nut linearly or the linear motion of the nut can cause the screw to rotate. A linear back-drive differential (see figure) would include two collinear shafts connected to two parts that are intended to engage in limited opposing rotations. The linear back-drive differential would also include a nut that would be free to translate along its axis but not to rotate. The inner surface of the nut would be right-hand threaded at one end and left-hand threaded at the opposite end to engage corresponding right- and left-handed threads on the shafts. A rotation and torque introduced into the system via one shaft would drive the nut in linear motion. The nut, in turn, would back-drive the other shaft, creating a reaction torque. Balls would reduce friction, making it possible for the shaft/nut coupling on each side to operate with 90 percent efficiency.

  16. cAMP prevents TNF-induced apoptosis through inhibiting DISC complex formation in rat hepatocytes.

    PubMed

    Bhattacharjee, Rajesh; Xiang, Wenpei; Wang, Yinna; Zhang, Xiaoying; Billiar, Timothy R

    2012-06-22

    Tumor necrosis factor α (TNF) is a pleiotropic proinflammatory cytokine that plays a role in immunity and the control of cell proliferation, cell differentiation, and apoptosis. The pleiotropic nature of TNF is due to the formation of different signaling complexes upon the binding of TNF to its receptor, TNF receptor type 1 (TNFR1). TNF induces apoptosis in various mammalian cells when the cells are co-treated with a transcription inhibitor like actinomycin D (ActD). When TNFR1 is activated, it recruits an adaptor protein, TNF receptor-associated protein with death domain (TRADD), through its cytoplasmic death effector domain (DED). TRADD, in turn, recruits other signaling proteins, including TNF receptor-associated protein 2 (TRAF2) and receptor-associated protein kinase (RIPK) 1, to form a complex. Subsequently, this complex combines with FADD and procaspase-8, converts into a death-inducing signaling complex (DISC) to induce apoptosis. Cyclic AMP (cAMP) is a second messenger that regulates various cellular processes such as cell proliferation, gene expression, and apoptosis. cAMP analogues are reported to act as anti-apoptotic agents in various cell types, including hepatocytes. We found that a cAMP analogue, dibutyryl cAMP (db-cAMP), inhibits TNF+ActD-induced apoptosis in rat hepatocytes. The protein kinase A (PKA) inhibitor KT-5720 reverses this inhibitory effect of cAMP on apoptosis. Cytoprotection by cAMP involves down-regulation of various apoptotic signal regulators like TRADD and FADD and inhibition of caspase-8 and caspase-3 cleavage. We also found that cAMP exerts its affect at the proximal level of TNF signaling by inhibiting the formation of the DISC complex upon the binding of TNF to TNFR1. In conclusion, our study shows that cAMP prevents TNF+ActD-induced apoptosis in rat hepatocytes by inhibiting DISC complex formation.

  17. PTEN induces apoptosis and cavitation via HIF-2-dependent Bnip3 upregulation during epithelial lumen formation

    PubMed Central

    Qi, Y; Liu, J; Saadat, S; Tian, X; Han, Y; Fong, G-H; Pandolfi, P P; Lee, L Y; Li, S

    2015-01-01

    The tumor suppressor phosphatase and tensin homolog (PTEN) dephosphorylates PIP3 and antagonizes the prosurvival PI3K-Akt pathway. Targeted deletion of PTEN in mice led to early embryonic lethality. To elucidate its role in embryonic epithelial morphogenesis and the underlying mechanisms, we used embryonic stem cell-derived embryoid body (EB), an epithelial cyst structurally similar to the periimplantation embryo. PTEN is upregulated during EB morphogenesis in parallel with apoptosis of core cells, which mediates EB cavitation. Genetic ablation of PTEN causes Akt overactivation, apoptosis resistance and cavitation blockade. However, rescue experiments using mutant PTEN and pharmacological inhibition of Akt suggest that the phosphatase activity of PTEN and Akt are not involved in apoptosis-mediated cavitation. Instead, hypoxia-induced upregulation of Bnip3, a proapoptotic BH3-only protein, mediates PTEN-dependent apoptosis and cavitation. PTEN inactivation inhibits hypoxia- and reactive oxygen species-induced Bnip3 elevation. Overexpression of Bnip3 in PTEN-null EBs rescues apoptosis of the core cells. Mechanistically, suppression of Bnip3 following PTEN loss is likely due to reduction of hypoxia-inducible factor-2α (HIF-2α) because forced expression of an oxygen-stable HIF-2α mutant rescues Bnip3 expression and apoptosis. Lastly, we show that HIF-2α is upregulated by PTEN at both transcriptional and posttranscriptional levels. Ablation of prolyl hydroxylase domain-containing protein 2 (PHD2) in normal EBs or inhibition of PHD activities in PTEN-null EBs stabilizes HIF-2α and induces Bnip3 and caspase-3 activation. Altogether, these results suggest that PTEN is required for apoptosis-mediated cavitation during epithelial morphogenesis by regulating the expression of HIF-2α and Bnip3. PMID:25394489

  18. BMP2 induces osteoblast apoptosis in a maturation state and noggin-dependent manner.

    PubMed

    Hyzy, Sharon L; Olivares-Navarrete, Rene; Schwartz, Zvi; Boyan, Barbara D

    2012-10-01

    Large doses of bone morphogenetic protein 2 (BMP2) are used clinically to induce bone formation in challenging bone defects. However, complications after treatment include swelling, ectopic bone formation, and adjacent bone resorption. While BMP2 can be effective, it is important to characterize the mechanism of the deleterious effects to optimize its use. The aim of this study was to determine the effect of BMP2 on apoptosis in osteoblast lineage cells and to determine the role of the BMP inhibitor Noggin in this process. Human mesenchymal stem cells (MSCs), immature osteoblast-like MG63 cells, and mature normal human osteoblasts (NHOst) were treated with BMP2. A model system of increased endogenous BMP signaling was created by silencing Noggin (shNOG-MG63). Finally, the BMP pathway regulating apoptosis in NHOst was examined using BMP signaling inhibitors (5Z-7-oxozeaenol, dorsomorphin, H-8). Apoptosis was characterized by caspase-3, BAX/BCL2, p53, and DNA fragmentation. BMP2 induced apoptosis in a cell-type dependent manner. While the effect was minor in MSCs, MG63 cells had modest increases and NHOst cells had robust increases apoptosis after BMP2 treatment. Apoptosis was significantly higher in shNOG-MG63 than MG63 cells. 5Z-7-oxozeaenol and dorsomorphin eliminated the BMP2-induced increase in DNA fragmentation in NHOst, suggesting roles for TAB/TAK1 and Smad signaling. These results indicate that the apoptotic effect of BMP2 is dependent on cell maturation state, inducing apoptosis in committed osteoblasts through Smad and TAB/TAK1 signaling, and is regulated by Noggin. Dose and delivery must be optimized in therapeutic applications of BMP2 to minimize complications.

  19. APOPTOSIS IN WHOLE MOUSE OVARIES

    EPA Science Inventory

    Apoptosis in Whole Mouse Ovaries
    Robert M. Zucker Susan C. Jeffay and Sally D. Perreault
    Reproductive Toxicology Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, 27711.

  20. [Apoptosis in chronic lymphocytic leukemia].

    PubMed

    Giordano, M

    2000-01-01

    Chronic lymphocytic leukemia of B cells (B-CLL) is the most prevalent leukemia in the Occidental Hemisphere. It is characterized by a progressive accumulation of monoclonal CD5+ B lymphocytes, with low amounts of surface Ig. Most B-CLL cells are arrested in the G0 phase of the cell cycle; therefore their accumulation in vivo appears to result from the inhibition of apoptosis which has been attributed to over-expression of the anti-apoptotic protein Bcl-2. When cultured in vitro, spontaneous apoptosis occurs, suggesting the existence in vivo of survival-promoting factors. We here show that non-malignant leukocytes, particularly monocytes and NK cells, are able to inhibit B-CLL cells apoptosis, at least in part, through the release of soluble factors. Neutralizing antibodies directed to interferon-gamma or IL-4 only partially abolish the protecting effects of accessory cells suggesting that they are not the main cytokines involved. Increased apoptosis of B-CLL cells is not associated with modifications in the expression of Bcl-2, Fas or Fas ligand. Considering that B-CLL is associated to autoimmune phenomena and recurrent infections due to hypogammaglobulinemia, it should be interesting to correlate the activation of immune responses with disease progression.

  1. Pancreatic carcinogenesis: apoptosis and angiogenesis.

    PubMed

    Onizuka, Shinya; Kawakami, Shunsuke; Taniguchi, Ken; Fujioka, Hikaru; Miyashita, Kosei

    2004-04-01

    Apoptosis and angiogenesis are critical biologic processes that are altered during carcinogenesis. Both apoptosis and angiogenesis may play an important role in pancreatic carcinogenesis. Despite numerous advances in the diagnosis and treatment of pancreatic cancer, its prognosis remains dismal and a new therapeutic approach is much needed. Recent research has revealed that apoptosis and angiogenesis are closely interrelated. Several reports show that a tumor suppresser gene that is expressed in pancreatic carcinoma and related to malignant potential can induce apoptosis and also inhibit angiogenesis. At present, it is generally accepted that tumor growth in cancers, including pancreatic cancer, depends on angiogenesis. We have identified 2 new angiogenesis inhibitors from a conditioned medium of human pancreatic carcinoma cell line (BxPC-3): antiangiogenic antithrombin III (aaAT-III) and vitamin D binding protein-macrophage activating factor (DBP-maf). These molecules were able to regress tumors in severe combined immunodeficiency disease (SCID) mice, demonstrating potent inhibition of endothelial cell proliferation. Moreover, the angiogenesis inhibitors induced tumor dormancy in the animal model. These results suggest that antiangiogenic therapy using angiogenesis inhibitors may become a new strategy for treatment of pancreatic cancer in the near future.

  2. Methods for determining Myc-induced apoptosis.

    PubMed

    Lu, Dan; Littlewood, Trevor D

    2013-01-01

    Although many oncoproteins promote cell growth and proliferation, some also possess the potential to induce cell death by apoptosis. Deregulated expression of the myc oncogene promotes apoptosis in both cultured cells and in some tissues in vivo. Here we describe techniques to detect Myc-induced apoptosis in vitro using flow cytometry and microscopy and in vivo using immunohistochemical staining.

  3. Driving Performance Under Alcohol in Simulated Representative Driving Tasks

    PubMed Central

    Kenntner-Mabiala, Ramona; Kaussner, Yvonne; Jagiellowicz-Kaufmann, Monika; Hoffmann, Sonja; Krüger, Hans-Peter

    2015-01-01

    Abstract Comparing drug-induced driving impairments with the effects of benchmark blood alcohol concentrations (BACs) is an approved approach to determine the clinical relevance of findings for traffic safety. The present study aimed to collect alcohol calibration data to validate findings of clinical trials that were derived from a representative test course in a dynamic driving simulator. The driving performance of 24 healthy volunteers under placebo and with 0.05% and 0.08% BACs was measured in a double-blind, randomized, crossover design. Trained investigators assessed the subjects’ driving performance and registered their driving errors. Various driving parameters that were recorded during the simulation were also analyzed. Generally, the participants performed worse on the test course (P < 0.05 for the investigators’ assessment) under the influence of alcohol. Consistent with the relevant literature, lane-keeping performance parameters were sensitive to the investigated BACs. There were significant differences between the alcohol and placebo conditions in most of the parameters analyzed. However, the total number of errors was the only parameter discriminating significantly between all three BAC conditions. In conclusion, data show that the present experimental setup is suitable for future psychopharmacological research. Thereby, for each drug to be investigated, we recommend to assess a profile of various parameters that address different levels of driving. On the basis of this performance profile, the total number of driving errors is recommended as the primary endpoint. However, this overall endpoint should be completed by a specifically sensitive parameter that is chosen depending on the effect known to be induced by the tested drug. PMID:25689289

  4. Magnetic compression laser driving circuit

    DOEpatents

    Ball, Don G.; Birx, Dan; Cook, Edward G.

    1993-01-01

    A magnetic compression laser driving circuit is disclosed. The magnetic compression laser driving circuit compresses voltage pulses in the range of 1.5 microseconds at 20 Kilovolts of amplitude to pulses in the range of 40 nanoseconds and 60 Kilovolts of amplitude. The magnetic compression laser driving circuit includes a multi-stage magnetic switch where the last stage includes a switch having at least two turns which has larger saturated inductance with less core material so that the efficiency of the circuit and hence the laser is increased.

  5. Magnetic compression laser driving circuit

    DOEpatents

    Ball, D.G.; Birx, D.; Cook, E.G.

    1993-01-05

    A magnetic compression laser driving circuit is disclosed. The magnetic compression laser driving circuit compresses voltage pulses in the range of 1.5 microseconds at 20 kilovolts of amplitude to pulses in the range of 40 nanoseconds and 60 kilovolts of amplitude. The magnetic compression laser driving circuit includes a multi-stage magnetic switch where the last stage includes a switch having at least two turns which has larger saturated inductance with less core material so that the efficiency of the circuit and hence the laser is increased.

  6. How to maintain chain drives

    SciTech Connect

    Wright, J.L. )

    1992-06-18

    Properly selected and maintained chain drives can be expected to give thousands of hours of reliable service. Selection is usually done just once. This paper reports on good maintenance which must be done regularly to keep the drive operating. An effective maintenance program for roller chain should include correct type and adequate amounts of lubrication, replacement of worn chains and sprockets, and elimination of drive interferences. It is important to set u a lubrication and inspection/correction schedule to ensure that all required maintenance is carried out.

  7. Phoning while driving II: a review of driving conditions influence.

    PubMed

    Collet, C; Guillot, A; Petit, C

    2010-05-01

    The first paper examined how the variables related to driving performance were impacted by the management of holding a phone conversation. However, the conditions under which this dual task is carried out are dependent upon a set of factors that may particularly influence the risk of crash. These conditions are defined by several independent variables, classified into five main categories: i) legislation; ii) phone type (hands-free or hand-held); iii) drivers' features regarding age, gender, personal individual profile and driving experience; iv) conversation content (casual or professional) and its context (held with passengers or with a cell (mobile) phone); v) driving conditions (actual or simulated driving, road type, traffic density and weather). These independent variables determine the general conditions. The way in which these factors are combined and interact one with another thus determines the risk that drivers undergo when a cell phone is used while driving. Finally, this review defined the general conditions of driving for which managing a phone conversation is likely to elicit a high risk of car crash or, conversely, may provide a situation of lower risk, with sufficient acceptance to ensure safety.

  8. Chemokines, macrophage inflammatory protein-2 and stromal cell-derived factor-1{alpha}, suppress amyloid {beta}-induced neurotoxicity

    SciTech Connect

    Raman, Dayanidhi; Milatovic, Snjezana-Zaja; Milatovic, Dejan; Fan, Guo-Huang; Richmond, Ann

    2011-11-15

    Alzheimer's disease (AD) is characterized by a progressive cognitive decline and accumulation of neurotoxic oligomeric peptides amyloid-{beta} (A{beta}). Although the molecular events are not entirely known, it has become evident that inflammation, environmental and other risk factors may play a causal, disruptive and/or protective role in the development of AD. The present study investigated the ability of the chemokines, macrophage inflammatory protein-2 (MIP-2) and stromal cell-derived factor-1{alpha} (SDF-1{alpha}), the respective ligands for chemokine receptors CXCR2 and CXCR4, to suppress A{beta}-induced neurotoxicity in vitro and in vivo. Pretreatment with MIP-2 or SDF-1{alpha} significantly protected neurons from A{beta}-induced dendritic regression and apoptosis in vitro through activation of Akt, ERK1/2 and maintenance of metalloproteinase ADAM17 especially with SDF-1{alpha}. Intra-cerebroventricular (ICV) injection of A{beta} led to reduction in dendritic length and spine density of pyramidal neurons in the CA1 area of the hippocampus and increased oxidative damage 24 h following the exposure. The A{beta}-induced morphometric changes of neurons and increase in biomarkers of oxidative damage, F{sub 2}-isoprostanes, were significantly inhibited by pretreatment with the chemokines MIP-2 or SDF-1{alpha}. Additionally, MIP-2 or SDF-1{alpha} was able to suppress the aberrant mislocalization of p21-activated kinase (PAK), one of the proteins involved in the maintenance of dendritic spines. Furthermore, MIP-2 also protected neurons against A{beta} neurotoxicity in CXCR2-/- mice, potentially through observed up regulation of CXCR1 mRNA. Understanding the neuroprotective potential of chemokines is crucial in defining the role for their employment during the early stages of neurodegeneration. -- Research highlights: Black-Right-Pointing-Pointer Neuroprotective ability of the chemokines MIP2 and CXCL12 against A{beta} toxicity. Black-Right-Pointing-Pointer MIP-2 or

  9. The Hydroxyl at Position C1 of Genipin Is the Active Inhibitory Group that Affects Mitochondrial Uncoupling Protein 2 in Panc-1 Cells

    PubMed Central

    Hou, Jianwei; Ding, Yue; Zhang, Tong; Zhang, Yong; Wang, Jianying; Shi, Chenchen; Fu, Wenwei; Cai, Zhenzhen

    2016-01-01

    Genipin (GNP) effectively inhibits uncoupling protein 2 (UCP2), which regulates the leakage of protons across the inner mitochondrial membrane. UCP2 inhibition may induce pancreatic adenocarcinoma cell death by increasing reactive oxygen species (ROS) levels. In this study, the hydroxyls at positions C10 (10-OH) and C1 (1-OH) of GNP were hypothesized to be the active groups that cause these inhibitory effects. Four GNP derivatives in which the hydroxyl at position C10 or C1 was replaced with other chemical groups were synthesized and isolated. Differences in the inhibitory effects of GNP and its four derivatives on pancreatic carcinoma cell (Panc-1) proliferation were assessed. The effects of GNP and its derivatives on apoptosis, UCP2 inhibition and ROS production were also studied to explore the relationship between GNP’s activity and its structure. The derivatives with 1-OH substitutions, geniposide (1-GNP1) and 1-ethyl-genipin (1-GNP2) lacked cytotoxic effects, while the other derivatives that retained 1-OH, 10-piv-genipin (10-GNP1) and 10-acetic acid-genipin (10-GNP2) exerted biological effects similar to those of GNP, even in the absence of 10-OH. Thus, 1-OH is the key functional group in the structure of GNP that is responsible for GNP’s apoptotic effects. These cytotoxic effects involve the induction of Panc-1 cell apoptosis through UCP2 inhibition and subsequent ROS production. PMID:26771380

  10. Actin-Related Protein 2 (ARP2) and Virus-Induced Filopodia Facilitate Human Respiratory Syncytial Virus Spread

    PubMed Central

    McCarty, Thomas; Martin, Scott E.; Le Nouën, Cyril; Buehler, Eugen; Chen, Yu-Chi; Smelkinson, Margery; Ganesan, Sundar; Fischer, Elizabeth R.; Brock, Linda G.; Liang, Bo; Munir, Shirin; Collins, Peter L.; Buchholz, Ursula J.

    2016-01-01

    Human respiratory syncytial virus (RSV) is an enveloped RNA virus that is the most important viral cause of acute pediatric lower respiratory tract illness worldwide, and lacks a vaccine or effective antiviral drug. The involvement of host factors in the RSV replicative cycle remains poorly characterized. A genome-wide siRNA screen in human lung epithelial A549 cells identified actin-related protein 2 (ARP2) as a host factor involved in RSV infection. ARP2 knockdown did not reduce RSV entry, and did not markedly reduce gene expression during the first 24 hr of infection, but decreased viral gene expression thereafter, an effect that appeared to be due to inhibition of viral spread to neighboring cells. Consistent with reduced spread, there was a 10-fold reduction in the release of infectious progeny virions in ARP2-depleted cells at 72 hr post-infection. In addition, we found that RSV infection induced filopodia formation and increased cell motility in A549 cells and that this phenotype was ARP2 dependent. Filopodia appeared to shuttle RSV to nearby uninfected cells, facilitating virus spread. Expression of the RSV F protein alone from a plasmid or heterologous viral vector in A549 cells induced filopodia, indicating a new role for the RSV F protein, driving filopodia induction and virus spread. Thus, this study identified roles for ARP2 and filopodia in RSV-induced cell motility, RSV production, and RSV cell-to-cell spread. PMID:27926942

  11. Apparatus for forming drive belts

    NASA Technical Reports Server (NTRS)

    Topits, A., Jr. (Inventor)

    1974-01-01

    An apparatus for manufacturing belts, such as seamless belts, is provided, the apparatus has relatively movable rollers that are mounted in an oven. A belt blank, for example, of a thin polyester film, is rotated on the rollers as heat is applied. Four rollers, each mounted on a separate roller assembly, are movable along appropriate tracks while a fifth centrally located roller is stationary. A pair of dc motors are operatively connected to a speed reduction gear assembly to provide a pair of rotating drive shafts that extend into the oven. One rotating shaft drives all of the rollers through a rotational gear assembly while the other drive shaft is capable of positioning the movable rollers through respective rotating threaded shafts. Control devices are provided for controlling the motors while measuring devices are operatively connected to the positional drive shaft to indicate the position of the rollers.

  12. Dangers of Texting While Driving

    MedlinePlus

    ... Privacy Policy Proceedings & Actions Proceedings and Actions Overview Electronic Comment Filing System (ECFS) Commission Documents (EDOCS) Most ... 000 drivers are using cell phones or manipulating electronic devices while driving, a number that has held ...

  13. Driving Speed vs Fuel Efficiency.

    ERIC Educational Resources Information Center

    Vest, Floyd

    1980-01-01

    A mathematical treatment of the relationship between driving speed and fuel efficiency is presented. The material involves applications of exponentials, logarithms, and elementary calculus, and is intended to be enrichment material for secondary and lower college mathematics classes. (MP)

  14. Quantum effects in warp drives

    NASA Astrophysics Data System (ADS)

    Finazzi, Stefano

    2013-09-01

    Warp drives are interesting configurations that, at least theoretically, provide a way to travel at superluminal speed. Unfortunately, several issues seem to forbid their realization. First, a huge amount of exotic matter is required to build them. Second, the presence of quantum fields propagating in superluminal warp-drive geometries makes them semiclassically unstable. Indeed, a Hawking-like high-temperature flux of particles is generated inside the warp-drive bubble, which causes an exponential growth of the energy density measured at the front wall of the bubble by freely falling observers. Moreover, superluminal warp drives remain unstable even if the Lorentz symmetry is broken by the introduction of regulating higher order terms in the Lagrangian of the quantum field. If the dispersion relation of the quantum field is subluminal, a black-hole laser phenomenon yields an exponential amplification of the emitted flux. If it is superluminal, infrared effects cause a linear growth of this flux.

  15. Power requirements for current drive

    NASA Astrophysics Data System (ADS)

    Boozer, Allen H.

    1988-03-01

    General formulas for the efficiency of current drive in toroidal plasmas are derived using entropy arguments. The highest possible efficiency for current drive in which a high-energy electron tail is formed is shown to be p=Erj, with p and j the power and current densities and Er≊0.09n14 V/m with n14 the electron density in units of 1014/cm.3 The electric field required to maintain the current in a runaway discharge is also shown to equal Er. If the plasma current is carried by near-Maxwellian electrons, waves that have a low phase velocity, compared to the energy of the electrons with which they interact, can drive a current with Ohmic efficiency, p=ηj2. Such waves were first discussed in the context of current drive by Fisch [Rev. Mod. Phys. 59, 175 (1987)].

  16. Mechanical drive for blood pump

    DOEpatents

    Bifano, N.J.; Pouchot, W.D.

    1975-07-29

    This patent relates to a highly efficient blood pump to be used as a replacement for a ventricle of the human heart to restore people disabled by heart disease. The mechanical drive of the present invention is designed to operate in conjunction with a thermoelectric converter power source. The mechanical drive system essentially converts the output of a rotary power into pulsatile motion so that the power demand from the thermoelectric converter remains essentially constant while the blood pump output is pulsed. (auth)

  17. Direct drive field actuator motors

    DOEpatents

    Grahn, A.R.

    1998-03-10

    A positive-drive field actuator motor is described which includes a stator carrying at least one field actuator which changes in dimension responsive to application of an energy field, and at least one drive shoe movable by the dimensional changes of the field actuator to contact and move a rotor element with respect to the stator. Various embodiments of the motor are disclosed, and the rotor element may be moved linearly or arcuately. 62 figs.

  18. [Vision and car driving ability].

    PubMed

    Wilhelm, Helmut

    2011-05-01

    Visual functions relevant for car driving are: Visual acuity, contrast and twilight vision, visual field, ocular motility and alignment and colour vision. Generally accepted and standardized tests are available for visual acuity and visual field. Maximum permissible values have been defined arbitrarily and are hardly supported by studies. European standards have been published comprising also contrast and twilight vision. When examining driving ability progressive and treatable ocular disorders such as cataract and glaucoma have to be considered.

  19. Direct drive field actuator motors

    SciTech Connect

    Grahn, Allen R.

    1998-01-01

    A positive-drive field actuator motor including a stator carrying at least one field actuator which changes in dimension responsive to application of an energy field, and at least one drive shoe movable by the dimensional changes of the field actuator to contact and move a rotor element with respect to the stator. Various embodiments of the motor are disclosed, and the rotor element may be moved linearly or arcuately.

  20. Low backlash direct drive actuator

    DOEpatents

    Kuklo, T.C.

    1994-10-25

    A low backlash direct drive actuator is described which comprises a motor such as a stepper motor having at least 200 steps per revolution; a two part hub assembly comprising a drive hub coaxially attached to the shaft of the motor and having a plurality of drive pins; a driven hub having a plurality of bores in one end thereof in alignment with the drive pins in the drive hub and a threaded shaft coaxially mounted in an opposite end of the driven hub; and a housing having a central bore therein into which are fitted the drive hub and driven hub, the housing having a motor mount on one end thereof to which is mounted the stepper motor, and a closed end portion with a threaded opening therein coaxial with the central bore in the housing and receiving therein the threaded shaft attached to the driven hub. Limit switches mounted to the housing cooperate with an enlarged lip on the driven hub to limit the lateral travel of the driven hub in the housing, which also acts to limit the lateral travel of the threaded shaft which functions as a lead screw. 10 figs.

  1. Low backlash direct drive actuator

    DOEpatents

    Kuklo, Thomas C.

    1994-01-01

    A low backlash direct drive actuator is described which comprises a motor such as a stepper motor having at least 200 steps per revolution; a two part hub assembly comprising a drive hub coaxially attached to the shaft of the motor and having a plurality of drive pins; a driven hub having a plurality of bores in one end thereof in alignment with the drive pins in the drive hub and a threaded shaft coaxially mounted in an opposite end of the driven hub; and a housing having a central bore therein into which are fitted the drive hub and driven hub, the housing having a motor mount on one end thereof to which is mounted the stepper motor, and a closed end portion with a threaded opening therein coaxial with the central bore in the housing and receiving therein the threaded shaft attached to the driven hub. Limit switches mounted to the housing cooperate with an enlarged lip on the driven hub to limit the lateral travel of the driven hub in the housing, which also acts to limit the lateral travel of the threaded shaft which functions as a lead screw.

  2. Special AT-rich Binding Protein-2 (SATB2) Differentially Affects Disease-causing p63 Mutant Proteins*

    PubMed Central

    Chung, Jacky; Grant, R. Ian; Kaplan, David R.; Irwin, Meredith S.

    2011-01-01

    p63, a p53 family member, is critical for proper skin and limb development and directly regulates gene expression in the ectoderm. Mice lacking p63 exhibit skin and craniofacial defects including cleft palate. In humans p63 mutations are associated with several distinct developmental syndromes. p63 sterile-α-motif domain, AEC (ankyloblepharon-ectodermal dysplasia-clefting)-associated mutations are associated with a high prevalence of orofacial clefting disorders, which are less common in EEC (ectrodactyly-ectodermal dysplasia-clefting) patients with DNA binding domain p63 mutations. However, the mechanisms by which these mutations differentially influence p63 function remain unclear, and interactions with other proteins implicated in craniofacial development have not been identified. Here, we show that AEC p63 mutations affect the ability of the p63 protein to interact with special AT-rich binding protein-2 (SATB2), which has recently also been implicated in the development of cleft palate. p63 and SATB2 are co-expressed early in development in the ectoderm of the first and second branchial arches, two essential sites where signaling is required for craniofacial patterning. SATB2 attenuates p63-mediated gene expression of perp (p53 apoptosis effector related to PMP-22), a critical downstream target gene during development, and specifically decreases p63 perp promoter binding. Interestingly, AEC but not EEC p63 mutations affect the ability of p63 to interact with SATB2 and the inhibitory effects of SATB2 on p63 transactivation of perp are most pronounced for AEC-associated p63 mutations. Our findings reveal a novel gain-of-function property of AEC-causing p63 mutations and identify SATB2 as the first p63 binding partner that differentially influences AEC and EEC p63 mutant proteins. PMID:21965674

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

    SciTech Connect

    Levitt, Randy J.; Georgescu, Maria-Magdalena; Pollak, Michael . E-mail: michael.pollak@mcgill.ca

    2005-11-04

    PTEN is a tumor suppressor gene whose loss of function is observed in {approx}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.

  4. Identification of potential molecular associations between chikungunya virus non-structural protein 2 and human host proteins.

    PubMed

    Rana, J; Gulati, S; Rajasekharan, S; Gupta, A; Chaudhary, V; Gupta, S

    2017-01-01

    Chikungunya virus (CHIKV) non-structural protein 2 (nsP2) is considered to be the master regulator of viral RNA replication and host responses generated during viral infection. This protein has two main functional domains: an N-terminal domain which exhibits NTPase, RNA triphosphatase and helicase activities and a C-terminal protease domain. Understanding how CHIKV nsP2 interacts with its host proteins is essential for elucidating all the required processes for viral replication and pathogenesis along with the identification of potential targets for antiviral therapy. In current study yeast two-hybrid (Y2H) screening of a human fetal brain cDNA library was performed using nsP2 protein as bait. The analysis identified seven host proteins (CCDC130, CPNE6, POLR2C, MAPK9, EIF4A2, EEF1A1 and EIF3I) as putative interactors of CHIKV nsP2 which were selected for further analysis based on their roles in host cellular machinery. The gene ontology analysis indicates that these proteins are mainly involved in apoptosis, transcription and translational mechanism of host cell. Domain mapping of nsP2 revealed that these associations are not random connections but instead they have functional significance. Further studies to identify the amino acid residues and their chemical interactions that may help in opening new possibilities for preventing these interactions, thus reducing chances of chikungunya infection were performed. This study expands the understanding of CHIKV-host interactions and is important for rational approaches of discovering new antiviral agents.

  5. Efficient Driving of Piezoelectric Transducers Using a Biaxial Driving Technique.

    PubMed

    Pichardo, Samuel; Silva, Rafael R C; Rubel, Oleg; Curiel, Laura

    2015-01-01

    Efficient driving of piezoelectric materials is desirable when operating transducers for biomedical applications such as high intensity focused ultrasound (HIFU) or ultrasound imaging. More efficient operation reduces the electric power required to produce the desired bioeffect or contrast. Our preliminary work [Cole et al. Journal of Physics: Condensed Matter. 2014;26(13):135901.] suggested that driving transducers by applying orthogonal electric fields can significantly reduce the coercivity that opposes ferroelectric switching. We present here the experimental validation of this biaxial driving technique using piezoelectric ceramics typically used in HIFU. A set of narrow-band transducers was fabricated with two sets of electrodes placed in an orthogonal configuration (following the propagation and the lateral mode). The geometry of the ceramic was chosen to have a resonance frequency similar for the propagation and the lateral mode. The average (± s.d.) resonance frequency of the samples was 465.1 (± 1.5) kHz. Experiments were conducted in which each pair of electrodes was driven independently and measurements of effective acoustic power were obtained using the radiation force method. The efficiency (acoustic/electric power) of the biaxial driving method was compared to the results obtained when driving the ceramic using electrodes placed only in the pole direction. Our results indicate that the biaxial method increases efficiency from 50% to 125% relative to the using a single electric field.

  6. Efficient Driving of Piezoelectric Transducers Using a Biaxial Driving Technique

    PubMed Central

    2015-01-01

    Efficient driving of piezoelectric materials is desirable when operating transducers for biomedical applications such as high intensity focused ultrasound (HIFU) or ultrasound imaging. More efficient operation reduces the electric power required to produce the desired bioeffect or contrast. Our preliminary work [Cole et al. Journal of Physics: Condensed Matter. 2014;26(13):135901.] suggested that driving transducers by applying orthogonal electric fields can significantly reduce the coercivity that opposes ferroelectric switching. We present here the experimental validation of this biaxial driving technique using piezoelectric ceramics typically used in HIFU. A set of narrow-band transducers was fabricated with two sets of electrodes placed in an orthogonal configuration (following the propagation and the lateral mode). The geometry of the ceramic was chosen to have a resonance frequency similar for the propagation and the lateral mode. The average (± s.d.) resonance frequency of the samples was 465.1 (± 1.5) kHz. Experiments were conducted in which each pair of electrodes was driven independently and measurements of effective acoustic power were obtained using the radiation force method. The efficiency (acoustic/electric power) of the biaxial driving method was compared to the results obtained when driving the ceramic using electrodes placed only in the pole direction. Our results indicate that the biaxial method increases efficiency from 50% to 125% relative to the using a single electric field. PMID:26418550

  7. [Apoptosis modulation by human papillomavirus].

    PubMed

    Jave-Suárez, Luis Felipe; Ratkovich-González, Sarah; Olimón-Andalón, Vicente; Aguilar-Lemarroy, Adriana

    2015-01-01

    One of the most important processes to keep the homeostasis in organisms is the apoptosis, also called programmed cell death. This mechanism works through two pathways: The intrinsic or mitochondrial, which responds to DNA damage and extern agents like UV radiation; and the extrinsic or receptor-mediated, which binds to their ligands to initiate the apoptotic trail. The evasion of apoptosis is one of the main causes of cellular transformation to malignity. Many viruses had shown capacity to modify the apoptotic process; among them is the human papillomavirus, which, by means of its oncoproteins, interferes in pathways, reacting with the receptors and molecules and participating in the death mechanism. This creates ideal conditions for cancer development.

  8. Studies on the expression of outer membrane protein 2 in escherichia coli.

    PubMed

    Fralick, J A; Diedrich, D L

    1982-01-01

    The relative level of protein 2 expressed in the outer membrane of strains of Escherichia coli K-12 lysogenized with bacteriophage PA-2 was found to be influenced by both the growth temperature and lc+ gene dosage. An increase in either of these parameters was accompanied by an increase in the level of protein 2 up to an apparent saturation level. Any increase in the amount of protein 2 was accompanied by a concomittant decrease in the amount of OmpF and OmpC porins. This inverse relationship led to the maintenance of an approximately constant protein mass per unit of peptidoglycan. Our results are discussed in light of recent genetic studies on the regulation of the OmpF and OmpC porins and can be explained through the competition of these three matrix proteins for a common export or insertion site.

  9. Driving performance and driver discomfort in an elevated and standard driving position during a driving simulation.

    PubMed

    Smith, Jordan; Mansfield, Neil; Gyi, Diane; Pagett, Mark; Bateman, Bob

    2015-07-01

    The primary purposes of a vehicle driver's seat, is to allow them to complete the driving task comfortably and safely. Within each class of vehicle (e.g. passenger, commercial, industrial, agricultural), there is an expected driving position to which a vehicle cabin is designed. This paper reports a study that compares two driving positions, in relation to Light Commercial Vehicles (LCVs), in terms of driver performance and driver discomfort. In the 'elevated' driving position, the seat is higher than usually used in road vehicles; this is compared to a standard driving position replicating the layout for a commercially available vehicle. It is shown that for a sample of 12 drivers, the elevated position did not, in general, show more discomfort than the standard position over a 60 min driving simulation, although discomfort increased with duration. There were no adverse effects shown for emergency stop reaction time or for driver headway for the elevated posture compared to the standard posture. The only body part that showed greater discomfort for the elevated posture compared to the standard posture was the right ankle. A second experiment confirmed that for 12 subjects, a higher pedal stiffness eliminated the ankle discomfort problem.

  10. Relationships between driving simulator performance and driving test results.

    PubMed

    de Winter, J C F; de Groot, S; Mulder, M; Wieringa, P A; Dankelman, J; Mulder, J A

    2009-02-01

    This article is considered relevant because: 1) car driving is an everyday and safety-critical task; 2) simulators are used to an increasing extent for driver training (related topics: training, virtual reality, human-machine interaction); 3) the article addresses relationships between performance in the simulator and driving test results--a relevant topic for those involved in driver training and the virtual reality industries; 4) this article provides new insights about individual differences in young drivers' behaviour. Simulators are being used to an increasing extent for driver training, allowing for the possibility of collecting objective data on driver proficiency under standardised conditions. However, relatively little is known about how learner drivers' simulator measures relate to on-road driving. This study proposes a theoretical framework that quantifies driver proficiency in terms of speed of task execution, violations and errors. This study investigated the relationships between these three measures of learner drivers' (n=804) proficiency during initial simulation-based training and the result of the driving test on the road, occurring an average of 6 months later. A higher chance of passing the driving test the first time was associated with making fewer steering errors on the simulator and could be predicted in regression analysis with a correlation of 0.18. Additionally, in accordance with the theoretical framework, a shorter duration of on-road training corresponded with faster task execution, fewer violations and fewer steering errors (predictive correlation 0.45). It is recommended that researchers conduct more large-scale studies into the reliability and validity of simulator measures and on-road driving tests.

  11. Type I interferons induce apoptosis by balancing cFLIP and caspase-8 independent of death ligands.

    PubMed

    Apelbaum, Amir; Yarden, Ganit; Warszawski, Shira; Harari, Daniel; Schreiber, Gideon

    2013-02-01

    Interferons induce a pleiotropy of responses through binding the same cell surface receptor. Here we investigated the molecular mechanism driving interferon-induced apoptosis. Using a nonbiased small interfering RNA (siRNA) screen, we show that silencing genes whose products are directly engaged in the initiation of interferon signaling completely abrogate the interferon antiproliferative response. Apoptosis-related genes such as the caspase-8, cFLIP, and DR5 genes specifically interfere with interferon-induced apoptosis, which we found to be independent of the activity of death ligands. The one gene for which silencing resulted in the strongest proapoptotic effect upon interferon signaling is the cFLIP gene, where silencing shortened the time of initiation of apoptosis from days to hours and increased dramatically the population of apoptotic cells. Thus, cFLIP serves as a regulator for interferon-induced apoptosis. A shift over time in the balance between cFLIP and caspase-8 results in downstream caspase activation and apoptosis. While gamma interferon (IFN-γ) also causes caspase-8 upregulation, we suggest that it follows a different path to apoptosis.

  12. Drive: Theory and Construct Validation

    PubMed Central

    Petrides, K. V.

    2016-01-01

    This article explicates the theory of drive and describes the development and validation of two measures. A representative set of drive facets was derived from an extensive corpus of human attributes (Study 1). Operationalised using an International Personality Item Pool version (the Drive:IPIP), a three-factor model was extracted from the facets in two samples and confirmed on a third sample (Study 2). The multi-item IPIP measure showed congruence with a short form, based on single-item ratings of the facets, and both demonstrated cross-informant reliability. Evidence also supported the measures’ convergent, discriminant, concurrent, and incremental validity (Study 3). Based on very promising findings, the authors hope to initiate a stream of research in what is argued to be a rather neglected niche of individual differences and non-cognitive assessment. PMID:27409773

  13. MULTIPLE DIFFERENTIAL ROTARY MECHANICAL DRIVE

    DOEpatents

    Smits, R.G.

    1964-01-28

    This patent relates to a mechanism suitable for such applications as driving two spaced-apart spools which carry a roll film strip under conditions where the film movement must be rapidly started, stopped, and reversed while maintaining a constant tension on the film. The basic drive is provided by a variable speed, reversible rnotor coupled to both spools through a first differential mechanism and driving both spools in the same direction. A second motor, providing a constant torque, is connected to the two spools through a second differential mechanism and is coupled to impart torque to one spool in a first direction anid to the other spool in the reverse direction thus applying a constant tension to the film passing over the two spools irrespective of the speed or direction of rotation thereof. (AEC)

  14. Multi-propeller drive system

    NASA Astrophysics Data System (ADS)

    Belenger, Robert V.

    1995-05-01

    A multipropeller drive system having a single input shaft for connection to an engine system, a differential gear assembly for dividing the driving force from the input drive shaft between a pair of output shafts, and a pair of laterally spaced propellers driven by the output shafts of the differential gear assembly is disclosed. The differential gear assembly operates in a manner wherein one output shaft, if required, is permitted to revolve at a different rate than the other output shaft. A pair of brake mechanisms acting on the output shafts of the differential gear assembly enable an operator to control the rotational speed of the respective propellers without modifying the engine speed or transmission settings.

  15. Future hard disk drive systems

    NASA Astrophysics Data System (ADS)

    Wood, Roger

    2009-03-01

    This paper briefly reviews the evolution of today's hard disk drive with the additional intention of orienting the reader to the overall mechanical and electrical architecture. The modern hard disk drive is a miracle of storage capacity and function together with remarkable economy of design. This paper presents a personal view of future customer requirements and the anticipated design evolution of the components. There are critical decisions and great challenges ahead for the key technologies of heads, media, head-disk interface, mechanics, and electronics.

  16. Imbalance between apoptosis and cell proliferation during early stages of mammary gland carcinogenesis in ACI rats.

    PubMed

    Kutanzi, Kristy R; Koturbash, Igor; Bronson, Roderick T; Pogribny, Igor P; Kovalchuk, Olga

    2010-12-10

    Estrogen and ionizing radiation are well-documented human breast carcinogens, yet the exact mechanisms of their deleterious effects on mammary gland remain to be discerned. Here we analyze the balance between cellular proliferation and apoptosis in the mammary glands of rats exposed to estrogen and X-ray radiation and the combined action of these carcinogenic agents. For the first time, we show that combined exposure to estrogen and radiation has a synergistic effect on cell proliferation in the mammary glands of ACI rats, as evidenced by a substantially greater magnitude of cell proliferation, especially after 12 and 18 weeks of treatment, when compared to mammary glands of rats exposed to estrogen or radiation alone. We also demonstrate that an imbalance between cell proliferation and apoptosis, rather than enhanced cell proliferation or apoptosis suppression alone, may be a driving force for carcinogenesis. Our studies further suggest that compromised functional activity of p53 may be one of the mechanisms responsible for the proliferation/apoptosis imbalance. In sum, the results of our study indicate that evaluation of the extent of cell proliferation and apoptosis before the onset of preneoplastic lesions may be a potential biomarker of breast cancer risk after exposure to breast carcinogens.

  17. Human papillomavirus oncoproteins and apoptosis (Review)

    PubMed Central

    JIANG, PEIYUE; YUE, YING

    2014-01-01

    The aim of this study was to review the literature and identify the association between human papillomavirus (HPV) oncoproteins and apoptosis. HPV-associated apoptosis may be primarily blocked by a number of oncoproteins, including E5, E6 and E7. E5 protein protects cells from tumor necrosis factor-associated apoptosis; the oncoprotein E6 predominantly inhibits apoptosis through the p53 pathway; and oncoprotein E7 is involved in apoptosis activation and inhibition. In addition, HPV oncoproteins are involved in activating or repressing the transcription of E6/E7. In conclusion, HPV oncoproteins, including E5, E6 and E7 protein, may interfere with apoptosis via certain regulatory principles. PMID:24348754

  18. 32 CFR 634.43 - Driving records.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... INVESTIGATIONS MOTOR VEHICLE TRAFFIC SUPERVISION Driving Records and the Traffic Point System § 634.43 Driving... intoxicating liquor (0.08% or greater on DOD installations; violation of civil law off post). C. Driving a... the same as the date of civil conviction, or the date that State or host-nation driving privileges...

  19. 32 CFR 634.43 - Driving records.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 4 2010-07-01 2010-07-01 true Driving records. 634.43 Section 634.43 National... INVESTIGATIONS MOTOR VEHICLE TRAFFIC SUPERVISION Driving Records and the Traffic Point System § 634.43 Driving... suspension or revocation actions. Table 5-1 of Part 634 Suspension/Revocation of Driving Privileges...

  20. 32 CFR 634.43 - Driving records.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 4 2014-07-01 2013-07-01 true Driving records. 634.43 Section 634.43 National... INVESTIGATIONS MOTOR VEHICLE TRAFFIC SUPERVISION Driving Records and the Traffic Point System § 634.43 Driving... suspension or revocation actions. Table 5-1 of Part 634 Suspension/Revocation of Driving Privileges...

  1. 32 CFR 634.43 - Driving records.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 4 2013-07-01 2013-07-01 false Driving records. 634.43 Section 634.43 National... INVESTIGATIONS MOTOR VEHICLE TRAFFIC SUPERVISION Driving Records and the Traffic Point System § 634.43 Driving... suspension or revocation actions. Table 5-1 of Part 634 Suspension/Revocation of Driving Privileges...

  2. 32 CFR 634.43 - Driving records.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 4 2012-07-01 2011-07-01 true Driving records. 634.43 Section 634.43 National... INVESTIGATIONS MOTOR VEHICLE TRAFFIC SUPERVISION Driving Records and the Traffic Point System § 634.43 Driving... suspension or revocation actions. Table 5-1 of Part 634 Suspension/Revocation of Driving Privileges...

  3. Driving and Age-Related Macular Degeneration

    ERIC Educational Resources Information Center

    Owsley, Cynthia; McGwin, Gerald, Jr.

    2008-01-01

    This article reviews the research literature on driving and age-related macular degeneration, which is motivated by the link between driving and the quality of life of older adults and their increased collision rate. It addresses the risk of crashes, driving performance, driving difficulty, self-regulation, and interventions to enhance, safety,…

  4. Basic principles of variable speed drives

    NASA Technical Reports Server (NTRS)

    Loewenthal, S. H.

    1973-01-01

    An understanding of the principles which govern variable speed drive operation is discussed for successful drive application. The fundamental factors of torque, speed ratio, and power as they relate to drive selection are discussed. The basic types of variable speed drives, their operating characteristics and their applications are also presented.

  5. OXIDATIVE STRESS ACTIVATES ANION EXCHANGE PROTEIN 2 AND AP-1 IN AIRWAY EPITHELIAL CELLS

    EPA Science Inventory

    Anion exchange protein 2 (AE2) is a membrane-bound protein that mediates chloride-bicarbonate exchange. In addition to regulating intracellular pH and cell volume, AE2 exports superoxide (O.) to the extracellular matrix in an HCO-dependent process. Given this ability to export O....

  6. Electronic 4-wheel drive control device

    NASA Technical Reports Server (NTRS)

    Hayato, S.; Takanori, S.; Shigeru, H.; Tatsunori, S.

    1984-01-01

    The internal rotation torque generated during operation of a 4-wheel drive vehicle is reduced using a control device whose clutch is attached to one part of the rear-wheel drive shaft. One torque sensor senses the drive torque associated with the rear wheel drive shaft. A second sensor senses the drive torque associated with the front wheel drive shaft. Revolution count sensors sense the revolutions of each drive shaft. By means of a microcomputer, the engagement of the clutch is changed to insure that the ratio of the torque sensors remains constant.

  7. Roller/Gear Drives For Robotic Manipulators

    NASA Technical Reports Server (NTRS)

    Anderson, William J.; Shipitalo, William

    1995-01-01

    Pitch/yaw roller/gear drive and wrist-roll roller/gear drive designed to incorporate several features desirable in robotic-joint actuators. Includes zero backlash, high efficiency, smooth motion (little ripple in torque and in speed ratio), and high degree of back-drivability. Pitch/yaw drive is novel two-axis drive containing combination of gears, rollers, and springs acting together eliminating backlash and cogging. Wrist-roll drive more-conventional single-axis drive offering advantages like those of pitch/yaw drive.

