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Sample records for autophagic components contribute

  1. Autophagic components contribute to hypersensitive cell death in Arabidopsis

    DEFF Research Database (Denmark)

    Hofius, Daniel; Schultz-Larsen, Torsten; Joensen, Jan;

    2009-01-01

    Autophagy has been implicated as a prosurvival mechanism to restrict programmed cell death (PCD) associated with the pathogen-triggered hypersensitive response (HR) during plant innate immunity. This model is based on the observation that HR lesions spread in plants with reduced autophagy gene ex...... contributes to HR PCD and can function in parallel with other prodeath pathways....

  2. Cotyledon cells of Vigna mungo seedlings use at least two distinct autophagic machineries for degradation of starch granules and cellular components.

    Science.gov (United States)

    Toyooka, K; Okamoto, T; Minamikawa, T

    2001-09-01

    alpha-Amylase is expressed in cotyledons of germinated Vigna mungo seeds and is responsible for the degradation of starch that is stored in the starch granule (SG). Immunocytochemical analysis of the cotyledon cells with anti-alpha-amylase antibody showed that alpha-amylase is transported to protein storage vacuole (PSV) and lytic vacuole (LV), which is converted from PSV by hydrolysis of storage proteins. To observe the insertion/degradation processes of SG into/in the inside of vacuoles, ultrastructural analyses of the cotyledon cells were conducted. The results revealed that SG is inserted into LV through autophagic function of LV and subsequently degraded by vacuolar alpha-amylase. The autophagy for SG was structurally similar to micropexophagy detected in yeast cells. In addition to the autophagic process for SG, autophagosome-mediated autophagy for cytoplasm and mitochondria was detected in the cotyledon cells. When the embryo axes were removed from seeds and the detached cotyledons were incubated, the autophagosome-mediated autophagy was observed, but the autophagic process for the degradation of SG was not detected, suggesting that these two autophagic processes were mediated by different cellular mechanisms. The two distinct autophagic processes were thought to be involved in the breakdown of SG and cell components in the cells of germinated cotyledon.

  3. ASSAYING OF AUTOPHAGIC PROTEIN DEGRADATION

    NARCIS (Netherlands)

    C. Bauvy; A.J. Meijer; P. Codogno

    2009-01-01

    Macroautophagy is a three-step process: (1) autophagosomes form and mature, (2) the autophagosomes fuse with lysosomes, and (3) the autophagic cargo is degraded in the lysosomes. It is this lysosomal degradation of the autophagic cargo that constitutes the autophagic flux. As in the case of metaboli

  4. Autophagic regulation of smooth muscle cell biology

    Science.gov (United States)

    Salabei, Joshua K.; Hill, Bradford G.

    2014-01-01

    Autophagy regulates the metabolism, survival, and function of numerous cell types, including those comprising the cardiovascular system. In the vasculature, changes in autophagy have been documented in atherosclerotic and restenotic lesions and in hypertensive vessels. The biology of vascular smooth muscle cells appears particularly sensitive to changes in the autophagic program. Recent evidence indicates that stimuli or stressors evoked during the course of vascular disease can regulate autophagic activity, resulting in modulation of VSMC phenotype and viability. In particular, certain growth factors and cytokines, oxygen tension, and pharmacological drugs have been shown to trigger autophagy in smooth muscle cells. Importantly, each of these stimuli has a redox component, typically associated with changes in the abundance of reactive oxygen, nitrogen, or lipid species. Collective findings support the hypothesis that autophagy plays a critical role in vascular remodeling by regulating smooth muscle cell phenotype transitions and by influencing the cellular response to stress. In this graphical review, we summarize current knowledge on the role of autophagy in the biology of the smooth muscle cell in (patho)physiology. PMID:25544597

  5. Autophagic regulation of smooth muscle cell biology

    Directory of Open Access Journals (Sweden)

    Joshua K. Salabei

    2015-04-01

    Full Text Available Autophagy regulates the metabolism, survival, and function of numerous cell types, including those comprising the cardiovascular system. In the vasculature, changes in autophagy have been documented in atherosclerotic and restenotic lesions and in hypertensive vessels. The biology of vascular smooth muscle cells appears particularly sensitive to changes in the autophagic program. Recent evidence indicates that stimuli or stressors evoked during the course of vascular disease can regulate autophagic activity, resulting in modulation of VSMC phenotype and viability. In particular, certain growth factors and cytokines, oxygen tension, and pharmacological drugs have been shown to trigger autophagy in smooth muscle cells. Importantly, each of these stimuli has a redox component, typically associated with changes in the abundance of reactive oxygen, nitrogen, or lipid species. Collective findings support the hypothesis that autophagy plays a critical role in vascular remodeling by regulating smooth muscle cell phenotype transitions and by influencing the cellular response to stress. In this graphical review, we summarize current knowledge on the role of autophagy in the biology of the smooth muscle cell in (pathophysiology.