  8. Drive reconfiguration mechanism for tracked robotic vehicle

    DOEpatents

    Willis, W. David

    2000-01-01

    Drive reconfiguration apparatus for changing the configuration of a drive unit with respect to a vehicle body may comprise a guide system associated with the vehicle body and the drive unit which allows the drive unit to rotate about a center of rotation that is located at about a point where the drive unit contacts the surface being traversed. An actuator mounted to the vehicle body and connected to the drive unit rotates the drive unit about the center of rotation between a first position and a second position.

  9. Apoptosis and Molecular Targeting Therapy in Cancer

    PubMed Central

    Hassan, Mohamed; Watari, Hidemichi; AbuAlmaaty, Ali; Ohba, Yusuke; Sakuragi, Noriaki

    2014-01-01

    Apoptosis is the programmed cell death which maintains the healthy survival/death balance in metazoan cells. Defect in apoptosis can cause cancer or autoimmunity, while enhanced apoptosis may cause degenerative diseases. The apoptotic signals contribute into safeguarding the genomic integrity while defective apoptosis may promote carcinogenesis. The apoptotic signals are complicated and they are regulated at several levels. The signals of carcinogenesis modulate the central control points of the apoptotic pathways, including inhibitor of apoptosis (IAP) proteins and FLICE-inhibitory protein (c-FLIP). The tumor cells may use some of several molecular mechanisms to suppress apoptosis and acquire resistance to apoptotic agents, for example, by the expression of antiapoptotic proteins such as Bcl-2 or by the downregulation or mutation of proapoptotic proteins such as BAX. In this review, we provide the main regulatory molecules that govern the main basic mechanisms, extrinsic and intrinsic, of apoptosis in normal cells. We discuss how carcinogenesis could be developed via defective apoptotic pathways or their convergence. We listed some molecules which could be targeted to stimulate apoptosis in different cancers. Together, we briefly discuss the development of some promising cancer treatment strategies which target apoptotic inhibitors including Bcl-2 family proteins, IAPs, and c-FLIP for apoptosis induction. PMID:25013758

  10. Apoptosis in cancer: from pathogenesis to treatment

    PubMed Central

    2011-01-01

    Apoptosis is an ordered and orchestrated cellular process that occurs in physiological and pathological conditions. It is also one of the most studied topics among cell biologists. An understanding of the underlying mechanism of apoptosis is important as it plays a pivotal role in the pathogenesis of many diseases. In some, the problem is due to too much apoptosis, such as in the case of degenerative diseases while in others, too little apoptosis is the culprit. Cancer is one of the scenarios where too little apoptosis occurs, resulting in malignant cells that will not die. The mechanism of apoptosis is complex and involves many pathways. Defects can occur at any point along these pathways, leading to malignant transformation of the affected cells, tumour metastasis and resistance to anticancer drugs. Despite being the cause of problem, apoptosis plays an important role in the treatment of cancer as it is a popular target of many treatment strategies. The abundance of literature suggests that targeting apoptosis in cancer is feasible. However, many troubling questions arise with the use of new drugs or treatment strategies that are designed to enhance apoptosis and critical tests must be passed before they can be used safely in human subjects. PMID:21943236

  11. Mycobacterium tuberculosis effectors interfering host apoptosis signaling.

    PubMed

    Liu, Minqiang; Li, Wu; Xiang, Xiaohong; Xie, Jianping

    2015-07-01

    Tuberculosis remains a serious human public health concern. The coevolution between its pathogen Mycobacterium tuberculosis and human host complicated the way to prevent and cure TB. Apoptosis plays subtle role in this interaction. The pathogen endeavors to manipulate the apoptosis via diverse effectors targeting key signaling nodes. In this paper, we summarized the effectors pathogen used to subvert the apoptosis, such as LpqH, ESAT-6/CFP-10, LAMs. The interplay between different forms of cell deaths, such as apoptosis, autophagy, necrosis, is also discussed with a focus on the modes of action of effectors, and implications for better TB control.

  12. Apoptosis-Dependent and Apoptosis-Independent Functions Bim in Prostate Cancer Cells

    DTIC Science & Technology

    2004-03-01

    AD_ Award Number: DAMD17-03-1-0146 TITLE: Apoptosis-Dependent and Apoptosis-Independent Functions of Bim in Prostate Cancer Cells PRINCIPAL...FUNDING NUMBERS Apoptosis-Dependent and Apoptosis-Independent Functions of DAMD17-03-1-0146 Bim in Prostate Cancer Cells 6. A UTHORs) Junwei Liu, M.D...extended cell survival have been implicated in prostate cancer (PCa) development and progression. We recently found that Bim , a BH3-only pro

  13. Autophagy and apoptosis in planarians.

    PubMed

    González-Estévez, Cristina; Saló, Emili

    2010-03-01

    Adult planarians are capable of undergoing regeneration and body remodelling in order to adapt to physical damage or extreme environmental conditions. Moreover, most planarians can tolerate long periods of starvation and during this time, they shrink from an adult size to, and sometimes beyond, the initial size at hatching. Indeed, these properties have made them a classic model to study stem cells and regeneration. Under such stressful conditions, food reserves from the gastrodermis and parenchyma are first used up and later the testes, copulatory organs and ovaries are digested. More surprisingly, when food is again made available to shrunken individuals, they grow back to adult size and all their reproductive structures reappear. These cycles of growth and shrinkage may occur over long periods without any apparent impairment to the individual, or to its future maturation and breeding capacities. This plasticity resides in a mesoderm tissue known as the parenchyma, which is formed by several differentiated non-proliferating cell types and only one mitotically active cell type, the neoblasts, which represent approximately 20-30% of the cells in the parenchyma. Neoblasts are generally thought to be somatic stem-cells that participate in the normal continuous turnover of all cell types in planarians. Hence, planarians are organisms that continuously adapt their bodies (morphallaxis) to different environmental stresses (i.e.: injury or starvation). This adaptation involves a variety of processes including proliferation, differentiation, apoptosis and autophagy, all of which are perfectly orchestrated and tightly regulated to remodel or restore the body pattern. While neoblast biology and body re-patterning are currently the subject of intense research, apoptosis and autophagy remain much less studied. In this review we will summarize our current understanding and hypotheses regarding where and when apoptosis and autophagy occur and fulfil an essential role in

  14. Methylselenium and Prostate Cancer Apoptosis

    DTIC Science & Technology

    2007-02-01

    deleted on chromosome 10) (20--22), which functions as a negative regulator of PI3K in part through lipid phosphatase activity (23). The ERK1/2 pathway is...ether lipid analogue (36), did not cause apoptosis at concentrations as high as 50 mM after 24 h exposure, but greatly sensitized LNCaP cells to MSeA...bearing phos- phatidylinositol ether lipid analog inhibitor (36) (Figure 5B) together made a compelling case. Furthermore, over- expression of a CA-AKT

  15. Virtual Rewards for Driving Green

    ERIC Educational Resources Information Center

    Pritchard, Josh

    2010-01-01

    Carbon dioxide from automobiles is a major contributor to global climate change. In "Virtual Rewards for Driving Green," Josh Pritchard proposes a computer application that will enable fuel-efficient drivers to earn "green" dollars with which to buy digital merchandise on the Web. Can getting items that exist only in cyberspace actually change a…

  16. Test-Driving Their Passions

    ERIC Educational Resources Information Center

    Davis, Noah

    2007-01-01

    This article describes how the Watson fellowships give recipients an opportunity to test-drive their passions and see if they could lead to a career path. Over the last 40 years, the Thomas J. Watson Foundation has awarded $29 million in fellowships to seniors graduating from 50 mostly top-tier colleges with fewer than 3,000 students. In 2007, 50…

  17. Driving and working with syncope.

    PubMed

    Barbic, Franca; Casazza, Giovanni; Zamunér, Antonio Roberto; Costantino, Giorgio; Orlandi, Mauro; Dipaola, Franca; Capitanio, Chiara; Achenza, Sara; Sheldon, Robert; Furlan, Raffaello

    2014-09-01

    Syncope is usually addressed in the Emergency Department (ED) by the doctor in charge of the clinical picture, i.e. the patient's risk is stratified, a diagnostic work-up is done and a prognosis is set. Patients are ultimately admitted to hospital or discharged. However, other aspects related to syncope may deeply affect their daily lives. These include how and when to return to work and to driving, the feelings about a recent loss of consciousness, and the potential relapse of syncope. This is particularly significant if the work setting is intrinsically hazardous. These patients need adequate clinical and psychological support. For patients with syncope, two main parameters should be considered regarding returning to work and to driving. The first is to evaluate the risk of syncope recurrence and the second is to consider the expected harm if syncope does indeed occur during these activities. In the present paper we detail the problem of driving (including professional driving) and work after syncope. We propose a new quantitative model that will guide the physician in stratifying the risk for patients who have had a previous syncope event. The new model considers the syncope recurrence risk, the job task duration, and features that facilitate a syncope during work. On the basis of these variables, the global risk index for a worker is calculated. Following appropriate validation, this method might help ED and occupational physicians in their decision-making process with the goal of safely readmitting syncope patients to the workplace.

  18. Hydromechanical transmission with hydrodynamic drive

    DOEpatents

    Orshansky, Jr., deceased, Elias; Weseloh, William E.

    1979-01-01

    This transmission has a first planetary gear assembly having first input means connected to an input shaft, first output means, and first reaction means, and a second planetary gear assembly having second input means connected to the first input means, second output means, and second reaction means connected directly to the first reaction means by a reaction shaft. First clutch means, when engaged, connect the first output means to an output shaft in a high driving range. A hydrodynamic drive is used; for example, a torque converter, which may or may not have a stationary case, has a pump connected to the second output means, a stator grounded by an overrunning clutch to the case, and a turbine connected to an output member, and may be used in a starting phase. Alternatively, a fluid coupling or other type of hydrodynamic drive may be used. Second clutch means, when engaged, for connecting the output member to the output shaft in a low driving range. A variable-displacement hydraulic unit is mechanically connected to the input shaft, and a fixed-displacement hydraulic unit is mechanically connected to the reaction shaft. The hydraulic units are hydraulically connected together so that when one operates as a pump the other acts as a motor, and vice versa. Both clutch means are connected to the output shaft through a forward-reverse shift arrangement. It is possible to lock out the torque converter after the starting phase is over.

  19. Promising Electric Aircraft Drive Systems

    NASA Technical Reports Server (NTRS)

    Dudley, Michael R.

    2010-01-01

    An overview of electric aircraft propulsion technology performance thresholds for key power system components is presented. A weight comparison of electric drive systems with equivalent total delivered energy is made to help identify component performance requirements, and promising research and development opportunities.

  20. Torque-Splitting Gear Drive

    NASA Technical Reports Server (NTRS)

    Kish, J.

    1991-01-01

    Geared drive train transmits torque from input shaft in equal parts along two paths in parallel, then combines torques in single output shaft. Scheme reduces load on teeth of meshing gears while furnishing redundancy to protect against failures. Such splitting and recombination of torques common in design of turbine engines.

  1. Mechanical planetary compensating drive system

    NASA Technical Reports Server (NTRS)

    Zeiger, R. J.; Gerdts, J. C., Jr.

    1973-01-01

    Drive enables two concentric output shafts to be controlled independently or rotated as a unit. Possible uses are pointing and tracking devices, rotary camera shutters with variable light control, gimbal systems with yaw and pitch movement, spectrometer mirror scanning devices, etc.

  2. Anomalous-viscosity current drive

    DOEpatents

    Stix, T.H.; Ono, M.

    1986-04-25

    The present invention relates to a method and apparatus for maintaining a steady-state current for magnetically confining the plasma in a toroidal magnetic confinement device using anomalous viscosity current drive. A second aspect of this invention relates to an apparatus and method for the start-up of a magnetically confined toroidal plasma.

  3. Cannabis Effects on Driving Skills

    PubMed Central

    Hartman, Rebecca L.; Huestis, Marilyn A.

    2013-01-01

    BACKGROUND Cannabis is the most prevalent illicit drug identified in impaired drivers. The effects of cannabis on driving continue to be debated, making prosecution and legislation difficult. Historically, delays in sample collection, evaluating the inactive Δ9-tetrahydrocannabinol (THC) metabolite 11-nor-9-carboxy-THC, and polydrug use have complicated epidemiologic evaluations of driver impairment after cannabis use. CONTENT We review and evaluate the current literature on cannabis’ effects on driving, highlighting the epidemiologic and experimental data. Epidemiologic data show that the risk of involvement in a motor vehicle accident (MVA) increases approximately 2-fold after cannabis smoking. The adjusted risk of driver culpability also increases substantially, particularly with increased blood THC concentrations. Studies that have used urine as the biological matrix have not shown an association between cannabis and crash risk. Experimental data show that drivers attempt to compensate by driving more slowly after smoking cannabis, but control deteriorates with increasing task complexity. Cannabis smoking increases lane weaving and impaired cognitive function. Critical-tracking tests, reaction times, divided-attention tasks, and lane-position variability all show cannabis-induced impairment. Despite purported tolerance in frequent smokers, complex tasks still show impairment. Combining cannabis with alcohol enhances impairment, especially lane weaving. SUMMARY Differences in study designs frequently account for inconsistencies in results between studies. Participant-selection bias and confounding factors attenuate ostensible cannabis effects, but the association with MVA often retains significance. Evidence suggests recent smoking and/or blood THC concentrations 2–5 ng/mL are associated with substantial driving impairment, particularly in occasional smokers. Future cannabis-and-driving research should emphasize challenging tasks, such as divided attention

  4. Apoptosis in oral lichen planus.

    PubMed

    Neppelberg, E; Johannessen, A C; Jonsson, R

    2001-10-01

    Apoptotic cell death may be a contributory cause of basal cell destruction in oral lichen planus (OLP). Therefore. the purpose of this study was to investigate the rate of apoptosis in OLP and the expression of two proteins (FasR and FasL) regulating this process. Biopsies from 18 patients with histologically diagnosed OLP were investigated, with comparison to normal oral mucosa of healthy persons. For visualisation of DNA fragmentation, the TUNEL method was used. In order to characterise the infiltrating cell population (CD3. CD4, CD8) and expression of FasR and FasL, we used an immunohistochemical technique. The results showed that T cells dominated in the subepithelial cell infiltrate. Within the epithelium the apoptotic cells were confined to the basal cell layer, and more apoptotic cells were seen in areas with basal cell degeneration and atrophic epithelium. There was a prominent expression of FasR/FasL in OLP. with a rather uniform distribution throughout the inflammatory cell infiltrate. In the epithelium, the FasR/FasL expression was more abundant in the basal cell area compared to the suprabasal cell layer. In conclusion, apoptosis within the epithelium is significantly increased in situ in OLP compared to normal oral mucosa, and seems to be related to the epithelial thickness.

  5. Stability and skill in driving.

    PubMed

    Treffner, Paul; Barrett, Rod; Petersen, Andrew

    2002-12-01

    Two experiments addressed the relation between postural stability, perceptual sensitivity, and stability of driving performance. A vehicle was fitted with differential GPS for measuring position and speed, position sensors for measuring brake and accelerator depression, force transducers for measuring door, console and footrest bracing forces, and an accelerometer for measuring the 3D accelerations of the vehicle. In Experiment 1, we investigated whether the initiation of deceleration and the control of braking might be due to sensitivity to the perceptual variable tau, which specifies time-to-contact (TTC), and in particular, whether its first derivative, tau-dot, is used to maintain a constant deceleration profile. Using both untrained experienced drivers (EDs) and trained driving instructors from the Holden Performance Driving Centre (HPDC), results confirmed that, regardless of skill level, tau-dot was maintained at a value close to 0.5 and, as predicted by Lee [Perception 5 (1976) 437], braking was initiated when TTC approximately 5 s. In Experiment 2, we wished to quantify the purported differences in driving behaviour between EDs and HPDC instructors during a variety of everyday manoeuvres. Results indicated that instructors utilised a different cornering trajectory, a different emergency braking strategy, and were able to perform a high-speed swerve and recovery task more effectively than the EDs. In general, the instructors applied greater bracing forces using the door and console compared with EDs. The instructors also applied greater footrest forces during emergency braking than did the EDs. The greater use of bracing by instructor drivers to resist g-forces represents a strategy of active stabilisation that enhances both postural stability, as well as overall stability and consistency of driving performance. Results are discussed with regard to the dynamics of perceptual-motor coordination, and how increased stability might improve sensitivity to

  6. THE ROLE OF APOPTOSIS IN NEUROTOXICOLOGY.

    EPA Science Inventory

    The role of apoptosis in neurodegeneration in developing animals and in adults has become increasingly apparent in the past ten years. Normal apoptosis occurs in the CNS from the embryonic stage through senescence, with different cells in each region of the nervous system having ...

  7. Apoptosis in immune-mediated diseases

    PubMed Central

    Sankari, S. Leena; Babu, N. Aravindha; Rajesh, E.; Kasthuri, M.

    2015-01-01

    Apoptosis plays a significant role in both the physiological and pathological process. A dysfunctional apoptotic system can lead to either excessive removal or prolonged survival of cells. Therefore, dysregulation is involved in the pathogenesis of a variety of immunological diseases. The present review aims to provide an overview regarding role of apoptosis in immune-mediated disease. PMID:26015710

  8. Local anesthetics induce human renal cell apoptosis.

    PubMed

    Lee, H Thomas; Xu, Hua; Siegel, Cory D; Krichevsky, Igor E

    2003-01-01

    Renal cell apoptosis contributes significantly to the pathogenesis of acute renal failure. Local anesthetics induce apoptosis in neuronal and lymphocytic cell lines. We examined the effects of chronic (48 h) local anesthetic treatment (lidocaine, bupivacaine and tetracaine) on human proximal tubular (HK-2) cells. Apoptosis induction was assessed by detecting poly(ADP)-ribose polymerase fragmentation, caspase activation, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) staining, DNA laddering and by cellular morphology. Cell death was quantified by measuring neutral red dye uptake and lactate dehydrogenase released into the cell culture medium. All 3 local anesthetics caused concentration-dependent cell death, induced HK-2 cell apoptosis and potentiated TNF-alpha induced apoptosis. Local anesthetics induced HK-2 cell apoptosis by activation of caspases 3, 6, 7, 8 and 9. ZVAD-fmk, a pan-caspase inhibitor, blocked the local anesthetic induced HK-2 cell apoptosis. Local anesthetics also inhibited the activities of anti-apoptotic kinases protein kinase B (Akt) and extracellular signal regulated mitrogen-activated protein kinase. Local anesthetic's pro-apoptotic effects are independent of sodium channel inhibition as tetrodotoxin, a selective voltage-gated sodium channel blocker, failed to mimic local anesthetic-mediated induction or potentiation of HK-2 cell apoptosis. We conclude that local anesthetics induce human renal cell apoptotic signaling by caspase activation and via inhibition of pro-survival signaling pathways.

  9. Apoptosis in mammalian oocytes: a review.

    PubMed

    Tiwari, Meenakshi; Prasad, Shilpa; Tripathi, Anima; Pandey, Ashutosh N; Ali, Irfan; Singh, Arvind K; Shrivastav, Tulsidas G; Chaube, Shail K

    2015-08-01

    Apoptosis causes elimination of more than 99% of germ cells from cohort of ovary through follicular atresia. Less than 1% of germ cells, which are culminated in oocytes further undergo apoptosis during last phases of oogenesis and depletes ovarian reserve in most of the mammalian species including human. There are several players that induce apoptosis directly or indirectly in oocytes at various stages of meiotic cell cycle. Premature removal of encircling granulosa cells from immature oocytes, reduced levels of adenosine 3',5'-cyclic monophosphate and guanosine 3',5'-cyclic monophosphate, increased levels of calcium (Ca(2+)) and oxidants, sustained reduced level of maturation promoting factor, depletion of survival factors, nutrients and cell cycle proteins, reduced meiotic competency, increased levels of proapoptotic as well as apoptotic factors lead to oocyte apoptosis. The BH3-only proteins also act as key regulators of apoptosis in oocyte within the ovary. Both intrinsic (mitochondria-mediated) as well as extrinsic (cell surface death receptor-mediated) pathways are involved in oocyte apoptosis. BID, a BH3-only protein act as a bridge between both apoptotic pathways and its cleavage activates cell death machinery of both the pathways inside the follicular microenvironment. Oocyte apoptosis leads to the depletion of ovarian reserve that directly affects reproductive outcome of various mammals including human. In this review article, we highlight some of the important players and describe the pathways involved during oocyte apoptosis in mammals.

  10. Among High School Seniors, Driving After Marijuana Use Surpasses Drunk Driving

    MedlinePlus

    ... Drunk Driving Among High School Seniors, Driving After Marijuana Use Surpasses Drunk Driving Email Facebook Twitter July ... in a vehicle whose driver had been using marijuana or another illicit drug, or had drunk 5 ...

  11. Sensory drive in cichlid speciation.

    PubMed

    Maan, Martine E; Hofker, Kees D; van Alphen, Jacques J M; Seehausen, Ole

    2006-06-01

    The role of selection in speciation is a central yet poorly understood problem in evolutionary biology. The rapid radiations of extremely colorful cichlid fish in African lakes have fueled the hypothesis that sexual selection can drive species divergence without geographical isolation. Here we present experimental evidence for a mechanism by which sexual selection becomes divergent: in two sibling species from Lake Victoria, female mating preferences for red and blue male nuptial coloration coincide with their context-independent sensitivities to red and blue light, which in turn correspond to a difference in ambient light in the natural habitat of the species. These results suggest that natural selection on visual performance, favoring different visual properties in different spectral environments, may lead to divergent sexual selection on male nuptial coloration. This interplay of ecological and sexual selection along a light gradient may provide a mechanism of rapid speciation through divergent sensory drive.

  12. Cancer Therapy Due to Apoptosis: Galectin-9

    PubMed Central

    Fujita, Koji; Iwama, Hisakazu; Oura, Kyoko; Tadokoro, Tomoko; Samukawa, Eri; Sakamoto, Teppei; Nomura, Takako; Tani, Joji; Yoneyama, Hirohito; Morishita, Asahiro; Himoto, Takashi; Hirashima, Mitsuomi; Masaki, Tsutomu

    2017-01-01

    Dysregulation of apoptosis is a major hallmark in cancer biology that might equip tumors with a higher malignant potential and chemoresistance. The anti-cancer activities of lectin, defined as a carbohydrate-binding protein that is not an enzyme or antibody, have been investigated for over a century. Recently, galectin-9, which has two distinct carbohydrate recognition domains connected by a linker peptide, was noted to induce apoptosis in thymocytes and immune cells. The apoptosis of these cells contributes to the development and regulation of acquired immunity. Furthermore, human recombinant galectin-9, hG9NC (null), which lacks an entire region of the linker peptide, was designed to resist proteolysis. The hG9NC (null) has demonstrated anti-cancer activities, including inducing apoptosis in hematological, dermatological and gastrointestinal malignancies. In this review, the molecular characteristics, history and apoptosis-inducing potential of galectin-9 are described. PMID:28045432

  13. Electric Drive Study. Volume 1

    DTIC Science & Technology

    1987-12-21

    necessary and identify by block number) FIELD j GROUP SUB-GROUP IElectric Drives, Motors, Homopolar Motors, Induction Motof’s, I-u I ’Propulsion Systems...E-I APPENDIX F. VEHICLE AND PROPULSION SYSTEM SPECIFICATIONS ..... .F-I APPENDIX G. HOMOPOLAR MACHINE DESCRIPTION ..... ............ G-1 APPENDIX H...System (19.5 Ton) ............... .. 62 5-22. Homopolar (DC) System (19.5 Ton).... . .. . 64 5-23. HF Induction AC System (19.5 Ton) (Split Power’Pack

  14. Electric vehicle drive train components

    SciTech Connect

    Silver, F.

    1994-12-31

    Power Control Systems has developed a family of electric vehicle drive systems that range from 65 horsepower through 300 horse power. These propulsion systems support vehicle applications ranging from light cars and pickups to buses and trucks weighing as much as 40,000 lbs (18,400 kg). These robust systems are designed specifically for automotive applications including safety, electromagnetic emissions, and environment ruggedness. Dolphin Drive Systems are very flexible. Their inverter controllers are programmable and can be provided as stand alone components matched to customer specified motors. A selection of pre-calibrated systems including motor and inverter/controller can be provided. Accessory tools are also available for customer self programming. Dolphin Drive Systems provide precision control of AC induction motors providing excellent torque-speed performance usually eliminating the need for multistage transmissions. In addition, they are very efficient over a wide speed/torque range. This provides for excellent power management over a variety of continuous speed and stop and go applications.

  15. Autophagy and apoptosis: where do they meet?

    PubMed

    Mukhopadhyay, Subhadip; Panda, Prashanta Kumar; Sinha, Niharika; Das, Durgesh Nandini; Bhutia, Sujit Kumar

    2014-04-01

    Autophagy and apoptosis are two important cellular processes with complex and intersecting protein networks; as such, they have been the subjects of intense investigation. Recent advances have elucidated the key players and their molecular circuitry. For instance, the discovery of Beclin-1's interacting partners has resulted in the identification of Bcl-2 as a central regulator of autophagy and apoptosis, which functions by interacting with both Beclin-1 and Bax/Bak respectively. When localized to the endoplasmic reticulum and mitochondria, Bcl-2 inhibits autophagy. Cellular stress causes the displacement of Bcl-2 from Beclin-1 and Bax, thereby triggering autophagy and apoptosis, respectively. The induction of autophagy or apoptosis results in disruption of complexes by BH3-only proteins and through post-translational modification. The mechanisms linking autophagy and apoptosis are not fully defined; however, recent discoveries have revealed that several apoptotic proteins (e.g., PUMA, Noxa, Nix, Bax, XIAP, and Bim) modulate autophagy. Moreover, autophagic proteins that control nucleation and elongation regulate intrinsic apoptosis through calpain- and caspase-mediated cleavage of autophagy-related proteins, which switches the cellular program from autophagy to apoptosis. Similarly, several autophagic proteins are implicated in extrinsic apoptosis. This highlights a dual cellular role for autophagy. On one hand, autophagy degrades damaged mitochondria and caspases, and on the other hand, it provides a membrane-based intracellular platform for caspase processing in the regulation of apoptosis. In this review, we highlight the crucial factors governing the crosstalk between autophagy and apoptosis and describe the mechanisms controlling cell survival and cell death.

  16. 30 CFR 77.406 - Drive belts.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Mechanical Equipment § 77.406 Drive belts. (a) Drive belts shall not be shifted while in motion unless the machines are provided with mechanical shifters. (b) Belt dressing shall not be applied while belts are...

  17. 30 CFR 77.406 - Drive belts.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Mechanical Equipment § 77.406 Drive belts. (a) Drive belts shall not be shifted while in motion unless the machines are provided with mechanical shifters. (b) Belt dressing shall not be applied while belts are...

  18. Preliminary screening of differentially expressed genes involved in methyl-CpG-binding protein 2 gene-mediated proliferation in human osteosarcoma cells.

    PubMed

    Meng, Gang; Li, Yi; Lv, YangFan; Dai, Huanzi; Zhang, Xi; Guo, Qiao-Nan

    2015-04-01

    Methyl-CpG-binding protein 2 (MeCP2) is essential in human brain development and has been linked to several cancer types and neuro-developmental disorders. This study aims to screen the MeCP2 related differentially expressed genes and discover the therapeutic targets for osteosarcoma. CCK8 assay was used to detect the proliferation and SaOS2 and U2OS cells. Apoptosis of cells was detected by flow cytometry analysis that monitored Annexin V-APC/7-DD binding and 7-ADD uptake simultaneously. Denaturing formaldehyde agarose gel electrophoresis was employed to examine the quality of total RNA 18S and 28S units. Gene chip technique was utilized to discover the differentially expressed genes correlated with MeCP2 gene. Differential gene screening criteria were used to screen the changed genes. The gene up-regulation or down-regulation more than 1.5 times was regarded as significant differential expression genes. The CCK8 results indicated that the cell proliferation of MeCP2 silencing cells (LV-MeCP2-RNAi) was significantly decreased compared to non-silenced cells (LV-MeCP2-RNAi-CN) (P < 0.05). MeCP2 silencing could also induce significant apoptosis compared to non-silenced cells (P < 0.05); 107 expression changed genes were screened from a total of 49,395 transcripts. Among the total 107 transcripts, 34 transcripts were up-regulated and 73 transcripts were down-regulated. There were five significant differentially expressed genes, including IGFBP4, HOXC8, LMO4, MDK, and CTGF, which correlated with the MeCP2 gene. The methylation frequency of CpG in IGFBP4 gene could achieve 55%. In conclusion, the differentially expressed IGFBP4, HOXC8, LMO4, MDK, and CTGF genes may be involved in MeCP2 gene-mediated proliferation and apoptosis in osteosarcoma cells.

  19. Semaphorins as mediators of neuronal apoptosis.

    PubMed

    Shirvan, A; Ziv, I; Fleminger, G; Shina, R; He, Z; Brudo, I; Melamed, E; Barzilai, A

    1999-09-01

    Shrinkage and collapse of the neuritic network are often observed during the process of neuronal apoptosis. However, the molecular and biochemical basis for the axonal damage associated with neuronal cell death is still unclear. We present evidence for the involvement of axon guidance molecules with repulsive cues in neuronal cell death. Using the differential display approach, an up-regulation of collapsin response mediator protein was detected in sympathetic neurons undergoing dopamine-induced apoptosis. A synchronized induction of mRNA of the secreted collapsin-1 and the intracellular collapsin response mediator protein that preceded commitment of neurons to apoptosis was detected. Antibodies directed against a conserved collapsin-derived peptide provided marked and prolonged protection of several neuronal cell types from dopamine-induced apoptosis. Moreover, neuronal apoptosis was inhibited by antibodies against neuropilin-1, a putative component of the semaphorin III/collapsin-1 receptor. Induction of neuronal apoptosis was also caused by exposure of neurons to semaphorin III-alkaline phosphatase secreted from 293EBNA cells. Anti-collapsin-1 antibodies were effective in blocking the semaphorin III-induced death process. We therefore suggest that, before their death, apoptosis-destined neurons may produce and secrete destructive axon guidance molecules that can affect their neighboring cells and thus transfer a "death signal" across specific and susceptible neuronal populations.

  20. Phytosphingosine induced mitochondria-involved apoptosis.

    PubMed

    Nagahara, Yukitoshi; Shinomiya, Takahisa; Kuroda, Sachiko; Kaneko, Naoki; Nishio, Reiji; Ikekita, Masahiko

    2005-02-01

    Sphingolipids are putative intracellular signal mediators in cell differentiation, growth inhibition, and apoptosis. Sphingosine, sphinganine, and phytosphingosine are structural analogs of sphingolipids and are classified as long-chain sphingoid bases. Sphingosine and sphinganine are known to play important roles in apoptosis. In the present study, we examined the phytosphingosine-induced apoptosis mechanism, focusing on mitochondria in human T-cell lymphoma Jurkat cells. Phytosphingosine significantly induced chromatin DNA fragmentation, which is a hallmark of apoptosis. Enzymatic activity measurements of caspases revealed that caspase-3 and caspase-9 are activated in phytosphingosine-induced apoptosis, but there is little activation of caspase-8 suggesting that phytosphingosine influences mitochondrial functions. In agreement with this hypothesis, a decrease in DeltaPsi(m) and the release of cytochrome c to the cytosol were observed upon phytosphingosine treatment. Furthermore, overexpression of mitochondria-localized anti-apoptotic protein Bcl-2 prevented phytosphingosine apoptotic stimuli. Western blot assays revealed that phytosphingosine decreases phosphorylated Akt and p70S6k. Dephosphorylation of Akt was partially inhibited by protein phosphatase inhibitor OA and OA attenuated phytosphingosine-induced apoptosis. Moreover, using a cell-free system, phytosphingosine directly reduced DeltaPsi(m). These results indicate that phytosphingosine perturbs mitochondria both directly and indirectly to induce apoptosis.

  1. 30 CFR 75.1727 - Drive belts.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Drive belts. 75.1727 Section 75.1727 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR COAL MINE SAFETY AND HEALTH MANDATORY SAFETY STANDARDS-UNDERGROUND COAL MINES Miscellaneous § 75.1727 Drive belts. (a) Drive belts shall not...

  2. 25 CFR 11.445 - Driving violations.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 25 Indians 1 2014-04-01 2014-04-01 false Driving violations. 11.445 Section 11.445 Indians BUREAU... ORDER CODE Criminal Offenses § 11.445 Driving violations. (a) A person who shall operate any vehicle in a manner dangerous to the public safety is guilty of reckless driving, a petty misdemeanor,...

  3. 25 CFR 11.445 - Driving violations.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 25 Indians 1 2012-04-01 2011-04-01 true Driving violations. 11.445 Section 11.445 Indians BUREAU... ORDER CODE Criminal Offenses § 11.445 Driving violations. (a) A person who shall operate any vehicle in a manner dangerous to the public safety is guilty of reckless driving, a petty misdemeanor,...

  4. 30 CFR 75.1727 - Drive belts.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Drive belts. 75.1727 Section 75.1727 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR COAL MINE SAFETY AND HEALTH MANDATORY SAFETY STANDARDS-UNDERGROUND COAL MINES Miscellaneous § 75.1727 Drive belts. (a) Drive belts shall not...

  5. 30 CFR 75.1727 - Drive belts.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Drive belts. 75.1727 Section 75.1727 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR COAL MINE SAFETY AND HEALTH MANDATORY SAFETY STANDARDS-UNDERGROUND COAL MINES Miscellaneous § 75.1727 Drive belts. (a) Drive belts shall not...

  6. 30 CFR 77.406 - Drive belts.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Drive belts. 77.406 Section 77.406 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR COAL MINE SAFETY AND HEALTH MANDATORY... Mechanical Equipment § 77.406 Drive belts. (a) Drive belts shall not be shifted while in motion unless...

  7. 30 CFR 77.406 - Drive belts.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Drive belts. 77.406 Section 77.406 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR COAL MINE SAFETY AND HEALTH MANDATORY... Mechanical Equipment § 77.406 Drive belts. (a) Drive belts shall not be shifted while in motion unless...

  8. 30 CFR 77.406 - Drive belts.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Drive belts. 77.406 Section 77.406 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR COAL MINE SAFETY AND HEALTH MANDATORY... Mechanical Equipment § 77.406 Drive belts. (a) Drive belts shall not be shifted while in motion unless...

  9. 25 CFR 11.445 - Driving violations.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 25 Indians 1 2011-04-01 2011-04-01 false Driving violations. 11.445 Section 11.445 Indians BUREAU... ORDER CODE Criminal Offenses § 11.445 Driving violations. (a) A person who shall operate any vehicle in a manner dangerous to the public safety is guilty of reckless driving, a petty misdemeanor,...

  10. 30 CFR 75.1727 - Drive belts.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Drive belts. 75.1727 Section 75.1727 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR COAL MINE SAFETY AND HEALTH MANDATORY SAFETY STANDARDS-UNDERGROUND COAL MINES Miscellaneous § 75.1727 Drive belts. (a) Drive belts shall not...

  11. 25 CFR 11.445 - Driving violations.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 25 Indians 1 2013-04-01 2013-04-01 false Driving violations. 11.445 Section 11.445 Indians BUREAU... ORDER CODE Criminal Offenses § 11.445 Driving violations. (a) A person who shall operate any vehicle in a manner dangerous to the public safety is guilty of reckless driving, a petty misdemeanor,...

  12. 25 CFR 11.445 - Driving violations.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 25 Indians 1 2010-04-01 2010-04-01 false Driving violations. 11.445 Section 11.445 Indians BUREAU... ORDER CODE Criminal Offenses § 11.445 Driving violations. (a) A person who shall operate any vehicle in a manner dangerous to the public safety is guilty of reckless driving, a petty misdemeanor,...

  13. 30 CFR 75.1727 - Drive belts.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Drive belts. 75.1727 Section 75.1727 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR COAL MINE SAFETY AND HEALTH MANDATORY SAFETY STANDARDS-UNDERGROUND COAL MINES Miscellaneous § 75.1727 Drive belts. (a) Drive belts shall not...

  14. Driving When You Have Parkinson's Disease

    MedlinePlus

    Driving When You Have Parkinson’s Disease DRIVEWELL You have been a safe driver for years. For you, driving means freedom and control. As you get older, ... it can interfere with your daily activities, including driving safely. Early symptoms vary from person to person, ...

  15. Measuring the Propensity to Drink and Drive

    ERIC Educational Resources Information Center

    Bertelli, Anthony M.; Richardson, Lilliard E., Jr.

    2007-01-01

    Laws such as 0.08 blood alcohol content, open container, and license revocation provide a policy framework for reducing drinking and driving. Drinking and driving behavior is difficult to assess; unlike property and violent crimes, where incidence statistics can approximate behavior, most drink-driving trips go undetected. The authors develop a…

  16. Metadherin facilitates podocyte apoptosis in diabetic nephropathy

    PubMed Central

    Liu, Wen-Ting; Peng, Fen-Fen; Li, Hong-Yu; Chen, Xiao-Wen; Gong, Wang-Qiu; Chen, Wen-Jing; Chen, Yi-Hua; Li, Pei-Lin; Li, Shu-Ting; Xu, Zhao-Zhong; Long, Hai-Bo

    2016-01-01

    Apoptosis, one of the major causes of podocyte loss, has been reported to have a vital role in diabetic nephropathy (DN) pathogenesis, and understanding the mechanisms underlying the regulation of podocyte apoptosis is crucial. Metadherin (MTDH) is an important oncogene, which is overexpressed in most cancers and responsible for apoptosis, metastasis, and poor patient survival. Here we show that the expression levels of Mtdh and phosphorylated p38 mitogen-activated protein kinase (MAPK) are significantly increased, whereas those of the microRNA-30 family members (miR-30s) are considerably reduced in the glomeruli of DN rat model and in high glucose (HG)-induced conditionally immortalized mouse podocytes (MPC5). These levels are positively correlated with podocyte apoptosis rate. The inhibition of Mtdh expression, using small interfering RNA, but not Mtdh overexpression, was shown to inhibit HG-induced MPC5 apoptosis and p38 MAPK pathway, and Bax and cleaved caspase 3 expression. This was shown to be similar to the effects of p38 MAPK inhibitor (SB203580). Furthermore, luciferase assay results demonstrated that Mtdh represents the target of miR-30s. Transient transfection experiments, using miR-30 microRNA (miRNA) inhibitors, led to the increase in Mtdh expression and induced the apoptosis of MPC5, whereas the treatment with miR-30 miRNA mimics led to the reduction in Mtdh expression and apoptosis of HG-induced MPC5 cells in comparison with their respective controls. Our results demonstrate that Mtdh is a potent modulator of podocyte apoptosis, and that it represents the target of miR-30 miRNAs, facilitating podocyte apoptosis through the activation of HG-induced p38 MAPK-dependent pathway. PMID:27882943

  17. [Endothelial cell apoptosis in erectile dysfunction].

    PubMed

    Jiang, Rui

    2012-10-01

    Erectile dysfunction (ED) is one of the most common male diseases, which seriously affects the patient's quality of life. The risk factors of ED include aging, diabetes, hypertension, hyperlipidemia, and unhealthy lifestyle, and its exact mechanism remains unclear. The apoptosis of endothelial cells in the corpus cavernosum penis may reduce NOS activity, block NO synthesis, and affect penile erection, and the mechanisms of their apoptosis vary with different causes of ED. This article updates the relationship between the apoptosis of endothelial cells and the development of ED.

  18. The Role of Mitochondria in Apoptosis*

    PubMed Central

    Wang, Chunxin; Youle, Richard J.

    2016-01-01

    Mitochondria play key roles in activating apoptosis in mammalian cells. Bcl-2 family members regulate the release of proteins from the space between the mitochondrial inner and outer membrane that, once in the cytosol, activate caspase proteases that dismantle cells and signal efficient phagocytosis of cell corpses. Here we review the extensive literature on proteins released from the intermembrane space and consider genetic evidence for and against their roles in apoptosis activation. We also compare and contrast apoptosis pathways in Caenorhabditis elegans, Drosophila melanogaster, and mammals that indicate major mysteries remaining to be solved. PMID:19659442

  19. Expression, purification, crystallization and preliminary X-ray crystallographic analysis of human histidine triad nucleotide-binding protein 2 (hHINT2)

    PubMed Central

    Dolot, Rafał; Włodarczyk, Artur; Bujacz, Grzegorz D.; Nawrot, Barbara

    2013-01-01

    Histidine triad nucleotide-binding protein 2 (HINT2) is a mitochondrial adenosine phosphoramidase mainly expressed in the pancreas, liver and adrenal gland. HINT2 possibly plays a role in apoptosis, as well as being involved in steroid biosynthesis, hepatic lipid metabolism and regulation of hepatic mitochondria function. The expression level of HINT2 is significantly down-regulated in hepatocellular carcinoma patients. To date, endogenous substrates for this enzyme, as well as the three-dimensional structure of human HINT2, are unknown. In this study, human HINT2 was cloned, overexpressed in Escherichia coli and purified. Crystallization was performed at 278 K using PEG 4000 as the main precipitant; the crystals, which belonged to the tetragonal space group P41212 with unit-cell parameters a = b = 76.38, c = 133.25 Å, diffracted to 2.83 Å resolution. Assuming two molecules in the asymmetric unit, the Matthews coefficient and the solvent content were calculated to be 2.63 Å3 Da−1 and 53.27%, respectively. PMID:23832208

  20. Expression, purification, crystallization and preliminary X-ray crystallographic analysis of human histidine triad nucleotide-binding protein 2 (hHINT2).

    PubMed

    Dolot, Rafał; Włodarczyk, Artur; Bujacz, Grzegorz D; Nawrot, Barbara

    2013-07-01

    Histidine triad nucleotide-binding protein 2 (HINT2) is a mitochondrial adenosine phosphoramidase mainly expressed in the pancreas, liver and adrenal gland. HINT2 possibly plays a role in apoptosis, as well as being involved in steroid biosynthesis, hepatic lipid metabolism and regulation of hepatic mitochondria function. The expression level of HINT2 is significantly down-regulated in hepatocellular carcinoma patients. To date, endogenous substrates for this enzyme, as well as the three-dimensional structure of human HINT2, are unknown. In this study, human HINT2 was cloned, overexpressed in Escherichia coli and purified. Crystallization was performed at 278 K using PEG 4000 as the main precipitant; the crystals, which belonged to the tetragonal space group P41212 with unit-cell parameters a = b = 76.38, c = 133.25 Å, diffracted to 2.83 Å resolution. Assuming two molecules in the asymmetric unit, the Matthews coefficient and the solvent content were calculated to be 2.63 Å(3) Da(-1) and 53.27%, respectively.

  1. Inactivation of bone morphogenetic protein 2 may predict clinical outcome and poor overall survival for renal cell carcinoma through epigenetic pathways.

    PubMed

    Mitsui, Yozo; Hirata, Hiroshi; Arichi, Naoko; Hiraki, Miho; Yasumoto, Hiroaki; Chang, Inik; Fukuhara, Shinichiro; Yamamura, Soichiro; Shahryari, Varahram; Deng, Guoren; Saini, Sharanjot; Majid, Shahana; Dahiya, Rajvir; Tanaka, Yuichiro; Shiina, Hiroaki

    2015-04-20

    We investigated whether impaired regulation of bone morphogenetic protein-2 (BMP-2) via epigenetic pathways is associated with renal cell carcinoma (RCC) pathogenesis. Expression and CpG methylation of the BMP-2 gene were analyzed using RCC cell lines, and 96 matched RCC and normal renal tissues. We also performed functional analysis using BMP-2 restored RCC cells. A significant association of BMP-2 mRNA expression was also found with advanced tumor stage and lymph node involvement, while lower BMP-2 mRNA expression was significantly associated with poor overall survival after radical nephrectomy. In RCC cells, BMP-2 restoration significantly inhibited cell proliferation, migration, invasion, and colony formation. In addition, BMP-2 overexpression induced p21(WAF1/CIP1) and p27(KIP1) expression, and cellular apoptosis in RCC cells. BMP-2 mRNA expression was significantly enhanced in RCC cells by 5-aza-2'-deoxycitidine treatment. The prevalence of BMP-2 promoter methylation was significantly greater and BMP-2 mRNA expression was significantly lower in RCC samples as compared to normal kidney samples. Furthermore, a significant correlation was found between BMP-2 promoter methylation and mRNA transcription in tumors. Aberrant BMP-2 methylation and the resultant loss of BMP-2 expression may be a useful molecular marker for designing improved diagnostic and therapeutic strategies for RCC.

  2. Inactivation of bone morphogenetic protein 2 may predict clinical outcome and poor overall survival for renal cell carcinoma through epigenetic pathways

    PubMed Central

    Mitsui, Yozo; Hirata, Hiroshi; Arichi, Naoko; Hiraki, Miho; Yasumoto, Hiroaki; Chang, Inik; Fukuhara, Shinichiro; Yamamura, Soichiro; Shahryari, Varahram; Deng, Guoren; Saini, Sharanjot; Majid, Shahana; Dahiya, Rajvir; Tanaka, Yuichiro; Shiina, Hiroaki

    2015-01-01

    We investigated whether impaired regulation of bone morphogenetic protein-2 (BMP-2) via epigenetic pathways is associated with renal cell carcinoma (RCC) pathogenesis. Expression and CpG methylation of the BMP-2 gene were analyzed using RCC cell lines, and 96 matched RCC and normal renal tissues. We also performed functional analysis using BMP-2 restored RCC cells. A significant association of BMP-2 mRNA expression was also found with advanced tumor stage and lymph node involvement, while lower BMP-2 mRNA expression was significantly associated with poor overall survival after radical nephrectomy. In RCC cells, BMP-2 restoration significantly inhibited cell proliferation, migration, invasion, and colony formation. In addition, BMP-2 overexpression induced p21WAF1/CIP1 and p27KIP1 expression, and cellular apoptosis in RCC cells. BMP-2 mRNA expression was significantly enhanced in RCC cells by 5-aza-2′-deoxycitidine treatment. The prevalence of BMP-2 promoter methylation was significantly greater and BMP-2 mRNA expression was significantly lower in RCC samples as compared to normal kidney samples. Furthermore, a significant correlation was found between BMP-2 promoter methylation and mRNA transcription in tumors. Aberrant BMP-2 methylation and the resultant loss of BMP-2 expression may be a useful molecular marker for designing improved diagnostic and therapeutic strategies for RCC. PMID:25797254

  3. DISCO interacting protein 2 determines direction of axon projection under the regulation of c-Jun N-terminal kinase in the Drosophila mushroom body.

    PubMed

    Nitta, Yohei; Sugie, Atsushi

    2017-04-07

    Precisely controlled axon guidance for complex neuronal wiring is essential for appropriate neuronal function. c-Jun N-terminal kinase (JNK) was found to play a role in axon guidance recently as well as in cell proliferation, protection and apoptosis. In spite of many genetic and molecular studies on these biological processes regulated by JNK, how JNK regulates axon guidance accurately has not been fully explained thus far. To address this question, we use the Drosophila mushroom body (MB) as a model since the α/β axons project in two distinct directions. Here we show that DISCO interacting protein 2 (DIP2) is required for the accurate direction of axonal guidance. DIP2 expression is under the regulation of Basket (Bsk), the Drosophila homologue of JNK. We additionally found that the Bsk/DIP2 pathway is independent from the AP-1 transcriptional factor complex pathway, which is directly activated by Bsk. In conclusion, our findings revealed DIP2 as a novel effector downstream of Bsk modulating the direction of axon projection.

  4. Fluid cooled vehicle drive module

    DOEpatents

    Beihoff, Bruce C.; Radosevich, Lawrence D.; Meyer, Andreas A.; Gollhardt, Neil; Kannenberg, Daniel G.

    2005-11-15

    An electric vehicle drive includes a support may receive one or more power electronic circuits. The support may aid in removing heat from the circuits through fluid circulating through the support. The support, in conjunction with other packaging features may form a shield from both external EM/RFI and from interference generated by operation of the power electronic circuits. Features may be provided to permit and enhance connection of the circuitry to external circuitry, such as improved terminal configurations. Modular units may be assembled that may be coupled to electronic circuitry via plug-in arrangements or through interface with a backplane or similar mounting and interconnecting structures.

  5. Driving trajectories in chaotic scattering.

    PubMed

    Macau, Elbert E N; Caldas, Iberê L

    2002-02-01

    In this work we introduce a general approach for targeting in chaotic scattering that can be used to find a transfer trajectory between any two points located inside the scattering region. We show that this method can be used in association with a control of chaos strategy to drive around and keep a particle inside the scattering region. As an illustration of how powerful this approach is, we use it in a case of practical interest in celestial mechanics in which it is desired to control the evolution of two satellites that evolve around a large central body.

  6. Computer-Aided Remote Driving

    NASA Technical Reports Server (NTRS)

    Wilcox, Brian H.

    1994-01-01

    System for remote control of robotic land vehicle requires only small radio-communication bandwidth. Twin video cameras on vehicle create stereoscopic images. Operator views cross-polarized images on two cathode-ray tubes through correspondingly polarized spectacles. By use of cursor on frozen image, remote operator designates path. Vehicle proceeds to follow path, by use of limited degree of autonomous control to cope with unexpected conditions. System concept, called "computer-aided remote driving" (CARD), potentially useful in exploration of other planets, military surveillance, firefighting, and clean-up of hazardous materials.

  7. Efficient alternatives for electric drives

    SciTech Connect

    Comnes, G.A.; Barnes, R.W.

    1987-11-01

    This analysis of industrial electric motors describes the current motor stock, its energy use and operating characteristics, and innovations that could change current use patterns. It provides calculations characterizing the economic attractiveness of several existing and potential options. One attractive option given particular attention is the adjustable-speed drive which can replace throttles or valves for many pumping operations. A major conclusion is that, throughout industry, options that are both energy-saving and economically attractive appear to penetrate markets more slowly than would be socially optimal. The final section examines characteristics of industry that may contribute to slow market penetration. 29 refs., 14 figs., 14 tabs.

  8. cAMP prevents TNF-induced apoptosis through inhibiting DISC complex formation in rat hepatocytes

    SciTech Connect

    Bhattacharjee, Rajesh; Xiang, Wenpei; Wang, Yinna; Zhang, Xiaoying

    2012-06-22

    Highlights: Black-Right-Pointing-Pointer cAMP blocks cell death induced by TNF and actinomycin D in cultured hepatocytes. Black-Right-Pointing-Pointer cAMP blocks NF-{kappa}B activation induced by TNF and actinomycin D. Black-Right-Pointing-Pointer cAMP blocks DISC formation following TNF and actinomycin D exposure. Black-Right-Pointing-Pointer cAMP blocks TNF signaling at a proximal step. -- Abstract: Tumor necrosis factor {alpha} (TNF) is a pleiotropic proinflammatory cytokine that plays a role in immunity and the control of cell proliferation, cell differentiation, and apoptosis. The pleiotropic nature of TNF is due to the formation of different signaling complexes upon the binding of TNF to its receptor, TNF receptor type 1 (TNFR1). TNF induces apoptosis in various mammalian cells when the cells are co-treated with a transcription inhibitor like actinomycin D (ActD). When TNFR1 is activated, it recruits an adaptor protein, TNF receptor-associated protein with death domain (TRADD), through its cytoplasmic death effector domain (DED). TRADD, in turn, recruits other signaling proteins, including TNF receptor-associated protein 2 (TRAF2) and receptor-associated protein kinase (RIPK) 1, to form a complex. Subsequently, this complex combines with FADD and procaspase-8, converts into a death-inducing signaling complex (DISC) to induce apoptosis. Cyclic AMP (cAMP) is a second messenger that regulates various cellular processes such as cell proliferation, gene expression, and apoptosis. cAMP analogues are reported to act as anti-apoptotic agents in various cell types, including hepatocytes. We found that a cAMP analogue, dibutyryl cAMP (db-cAMP), inhibits TNF + ActD-induced apoptosis in rat hepatocytes. The protein kinase A (PKA) inhibitor KT-5720 reverses this inhibitory effect of cAMP on apoptosis. Cytoprotection by cAMP involves down-regulation of various apoptotic signal regulators like TRADD and FADD and inhibition of caspase-8 and caspase-3 cleavage. We also found

  9. Engine starter and accessory drive system

    SciTech Connect

    Stockton, T.R.

    1986-10-07

    An engine starter and accessory drive system is described which consists of: an accessory drive means; a planetary gearset having a sun gear driveably connected to the accessory drive means, a ring gear, a carrier and planet pinions rotatably mounted on the carrier, fixed to the engine crankshaft, meshing with the sun gear and with the ring gear; means for holding the ring gear against rotation; and a starter motor and first clutch means for providing a one-way driving connection between the motor and the accessory drive means.

  10. Voight variable speed drive. [for windpowered generator

    NASA Technical Reports Server (NTRS)

    Tompkin, J.

    1973-01-01

    The variable speed drive transmission is mounted within the gondola and connected with the wind turbine blades and the hub. This unit is designed for the production of ac power. The turbine turns by means of the variable speed drive and a set of synchronous three phase generators. This motion is controlled automatically by two wind rosettes in such a way that the wind turbine always opposes the wind direction. The Voight variable speed drive is a mechanical variable positive drive gear transmission. It has an unlimited power and torque transmission, a constant ratio with high degree of accuracy, a speed variation over a wide range, and a nonslip drive.

  11. 32 CFR 634.14 - Restoration of driving privileges upon acquittal of intoxicated driving.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 4 2014-07-01 2013-07-01 true Restoration of driving privileges upon acquittal of intoxicated driving. 634.14 Section 634.14 National Defense Department of Defense (Continued... SUPERVISION Driving Privileges § 634.14 Restoration of driving privileges upon acquittal of...

  12. 32 CFR 634.14 - Restoration of driving privileges upon acquittal of intoxicated driving.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 4 2012-07-01 2011-07-01 true Restoration of driving privileges upon acquittal of intoxicated driving. 634.14 Section 634.14 National Defense Department of Defense (Continued... SUPERVISION Driving Privileges § 634.14 Restoration of driving privileges upon acquittal of...

  13. 32 CFR 634.14 - Restoration of driving privileges upon acquittal of intoxicated driving.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 4 2013-07-01 2013-07-01 false Restoration of driving privileges upon acquittal of intoxicated driving. 634.14 Section 634.14 National Defense Department of Defense (Continued... SUPERVISION Driving Privileges § 634.14 Restoration of driving privileges upon acquittal of...

  14. 32 CFR 634.14 - Restoration of driving privileges upon acquittal of intoxicated driving.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 4 2010-07-01 2010-07-01 true Restoration of driving privileges upon acquittal of intoxicated driving. 634.14 Section 634.14 National Defense Department of Defense (Continued... SUPERVISION Driving Privileges § 634.14 Restoration of driving privileges upon acquittal of...

  15. 32 CFR 634.14 - Restoration of driving privileges upon acquittal of intoxicated driving.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 4 2011-07-01 2011-07-01 false Restoration of driving privileges upon acquittal of intoxicated driving. 634.14 Section 634.14 National Defense Department of Defense (Continued... SUPERVISION Driving Privileges § 634.14 Restoration of driving privileges upon acquittal of...

  16. IGF-binding protein 2 is a candidate target of therapeutic potential in cancer.

    PubMed

    Yao, Xiaofeng; Sun, Shanshan; Zhou, Xuan; Guo, Wenyu; Zhang, Lun

    2016-02-01

    Insulin-like growth factor (IGF)-binding protein 2(IGFBP2), a key member of IGF family, has been reported as a notable oncogene in most human epithelium cancers. Increasing evidences suggested that IGFBP2 might be a candidate target of therapuetic potential by regulating key cancer metastasis and invasion-associated signaling networks, but there is still confusion about the mechanism on how IGFBP2 takes part in these processes. In this review, we summarized the current points of view that IGFBP2 functions in signaling pathways during tumorigenesis and tumor progression and discussed its potential clinical applications as a therapeutic target.

  17. Crystal structure of the TLDc domain of oxidation resistance protein 2 from zebrafish.

    PubMed

    Blaise, Mickaël; Alsarraf, Husam M A B; Wong, Jaslyn E M M; Midtgaard, Søren Roi; Laroche, Fabrice; Schack, Lotte; Spaink, Herman; Stougaard, Jens; Thirup, Søren

    2012-06-01

    The oxidation resistance proteins (OXR) help to protect eukaryotes from reactive oxygen species. The sole C-terminal domain of the OXR, named TLDc is sufficient to perform this function. However, the mechanism by which oxidation resistance occurs is poorly understood. We present here the crystal structure of the TLDc domain of the oxidation resistance protein 2 from zebrafish. The structure was determined by X-ray crystallography to atomic resolution (0.97Å) and adopts an overall globular shape. Two antiparallel β-sheets form a central β-sandwich, surrounded by two helices and two one-turn helices. The fold shares low structural similarity to known structures.

  18. Improving time to optimal Staphylococcus aureus treatment using a penicillin-binding protein 2a assay.

    PubMed

    Rao, Sonia N; Wang, Sheila K; Gonzalez Zamora, Jose; Hanson, Amy P; Polisetty, Radhika S; Singh, Kamaljit

    2016-12-01

    The penicillin-binding protein 2a (PBP2a) assay is a quick, accurate and inexpensive test for determining methicillin susceptibility in Staphylococcus aureus. A pre-post-study design was conducted using a PBP2a assay with and without the impact of an antimicrobial stewardship intervention to improve time to optimal therapy for methicillin-susceptible and methicillin-resistant S. aureus isolates. Our results demonstrate significantly improved time to optimal therapy and support the use of a PBP2a assay as part of an programme for all healthcare facilities, especially those with limited resources.

  19. Myocardial apoptosis in heart disease: does the emperor have clothes?

    PubMed

    Jose Corbalan, J; Vatner, Dorothy E; Vatner, Stephen F

    2016-05-01

    Since the discovery of a novel mechanism of cell death that differs from traditional necrosis, i.e., apoptosis, there have been numerous studies concluding that increased apoptosis augments myocardial infarction and heart failure and that limiting apoptosis protects the heart. Importantly, the vast majority of cells in the heart are non-myocytes with only roughly 30 % myocytes, yet almost the entire field studying apoptosis in the heart has disregarded non-myocyte apoptosis, e.g., only 4.7 % of 423 studies on myocardial apoptosis in the past 3 years quantified non-myocyte apoptosis. Accordingly, we reviewed the history of apoptosis in the heart focusing first on myocyte apoptosis, followed by the history of non-myocyte apoptosis in myocardial infarction and heart failure. Apoptosis of several of the major non-myocyte cell types in the heart (cardiac fibroblasts, endothelial cells, vascular smooth muscle cells, macrophages and leukocytes) may actually be responsible for affecting the severity of myocardial infarction and heart failure. In summary, even though it is now known that the majority of apoptosis in the heart occurs in non-myocytes, very little work has been done to elucidate the mechanisms by which non-myocyte apoptosis might be responsible for the adverse effects of apoptosis in myocardial infarction and heart failure. The goal of this review is to provide an impetus for future work in this field on non-myocyte apoptosis that will be required for a better understanding of the role of apoptosis in the heart.

  20. Asymmetric relationship between driving and safety skills.

    PubMed

    Sümer, Nebi; Ozkan, Türker; Lajunen, Timo

    2006-07-01

    We hypothesized that the combination of self reported high ratings of driving skills and low ratings of safety skills creates a serious risk for road accident involvement. This study was aimed at investigating the asymmetric interplay between driving and safety skills among Turkish drivers (N=785) using the Driving Skills Inventory [Lajunen, T., Summala, H., 1995. Driver experience, personality, and skill and safety motive dimensions in drivers' self-assessments. Pers. Indiv. Differ. 19, 307-318]. The assumed asymmetric interactions were tested on a number of outcome variables representing risky driving using moderated regression analyses. The results revealed that driving skills moderated the effects of safety skills on six out of the eight outcome variables including the number of accidents, tickets, overtaking tendencies, speed on motorways, and aggressive driving style. Results suggested that high levels of safety skills buffer the negative effect of overconfidence resulting from exaggerated ratings of self-reported driving skills.

  1. Driving Extreme Efficiency to Market

    NASA Astrophysics Data System (ADS)

    Garbesi, Karina

    2014-03-01

    The rapid development of extremely energy efficient appliances and equipment is essential to curtail catastrophic climate disruption. This will require the on-going development of products that apply all best-practices and that take advantage of the synergies of hybridization and building integration. Beyond that, it requires the development of new disruptive technologies and concepts. To facilitate these goals, in 2011 the Lawrence Berkeley National Laboratory and the U.S. Department of Energy launched the Max Tech and Beyond Design Competition for Ultra-Low-Energy-Use Appliances and Equipment. Now in its third year, the competition supports faculty-lead student design teams at U.S. universities to develop and test new technology prototypes. This talk describes what the competition and the Max Tech Program are doing to drive such rapid technology progress and to facilitate the entry to the market of successful Max Tech prototypes. The talk also initiates a discussion of physicists' unique role in driving that technology progress faster and farther. Emerging Technologies, Building Technologies Office, U.S. Department of Energy.

  2. Four-wheel drive car

    SciTech Connect

    Ashikawa, N.

    1986-03-25

    A drive train in a four-wheel drive vehicle is described having an engine mounted on one end with a crankshaft oriented transverse to the direction of vehicle travel which consists of: a transmission having an output gear driven by the crankshaft and rotatable around an axis parallel to the axis of the crankshaft; a reduction gear operatively engaged with the output gear; a first differential gear having a gear and being concentrically engaged with the reduction gear to transmit the output of the reduction gear in a divided manner; a second differential gear transmitting power from one output of the differential gear to left and right wheels of the one end of the vehicle; a transmission gear meshing with the gear of the first differential gear for transmitting power from another output of the first differential gear in a direction generally perpendicular to the crankshaft through a propeller shaft to the other end of the vehicle, opposite the one end; a third differential gear receiving power from the propeller shaft for transmitting power to left and right wheels on the other end; and wherein a mesh portion where the transmission gear meshes with the gear of the first differential gear is closer to the crankshaft axis of engine than is the axis of the reduction gear.

  3. Molecular mechanisms of UV-induced apoptosis.

    PubMed

    Kulms, D; Schwarz, T

    2000-10-01

    Sunburn cells, single standing cells with typical morphologic features occurring in UV-exposed skin, have been recognized as keratinocytes undergoing apoptosis following UV irradiation. Induction of apoptosis following UV exposure appears to be a protective mechanism, getting rid off severely damaged cells that bear the risk of malignant transformation. UV-mediated apoptosis is a highly complex process in which different molecular pathways are involved. These include DNA damage, activation of the tumor suppressor gene p53, triggering of cell death receptors either directly by UV or by autocrine release of death ligands, mitochondrial damage and cytochrome C release. Detailed knowledge about the interplay between these pathways will increase our understanding of photocarcinogenesis. This review briefly discusses recent findings concerning the molecular mechanisms underlying UV-induced apoptosis.

  4. Autophagy and apoptosis in liver injury.

    PubMed

    Wang, Kewei

    2015-01-01

    Apoptosis is a primary characteristic in the pathogenesis of liver disease. Hepatic apoptosis is regulated by autophagic activity. However, mechanisms mediating their interaction remain to be determined. Basal level of autophagy ensures the physiological turnover of old and damaged organelles. Autophagy also is an adaptive response under stressful conditions. Autophagy can control cell fate through different cross-talk signals. A complex interplay between hepatic autophagy and apoptosis determines the degree of hepatic apoptosis and the progression of liver disease as demonstrated by pre-clinical models and clinical trials. This review summarizes recent advances on roles of autophagy that plays in pathophysiology of liver. The autophagic pathway can be a novel therapeutic target for liver disease.

  5. [Apoptosis and thymocyte development (epithelial cells as inducers of thymocyte apoptosis)].

    PubMed

    Iarilin, A A; Bulanova, E G; Sharova, N I; Budagian, V M

    1998-01-01

    Apoptosis, together with proliferation, is a main factor of selection of the clones of developing T-lymphocytes: the clones not supported by positive selection are subject to apoptosis and apoptosis accounts for discarding of potentially autoaggressive clones, i.e., for negative selection in the thymus and peripheral lymphoid tissue. Realization of apoptosis at different stages of the development of T-lymphocytes depends to a varying extent on Fas, Bcl-2, p53, and other regulators. The dendritic cells are the main cell type, the contact with determines apoptosis of T-lymphocytes. A possible role of the epithelial cells was shown in few models (on murine cells) and was not practically studied. We obtained a line of epithelial cells of the human thymus cells HTSC, cocultivation with which induces apoptosis of immature thymocytes and blood T-cells activated by mitogens. Development of apoptosis is suppressed by inhibitors of protein and RNA synthesis, chelators Ca2+, ions Zn2+, and factors destroying the cytoskeleton components. In this model, interaction of pairs of molecules CD4-HLA class II and LFA-1-ICAM-1. When in contact with the HTSC cells, the thymocytes of mice mutant for Fas-receptor (line MRL.lpr) are subject to apoptosis, but when this receptor is present, it affects the development of apoptosis.

  6. Modulation of apoptosis by cancer chemopreventive agents.

    PubMed

    D'Agostini, Francesco; Izzotti, Alberto; Balansky, Roumen M; Bennicelli, Carlo; De Flora, Silvio

    2005-12-11

    A review of almost 2000 studies showed that the large majority of 39 putative cancer chemopreventive agents induced "spontaneous" apoptosis. Inhibition of the programmed cell death triggered by a variety of stimuli was consistently reported only with ascorbic acid, alpha-tocopherol, and N-acetylcysteine (NAC). We performed experimental studies in rodents exposed to cigarette smoke, either mainstream (MCS) or environmental (ECS), and UV-A/B-containing light. The nonsteroidal anti-inflammatory drug sulindac did not affect the apoptotic process in the skin of light-exposed mice and in the lungs of ECS-exposed mice. Likewise, 5,6-benzoflavone, indole-3-carbinol, 1,2-dithiole-3-thione and oltipraz failed to modulate apoptosis in the respiratory tract of ECS-exposed rats. Phenethyl isothiocyanate further enhanced the frequency of apoptosis in pulmonary alveolar macrophages and bronchial epithelial cells, and upregulated several genes in the lung of ECS-exposed rats. Both individually and in combination with oltipraz, NAC inhibited apoptosis in the respiratory tract of rats exposed either to MCS or ECS. Moreover, NAC attenuated the ECS-related overexpression of proapoptotic genes and normalized the levels of proapoptotic proteins in rat lung. The transplacental administration of NAC to mice considerably attenuated gene overexpression in the liver of fetuses exposed to ECS throughout pregnancy. Inhibition of apoptosis by chemopreventive agents reflects their ability to counteract certain upstream signals, such as genotoxic damage, redox imbalances, and other forms of cellular stress that trigger apoptosis. On the other hand, enhancement of apoptosis is a double-edged sword, since it represents a protective mechanism in carcinogenesis but may contribute to the pathogenesis of other degenerative diseases. We suggest that stimulation of apoptosis by so many chemopreventive agents, as reported in the literature, may often reflect the occurrence of toxic effects at high doses.

  7. Beta Catenin in Prostate Cancer Apoptosis

    DTIC Science & Technology

    2014-04-01

    insensitive cell types to determine whether this apoptosis pathway is only specific to androgen sensitive cell types. In order to determine the role of β...obtained: Effect of TRAIL-TZD combination on the apoptosis potential and β-catenin expression of androgen sensitive and androgen insensitive prostate...and 22RV1) and androgen insensitive (DU145 and PC3) prostate cancer cells were treated with either DMSO or a combination of 100ng/ml TRAIL and

  8. Molecular Mechanisms and Apoptosis in Pdt

    NASA Astrophysics Data System (ADS)

    Krammer, Barbara; Verwanger, Thomas

    2010-04-01

    Photodynamic Therapy (PDT) is a successful new therapy for malignant and non-malignant diseases. It is based on the activation of a photosensitizing dye by visible light in the target tissue, followed by production of cytotoxic substances. The article gives a short overview on the field of PDT with main focus on molecular mechanisms and apoptosis. It includes photodynamic principles, clinical application and procedures, biological effects, molecular mechanisms of damage processing and apoptosis.

  9. Mechanisms of Neuronal Apoptosis In Vivo

    DTIC Science & Technology

    2004-02-01

    agents , radiation, viruses, and after seizures, trauma, limb amputation, and hypoxic-ischemia caused by cardiac arrest, stroke, asphyxiation, and...acid), and chemical warfare agents such as organophosphate compounds (soman) and mycotoxins (T-2 toxin). Acute neurological injury is also caused by...apoptosis Cells that have sustained DNA damage from reactive oxygen species (ROS) and other genotoxic agents undergo apoptosis by engaging molecular cascades

  10. Trends in global warming and evolution of matrix protein 2 family from influenza A virus.

    PubMed

    Yan, Shao-Min; Wu, Guang

    2009-12-01

    The global warming is an important factor affecting the biological evolution, and the influenza is an important disease that threatens humans with possible epidemics or pandemics. In this study, we attempted to analyze the trends in global warming and evolution of matrix protein 2 family from influenza A virus, because this protein is a target of anti-flu drug, and its mutation would have significant effect on the resistance to anti-flu drugs. The evolution of matrix protein 2 of influenza A virus from 1959 to 2008 was defined using the unpredictable portion of amino-acid pair predictability. Then the trend in this evolution was compared with the trend in the global temperature, the temperature in north and south hemispheres, and the temperature in influenza A virus sampling site, and species carrying influenza A virus. The results showed the similar trends in global warming and in evolution of M2 proteins although we could not correlate them at this stage of study. The study suggested the potential impact of global warming on the evolution of proteins from influenza A virus.

  11. Estrogens sensitize anterior pituitary gland to apoptosis.

    PubMed

    Pisera, D; Candolfi, M; Navarra, S; Ferraris, J; Zaldivar, V; Jaita, G; Castro, M G; Seilicovich, A

    2004-10-01

    Tissue homeostasis results from a balance between cell proliferation and cell death by apoptosis. Estradiol affects proliferation as well as apoptosis in hormone-dependent tissues. In the present study, we investigated the apoptotic response of the anterior pituitary gland to lipopolysaccharide (LPS) in cycling female rats, and the influence of estradiol in this response in ovariectomized (OVX) rats. The OVX rats were chronically estrogenized with implanted Silastic capsules containing 1 mg of 17beta-estradiol (E2). Cycling or OVX and E2-treated rats were injected with LPS (250 microg/rat ip). Apoptosis was determined by the terminal deoxynucleotidyl-mediated dUTP nick-end labeling (TUNEL) method in sections of the anterior pituitary gland and spleen. Chronic estrogenization induced apoptosis in the anterior pituitary gland. Acute endotoxemia triggered apoptosis of cells in the anterior pituitary gland of E2-treated rats but not of OVX rats. No differences were observed in the apoptotic response to LPS in spleen between OVX and E2-treated rats. The apoptotic response of the anterior pituitary to LPS was variable along the estrous cycle, being higher at proestrus than at estrus or diestrus I. Approximately 75% of the apoptotic cells were identified as lactotropes by immunofluorescence. In conclusion, our results indicate that estradiol induces apoptosis and enables the proapoptotic action of LPS in the anterior pituitary gland. Also, our study suggests that estrogens may be involved in anterior pituitary cell renewal during the estrous cycle, sensitizing lactotropes to proapoptotic stimuli.

  12. Mitochondrial Ceramide and the Induction of Apoptosis

    PubMed Central

    Siskind, Leah J.

    2007-01-01

    In most cell types, a key event in apoptosis is the release of proapoptotic intermembrane space proteins from mitochondria to the cytoplasm. In general, it is the release of these intermembrane space proteins that is responsible for the activation of caspases and DNases that are responsible for the execution of apoptosis. The mechanism for the increased permeability of the mitochondrial outer membrane during the induction phase of apoptosis is currently unknown and highly debated. This review will focus on one such proposed mechanism, namely, the formation of ceramide channels in the mitochondrial outer membrane. Ceramides are known to play a major regulatory role in apoptosis by inducing the release of proapoptotic proteins from the mitochondria. As mitochondria are known to contain the enzymes responsible for the synthesis and hydrolysis of ceramide, there exists a mechanism for regulating the level of ceramide in mitochondria. In addition, mitochondrial ceramide levels have been shown to be elevated prior to the induction phase of apoptosis. Ceramide has been shown to form large protein permeable channels in planar phospholipid and mitochondrial outer membranes. Thus, ceramide channels are good candidates for the pathway with which proapoptotic proteins are released from mitochondria during the induction phase of apoptosis. PMID:16167171

  13. DPI induces mitochondrial superoxide-mediated apoptosis.

    PubMed

    Li, Nianyu; Ragheb, Kathy; Lawler, Gretchen; Sturgis, Jennie; Rajwa, Bartek; Melendez, J Andres; Robinson, J Paul

    2003-02-15

    The iodonium compounds diphenyleneiodonium (DPI) and diphenyliodonium (IDP) are well-known phagocyte NAD(P)H oxidase inhibitors. However, it has been shown that at high concentrations they can inhibit the mitochondrial respiratory chain as well. Since inhibition of the mitochondrial respiratory chain has been shown to induce superoxide production and apoptosis, we investigated the effect of iodonium compounds on mitochondria-derived superoxide and apoptosis. Mitochondrial superoxide production was measured on both cultured cells and isolated rat-heart submitochondrial particles. Mitochondria function was examined by monitoring mitochondrial membrane potential. Apoptotic pathways were studied by measuring cytochrome c release and caspase 3 activation. Apoptosis was characterized by detecting DNA fragmentation on agarose gel and measuring propidium iodide- (PI-) stained subdiploid cells using flow cytometry. Our results showed that DPI could induce mitochondrial superoxide production. The same concentration of DPI induced apoptosis by decreasing mitochondrial membrane potential and releasing cytochrome c. Addition of antioxidants or overexpression of MnSOD significantly reduced DPI-induced mitochondrial damage, cytochrome c release, caspase activation, and apoptosis. These observations suggest that DPI can induce apoptosis via induction of mitochondrial superoxide. DPI-induced mitochondrial superoxide production may prove to be a useful model to study the signaling pathways of mitochondrial superoxide.

  14. The antifungal plant defensin RsAFP2 from radish induces apoptosis in a metacaspase independent way in Candida albicans.

    PubMed

    Aerts, An M; Carmona-Gutierrez, Didac; Lefevre, Sophie; Govaert, Gilmer; François, Isabelle E J A; Madeo, Frank; Santos, Renata; Cammue, Bruno P A; Thevissen, Karin

    2009-08-06

    We show that the antifungal plant defensin Raphanus sativus antifungal protein 2 (RsAFP2) from radish induces apoptosis and concomitantly triggers activation of caspases or caspase-like proteases in the human pathogen Candida albicans. Furthermore, we demonstrate that deletion of C. albicans metacaspase 1, encoding the only reported (putative) caspase in C. albicans, significantly affects caspase activation by the apoptotic stimulus acetic acid, but not by RsAFP2. To our knowledge, this is the first report on the induction of apoptosis with concomitant caspase activation by a defensin in this pathogen. Moreover, our data point to the existence of at least two different types of caspases or caspase-like proteases in C. albicans.

  15. Circuit for Driving Piezoelectric Transducers

    NASA Technical Reports Server (NTRS)

    Randall, David P.; Chapsky, Jacob

    2009-01-01

    The figure schematically depicts an oscillator circuit for driving a piezoelectric transducer to excite vibrations in a mechanical structure. The circuit was designed and built to satisfy application-specific requirements to drive a selected one of 16 such transducers at a regulated amplitude and frequency chosen to optimize the amount of work performed by the transducer and to compensate for both (1) temporal variations of the resonance frequency and damping time of each transducer and (2) initially unknown differences among the resonance frequencies and damping times of different transducers. In other words, the circuit is designed to adjust itself to optimize the performance of whichever transducer is selected at any given time. The basic design concept may be adaptable to other applications that involve the use of piezoelectric transducers in ultrasonic cleaners and other apparatuses in which high-frequency mechanical drives are utilized. This circuit includes three resistor-capacitor networks that, together with the selected piezoelectric transducer, constitute a band-pass filter having a peak response at a frequency of about 2 kHz, which is approximately the resonance frequency of the piezoelectric transducers. Gain for generating oscillations is provided by a power hybrid operational amplifier (U1). A junction field-effect transistor (Q1) in combination with a resistor (R4) is used as a voltage-variable resistor to control the magnitude of the oscillation. The voltage-variable resistor is part of a feedback control loop: Part of the output of the oscillator is rectified and filtered for use as a slow negative feedback to the gate of Q1 to keep the output amplitude constant. The response of this control loop is much slower than 2 kHz and, therefore, does not introduce significant distortion of the oscillator output, which is a fairly clean sine wave. The positive AC feedback needed to sustain oscillations is derived from sampling the current through the

  16. Optimizing digital 8mm drive performance

    NASA Technical Reports Server (NTRS)

    Schadegg, Gerry

    1993-01-01

    The experience of attaching over 350,000 digital 8mm drives to 85-plus system platforms has uncovered many factors which can reduce cartridge capacity or drive throughput, reduce reliability, affect cartridge archivability and actually shorten drive life. Some are unique to an installation. Others result from how the system is set up to talk to the drive. Many stem from how applications use the drive, the work load that's present, the kind of media used and, very important, the kind of cleaning program in place. Digital 8mm drives record data at densities that rival those of disk technology. Even with technology this advanced, they are extremely robust and, given proper usage, care and media, should reward the user with a long productive life. The 8mm drive will give its best performance using high-quality 'data grade' media. Even though it costs more, good 'data grade' media can sustain the reliability and rigorous needs of a data storage environment and, with proper care, give users an archival life of 30 years or more. Various factors, taken individually, may not necessarily produce performance or reliability problems. Taken in combination, their effects can compound, resulting in rapid reductions in a drive's serviceable life, cartridge capacity, or drive performance. The key to managing media is determining the importance one places upon their recorded data and, subsequently, setting media usage guidelines that can deliver data reliability. Various options one can implement to optimize digital 8mm drive performance are explored.

  17. Driving, brain injury and assistive technology.

    PubMed

    Lane, Amy K; Benoit, Dana

    2011-01-01

    Individuals with brain injury often present with cognitive, physical and emotional impairments which impact their ability to resume independence in activities of daily living. Of those activities, the resumption of driving privileges is cited as one of the greatest concerns by survivors of brain injury. The integration of driving fundamentals within the hierarchical model proposed by Keskinen represents the complexity of skills and behaviors necessary for driving. This paper provides a brief review of specific considerations concerning the driver with TBI and highlights current vehicle technology which has been developed by the automotive industry and by manufacturers of adaptive driving equipment that may facilitate the driving task. Adaptive equipment technology allows for compensation of a variety of operational deficits, whereas technological advances within the automotive industry provide drivers with improved safety and information systems. However, research has not yet supported the use of such intelligent transportation systems or advanced driving systems for drivers with brain injury. Although technologies are intended to improve the safety of drivers within the general population, the potential of negative consequences for drivers with brain injury must be considered. Ultimately, a comprehensive driving evaluation and training by a driving rehabilitation specialist is recommended for individuals with brain injury. An understanding of the potential impact of TBI on driving-related skills and knowledge of current adaptive equipment and technology is imperative to determine whether return-to-driving is a realistic and achievable goal for the individual with TBI.

  18. Driving and attention deficit hyperactivity disorder.

    PubMed

    Fuermaier, Anselm B M; Tucha, Lara; Evans, Ben Lewis; Koerts, Janneke; de Waard, Dick; Brookhuis, Karel; Aschenbrenner, Steffen; Thome, Johannes; Lange, Klaus W; Tucha, Oliver

    2017-02-01

    Adults with attention deficit hyperactivity disorder (ADHD) suffer from various impairments of cognitive, emotional and social functioning, which can have considerable consequences for many areas of daily living. One of those areas is driving a vehicle. Driving is an important activity of everyday life and requires an efficient interplay between multiple cognitive, perceptual, and motor skills. In the present study, a selective review of the literature on driving-related difficulties associated with ADHD is performed, seeking to answer whether individuals with ADHD show increased levels of unsafe driving behaviours, which cognitive (dys)functions of individuals with ADHD are related to driving difficulty, and whether pharmacological treatment significantly improves the driving behaviour of individuals with ADHD. The available research provides convincing evidence that individuals with ADHD have different and more adverse driving outcomes than individuals without the condition. However, it appears that not all individuals with ADHD are affected uniformly. Despite various cognitive functions being related with driving difficulties, these functions do not appear helpful in detecting high risk drivers with ADHD, nor in predicting driving outcomes in individuals with ADHD, since impairments in these functions are defining criteria for the diagnoses of ADHD (e.g., inattention and impulsivity). Pharmacological treatment of ADHD, in particular stimulant drug treatment, appears to be beneficial to the driving difficulties experienced by individuals with ADHD. However, additional research is needed, in particular further studies that address the numerous methodological weaknesses of many of the previous studies.

  19. Current Drive in Recombining Plasma

    SciTech Connect

    P.F. Schmit and N.J. Fisch

    2012-05-15

    The Langevin equations describing the average collisional dynamics of suprathermal particles in nonstationary plasma remarkably admit an exact analytical solution in the case of recombining plasma. The current density produced by arbitrary particle fluxes is derived including the effect of charge recombination. Since recombination has the effect of lowering the charge density of the plasma, thus reducing the charged particle collisional frequencies, the evolution of the current density can be modified substantially compared to plasma with fixed charge density. The current drive efficiency is derived and optimized for discrete and continuous pulses of current, leading to the discovery of a nonzero "residual" current density that persists indefinitely under certain conditions, a feature not present in stationary plasmas.

  20. Subduction Drive of Plate Tectonics

    NASA Astrophysics Data System (ADS)

    Hamilton, W. B.

    2003-12-01

    Don Anderson emphasizes that plate tectonics is self-organizing and is driven by subduction, which rights the density inversion generated as oceanic lithosphere forms by cooling of asthenosphere from the top. The following synthesis owes much to many discussions with him. Hinge rollback is the key to kinematics, and, like the rest of actual plate behavior, is incompatible with bottom-up convection drive. Subduction hinges (which are under, not in front of, thin leading parts of arcs and overriding plates) roll back into subducting plates. The Pacific shrinks because bounding hinges roll back into it. Colliding arcs, increasing arc curvatures, back-arc spreading, and advance of small arcs into large plates also require rollback. Forearcs of overriding plates commonly bear basins which preclude shortening of thin plate fronts throughout periods recorded by basin strata (100 Ma for Cretaceous and Paleogene California). This requires subequal rates of advance and rollback, and control of both by subduction. Convergence rate is equal to rates of rollback and advance in many systems but is greater in others. Plate-related circulation probably is closed above 650 km. Despite the popularity of concepts of plumes from, and subduction into, lower mantle, there is no convincing evidence for, and much evidence against, penetration of the 650 in either direction. That barrier not only has a crossing-inhibiting negative Clapeyron slope but also is a compositional boundary between fractionated (not "primitive"), sluggish lower mantle and fertile, mobile upper mantle. Slabs sink more steeply than they dip. Slabs older than about 60 Ma when their subduction began sink to, and lie down on and depress, the 650-km discontinuity, and are overpassed, whereas younger slabs become neutrally buoyant in mid-upper mantle, into which they are mixed as they too are overpassed. Broadside-sinking old slabs push all upper mantle, from base of oceanic lithosphere down to the 650, back under

  1. Driving Task: How Older Drivers' On-Road Driving Performance Relates to Abilities, Perceptions, and Restrictions.

    PubMed

    Koppel, Sjaan; Charlton, Judith L; Langford, Jim; Di Stefano, Marilyn; MacDonald, Wendy; Vlahodimitrakou, Zafiroula; Mazer, Barbara L; Gelinas, Isabelle; Vrkljan, Brenda; Eliasz, Kinga; Myers, Anita; Tuokko, Holly A; Marshall, Shawn C

    2016-06-01

    This study examined a cohort of 227 older drivers and investigated the relationship between performance on the electronic Driver Observation Schedule (eDOS) driving task and: (1) driver characteristics; (2) functional abilities; (3) perceptions of driving comfort and abilities; and (4) self-reported driving restrictions. Participants (male: 70%; age: M = 81.53 years, SD = 3.37 years) completed a series of functional ability measures and scales on perceived driving comfort, abilities, and driving restrictions from the Year 2 Candrive/Ozcandrive assessment protocol, along with an eDOS driving task. Observations of participants' driving behaviours during the driving task were recorded for intersection negotiation, lane-changing, merging, low-speed maneuvers, and maneuver-free driving. eDOS driving task scores were high (M = 94.74; SD = 5.70) and significantly related to participants' perceived driving abilities, reported frequency of driving in challenging situations, and number of driving restrictions. Future analyses will explore potential changes in driving task scores over time.

  2. Personal and situational influences on drink driving and sober driving among a cohort of young adults

    PubMed Central

    Morrison, L; Begg, D; Langley, J

    2002-01-01

    Objectives: To compare personal and situational influences on incidents involving drink driving with those involving sober driving. Methods: Information on a range of road safety practices was sought in face to face interviews conducted with 969 members of the Dunedin Multidisciplinary Health and Development Study cohort at age 26 years. A total of 750 study members reported an incident that involved the opportunity to consume alcohol and also travel by motor vehicle. Of these, 87 were classified as "drink drive incidents" and 663 as "sober drive incidents". Results: Study members who were male, of lower socioeconomic status, had no school qualifications, or were dependent on alcohol or marijuana at age 21 were significantly more likely to report a drink drive incident at age 26. Compared with the sober drive incidents, the drink drive incidents were more commonly associated with driving alone, drinking at bars, and no advanced planning. For drink drive incidents the amount of alcohol consumed was influenced by the conviviality of the occasion, whereas for sober drive incidents it was the need to drive. One quarter of those reporting drink drive incidents stated they had used marijuana and/or LSD at the event at which they drank. Conclusions: Drink drive and sober drive incidents differed, particularly with regard to decisions made before the event. Prevention efforts could usefully be targeted toward these decisions. PMID:12120828

  3. Temporal shift in methyl-CpG binding protein 2 expression in a mouse model of Rett syndrome.

    PubMed

    Metcalf, B M; Mullaney, B C; Johnston, M V; Blue, M E

    2006-01-01

    Rett syndrome is an X-linked neurodevelopmental disorder caused by mutations in methyl-CpG binding protein 2. Females with identical mutations in the methyl-CpG binding protein 2 gene can display varying severity of symptoms, suggesting that other factors such as X-chromosome inactivation affect phenotypic expression in Rett syndrome. Although X-chromosome inactivation is random and balanced in the blood and brain of the majority of girls with classic Rett syndrome, skewing in the ratio of expression of the mutant methyl-CpG binding protein 2-X to the wildtype-X affects the severity of symptoms. In this study, the pattern of immunostaining for methyl-CpG binding protein 2 was compared with that of neuronal nuclei specific protein, a pan-neuronal marker, to assess X-chromosome inactivation in a Rett syndrome mouse model. The number of cortical neurons and cortical volume were assessed by unbiased stereological measurements in younger adult (7-9 week old) wildtype (wildtype/methyl-CpG binding protein 2+/+), female heterozygous (heterozygous/methyl-CpG binding protein 2+/-), and null (methyl-CpG binding protein 2-/y) male mice and in older adult (24-95 week old) wildtype and heterozygous mice. The results showed that the number of neuronal nuclei specific protein-positive cells and cortical volume did not differ by genotype or age. However, younger adult heterozygous mice had significantly fewer methyl-CpG binding protein 2 cells and the pattern of methyl-CpG binding protein 2 staining was less distinct than in younger adult wildtype mice. However, in older adult heterozygous mice, the number and pattern of methyl-CpG binding protein 2-expressing neurons were similar to the wildtype. The ratio of methyl-CpG binding protein 2 to neuronal nuclei specific protein-stained neurons, a potential measure of X-chromosome inactivation, was close to 50% in the younger adult heterozygous mice, but nearly 70% in the older adult heterozygous mice. These results suggest that X

  4. Modulation of apoptosis and viral latency - an axis to be well understood for successful cure of human immunodeficiency virus.

    PubMed

    Timilsina, Uddhav; Gaur, Ritu

    2016-04-01

    Human immunodeficiency virus (HIV) is the causative agent of the deadly disease AIDS, which is characterized by the progressive decline of CD4(+)T-cells. HIV-1-encoded proteins such as envelope gp120 (glycoprotein gp120), Tat (trans-activator of transcription), Nef (negative regulatory factor), Vpr (viral protein R), Vpu (viral protein unique) and protease are known to be effective in modulating host cell signalling pathways that lead to an alteration in apoptosis of both HIV-infected and uninfected bystander cells. Depending on the stage of the virus life cycle and host cell type, these viral proteins act as mediators of pro- or anti-apoptotic signals. HIV latency in viral reservoirs is a persistent phenomenon that has remained beyond the control of the human immune system. To cure HIV infections completely, it is crucial to reactivate latent HIV from cellular pools and to drive these apoptosis-resistant cells towards death. Several previous studies have reported the role of HIV-encoded proteins in apoptosis modulation, but the molecular basis for apoptosis evasion of some chronically HIV-infected cells and reactivated latently HIV-infected cells still needs to be elucidated. The current review summarizes our present understanding of apoptosis modulation in HIV-infected cells, uninfected bystander cells and latently infected cells, with a focus on highlighting strategies to activate the apoptotic pathway to kill latently infected cells.

  5. Roles and regulation of autophagy and apoptosis in the remodelling of the lepidopteran midgut epithelium during metamorphosis

    PubMed Central

    Romanelli, Davide; Casartelli, Morena; Cappellozza, Silvia; de Eguileor, Magda; Tettamanti, Gianluca

    2016-01-01

    We previously showed that autophagy and apoptosis occur in the removal of the lepidopteran larval midgut during metamorphosis. However, their roles in this context and the molecular pathways underlying their activation and regulation were only hypothesized. The results of the present study better clarify the timing of the activation of these two processes: autophagic and apoptotic genes are transcribed at the beginning of metamorphosis, but apoptosis intervenes after autophagy. To investigate the mechanisms that promote the activation of autophagy and apoptosis, we designed a set of experiments based on injections of 20-hydroxyecdysone (20E). Our data demonstrate that autophagy is induced at the end of the last larval stage by the 20E commitment peak, while the onset of apoptosis occurs concomitantly with the 20E metamorphic peak. By impairing autophagic flux, the midgut epithelium degenerated faster, and higher caspase activity was observed compared to controls, whereas inhibiting caspase activation caused a severe delay in epithelial degeneration. Our data demonstrate that autophagy plays a pro-survival function in the silkworm midgut during metamorphosis, while apoptosis is the major process that drives the demise of the epithelium. The evidence collected in this study seems to exclude the occurrence of autophagic cell death in this setting. PMID:27609527

  6. Roles and regulation of autophagy and apoptosis in the remodelling of the lepidopteran midgut epithelium during metamorphosis.

    PubMed

    Romanelli, Davide; Casartelli, Morena; Cappellozza, Silvia; de Eguileor, Magda; Tettamanti, Gianluca

    2016-09-09

    We previously showed that autophagy and apoptosis occur in the removal of the lepidopteran larval midgut during metamorphosis. However, their roles in this context and the molecular pathways underlying their activation and regulation were only hypothesized. The results of the present study better clarify the timing of the activation of these two processes: autophagic and apoptotic genes are transcribed at the beginning of metamorphosis, but apoptosis intervenes after autophagy. To investigate the mechanisms that promote the activation of autophagy and apoptosis, we designed a set of experiments based on injections of 20-hydroxyecdysone (20E). Our data demonstrate that autophagy is induced at the end of the last larval stage by the 20E commitment peak, while the onset of apoptosis occurs concomitantly with the 20E metamorphic peak. By impairing autophagic flux, the midgut epithelium degenerated faster, and higher caspase activity was observed compared to controls, whereas inhibiting caspase activation caused a severe delay in epithelial degeneration. Our data demonstrate that autophagy plays a pro-survival function in the silkworm midgut during metamorphosis, while apoptosis is the major process that drives the demise of the epithelium. The evidence collected in this study seems to exclude the occurrence of autophagic cell death in this setting.

  7. Application of traction drives as servo mechanisms

    NASA Technical Reports Server (NTRS)

    Loewenthal, S. H.; Rohn, D. A.; Steinetz, B. M.

    1985-01-01

    The suitability of traction drives for a wide class of aerospace control mechanisms is examined. Potential applications include antenna or solar array drive positioners, robotic joints, control moment gyro (CMG) actuators and propeller pitch change mechanisms. In these and similar applications the zero backlash, high torsional stiffness, low hysteresis and torque ripple characteristics of traction drives are of particular interest, as is the ability to run without liquid lubrication in certain cases. Wear and fatigue considerations for wet and dry operation are examined along with the tribological performance of several promising self lubricating polymers for traction contracts. The speed regulation capabilities of variable ratio traction drives are reviewed. A torsional stiffness analysis described suggests that traction contacts are relatively stiff compared to gears and are significantly stiffer than the other structural elements in the prototype CMG traction drive analyzed. Discussion is also given of an advanced turboprop propeller pitch change mechanism that incorporates a traction drive.

  8. Parkinson's disease and issues related to driving.

    PubMed

    Uitti, Ryan J

    2009-12-01

    Driving a motor vehicle represents an important activity associated with personal independence and freedom. Being told that one can no longer drive is itself associated with loss of independence, depression, low self-esteem and reduced activities [1,2]. Patients with Parkinson's disease (PD), therefore, understandably wish to continue to be able to maintain their ability to drive automobiles, motorcycles, airplanes, and boats, etc. The ability to determine if and when a PD patient is no longer fit to drive a motor vehicle is important for maintaining safety for the PD patient and the public. There are numerous requirements for being able to drive a motor vehicle safely. When any of these capacities deteriorate, the ability to drive safely may be lost. This review will concentrate upon common issues that would be peculiar to patients with PD.

  9. Electric vehicle drive train with contactor protection

    DOEpatents

    Konrad, C.E.; Benson, R.A.

    1994-11-29

    A drive train for an electric vehicle includes a traction battery, a power drive circuit, a main contactor for connecting and disconnecting the traction battery and the power drive circuit, a voltage detector across contacts of the main contactor, and a controller for controlling the main contactor to prevent movement of its contacts to the closed position when the voltage across the contacts exceeds a predetermined threshold, to thereby protect the contacts of the contactor. The power drive circuit includes an electric traction motor and a DC-to-AC inverter with a capacitive input filter. The controller also inhibits the power drive circuit from driving the motor and thereby discharging the input capacitor if the contacts are inadvertently opened during motoring. A precharging contactor is controlled to charge the input filter capacitor prior to closing the main contactor to further protect the contacts of the main contactor. 3 figures.

  10. Electric vehicle drive train with contactor protection

    DOEpatents

    Konrad, Charles E.; Benson, Ralph A.

    1994-01-01

    A drive train for an electric vehicle includes a traction battery, a power drive circuit, a main contactor for connecting and disconnecting the traction battery and the power drive circuit, a voltage detector across contacts of the main contactor, and a controller for controlling the main contactor to prevent movement of its contacts to the closed position when the voltage across the contacts exceeds a predetermined threshold, to thereby protect the contacts of the contactor. The power drive circuit includes an electric traction motor and a DC-to-AC inverter with a capacitive input filter. The controller also inhibits the power drive circuit from driving the motor and thereby discharging the input capacitor if the contacts are inadvertently opened during motoring. A precharging contactor is controlled to charge the input filter capacitor prior to closing the main contactor to further protect the contacts of the main contactor.