  6. Consistent estimation of Gibbs energy using component contributions.

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    Elad Noor

    Full Text Available Standard Gibbs energies of reactions are increasingly being used in metabolic modeling for applying thermodynamic constraints on reaction rates, metabolite concentrations and kinetic parameters. The increasing scope and diversity of metabolic models has led scientists to look for genome-scale solutions that can estimate the standard Gibbs energy of all the reactions in metabolism. Group contribution methods greatly increase coverage, albeit at the price of decreased precision. We present here a way to combine the estimations of group contribution with the more accurate reactant contributions by decomposing each reaction into two parts and applying one of the methods on each of them. This method gives priority to the reactant contributions over group contributions while guaranteeing that all estimations will be consistent, i.e. will not violate the first law of thermodynamics. We show that there is a significant increase in the accuracy of our estimations compared to standard group contribution. Specifically, our cross-validation results show an 80% reduction in the median absolute residual for reactions that can be derived by reactant contributions only. We provide the full framework and source code for deriving estimates of standard reaction Gibbs energy, as well as confidence intervals, and believe this will facilitate the wide use of thermodynamic data for a better understanding of metabolism.

  7. Understanding how components of organisations contribute to attacks

    NARCIS (Netherlands)

    Gu, Min; Aslanyan, Zaruhi; Probst, Christian W.

    2016-01-01

    Attacks on organisations today explore many different layers, including buildings infrastructure, IT infrastructure, and human factor – the physical, virtual, and social layer. Identifying possible attacks, understanding their impact, and attributing their origin and contributing factors is difficul

  8. Understanding How Components of Organisations Contribute to Attacks

    DEFF Research Database (Denmark)

    Gu, Min; Aslanyan, Zaruhi; Probst, Christian W.

    2016-01-01

    components quickly results in a large quantity of interrelations, which are hard to grasp. In this work we present several approaches for visualising attributes of attacks such as likelihood of success, impact, and required time or skill level. The resulting visualisations provide a link between attacks...

  9. Chikungunya triggers an autophagic process which promotes viral replication

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    Briant Laurence

    2011-09-01

    Full Text Available Abstract Background Chikungunya Virus (ChikV surprised by a massive re-emerging outbreak in Indian Ocean in 2006, reaching Europe in 2007 and exhibited exceptional severe physiopathology in infants and elderly patients. In this context, it is important to analyze the innate immune host responses triggered against ChikV. Autophagy has been shown to be an important component of the innate immune response and is involved in host defense elimination of different pathogens. However, the autophagic process was recently observed to be hijacked by virus for their own replication. Here we provide the first evidence that hallmarks of autophagy are specifically found in HEK.293 infected cells and are involved in ChikV replication. Methods To test the capacity of ChikV to mobilize the autophagic machinery, we performed fluorescence microscopy experiments on HEK.GFP.LC3 stable cells, and followed the LC3 distribution during the time course of ChikV infection. To confirm this, we performed electron microscopy on HEK.293 infected cells. To test the effect of ChikV-induced-autophagy on viral replication, we blocked the autophagic process, either by pharmacological (3-MA or genetic inhibition (siRNA against the transcript of Beclin 1, an autophagic protein, and analyzed the percentage of infected cells and the viral RNA load released in the supernatant. Moreover, the effect of induction of autophagy by Rapamycin on viral replication was tested. Results The increasing number of GFP-LC3 positive cells with a punctate staining together with the enhanced number of GFP-LC3 dots per cell showed that ChikV triggered an autophagic process in HEK.293 infected cells. Those results were confirmed by electron microscopy analysis since numerous membrane-bound vacuoles characteristic of autophagosomes were observed in infected cells. Moreover, we found that inhibition of autophagy, either by biochemical reagent and RNA interference, dramatically decreases ChikV replication

  10. Targeting autophagic pathways for cancer drug discovery

    Institute of Scientific and Technical Information of China (English)