  11. Chondrocyte Apoptosis in the Pathogenesis of Osteoarthritis

    PubMed Central

    Hwang, Hyun Sook; Kim, Hyun Ah

    2015-01-01

    Apoptosis is a highly-regulated, active process of cell death involved in development, homeostasis and aging. Dysregulation of apoptosis leads to pathological states, such as cancer, developmental anomalies and degenerative diseases. Osteoarthritis (OA), the most common chronic joint disease in the elderly population, is characterized by progressive destruction of articular cartilage, resulting in significant disability. Because articular cartilage depends solely on its resident cells, the chondrocytes, for the maintenance of extracellular matrix, the compromising of chondrocyte function and survival would lead to the failure of the articular cartilage. The role of subchondral bone in the maintenance of proper cartilage matrix has been suggested as well, and it has been proposed that both articular cartilage and subchondral bone interact with each other in the maintenance of articular integrity and physiology. Some investigators include both articular cartilage and subchondral bone as targets for repairing joint degeneration. In late-stage OA, the cartilage becomes hypocellular, often accompanied by lacunar emptying, which has been considered as evidence that chondrocyte death is a central feature in OA progression. Apoptosis clearly occurs in osteoarthritic cartilage; however, the relative contribution of chondrocyte apoptosis in the pathogenesis of OA is difficult to evaluate, and contradictory reports exist on the rate of apoptotic chondrocytes in osteoarthritic cartilage. It is not clear whether chondrocyte apoptosis is the inducer of cartilage degeneration or a byproduct of cartilage destruction. Chondrocyte death and matrix loss may form a vicious cycle, with the progression of one aggravating the other, and the literature reveals that there is a definite correlation between the degree of cartilage damage and chondrocyte apoptosis. Because current treatments for OA act only on symptoms and do not prevent or cure OA, chondrocyte apoptosis would be a valid

  12. CASPASE CONTROL: PROTAGONISTS OF CANCER CELL APOPTOSIS

    PubMed Central

    Fiandalo, M.V.; Kyprianou, N.

    2013-01-01

    Emergence of castration-resistant metastatic prostate cancer is due to activation of survival pathways, including apoptosis suppression and anoikis resistance, and increased neovascularization. Thus targeting of apoptotic players is of critical significance in prostate cancer therapy since loss of apoptosis and resistance to anoikis are critical in aberrant malignant growth, metastasis and conferring therapeutic failure. The majority of therapeutic agents act through intrinsic mitochondrial, extrinsic death receptor pathways or endoplasmic reticulum stress pathways to induce apoptosis. Current therapeutic strategies target restoring regulatory molecules that govern the pro-survival pathways such as PTEN which regulates AKT activity. Other strategies focus on reactivating the apoptotic pathways either by down-regulating anti-apoptotic players such as BCL-2 or by up-regulating pro-apoptotic protein families, most notably, the caspases. Caspases are a family of cystine proteases which serve critical roles in apoptotic and inflammatory signaling pathways. During tumorigenesis, significant loss or inactivation of lead members in the caspase family leads to impairing apoptosis induction, causing a dramatic imbalance in the growth dynamics, ultimately resulting in aberrant growth of human cancers. Recent exploitation of apoptosis pathways towards re-instating apoptosis induction via caspase re-activation has provided new molecular platforms for the development of therapeutic strategies effective against advanced prostate cancer as well as other solid tumors. This review will discuss the current cellular landscape featuring the caspase family in tumor cells and their activation via pharmacologic intervention towards optimized anti-cancer therapeutic modalities. This article is part of a Special Issue entitled “Apoptosis: Four Decades Later”. PMID:23070001

  13. Apoptosis predominates in nonmyocytes in heart failure.

    PubMed

    Park, Misun; Shen, You-Tang; Gaussin, Vinciane; Heyndrickx, Guy R; Bartunek, Jozef; Resuello, Ranillo R G; Natividad, Filipinas F; Kitsis, Richard N; Vatner, Dorothy E; Vatner, Stephen F

    2009-08-01

    The goal of this investigation was to determine the distribution of myocardial apoptosis in myocytes and nonmyocytes in primates and patients with heart failure (HF). Almost all clinical cardiologists and cardiovascular investigators believe that myocyte apoptosis is considered to be a cardinal sign of HF and a major factor in its pathogenesis. However, with the knowledge that 75% of the number of cells in the heart are nonmyocytes, it is important to determine whether the apoptosis in HF is occurring in myocytes or in nonmyocytes. We studied both a nonhuman primate model of chronic HF, induced by rapid pacing 2-6 mo after myocardial infarction (MI), and biopsies from patients with ischemic cardiomyopathy. Dual labeling with a cardiac muscle marker was used to discriminate apoptosis in myocytes versus nonmyocytes. Left ventricular ejection fraction decreased following MI (from 78% to 60%) and further with HF (35%, P < 0.05). As expected, total apoptosis was increased in the myocardium following recovery from MI (0.62 cells/mm(2)) and increased further with the development of HF (1.91 cells/mm(2)). Surprisingly, the majority of apoptotic cells in MI and MI + HF, and in both the adjacent and remote areas, were nonmyocytes. This was also observed in myocardial biopsies from patients with ischemic cardiomyopathy. We found that macrophages contributed the largest fraction of apoptotic nonmyocytes (41% vs. 18% neutrophils, 16% fibroblast, and 25% endothelial and other cells). Although HF in the failing human and monkey heart is characterized by significant apoptosis, in contrast to current concepts, the apoptosis in nonmyocytes was eight- to ninefold greater than in myocytes.

  14. Apoptosis predominates in nonmyocytes in heart failure

    PubMed Central

    Park, Misun; Shen, You-Tang; Gaussin, Vinciane; Heyndrickx, Guy R.; Bartunek, Jozef; Resuello, Ranillo R. G.; Natividad, Filipinas F.; Kitsis, Richard N.; Vatner, Dorothy E.; Vatner, Stephen F.

    2009-01-01

    The goal of this investigation was to determine the distribution of myocardial apoptosis in myocytes and nonmyocytes in primates and patients with heart failure (HF). Almost all clinical cardiologists and cardiovascular investigators believe that myocyte apoptosis is considered to be a cardinal sign of HF and a major factor in its pathogenesis. However, with the knowledge that 75% of the number of cells in the heart are nonmyocytes, it is important to determine whether the apoptosis in HF is occurring in myocytes or in nonmyocytes. We studied both a nonhuman primate model of chronic HF, induced by rapid pacing 2–6 mo after myocardial infarction (MI), and biopsies from patients with ischemic cardiomyopathy. Dual labeling with a cardiac muscle marker was used to discriminate apoptosis in myocytes versus nonmyocytes. Left ventricular ejection fraction decreased following MI (from 78% to 60%) and further with HF (35%, P < 0.05). As expected, total apoptosis was increased in the myocardium following recovery from MI (0.62 cells/mm2) and increased further with the development of HF (1.91 cells/mm2). Surprisingly, the majority of apoptotic cells in MI and MI + HF, and in both the adjacent and remote areas, were nonmyocytes. This was also observed in myocardial biopsies from patients with ischemic cardiomyopathy. We found that macrophages contributed the largest fraction of apoptotic nonmyocytes (41% vs. 18% neutrophils, 16% fibroblast, and 25% endothelial and other cells). Although HF in the failing human and monkey heart is characterized by significant apoptosis, in contrast to current concepts, the apoptosis in nonmyocytes was eight- to ninefold greater than in myocytes. PMID:19465551

  15. Life Analysis of Multiroller Planetary Traction Drive

    DTIC Science & Technology

    1981-04-01

    Nasvytis eUltirollcr Traction Drive. The analysis was based on the Lundberg- Palmgren method for rolling- element bearing life prediction. Life...a steel rail. There are dozens bearing life. The effect of stress, stressed volume, of traction drive designs, distinguished by the and depth to the...clene¶,t bearing materials, lubrication and traction drive concept. Cleaner steels (vacuum design were considered as well as the potentially induction

  16. Optimal Sector Sampling for Drive Triage

    DTIC Science & Technology

    2013-06-01

    known files, which we call target data, that could help identify a drive holding evidence such as child pornography or malware. Triage is needed to sift...we call target data, that could help identify a drive holding evidence such as child pornography or malware. Triage is needed to sift through drives...situations where the user is looking for known data.1 One example is a law enforcement officer searching for evidence of child pornography from a large num

  17. A new driving circuit for IGBT devices

    SciTech Connect

    Licitra, C.; Musumeci, S.; Raciti, A.; Galluzzo, A.U.; Letor, R.; Melito, M.

    1995-05-01

    IGBT devices are increasingly used in power electronic equipment due to their high power handling capability. This paper deals with the problems that concern the turn-on, turn-off, and short-circuit of these devices. An optimal new driving circuit is proposed which gives excellent device output performances. Experimental oscillogram traces of transient condition tests are given, which demonstrate the advantages of using the new driving circuit. The suitability of the driving circuit for integration is analyzed.

  18. Get the message: distracted driving and teens.

    PubMed

    Adeola, Ruth; Gibbons, Mallory

    2013-01-01

    Distracted driving is a growing problem in the United States. With the integration of wireless devices into everyday life, cell phone use behind the wheel is a distraction requiring increasing concern. Teen drivers are most susceptible to the dangers of distracted driving as made evident in the overrepresentation of teens in distraction-related motor vehicle crashes. This article describes the causes, consequences, and statistics related to distracted driving in teenagers and an injury prevention program for teenagers.

  19. Driving Retirement in Older Adults with Dementia

    PubMed Central

    Croston, Jami; Meuser, Thomas M.; Berg-Weger, Marla; Grant, Elizabeth A.; Carr, David B.

    2010-01-01

    In order to characterize the driving and mobility status of older adults with dementia, a questionnaire was mailed to 527 informants; 119 were returned. The majority of patients were diagnosed with Dementia of the Alzheimer’s Type. Only 28% were actively driving at the time of survey. Informants rated 53% of current or recently retired drivers as potentially unsafe. Few informants reported using community/educational resources. Individuals with progressive dementia retire from driving for differing reasons, many subsequent to family recognition of impaired driving performance. Opportunities for education and supportive assistance exist but are underutilized. PMID:20161565

  20. Women drive better if not stereotyped.

    PubMed

    Moè, Angelica; Cadinu, Mara; Maass, Anne

    2015-12-01

    A commonly held stereotype is that women are poor drivers. This stereotype is recognized and endorsed by women and girls very early on, long before taking their driving licence, nevertheless they are less involved in accidents and drive safer and less fast than men. In line with the stereotype threat theory, the present study tests the hypothesis that making the driving stereotype salient will lead women to underperform in a driving simulation task. In Experiment 1women in the stereotype threat condition were told that the aim of the study was to detect gender differences in driving whereas in a control condition no study aim was provided. In Experiment 2, two conditions were compared: stereotype threat (same instructions as in Experiment 1), and stereotype boost (the alleged goal was to compare driving ability of young vs. old people). As predicted, the results of both experiments showed that women under stereotype threat, as compared to either control or stereotype boost participants, doubled the number of mistakes. Nevertheless, they overall expected/self-reported to drive/have driven poorly. Importantly, their level of expectation was a significant predictor of their actual driving performance only in the stereotype threat condition. Implications of these effects of stereotype threat on women's driving performance and self-assessment are discussed.

  1. Camshaft driving device for internal combustion engine

    SciTech Connect

    Ebesu, H.

    1988-06-14

    A camshaft driving device for use in a double overhead cam type internal combustion engine having a cylinder block, an upper deck formed at an upper portion of the cylinder block, a cylinder head disposed on the cylinder block, a driving shaft rotatably mounted at a lower portion of the cylinder block, and a pair of camshafts rotatably mounted at an upper portion of the cylinder head, is described comprising: driving force transmitting endless chain members engaging in the reduction gear means for transmitting a driving force from the driving shaft to the pair of camshaft through the reduction gear means. The camshaft driving device further including chain tensioners for tightening the chain, a nozzle means for supplying a lubricating oil to the driving force chain members on the side of the drive shaft and an oil guide wall formed immediately above the sprocket of the transmitting portion of the reduction gear means at a lower end portion of the journal boss and lapping thereover both in the radial direction and in the axial direction of the driving shaft. A mounting boss for mounting the reduction gear means thereon is formed on the upper deck of the cylinder block.

  2. Risky driving and lifestyles in adolescence.

    PubMed

    Bina, Manuela; Graziano, Federica; Bonino, Silvia

    2006-05-01

    Several studies have shown that risky driving is especially prevalent among young drivers and recent research has pointed out that driving in adolescence should be investigated in the more general context of adolescent development. The first aim of this contribution was to analyze involvement in risky driving in a normative sample of 645 Italian adolescents, boys and girls, aged 14-17, through a self-report questionnaire. A second aim was to evaluate the association between risky driving and lifestyle, defined as involvement in other health risk behaviors and leisure activities. The main results showed that many adolescents drove cars and motorcycles without the required driving license and the most frequent offences were speeding and failure to maintain a safe braking distance. Gender and age differences were also investigated. Results concerning the association between risky driving and lifestyle showed that risky driving was not an isolated behavior. Boys who displayed risky driving practices were more likely to adopt a lifestyle characterized by high involvement in antisocial behaviors, tobacco smoking, comfort eating and time spent in non-organized activities with friends. Girls involved in risky driving were more likely to be involved in other risk-taking behaviors, antisocial behaviors and drug use.

  3. Metal band drives in spacecraft mechanisms

    NASA Technical Reports Server (NTRS)

    Maus, Daryl

    1993-01-01

    Transmitting and changing the characteristics of force and stroke is a requirement in nearly all mechanisms. Examples include changing linear to rotary motion, providing a 90 deg change in direction, and amplifying stroke or force. Requirements for size, weight, efficiency and reliability create unique problems in spacecraft mechanisms. Flexible metal band and cam drive systems provide powerful solutions to these problems. Band drives, rack and pinion gears, and bell cranks are compared for effectiveness. Band drive issues are discussed including materials, bend radius, fabrication, attachment and reliability. Numerous mechanisms are shown which illustrate practical applications of band drives.

  4. Axonal pruning is actively regulated by the microtubule-destabilizing protein kinesin superfamily protein 2A.

    PubMed

    Maor-Nof, Maya; Homma, Noriko; Raanan, Calanit; Nof, Aviv; Hirokawa, Nobutaka; Yaron, Avraham

    2013-04-25

    Extensive axonal pruning and neuronal cell death are critical events for the development of the nervous system. Like neuronal cell death, axonal elimination occurs in discrete steps; however, the regulators of these processes remain mostly elusive. Here, we identify the kinesin superfamily protein 2A (KIF2A) as a key executor of microtubule disassembly and axonal breakdown during axonal pruning. Knockdown of Kif2a, but not other microtubule depolymerization or severing proteins, protects axonal microtubules from disassembly upon trophic deprivation. We further confirmed and extended this result to demonstrate that the entire degeneration process is delayed in neurons from the Kif2a knockout mice. Finally, we show that the Kif2a-null mice exhibit normal sensory axon patterning early during development, but abnormal target hyperinnervation later on, as they compete for limited skin-derived trophic support. Overall, these findings reveal a central regulatory mechanism of axonal pruning during development.

  5. Amyloid precursor protein and amyloid precursor-like protein 2 in cancer

    PubMed Central

    Pandey, Poomy; Sliker, Bailee; Peters, Haley L.; Tuli, Amit; Herskovitz, Jonathan; Smits, Kaitlin; Purohit, Abhilasha; Singh, Rakesh K.; Dong, Jixin; Batra, Surinder K.; Coulter, Donald W.; Solheim, Joyce C.

    2016-01-01

    Amyloid precursor protein (APP) and its family members amyloid precursor-like protein 1 (APLP1) and amyloid precursor-like protein 2 (APLP2) are type 1 transmembrane glycoproteins that are highly conserved across species. The transcriptional regulation of APP and APLP2 is similar but not identical, and the cleavage of both proteins is regulated by phosphorylation. APP has been implicated in Alzheimer's disease causation, and in addition to its importance in neurology, APP is deregulated in cancer cells. APLP2 is likewise overexpressed in cancer cells, and APLP2 and APP are linked to increased tumor cell proliferation, migration, and invasion. In this present review, we discuss the unfolding account of these APP family members’ roles in cancer progression and metastasis. PMID:26840089

  6. Irradiated human chondrocytes expressing bone morphogenetic protein 2 promote healing of osteoporotic bone fracture in rats.

    PubMed

    Yi, Youngsuk; Choi, Kyoung Baek; Lim, Chae-Lyul; Hyun, Jong-Pil; Lee, Hyeon-Youl; Lee, Kun Bok; Yun, Lillian; Ayverdi, Asli; Hwang, Sally; Yip, Vivian; Noh, Moon Jong; Lee, Kwan Hee

    2009-10-01

    Bone morphogenetic protein 2 (BMP2) was selected as a transgene to regenerate osteoporotic bone defects after several BMPs were tested using a bone formation study in nude mice. Human chondrocytes were transduced with a BMP2-containing retroviral vector, and single clones were selected. The cells were characterized over numerous passages for growth and BMP2 expression. The single clones were irradiated and tested for viability. BMP2 expression lasted for 3 weeks before dying off completely after approximately 1 month. Irradiated and non-irradiated transduced chondrocytes successfully healed fractures in osteoporotic rats induced by ovariectomy. The osteoinducing effect of irradiated cells was better than that of their non-irradiated counterparts or a chondrocytes-only control. This study showed that delivering BMP2 from the transduced and irradiated chondrocytes could be an effective and safe method of repairing osteoporotic bone fractures.

  7. Structure and phosphorylation of microtubule-associated protein 2 (MAP 2).

    PubMed Central

    Vallee, R

    1980-01-01

    Chymotryptic fragments of microtubule-associated protein 2 (MAP 2) containing the portion of the molecule responsible for promoting microtubule assembly were identified. These assembly-promoting fragments displaced intact MAP 2, but not MAP 1, from assembled microtubules. This indicates that the association of MAP 2 with the microtubule surface is reversible. Both the assembly-promoting fragments and fragments representing the portion of the MAP 2 molecule observed as a projection on the microtubule surface were found to contain sites for endogenous cyclic AMP-dependent phosphorylation. The projection fragments were capable of endogenous phosphorylation even after their physical separation from microtubules. This suggests an intimate association of a kinase activity with the projections. Detailed analysis of the properties of the chymotryptic fragments of MAP 2 has led to a map of the molecule showing the major sites of proteolytic attack and the sites of phosphorylation. Images PMID:6251448

  8. Dynamic regulation of uncoupling protein 2 content in INS-1E insulinoma cells.

    PubMed

    Azzu, Vian; Affourtit, Charles; Breen, Eamon P; Parker, Nadeene; Brand, Martin D

    2008-10-01

    Uncoupling protein 2 (UCP2) regulates glucose-stimulated insulin secretion in pancreatic beta-cells. UCP2 content, measured by calibrated immunoblot in INS-1E insulinoma cells (a pancreatic beta-cell model) grown in RPMI medium, and INS-1E mitochondria, was 2.0 ng/million cells (7.9 ng/mg mitochondrial protein). UCP2 content was lower in cells incubated without glutamine and higher in cells incubated with 20 mM glucose, and varied from 1.0-4.4 ng/million cells (2.7-14.5 ng/mg mitochondrial protein). This dynamic response to nutrients was achieved by varied expression rates against a background of a very short UCP2 protein half-life of about 1 h.

  9. Structural Basis for Host Membrane Remodeling Induced by Protein 2B of Hepatitis A Virus

    PubMed Central

    Vives-Adrián, Laia; Garriga, Damià; Buxaderas, Mònica; Fraga, Joana; Pereira, Pedro José Barbosa

    2015-01-01

    ABSTRACT The complexity of viral RNA synthesis and the numerous participating factors require a mechanism to topologically coordinate and concentrate these multiple viral and cellular components, ensuring a concerted function. Similarly to all other positive-strand RNA viruses, picornaviruses induce rearrangements of host intracellular membranes to create structures that act as functional scaffolds for genome replication. The membrane-targeting proteins 2B and 2C, their precursor 2BC, and protein 3A appear to be primarily involved in membrane remodeling. Little is known about the structure of these proteins and the mechanisms by which they induce massive membrane remodeling. Here we report the crystal structure of the soluble region of hepatitis A virus (HAV) protein 2B, consisting of two domains: a C-terminal helical bundle preceded by an N-terminally curved five-stranded antiparallel β-sheet that displays striking structural similarity to the β-barrel domain of enteroviral 2A proteins. Moreover, the helicoidal arrangement of the protein molecules in the crystal provides a model for 2B-induced host membrane remodeling during HAV infection. IMPORTANCE No structural information is currently available for the 2B protein of any picornavirus despite it being involved in a critical process in viral factory formation: the rearrangement of host intracellular membranes. Here we present the structure of the soluble domain of the 2B protein of hepatitis A virus (HAV). Its arrangement, both in crystals and in solution under physiological conditions, can help to understand its function and sheds some light on the membrane rearrangement process, a putative target of future antiviral drugs. Moreover, this first structure of a picornaviral 2B protein also unveils a closer evolutionary relationship between the hepatovirus and enterovirus genera within the Picornaviridae family. PMID:25589659

  10. Turning Bone Morphogenetic Protein 2 (BMP2) on and off in Mesenchymal Cells.

    PubMed

    Rogers, Melissa B; Shah, Tapan A; Shaikh, Nadia N

    2015-10-01

    The concentration, location, and timing of bone morphogenetic protein 2 (BMP2, HGNC:1069, GeneID: 650) gene expression must be precisely regulated. Abnormal BMP2 levels cause congenital anomalies and diseases involving the mesenchymal cells that differentiate into muscle, fat, cartilage, and bone. The molecules and conditions that influence BMP2 synthesis are diverse. Understandably, complex mechanisms control Bmp2 gene expression. This review includes a compilation of agents and conditions that can induce Bmp2. The currently known trans-regulatory factors and cis-regulatory elements that modulate Bmp2 expression are summarized and discussed. Bone morphogenetic protein 2 (BMP2, HGNC:1069, GeneID: 650) is a classical morphogen; a molecule that acts at a distance and whose concentration influences cell behavior. In mesenchymal cells, the concentration of BMP2 influences myogenesis, adipogenesis, chondrogenesis, and osteogenesis. Because the amount, timing, and location of BMP2 synthesis influence the allocation of cells to muscle, fat, cartilage, and bone, the mechanisms that regulate the Bmp2 gene are crucial. Key early mesodermal events that require precise Bmp2 regulation include heart specification and morphogenesis. Originally named for its osteoinductive properties, healing fractures requires BMP2. The human Bmp2 gene also has been linked to osteoporosis and osteoarthritis. In addition, all forms of pathological calcification in the vasculature and in cardiac valves involve the pro-osteogenic BMP2. The diverse tissues, mechanisms, and diseases influenced by BMP2 are too numerous to list here (see OMIM: 112261). However, in all BMP2-influenced pathologies, changes in the behavior and differentiation of pluripotent mesenchymal cells are a recurring theme. Consequently, much effort has been devoted to identifying the molecules and conditions that influence BMP2 synthesis and the complex mechanisms that control Bmp2 gene expression. This review begins with an

  11. Evaluation of Apoptosis in Immunotoxicity Testing

    PubMed Central

    Nagarkatti, Mitzi; Rieder, Sadiye Amcaoglu; Vakharia, Dilip; Nagarkatti, Prakash S.

    2014-01-01

    Immunotoxicity testing is important in determining the toxic effects of chemical substances, medicinal products, airborne pollutants, cosmetics, medical devices, and food additives. The immune system of the host is a direct target of these toxicants, and the adverse effects include serious health complications such as susceptibility to infections, cancer, allergic reactions, and autoimmune diseases. One way to investigate the harmful effects of different chemicals is to study apoptosis in immune cell populations. Apoptosis is defined as the programmed cell death, and in general, this process helps in development and maintains homeostasis. However, in the case of an insult by a toxicant, apoptosis of the immune cells can lead to immunosuppression resulting in the development of cancer and the inability to fight infections. Apoptosis is characterized by cell shrinkage, nuclear condensation, changes in cell membrane and mitochondria, DNA fragmentation into 200 base oligomers, and protein degradation by caspases. Various methods are employed in order to investigate apoptosis. These methods include direct measurement of apoptotic cells with flow cytometry and in situ labeling, as well as RNA, DNA, and protein assays that are indicative of apoptotic molecules. PMID:19967519

  12. Estrogen Regulation of Apoptosis in Osteoblasts

    PubMed Central

    Bradford, Peter G; Gerace, Ken V; Roland, Renée L; Chrzan, Brian G

    2010-01-01

    Dysregulated apoptosis is a critical failure associated with prominent degenerative diseases including osteoporosis. In bone, estrogen deficiency has been associated with accelerated osteoblast apoptosis and susceptibility to osteoporotic fractures. Hormone therapy continues to be an effective option for preventing osteoporosis and bone fractures. Induction of apoptosis in G-292 human osteoblastic cells by exposure to etoposide or the inflammatory cytokine TNFα promoted acute caspase-3/7 activity and this increased activity was inhibited by pretreatment with estradiol. Etoposide also increased the expression of a battery of apoptosis-promoting genes and this expression was also inhibited by estradiol. Among the apoptotic genes whose expression was inhibited by estradiol was ITPR1, which encodes the type 1 InsP3R. InsP3Rs are intracellular calcium channels and key proapoptotic mediators. Estradiol via estrogen receptor β1 suppresses ITPR1 gene transcription in G-292 cells. These analyses suggest that an underlying basis of the beneficial activity of estrogens in combating osteoporosis may involve the prevention of apoptosis in osteoblasts and that a key event in this process is the repression of apoptotic gene expression and inhibition of caspase-3/7. PMID:19426747

  13. Evaluation of apoptosis in immunotoxicity testing.

    PubMed

    Nagarkatti, Mitzi; Rieder, Sadiye Amcaoglu; Vakharia, Dilip; Nagarkatti, Prakash S

    2010-01-01

    Immunotoxicity testing is important in determining the toxic effects of chemical substances, medicinal products, airborne pollutants, cosmetics, medical devices, and food additives. The immune system of the host is a direct target of these toxicants, and the adverse effects include serious health complications such as susceptibility to infections, cancer, allergic reactions, and autoimmune diseases. One way to investigate the harmful effects of different chemicals is to study apoptosis in immune cell populations. Apoptosis is defined as the programmed cell death, and in general, this process helps in development and maintains homeostasis. However, in the case of an insult by a toxicant, apoptosis of the immune cells can lead to immunosuppression resulting in the development of cancer and the inability to fight infections. Apoptosis is characterized by cell shrinkage, nuclear condensation, changes in cell membrane and mitochondria, DNA fragmentation into 200 base oligomers, and protein degradation by caspases. Various methods are employed in order to investigate apoptosis. These methods include direct measurement of apoptotic cells with flow cytometry and in situ labeling, as well as RNA, DNA, and protein assays that are indicative of apoptotic molecules.

  14. Apoptosis of beta cells in diabetes mellitus.

    PubMed

    Anuradha, Rachakatla; Saraswati, Mudigonda; Kumar, Kishore G; Rani, Surekha H

    2014-11-01

    Diabetes mellitus is a multifactorial metabolic disorder characterized by hyperglycemia. Apoptosis in beta cells has been observed in response to diverse stimuli, such as glucose, cytokines, free fatty acids, leptin, and sulfonylureas, leading to the activation of polyol, hexosamine, and diacylglycerol/protein kinase-C (DAG/PKC) pathways that mediate oxidative and nitrosative stress causing the release of different cytokines. Cytokines induce the expression of Fas and tumor necrosis factor-alpha (TNF-α) by activating the transcription factor, nuclear factor-κb, and signal transducer and activator of transcription 1 (STAT-1) in the β cells in the extrinsic pathway of apoptosis. Cytokines produced in beta cells also induce proapoptotic members of the intrinsic pathway of apoptosis. The genetic alterations in apoptosis signaling machinery and the pathogenesis of diabetes include Fas, FasL, Akt, caspases, calpain-10, and phosphatase and tensin homolog (Pten). The other gene products that are involved in diabetes are nitric oxide synthase-2 (NOS2), small ubiquitin-like modifier (SUMO), apolipoprotein CIII (ApoCIII), forkhead box protein O1 (FOXO1), and Kruppel-like zinc finger protein Gli-similar 3 (GLIS3). The gene products having antiapoptotic nature are Bcl-2 and Bcl-XL. Epigenetic mechanisms play an important role in type I and type II diabetes. Further studies on the apoptotic genes and gene products in diabetics may be helpful in pharmacogenomics and individualized treatment along with antioxidants targeting apoptosis in diabetes.

  15. Sodium nitroprusside induces apoptosis of rabbit chondrocytes

    NASA Astrophysics Data System (ADS)

    Liang, Qian; Wang, Xiao-Ping; Chen, Tong-Sheng

    2013-02-01

    Osteoarthritis (OA) is characterized by a slowly progressing degradation of the matrix and destruction of articular cartilage. Apoptosis of chondrocyte is accounted for the mechanism of OA. Nitric oxide (NO), as a stimulus, has been shown to induce chondrocyte apoptosis by activating the matrix metalloproteinases (MMPs), increasing the expression of cyclooxygenase 2 (COX-2) and the level of prostaglandin E2 (PGE2), inhibiting the proteoglycan synthesis and type II collagen expression. In this study, sodium nitroprusside (SNP) was administered to be the NO donor to explore the mechanism of NO-induced apoptosis of rabbit chondrocytes obtained from six weeks old New Zealand rabbits. CCK-8 assay revealed the inhibitory effect of SNP on cell viability. We used flow cytometry (FCM) to assess the form of cell death by Annexin-V/propidium iodide (PI) double staining, and evaluate the change of mitochondrial membrane potential (ΔΨm). We found that the SNP induced chondrocyte apoptosis in a dose- and time-dependent manner and an observable reduction of ΔΨm. In conclusion, our findings indicate that SNP induces apoptosis of rabbit chondrocytes via a mitochondria-mediated pathway.

  16. BASP1 Promotes Apoptosis in Diabetic Nephropathy

    PubMed Central

    Sanchez-Niño, Maria Dolores; Sanz, Ana Belen; Lorz, Corina; Gnirke, Andrea; Rastaldi, Maria Pia; Nair, Viji; Egido, Jesus; Ruiz-Ortega, Marta

    2010-01-01

    Apoptosis contributes to the development of diabetic nephropathy (DN), but the mechanisms that lead to diabetes-induced cell death are not fully understood. Here, we combined a functional genomics screen for cDNAs that induce apoptosis in vitro with transcriptional profiling of renal biopsies from patients with DN. Twelve of the 138 full-length cDNAs that induced cell death in human embryonic kidney cells matched upregulated mRNA transcripts in tissue from human DN. Confirmatory screens identified induction of BASP1 in tubular cross sections of human DN tissue. In vitro, apoptosis-inducing conditions such as serum deprivation, high concentrations of glucose, and proinflammatory cytokines increased BASP1 mRNA and protein in human tubular epithelial cells. In normal cells, BASP1 localized to the cytoplasm, but in apoptotic cells, it colocalized with actin in the periphery. Overexpression of BASP1 induced cell death with features of apoptosis; conversely, small interfering RNA (siRNA)-mediated knockdown of BASP1 protected tubular cells from apoptosis. Supporting possible involvement of BASP1 in renal disease other than DN, we also observed significant upregulation of renal BASP1 in spontaneously hypertensive rats and a trend toward increased tubulointerstitial BASP1 mRNA in human hypertensive nephropathy. In summary, a combined functional genomics approach identified BASP1 as a proapoptotic factor in DN and possibly also in hypertensive nephropathy. PMID:20110383

  17. Caspase activation inhibits proteasome function during apoptosis.

    PubMed

    Sun, Xiao-Ming; Butterworth, Michael; MacFarlane, Marion; Dubiel, Wolfgang; Ciechanover, Aaron; Cohen, Gerald M

    2004-04-09

    The ubiquitin/proteasome system regulates protein turnover by degrading polyubiquitinated proteins. To date, all studies on the relationship of apoptosis and the proteasome have emphasized the key role of the proteasome in the regulation of apoptosis, by virtue of its ability to degrade regulatory molecules involved in apoptosis. We now demonstrate how induction of apoptosis may regulate the activity of the proteasome. During apoptosis, caspase activation results in the cleavage of three specific subunits of the 19S regulatory complex of the proteasome: S6' (Rpt5) and S5a (Rpn10), whose role is to recognize polyubiquitinated substrates of the proteasome, and S1 (Rpn2), which with S5a and S2 (Rpn1) holds together the lid and base of the 19S regulatory complex. This caspase-mediated cleavage inhibits the proteasomal degradation of ubiquitin-dependent and -independent cellular substrates, including proapoptotic molecules such as Smac, so facilitating the execution of the apoptotic program by providing a feed-forward amplification loop.

  18. Analysis of cache for streaming tape drive

    NASA Technical Reports Server (NTRS)

    Chinnaswamy, V.

    1993-01-01

    A tape subsystem consists of a controller and a tape drive. Tapes are used for backup, data interchange, and software distribution. The backup operation is addressed. During a backup operation, data is read from disk, processed in CPU, and then sent to tape. The processing speeds of a disk subsystem, CPU, and a tape subsystem are likely to be different. A powerful CPU can read data from a fast disk, process it, and supply the data to the tape subsystem at a faster rate than the tape subsystem can handle. On the other hand, a slow disk drive and a slow CPU may not be able to supply data fast enough to keep a tape drive busy all the time. The backup process may supply data to tape drive in bursts. Each burst may be followed by an idle period. Depending on the nature of the file distribution in the disk, the input stream to the tape subsystem may vary significantly during backup. To compensate for these differences and optimize the utilization of a tape subsystem, a cache or buffer is introduced in the tape controller. Most of the tape drives today are streaming tape drives. A streaming tape drive goes into reposition when there is no data from the controller. Once the drive goes into reposition, the controller can receive data, but it cannot supply data to the tape drive until the drive completes its reposition. A controller can also receive data from the host and send data to the tape drive at the same time. The relationship of cache size, host transfer rate, drive transfer rate, reposition, and ramp up times for optimal performance of the tape subsystem are investigated. Formulas developed will also show the advantages of cache watermarks to increase the streaming time of the tape drive, maximum loss due to insufficient cache, tradeoffs between cache and reposition times and the effectiveness of cache on a streaming tape drive due to idle times or interruptions due in host transfers. Several mathematical formulas are developed to predict the performance of the tape

  19. Empathic concern drives costly altruism

    PubMed Central

    FeldmanHall, Oriel; Dalgleish, Tim; Evans, Davy; Mobbs, Dean

    2015-01-01

    Why do we self-sacrifice to help others in distress? Two competing theories have emerged, one suggesting that prosocial behavior is primarily motivated by feelings of empathic other-oriented concern, the other that we help mainly because we are egoistically focused on reducing our own discomfort. Here we explore the relationship between costly altruism and these two sub-processes of empathy, specifically drawing on the caregiving model to test the theory that trait empathic concern (e.g. general tendency to have sympathy for another) and trait personal distress (e.g. predisposition to experiencing aversive arousal states) may differentially drive altruistic behavior. We find that trait empathic concern – and not trait personal distress – motivates costly altruism, and this relationship is supported by activity in the ventral tegmental area, caudate and subgenual anterior cingulate, key regions for promoting social attachment and caregiving. Together, this data helps identify the behavioral and neural mechanisms motivating costly altruism, while demonstrating that individual differences in empathic concern-related brain responses can predict real prosocial choice. PMID:25462694

  20. Variable frequency drive applications guide

    SciTech Connect

    Laloudakis, D.J.

    1991-10-01

    Traditionally, fans and pumps have been designed to be capable of handling the maximum demand of the system in which they are installed. However, quite often the actual demand can vary and it can be much lower than the original design capacity. These situations have been corrected in the past through additions of outlet dampers to fans or throttling valves to pumps. While these can be effective and simple controls they severely affect the efficiency of the system. Variable frequency (speed) is the most efficient means of capacity control. The most cost effective method of achieving variable speed capacity control is using AC adjustable frequency drives. AC adjustable frequency controls convert any fixed speed AC motor into an adjustable speed device. Adjusting the speed of a motor, by controlling the frequency of the AC power to that motor, reduces its horsepower requirements. According to pump and fan laws, capacity is proportional to speed while horsepower is proportional to the cube of the speed. Therefore, by reducing the speed of an AC motor by 20 percent the horsepower requirement is reduced by nearly 50 percent. Reduced speed through variable frequency control allows for flexibility of meeting changing weather and comfort requirements without operating costly equipment at full capacity.

  1. Drive Electric Vermont Case Study

    SciTech Connect

    Wagner, Fred; Roberts, Dave; Francfort, Jim; White, Sera

    2016-03-01

    Currently in the United States, the heavy majority of plug-in electric vehicle (PEV) sales have been in highly conducive, selected, metropolitan areas; opposed to more broad distribution across the country. The U.S. Department of Energy’s EV Everywhere Grand Challenge is looking carefully at the barriers and opportunities that exist to enable small and midsize communities to partake in the PEV market and benefit from the economic and environmental advantages of PEVs. In order to gain insight into these challenges and barriers, DOE selected a success story (i.e., Drive Electric Vermont) as the subject of this case study, as the state of Vermont is tied with Detroit, Michigan in having the highest percentage of 2014 (most recent complete data) PEV registrations for cold weather U.S. cities and has seen more than a sixfold increase in charging stations over the last three years. The overall objective of this case study was to use the lessons learned from Drive Electric Vermont to determine what activities are most effective at encouraging acquisitions of PEVs and deployment of charging infrastructure in small to midsize communities, prioritizing and sequencing their implementation, identifying robust means for extrapolation, and applying this understanding to other small to midsize communities across the nation. The Drive Electric Vermont Program was formed in 2012 with a goal of increasing the use of electrified transportation in Vermont through policy development, education and outreach, and infrastructure development. The Drive Electric Vermont Program can be broadly broken into four components: (1) strategic planning/leadership, (2) stakeholder/partnership development, (3) education and outreach, and (4) incentives. The early phases of the program focused heavily on strategic planning, and stakeholder and partnership development, followed by a transition to education and outreach activities, charging infrastructure development, and grant and incentive programs

  2. The Thermodynamics of Drunk Driving

    NASA Astrophysics Data System (ADS)

    Thompson, Robert Q.

    1997-05-01

    Chemical and instrumental tests for driving under the influence of alcohol (DUI) measure the concentration of ethanol in the breath (BrAC), while state DUI laws are described in terms of blood alcohol concentration (BAC). Consequently, accurate and fair conversion from BrAC to BAC is crucial to the judicial process. Theoretical treatment of the water-air-ethanol equilibrium system and the related blood-breath-ethanol system, based on principles from general chemistry and biology, yields an equation relating the ratio of BAC to BrAC to the absolute temperature of the breath, the fraction of water in the blood, and the enthalpy and entropy of vaporization of ethanol from aqueous solution. The model equation predicts an average value for the ratio of 2350+100, not significantly different from reported experimental values. An exponential temperature dependence is predicted and has been confirmed experimentally as well. Biological, chemical, and instrumental variables are described along with their contributions to the overall uncertainty in the value of BrAC/BAC. While the forensic science community uses, and debates, a fixed ratio of 2100, the theoretical model suggests that a value of 1880 should be used to reduce the fraction of false positives to <1%.

  3. Redundant arrays of IDE drives

    SciTech Connect

    D.A. Sanders et al.

    2002-01-02

    The authors report tests of redundant arrays of IDE disk drives for use in offline high energy physics data analysis. Parts costs of total systems using commodity EIDE disks are now at the $4000 per Terabyte level. Disk storage prices have now decreased to the point where they equal the cost per Terabyte of Storage Technology tape silos. The disks, however, offer far better granularity; even small institutions can afford to deploy systems. The tests include reports on software RAID-5 systems running under Linux 2.4 using Promise Ultra 100{trademark} disk controllers. RAID-5 protects data in case of a single disk failure by providing parity bits. Tape backup is not required. Journaling file systems are used to allow rapid recovery from crashes. The data analysis strategy is to encapsulate data and CPU processing power. Analysis for a particular part of a data set takes place on the PC where the data resides. The network is only used to put results together. They explore three methods of moving data between sites; internet transfers, not pluggable IDE disks in FireWire cases, and DVD-R disks.

  4. The Queerness of the Drive.

    PubMed

    de Lauretis, Teresa

    2017-02-16

    The view of sexuality Freud first proposed in the Three Essays on the Theory of Sexuality contains a discrepancy between the sexuality perverse and polymorphous described in the first two essays, and the biologically directed, reproductive sexuality of the third essay. According to Jean Laplanche, the theorist of psychoanalysis who is Freud's closest reader and translator, the discrepancy is due to two contradictory opinions Freud apparently held at different moments of his writing: one, that sexuality is exogenous, an effect of seduction by adults; two, that sexuality is endogenous, innate in the human biological organism. This paper focuses on Laplanche's elucidation of two aspects of sexuality present in each adult: an instinctual, hormonally based and ultimately reproductive sexual impulse, which begins at puberty, and the drive-based sexual impulses first theorized by Freud as polymorphous-perverse infantile sexuality, which begin in infancy and continue to be active thoughout the individual's life. Laplanche's rereading of Freud leads to a more complex understanding of sexuality as always deviant, in one way or another and to a greater or lesser degree, from the established social norms. So-called sexual deviance, therefore, is not a problem within the sexual but an issue within the social field.

  5. Control rod drive hydraulic system

    DOEpatents

    Ose, Richard A.

    1992-01-01

    A hydraulic system for a control rod drive (CRD) includes a variable output-pressure CR pump operable in a charging mode for providing pressurized fluid at a charging pressure, and in a normal mode for providing the pressurized fluid at a purge pressure, less than the charging pressure. Charging and purge lines are disposed in parallel flow between the CRD pump and the CRD. A hydraulic control unit is disposed in flow communication in the charging line and includes a scram accumulator. An isolation valve is provided in the charging line between the CRD pump and the scram accumulator. A controller is operatively connected to the CRD pump and the isolation valve and is effective for opening the isolation valve and operating the CRD pump in a charging mode for charging the scram accumulator, and closing the isolation valve and operating the CRD pump in a normal mode for providing to the CRD through the purge line the pressurized fluid at a purge pressure lower than the charging pressure.

  6. Drive for muscularity and drive for thinness: the impact of pro-anorexia websites.

    PubMed

    Juarez, Lilia; Soto, Ernesto; Pritchard, Mary E

    2012-01-01

    In recent years, websites that stress the message of thinness as the ideal and only choice have surfaced on the internet. The possibility that pro-anorexia websites may reinforce restrictive eating and exercise behaviors is an area of concern. In addition, friends may be influencing one another to view these websites, further contributing to drive for thinness in women and drive for muscularity in men. Three hundred male and female undergraduate psychology students responded to questionnaires assessing: internalization of pro-anorexia website content, internalization of general media content, influence of friends to view pro-anorexia websites, peer influence, drive for muscularity, and drive for thinness. Results showed internalization of pro-anorexia website content was positively correlated with drive for thinness in women, and negatively correlated with drive for muscularity in men. Internalization of pro-anorexia website content was found to be related to both drive for thinness in women and drive for muscularity in men.

  7. Gender invariance and correlates of the drive for leanness scale.

    PubMed

    Tod, David; Hall, Gareth; Edwards, Christian

    2012-09-01

    We examined the drive for leanness scale's gender invariance and its relationships with health-related behavior and body image-related drives. Men (N=342) and women (N=309) attending British universities completed the drive for leanness scale, drive for thinness scale, drive for muscularity scale, and a demographic inventory. Support for configural and metric, but not scalar, invariance emerged. Drive for leanness was positively correlated with weight training frequency, supplement use, drive for thinness, and drive for muscularity in both genders. Results provide guidance on comparing drive for leanness scale scores across gender and contribute to a coherent understanding of the drive for leanness and its correlates.

  8. Mental workload when driving in a simulator: effects of age and driving complexity.

    PubMed

    Cantin, Vincent; Lavallière, Martin; Simoneau, Martin; Teasdale, Normand

    2009-07-01

    Driving errors for older drivers may result from a higher momentary mental workload resulting from complex driving situations, such as intersections. The present study examined if the mental workload of young and older active drivers vary with the difficulty of the driving context. We adopted the probe reaction time (RT) technique to measure the workload while driving in a simulator. The technique provided clear instructions about the primary (driving) and secondary (RT) tasks. To avoid structural interference, the secondary task consisted of responding as rapidly as possible with a vocal response ("top") to an auditory stimulus. Participants drove through a continuous 26.4-km scenario including rural and urban sections and probes (stimuli) were given in a baseline static condition and in three different driving contexts embedded into the overall driving scenario. Specifically, stimuli were given randomly when (a) driving on straight roads at a constant speed, (b) approaching intersections for which the driver had to stop the car, and (c) when overtaking a slower vehicle. Unless a driving error was made, drivers did not need any emergency responses. Reaction time was defined as the temporal interval between the auditory stimulus and the onset of the corresponding verbal response detected from the analog signal of a piezo-electric microphone fixed on a headset (ms accuracy). Baseline RTs were similar for both groups. Both groups showed longer RTs when driving and RTs increased as the complexity of the driving contexts increased (driving straights, intersections, overtaking maneuvers). Compared to younger drivers, however, older drivers showed longer RTs for all driving contexts and the most complex driving context (overtaking maneuvers) yielded a disproportionate increase. In conclusion, driving leads to a greater mental workload for the older drivers than for the younger drivers and this effect was exacerbated by the more complex driving context (overtaking

  9. Apoptosis in the aged dog brain.

    PubMed

    Kiatipattanasakul, W; Nakamura, S; Hossain, M M; Nakayama, H; Uchino, T; Shumiya, S; Goto, N; Doi, K

    1996-09-01

    Apoptosis similar to that seen in Alzheimer's disease patients was found in the brain of aged dogs by the TUNEL method of detecting in situ DNA fragmentation. Apoptosis was observed in both neurons and glial cells, and was morphologically characterized by round and swollen cytoplasm and aggregated nuclear chromatin, although these changes were slight. Neurons and astrocytes in the gray matter and oligodendrocytes in the white matter were affected. The number of ApopTag-positive brain cells increased slightly with age, but was not correlated to the number of senile plaques. A good correlation between the number of ApopTag-positive cells and the dementia index was clearly found. The present study indicates that brain cell apoptosis could account for dementia in aged dogs and suggested that aged dogs may be useful as a simplified animal model for Alzheimer's disease in man.

  10. Cerulein Pancreatitis: Oxidative Stress, Inflammation, and Apoptosis

    PubMed Central

    2008-01-01

    Cerulein pancreatitis is similar to human edematous pancreatitis, manifesting with dysregulation of digestive enzyme production and cytoplasmic vacuolization, the death of acinar cells, edema formation, and infiltration of inflammatory cells into the pancreas. Reactive oxygen species are involved in nuclear factor-κB activation, cytokine expression, apoptosis and pathogenesis of pancreatitis. There is recent evidence that cerulein activates NADPH oxidase, which is a major source of reactive oxygen species during inflammation and apoptosis in pancreatic acinar cells. In addition, the Janus kinase/signal transducer and activator of transcription pathway has been suggested as being involved in inflammatory signaling in the pancreas. This review discusses the involvement of oxidative stress in inflammation and apoptosis in pancreatic acinar cells stimulated with cerulein as an in vitro model of pancreatitis. PMID:20485614

  11. Control of apoptosis by Drosophila DCAF12.

    PubMed

    Hwangbo, Dae-Sung; Biteau, Benoit; Rath, Sneha; Kim, Jihyun; Jasper, Heinrich

    2016-05-01

    Regulated Apoptosis (Programmed Cell Death, PCD) maintains tissue homeostasis in adults, and ensures proper growth and morphogenesis of tissues during development of metazoans. Accordingly, defects in cellular processes triggering or executing apoptotic programs have been implicated in a variety of degenerative and neoplastic diseases. Here, we report the identification of DCAF12, an evolutionary conserved member of the WD40-motif repeat family of proteins, as a new regulator of apoptosis in Drosophila. We find that DCAF12 is required for Diap1 cleavage in response to pro-apoptotic signals, and is thus necessary and sufficient for RHG (Reaper, Hid, and Grim)-mediated apoptosis. Loss of DCAF12 perturbs the elimination of supernumerary or proliferation-impaired cells during development, and enhances tumor growth induced by loss of neoplastic tumor suppressors, highlighting the wide requirement for DCAF12 in PCD.

  12. Apoptosis in Drosophila: which role for mitochondria?

    PubMed

    Clavier, Amandine; Rincheval-Arnold, Aurore; Colin, Jessie; Mignotte, Bernard; Guénal, Isabelle

    2016-03-01

    It is now well established that the mitochondrion is a central regulator of mammalian cell apoptosis. However, the importance of this organelle in non-mammalian apoptosis has long been regarded as minor, mainly because of the absence of a crucial role for cytochrome c in caspase activation. Recent results indicate that the control of caspase activation and cell death in Drosophila occurs at the mitochondrial level. Numerous proteins, including RHG proteins and proteins of the Bcl-2 family that are key regulators of Drosophila apoptosis, constitutively or transiently localize in mitochondria. These proteins participate in the cell death process at different levels such as degradation of Diap1, a Drosophila IAP, production of mitochondrial reactive oxygen species or stimulation of the mitochondrial fission machinery. Here, we review these mitochondrial events that might have their counterpart in human.

  13. Rapamycin drives selection against a pathogenic heteroplasmic mitochondrial DNA mutation.

    PubMed

    Dai, Ying; Zheng, Kangni; Clark, Joanne; Swerdlow, Russell H; Pulst, Stefan M; Sutton, James P; Shinobu, Leslie A; Simon, David K

    2014-02-01

    Mitochondrial DNA (mtDNA) mutations cause a variety of mitochondrial disorders for which effective treatments are lacking. Emerging data indicate that selective mitochondrial degradation through autophagy (mitophagy) plays a critical role in mitochondrial quality control. Inhibition of mammalian target of rapamycin (mTOR) kinase activity can activate mitophagy. To test the hypothesis that enhancing mitophagy would drive selection against dysfunctional mitochondria harboring higher levels of mutations, thereby decreasing mutation levels over time, we examined the impact of rapamycin on mutation levels in a human cytoplasmic hybrid (cybrid) cell line expressing a heteroplasmic mtDNA G11778A mutation, the most common cause of Leber's hereditary optic neuropathy. Inhibition of mTORC1/S6 kinase signaling by rapamycin induced colocalization of mitochondria with autophagosomes, and resulted in a striking progressive decrease in levels of the G11778A mutation and partial restoration of ATP levels. Rapamycin-induced upregulation of mitophagy was confirmed by electron microscopic evidence of increased autophagic vacuoles containing mitochondria-like organelles. The decreased mutational burden was not due to rapamycin-induced cell death or mtDNA depletion, as there was no significant difference in cytotoxicity/apoptosis or mtDNA copy number between rapamycin and vehicle-treated cells. These data demonstrate the potential for pharmacological inhibition of mTOR kinase activity to activate mitophagy as a strategy to drive selection against a heteroplasmic mtDNA G11778A mutation and raise the exciting possibility that rapamycin may have therapeutic potential for the treatment of mitochondrial disorders associated with heteroplasmic mtDNA mutations, although further studies are needed to determine if a similar strategy will be effective for other mutations and other cell types.

  14. 75 FR 47888 - IntelliDriveSM

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-08-09

    ... IntelliDrive\\SM\\ be used to support real-time performance-based management of roadways, transit systems...-time or near real-time performance-based management applications or tools be demonstrated? 5. There are... Management Demonstrations; Request for Information \\1\\ IntelliDrive is a service mark of the U.S....

  15. Epilepsy and driving: current status of research.

    PubMed

    L Devlin, Anna; Odell, Morris; L Charlton, Judith; Koppel, Sjaanie

    2012-12-01

    In many parts of the world, licensing guidelines state that drivers with medical conditions such as epilepsy are restricted or prohibited from driving. These guidelines are sometimes subjective and not strongly evidence-based, rendering the task of assessing fitness to drive a complex one. Determining fitness to drive is not only essential for maintaining the safety of individual drivers but has implications for the community at large. It is therefore important to review the current state of knowledge regarding epilepsy and driving in order to aid health professionals required to assess fitness to drive and to guide future research directions. This review outlines the functional impairments related to epilepsy and driving, treatment and management issues, motor vehicle crash risk for drivers with epilepsy, estimates of predicted seizure occurrence and concludes with a discussion of the international licensing guidelines and relevant legal issues. More comprehensive research, including investigation into the effects of antiepileptic medication on driving, could aid in the development of policies and guidelines for assessing fitness to drive.

  16. Dynamics and control of instrumented harmonic drives

    NASA Technical Reports Server (NTRS)

    Kazerooni, H.; Ellis, S. R. (Principal Investigator)

    1995-01-01

    Since torque in harmonic drives is transmitted by a pure couple, harmonic drives do not generate radial forces and therefore can be instrumented with torque sensors without interference from radial forces. The installation of torque sensors on the stationary component of harmonic drives (the Flexipline cup in this research work) produce backdrivability needed for robotic and telerobotic compliant maneuvers. Backdrivability of a harmonic drive, when used as torque increaser, means that the output shaft can be rotated via finite amount of torque. A high ratio harmonic drive is non-backdrivable because its output shaft cannot be turned by applying a torque on it. This article first develops the dynamic behavior of a harmonic drive, in particular the non-backdrivability, in terms of a sensitivity transfer function. The instrumentation of the harmonic drive with torque sensor is then described. This leads to a description of the control architecture which allows modulation of the sensitivity transfer function within the limits established by the closed-loop stability. A set of experiments on an active hand controller, powered by a DC motor coupled to an instrumented harmonic drive, is given to exhibit this method's limitations.

  17. 49 CFR 236.778 - Piece, driving.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 4 2014-10-01 2014-10-01 false Piece, driving. 236.778 Section 236.778 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Piece, driving. A crank secured to a locking shaft by means of which horizontal movement is imparted...

  18. 49 CFR 236.778 - Piece, driving.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Piece, driving. 236.778 Section 236.778 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Piece, driving. A crank secured to a locking shaft by means of which horizontal movement is imparted...

  19. 49 CFR 236.778 - Piece, driving.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 4 2011-10-01 2011-10-01 false Piece, driving. 236.778 Section 236.778 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Piece, driving. A crank secured to a locking shaft by means of which horizontal movement is imparted...

  20. 77 FR 61048 - Distracted Driving Grant Program

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-10-05

    ... National Highway Traffic Safety Administration Distracted Driving Grant Program AGENCY: National Highway... Transportation (DOT) announced the availability of funding authorized for distracted driving grants on August 24... Progress in the 21st Century Act'' (MAP-21), Public Law 112-141, which created a new distracted...

  1. 49 CFR 236.778 - Piece, driving.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 4 2013-10-01 2013-10-01 false Piece, driving. 236.778 Section 236.778 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Piece, driving. A crank secured to a locking shaft by means of which horizontal movement is imparted...

  2. 49 CFR 236.778 - Piece, driving.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 4 2012-10-01 2012-10-01 false Piece, driving. 236.778 Section 236.778 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Piece, driving. A crank secured to a locking shaft by means of which horizontal movement is imparted...

  3. Safety Education in Driving. 2nd Revision.

    ERIC Educational Resources Information Center

    Ohio State Univ., Columbus. Vocational Instructional Materials Lab.

    Intended for driving instruction students, this publication contains instructional materials for safety education. It contains six sections on facts and figures; defensive driving; safety devices; restraints; emergency situations; and other highway users. Each section consists of reading material followed by an activity or activities. A total of…

  4. Older Drivers: How Health Affects Driving

    MedlinePlus

    ... loss of consciousness or a seizure. People with diabetes-related complications should consult their healthcare team for guidance on driving. (Watch the video to learn more about driving with diabetes.) Macular degeneration can distort a person’s central vision ...

  5. Apoptosis and Necrosis in the Liver

    PubMed Central

    Guicciardi, Maria Eugenia; Malhi, Harmeet; Mott, Justin L.; Gores, Gregory J.

    2013-01-01

    Because of its unique function and anatomical location, the liver is exposed to a multitude of toxins and xenobiotics, including medications and alcohol, as well as to infection by hepatotropic viruses, and therefore, is highly susceptible to tissue injury. Cell death in the liver occurs mainly by apoptosis or necrosis, with apoptosis also being the physiologic route to eliminate damaged or infected cells and to maintain tissue homeostasis. Liver cells, especially hepatocytes and cholangiocytes, are particularly susceptible to death receptor-mediated apoptosis, given the ubiquitous expression of the death receptors in the organ. In a quite unique way, death receptor-induced apoptosis in these cells is mediated by both mitochondrial and lysosomal permeabilization. Signaling between the endoplasmic reticulum and the mitochondria promotes hepatocyte apoptosis in response to excessive free fatty acid generation during the metabolic syndrome. These cell death pathways are partially regulated by microRNAs. Necrosis in the liver is generally associated with acute injury (i.e., ischemia/reperfusion injury) and has been long considered an unregulated process. Recently, a new form of “programmed” necrosis (named necroptosis) has been described: the role of necroptosis in the liver has yet to be explored. However, the minimal expression of a key player in this process in the liver suggests this form of cell death may be uncommon in liver diseases. Because apoptosis is a key feature of so many diseases of the liver, therapeutic modulation of liver cell death holds promise. An updated overview of these concepts is given in this article. PMID:23720337

  6. A Difficult Journey: Reflections on Driving and Driving Cessation From a Team of Clinical Researchers.

    PubMed

    Liddle, Jacki; Gustafsson, Louise; Mitchell, Geoffrey; Pachana, Nancy A

    2017-02-01

    Recognizing the clinical importance and safety and well-being implications for the population, a multidisciplinary team has been researching older drivers and driving cessation issues for more than 15 years. Using empirical approaches, the team has explored quality of life and participation outcomes related to driving and nondriving for older people and has developed interventions to improve outcomes after driving cessation. The team members represent occupational therapists, medical practitioners, and clinical and neuropsychologists. While building the evidence base for driving- and driving cessation-related clinical practice, the researchers have also had first-hand experiences of interruptions to their own or parents' driving; involvement of older family members in road crashes; and provision of support during family members' driving assessment and cessation. This has led to reflection on their understandings and re-evaluation and refocusing of their perspectives in driving cessation research. This work will share the narratives of the authors and note their developing perspectives and foci within research as well as their clinical practice. Personal reflections have indicated the far-reaching implications for older drivers and family members of involvement in road crashes: the potential for interruptions to driving as a time for support and future planning and the conflicting and difficult roles of family members within the driving cessation process. Overall the lived, personal experience of the authors has reinforced the complex nature of driving and changes to driving status for the driver and their support team and the need for further research and support.

  7. DRIVE Analysis Tool Generates Custom Vehicle Drive Cycles Based on Real-World Data (Fact Sheet)

    SciTech Connect

    Not Available

    2013-04-01

    This fact sheet from the National Renewable Energy Laboratory describes the Drive-Cycle Rapid Investigation, Visualization, and Evaluation (DRIVE) analysis tool, which uses GPS and controller area network data to characterize vehicle operation and produce custom vehicle drive cycles, analyzing thousands of hours of data in a matter of minutes.

  8. Educational Biofeedback Driving Simulator as a Drink-Driving Prevention Strategy.

    ERIC Educational Resources Information Center

    Howat, Peter; And Others

    1991-01-01

    Used experimental driving simulator as basis for strategy to encourage a reduction in drunk driving prevalence using adult male subjects (n=36) who participated in a study group and controls (n=36). Results indicated study group subjects significantly decreased their drunk driving compared to the control group. (ABL)

  9. Young, Drunk, Dangerous and Driving: Underage Drinking and Driving Research Findings.

    ERIC Educational Resources Information Center

    Little, Robert; Clontz, Kenneth

    1994-01-01

    Summarizes major, recent research findings concerning illegal alcohol use and intoxicated driving among American youth. Examines what research revealed about the nature of underage drinking and driving; what health, social, and legal ramifications are associated with drinking and driving; and what characteristics and behavioral patterns are found…

  10. DriveWise: An Interdisciplinary Hospital-Based Driving Assessment Program

    ERIC Educational Resources Information Center

    O'Connor, Margaret G.; Kapust, Lissa R.; Hollis, Ann M.

    2008-01-01

    Health care professionals working with the elderly have opportunities through research and clinical practice to shape public policy affecting the older driver. This article describes DriveWise, an interdisciplinary hospital-based driving assessment program developed in response to clinical concerns about the driving safety of individuals with…

  11. Deep brain stimulation to reduce sexual drive

    PubMed Central

    Fuss, Johannes; Auer, Matthias K.; Biedermann, Sarah V.; Briken, Peer; Hacke, Werner

    2015-01-01

    To date there are few treatment options to reduce high sexual drive or sexual urges in paraphilic patients with a risk for sexual offending. Pharmacological therapy aims to reduce sexual drive by lowering testosterone at the cost of severe side effects. We hypothesize that high sexual drive could also be reduced with deep brain stimulation (DBS) of circuits that generate sexual drive. This approach would help to avoid systemic side effects of antiandrogenic drug therapies. So far the best investigated target to reduce sexual drive is the ventromedial hypothalamus, which was lesioned unilaterally and bilaterally by stereotaxic interventions in paraphilic patients in the 1970s. Here, we discuss DBS as a treatment strategy in patients with severe paraphilic disorders with a serious risk of sexual offending. There are profound ethical and practical issues associated with DBS treatment of paraphilic patients that must be solved before considering such a treatment approach. PMID:26057198

  12. Special Considerations in Distracted Driving with Teens

    PubMed Central

    Durbin, Dennis R; McGehee, Daniel V; Fisher, Donald; McCartt, Anne

    2014-01-01

    Novice teen drivers have long been known to have an increased risk of crashing, as well as increased tendencies toward unsafe and risky driving behaviors. Teens are unique as drivers for several reasons, many of which have implications specifically in the area of distracted driving. This paper reviews several of these features, including the widespread prevalence of mobile device use by teens, their lack of driving experience, the influence of peer passengers as a source of distraction, the role of parents in influencing teens’ attitudes and behaviors relevant to distracted driving and the impact of laws designed to prevent mobile device use by teen drivers. Recommendations for future research include understanding how engagement in a variety of secondary tasks by teen drivers affects their driving performance or crash risk; understanding the respective roles of parents, peers and technology in influencing teen driver behavior; and evaluating the impact of public policy on mitigating teen crash risk related to driver distraction. PMID:24776228

  13. Novel method for driving the ultrasonic motor.

    PubMed

    Kim, Hyeoung woo; Dong, Shuxiang; Laoratanakul, Pitak; Uchino, Kenji; Park, Tae gone

    2002-10-01

    This paper reports a novel driving method for an annular plate-type ultrasonic motor. Instead of the direct current/alternating current (DC/AC) converter type driver using conventional electromagnetic transformer, a compact disc-type piezoelectric transformer is used to obtain high voltage output for driving the ultrasonic motor. The piezoelectric transformer is operated in the radial vibration mode at resonance frequency close to the resonance frequency of the ultrasonic motor. Later, it was found that the piezoelectric transformer could drive the ultrasonic motor, even if their resonance frequencies are not exactly the same by incorporating the matching network in the circuit. The maximum speed of the ultrasonic motor obtained by using this driving method is over 300 rpm. It is believed that the results of this study will have impact on the integration and miniaturization of the ultrasonic motor and its driving circuit.

  14. Constant four wheel drive vehicle transaxle

    SciTech Connect

    Weismann, P.H.; Cameron, D.

    1986-04-15

    A dual differential four-wheel drive assembly is described adapted for a two-wheel drive front transaxle vehicle having an internal combustion engine with a transverse oriented crankshaft for driving the vehicle with front and rear pairs of road wheels, a transmission gear unit for the transaxle including transverse input and output shafts, and right and left laterally extending front axle drive shafts, each drive shaft having front wheel mounting means on its outboard end. The dual differential assembly consists of: housing means having a laterally extending passage therethrough aligned on a transverse axis, the housing means having first and second differential casings for associated first and second bevel gear differentials, the casings supported in laterally spaced alignment for rotation about the transverse axis, each first and second differential casing enclosing inboard and outboard side gears in meshing relation with planetary pinion gears, each casing having opposed inboard and outboard axial extensions thereon.

  15. B Chromosomes - A Matter of Chromosome Drive.

    PubMed

    Houben, Andreas

    2017-01-01

    B chromosomes are supernumerary chromosomes which are often preferentially inherited, deviating from usual Mendelian segregation. The balance between the so-called chromosome drive and the negative effects that the presence of Bs applies on the fitness of their host determines the frequency of Bs in a particular population. Drive is the key for understanding most B chromosomes. Drive occurs in many ways at pre-meiotic, meiotic or post-meiotic divisions, but the molecular mechanism remains unclear. The cellular mechanism of drive is reviewed based on the findings obtained for the B chromosomes of rye, maize and other species. How novel analytical tools will expand our ability to uncover the biology of B chromosome drive is discussed.

  16. Adjustable Speed Drive Study, Part 1.

    SciTech Connect

    Wallace, Alan K.; Oregon State University. Dept. of Electrical and Computer Engineering.

    1989-08-01

    Advances in speed control for motors in recent years, notably those in power electronics, have widened the range of application for several adjustable speed drive (ASD) types to include the smaller horsepower sizes. The dc motor drive, formerly in almost universal use for speed control, is being challenged by the high efficiency induction motor/pulse width modulation (PWM) drive; and for special small horsepower size applications, by the permanent magnet motor/PWM inverter drive or by the switched reluctance motor drive. The main characteristics of the several ASD types suitable for small horsepower size applications are discussed, as well as their unwanted side effects: poor power factor, harmonic distortion of the supply, acoustic noise, and electromagnetic interference. A procedure is recommended for determining which, if any, ASD to use. 31 figs., 6 tabs.

  17. Adjustable Speed Drive Study, Part 2.

    SciTech Connect

    Wallace, Alan K.; Oregon State University. Dept. of Electrical and Computer Engineering.

    1989-08-01

    Advances in speed control for motors in recent years, notably those in power electronics, have widened the range of application for several adjustable speed drive (ASD) types to include the smaller horsepower sizes. The DC motor drive, formerly in almost universal use for speed control, is being challenged by the high efficiency induction motor/pulse width modulation (PWM) drive; and for special small horsepower size applications, by the permanent magnet motor/PWM inverter drive or by the switched reluctance motor drive. The main characteristics of the several ASD types suitable for small horsepower size applications are discussed, as well as their unwanted side effects: poor power factor, harmonic distortion of the supply, acoustic noise, and electromagnetic interference. A procedure is recommended for determining which, if any, ASD to use.

  18. Development of a paddle drive mechanism

    NASA Astrophysics Data System (ADS)

    Hashimoto, Hidekazu; Honda, Toshio; Ohhashi, Toshiro; Wachi, Shigeo; Kai, Kouji

    The paddle drive system is a key element in a three axis stabilized spacecraft, consisting of paddle drive mechanism (PDM) and paddle drive electronics (PDE). The PDM rotates the solar array paddle and transmits electrical power and signals to spacecraft. The PDE drives and controls the PDM. The investigation and design study were initiated in early 1979. The design goal of the PDM is to handle more than 3kW of electrical power with a ten year life. The hardware development was started in early 1983, as a five year program. This paper presents the results of environmental tests and a thermal vacuum life test for the various PDM elements, such as the slip ring assembly, the stepper motor, the harmonic drive, the ratchet clutch, the spur gears, the bearings and the position indicator.

  19. Bootstrapped tokamak with oscillating field current drive

    SciTech Connect

    Weening, R.H. )

    1993-07-01

    A magnetic helicity conserving mean-field Ohm's law is used to study bootstrapped tokamaks with oscillating field current drive. The Ohm's law leads to the conclusion that the tokamak bootstrap effect can convert the largely alternating current of oscillating field current drive into a direct toroidal plasma current. This plasma current rectification is due to the intrinsically nonlinear nature of the tokamak bootstrap effect, and suggests that it may be possible to maintain the toroidal current of a tokamak reactor by supplementing the bootstrap current with oscillating field current drive. Steady-state tokamak fusion reactors operating with oscillating field current drive could provide an alternative to tokamak reactors operating with external current drive.

  20. DriveID: safety innovation through individuation.

    PubMed

    Sawyer, Ben; Teo, Grace; Mouloua, Mustapha

    2012-01-01

    The driving task is highly complex and places considerable perceptual, physical and cognitive demands on the driver. As driving is fundamentally an information processing activity, distracted or impaired drivers have diminished safety margins compared with non- distracted drivers (Hancock and Parasuraman, 1992; TRB 1998 a & b). This competition for sensory and decision making capacities can lead to failures that cost lives. Some groups, teens and elderly drivers for example, have patterns of systematically poor perceptual, physical and cognitive performance while driving. Although there are technologies developed to aid these different drivers, these systems are often misused and underutilized. The DriveID project aims to design and develop a passive, automated face identification system capable of robustly identifying the driver of the vehicle, retrieve a stored profile, and intelligently prescribing specific accident prevention systems and driving environment customizations.

  1. Inbreeding drives maize centromere evolution.

    PubMed

    Schneider, Kevin L; Xie, Zidian; Wolfgruber, Thomas K; Presting, Gernot G

    2016-02-23

    Functional centromeres, the chromosomal sites of spindle attachment during cell division, are marked epigenetically by the centromere-specific histone H3 variant cenH3 and typically contain long stretches of centromere-specific tandem DNA repeats (∼1.8 Mb in maize). In 23 inbreds of domesticated maize chosen to represent the genetic diversity of maize germplasm, partial or nearly complete loss of the tandem DNA repeat CentC precedes 57 independent cenH3 relocation events that result in neocentromere formation. Chromosomal regions with newly acquired cenH3 are colonized by the centromere-specific retrotransposon CR2 at a rate that would result in centromere-sized CR2 clusters in 20,000-95,000 y. Three lines of evidence indicate that CentC loss is linked to inbreeding, including (i) CEN10 of temperate lineages, presumed to have experienced a genetic bottleneck, contain less CentC than their tropical relatives; (ii) strong selection for centromere-linked genes in domesticated maize reduced diversity at seven of the ten maize centromeres to only one or two postdomestication haplotypes; and (iii) the centromere with the largest number of haplotypes in domesticated maize (CEN7) has the highest CentC levels in nearly all domesticated lines. Rare recombinations introduced one (CEN2) or more (CEN5) alternate CEN haplotypes while retaining a single haplotype at domestication loci linked to these centromeres. Taken together, this evidence strongly suggests that inbreeding, favored by postdomestication selection for centromere-linked genes affecting key domestication or agricultural traits, drives replacement of the tandem centromere repeats in maize and other crop plants. Similar forces may act during speciation in natural systems.

  2. Recombination Drives Vertebrate Genome Contraction

    PubMed Central

    Nam, Kiwoong; Ellegren, Hans

    2012-01-01

    Selective and/or neutral processes may govern variation in DNA content and, ultimately, genome size. The observation in several organisms of a negative correlation between recombination rate and intron size could be compatible with a neutral model in which recombination is mutagenic for length changes. We used whole-genome data on small insertions and deletions within transposable elements from chicken and zebra finch to demonstrate clear links between recombination rate and a number of attributes of reduced DNA content. Recombination rate was negatively correlated with the length of introns, transposable elements, and intergenic spacer and with the rate of short insertions. Importantly, it was positively correlated with gene density, the rate of short deletions, the deletion bias, and the net change in sequence length. All these observations point at a pattern of more condensed genome structure in regions of high recombination. Based on the observed rates of small insertions and deletions and assuming that these rates are representative for the whole genome, we estimate that the genome of the most recent common ancestor of birds and lizards has lost nearly 20% of its DNA content up until the present. Expansion of transposable elements can counteract the effect of deletions in an equilibrium mutation model; however, since the activity of transposable elements has been low in the avian lineage, the deletion bias is likely to have had a significant effect on genome size evolution in dinosaurs and birds, contributing to the maintenance of a small genome. We also demonstrate that most of the observed correlations between recombination rate and genome contraction parameters are seen in the human genome, including for segregating indel polymorphisms. Our data are compatible with a neutral model in which recombination drives vertebrate genome size evolution and gives no direct support for a role of natural selection in this process. PMID:22570634

  3. MicroRNA-133a-1 regulates inflammasome activation through uncoupling protein-2.

    PubMed

    Bandyopadhyay, Sayantani; Lane, Troy; Venugopal, Rajanbabu; Parthasarathy, Prasanna Tamarapu; Cho, Young; Galam, Lakshmi; Lockey, Richard; Kolliputi, Narasaiah

    2013-09-27

    Inflammasomes are multimeric protein complexes involved in the processing of IL-1β through Caspase-1 cleavage. NLRP3 is the most widely studied inflammasome, which has been shown to respond to a large number of both endogenous and exogenous stimuli. Although studies have begun to define basic pathways for the activation of inflammasome and have been instrumental in identifying therapeutics for inflammasome related disorders; understanding the inflammasome activation at the molecular level is still incomplete. Recent functional studies indicate that microRNAs (miRs) regulate molecular pathways and can lead to diseased states when hampered or overexpressed. Mechanisms involving the miRNA regulatory network in the activation of inflammasome and IL-1β processing is yet unknown. This report investigates the involvement of miR-133a-1 in the activation of inflammasome (NLRP3) and IL-1β production. miR-133a-1 is known to target the mitochondrial uncoupling protein 2 (UCP2). The role of UCP2 in inflammasome activation has remained elusive. To understand the role of miR-133a-1 in regulating inflammasome activation, we either overexpressed or suppressed miR-133a-1 in differentiated THP1 cells that express the NLRP3 inflammasome. Levels of Caspase-1 and IL-1β were analyzed by Western blot analysis. For the first time, we showed that overexpression of miR-133a-1 increases Caspase-1 p10 and IL-1β p17 cleavage, concurrently suppressing mitochondrial uncoupling protein 2 (UCP2). Surprisingly, our results demonstrated that miR-133A-1 controls inflammasome activation without affecting the basal expression of the individual inflammasome components NLRP3 and ASC or its immediate downstream targets proIL-1β and pro-Caspase-1. To confirm the involvement of UCP2 in the regulation of inflammasome activation, Caspase-1 p10 and IL-1β p17 cleavage in UCP2 of overexpressed and silenced THP1 cells were studied. Suppression of UCP2 by siRNA enhanced the inflammasome activity stimulated

  4. Mitochondrial DNA damage induces apoptosis in senescent cells

    PubMed Central

    Laberge, R-M; Adler, D; DeMaria, M; Mechtouf, N; Teachenor, R; Cardin, G B; Desprez, P-Y; Campisi, J; Rodier, F

    2013-01-01

    Senescence is a cellular response to damage and stress. The senescence response prevents cancer by suppressing the proliferation of cells with a compromised genome and contributes to optimal wound healing in normal tissues. Persistent senescent cells are also thought to drive aging and age-associated pathologies through their secretion of inflammatory factors that modify the tissue microenvironment and alter the function of nearby normal or transformed cells. Understanding how senescent cells alter the microenvironment would be aided by the ability to induce or eliminate senescent cells at will in vivo. Here, we combine the use of the synthetic nucleoside analog ganciclovir (GCV) with herpes simplex virus thymidine kinase (HSVtk) activity to create or eliminate senescent human cells. We show that low concentrations of GCV induce senescence through the accumulation of nuclear DNA damage while higher concentrations of GCV, similar to those used in vivo, kill non-dividing senescent cells via mitochondrial DNA (mtDNA) damage and caspase-dependent apoptosis. Using this system, we effectively eliminated xenografted normal human senescent fibroblasts or induced senescence in human breast cancer cells in vivo. Thus, cellular senescence and mtDNA damage are outcomes of synthetic nucleoside analog treatment, indicating that the GCV–HSVtk combination can be used effectively to promote the targeted formation or eradication of senescent cells. PMID:23868060

  5. Mitochondrial DNA damage induces apoptosis in senescent cells.

    PubMed

    Laberge, R-M; Adler, D; DeMaria, M; Mechtouf, N; Teachenor, R; Cardin, G B; Desprez, P-Y; Campisi, J; Rodier, F

    2013-07-18

    Senescence is a cellular response to damage and stress. The senescence response prevents cancer by suppressing the proliferation of cells with a compromised genome and contributes to optimal wound healing in normal tissues. Persistent senescent cells are also thought to drive aging and age-associated pathologies through their secretion of inflammatory factors that modify the tissue microenvironment and alter the function of nearby normal or transformed cells. Understanding how senescent cells alter the microenvironment would be aided by the ability to induce or eliminate senescent cells at will in vivo. Here, we combine the use of the synthetic nucleoside analog ganciclovir (GCV) with herpes simplex virus thymidine kinase (HSVtk) activity to create or eliminate senescent human cells. We show that low concentrations of GCV induce senescence through the accumulation of nuclear DNA damage while higher concentrations of GCV, similar to those used in vivo, kill non-dividing senescent cells via mitochondrial DNA (mtDNA) damage and caspase-dependent apoptosis. Using this system, we effectively eliminated xenografted normal human senescent fibroblasts or induced senescence in human breast cancer cells in vivo. Thus, cellular senescence and mtDNA damage are outcomes of synthetic nucleoside analog treatment, indicating that the GCV-HSVtk combination can be used effectively to promote the targeted formation or eradication of senescent cells.

  6. Downregulation of the CCK-B receptor in pancreatic cancer cells blocks proliferation and promotes apoptosis

    PubMed Central

    Fino, Kristin K.; Matters, Gail L.; McGovern, Christopher O.; Gilius, Evan L.

    2012-01-01

    Gastrin stimulates the growth of pancreatic cancer cells through the activation of the cholecystokinin-B receptor (CCK-BR), which has been found to be overexpressed in pancreatic cancer. In this study, we proposed that the CCK-BR drives growth of pancreatic cancer; hence, interruption of CCK-BR activity could potentially be an ideal target for cancer therapeutics. The effect of CCK-BR downregulation in the human pancreatic adenocarcinoma cells was examined by utilizing specific CCK-BR-targeted RNA interference reagents. The CCK-BR receptor expression was both transiently and stably downregulated by transfection with selective CCK-BR small-interfering RNA or short-hairpin RNA, respectively, and the effects on cell growth and apoptosis were assessed. CCK-BR downregulation resulted in reduced cancer cell proliferation, decreased DNA synthesis, and cell cycle arrest as demonstrated by an inhibition of G1 to S phase progression. Furthermore, CCK-BR downregulation increased caspase-3 activity, TUNEL-positive cells, and decreased X-linked inhibitor of apoptosis protein expression, suggesting apoptotic activity. Pancreatic cancer cell mobility was decreased when the CCK-BR was downregulated, as assessed by a migration assay. These results show the importance of the CCK-BR in regulation of growth and apoptosis in pancreatic cancer. Strategies to decrease the CCK-BR expression and activity may be beneficial for the development of new methods to improve the treatment for patients with pancreatic cancer. PMID:22442157

  7. Stress response and apoptosis in pro- and antiinflammatory macrophages.

    PubMed

    Malyshev, I Yu; Kruglov, S V; Bakhtina, L Yu; Malysheva, E V; Zubin, M; Norkin, M

    2004-08-01

    We showed that stress response and apoptosis in macrophages depend on the phenotype of their secretory activity and specific biological and physical characteristics of the factor inducing stress-response or apoptosis.

  8. Causal Network Models for Predicting Compound Targets and Driving Pathways in Cancer.

    PubMed

    Jaeger, Savina; Min, Junxia; Nigsch, Florian; Camargo, Miguel; Hutz, Janna; Cornett, Allen; Cleaver, Stephen; Buckler, Alan; Jenkins, Jeremy L

    2014-06-01

    Gene-expression data are often used to infer pathways regulating transcriptional responses. For example, differentially expressed genes (DEGs) induced by compound treatment can help characterize hits from phenotypic screens, either by correlation with known drug signatures or by pathway enrichment. Pathway enrichment is, however, typically computed with DEGs rather than "upstream" nodes that are potentially causal of "downstream" changes. Here, we present graph-based models to predict causal targets from compound-microarray data. We test several approaches to traversing network topology, and show that a consensus minimum-rank score (SigNet) beat individual methods and could highly rank compound targets among all network nodes. In addition, larger, less canonical networks outperformed linear canonical interactions. Importantly, pathway enrichment using causal nodes rather than DEGs recovers relevant pathways more often. To further validate our approach, we used integrated data sets from the Cancer Genome Atlas to identify driving pathways in triple-negative breast cancer. Critical pathways were uncovered, including the epidermal growth factor receptor 2-phosphatidylinositide 3-kinase-AKT-MAPK growth pathway andATR-p53-BRCA DNA damage pathway, in addition to unexpected pathways, such as TGF-WNT cytoskeleton remodeling, IL12-induced interferon gamma production, and TNFR-IAP (inhibitor of apoptosis) apoptosis; the latter was validated by pooled small hairpin RNA profiling in cancer cells. Overall, our approach can bridge transcriptional profiles to compound targets and driving pathways in cancer.

  9. Driving under the influence of cannabis: links with dangerous driving, psychological predictors, and accident involvement.

    PubMed

    Richer, Isabelle; Bergeron, Jacques

    2009-03-01

    Driving under the influence of cannabis (DUIC) has become a growing concern. Studies investigating the impact of DUIC on traffic safety have shown evidence that, during the acute period of cannabis intoxication, cannabis diminishes driving faculties and is associated with an elevated risk of collision. However, DUIC drivers seem to exhibit a general reckless driving style that may contribute to an over-estimation of DUIC-related collisions among this group. In this study, we investigated DUIC drivers with respect to self-reported dangerous driving habits (e.g., risky driving, aggressive driving and negative emotional driving), behaviours observed in a driving simulator, psychological predictors and crash involvement. Results suggest that DUIC is associated with self-reported and observed risky driving and negative emotional driving. We also found that sensation seeking and impulsivity are independent psychological predictors of DUIC. Finally, a trend suggests that self-reported DUIC is associated with an increased risk of being involved in a car accident, after controlling for dangerous driving and demographic variables. Implications for interventions are discussed.

  10. Capillary morphogenesis protein-2 is the major receptor mediating lethality of anthrax toxin in vivo.

    PubMed

    Liu, Shihui; Crown, Devorah; Miller-Randolph, Sharmina; Moayeri, Mahtab; Wang, Hailun; Hu, Haijing; Morley, Thomas; Leppla, Stephen H

    2009-07-28

    Anthrax toxin, a major virulence factor of Bacillus anthracis, gains entry into target cells by binding to either of 2 von Willebrand factor A domain-containing proteins, tumor endothelium marker-8 (TEM8) and capillary morphogenesis protein-2 (CMG2). The wide tissue expression of TEM8 and CMG2 suggest that both receptors could play a role in anthrax pathogenesis. To explore the roles of TEM8 and CMG2 in normal physiology, as well as in anthrax pathogenesis, we generated TEM8- and CMG2-null mice and TEM8/CMG2 double-null mice by deleting TEM8 and CMG2 transmembrane domains. TEM8 and CMG2 were found to be dispensable for mouse development and life, but both are essential in female reproduction in mice. We found that the lethality of anthrax toxin for mice is mostly mediated by CMG2 and that TEM8 plays only a minor role. This is likely because anthrax toxin has approximately 11-fold higher affinity for CMG2 than for TEM8. Finally, the CMG2-null mice are also shown to be highly resistant to B. anthracis spore infection, attesting to the importance of both anthrax toxin and CMG2 in anthrax infections.

  11. Slit-Robo GTPase-Activating Protein 2 as a metastasis suppressor in osteosarcoma

    PubMed Central

    Marko, Tracy A.; Shamsan, Ghaidan A.; Edwards, Elizabeth N.; Hazelton, Paige E.; Rathe, Susan K.; Cornax, Ingrid; Overn, Paula R.; Varshney, Jyotika; Diessner, Brandon J.; Moriarity, Branden S.; O’Sullivan, M. Gerard; Odde, David J.; Largaespada, David A.

    2016-01-01

    Osteosarcoma is the most common primary bone tumor, with metastatic disease responsible for most treatment failure and patient death. A forward genetic screen utilizing Sleeping Beauty mutagenesis in mice previously identified potential genetic drivers of osteosarcoma metastasis, including Slit-Robo GTPase-Activating Protein 2 (Srgap2). This study evaluates the potential role of SRGAP2 in metastases-associated properties of osteosarcoma cell lines through Srgap2 knockout via the CRISPR/Cas9 nuclease system and conditional overexpression in the murine osteosarcoma cell lines K12 and K7M2. Proliferation, migration, and anchorage independent growth were evaluated. RNA sequencing and immunohistochemistry of human osteosarcoma tissue samples were used to further evaluate the potential role of the Slit-Robo pathway in osteosarcoma. The effects of Srgap2 expression modulation in the murine OS cell lines support the hypothesis that SRGAP2 may have a role as a suppressor of metastases in osteosarcoma. Additionally, SRGAP2 and other genes in the Slit-Robo pathway have altered transcript levels in a subset of mouse and human osteosarcoma, and SRGAP2 protein expression is reduced or absent in a subset of primary tumor samples. SRGAP2 and other axon guidance proteins likely play a role in osteosarcoma metastasis, with loss of SRGAP2 potentially contributing to a more aggressive phenotype. PMID:27966608

  12. Pravastatin activates activator protein 2 alpha to argument the angiotensin II-induced abdominal aortic aneurysms.

    PubMed

    Ma, Hui; Liang, Wen-Jing; Shan, Mei-Rong; Wang, Xue-Qing; Zhou, Sheng-Nan; Chen, Yuan; Guo, Tao; Li, Peng; Yu, Hai-Ya; Liu, Chao; Yin, Ya-Ling; Wang, Yu-Lin; Dong, Bo; Pang, Xin-Yan; Wang, Shuang-Xi

    2017-02-04

    We have previously reported that activation of AMP-activated kinase alpha 2 (AMPKα2) by nicotine or angiotensin II (AngII) instigates formation of abdominal aortic aneurysms (AAA) in Apoe-/- mice. Statins, used to treat hyperlipidemia widely, activate AMPK in vascular cells. We sought to examine the effects of pravastatin on AAA formation and uncover the molecular mechanism. The AAA model was induced by AngII and evaluated by incidence, elastin degradation, and maximal abdominal aortic diameter in Apoe-/- mice. The phosphorylated levels of AMPKα2 and activator protein 2 alpha (AP-2α) were examined in cultured vascular smooth muscle cells (VSMCs) or in mice. We observed that pravastatin (50 mg/kg/day, 8 weeks) remarkably increased the AngII-induced AAA incidence in mice. In VSMCs, pravastatin increased the levels of pAMPK, pAP-2α, and MMP2 in both basal and AngII-stressed conditions, which were abolished by tempol and compound C. Pravastatin-upregulated MMP2 was abrogated by AMPKα2 or AP-2α siRNA. Lentivirus-mediated gene silence of AMPKα2 or AP-2α abolished pravastatin-worsened AAA formations in AngII-infused Apoe-/- mice. Clinical investigations demonstrated that both AMPKα2 and AP-2α phosphorylations were increased in AAA patients or human subjects taking pravastatin. In conclusion, pravastatin promotes AAA formation through AMPKα2-dependent AP-2α activations.

  13. Enzymatic crosslinking and degradation of gelatin as a switch for bone morphogenetic protein-2 activity.

    PubMed

    Kuwahara, Kenrick; Fang, Josephine Y; Yang, Zhi; Han, Bo

    2011-12-01

    Current therapies for tissue regeneration rely on the presence or direct delivery of growth factors to sites of repair. Bone morphogenetic protein-2 (BMP-2), combined with a carrier (usually collagen), is clinically proven to induce new bone formation during spinal fusion and nonunion repair. However, due to BMP-2's short half-life and its diffusive properties, orders of magnitude above physiological levels are required to ensure effectiveness. In addition, a high dose of this multifunctional growth factor is known to induce adverse effects in patients. To circumvent these challenges, we proposed and tested a new approach for BMP-2 delivery, by controlling BMP activity via carrier binding and localized proteolysis. BMP-2 was covalently bound to gelatin through site-specific enzymatic crosslinking using a microbial transglutaminase. Binding of BMP-2 to gelatin can completely switch off BMP-2 activity, as evidenced by loss of its transdifferentiating ability toward C2C12 promyoblasts. When gelatin sequestered BMP-2 is incubated with either microbial collagenase or tissue-derived matrix metalloproteinases, BMP-2 activity is fully restored. The activity of released BMP-2 correlates with the protease activity in a dose- and time-dependent manner. This observation suggests a novel way of delivering BMP-2 and controlling its activity. This improved delivery method, which relies on a physiological feedback, should enhance the known potential of this and other growth factors for tissue repair and regeneration.

  14. Latent TGF-β binding protein 2 and 4 have essential overlapping functions in microfibril development

    PubMed Central

    Fujikawa, Yusuke; Yoshida, Hideyuki; Inoue, Tadashi; Ohbayashi, Tetsuya; Noda, Kazuo; von Melchner, Harald; Iwasaka, Toshiji; Shiojima, Ichiro; Akama, Tomoya O.; Nakamura, Tomoyuki

    2017-01-01

    Microfibrils are exracellular matrix components necessary for elastic fiber assembly and for suspending lenses. We previously reported that latent TGF-β binding protein 2 (LTBP-2), a microfibril-associated protein, is required for forming stable microfibril bundles in ciliary zonules. However, it was not understood why Ltbp2 null mice only showed an eye-specific phenotype, whereas LTBP-2 is abundantly expressed in other tissues containing microfibrils in wild type mice. Here, we show that LTBP-4, another microfibril-associated protein, compensates for the loss of LTBP-2 in microfibril formation. Ltbp2/4S double knockout (DKO) mice showed increased lethality due to emphysema, which was much more severe than that found in Ltbp4S null mice. Elastic fibers in the lungs of Ltbp2/4S DKO mice were severely disorganized and fragmented. Cultured mouse embryonic fibroblasts (MEFs) from Ltbp2/4S DKO embryos developed reduced microfibril meshwork in serum-free conditions, whereas the microfibril formation was restored by the addition of either recombinant LTBP-2 or -4. Finally, ectopic expression of LTBP-4 in the whole body restored ciliary zonule microfibril bundles in the eyes of Ltbp2 null mice. These data suggest that LTBP-2 and -4 have critical overlapping functions in forming the robust structure of microfibrils in vitro and in vivo. PMID:28252045

  15. Activation of activator protein 2 alpha by aspirin alleviates atherosclerotic plaque growth and instability in vivo

    PubMed Central

    Yang, Jing-Jing; Li, Peng; Wang, Fu; Liang, Wen-Jing; Ma, Hui; Chen, Yuan; Ma, Zhi-Min; Li, Quan-Zhong; Peng, Qi-Sheng; Zhang, Yun; Wang, Shuang-Xi

    2016-01-01

    Aims Aspirin has been used for the secondary prevention and treatment of cardiovascular disease for several decades. We investigated the roles of transcriptional factor activator protein 2α (AP-2α) in the beneficial effects of aspirin in the growth and vulnerability of atherosclerotic plaque. Methods and Results In mice deficient of apolipoprotein E (Apoe-/-), aspirin (20, 50 mg/kg/day) suppressed the progression of atherosclerosis in aortic roots and increased the plaque stability in carotid atherosclerotic plaques induced by collar-placement. In vivo lentivirus-mediated RNA interference of AP-2α reversed the inhibitory effects of aspirin on atherosclerosis in Apoe-/- mice. Mechanically, aspirin increased AP-2α phosphorylation and its activity, upregulated IkBα mRNA and protein levels, and reduced oxidative stress in cultured vascular smooth muscle cells. Furthermore, deficiency of AP-2α completely abolished aspirin-induced upregulation of IkBα levels and inhibition of oxidative stress in Apoe-/- mice. Clinically, conventional doses of aspirin increased AP-2α phosphorylation and IkBα protein expression in humans subjects. Conclusion Aspirin activates AP-2α to upregulate IkBα gene expression, resulting in attenuations of plaque development and instability in atherosclerosis. PMID:27391154

  16. Disruption of chromodomain helicase DNA binding protein 2 (CHD2) causes scoliosis.

    PubMed

    Kulkarni, Shashikant; Nagarajan, Prabakaran; Wall, Jonathan; Donovan, Diana J; Donell, Robert L; Ligon, Azra H; Venkatachalam, Sundaresan; Quade, Bradley J

    2008-05-01

    Herein we characterize an apparently balanced de novo translocation, t(X;15)(p22.2;q26.1)dn, in a female patient with scoliosis, hirsutism, learning problems, and developmental delay (DGAP025). Other clinical findings include a high-arched palate, 2-3 syndactyly of the toes, and mildly elevated serum testosterone. No known or predicted genes are disrupted by the Xp22.2 breakpoint. The 15q26.1 breakpoint disrupts chromodomain helicase DNA binding protein 2 (CHD2). Another member of the chromatin-remodeling gene family, CHD7, has been associated with a defined constellation of congenital anomalies known as coloboma, heart anomaly, choanal atresia, mental retardation, genital and ear anomalies syndrome (CHARGE) and idiopathic scoliosis. Monosomy of 15q26 also has been associated with a spectrum of congenital abnormalities and growth retardation that overlaps with those of DGAP025. To provide a biological correlate, we characterized a mutant mouse model with Chd2 disruption that is associated with embryonic and perinatal lethality. Expression analysis indicated that Chd2 is expressed in the heart, forebrain, extremities, facial and dorsal regions during specific times of embryonic development. Chd2(+/m) mice showed pronounced lordokyphosis, reduced body fat, postnatal runting, and growth retardation. These data suggest that haploinsufficiency for CHD2 could result in a complex of abnormal human phenotypes that includes scoliosis and possibly features similar to CHARGE syndrome.

  17. Recombinant antibodies specific for the Plasmodium falciparum histidine-rich protein 2

    PubMed Central

    Ravaoarisoa, Elisabeth; Zamanka, Halima; Fusai, Thierry; Bellalou, Jacques; Bedouelle, Hugues; Mercereau-Puijalon, Odile

    2010-01-01

    Early diagnosis and appropriate treatment are key elements of malaria control programs in endemic areas. A major step forward in recent years has been the production and use of rapid diagnostic tests (RDTs) in settings where microscopy is impracticable. Many current RDTs target the Plasmodium falciparum histidine-rich protein 2 (PfHRP2) released in the plasma of infected individuals. These RDTs have had an indisputably positive effect on malaria management, but still present several limitations, including the poor characterization of the commercial monoclonal antibodies (mAbs) used for PfHRP2 detection, variable sensitivity and specificity and high costs. RDT use is further limited by impaired stability caused by temperature fluctuations during transport and uncontrolled storage in field-based facilities. To circumvent such drawbacks, an alternative could be the development of well-characterized, stabilized recombinant antibodies, with high binding affinity and specificity. Here, we report the characterization of the cDNA sequences encoding the Fab fragment of F1110 and F1546, two novel anti-PfHRP2 mAbs. FabF1546 was produced in the Escherichia coli periplasm. Its properties of binding to the parasite and to a recombinant PfHRP-2 antigen were similar to those of the parental mAb. As the affinity and stability of recombinant antibodies can be improved by protein engineering, our results open a novel approach for the development of an improved RDT for malaria diagnosis. PMID:20581462

  18. Plasma Surface Modification for Immobilization of Bone Morphogenic Protein-2 on Polycaprolactone Scaffolds

    NASA Astrophysics Data System (ADS)

    Kim, Byung Hoon; Myung, Sung Woon; Jung, Sang Chul; Ko, Yeong Mu

    2013-11-01

    The immobilization of recombinant human bone formation protein-2 (rhBMP-2) on polycaprolactone (PCL) scaffolds was performed by plasma polymerization. RhBMP-2, which induces osteoblast differentiation in various cell types, is a growth factor that plays an important role in bone formation and repair. The surface of the PCL scaffold was functionalized with the carboxyl groups of plasma-polymerized acrylic acid (PPAA) thin films. Plasma polymerization was carried out at a discharge power of 60 W at an acrylic acid flow rate of 7 sccm for 5 min. The PPAA thin film exhibited moderate hydrophilic properties and possessed a high density of carboxyl groups. Carboxyl groups and rhBMP-2 on the PCL scaffolds surface were identified by attenuated total reflection Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy, respectively. The alkaline phosphatase activity assay showed that the rhBMP-2 immobilized PCL scaffold increased the level of MG-63 cell differentiation. Plasma surface modification for the preparation of biomaterials, such as biofunctionalized polymer scaffolds, can be used for the binding of bioactive molecules in tissue engineering.

  19. Iron-independent phosphorylation of iron regulatory protein 2 regulates ferritin during the cell cycle.

    PubMed

    Wallander, Michelle L; Zumbrennen, Kimberly B; Rodansky, Eva S; Romney, S Joshua; Leibold, Elizabeth A

    2008-08-29

    Iron regulatory protein 2 (IRP2) is a key iron sensor that post-transcriptionally regulates mammalian iron homeostasis by binding to iron-responsive elements (IREs) in mRNAs that encode proteins involved in iron metabolism (e.g. ferritin and transferrin receptor 1). During iron deficiency, IRP2 binds IREs to regulate mRNA translation or stability, whereas during iron sufficiency IRP2 is degraded by the proteasome. Here, we identify an iron-independent IRP2 phosphorylation site that is regulated by the cell cycle. IRP2 Ser-157 is phosphorylated by Cdk1/cyclin B1 during G(2)/M and is dephosphorylated during mitotic exit by the phosphatase Cdc14A. Ser-157 phosphorylation during G(2)/M reduces IRP2 RNA-binding activity and increases ferritin synthesis, whereas Ser-157 dephosphorylation during mitotic exit restores IRP2 RNA-binding activity and represses ferritin synthesis. These data show that reversible phosphorylation of IRP2 during G(2)/M has a role in modulating the iron-independent expression of ferritin and other IRE-containing mRNAs during the cell cycle.

  20. Angiopoietin-like protein 2 induces proinflammatory responses in peritoneal cells

    PubMed Central

    Umikawa, Masato; Umikawa, Asako; Asato, Tsuyoshi; Takei, Kimiko; Matsuzaki, Goro; Kariya, Ken-ichi; Zhang, Cheng Cheng

    2015-01-01

    Monocytes and macrophages are important effectors and regulators of inflammation, and both their differentiation and activation are regulated strictly in response to environmental cues. Angiopoietin-like protein 2 (Angptl2) is a multifaceted protein, displaying many physiological and pathological functions in inflammation, angiogenesis, hematopoiesis, and tumor development. Although recent studies implicate Angptl2 in chronic inflammation, the mechanisms of inflammation caused by Angptl2 remain unclear. The purpose of the present study was to elucidate the role of Angptl2 in inflammation by understanding the effects of Angptl2 on monocytes/macrophages. We showed that Angptl2 directly activates resident murine peritoneal monocytes and macrophages and induces a drastic upregulation of the transcription of several inflammatory genes including nitric oxide synthase 2 and prostaglandin-endoperoxide synthase 2, and several proinflammatory cytokine genes such as interleukin (IL)-1β, IL-6, TNFα, and CSF2, along with activation of ERK, JNK, p38, and nuclear factor kappa B signaling pathways. Concordantly, proinflammatory cytokines IL-1β, IL-6, TNFα, and GM-CSF, were rapidly elavated from murine peritoneal monocytes and macrophages. These results demonstrate a novel role for Angptl2 in inflammation via the direct activation of peritoneal monocytes and macrophages. PMID:26435501

  1. Submicellar bile salts stimulate phosphatidylcholine transfer activity of sterol carrier protein 2.

    PubMed

    Leonard, A N; Cohen, D E

    1998-10-01

    To explore a potential role for sterol carrier protein 2 (SCP2, also known as non-specific lipid transfer protein) in hepatocellular phospholipid trafficking, we examined the influence of submicellar bile salt concentrations on phosphatidylcholine (PC) transfer activity of SCP2. We measured rate constants for first-order transfer of sn-1 palmitoyl, sn-2 parinaroyl PC, a naturally fluorescent self-quenching phospholipid between model membranes. Purified bovine liver SCP2 promoted transfer of PC from donor to acceptor small unilamellar vesicles. Taurine- and glycine-conjugated bile salts (anionic steroid detergent-like molecules), at concentrations well below their critical micellar concentrations, stimulated PC transfer activity of SCP2 80- to 140-fold. Rate constants increased in proportion to bile salt concentration, temperature, and bile salt-membrane binding affinity. Sodium taurofusidate, a conjugated fungal bile salt analog, also activated PC transfer whereas no effect was observed with the anionic and non-ionic straight chain detergents sodium dodecyl sulfate and octylglucoside, respectively. Thermodynamic and kinetic analyses of PC transfer support a mechanism in which bile salts stimulate SCP2 activity by partitioning into donor vesicles and enhancing membrane association of SCP2. These results imply that under physiological conditions, SCP2 may contribute to hepatocellular selection and transport of biliary PCs.

  2. Uncoupling protein 2 negatively regulates glucose-induced glucagon-like peptide 1 secretion.

    PubMed

    Zhang, Hongjie; Li, Jing; Liang, Xiangying; Luo, Yun; Zen, Ke; Zhang, Chen-Yu

    2012-04-01

    It is known that endogenous levels of the incretin hormone glucagon-like peptide 1 (GLP1) can be enhanced by various secretagogues, but the mechanism underlying GLP1 secretion is still not fully understood. We assessed the possible effect of uncoupling protein 2 (UCP2) on GLP1 secretion in mouse intestinal tract and NCI-H716 cells, a well-characterized human enteroendocrine L cell model. Localization of UCP2 and GLP1 in the gastrointestinal tract was assessed by immunofluorescence staining. Ucp2 mRNA levels in gut were analyzed by quantitative RT-PCR. Human NCI-H716 cells were transiently transfected with siRNAs targeting UCP2. The plasma and ileum tissue levels of GLP1 (7-36) amide were measured using an ELISA kit. UCP2 was primarily expressed in the mucosal layer and colocalized with GLP1 in gastrointestinal mucosa. L cells secreting GLP1 also expressed UCP2. After glucose administration, UCP2-deficient mice showed increased glucose-induced GLP1 secretion compared with wild-type littermates. GLP1 secretion increased after NCI-H716 cells were transfected with siRNAs targeting UCP2. UCP2 was markedly upregulated in ileum tissue from ob/ob mice, and GLP1 secretion decreased compared with normal mice. Furthermore, GLP1 secretion increased after administration of genipin by oral gavage. Taken together, these results reveal an inhibitory role of UCP2 in glucose-induced GLP1 secretion.

  3. A mathematical model of the sterol regulatory element binding protein 2 cholesterol biosynthesis pathway.

    PubMed

    Bhattacharya, Bonhi S; Sweby, Peter K; Minihane, Anne-Marie; Jackson, Kim G; Tindall, Marcus J

    2014-05-21

    Cholesterol is one of the key constituents for maintaining the cellular membrane and thus the integrity of the cell itself. In contrast high levels of cholesterol in the blood are known to be a major risk factor in the development of cardiovascular disease. We formulate a deterministic nonlinear ordinary differential equation model of the sterol regulatory element binding protein 2 (SREBP-2) cholesterol genetic regulatory pathway in a hepatocyte. The mathematical model includes a description of genetic transcription by SREBP-2 which is subsequently translated to mRNA leading to the formation of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), a main regulator of cholesterol synthesis. Cholesterol synthesis subsequently leads to the regulation of SREBP-2 via a negative feedback formulation. Parameterised with data from the literature, the model is used to understand how SREBP-2 transcription and regulation affects cellular cholesterol concentration. Model stability analysis shows that the only positive steady-state of the system exhibits purely oscillatory, damped oscillatory or monotic behaviour under certain parameter conditions. In light of our findings we postulate how cholesterol homeostasis is maintained within the cell and the advantages of our model formulation are discussed with respect to other models of genetic regulation within the literature.

  4. Numerous phosphates of microtubule-associated protein 2 in living rat brain

    SciTech Connect

    Tsuyama, S.; Terayama, Y.; Matsuyama, S.

    1987-08-05

    Microtubule-associated protein 2 (MAP 2) purified from microwave-irradiated rat head contained about 46 esterified phosphates (mole/mol), which were not bound covalently to lipids and did not assemble with microtubules. After some phosphates were released by calf intestinal alkaline phosphatase, the phosphate content of MAP-2 decreased to 16 mol of phosphate and the protein assembled in vitro. MAP-2 purified after microtubule assembly cycles and also the cytosolic heat-stable fraction without assembly cycles had 10 mol of phosphate, and both assembled with microtubules. The MAP-2 with 46 phosphates and that with 10 had different pI in isoelectric focusing, but the components, MAP-2a and -2b, were always near each other. In high-pressure liquid chromatography, MAP-2 containing 46 mol of phosphate appeared after that 10 mol of phosphate. Phosphoserine, phosphothreonine, and phosphotyrosine were recovered from tryptic digestion of MAP-2 with 46 mol of phosphate. These findings suggest that two kinds of MAP-2, one with 46 phosphates and not bound to tubulin and the other with 10-16 phosphates and bound to tubulin, are present in the living rat brain.

  5. Preferential increase in the hippocampal synaptic vesicle protein 2A (SV2A) by pentylenetetrazole kindling.

    PubMed

    Ohno, Yukihiro; Ishihara, Shizuka; Terada, Ryo; Kikuta, Miki; Sofue, Nobumasa; Kawai, Yoshiko; Serikawa, Tadao; Sasa, Masashi

    2009-12-18

    The present study evaluated the expressional levels of synaptic vesicle protein 2A (SV2A) and other secretary machinery proteins (i.e., soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes, Munc18-1, N-ethylmaleimide-sensitive factor (NSF) and soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP)) in a pentylenetetrazole (PTZ) kindling model. Repeated administration of sub-convulsive PTZ (40 mg/kg, i.p.) progressively increased seizure susceptibility in mice and consistently induced clonic seizures in most animals tested at 15 days after the treatment. Western blot analysis revealed that, among the secretary machinery proteins examined, hippocampal SV2A was selectively elevated by PTZ kindling. PTZ kindling-induced SV2A expression appeared region-specific and the SV2A levels in the cerebral cortex or cerebellum were unaltered. In addition, SV2A expression by PTZ kindling was prominent in the hilar region of the dentate gyrus (DG) where GABAergic interneurons are located, but not in other hippocampal regions (e.g., the stratum lucidum of the CA3 and synaptic layers surrounding CA1 or CA3 pyramidal neurons). These findings suggest that PTZ kindling preferentially elevates SV2A expression in the hippocampus probably as a compensatory mechanism to activate the inhibitory neurotransmission.

  6. ING2 (inhibitor of growth protein-2) plays a crucial role in preimplantation development.

    PubMed

    Zhou, Lin; Wang, Pei; Zhang, Juanjuan; Heng, Boon Chin; Tong, Guo Qing

    2016-02-01

    ING2 (inhibitor of growth protein-2) is a member of the ING-gene family and participates in diverse cellular processes involving tumor suppression, DNA repair, cell cycle regulation, and cellular senescence. As a subunit of the Sin3 histone deacetylase complex co-repressor complex, ING2 binds to H3K4me3 to regulate chromatin modification and gene expression. Additionally, ING2 recruits histone methyltransferase (HMT) activity for gene repression, which is independent of the HDAC class I or II pathway. However, the physiological function of ING2 in mouse preimplantation embryo development has not yet been characterized previously. The expression, localization and function of ING2 during preimplantation development were investigated in this study. We showed increasing expression of ING2 within the nucleus from the 4-cell embryo stage onwards; and that down-regulation of ING2 expression by endoribonuclease-prepared small interfering RNA (esiRNA) microinjection results in developmental arrest during the morula to blastocyst transition. Embryonic cells microinjected with ING2-specific esiRNA exhibited decreased blastulation rate compared to the negative control. Further investigation of the underlying mechanism indicated that down-regulation of ING2 significantly increased expression of p21, whilst decreasing expression of HDAC1. These results suggest that ING2 may play a crucial role in the process of preimplantation embryo development through chromatin regulation.

  7. Sterol carrier protein-2 localization in endoplasmic reticulum and role in phospholipid formation.

    PubMed

    Starodub, O; Jolly, C A; Atshaves, B P; Roths, J B; Murphy, E J; Kier, A B; Schroeder, F

    2000-10-01

    Although sterol carrier protein-2 (SCP-2; also called nonspecific lipid transfer protein) binds fatty acids and fatty acyl-CoAs, its role in fatty acid metabolism is not fully understood. L-cell fibroblasts stably expressing SCP-2 were used to resolve the relationship between SCP-2 intracellular location and fatty acid transacylation in the endoplasmic reticulum. Indirect immunofluorescence double labeling and laser scanning confocal microscopy detected SCP-2 in peroxisomes > endoplasmic reticulum > mitochondria > lysosomes. SCP-2 enhanced incorporation of exogenous [(3)H]oleic acid into phospholipids and triacylglycerols of overexpressing cells 1.6- and 2.5-fold, respectively, stimulated microsomal incorporation of [1-(14)C]oleoyl-CoA into phosphatidic acid in vitro 13-fold, and exhibited higher specificity for unsaturated versus saturated fatty acyl-CoA. SCP-2 enhanced the rate-limiting step in microsomal phosphatidic acid biosynthesis mediated by glycerol-3-phosphate acyltransferase. SCP-2 also enhanced microsomal acyl-chain remodeling of phosphatidylethanolamine up to fivefold and phosphatidylserine twofold, depending on the specific fatty acyl-CoA, but had no effect on other phospholipid classes. In summary, these results were consistent with a role for SCP-2 in phospholipid synthesis in the endoplasmic reticulum.

  8. Influences of reduced expression of maternal bone morphogenetic protein 2 on mouse embryonic development.

    PubMed

    Singh, A P; Castranio, T; Scott, G; Guo, D; Harris, M A; Ray, M; Harris, S E; Mishina, Y

    2008-01-01

    Bone morphogenetic protein 2 (BMP2) was originally found by its osteoinductive ability, and recent genetic analyses have revealed that it plays critical roles during early embryogenesis, cardiogenesis, decidualization as well as skeletogenesis. In the course of evaluation of the conditional allele for Bmp2, we found that the presence of a neo cassette, a selection marker needed for gene targeting events in embryonic stem cells, in the 3' untranslated region of exon 3 of Bmp2, reduced the expression levels of Bmp2 both in embryonic and maternal mouse tissues. Some of the embryos that were genotyped as transheterozygous for the floxed allele with the neo cassette over the conventional null allele (fn/-) showed a lethal phenotype including defects in cephalic neural tube closure and ventral abdominal wall closure. The number of embryos exhibiting these abnormalities was increased when, due to different genotypes, expression levels of Bmp2 in maternal tissues were lower. These results suggest that the expression levels of Bmp2 in both embryonic and maternal tissues influence the normal neural tube closure and body wall closure with different thresholds.

  9. Musashi RNA-binding protein 2 regulates estrogen receptor 1 function in breast cancer.

    PubMed

    Kang, M-H; Jeong, K J; Kim, W Y; Lee, H J; Gong, G; Suh, N; Győrffy, B; Kim, S; Jeong, S-Y; Mills, G B; Park, Y-Y

    2017-03-23

    Musashi RNA-binding protein 2 (MSI2) has important roles in human cancer. However, the regulatory mechanisms by which MSI2 alters breast cancer pathophysiology have not been clearly identified. Here we demonstrate that MSI2 directly regulates estrogen receptor 1 (ESR1), which is a well-known therapeutic target and has been shown to reflect clinical outcomes in breast cancer. Based on gene expression data analysis, we found that MSI2 expression was highly enriched in estrogen receptor (ER)-positive breast cancer and that MSI2 expression was significantly correlated with ESR1 expression, including expression of ESR1 downstream target genes. In addition, MSI2 levels were associated with clinical outcomes. MSI2 influenced breast cancer cell growth by altering ESR1 function. MSI2 alters ESR1 by binding specific sites in ESR1 RNA and by increasing ESR1 protein stability. Taken together, our findings identified a novel regulatory mechanism of MSI2 as an upstream regulator of ESR1 and revealed the clinical relevance of the RNA-binding protein MSI2 in breast cancer.

  10. Angiopoietin-like protein 2 as a potential biomarker for colorectal cancer

    PubMed Central

    YOSHINAGA, TAKUMA; SHIGEMITSU, TAKAMASA; NISHIMATA, HIROTO; KITAZONO, MASAKI; HORI, EMIKO; TOMIYOSHI, AYAKO; TAKEI, TAKAYUKI; YOSHIDA, MASAHIRO

    2015-01-01

    Colorectal cancer (CRC) is the third most common malignancy worldwide. Disease progression leads to its spread to other organs, such as the liver, and is associated with higher mortality rates. Early CRC detection is therefore crucial for maximizing the chances of complete cure. The measurement of serum-based tumor biomarkers has shown great potential for the detection of CRC. In this study, we investigated the feasibility of using angiopoietin-like protein 2 (ANGPTL2) as a candidate biomarker for CRC. We first investigated ANGPTL2 expression in 7 CRC cell lines, among which Colo320, NCC-CoCK-115P, Caco-2 and Colo205 exhibited comparatively high ANGPTL2 expression. The serum levels of ANGPTL2 in CRC patients (3.45±1.30 ng/ml) were higher compared with those in healthy controls (2.74±0.64 ng/ml) (P<0.05). A receiver operating characteristic analysis demonstrated that the diagnostic performance of ANGPTL2 was marginally lower compared with that of the established biomarker C-reactive protein, but higher compared with that of carbohydrate antigen 19-9. These results suggested that the simultaneous measurement of ANGPTL2, along with previously established serum biomarkers, may increase the likelihood of early detection of CRC. PMID:26623054

  11. A novel cranioplasty technique incorporating cancellous femoral bone and recombinant bone morphogenic protein 2.

    PubMed

    Wang, Frederick; Hoang, Don; Medvecky, Michael; Amankulor, Nduka; Teng, Edward; Narayan, Deepak

    2012-07-01

    Large calvarial defects in the setting of chronic infection and limited autologous donor sites present challenging problems for the reconstructive surgeon. We report on a novel osteogenic implant as a potential calvarial reconstruction solution. Two patients with an extensive history of severe traumatic brain injury and multiple cranial operations desired delayed calvarial reconstruction subsequent to removal of infected acrylic and titanium implants. These patients underwent harvesting of cancellous femoral bone and bone marrow, which was placed between 2 layers of recombinant bone morphogenic protein 2 impregnated in acellular collagen sponges and an outer layer of sturdily pliable Vicryl mesh to create a moldable osteogenic implant construct. The construct was molded into the shape of the defect and secured with sutures to the skull surrounding the defect. The osteogenic implant showed evidence of bone formation and maintained coverage over the original calvarial defect at 26 months postoperatively as well as subjective satisfaction by both patients and the senior surgeon. This technically straightforward technique with acceptable functional and aesthetic outcomes may be useful to reconstructing selected calvarial defects.

  12. Increased expression of lysosome membrane protein 2 in glomeruli of patients with idiopathic membranous nephropathy.

    PubMed

    Rood, Ilse M; Merchant, Michael L; Wilkey, Daniel W; Zhang, Terry; Zabrouskov, Vlad; van der Vlag, Johan; Dijkman, Henry B; Willemsen, Brigith K; Wetzels, Jack F; Klein, Jon B; Deegens, Jeroen K

    2015-11-01

    Urinary microvesicles constitute a rich source of membrane-bound and intracellular proteins that may provide important clues of pathophysiological mechanisms in renal disease. In the current study, we analyzed and compared the proteome of urinary microvesicles from patients with idiopathic membranous nephropathy (iMN), idiopathic focal segmental glomerulosclerosis (iFSGS), and normal controls using an approach that combined both proteomics and pathology analysis. Lysosome membrane protein-2 (LIMP-2) was increased greater than twofold in urinary microvesicles obtained from patients with iMN compared to microvesicles of patients with iFSGS and normal controls. Immunofluorescence analysis of renal biopsies confirmed our proteomics findings that LIMP-2 was upregulated in glomeruli from patients with iMN but not in glomeruli of diseased patients (iFSGS, minimal change nephropathy, IgA nephropathy, membranoproliferative glomerulonephritis) and normal controls. Confocal laser microscopy showed co-localization of LIMP-2 with IgG along the glomerular basement membrane. Serum antibodies against LIMP-2 could not be detected. In conclusion, our data show the value of urinary microvesicles in biomarker discovery and provide evidence for de novo expression of LIMP-2 in glomeruli of patients with iMN.

  13. Uncoupling protein 2 in the glial response to stress: implications for neuroprotection.

    PubMed

    Hass, Daniel T; Barnstable, Colin J

    2016-08-01

    Reactive oxygen species (ROS) are free radicals thought to mediate the neurotoxic effects of several neurodegenerative disorders. In the central nervous system, ROS can also trigger a phenotypic switch in both astrocytes and microglia that further aggravates neurodegeneration, termed reactive gliosis. Negative regulators of ROS, such as mitochondrial uncoupling protein 2 (UCP2) are neuroprotective factors that decrease neuron loss in models of stroke, epilepsy, and parkinsonism. However, it is unclear whether UCP2 acts purely to prevent ROS production, or also to prevent gliosis. In this review article, we discuss published evidence supporting the hypothesis that UCP2 is a neuroprotective factor both through its direct effects in decreasing mitochondrial ROS and through its effects in astrocytes and microglia. A major effect of UCP2 activation in glia is a change in the spectrum of secreted cytokines towards a more anti-inflammatory spectrum. There are multiple mechanisms that can control the level or activity of UCP2, including a variety of metabolites and microRNAs. Understanding these mechanisms will be key to exploitingthe protective effects of UCP2 in therapies for multiple neurodegenerative conditions.

  14. Uncoupling protein 2 in the glial response to stress: implications for neuroprotection

    PubMed Central

    Hass, Daniel T.; Barnstable, Colin J.

    2016-01-01

    Reactive oxygen species (ROS) are free radicals thought to mediate the neurotoxic effects of several neurodegenerative disorders. In the central nervous system, ROS can also trigger a phenotypic switch in both astrocytes and microglia that further aggravates neurodegeneration, termed reactive gliosis. Negative regulators of ROS, such as mitochondrial uncoupling protein 2 (UCP2) are neuroprotective factors that decrease neuron loss in models of stroke, epilepsy, and parkinsonism. However, it is unclear whether UCP2 acts purely to prevent ROS production, or also to prevent gliosis. In this review article, we discuss published evidence supporting the hypothesis that UCP2 is a neuroprotective factor both through its direct effects in decreasing mitochondrial ROS and through its effects in astrocytes and microglia. A major effect of UCP2 activation in glia is a change in the spectrum of secreted cytokines towards a more anti-inflammatory spectrum. There are multiple mechanisms that can control the level or activity of UCP2, including a variety of metabolites and microRNAs. Understanding these mechanisms will be key to exploitingthe protective effects of UCP2 in therapies for multiple neurodegenerative conditions. PMID:27651753

  15. Structure of Dehydroergosterol Monohydrate and Interaction with Sterol Carrier Protein-2

    PubMed Central

    McIntosh, Avery L.; Atshaves, Barbara P.; Gallegos, Adalberto M.; Storey, Stephen M.; Reibenspies, Joseph H.; Kier, Ann B.; Meyer, Edgar; Schroeder, Friedhelm

    2008-01-01

    Dehydroergosterol [ergosta-5,7,9(11),22-tetraen-3β-ol] is a naturally-occurring, fluorescent sterol utilized extensively to probe membrane cholesterol distribution, cholesterol-protein interactions, and intracellular cholesterol transport both in vitro and in vivo. In aqueous solutions, the low solubility of dehydroergosterol results in the formation of monohydrate crystals similar to cholesterol. Low temperature x-ray diffraction analysis reveals that dehydroergosterol monohydrate crystallizes in the space group P21 with 4 molecules in the unit cell and monoclinic crystal parameters a = 9.975(1)Å, b = 7.4731(9)Å, c = 34.054(4)Å, and β = 92.970(2)° somewhat similar to ergosterol monohydrate. The molecular arrangement is in a slightly closer packed bilayer structure resembling cholesterol monohydrate. Since dehydroergosterol fluorescence emission undergoes a quantum yield enhancement and red-shift of its maximum wavelength when crystallized, formation or disruption of microcrystals was monitored with high sensitivity using cuvette-based spectroscopy and multi-photon laser scanning imaging microscopy (MPLSM). This manuscript reports on the dynamical effect of sterol carrier protein-2 (SCP-2) interacting between aqueous dispersions of dehydroergosterol monohydrate microcrystal donors and acceptors consisting not only of model membranes but also vesicles derived from plasma membranes isolated by biochemical fractionation and affinity purification from Madin-Darby canine kidney cells. Furthermore, this study provides real-time measurements of the effect of increased SCP-2 levels on the rate of disappearance of dehydroergosterol microcrystals in living cells. PMID:19020914

  16. Quantitative Immunofluorescent Blotting of the Multidrug Resistance-associated Protein 2 (MRP2)

    PubMed Central

    Gerk, Phillip M.

    2011-01-01

    Introduction Quantitation of the expression levels of proteins involved in drug transport and disposition is needed to overcome limitations of film-based detection of chemiluminescent immunoblots. Purpose The purpose was to describe and validate a quantitative immunofluorescent blotting method for detection of ATP-Binding Cassette Transporter Isoform C2/Multidrug Resistance-associated Protein 2 (ABCC2/MRP2). Methods Western blotting was performed by electrophoresis of membrane vesicle protein isolated from Sf9 cells overexpressing MRP2 subsequently blotting with infrared labeled secondary antibody. The bound complex was detected using the Odyssey Infrared Imaging System (Li-Cor; Lincoln, NE). The images were analyzed using the Odyssey Application Software to obtain the integrated intensities, followed by linear regression of the intensity data. Results The limits of quantitation for the time-insensitive technique described here were from 0.001μg to 0.5μg of total membrane protein, the coefficient of variation of the slope was 8.9%; r2 values were 0.986 ± 0.012. The utility and sensitivity of this technique was demonstrated in quantitating expression of MRP2 in human placental tissue samples, in which MRP2 was present in low abundance. Discussion The immunofluorescent blotting technique described provides sensitive, reproducible, and quantitative determinations of large, integral membrane proteins such as MRP2, all with potential long-term cost savings. PMID:21277982

  17. Structural insights into Cydia pomonella pheromone binding protein 2 mediated prediction of potentially active semiochemicals

    PubMed Central

    Tian, Zhen; Liu, Jiyuan; Zhang, Yalin

    2016-01-01

    Given the advantages of behavioral disruption application in pest control and the damage of Cydia pomonella, due progresses have not been made in searching active semiochemicals for codling moth. In this research, 31 candidate semiochemicals were ranked for their binding potential to Cydia pomonella pheromone binding protein 2 (CpomPBP2) by simulated docking, and this sorted result was confirmed by competitive binding assay. This high predicting accuracy of virtual screening led to the construction of a rapid and viable method for semiochemicals searching. By reference to binding mode analyses, hydrogen bond and hydrophobic interaction were suggested to be two key factors in determining ligand affinity, so is the length of molecule chain. So it is concluded that semiochemicals of appropriate chain length with hydroxyl group or carbonyl group at one head tended to be favored by CpomPBP2. Residues involved in binding with each ligand were pointed out as well, which were verified by computational alanine scanning mutagenesis. Progress made in the present study helps establish an efficient method for predicting potentially active compounds and prepares for the application of high-throughput virtual screening in searching semiochemicals by taking insights into binding mode analyses. PMID:26928635

  18. Overexpression of adenylate cyclase-associated protein 2 is a novel prognostic marker in malignant melanoma.

    PubMed

    Masugi, Yohei; Tanese, Keiji; Emoto, Katsura; Yamazaki, Ken; Effendi, Kathryn; Funakoshi, Takeru; Mori, Mariko; Sakamoto, Michiie

    2015-12-01

    Malignant melanoma is one of the lethal malignant tumors worldwide. Previously we reported that adenylate cyclase-associated protein 2 (CAP2), which is a well-conserved actin regulator, was overexpressed in hepatocellular carcinoma; however, CAP2 expression in other clinical cancers remains unclear. The aim of the current study was to clarify the clinicopathological significance of CAP2 overexpression in malignant melanoma. Immunohistochemical analyses revealed that many melanoma cells exhibited diffuse cytoplasmic expression of CAP2, whereas no normal melanocytes showed detectable immunostaining for CAP2. A high level of CAP2 expression was seen in 14 of 50 melanomas and was significantly correlated with greater tumor thickness and nodular melanoma subtypes. In addition, a high level of CAP2 expression was associated with poor overall survival in univariate and multivariate analyses. For 13 patients, samples of primary and metastatic melanoma tissue were available: four patients exhibited higher levels of CAP2 expression in metastatic tumor compared to the primary site, whereas no patient showed lower levels of CAP2 expression in metastatic melanomas. Our findings show that CAP2 overexpression is a novel prognostic marker in malignant melanoma and that CAP2 expression seems to increase stepwise during tumor progression, suggesting the involvement of CAP2 in the aggressive behavior of malignant melanoma.

  19. Interaction and dynamics of homologous pairing protein 2 (HOP2) and DNA studied by MD simulation

    NASA Astrophysics Data System (ADS)

    Moktan, Hem; Pezza, Roberto; Zhou, Donghua

    2015-03-01

    The homologous pairing protein 2 (Hop2) plays an important role in meiosis and DNA repair. Together with protein Mnd1, Hop2 enhances the strand invasion activity of recombinase Dmc1 by over 30 times, facilitating proper synapsis of homologous chromosomes. We recently determined the NMR structure of the N-terminal domain of Hop2 and proposed a model of Protein-DNA complex based on NMR chemical shift perturbations and mutagenesis studies (Moktan, J Biol Chem 2014 10.1074/jbc.M114.548180). However structure and dynamics of the complex have not been studied at the atomic level yet. Here, we used classical MD simulations to study the interactions between the N-terminal HOP2 and DNA. The simulated results indicate that helix3 (H3) interacts with DNA in major groove and wing1 (W1) interacts mostly in minor groove mainly via direct hydrogen bonds. Also it is found that binding leads to reduced fluctuations in both protein and DNA. Several water bridge interactions have been identified. The residue-wise contributions to the interaction energy were evaluated. Also the functional motion of the protein is analyzed using principal component analysis. The results confirmed the importance of H3 and W1 for the stability of the complex, which is consistent with our previous experimental studies.

  20. Large Variation in Detection of Histidine-Rich Protein 2 in Plasmodium falciparum Isolates from Colombia

    PubMed Central

    Pava, Zuleima; Echeverry, Diego F.; Díaz, Gustavo; Murillo, Claribel

    2010-01-01

    Most rapid diagnostic tests (RDTs) available use histidine-rich protein 2 (HRP2) as a target. However, it has been reported that sequence variations of this protein affects its sensitivity. Currently, there is insufficient evidence for HRP2 variability in Plasmodium falciparum isolates from Colombia and its relationship with RDT performance. To determine possible geographic differences and their effects on the performance of RDTs, 22 blood samples from patients with P. falciparum malaria from Tumaco and Buenaventura, Colombia were assessed by measurement of HRP2 concentration by an HRP2 enzyme-linked immunosorbent assay, RDTs, and thick blood smear. Statistical analysis showed an association between RDT performance and HRP2 concentrations. No significant difference was found between locations. A large variation of antigen concentration in samples was found at same parasitemia. In contrast to previously reports, there was no correlation between initial parasitemia and HRP2 concentration. Our results indicate that antigen quantity should be studied more carefully because the sensitivity of the RDT is affected more by antigen concentration than by parasitemia. PMID:20889875

  1. Identification of Motile Sperm Domain–Containing Protein 2 as Regulator of Human Monocyte Migration

    PubMed Central

    Yacov, Niva; Salem, Yaniv; Propheta-Meiran, Oshrat; Ishai, Eti; Breitbart, Eyal

    2017-01-01

    Binding of chemokines to their cognate receptors on monocytes instigates a cascade of events that directs these cells to migrate to sites of inflammation and cancerous tissues. Although targeting of selected chemokine receptors on monocytes exhibited preclinical efficacy, attempts to translate these studies to the clinic have failed thus far, possibly due to redundancy of the target receptor. We reveal that motile sperm domain–containing protein 2 (MOSPD2), a protein with a previously unknown function, regulates monocyte migration in vitro. This protein was found to be expressed on the cytoplasmic membrane of human monocytes. Silencing or neutralizing MOSPD2 in monocytes restricted their migration when induced by different chemokines. Mechanistically, silencing MOSPD2 inhibited signaling events following chemokine receptor ligation. When tested for expression in other immune cell subsets, MOSPD2 was apparent also, though less abundantly, in neutrophils, but not in lymphocytes. Thus, in the presence of neutralizing Abs, neutrophil migration was inhibited to some extent whereas lymphocyte migration remained intact. In view of these results, we suggest MOSPD2 as a potential target protein for treating diseases in which monocyte and neutrophil accumulation is correlated with pathogenesis. PMID:28137892

  2. Purification of bone morphogenetic protein-2 from refolding mixtures using mixed-mode membrane chromatography.

    PubMed

    Gieseler, Gesa; Pepelanova, Iliyana; Stuckenberg, Lena; Villain, Louis; Nölle, Volker; Odenthal, Uwe; Beutel, Sascha; Rinas, Ursula; Scheper, Thomas

    2017-01-01

    In this study, we present the development of a process for the purification of recombinant human bone morphogenetic protein-2 (rhBMP-2) using mixed-mode membrane chromatography. RhBMP-2 was produced as inclusion bodies in Escherichia coli. In vitro refolding using rapid dilution was carried out according to a previously established protocol. Different membrane chromatography phases were analyzed for their ability to purify BMP-2. A membrane phase with salt-tolerant properties resulting from mixed-mode ligand chemistry was able to selectively purify BMP-2 dimer from refolding mixtures. No further purification or polishing steps were necessary and high product purity was obtained. The produced BMP-2 exhibited a biological activity of 7.4 × 10(5) U/mg, comparable to commercial preparations. Mixed-mode membrane chromatography can be a valuable tool for the direct purification of proteins from solutions with high-conductivity, for example refolding buffers. In addition, in this particular case, it allowed us to circumvent the use of heparin-affinity chromatography, thus allowing the design of an animal-component-free process.

  3. Immunologically relevant strain polymorphism in the Amastigote Surface Protein 2 of Trypanosoma cruzi.

    PubMed

    Claser, Carla; Espíndola, Noeli Maria; Sasso, Gisela; Vaz, Adelaide José; Boscardin, Silvia B; Rodrigues, Mauricio M

    2007-07-01

    Several evidences suggest that the Amastigote Surface Protein-2 (ASP-2) of Trypanosoma cruzi is an important target for immunity during infection. Based on this, we considered it important to evaluate its strain polymorphism. Initially, we observed the presence of conserved cross-reactive epitopes in amastigotes of all parasite strains tested. In addition, the predicted amino acid sequences of the genes isolated from the cDNA of amastigotes of CL-Brener, Tulahuen, Colombian and G strains displayed a high degree of identity (>80%) to the previously described genes of ASP-2. Unexpectedly, Sylvio X10/4 and G strains expressed a new isoform of ASP-2 with limited identity to the previously described genes, but with a high degree of identity when compared to each other. Immunological studies confirmed the presence of cross-reactive epitopes between recombinant proteins representing the different isoforms of ASP-2. However, the genetic vaccination of mice with the new isoform of asp-2 gene expressed by the G strain failed to provide the same degree of protective immunity to a challenge by parasites of the Y strain as did asp-2 genes of Y or CL-Brener strains. In summary, we found that few strains can express different isoforms of ASP-2 which may not share cross-protective epitopes.

  4. Induction by leptin of uncoupling protein-2 and enzymes of fatty acid oxidation

    PubMed Central

    Zhou, Yan-Ting; Shimabukuro, Michio; Koyama, Kazunori; Lee, Young; Wang, May-Yun; Trieu, Falguni; Newgard, Christopher B.; Unger, Roger H.

    1997-01-01

    We have studied mechanisms by which leptin overexpression, which reduces body weight via anorexic and thermogenic actions, induces triglyceride depletion in adipocytes and nonadipocytes. Here we show that leptin alters in pancreatic islets the mRNA of the genes encoding enzymes of free fatty acid metabolism and uncoupling protein-2 (UCP-2). In animals infused with a recombinant adenovirus containing the leptin cDNA, the levels of mRNAs encoding enzymes of mitochondrial and peroxisomal oxidation rose 2- to 3-fold, whereas mRNA encoding an enzyme of esterification declined in islets from hyperleptinemic rats. Islet UCP-2 mRNA rose 6-fold. All in vivo changes occurred in vitro in normal islets cultured with recombinant leptin, indicating direct extraneural effects. Leptin overexpression increased UCP-2 mRNA by more than 10-fold in epididymal, retroperitoneal, and subcutaneous fat tissue of normal, but not of leptin–receptor-defective obese rats. By directly regulating the expression of enzymes of free fatty acid metabolism and of UCP-2, leptin controls intracellular triglyceride content of certain nonadipocytes, as well as adipocytes. PMID:9177227

  5. Effects of Osseointegration by Bone Morphogenetic Protein-2 on Titanium Implants In Vitro and In Vivo

    PubMed Central

    Teng, Fu-Yuan; Chen, Wen-Cheng; Wang, Yin-Lai; Hung, Chun-Cheng; Tseng, Chun-Chieh

    2016-01-01

    This study designed a biomimetic implant for reducing healing time and achieving early osseointegration to create an active surface. Bone morphogenetic protein-2 (BMP-2) is a strong regulator protein in osteogenic pathways. Due to hardly maintaining BMP-2 biological function and specificity, BMP-2 efficient delivery on implant surfaces is the main challenge for the clinic application. In this study, a novel method for synthesizing functionalized silane film for superior modification with BMP-2 on titanium surfaces is proposed. Three groups were compared with and without BMP-2 on modified titanium surfaces in vitro and in vivo: mechanical grinding; electrochemical modification through potentiostatic anodization (ECH); and sandblasting, alkali heating, and etching (SMART). Cell tests indicated that the ECH and SMART groups with BMP-2 markedly promoted D1 cell activity and differentiation compared with the groups without BMP-2. Moreover, the SMART group with a BMP-2 surface markedly promoted early alkaline phosphatase expression in the D1 cells compared with the other surface groups. Compared with these groups in vivo, SMART silaning with BMP-2 showed superior bone quality and created contact areas between implant and surrounding bones. The SMART group with BMP-2 could promote cell mineralization in vitro and osseointegration in vivo, indicating potential clinical use. PMID:26977141

  6. Neural development is dependent on the function of specificity protein 2 in cell cycle progression

    PubMed Central

    Liang, Huixuan; Xiao, Guanxi; Yin, Haifeng; Hippenmeyer, Simon; Horowitz, Jonathan M.; Ghashghaei, H. Troy

    2013-01-01

    Faithful progression through the cell cycle is crucial to the maintenance and developmental potential of stem cells. Here, we demonstrate that neural stem cells (NSCs) and intermediate neural progenitor cells (NPCs) employ a zinc-finger transcription factor specificity protein 2 (Sp2) as a cell cycle regulator in two temporally and spatially distinct progenitor domains. Differential conditional deletion of Sp2 in early embryonic cerebral cortical progenitors, and perinatal olfactory bulb progenitors disrupted transitions through G1, G2 and M phases, whereas DNA synthesis appeared intact. Cell-autonomous function of Sp2 was identified by deletion of Sp2 using mosaic analysis with double markers, which clearly established that conditional Sp2-null NSCs and NPCs are M phase arrested in vivo. Importantly, conditional deletion of Sp2 led to a decline in the generation of NPCs and neurons in the developing and postnatal brains. Our findings implicate Sp2-dependent mechanisms as novel regulators of cell cycle progression, the absence of which disrupts neurogenesis in the embryonic and postnatal brain. PMID:23293287

  7. Diversity of the Superfamily of Phloem Lectins (Phloem Protein 2) in Angiosperms1

    PubMed Central

    Dinant, Sylvie; Clark, Anna M.; Zhu, Yanmin; Vilaine, Françoise; Palauqui, Jean-Christophe; Kusiak, Chantal; Thompson, Gary A.

    2003-01-01

    Phloem protein 2 (PP2) is one of the most abundant and enigmatic proteins in the phloem sap. Although thought to be associated with structural P-protein, PP2 is translocated in the assimilate stream where its lectin activity or RNA-binding properties can exert effects over long distances. Analyzing the diversity of these proteins in vascular plants led to the identification of PP2-like genes in species from 17 angiosperm and gymnosperm genera. This wide distribution of PP2 genes in the plant kingdom indicates that they are ancient and common in vascular plants. Their presence in cereals and gymnosperms, both of which lack structural P-protein, also supports a wider role for these proteins. Within this superfamily, PP2 proteins have considerable size polymorphism. This is attributable to variability in the length of the amino terminus that extends from a highly conserved domain. The conserved PP2 domain was identified in the proteins encoded by six genes from several cucurbits, celery (Apium graveolens), and Arabidopsis that are specifically expressed in the sieve element-companion cell complex. The acquisition of additional modular domains in the amino-terminal extensions of other PP2-like proteins could reflect divergence from its phloem function. PMID:12529520

  8. Stimulation of bone healing by sustained bone morphogenetic protein 2 (BMP-2) delivery.

    PubMed

    Faßbender, Mirja; Minkwitz, Susann; Strobel, Catrin; Schmidmaier, Gerhard; Wildemann, Britt

    2014-05-14

    The aim of the study was to investigate the effect of a sustained release of bone morphogenetic protein2 (BMP-2) incorporated in a polymeric implant coating on bone healing. In vitro analysis revealed a sustained, but incomplete BMP-2 release until Day 42. For the in vivo study, the rat tibia osteotomy was stabilized either with control or BMP-2 coated wires, and the healing progress was followed by micro computed tomography (µCT), biomechanical testing and histology at Days 10, 28, 42 and 84. MicroCT showed an accelerated formation of mineralized callus, as well as remodeling and an increase of mineralized/total callus volume (p=0.021) at Day 42 in the BMP-2 group compared to the control. Histology revealed an increased callus mineralization at Days 42 and 84 (p=0.006) with reduced cartilage at Day 84 (p=0.004) in the BMP-2 group. Biomechanical stiffness was significantly higher in the BMP-2 group (p=0.045) at Day 42. In summary, bone healing was enhanced after sustained BMP-2 application compared to the control. Using the same drug delivery system, but a burst release of BMP-2, a previous published study showed a similar positive effect on bone healing. Distinct differences in the healing outcome might be explained due to the different BMP release kinetics and dosages. However, further studies are necessary to adapt the optimal release profiles to physiological mechanisms.

  9. A comprehensive clinical review of recombinant human bone morphogenetic protein-2 (INFUSE® Bone Graft)

    PubMed Central

    Peckham, Steven M.; Badura, Jeffrey M.

    2007-01-01

    The combination of recombinant human bone morphogenetic protein-2 (rhBMP-2) on an absorbable collagen sponge (ACS) carrier has been shown to induce bone formation in a number of preclinical and clinical investigations. In 2002, rhBMP-2/ACS at a 1.5-mg/cc concentration (INFUSE® Bone Graft, Medtronic Spinal and Biologics, Memphis, TN) was FDA-approved as an autograft replacement for certain interbody spinal fusion procedures. In 2004, INFUSE® Bone Graft was approved for open tibial fractures with an intermedullary (IM) nail fixation. Most recently, in March 2007, INFUSE® Bone Graft was approved as an alternative to autogenous bone grafts for sinus augmentations, and for localised alveolar ridge augmentations for defects associated with extraction sockets. The culmination of extensive preclinical and clinical research and three FDA approvals makes rhBMP-2 one of the most studied, published and significant advances in orthopaedics. This review article summarises a number of clinical findings of rhBMP-2/ACS, including the FDA-approved investigational device exemption (IDE) studies used in gaining the aforementioned approvals. PMID:17639384

  10. Identification of Motile Sperm Domain-Containing Protein 2 as Regulator of Human Monocyte Migration.

    PubMed

    Mendel, Itzhak; Yacov, Niva; Salem, Yaniv; Propheta-Meiran, Oshrat; Ishai, Eti; Breitbart, Eyal

    2017-03-01

    Binding of chemokines to their cognate receptors on monocytes instigates a cascade of events that directs these cells to migrate to sites of inflammation and cancerous tissues. Although targeting of selected chemokine receptors on monocytes exhibited preclinical efficacy, attempts to translate these studies to the clinic have failed thus far, possibly due to redundancy of the target receptor. We reveal that motile sperm domain-containing protein 2 (MOSPD2), a protein with a previously unknown function, regulates monocyte migration in vitro. This protein was found to be expressed on the cytoplasmic membrane of human monocytes. Silencing or neutralizing MOSPD2 in monocytes restricted their migration when induced by different chemokines. Mechanistically, silencing MOSPD2 inhibited signaling events following chemokine receptor ligation. When tested for expression in other immune cell subsets, MOSPD2 was apparent also, though less abundantly, in neutrophils, but not in lymphocytes. Thus, in the presence of neutralizing Abs, neutrophil migration was inhibited to some extent whereas lymphocyte migration remained intact. In view of these results, we suggest MOSPD2 as a potential target protein for treating diseases in which monocyte and neutrophil accumulation is correlated with pathogenesis.

  11. Clinical Manifestations in Paroxysmal Kinesigenic Dyskinesia Patients with Proline-Rich Transmembrane Protein 2 Gene Mutation

    PubMed Central

    Youn, Jinyoung; Kim, Ji Sun; Lee, Munhyang; Lee, Jeehun; Roh, Hakjae

    2014-01-01

    Background and Purpose Given the diverse phenotypes including combined non-dyskinetic symptoms in patients harboring mutations of the gene encoding proline-rich transmembrane protein 2 (PRRT2), the clinical significance of these mutations in paroxysmal kinesigenic dyskinesia (PKD) is questionable. In this study, we investigated the clinical characteristics of PKD patients with PRRT2 mutations. Methods Familial and sporadic PKD patients were enrolled and PRRT2 gene sequencing was performed. Demographic and clinical data were compared between PKD patients with and without a PRRT2 mutation. Results Among the enrolled PKD patients (8 patients from 5 PKD families and 19 sporadic patients), PRRT2 mutations were detected in 3 PKD families (60%) and 2 sporadic cases (10.5%). All familial patients with a PRRT2 gene mutation had the c.649dupC mutation, which is the most commonly reported mutation. Two uncommon mutations (c.649delC and c.629dupC) were detected only in the sporadic cases. PKD patients with PRRT2 mutation were younger at symptom onset and had more non-dyskinetic symptoms than those without PRRT2 mutation. However, the characteristics of dyskinetic movement did not differ between the two groups. Conclusions This is the first study of PRRT2 mutations in Korea. The presence of a PRRT2 mutation was more strongly related to familial PKD, and was clinically related with earlier age of onset and common non-dyskinetic symptoms in PKD patients. PMID:24465263

  12. Oxysterol-related-binding-protein related Protein-2 (ORP2) regulates cortisol biosynthesis and cholesterol homeostasis.

    PubMed

    Escajadillo, Tamara; Wang, Hongxia; Li, Linda; Li, Donghui; Sewer, Marion B

    2016-05-15

    Oxysterol binding protein-related protein 2 (ORP2) is a lipid binding protein that has been implicated in various cellular processes, including lipid sensing, cholesterol efflux, and endocytosis. We recently identified ORP2 as a member of a protein complex that regulates glucocorticoid biosynthesis. Herein, we examine the effect of silencing ORP2 on adrenocortical function and show that the ORP2 knockdown cells exhibit reduced amounts of multiple steroid metabolites, including progesterone, 11-deoxycortisol, and cortisol, but have increased concentrations of androgens, and estrogens. Moreover, silencing ORP2 suppresses the expression of most proteins required for cortisol production and reduces the expression of steroidogenic factor 1 (SF1). ORP2 silencing also increases cellular cholesterol, concomitant with decreased amounts of 22-hydroxycholesterol and 7-ketocholesterol, two molecules that have been shown to bind to ORP2. Further, we show that ORP2 binds to liver X receptor (LXR) and is required for nuclear LXR expression. LXR and ORP2 are recruited to the CYP11B1 promoter in response to cAMP signaling. Additionally, ORP2 is required for the expression of other LXR target genes, including ABCA1 and the LDL receptor (LDLR). In summary, we establish a novel role for ORP2 in regulating steroidogenic capacity and cholesterol homeostasis in the adrenal cortex.

  13. Slit-Robo GTPase-Activating Protein 2 as a metastasis suppressor in osteosarcoma.

    PubMed

    Marko, Tracy A; Shamsan, Ghaidan A; Edwards, Elizabeth N; Hazelton, Paige E; Rathe, Susan K; Cornax, Ingrid; Overn, Paula R; Varshney, Jyotika; Diessner, Brandon J; Moriarity, Branden S; O'Sullivan, M Gerard; Odde, David J; Largaespada, David A

    2016-12-14

    Osteosarcoma is the most common primary bone tumor, with metastatic disease responsible for most treatment failure and patient death. A forward genetic screen utilizing Sleeping Beauty mutagenesis in mice previously identified potential genetic drivers of osteosarcoma metastasis, including Slit-Robo GTPase-Activating Protein 2 (Srgap2). This study evaluates the potential role of SRGAP2 in metastases-associated properties of osteosarcoma cell lines through Srgap2 knockout via the CRISPR/Cas9 nuclease system and conditional overexpression in the murine osteosarcoma cell lines K12 and K7M2. Proliferation, migration, and anchorage independent growth were evaluated. RNA sequencing and immunohistochemistry of human osteosarcoma tissue samples were used to further evaluate the potential role of the Slit-Robo pathway in osteosarcoma. The effects of Srgap2 expression modulation in the murine OS cell lines support the hypothesis that SRGAP2 may have a role as a suppressor of metastases in osteosarcoma. Additionally, SRGAP2 and other genes in the Slit-Robo pathway have altered transcript levels in a subset of mouse and human osteosarcoma, and SRGAP2 protein expression is reduced or absent in a subset of primary tumor samples. SRGAP2 and other axon guidance proteins likely play a role in osteosarcoma metastasis, with loss of SRGAP2 potentially contributing to a more aggressive phenotype.

  14. Structure and Function of the Sterol Carrier Protein-2 N-Terminal Presequence†

    PubMed Central

    Martin, Gregory G.; Hostetler, Heather A.; McIntosh, Avery L.; Tichy, Shane E.; Williams, Brad J.; Russell, David H.; Berg, Jeremy M.; Spencer, Thomas A.; Ball, Judith; Kier, Ann B.; Schroeder, Friedhelm

    2008-01-01

    Although sterol carrier protein-2 (SCP-2) is encoded as a precursor protein (proSCP-2), little is known regarding the structure and function of the 20-amino acid N-terminal presequence. As shown herein, the presequence contains significant secondary structure and alters SCP-2: (i) secondary structure (CD), (ii) tertiary structure (aqueous exposure of Trp shown by UV absorbance, fluorescence, fluorescence quenching), (iii) ligand binding site [Trp response to ligands, peptide cross-linked by photoactivatable free cholesterol (FCBP)], (iv) selectivity for interaction with anionic phospholipid-rich membranes, (v) interaction with a peroxisomal import protein [FRET studies of Pex5p(C) binding], the N-terminal presequence increased SCP-2’s affinity for Pex5p(C) by 10-fold, and (vi) intracellular targeting in living and fixed cells (confocal microscopy). Nearly 5-fold more SCP-2 than proSCP-2 colocalized with plasma membrane lipid rafts/caveolae (AF488-CTB), 2.8-fold more SCP-2 than proSCP-2 colocalized with a mitochondrial marker (Mitotracker), but nearly 2-fold less SCP-2 than proSCP-2 colocalized with peroxisomes (AF488-antibody to PMP70). These data indicate the importance of the N-terminal presequence in regulating SCP-2 structure, cholesterol localization within the ligand binding site, membrane association, and, potentially, intracellular targeting. PMID:18465878

  15. Structural insights into Cydia pomonella pheromone binding protein 2 mediated prediction of potentially active semiochemicals

    NASA Astrophysics Data System (ADS)

    Tian, Zhen; Liu, Jiyuan; Zhang, Yalin

    2016-03-01

    Given the advantages of behavioral disruption application in pest control and the damage of Cydia pomonella, due progresses have not been made in searching active semiochemicals for codling moth. In this research, 31 candidate semiochemicals were ranked for their binding potential to Cydia pomonella pheromone binding protein 2 (CpomPBP2) by simulated docking, and this sorted result was confirmed by competitive binding assay. This high predicting accuracy of virtual screening led to the construction of a rapid and viable method for semiochemicals searching. By reference to binding mode analyses, hydrogen bond and hydrophobic interaction were suggested to be two key factors in determining ligand affinity, so is the length of molecule chain. So it is concluded that semiochemicals of appropriate chain length with hydroxyl group or carbonyl group at one head tended to be favored by CpomPBP2. Residues involved in binding with each ligand were pointed out as well, which were verified by computational alanine scanning mutagenesis. Progress made in the present study helps establish an efficient method for predicting potentially active compounds and prepares for the application of high-throughput virtual screening in searching semiochemicals by taking insights into binding mode analyses.

  16. A mathematical model of the sterol regulatory element binding protein 2 cholesterol biosynthesis pathway

    PubMed Central

    Bhattacharya, Bonhi S.; Sweby, Peter K.; Minihane, Anne-Marie; Jackson, Kim G.; Tindall, Marcus J.

    2014-01-01

    Cholesterol is one of the key constituents for maintaining the cellular membrane and thus the integrity of the cell itself. In contrast high levels of cholesterol in the blood are known to be a major risk factor in the development of cardiovascular disease. We formulate a deterministic nonlinear ordinary differential equation model of the sterol regulatory element binding protein 2 (SREBP-2) cholesterol genetic regulatory pathway in a hepatocyte. The mathematical model includes a description of genetic transcription by SREBP-2 which is subsequently translated to mRNA leading to the formation of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), a main regulator of cholesterol synthesis. Cholesterol synthesis subsequently leads to the regulation of SREBP-2 via a negative feedback formulation. Parameterised with data from the literature, the model is used to understand how SREBP-2 transcription and regulation affects cellular cholesterol concentration. Model stability analysis shows that the only positive steady-state of the system exhibits purely oscillatory, damped oscillatory or monotic behaviour under certain parameter conditions. In light of our findings we postulate how cholesterol homeostasis is maintained within the cell and the advantages of our model formulation are discussed with respect to other models of genetic regulation within the literature. PMID:24444765

  17. Drive for thinness and drive for muscularity: opposite ends of the continuum or separate constructs?

    PubMed

    Kelley, Courtney C Galliger; Neufeld, Jennie M; Musher-Eizenman, Dara R

    2010-01-01

    The goal of this study was to examine whether the drive for thinness and the drive for muscularity occur concurrently among late adolescents and to understand the body attitudes associated with desiring a thinner and/or a more muscular physique. Participants included 235 college freshmen who participated in a larger study of body image and eating attitudes. The majority of individuals reported having both a high drive for thinness and a high drive for muscularity (65.4%). Additionally, the presence of both drives significantly predicted body compulsivity and body anxiety among females, and body-esteem among males. Results of the current study provide considerable evidence that a drive for thinness and a drive for muscularity are not mutually exclusive. Furthermore, the degree to which an individual strives for thinness and/or muscularity has differential effects on their body attitudes.

  18. High-powered vehicle drive train

    SciTech Connect

    Kraus, C.E.

    1987-09-15

    This patent describes a vehicle comprising: an engine having an infinitely variable transmission operatively coupled for transmitting engine power to the transmission's input shaft with the transmission output shaft being operatively connected to the vehicle's drive wheels. The transmission comprising a planetary drive structure includes a drive ring gear carrying a first gear in engagement with a drive gear on the input shaft for rotation of the drive ring gear with the input shaft, a central sun gear and planetary gear members disposed in the annular space between, and in engagement with the drive ring gear and the sun gear and rotatably supported on a planetary carrier. The carrier is supported for rotation with the transmission output shaft and an infinitely variable toroidal traction roller transmission structure including two parallel toridal transmissions having a central input toric disc structure common to both toroidal transmissions and operatively connected to the input shaft. The output toric discs being mounted on a shaft associated with the sun gear of the planetary drive.

  19. [Car driving, cognitive aging and Alzheimer disease].

    PubMed

    Fabrigoule, Colette; Lafont, Sylviane

    2015-10-01

    Older drivers are more numerous on the roads. They are expert drivers, but with increasing age certain physiological changes can interfere with driving, which is a complex activity of daily living. Older drivers are involved in fewer accidents than younger drivers, but they have a higher accident rate per kilometer driven. The elderly are heavily represented in the balance sheet of road deaths, being motorists or pedestrians. This high mortality is largely explained by their physical frailty. In the presence of deficits, self-regulation of driving habits, changes/reductions or stopping in driving activity occur in the elderly. But cognitive deficits are associated with an increased risk of accidents. Among drivers with Alzheimer's disease, there is a heterogeneity of driving ability, making difficult the advisory role of a physician for driving. A protocol for physicians was developed to assess cognitive impairments that may affect driving in an elderly patient. The car plays an important role in the autonomy of the elderly and patient advice on stopping driving should take into account the risk/benefit ratio.

  20. Installation considerations for IGBT AC drives

    SciTech Connect

    Skibinski, G.L.

    1997-06-01

    In the last four years, Adjustable Speed ac Drive (ASD) manufacturers have migrated from Bipolar Junction Transistor (BJT) semiconductors to Insulated Gate Bipolar Transistors (IGBTs) as the preferred Output switching device. The advantage of IGBTs over BJTs is that device rise and fall time switching capability is 5 - 10 times faster, resulting in lower device switching loss and a more efficient drive. However, for a similar motor cable length as the BJT drive, the faster output voltage risetime of the IGBT drive may increase the dielectric voltage stress on the motor and cable due to a phenomenon called reflected wave. Faster output dv/dt transitions of IGBT drives also increase the possibility for phenomenon such as increased Common Mode (CM) electrical noise, Electromagnetic Interference (EMI) problems and increased capacitive cable charging current problems. Also, recent experience suggests any Pulse Width Modulated (PWM) drive with a steep fronted output voltage wave form may increase motor shaft voltage and lead to a bearing current phenomenon known as fluting. This paper provides a basic understanding of these issues, as well as solutions, to insure a successful drive system installation.

  1. Chapter 18: Variable Frequency Drive Evaluation Protocol

    SciTech Connect

    Romberger, J.

    2014-11-01

    An adjustable-speed drive (ASD) includes all devices that vary the speed of a rotating load, including those that vary the motor speed and linkage devices that allow constant motor speed while varying the load speed. The Variable Frequency Drive Evaluation Protocol presented here addresses evaluation issues for variable-frequency drives (VFDs) installed on commercial and industrial motor-driven centrifugal fans and pumps for which torque varies with speed. Constant torque load applications, such as those for positive displacement pumps, are not covered by this protocol. Other ASD devices, such as magnetic drive, eddy current drives, variable belt sheave drives, or direct current motor variable voltage drives, are also not addressed. The VFD is by far the most common type of ASD hardware. With VFD speed control on a centrifugal fan or pump motor, energy use follows the affinity laws, which state that the motor electricity demand is a cubic relationship to speed under ideal conditions. Therefore, if the motor runs at 75% speed, the motor demand will ideally be reduced to 42% of full load power; however, with other losses it is about 49% of full load power.

  2. Apoptosis: getting rid of the bodies.

    PubMed

    Fadok, V A; Henson, P M

    1998-09-24

    Cells that die by apoptosis need to be removed before lysis to preserve tissue integrity and function. Recent studies have identified components of the uptake machinery used by phagocytes, but much remains to be learnt, particularly about the recognition mechanisms and their coupling to the uptake machinery.

  3. Signaling Pathways in Cardiac Myocyte Apoptosis

    PubMed Central

    Xia, Peng; Liu, Yuening

    2016-01-01

    Cardiovascular diseases, the number 1 cause of death worldwide, are frequently associated with apoptotic death of cardiac myocytes. Since cardiomyocyte apoptosis is a highly regulated process, pharmacological intervention of apoptosis pathways may represent a promising therapeutic strategy for a number of cardiovascular diseases and disorders including myocardial infarction, ischemia/reperfusion injury, chemotherapy cardiotoxicity, and end-stage heart failure. Despite rapid growth of our knowledge in apoptosis signaling pathways, a clinically applicable treatment targeting this cellular process is currently unavailable. To help identify potential innovative directions for future research, it is necessary to have a full understanding of the apoptotic pathways currently known to be functional in cardiac myocytes. Here, we summarize recent progress in the regulation of cardiomyocyte apoptosis by multiple signaling molecules and pathways, with a focus on the involvement of these pathways in the pathogenesis of heart disease. In addition, we provide an update regarding bench to bedside translation of this knowledge and discuss unanswered questions that need further investigation. PMID:28101515

  4. Oligodendroglial degeneration in distemper: apoptosis or necrosis?

    PubMed

    Schobesberger, M; Zurbriggen, A; Summerfield, A; Vandevelde, M; Griot, C

    1999-03-01

    Canine distemper virus (CDV) causes a multifocal demyelinating disease in dogs. It was previously shown that the initial demyelinating lesions are directly virus induced since a correlation between the occurrence of demyelination and CDV replication in white matter cells was observed. During the course of infection oligodendrocytes undergo distinct morphological alterations, partly due to a restricted CDV infection of these cells, and eventually disappear from the lesions. This phenomenon has been described in vivo as well as in vitro. However, the reason for the morphological alterations and the following oligodendroglial depletion remained unclear. Since virus infection can induce cell death, it was investigated whether apoptosis or necrosis plays a role in the pathogenesis of demyelination in canine distemper. In brain tissue sections from dogs with acute distemper apoptotic cells were not detected within the demyelinating lesions using morphological and biochemical cell death criteria. In chronic distemper, apoptotic cells - presumably inflammatory cells - were seen within the perivascular cuffs. These in vivo findings were correlated to the in vitro situation using CDV-infected primary dog brain cell cultures as well as Vero cells. Infection with culture-adapted CDV lead to massive necrosis but not to apoptosis. After infection with virulent CDV neither apoptosis nor necrosis was a predominant feature in either culture system. These findings suggest that virus-induced demyelination in canine distemper is not the direct consequence of apoptosis or necrosis. It is speculated that another mechanism must be responsible for the observed morphological alterations of oligodendrocytes, ultimately leading to demyelination.

  5. A novel method for detection of apoptosis

    SciTech Connect

    Zagariya, Alexander M.

    2012-04-15

    There are two different Angiotensin II (ANG II) peptides in nature: Human type (ANG II) and Bovine type (ANG II*). These eight amino acid peptides differ only at position 5 where Valine is replaced by Isoleucine in the Bovine type. They are present in all species studied so far. These amino acids are different by only one atom of carbon. This difference is so small, that it will allow any of ANG II, Bovine or Human antibodies to interact with all species and create a universal method for apoptosis detection. ANG II concentrations are found at substantially higher levels in apoptotic, compared to non-apoptotic, tissues. ANG II accumulation can lead to DNA damage, mutations, carcinogenesis and cell death. We demonstrate that Bovine antiserum can be used for universal detection of apoptosis. In 2010, the worldwide market for apoptosis detection reached the $20 billion mark and significantly increases each year. Most commercially available methods are related to Annexin V and TUNNEL. Our new method based on ANG II is more widely known to physicians and scientists compared to previously used methods. Our approach offers a novel alternative for assessing apoptosis activity with enhanced sensitivity, at a lower cost and ease of use.

  6. Excitotoxins in neuronal apoptosis and necrosis.

    PubMed

    Nicotera, P; Lipton, S A

    1999-06-01

    Neuronal loss is common to many neurodegenerative diseases. Although necrosis is a common histopathologic feature observed in neuropathologic conditions, evidence is increasing that apoptosis can significantly contribute to neuronal demise. The prevalence of either type of cell death, apoptosis or necrosis, and the relevance for the progression of disease is still unclear. The debate on the occurrence and prevalence of one or the other type of death in pathologic conditions such as stroke or neurotoxic injury may in part be resolved by the proposal that different types of cell death within a tissue reflect either partial or complete execution of a common death program. Apoptosis is an active process of cell destruction, characterized morphologically by cell shrinkage, chromatin aggregation with extensive genomic fragmentation, and nuclear pyknosis. In contrast, necrosis is characterized by cell swelling, linked to rapid energy loss, and generalized disruption of ionic and internal homeostasis. This swiftly leads to membrane lysis, release of intracellular constituents that evoke a local inflammatory reaction, edema, and injury to the surrounding tissue. During the past few years, our laboratories have studied the signals and mechanisms responsible for induction or prevention of apoptosis/necrosis in neuronal injury and this is the subject of this review.

  7. Fluorescence spectroscopy to assess apoptosis in myocardium

    NASA Astrophysics Data System (ADS)

    Ranji, Mahsa; Matsubara, Muneaki; Grosso, Michael A.; Jaggard, Dwight L.; Chance, Britton; Gorman, Robert C.; Gorman, Joseph H., III

    2007-02-01

    Apoptosis induced mitochondrial destruction and dysfunction has been shown to play an important role in the pathogenesis of both acute cardiac ischemia-reperfusion injury and chronic myocardial infarction-induced ventricular remodeling. Unfortunately this understanding has not translated into effective therapeutic strategies for either condition-mostly due to an inability to assess mitochondrial dysfunction/apoptosis effectively in humans. All current measures of apoptosis are pseudo-quantitative and require invasive tissue biopsy. Our group has developed an optical, non-tissue destructive catheter based device that allows the quantitative regional assessment of this pathological process in vivo. This instrument has been designed to acquire fluorescence signals of intrinsic mitochondrial fluorophores, Nicotinamide Adenine Dinucleotide (NAD) and Flavoprotein (FP). The normalized ratio of these fluorophores (FP/FP+NADH) called the redox ratio, is an indicator of the in vivo mitochondrial dysfunction. 1-3 We have demonstrated in a rabbit reperfusion model of apoptotic myocyte injury that this redox ratio is drastically increased which is consistent with profound apoptosis-induced "unhinging" of the mitochondrial respiratory function.

  8. THE ROLE OF APOPTOSIS IN NEUROTOXICOLOGY

    EPA Science Inventory

    Apoptosis, a form of programmed cell death, occurs in the nervous system throughout development, but with a preponderance of cell death occurring during the prenatal and perinatal periods. Aberrant periods of increased or decreased cell death, induced by toxicants in air, water,...

  9. Apoptosis regulates notochord development in Xenopus

    PubMed Central

    Malikova, Marina; Van Stry, Melanie

    2009-01-01

    The notochord is the defining characteristic of the chordate embryo, and plays critical roles as a signaling center and as the primitive skeleton. In this study we show that early notochord development in Xenopus embryos is regulated by apoptosis. We find apoptotic cells in the notochord beginning at the neural groove stage and increasing in number as the embryo develops. These dying cells are distributed in an anterior to posterior pattern that is correlated with notochord extension through vacuolization. In axial mesoderm explants, inhibition of this apoptosis causes the length of the notochord to approximately double compared to controls. In embryos however, inhibition of apoptosis decreases the length of the notochord and it is severely kinked. This kinking also spreads from the anterior with developmental stage such that by the tadpole stage, the notochord lacks any recognizable structure, although notochord markers are expressed in a normal temporal pattern. Extension of the somites and neural plate mirror that of the notochord in these embryos, and the somites are severely disorganized. These data indicate that apoptosis is required for normal notochord development during the formation of the anterior-posterior axis, and its role in this process is discussed. PMID:17920580

  10. Measuring apoptosis in mammals in vivo.

    PubMed

    Newbold, Andrea; Martin, Ben P; Cullinane, Carleen; Bots, Michael

    2014-11-03

    Apoptosis is a mode of cell death that is essential in multicellular organisms for the removal of superfluous, damaged, or potentially dangerous cells during development, infection, or normal tissue homeostasis. To prevent inflammation, cells undergoing apoptosis produce "find-me" signals that trigger the recruitment of phagocytes, which clear the apoptotic cells on recognition of "eat-me" signals. Despite the loss of billions of cells per day by apoptosis in the human body, the number of apoptotic cells found in healthy tissue is surprisingly low and reflects the efficiency of this process. However, in certain conditions (e.g., in cancer cells responding to chemotherapy), the number of apoptotic cells is too high to be efficiently cleared by phagocytes, and apoptotic cells can be observed. In these situations, the detection of apoptosis may be helpful in monitoring disease progression as well as in predicting the responses of tumors to anticancer therapies. Here we introduce various methods for monitoring apoptotic cells in vivo using a murine model of B-cell lymphoma and a solid tumor xenograft.

  11. Neuronal remodeling and apoptosis require VCP-dependent degradation of the apoptosis inhibitor DIAP1

    PubMed Central

    Rumpf, Sebastian; Lee, Sung Bae; Jan, Lily Yeh; Jan, Yuh Nung

    2011-01-01

    The regulated degeneration of axons or dendrites (pruning) and neuronal apoptosis are widely used during development to determine the specificity of neuronal connections. Pruning and apoptosis often share similar mechanisms; for example, developmental dendrite pruning of Drosophila class IV dendritic arborization (da) neurons is induced by local caspase activation triggered by ubiquitin-mediated degradation of the caspase inhibitor DIAP1. Here, we examined the function of Valosin-containing protein (VCP), a ubiquitin-selective AAA chaperone involved in endoplasmic reticulum-associated degradation, autophagy and neurodegenerative disease, in Drosophila da neurons. Strong VCP inhibition is cell lethal, but milder inhibition interferes with dendrite pruning and developmental apoptosis. These defects are associated with impaired caspase activation and high DIAP1 levels. In cultured cells, VCP binds to DIAP1 in a ubiquitin- and BIR domain-dependent manner and facilitates its degradation. Our results establish a new link between ubiquitin, dendrite pruning and the apoptosis machinery. PMID:21343367

  12. Fitness to Drive of Psychiatric Patients

    PubMed Central

    De las Cuevas, Carlos; Sanz, Emilio J.

    2008-01-01

    Background: Driving a motor vehicle could be central to the functional autonomy of patients with psychiatric illnesses. For patients, a driver's license could mean independence, the ability to care for themselves, and the freedom to travel when they wish. However, both psychiatric disorders and psychiatric drug treatments can produce changes in perception, information processing and integration, and psychomotor activity that can disturb and/or interfere with the ability to drive safely. Objective: To assess the fitness to drive of psychiatric outpatients in a sample representative of current clinical practice. Method: Cognitive functioning and psychomotor performance of 208 consecutive psychiatric outpatients treated in a community mental health center in the Canary Islands (Spain) were assessed in different clinical situations. The LNDETER 100 battery, an electronic assessment unit–based measurement that consists of 5 screenbased tests, was used to assess concentrated attention and resistance to monotony, multiple discriminative reactions and their correctness, anticipation of speed, bimanual coordination, and the decision making process and tendency to assume risk. The study was conducted from July 2007 to September 2007. Results: Of 208 patients, only 33 had scores compatible with the requirements of a driver's license, and 84% failed at least 1 of the required tests. Of patients with a driver's license who drive almost every day, 79.5% registered scores that would not allow obtaining or renewal of the license. None of the driving patients studied notified the traffic authorities that they had a psychiatric condition that may affect safe driving. No patient stopped driving, although 10% of them recognized that their ability to drive was somehow damaged. Conclusion: Guidance on how best to formulate and deliver recommendations on driving fitness in stable psychiatric patients is lacking and much needed. PMID:19158977

  13. Driving gear interaxle differential assembly for all-wheel-drive vehicles

    SciTech Connect

    Ashikawa, N.; Friedrich, K.; Lanzer, H.

    1986-05-20

    A driving gear is described for all-wheel-drive vehicles, comprising a reduction gear meshed with an output gear in a transmission, a planetary gear type interaxle differential gear arranged concentrically with the reduction gear so as to output the driving force therefrom into front and rear interwheel differential gears in a divided manner, a driving shaft provided through and concentrically with the interaxle differential gear so as to transmit one output therefrom to one of the two interwheel differential gears, and a driving gear member mounted on the driving shaft so that the driving gear member can be rotated relatively thereto, so as to transmit the other output from the interaxle differential gear to the other interwheel differential gear. The interaxle differential gear consists of a planetary carrier mounted rotatably on the driving shaft on the side of the driving gear member so as to form a clearance between the planetary carrier and the driving shaft, a support member mounted rotatably on the driving shaft so as to be opposed to the planetary carrier, and a ring gear, pinions and a sun gear which are provided between the planetary carrier and the support member, a connecting member which joins the ring gear and the driving shaft together being provided between the pinions and the support member. The driving shaft is provided with a spline for joining the connecting member thereto, the driving gear member being provided with a hub formed integrally therewith, extending from the clearance into the interaxle differential gear and having a connecting portion joined to the sun gear. The reduction gear is formed unitarily with the planetary carrier and the support member.

  14. Assessment of driving-related performance in chronic whiplash using an advanced driving simulator.

    PubMed

    Takasaki, Hiroshi; Treleaven, Julia; Johnston, Venerina; Rakotonirainy, Andry; Haines, Andrew; Jull, Gwendolen

    2013-11-01

    Driving is often nominated as problematic by individuals with chronic whiplash associated disorders (WAD), yet driving-related performance has not been evaluated objectively. The purpose of this study was to test driving-related performance in persons with chronic WAD against healthy controls of similar age, gender and driving experience to determine if driving-related performance in the WAD group was sufficiently impaired to recommend fitness to drive assessment. Driving-related performance was assessed using an advanced driving simulator during three driving scenarios; freeway, residential and a central business district (CBD). Total driving duration was approximately 15min. Five driving tasks which could cause a collision (critical events) were included in the scenarios. In addition, the effect of divided attention (identify red dots projected onto side or rear view mirrors) was assessed three times in each scenario. Driving performance was measured using the simulator performance index (SPI) which is calculated from 12 measures. z-Scores for all SPI measures were calculated for each WAD subject based on mean values of the control subjects. The z-scores were then averaged for the WAD group. A z-score of ≤-2 indicated a driving failing grade in the simulator. The number of collisions over the five critical events was compared between the WAD and control groups as was reaction time and missed response ratio in identifying the red dots. Seventeen WAD and 26 control subjects commenced the driving assessment. Demographic data were comparable between the groups. All subjects completed the freeway scenario but four withdrew during the residential and eight during the CBD scenario because of motion sickness. All scenarios were completed by 14 WAD and 17 control subjects. Mean z-scores for the SPI over the three scenarios was statistically lower in the WAD group (-0.3±0.3; P<0.05) but the score was not below the cut-off point for safe driving. There were no

  15. Magnetostrictive Roller-Drive Stepping Motor

    NASA Technical Reports Server (NTRS)

    Vranish, John M.

    1993-01-01

    Proposed motor based on magnetostrictive effect provides stepped angular motion with angular increments of order of 100 microradians. Driven to repeat stepping cycle rapidly enough to achieve maximum speed of about 20 rpm, provides torque an order of magnitude greater than electric motors, and brakes itself when power turned off. Magnetostrictive rods in electromagnet coils push against drive plate, causing it to rotate slightly. This slight rotation jams conical rollers between cam surfaces on outer drive ring and split drum, so rollers transmit rotation to drum. Suitable for precise, high-torque, fail-safe-braking, direct drive of robot joint, without bulk and weight of additional brake mechanism and gear train.

  16. Control rod drive for reactor shutdown

    DOEpatents

    McKeehan, Ernest R.; Shawver, Bruce M.; Schiro, Donald J.; Taft, William E.

    1976-01-20

    A means for rapidly shutting down or scramming a nuclear reactor, such as a liquid metal-cooled fast breeder reactor, and serves as a backup to the primary shutdown system. The control rod drive consists basically of an in-core assembly, a drive shaft and seal assembly, and a control drive mechanism. The control rod is driven into the core region of the reactor by gravity and hydraulic pressure forces supplied by the reactor coolant, thus assuring that common mode failures will not interfere with or prohibit scramming the reactor when necessary.

  17. Microwave heating and current drive in tokamaks

    SciTech Connect

    Cohen, B.I.; Cohen, R.H.; Kerbel, G.D.; Logan, B.G.; Matsuda, Y.; McCoy, M.G.; Nevins, W.M.; Rognlien, T.D.; Smith, G.R.; Harvey, R.W.; Kritz, A.H.; Bonoli, P.T.; Porkolab, M.

    1988-08-23

    The use of powerful microwave sources provide unique opportunities for novel and efficient heating and current-drive schemes in the electron-cyclotron and lower-hybrid ranges of frequencies. Free- electron lasers and relativistic klystrons are new sources that have a number of technical advantages over conventional, lower-intensity sources; their use can lead to improved current-drive efficiencies and better penetration into a reactor-grade plasma in specific cases. This paper reports on modeling of absorption and current drive, in intense-pulse and quasilinear regimes, and on analysis of parametric instabilities and self-focusing. 16 refs., 2 figs.

  18. Bidirectional Drive-And-Brake Mechanism

    NASA Technical Reports Server (NTRS)

    Swan, Scott A.

    1991-01-01

    Vehicle that crawls along monorail combines features of both bicycle and railroad handcar. Bidirectional drive-and-brake mechanism includes selectable-pawl-and-ratchet overrunning clutch (drive mechanism) and mating stationary and rotating conical surfaces pressing against each other (brake mechanism). Operates similarly to bicycle drive-and-brake mechanism except limits rotation of sprocket in both directions and brakes at both limits. Conceived for use by astronaut traveling along structure in outer space, concept also applied on Earth to make very small railraod handcars or crawling vehicles for use on large structures, in pipelines under construction, or underwater.

  19. Wind turbine ring/shroud drive system

    DOEpatents

    Blakemore, Ralph W.

    2005-10-04

    A wind turbine capable of driving multiple electric generators having a ring or shroud structure for reducing blade root bending moments, hub loads, blade fastener loads and pitch bearing loads. The shroud may further incorporate a ring gear for driving an electric generator. In one embodiment, the electric generator may be cantilevered from the nacelle such that the gear on the generator drive shaft is contacted by the ring gear of the shroud. The shroud also provides protection for the gearing and aids in preventing gear lubricant contamination.

  20. Power transmission for four-wheel drive vehicle

    SciTech Connect

    Tsuzuki, I.

    1987-03-17

    A power transmission is described for a vehicle having front and rear wheel drive and a prime mover, the transmission comprising: a change-speed gearing operatively disposed in a transmission casing secured to the prime mover, the gearing including an input shaft drivingly connected to the prime mover, and an output shaft drivingly connected to the input shaft; a first drive shaft drivingly connected to the front wheels; a second drive shaft coaxial with the first drive shaft and drivingly connected to the rear wheels; and an intermediate differential unit drivingly interconnecting the output shaft and the first and second drive shafts, the differential unit comprising: an input gear coaxially surrounding the first drive shaft and drivingly connected to the output shaft; coaxial planetary gear sets providing a plurality of drive power trains at different gear ratios, each of the gear set including sun, planet and ring gears. The gear sets are drivingly connected to one of the input gear and second drive shaft, and a portion of the other of the input gear and second drive shaft coaxially surround and define the ring gears of the gear sets; and means drivingly connected to the first drive shaft for selectively engaging one of the gear sets into driving connection with the first and second drive shafts.

  1. Apoptosis and autophagy as mechanisms of dinoflagellate symbiont release during cnidarian bleaching: every which way you lose.

    PubMed

    Dunn, Simon R; Schnitzler, Christine E; Weis, Virginia M

    2007-12-22

    Cnidarian bleaching results from the breakdown in the symbiosis between the host cnidarian and its dinoflagellate symbiont. Coral bleaching in recent years has increasingly caused degradation and mortality of coral reefs on a global scale. Although much is understood about the environmental causes of bleaching, the underlying cellular mechanisms of symbiont release that drive the process are just beginning to be described. In this study, we investigated the roles of two cellular pathways, host cell apoptosis and autophagy, in the bleaching process of the symbiotic anemone Aiptasia pallida. Host cell apoptosis was experimentally manipulated using gene knockdown of an anemone caspase by RNA interference, chemical inhibition of caspase using ZVAD-fmk and an apoptosis-inducer wortmannin. Autophagy was manipulated by chemical inhibition using wortmannin or induction using rapamycin. The applications of multiple single treatments resulted in some increased bleaching in anemones under control conditions but no significant drop in bleaching in individuals subjected to a hyperthermic stress. These results indicated that no single pathway is responsible for symbiont release during bleaching. However, when multiple inhibitors were applied simultaneously to block both apoptosis and autophagy, there was a significant reduction in bleaching in heat-stressed anemones. Our results allow us to formulate a model for cellular processes involved in the control of cnidarian bleaching where apoptosis and autophagy act together in a see-saw mechanism such that if one is inhibited the other is induced. Similar interconnectivity between apoptosis and autophagy has previously been shown in vertebrates including involvement in an innate immune response to pathogens and parasites. This suggests that the bleaching response could be a modified immune response that recognizes and removes dysfunctional symbionts.

  2. Noscapine induces apoptosis in human glioma cells by an apoptosis-inducing factor-dependent pathway.

    PubMed

    Newcomb, Elizabeth W; Lukyanov, Yevgeniy; Smirnova, Iva; Schnee, Tona; Zagzag, David

    2008-07-01

    Previously, we identified noscapine as a small molecule inhibitor of the hypoxia-inducible factor-1 pathway in hypoxic human glioma cells and human umbilical vein endothelial cells. Noscapine is a nontoxic ingredient in cough medicine currently used in clinical trials for patients with non-Hodgkin's lymphoma or chronic lymphocytic leukemia to assess antitumor efficacy. Here, we have evaluated the sensitivity of four human glioma cell lines to noscapine-induced apoptosis. Noscapine was a potent inhibitor of proliferation and inducer of apoptosis. Induction of apoptosis was associated with activation of the c-jun N-terminal kinase signaling pathway concomitant with inactivation of the extracellular signal regulated kinase signaling pathway and phosphorylation of the antiapoptotic protein Bcl-2. Noscapine-induced apoptosis was associated with the release of mitochondrial proteins apoptosis-inducing factor (AIF) and/or cytochrome c. In some glioma cell lines, only AIF release occurred without cytochrome c release or poly (ADP-ribose) polymerase cleavage. Knock-down of AIF decreased noscapine-induced apoptosis. Our results suggest the potential importance of noscapine as a novel agent for use in patients with glioblastoma owing to its low toxicity profile and its potent anticancer activity.

  3. Inhibition of histone deacetylases by chlamydocin induces apoptosis and proteasome-mediated degradation of survivin.

    PubMed

    De Schepper, Stefanie; Bruwiere, Hélène; Verhulst, Tinne; Steller, Ulf; Andries, Luc; Wouters, Walter; Janicot, Michel; Arts, Janine; Van Heusden, Jim

    2003-02-01

    The naturally occurring cyclic tetrapeptide chlamydocin is a very potent inhibitor of cell proliferation. Here we show that chlamydocin is a highly potent histone deacetylase (HDAC) inhibitor, inhibiting HDAC activity in vitro with an IC(50) of 1.3 nM. Like other HDAC inhibitors, chlamydocin induces the accumulation of hyperacetylated histones H3 and H4 in A2780 ovarian cancer cells, increases the expression of p21(cip1/waf1), and causes an accumulation of cells in G(2)/M phase of the cell cycle. In addition, chlamydocin induces apoptosis by activating caspase-3, which in turn leads to the cleavage of p21(cip1/waf1) into a 15-kDa breakdown product and drives cells from growth arrest into apoptosis. Concomitant with the activation of caspase-3 and cleavage of p21(cip1/waf1), chlamydocin decreases the protein level of survivin, a member of the inhibitor of apoptosis protein family that is selectively expressed in tumors. Although our data indicate a potential link between degradation of survivin and activation of the apoptotic pathway induced by HDAC inhibitors, stable overexpression of survivin does not suppress the activation of caspase-3 or cleavage of p21(cip1/waf1) induced by chlamydocin treatment. The decrease of survivin protein level is mediated by degradation via proteasomes since it can be inhibited by specific proteasome inhibitors. Taken together, our results show that induction of apoptosis by chlamydocin involves caspase-dependent cleavage of p21(cip1/waf1), which is strikingly associated with proteasome-mediated degradation of survivin.

  4. RIPK1 ensures intestinal homeostasis by protecting the epithelium against apoptosis.

    PubMed

    Takahashi, Nozomi; Vereecke, Lars; Bertrand, Mathieu J M; Duprez, Linde; Berger, Scott B; Divert, Tatyana; Gonçalves, Amanda; Sze, Mozes; Gilbert, Barbara; Kourula, Stephanie; Goossens, Vera; Lefebvre, Sylvie; Günther, Claudia; Becker, Christoph; Bertin, John; Gough, Peter J; Declercq, Wim; van Loo, Geert; Vandenabeele, Peter

    2014-09-04

    Receptor interacting protein kinase 1 (RIPK1) has an essential role in the signalling triggered by death receptors and pattern recognition receptors. RIPK1 is believed to function as a node driving NF-κB-mediated cell survival and inflammation as well as caspase-8 (CASP8)-dependent apoptotic or RIPK3/MLKL-dependent necroptotic cell death. The physiological relevance of this dual function has remained elusive because of the perinatal death of RIPK1 full knockout mice. To circumvent this problem, we generated RIPK1 conditional knockout mice, and show that mice lacking RIPK1 in intestinal epithelial cells (IECs) spontaneously develop severe intestinal inflammation associated with IEC apoptosis leading to early death. This early lethality was rescued by antibiotic treatment, MYD88 deficiency or tumour-necrosis factor (TNF) receptor 1 deficiency, demonstrating the importance of commensal bacteria and TNF in the IEC Ripk1 knockout phenotype. CASP8 deficiency, but not RIPK3 deficiency, rescued the inflammatory phenotype completely, indicating the indispensable role of RIPK1 in suppressing CASP8-dependent apoptosis but not RIPK3-dependent necroptosis in the intestine. RIPK1 kinase-dead knock-in mice did not exhibit any sign of inflammation, suggesting that RIPK1-mediated protection resides in its kinase-independent platform function. Depletion of RIPK1 in intestinal organoid cultures sensitized them to TNF-induced apoptosis, confirming the in vivo observations. Unexpectedly, TNF-mediated NF-κB activation remained intact in these organoids. Our results demonstrate that RIPK1 is essential for survival of IECs, ensuring epithelial homeostasis by protecting the epithelium from CASP8-mediated IEC apoptosis independently of its kinase activity and NF-κB activation.

  5. Distracted driving: prevalence, problems, and prevention.

    PubMed

    Overton, Tiffany L; Rives, Terry E; Hecht, Carrie; Shafi, Shahid; Gandhi, Rajesh R

    2015-01-01

    While the number of motor vehicle crashes has declined over the years, crashes resulting from distracted driving are increasing in the United States resulting in significant morbidity and mortality. The national public seems to be aware of the dangers associated with using technology while driving, but continues to engage in this dangerous behaviour, and may be unaware of or underestimate the impact of cell phone use on their own driving performance. Problems associated with distracted driving are not limited to novice or teenage drivers; multifaceted universal prevention efforts aimed at impacting large segments of the population may have the greatest impact. Legislation limiting drivers' cell phone use has had little impact, possibly due to low regulation and enforcement. Behaviour change programmes, improved vehicle safety, and public awareness campaigns have been developed as potential preventive efforts to reduce accidents caused by distracted drivers.

  6. Drive of nuclear reactor's control element

    SciTech Connect

    Anikin, A.A.; But, V.G.; Nikolaev, V.P.; Silvanovich, A.A.

    1980-12-09

    According to the invention, the drive of a nuclear reactor's control element comprises an electromotor having a stator and a rotor composed lengthwise of two parts whose total length is equal to that of the active part of the stator. One part of the rotor is a solid cylinder-shaped member. The other part of the rotor comprises at least three double-arm rocking levers, the pivot axes of which are parallel to the axis of a drive screw. One arm of each of said levers is a rotor pole. The other arm of each of said levers carries a roller, the axis of rotation of which is parallel to the axis of the drive screw. Said rollers make up a detachable roller nut which interacts with the drive screw under the action of an electromagnetic field.

  7. Drive-Reinforcement Learning System Applications

    DTIC Science & Technology

    1992-07-31

    evidence suggests that D-R would be effective in control system applications outside the robotics arena.... Drive- Reinforcement Learning , Neural Network Controllers, Robotics, Manipulator Kinematics, Dynamics and Control.

  8. Driving violations observed: an Australian study.

    PubMed

    Glendon, A Ian

    2007-08-01

    This study analyses 2,765 cases of driving behaviours in three Australian states - New South Wales, Queensland and Victoria. Data were gathered from in-car coordinated video and audio recording sequences in free-flowing traffic along two-, three- and four-lane highways with varying speed limits on all days of the week in daylight and fine weather conditions. Explanatory variables included driver age group and gender, passenger characteristics and vehicle age and type. Response variables included driving violations and other driving behaviours, including lane use, speeding, close following (tailgating), driver's hands position and mobile phone use. Data were analysed qualitatively and quantitatively. By focusing upon vehicle and driver characteristics, and their impact on driving behaviours, including identified violations, this study explores some implications both for future research and for traffic policy makers.

  9. How mantle slabs drive plate tectonics.

    PubMed

    Conrad, Clinton P; Lithgow-Bertelloni, Carolina

    2002-10-04

    The gravitational pull of subducted slabs is thought to drive the motions of Earth's tectonic plates, but the coupling between slabs and plates is not well established. If a slab is mechanically attached to a subducting plate, it can exert a direct pull on the plate. Alternatively, a detached slab may drive a plate by exciting flow in the mantle that exerts a shear traction on the base of the plate. From the geologic history of subduction, we estimated the relative importance of "pull" versus "suction" for the present-day plates. Observed plate motions are best predicted if slabs in the upper mantle are attached to plates and generate slab pull forces that account for about half of the total driving force on plates. Slabs in the lower mantle are supported by viscous mantle forces and drive plates through slab suction.

  10. Chain friction system gives positive, reversible drive

    NASA Technical Reports Server (NTRS)

    Davidsen, J. S.

    1964-01-01

    By cementing a strip of an elastomer to the smooth metal rim of the pulley and neoprene covered idlers providing suitable tension to the chain around the pulley, a positive reversible drive is accomplished more quietly and with less vibration.

  11. Universal power transistor base drive control unit

    DOEpatents

    Gale, Allan R.; Gritter, David J.

    1988-01-01

    A saturation condition regulator system for a power transistor which achieves the regulation objectives of a Baker clamp but without dumping excess base drive current into the transistor output circuit. The base drive current of the transistor is sensed and used through an active feedback circuit to produce an error signal which modulates the base drive current through a linearly operating FET. The collector base voltage of the power transistor is independently monitored to develop a second error signal which is also used to regulate base drive current. The current-sensitive circuit operates as a limiter. In addition, a fail-safe timing circuit is disclosed which automatically resets to a turn OFF condition in the event the transistor does not turn ON within a predetermined time after the input signal transition.

  12. Universal power transistor base drive control unit

    DOEpatents

    Gale, A.R.; Gritter, D.J.

    1988-06-07

    A saturation condition regulator system for a power transistor is disclosed which achieves the regulation objectives of a Baker clamp but without dumping excess base drive current into the transistor output circuit. The base drive current of the transistor is sensed and used through an active feedback circuit to produce an error signal which modulates the base drive current through a linearly operating FET. The collector base voltage of the power transistor is independently monitored to develop a second error signal which is also used to regulate base drive current. The current-sensitive circuit operates as a limiter. In addition, a fail-safe timing circuit is disclosed which automatically resets to a turn OFF condition in the event the transistor does not turn ON within a predetermined time after the input signal transition. 2 figs.

  13. Impediment to Spirit Drive on Sol 1806

    NASA Technical Reports Server (NTRS)

    2009-01-01

    The hazard avoidance camera on the front of NASA's Mars Exploration Rover Spirit took this image after a drive by Spirit on the 1,806th Martian day, or sol, (January 31, 2009) of Spirit's mission on the surface of Mars.

    The wheel at the bottom right of the image is Spirit's right-front wheel. Because that wheel no longer turns, Spirit drives backwards dragging that wheel. The drive on Sol 1806 covered about 30 centimeters (1 foot). The rover team had planned a longer drive, but Spirit stopped short, apparently from the right front wheel encountering the partially buried rock visible next to that wheel.

    The hazard avoidance cameras on the front and back of the rover provide wide-angle views. The hill on the horizon in the right half of this image is Husband Hill. Spirit reached the summit of Husband Hill in 2005.

  14. Oxidized alginate hydrogels for bone morphogenetic protein-2 delivery in long bone defects.

    PubMed

    Priddy, Lauren B; Chaudhuri, Ovijit; Stevens, Hazel Y; Krishnan, Laxminarayanan; Uhrig, Brent A; Willett, Nick J; Guldberg, Robert E

    2014-10-01

    Autograft treatment of large bone defects and fracture non-unions is complicated by limited tissue availability and donor site morbidity. Polymeric biomaterials such as alginate hydrogels provide an attractive tissue engineering alternative due to their biocompatibility, injectability, and tunable degradation rates. Irradiated RGD-alginate hydrogels have been used to deliver proteins such as bone morphogenetic protein-2 (BMP-2), to promote bone regeneration and restoration of function in a critically sized rat femoral defect model. However, slow degradation of irradiated alginate hydrogels may impede integration and remodeling of the regenerated bone to its native architecture. Oxidation of alginate has been used to promote degradation of alginate matrices. The objective of this study was to evaluate the effects of alginate oxidation on BMP-2 release and bone regeneration. We hypothesized that oxidized-irradiated alginate hydrogels would elicit an accelerated release of BMP-2, but degrade faster in vivo, facilitating the formation of higher quality, more mature bone compared to irradiated alginate. Indeed, oxidation of irradiated alginate did accelerate in vitro BMP-2 release. Notably, the BMP-2 retained within both constructs was bioactive at 26days, as observed by induction of alkaline phosphatase activity and positive Alizarin Red S staining of MC3T3-E1 cells. From the in vivo study, robust bone regeneration was observed in both groups through 12weeks by radiography, micro-computed tomography analyses, and biomechanical testing. Bone mineral density was significantly greater for the oxidized-irradiated alginate group at 8weeks. Histological analyses of bone defects revealed enhanced degradation of oxidized-irradiated alginate and suggested the presence of more mature bone after 12weeks of healing.

  15. Demineralized dentin matrix combined with recombinant human bone morphogenetic protein-2 in rabbit calvarial defects

    PubMed Central

    2016-01-01

    Objectives The aim of this study was to compare the osteogenic effects of demineralized dentin matrix (DDM) combined with recombinant human bone morphogenetic protein-2 (rhBMP-2) in rabbit calvarial defects with DDM and anorganic bovine bone (ABB) combined with rhBMP-2. Materials and Methods Four round defects with 8-mm diameters were created in each rabbit calvaria. Each defect was treated with one of the following: 1) DDM, 2) ABB/rhBMP-2, or 3) DDM/rhBMP-2. The rhBMP-2 was combined with DDM and ABB according to a stepwise dry and dip lyophilizing protocol. Histological and microcomputed tomography (µCT) analyses were performed to measure the amount of bone formation and bone volume after 2- and 8-week healing intervals. Results Upon histological observation at two weeks, the DDM and ABB/rhBMP-2 groups showed osteoconductive bone formation, while the DDM/rhBMP-2 group showed osteoconductive and osteoinductive bone formation. New bone formation was higher in DDM/rhBMP-2, DDM and ABB decreasing order. The amounts of bone formation were very similar at two weeks; however, at eight weeks, the DDM/rhBMP-2 group showed a two-fold greater amount of bone formation compared to the DDM and ABB/rhBMP-2 groups. The µCT analysis showed markedly increased bone volume in the DDM/rhBMP-2 group at eight weeks compared with that of the DDM group. Notably, there was a slight decrease in bone volume in the ABB/rhBMP-2 group at eight weeks. There were no significant differences among the DDM, ABB/rhBMP-2, and DDM/rhBMP-2 groups at two or eight weeks. Conclusion Within the limitations of this study, DDM appears to be a suitable carrier for rhBMP-2 in orthotopic sites. PMID:27162749

  16. Synaptic vesicle protein2A decreases in amygdaloid-kindling pharmcoresistant epileptic rats.

    PubMed

    Shi, Jing; Zhou, Feng; Wang, Li-kun; Wu, Guo-feng

    2015-10-01

    Synaptic vesicle protein 2A (SV2A) involvement has been reported in the animal models of epilepsy and in human intractable epilepsy. The difference between pharmacosensitive epilepsy and pharmacoresistant epilepsy remains poorly understood. The present study aimed to observe the hippocampus SV2A protein expression in amygdale-kindling pharmacoresistant epileptic rats. The pharmacosensitive epileptic rats served as control. Amygdaloid-kindling model of epilepsy was established in 100 healthy adult male Sprague-Dawley rats. The kindled rat model of epilepsy was used to select pharmacoresistance by testing their seizure response to phenytoin and phenobarbital. The selected pharmacoresistant rats were assigned to a pharmacoresistant epileptic group (PRE group). Another 12 pharmacosensitive epileptic rats (PSE group) served as control. Immunohistochemistry, real-time PCR and Western blotting were used to determine SV2A expression in the hippocampus tissue samples from both the PRE and the PSE rats. Immunohistochemistry staining showed that SV2A was mainly accumulated in the cytoplasm of the neurons, as well as along their dendrites throughout all subfields of the hippocampus. Immunoreactive staining level of SV2A-positive cells was 0.483 ± 0.304 in the PRE group and 0.866 ± 0.090 in the PSE group (P < 0.05). Real-time PCR analysis demonstrated that 2(-ΔΔCt) value of SV2A mRNA was 0.30 ± 0.43 in the PRE group and 0.76 ± 0.18 in the PSE group (P < 0.05). Western blotting analysis obtained the similar findings (0.27 ± 0.21 versus 1.12 ± 0.21, P < 0.05). PRE rats displayed a significant decrease of SV2A in the brain. SV2A may be associated with the pathogenesis of intractable epilepsy of the amygdaloid-kindling rats.

  17. Salicylic Acid-Based Polymers for Guided Bone Regeneration Using Bone Morphogenetic Protein-2

    PubMed Central

    Subramanian, Sangeeta; Mitchell, Ashley; Yu, Weiling; Snyder, Sabrina; Uhrich, Kathryn

    2015-01-01

    Bone morphogenetic protein-2 (BMP-2) is used clinically to promote spinal fusion, treat complex tibia fractures, and to promote bone formation in craniomaxillofacial surgery. Excessive bone formation at sites where BMP-2 has been applied is an established complication and one that could be corrected by guided tissue regeneration methods. In this study, anti-inflammatory polymers containing salicylic acid [salicylic acid-based poly(anhydride-ester), SAPAE] were electrospun with polycaprolactone (PCL) to create thin flexible matrices for use as guided bone regeneration membranes. SAPAE polymers hydrolyze to release salicylic acid, which is a nonsteroidal anti-inflammatory drug. PCL was used to enhance the mechanical integrity of the matrices. Two different SAPAE-containing membranes were produced and compared: fast-degrading (FD-SAPAE) and slow-degrading (SD-SAPAE) membranes that release salicylic acid at a faster and slower rate, respectively. Rat femur defects were treated with BMP-2 and wrapped with FD-SAPAE, SD-SAPAE, or PCL membrane or were left unwrapped. The effects of different membranes on bone formation within and outside of the femur defects were measured by histomorphometry and microcomputed tomography. Bone formation within the defect was not affected by membrane wrapping at BMP-2 doses of 12 μg or more. In contrast, the FD-SAPAE membrane significantly reduced bone formation outside the defect compared with all other treatments. The rapid release of salicylic acid from the FD-SAPAE membrane suggests that localized salicylic acid treatment during the first few days of BMP-2 treatment can limit ectopic bone formation. The data support development of SAPAE polymer membranes for guided bone regeneration applications as well as barriers to excessive bone formation. PMID:25813520

  18. Epithelial membrane protein 2 (EMP2) deficiency alters placental angiogenesis, mimicking features of human placental insufficiency.

    PubMed

    Williams, Carmen J; Chu, Alison; Jefferson, Wendy N; Casero, David; Sudhakar, Deepthi; Khurana, Nevil; Hogue, Claire P; Aryasomayajula, Chinmayi; Patel, Priya; Sullivan, Peggy; Padilla-Banks, Elizabeth; Mohandessi, Shabnam; Janzen, Carla; Wadehra, Madhuri

    2017-03-14

    Epithelial membrane protein-2 (EMP2) is a tetraspan protein predicted to regulate placental development. Highly expressed in secretory endometrium and trophectoderm cells, previous studies suggest that it may regulate implantation by orchestrating the surface expression of integrins and other membrane proteins. In order to test the role of EMP2 in pregnancy, mice lacking EMP2 (Emp2(-/-) ) were generated. Emp2(-/-) females are fertile but have reduced litter sizes when carrying Emp2(-/-) but not Emp2(+/-) fetuses. Placentas of Emp2(-/-) fetuses exhibit dysregulation in pathways related to neoangiogenesis, coagulation, and oxidative stress, and have increased fibrin deposition and altered vasculature. Given that these findings often occur due to placental insufficiency resulting in an oxygen-poor environment, the expression of hypoxia-inducible factor-1 alpha (HIF-1α) was examined. Placentas from Emp2(-/-) fetuses had increased total HIF-1α expression in large part through an increase in uterine NK (uNK) cells, demonstrating a unique interplay between uNK cells and trophoblasts modulated through EMP2. To determine if these results translated to human pregnancy, placentas from normal, term deliveries or those complicated by placental insufficiency resulting in intrauterine growth restriction (IUGR) were stained for EMP2. EMP2 was significantly reduced in both villous and extravillous trophoblast populations in IUGR placentas. Experiments in vitro using human trophoblast cells lines indicate that EMP2 modulates angiogenesis by altering HIF-1α expression. Our results reveal a novel role for EMP2 in regulating trophoblast function and vascular development in mice and humans and suggest it may be a new biomarker for placental insufficiency.

  19. Transcription factor activating protein 2 beta (TFAP2B) mediates noradrenergic neuronal differentiation in neuroblastoma.

    PubMed

    Ikram, Fakhera; Ackermann, Sandra; Kahlert, Yvonne; Volland, Ruth; Roels, Frederik; Engesser, Anne; Hertwig, Falk; Kocak, Hayriye; Hero, Barbara; Dreidax, Daniel; Henrich, Kai-Oliver; Berthold, Frank; Nürnberg, Peter; Westermann, Frank; Fischer, Matthias

    2016-02-01

    Neuroblastoma is an embryonal pediatric tumor that originates from the developing sympathetic nervous system and shows a broad range of clinical behavior, ranging from fatal progression to differentiation into benign ganglioneuroma. In experimental neuroblastoma systems, retinoic acid (RA) effectively induces neuronal differentiation, and RA treatment has been therefore integrated in current therapies. However, the molecular mechanisms underlying differentiation are still poorly understood. We here investigated the role of transcription factor activating protein 2 beta (TFAP2B), a key factor in sympathetic nervous system development, in neuroblastoma pathogenesis and differentiation. Microarray analyses of primary neuroblastomas (n = 649) demonstrated that low TFAP2B expression was significantly associated with unfavorable prognostic markers as well as adverse patient outcome. We also found that low TFAP2B expression was strongly associated with CpG methylation of the TFAP2B locus in primary neuroblastomas (n = 105) and demethylation with 5-aza-2'-deoxycytidine resulted in induction of TFAP2B expression in vitro, suggesting that TFAP2B is silenced by genomic methylation. Tetracycline inducible re-expression of TFAP2B in IMR-32 and SH-EP neuroblastoma cells significantly impaired proliferation and cell cycle progression. In IMR-32 cells, TFAP2B induced neuronal differentiation, which was accompanied by up-regulation of the catecholamine biosynthesizing enzyme genes DBH and TH, and down-regulation of MYCN and REST, a master repressor of neuronal genes. By contrast, knockdown of TFAP2B by lentiviral transduction of shRNAs abrogated RA-induced neuronal differentiation of SH-SY5Y and SK-N-BE(2)c neuroblastoma cells almost completely. Taken together, our results suggest that TFAP2B is playing a vital role in retaining RA responsiveness and mediating noradrenergic neuronal differentiation in neuroblastoma.

  20. Salicylic Acid-Based Polymers for Guided Bone Regeneration Using Bone Morphogenetic Protein-2.

    PubMed

    Subramanian, Sangeeta; Mitchell, Ashley; Yu, Weiling; Snyder, Sabrina; Uhrich, Kathryn; O'Connor, J Patrick

    2015-07-01

    Bone morphogenetic protein-2 (BMP-2) is used clinically to promote spinal fusion, treat complex tibia fractures, and to promote bone formation in craniomaxillofacial surgery. Excessive bone formation at sites where BMP-2 has been applied is an established complication and one that could be corrected by guided tissue regeneration methods. In this study, anti-inflammatory polymers containing salicylic acid [salicylic acid-based poly(anhydride-ester), SAPAE] were electrospun with polycaprolactone (PCL) to create thin flexible matrices for use as guided bone regeneration membranes. SAPAE polymers hydrolyze to release salicylic acid, which is a nonsteroidal anti-inflammatory drug. PCL was used to enhance the mechanical integrity of the matrices. Two different SAPAE-containing membranes were produced and compared: fast-degrading (FD-SAPAE) and slow-degrading (SD-SAPAE) membranes that release salicylic acid at a faster and slower rate, respectively. Rat femur defects were treated with BMP-2 and wrapped with FD-SAPAE, SD-SAPAE, or PCL membrane or were left unwrapped. The effects of different membranes on bone formation within and outside of the femur defects were measured by histomorphometry and microcomputed tomography. Bone formation within the defect was not affected by membrane wrapping at BMP-2 doses of 12 μg or more. In contrast, the FD-SAPAE membrane significantly reduced bone formation outside the defect compared with all other treatments. The rapid release of salicylic acid from the FD-SAPAE membrane suggests that localized salicylic acid treatment during the first few days of BMP-2 treatment can limit ectopic bone formation. The data support development of SAPAE polymer membranes for guided bone regeneration applications as well as barriers to excessive bone formation.

  1. Activator Protein 2α Mediates Parathyroid TGF-α Self-Induction in Secondary Hyperparathyroidism

    PubMed Central

    Arcidiacono, Maria Vittoria; Cozzolino, Mario; Spiegel, Noah; Tokumoto, Masanori; Yang, Jing; Lu, Yan; Sato, Tetsuhiko; Lomonte, Carlo; Basile, Carlo; Slatopolsky, Eduardo; Dusso, Adriana S.

    2008-01-01

    In secondary hyperparathyroidism, enhanced expression of TGF-α in the parathyroid leads to its own upregulation, generating a feed-forward loop for TGF-α activation of its receptor, EGFR receptor (EGFR), which promotes parathyroid hyperplasia. These studies examined the role of activator protein 2α (AP2), an inducer of TGF-α gene transcription, in the upregulation of parathyroid TGF-α in secondary hyperparathyroidism. In rat and human secondary hyperparathyroidism, parathyroid AP2 expression strongly correlated with TGF-α levels and with the rate of parathyroid growth, as expected. Furthermore, the increases in rat parathyroid content of AP2 and its binding to a consensus AP2 DNA sequence preceded the increase in TGF-α induced by high dietary phosphate. More significant, in A431 cells, which provide a model of enhanced TGF-α and TGF-α self-induction, mutating the core AP2 site of the human TGF-α promoter markedly impaired promoter activity induced by endogenous or exogenous TGF-α. Important for therapy, in five-sixths nephrectomized rats fed high-phosphate diets, inhibition of parathyroid TGF-α self-induction using erlotinib, a highly specific inhibitor of TGF-α/EGFR-driven signals, reduced AP2 expression dosage dependently. This suggests that the increases in parathyroid AP2 occur downstream of EGFR activation by TGF-α and are required for TGF-α self-induction. Indeed, in A431 cells, erlotinib inhibition of TGF-α self-induction caused parallel reductions in AP2 expression and nuclear localization, as well as TGF-α mRNA and protein levels. In summary, increased AP2 expression and transcriptional activity at the TGF-α promoter determine the severity of the hyperplasia driven by parathyroid TGF-α self-upregulation in secondary hyperparathyroidism. PMID:18579641

  2. Jun Dimerization Protein 2 Activates Mc2r Transcriptional Activity: Role of Phosphorylation and SUMOylation

    PubMed Central

    Wang, Chiung-Min; Wang, Raymond X.; Liu, Runhua; Yang, Wei-Hsiung

    2017-01-01

    Jun dimerization protein 2 (JDP2), a basic leucine zipper transcription factor, is involved in numerous biological and cellular processes such as cancer development and regulation, cell-cycle regulation, skeletal muscle and osteoclast differentiation, progesterone receptor signaling, and antibacterial immunity. Though JDP2 is widely expressed in mammalian tissues, its function in gonads and adrenals (such as regulation of steroidogenesis and adrenal development) is largely unknown. Herein, we find that JDP2 mRNA and proteins are expressed in mouse adrenal gland tissues. Moreover, overexpression of JDP2 in Y1 mouse adrenocortical cancer cells increases the level of melanocortin 2 receptor (MC2R) protein. Notably, Mc2r promoter activity is activated by JDP2 in a dose-dependent manner. Next, by mapping the Mc2r promoter, we show that cAMP response elements (between −1320 and −720-bp) are mainly required for Mc2r activation by JDP2 and demonstrate that −830-bp is the major JDP2 binding site by real-time chromatin immunoprecipitation (ChIP) analysis. Mutations of cAMP response elements on Mc2r promoter disrupts JDP2 effect. Furthermore, we demonstrate that removal of phosphorylation of JDP2 results in attenuated transcriptional activity of Mc2r. Finally, we show that JDP2 is a candidate for SUMOylation and SUMOylation affects JDP2-mediated Mc2r transcriptional activity. Taken together, JDP2 acts as a novel transcriptional activator of the mouse Mc2r gene, suggesting that JDP2 may have physiological functions as a novel player in MC2R-mediated steroidogenesis as well as cell signaling in adrenal glands. PMID:28146118

  3. Bone morphogenetic protein-2-encapsulated grafted-poly-lactic acid-polycaprolactone nanoparticles promote bone repair.

    PubMed

    Xu, Xiaojun; Yang, Jun; Ding, Lifeng; Li, Jianjun

    2015-01-01

    The aim of this study is to test the efficacy of a novel tissue-engineered bone in repairing bone defects, using poly-lactic-acid-polycaprolactone (PLA-PCL) scaffolding seeded with PEG-bone morphogenetic protein-2 (BMP-2)-transfected rBMSCs (rabbit bone marrow stromal cells). The rBMSCs were transfected with PEG/BMP-2 or liposome/BMP-2, and then implanted into a PLA-PCL tissue-engineered bone. The protein level of BMP-2 was assessed by Western blot analysis and immunohistochemistry. ELISA was used to measure the amount of BMP-2 secreted in the culture media. The mRNA level of BMP-2 and osteocalcin was assayed quantitatively by real-time PCR. The middle portion of the bilateral radius in New Zealand rabbits was excised and implanted with tissue-engineered bone, and the modified areas were monitored by X-ray, hematoxylin-eosin staining, and immunohistochemistry staining of BMP-2. PEG-BMP-2 nanoparticles (NPs) and BMP-2-loaded PEG-PLA-PCL tissue-engineered bones were successfully constructed. The novel PEG-PLA-PCL NPs/DNA complex was a superior option for transfecting BMP-2 in rBMSCs compared to normal liposomes Moreover, the mRNA level of osteocalcin and alkaline phosphatase activity was also elevated upon transfection of BMP-2-encapsulated NPs. In vivo implants with BMP-2-carried tissue-engineered bone exhibited dramatic augmentation of BMP-2 and effective bone formation in the rabbit ectopic model. The PEG-PLA-PCL NPs/BMP-2 complex had an advantageous effect on bone repair, which provided an important theoretic basis for potential clinical treatments.

  4. The evaluation of lyophilized polymer matrices for administering recombinant human bone morphogenetic protein-2.

    PubMed

    Duggirala, S S; Rodgers, J B; DeLuca, P P

    1996-07-01

    Novel unitary devices, prepared by lyophilization of viscous solutions of sodium carboxymethylcellulose (CMC) and methylcellulose (MC), were evaluated as sustained-release delivery systems for recombinant human bone morphogenetic protein-2 (rhBMP-2). In vitro characterization of the unitary devices, which contained rhBMP-2-loaded poly (d,l lactide-co-glycolide) (PLGA) bioerodible particles (BEPs), was conducted over a 2-month period. Determinations included buffer uptake, mass and molecular weight loss and rhBMP-2 release from the unitary devices. CMC devices imbibed approximately 16 times their weight of buffer, while with MC, equilibrium uptake was approximately 6 times the dry weight of the devices. Overall mass loss percentages were approximately 55 and 35%, respectively, for CMC and MC devices. rhBMP-2 release from the devices was essentially a triphasic process: an initial phase during which "free" protein (rhBMP-2 present on the surface and within the pores of the PLGA BEPs) was released, a lag period during which no release was discerned, and then release of "bound" rhBMP-2 (protein adsorbed to the BEPs). The release of bound protein correlated with the mass loss of the polymer which began after 3 weeks. Release from the unitary devices was lower than that from the BEPs alone, due to a retardation effect of the gelled CMC/MC polymers. In rabbits in which full-thickness cranial bone defects were created, the implants were well tolerated and induced significant new bone growth during an 8-week evaluation period. The CMC devices appear to have induced bone earlier (at 2 weeks), but this did not affect eventual 8-week results. CMC devices without rhBMP-2 appeared to provide some bone conduction, in contrast to the blank MC devices.

  5. A Novel Topology of Proline-rich Transmembrane Protein 2 (PRRT2)

    PubMed Central

    Rossi, Pia; Sterlini, Bruno; Castroflorio, Enrico; Marte, Antonella; Onofri, Franco; Valtorta, Flavia; Maragliano, Luca; Corradi, Anna; Benfenati, Fabio

    2016-01-01

    Proline-rich transmembrane protein 2 (PRRT2) has been identified as the single causative gene for a group of paroxysmal syndromes of infancy, including epilepsy, paroxysmal movement disorders, and migraine. On the basis of topology predictions, PRRT2 has been assigned to the recently characterized family of Dispanins, whose members share the two-transmembrane domain topology with a large N terminus and short C terminus oriented toward the outside of the cell. Because PRRT2 plays a role at the synapse, it is important to confirm the exact orientation of its N and C termini with respect to the plasma membrane to get clues regarding its possible function. Using a combination of different experimental approaches, including live immunolabeling, immunogold electron microscopy, surface biotinylation and computational modeling, we demonstrate a novel topology for this protein. PRRT2 is a type II transmembrane protein in which only the second hydrophobic segment spans the plasma membrane, whereas the first one is associated with the internal surface of the membrane and forms a helix-loop-helix structure without crossing it. Most importantly, the large proline-rich N-terminal domain is not exposed to the extracellular space but is localized intracellularly, and only the short C terminus is extracellular (Ncyt/Cexo topology). Accordingly, we show that PRRT2 interacts with the Src homology 3 domain-bearing protein Intersectin 1, an intracellular protein involved in synaptic vesicle cycling. These findings will contribute to the clarification of the role of PRRT2 at the synapse and the understanding of pathogenic mechanisms on the basis of PRRT2-related neurological disorders. PMID:26797119

  6. Analysis of Recombinant Human Bone Morphogenetic Protein-2 Use in the Treatment of Lumbar Degenerative Spondylolisthesis

    PubMed Central

    Yao, Qingqiang; Cohen, Jeremiah R.; Buser, Zorica; Park, Jong-Beom; Brodke, Darrel S.; Meisel, Hans-Joerg; Youssef, Jim A.; Wang, Jeffrey C.; Yoon, S. Tim

    2016-01-01

    Study Design Retrospective database review. Objective To identify trends of the recombinant human bone morphogenetic protein-2 (rhBMP-2) use in the treatment of lumbar degenerative spondylolisthesis (LDS). Methods PearlDiver Patient Record Database was used to identify patients who underwent lumbar fusion for LDS between 2005 and 2011. The distribution of bone morphogenetic protein use rate (BR) in various surgical procedures was recorded. Patient numbers, reoperation numbers, BR, and per year BR (PYBR) were stratified by geographic region, gender, and age. Results There were 11,335 fusion surgeries, with 3,461 cases using rhBMP-2. Even though PYRB increased between 2005 and 2008, there was a significant decrease in 2010 for each procedure: 404 (34.5%) for posterior interbody fusion, 1,282 (34.3%) for posterolateral plus posterior interbody fusion (PLPIF), 1,477 (29.2%) for posterolateral fusion, and 335 (22.4%) for anterior lumbar interbody fusion. In patients using rhBMP-2, the reoperation rate was significantly lower than in patients not using rhBMP-2 (0.69% versus 1.07%, p < 0.0001). Male patients had higher PYBR compared with female patients in 2008 and 2009 (p < 0.05). The West region and PLPIF had the highest BR and PYBR. Conclusions Our data shows that the revision rates were significantly lower in patients treated with rhBMP-2 compared with patients not treated with rhBMP-2. Furthermore, rhBMP-2 use in LDS varied by year, region, gender, and type of fusion technique. In the West region, the posterior approach and patients 65 to 69 years of age had the highest rate of rhBMP-2 use. PMID:27853658

  7. Hydrogel Delivery of Mesenchymal Stem Cell–Expressing Bone Morphogenetic Protein-2 Enhances Bone Defect Repair

    PubMed Central

    Hsiao, Hui-Yi; Yang, Shu-Rui; Brey, Eric M.; Chu, I-Ming

    2016-01-01

    Background: The application of bone tissue engineering for repairing bone defects has gradually shown some satisfactory progress. One of the concerns raising scientific attention is the poor supply of growth factors. A number of growth factor delivery approaches have been developed for promoting bone formation. However, there is no systematic comparison of those approaches on efficiency of neobone formation. In this study, the approaches using periosteum, direct supply of growth factors, or gene transfection of growth factors were evaluated to determine the osteogenic capacity on the repair of bone defect. Methods: In total, 42 male 21-week-old Sprague-Dawley rats weighing 250 to 400 g were used as the bone defect model to evaluate the bone repair efficiency. Various tissue engineered constructs of poly(ethylene glycol)-poly(l-lactic acid) (PEG-PLLA) copolymer hydrogel with periosteum, with external supply of bone morphogenetic protein-2 (BMP2), or with BMP2-transfected bone marrow–derived mesenchymal stem cells (BMMSCs) were filled in a 7-mm bone defect region. Animals were euthanized at 3 months, and the hydrogel constructs were harvested. The evaluation with histological staining and radiography analysis were performed for the volume of new bone formation. Results: The PEG-PLLA scaffold with BMMSCs promotes bone regeneration with the addition of periosteum. The group with BMP2-transfected BMMSCs demonstrated the largest volume of new bone among all the testing groups. Conclusions: Altogether, the results of this study provide the evidence that the combination of PEG-PLLA hydrogels with BMMSCs and sustained delivery of BMP2 resulted in the maximal bone regeneration. PMID:27622106

  8. Involvement of multidrug resistance-associated protein 2 in intestinal secretion of grepafloxacin in rats.

    PubMed

    Naruhashi, Kazumasa; Tamai, Ikumi; Inoue, Natsuko; Muraoka, Hiromi; Sai, Yoshimichi; Suzuki, Nagao; Tsuji, Akira

    2002-02-01

    We investigated the contribution of multidrug resistance-associated protein 2 (MRP2) to the secretory transport of grepafloxacin and compared its functional role with that of P-glycoprotein (P-gp) by using Sprague-Dawley rats (SDRs) and Eisai hyperbilirubinemic rats (EHBRs), in which MRP2 is hereditarily defective. In intestinal tissue from SDRs mounted in Ussing chambers, the level of transport in the direction from the serosal layer to the mucosal layer was twofold greater than that in the direction from the mucosal layer to the serosal layer. This secretory transport of grepafloxacin was diminished by both probenecid, an MRP2 inhibitor, and cyclosporine, a P-gp inhibitor. In intestinal tissue from EHBRs, the secretory transport of grepafloxacin was lower than that in intestinal tissue from SDRs and was inhibited by cyclosporine but not by probenecid. The absorption of grepafloxacin from intestinal loops in SDRs was in the order of duodenum > jejunum > ileum and was increased by cyclosporine but not by probenecid. The absorption in EHBRs was not higher than that in SDRs. The intestinal secretory clearance in SDRs after intravenous administration of grepafloxacin was shown to be greater for the ileum than for the duodenum, which is in good agreement with the previously reported regional expression profile of MRP2 mRNA. The intestinal secretory clearance was lower in EHBRs than in SDRs. Accordingly, in addition to P-gp, MRP2 might play a role in the secretory transport of grepafloxacin. The function of MRP2 in facilitating grepafloxacin transport in the secretory direction is more pronounced both in vitro and in vivo, while the restriction of entry from the lumen into the cell by MRP2 seems to be negligible, compared with that by P-gp, in the case of grepafloxacin.

  9. The Role of Uncoupling Protein 2 During Myocardial Dysfunction in a Canine Model of Endotoxin Shock.

    PubMed

    Wang, Xiaoting; Liu, Dawei; Chai, Wenzhao; Long, Yun; Su, Longxiang; Yang, Rongli

    2015-03-01

    To explore the role of uncoupling protein 2 (UCP2) during myocardial dysfunction in a canine model of endotoxin shock, 26 mongrel canines were randomly divided into the following four groups: A (control group; n = 6), B2 (shock after 2 h; n = 7), B4 (shock after 4 h; n = 7), and B6 (shock after 6 h; n = 6). Escherichia coli endotoxin was injected into the canines via the central vein, and hemodynamics were monitored. Energy metabolism, UCP2 mRNA and protein expression, and UCP2 localization were analyzed, and the correlation between energy metabolism changes, and UCP2 expression was determined. After the canine endotoxin shock model was successfully established, the expression of UCP2 mRNA and protein was found to increase, with later time points showing significant increases (P < 0.05). Immunofluorescence assays of UCP2 in heart tissue showed that UCP2 was localized in the cytoplasm, and its expression pattern was the same as that found in the mRNA and protein analyses. The energy metabolism results revealed that the ADP levels increased, but the ATP and phosphocreatine (PCr) levels and ATP/ADP and PCr/ATP ratios decreased in the model. In particular, the PCr/ATP ratio was significantly different from that of the control group 6 h after shock (P < 0.05). Furthermore, correlation analysis showed that the UCP2 protein and mRNA levels were negatively correlated with myocardial energy levels. In summary, decreased energy synthesis can occur in the myocardium during endotoxin shock, and UCP2 may play an important role in this process. The negative correlation between UCP2 expression and energy metabolism requires further study, as the results might contribute to the treatment of sepsis with heart failure.

  10. Methyl Binding Domain Protein 2 (MBD2) dependent proliferation and survival of breast cancer cells

    PubMed Central

    Mian, Omar Y.; Wang, Shou Zhen; Zhu, Sheng Zu; Gnanapragasam, Merlin N.; Graham, Laura; Bear, Harry D.; Ginder, Gordon D.

    2011-01-01

    Methyl Cytosine Binding Domain Protein 2 (MBD2) has been shown to bind to and mediate repression of methylated tumor suppressor genes in cancer cells, where re-patterning of CpG methylation and associated gene silencing is common. We have investigated the role of MBD2 in breast cancer cell growth and tumor suppressor gene expression. We show that stable shRNA mediated knockdown of MBD2 leads to growth suppression of cultured human mammary epithelial cancer lines, SK-BR-3, MDA-MB-231, and MDA-MB-435. The peak anti-proliferative occurs only after sustained, stable MBD2 knockdown. Once established, the growth inhibition persists over time and leads to a markedly decreased propensity for aggressive breast cancer cell lines to form in vivo xenograft tumors in BALB/C nu/nu mice. The growth effects of MBD2 knockdown are accompanied by de-repression of tumor suppressor genes including DAPK1 and KLK10. Chromatin immunoprecipitation assays and bisulfite sequencing demonstrate MBD2 binding directly to the hyper-methylated and CpG-rich promoters of both DAPK1 and KLK10. Remarkably, the promoter CpG-island associated methylation of these genes remained stable despite robust transcriptional activation in MBD2 knockdown cells. Expression of a shRNA-resistant MBD2 protein resulted in restoration of growth and re-silencing of the MBD2 dependent tumor suppressor genes. Our data suggest that uncoupling CpG-methylation from repressive chromatin remodeling and histone modifications by removing MBD2 is sufficient to initiate and maintain tumor suppressor gene transcription and suppress neoplastic cell growth. These results demonstrate a role for MBD2 in cancer progression and provide support for the prospect of targeting MBD2 therapeutically in aggressive breast cancers. PMID:21693597

  11. Intestinal multidrug resistance-associated protein 2 is down-regulated in fructose-fed rats.

    PubMed

    Londero, Ana Sofía; Arana, Maite Rocío; Perdomo, Virginia Gabriela; Tocchetti, Guillermo Nicolás; Zecchinati, Felipe; Ghanem, Carolina Inés; Ruiz, María Laura; Rigalli, Juan Pablo; Mottino, Aldo Domingo; García, Fabiana; Villanueva, Silvina Stella Maris

    2017-02-01

    Expression and activity of jejunal multidrug resistance-associated protein 2 (Mrp2) and glutathione-S-transferase (GST) were examined in fructose fed Wistar rats, an experimental model of metabolic syndrome. Animals were fed on (a) control diet or (b) control diet plus 10% w/vol fructose in the drinking water. Mrp2 and the α class of GST proteins as well as their corresponding mRNAs were decreased, suggesting a transcriptional regulation by fructose. Confocal microscopy studies reaffirmed down-regulation of Mrp2. Everted intestinal sacs were incubated with 1-chloro-2,4-dinitrobenzene in the mucosal compartment, and the glutathione-conjugated derivative, dinitrophenyl- S-glutathione (DNP-SG; model Mrp2 substrate), was measured in the same compartment to estimate Mrp2 activity. Excretion of DNP-SG was substantially decreased by fructose treatment, consistent with simultaneous down-regulation of Mrp2 and GST. In addition, the effect of fructose on intestinal barrier function exerted by Mrp2 was evaluated in vivo using valsartan, a recognized Mrp2 substrate of therapeutic use. After intraduodenal administration as a bolus, intestinal absorption of valsartan was increased in fructose-drinking animals. Fructose administration also induced oxidative stress in intestinal tissue as demonstrated by significant increases of intestinal lipid peroxidation end products and activity of the antioxidant enzyme superoxide dismutase, by a decreased GSH/GSSG ratio. Moreover, fructose treatment conduced to increased intestinal levels of the proinflammatory cytokines IL-β1 and IL-6. Collectively, our results demonstrate that metabolic syndrome-like conditions, induced by a fructose-rich diet, result in down-regulation of intestinal Mrp2 expression and activity and consequently in an impairment of its barrier function.

  12. The effect of nicotine on osteoinduction by recombinant human bone morphogenetic protein 2.

    PubMed

    Tamura, K; Togo, Y; Kaihara, S; Hussain, A; Takahashi, K; Bessho, K

    2014-08-01

    Nicotine, one of the constituents of tobacco, is known to have an adverse effect on human health. We sought to clarify the interaction between nicotine and recombinant human bone morphogenetic protein 2 (rhBMP-2) in terms of osteogenesis in vitro and osteoinduction in vivo. Nicotine did not inhibit or stimulate alkaline phosphatase (ALP) activity or the amount of osteocalcin in C2C12 cells in the presence of rhBMP-2 in vitro. Ectopic bone formation using a collagen sponge containing rhBMP-2 was evaluated with and without nicotine after 21 days using radiographic, histological, biochemical, and immunohistochemical analyses. ALP activity in the medium-dose group (2.2±0.9IU/mg protein; P=0.047) and the high-dose group (2.0±0.1IU/mg protein; P=0.03) was significantly lower than in the control group. The calcium content in the medium-dose group (35.4±12.9μg/mg tissue; P=0.0099) and high-dose group (34.8±10.5μg/mg tissue; P=0.006) was significantly lower than in the control group. The number of vascular endothelial growth factor-positive cells in the high-dose group (671.9±57.3cells/mm(2); P=0.03) was significantly lower than in the control group. Results showed that nicotine did not inhibit the stimulatory effect of rhBMP-2 in vitro, but a high dose of nicotine inhibited bone formation in vivo by adversely affecting vascularization.

  13. Capillary morphogenesis protein-2 is required for mouse parturition by maintaining uterine collagen homeostasis.

    PubMed

    Peters, Diane E; Zhang, Yi; Molinolo, Alfredo A; Miller-Randolph, Sharmina; Szabo, Roman; Bugge, Thomas H; Leppla, Stephen H; Liu, Shihui

    2012-06-08

    Capillary morphogenesis protein-2 (CMG2) functions as an anthrax toxin receptor that plays an essential role in anthrax pathogenesis. Although mutations in CMG2 have been identified to cause two human autosomal recessive disorders, Juvenile Hyaline Fibromatosis and Infantile Systemic Hyalinosis, both characterized by excess hyaline material deposition in connective tissues, the physiologic function of CMG2 remains elusive. To study the roles of CMG2 in normal physiology, here we performed detailed histological analyses of the CMG2-null mice we generated previously. While no morphological or histological defects were observed in CMG2(-/-) male mice, CMG2(-/-) female mice were unable to produce any offspring due to a defect in parturition. We found that deletion of CMG2 resulted in a diffuse deposition of collagen within the myometrium of CMG2(-/-) females, causing remarkable morphological changes to their uteri. This collagen accumulation also led to loss of smooth muscle cells in the myometrium of CMG2(-/-) mice, apparently disabling uterine contractile function during parturition. As a consequence, even though pregnant CMG2(-/-) mice were able to carry the gestation to full term, they were unable to deliver pups. However, the fully-developed fetuses could be successfully delivered by Cesarean section and survived to adulthood when fostered. Our results demonstrate that CMG2 is not required for normal mouse embryonic development but is indispensable for murine parturition. In parallel to its role in anthrax toxin binding and internalization, herein we provide evidence that CMG2 may function as a collagen receptor which is essential for maintaining collagen homeostasis in the uterus.

  14. Injectable hydrogels embedded with alginate microspheres for controlled delivery of bone morphogenetic protein-2.

    PubMed

    Zhu, Youjia; Wang, Jiulong; Wu, Jingjing; Zhang, Jun; Wan, Ying; Wu, Hua

    2016-03-23

    Some delivery carriers with injectable characteristics were built using the thermosensitive chitosan/dextran-polylactide/glycerophosphate hydrogel and selected alginate microspheres for the controllable release of bone morphogenetic protein-2 (BMP-2). BMP-2 was first loaded into the microspheres with an average size of around 20 μm and the resulting microspheres were then embedded into the gel in order to achieve well-controlled BMP-2 release. The microsphere-embedded gels show their incipient gelation temperature at around 32 °C and pH at about 7.1. Some gels had their elastic modulus close to 1400 Pa and the ratio of elastic modulus to viscous modulus at around 34, revealing that they behaved like mechanically strong gels. Optimized microsphere-embedded gels were found to be able to administer the BMP-2 release without significant initial burst release in an approximately linear manner over a period of time longer than four weeks. The release rate and the released amount of BMP-2 from these gels could be regulated individually or cooperatively by the initial BMP-2 load and the dextran-polylactide content in the gels. Measurements of the BMP-2 induced alkaline phosphatase activity in C2C12 cells confirmed that C2C12 cells responded to BMP-2 in a dose-dependent way and the released BMP-2 from the microsphere-embedded gels well retained their bioactivity. In vivo assessment of some gels revealed that the released BMP-2 maintained its osteogenesis functions.

  15. Alternatively spliced myeloid differentiation protein-2 inhibits TLR4-mediated lung inflammation.

    PubMed

    Tumurkhuu, Gantsetseg; Dagvadorj, Jargalsaikhan; Jones, Heather D; Chen, Shuang; Shimada, Kenichi; Crother, Timothy R; Arditi, Moshe

    2015-02-15

    We previously identified a novel alternatively spliced isoform of human myeloid differentiation protein-2 (MD-2s) that competitively inhibits binding of MD-2 to TLR4 in vitro. In this study, we investigated the protective role of MD-2s in LPS-induced acute lung injury by delivering intratracheally an adenovirus construct that expressed MD-2s (Ad-MD-2s). After adenovirus-mediated gene transfer, MD-2s was strongly expressed in lung epithelial cells and readily detected in bronchoalveolar lavage fluid. Compared to adenovirus serotype 5 containing an empty vector lacking a transgene control mice, Ad-MD-2s delivery resulted in significantly less LPS-induced inflammation in the lungs, including less protein leakage, cell recruitment, and expression of proinflammatory cytokines and chemokines, such as IL-6, keratinocyte chemoattractant, and MIP-2. Bronchoalveolar lavage fluid from Ad-MD-2s mice transferred into lungs of naive mice before intratracheal LPS challenge diminished proinflammatory cytokine levels. As house dust mite (HDM) sensitization is dependent on TLR4 and HDM Der p 2, a structural homolog of MD-2, we also investigated the effect of MD-2s on HDM-induced allergic airway inflammation. Ad-MD-2s given before HDM sensitization significantly inhibited subsequent allergic airway inflammation after HDM challenge, including reductions in eosinophils, goblet cell hyperplasia, and IL-5 levels. Our study indicates that the alternatively spliced short isoform of human MD-2 could be a potential therapeutic candidate to treat human diseases induced or exacerbated by TLR4 signaling, such as Gram-negative bacterial endotoxin-induced lung injury and HDM-triggered allergic lung inflammation.

  16. Alternatively spliced myeloid differentiation protein-2 (MD-2s) protein inhibits TLR4-mediated lung inflammation

    PubMed Central

    Tumurkhuu, Gantsetseg; Dagvadorj, Jargalsaikhan; Jones, Heather D.; Chen, Shuang; Shimada, Kenichi; Crother, Timothy R.; Arditi, Moshe

    2014-01-01

    We previously identified a novel alternatively spliced isoform of human myeloid differentiation protein-2 (MD-2s) that competitively inhibits binding of MD-2 to TLR4 in vitro. Here we investigated the protective role of MD-2s in LPS-induced acute lung injury by delivering intracheally (i.t.) an adenovirus construct that expressed MD-2s (Ad-MD-2s). After adenovirus-mediated gene transfer, MD-2s was strongly expressed in lung epithelial cells and readily detected in bronchoalveolar lavage fluid (BALF). Compared to Ad-EV control mice, Ad-MD-2s delivery resulted in significantly less LPS-induced inflammation in the lungs, including less protein leakage, cell recruitment, and expression of proinflammatory cytokines and chemokines, such as IL-6, KC, and MIP-2. BALF from Ad-MD-2s mice transferred into lungs of naive mice before i.t. LPS challenge diminished pro-inflammatory cytokine levels. As house dust mite (HDM) sensitization is dependent on TLR4 and HDM Der p 2, a structural homolog of MD-2, we also investigated the effect of MD-2s on house dust mite (HDM)-induced allergic airway inflammation. Ad-MD-2s given before HDM sensitization significantly inhibited subsequent allergic airway inflammation after HDM challenge, including reductions in eosinophils, goblet cell hyperplasia, and IL-5 levels. Our study indicates that the alternatively spliced short isoform of human MD-2 could be a potential therapeutic candidate to treat human diseases induced or exacerbated by TLR4 signaling, such as Gram-negative bacterial endotoxin-induced lung injury and house dust mite-triggered allergic lung inflammation. PMID:25576596

  17. Ribosomal protein S6 associates with alphavirus nonstructural protein 2 and mediates expression from alphavirus messages.

    PubMed

    Montgomery, Stephanie A; Berglund, Peter; Beard, Clayton W; Johnston, Robert E

    2006-08-01

    Although alphaviruses dramatically alter cellular function within hours of infection, interactions between alphaviruses and specific host cellular proteins are poorly understood. Although the alphavirus nonstructural protein 2 (nsP2) is an essential component of the viral replication complex, it also has critical auxiliary functions that determine the outcome of infection in the host. To gain a better understanding of nsP2 function, we sought to identify cellular proteins with which Venezuelan equine encephalitis virus nsP2 interacted. We demonstrate here that nsP2 associates with ribosomal protein S6 (RpS6) and that nsP2 is present in the ribosome-containing fractions of a polysome gradient, suggesting that nsP2 associates with RpS6 in the context of the whole ribosome. This result was noteworthy, since viral replicase proteins have seldom been described in direct association with components of the ribosome. The association of RpS6 with nsP2 was detected throughout the course of infection, and neither the synthesis of the viral structural proteins nor the presence of the other nonstructural proteins was required for RpS6 interaction with nsP2. nsP1 also was associated with RpS6, but other nonstructural proteins were not. RpS6 phosphorylation was dramatically diminished within hours after infection with alphaviruses. Furthermore, a reduction in the level of RpS6 protein expression led to diminished expression from alphavirus subgenomic messages, whereas no dramatic diminution in cellular translation was observed. Taken together, these data suggest that alphaviruses alter the ribosome during infection and that this alteration may contribute to differential translation of host and viral messages.

  18. Bone morphogenetic protein-2 gene controls tooth root development in coordination with formation of the periodontium

    PubMed Central

    Rakian, Audrey; Yang, Wu-Chen; Gluhak-Heinrich, Jelica; Cui, Yong; Harris, Marie A; Villarreal, Demitri; Feng, Jerry Q; MacDougall, Mary; Harris, Stephen E

    2013-01-01

    Formation of the periodontium begins following onset of tooth-root formation in a coordinated manner after birth. Dental follicle progenitor cells are thought to form the cementum, alveolar bone and Sharpey's fibers of the periodontal ligament (PDL). However, little is known about the regulatory morphogens that control differentiation and function of these progenitor cells, as well as the progenitor cells involved in crown and root formation. We investigated the role of bone morphogenetic protein-2 (Bmp2) in these processes by the conditional removal of the Bmp2 gene using the Sp7-Cre-EGFP mouse model. Sp7-Cre-EGFP first becomes active at E18 in the first molar, with robust Cre activity at postnatal day 0 (P0), followed by Cre activity in the second molar, which occurs after P0. There is robust Cre activity in the periodontium and third molars by 2 weeks of age. When the Bmp2 gene is removed from Sp7+ (Osterix+) cells, major defects are noted in root, cellular cementum and periodontium formation. First, there are major cell autonomous defects in root-odontoblast terminal differentiation. Second, there are major alterations in formation of the PDLs and cellular cementum, correlated with decreased nuclear factor IC (Nfic), periostin and α-SMA+ cells. Third, there is a failure to produce vascular endothelial growth factor A (VEGF-A) in the periodontium and the pulp leading to decreased formation of the microvascular and associated candidate stem cells in the Bmp2-cKOSp7-Cre-EGFP. Fourth, ameloblast function and enamel formation are indirectly altered in the Bmp2-cKOSp7-Cre-EGFP. These data demonstrate that the Bmp2 gene has complex roles in postnatal tooth development and periodontium formation. PMID:23807640

  19. Structure of Human Pancreatic Lipase-Related Protein 2 with the Lid in an Open Conformation

    SciTech Connect

    Eydoux, Cecilia; Spinelli, Silvia; Davis, Tara L.; Walker, John R.; Seitova, Alma; Dhe-Paganon, Sirano; De Caro, Alain; Cambillau, Christian; Carriere, Frederic

    2008-10-02

    Access to the active site of pancreatic lipase (PL) is controlled by a surface loop, the lid, which normally undergoes conformational changes only upon addition of lipids or amphiphiles. Structures of PL with their lids in the open and functional conformation have required cocrystallization with amphiphiles. Here we report two crystal structures of wild-type and unglycosylated human pancreatic lipase-related protein 2 (HPLRP2) with the lid in an open conformation in the absence of amphiphiles. These structures solved independently are strikingly similar, with some residues of the lid being poorly defined in the electron-density map. The open conformation of the lid is however different from that previously observed in classical liganded PL, suggesting different kinetic properties for HPLRP2. Here we show that the HPLRP2 is directly inhibited by E600, does not present interfacial activation, and acts preferentially on substrates forming monomers or small aggregates (micelles) dispersed in solution like monoglycerides, phospholipids and galactolipids, whereas classical PL displays reverse properties and a high specificity for unsoluble substrates like triglycerides and diglycerides forming oil-in-water interfaces. These biochemical properties imply that the lid of HPLRP2 is likely to spontaneously adopt in solution the open conformation observed in the crystal structure. This open conformation generates a large cavity capable of accommodating the digalactose polar head of galactolipids, similar to that previously observed in the active site of the guinea pig PLRP2, but absent from the classical PL. Most of the structural and kinetic properties of HPLRP2 were found to be different from those of rat PLRP2, the structure of which was previously obtained with the lid in a closed conformation. Our findings illustrate the essential role of the lid in determining the substrate specificity and the mechanism of action of lipases.

  20. Structure of human pancreatic lipase-related protein 2 with the lid in an open conformation.

    PubMed

    Eydoux, Cécilia; Spinelli, Silvia; Davis, Tara L; Walker, John R; Seitova, Alma; Dhe-Paganon, Sirano; De Caro, Alain; Cambillau, Christian; Carrière, Frédéric

    2008-09-09

    Access to the active site of pancreatic lipase (PL) is controlled by a surface loop, the lid, which normally undergoes conformational changes only upon addition of lipids or amphiphiles. Structures of PL with their lids in the open and functional conformation have required cocrystallization with amphiphiles. Here we report two crystal structures of wild-type and unglycosylated human pancreatic lipase-related protein 2 (HPLRP2) with the lid in an open conformation in the absence of amphiphiles. These structures solved independently are strikingly similar, with some residues of the lid being poorly defined in the electron-density map. The open conformation of the lid is however different from that previously observed in classical liganded PL, suggesting different kinetic properties for HPLRP2. Here we show that the HPLRP2 is directly inhibited by E600, does not present interfacial activation, and acts preferentially on substrates forming monomers or small aggregates (micelles) dispersed in solution like monoglycerides, phospholipids and galactolipids, whereas classical PL displays reverse properties and a high specificity for unsoluble substrates like triglycerides and diglycerides forming oil-in-water interfaces. These biochemical properties imply that the lid of HPLRP2 is likely to spontaneously adopt in solution the open conformation observed in the crystal structure. This open conformation generates a large cavity capable of accommodating the digalactose polar head of galactolipids, similar to that previously observed in the active site of the guinea pig PLRP2, but absent from the classical PL. Most of the structural and kinetic properties of HPLRP2 were found to be different from those of rat PLRP2, the structure of which was previously obtained with the lid in a closed conformation. Our findings illustrate the essential role of the lid in determining the substrate specificity and the mechanism of action of lipases.