    Bo Liu; Jin-Ku Bao; Jin-Ming Yang; Yan Cheng

    2013-01-01

    Autophagy,an evolutionarily conserved lysosomal degradation process,has drawn an increasing amount of attention in recent years for its role in a variety of human diseases,such as cancer.Notably,autophagy plays an important role in regulating several survival and death signaling pathways that determine cell fate in cancer.To date,substantial evidence has demonstrated that some key autophagic mediators,such as autophagy-related genes (ATGs),PI3K,mTOR,p53,and Beclin-1,may play crucial roles in modulating autophagic activity in cancer initiation and progression.Because autophagy-modulating agents such as rapamycin and chloroquine have already been used clinically to treat cancer,it is conceivable that targeting autophagic pathways may provide a new opportunity for discovery and development of more novel cancer therapeutics.With a deeper understanding of the regulatory mechanisms governing autophagy,we will have a better opportunity to facilitate the exploitation of autophagy as a target for therapeutic intervention in cancer.This review discusses the current status of targeting autophagic pathways as a potential cancer therapy.

  11. Autophagic flux regulates microglial phenotype according to the time of oxygen-glucose deprivation/reperfusion.

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    Xia, Cong-Yuan; Zhang, Shuai; Chu, Shi-Feng; Wang, Zhen-Zhen; Song, Xiu-Yun; Zuo, Wei; Gao, Yan; Yang, Peng-Fei; Chen, Nai-Hong

    2016-10-01

    Microglial phenotype alternation is a potential novel pathogenic mechanism for cerebral ischemia. Cerebral ischemia induced autophagy aggravates inflammation and neural injury. However, the effect of autophagy in the modulation of microglial phenotype is still unknown. In this study, we investigated the role of autophagic flux in the alternation of microglial phenotype following oxygen glucose deprivation/reperfusion (OGD/R) in BV-2 cells. Inhibition of autophagic flux by NH4Cl exposure significantly increased the level of microtubule-associated protein 1 light chain 3 (LC3)-II and p62 in control and OGD/R (12h, 24h and 48h) groups, but did not change their expression in OGD/R 72h group, indicating that autophagic flux was inhibited at OGD/R 72h. Once autophagic flux was inhibited at OGD/R 72h or at OGD/R 24h (with NH4Cl), BV-2 cells mainly showed M1 phenotype with increased tumor necrosis factor alpha (TNF-α), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and decreased M2 markers including interleukin-10 (IL-10), Arginase 1 (Arg-1), and brain derived neurotrophic factor (BDNF). Further study indicated that inhibition of autophagic flux activated NF-κB pathway and decreased the activity of cAMP-response element binding protein (CREB), which contributed to the alternation of microglial phenotype. Therefore, inhibition of autophagic flux regulated the alternation of microglial phenotype by modulating the balance between NF-κB and CREB.

  12. The Autophagic Machinery in Enterovirus Infection

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    Jeffrey K. F. Lai

    2016-01-01

    Full Text Available The Enterovirus genus of the Picornaviridae family comprises many important human pathogens, including polioviruses, rhinovirus, enterovirus A71, and enterovirus D68. They cause a wide variety of diseases, ranging from mild to severe life-threatening diseases. Currently, no effective vaccine is available against enteroviruses except for poliovirus. Enteroviruses subvert the autophagic machinery to benefit their assembly, maturation, and exit from host. Some enteroviruses spread between cells via a process described as autophagosome-mediated exit without lysis (AWOL. The early and late phases of autophagy are regulated through various lipids and their metabolizing enzymes. Some of these lipids and enzymes are specifically regulated by enteroviruses. In the present review, we summarize the current understanding of the regulation of autophagic machinery by enteroviruses, and provide updates on recent developments in this field.

  13. Autophagic clearance of bacterial pathogens: molecular recognition of intracellular microorganisms.

    Science.gov (United States)

    Pareja, Maria Eugenia Mansilla; Colombo, Maria I

    2013-01-01

    Autophagy is involved in several physiological and pathological processes. One of the key roles of the autophagic pathway is to participate in the first line of defense against the invasion of pathogens, as part of the innate immune response. Targeting of intracellular bacteria by the autophagic machinery, either in the cytoplasm or within vacuolar compartments, helps to control bacterial proliferation in the host cell, controlling also the spreading of the infection. In this review we will describe the means used by diverse bacterial pathogens to survive intracellularly and how they are recognized by the autophagic molecular machinery, as well as the mechanisms used to avoid autophagic clearance.

  14. How do different components of Effortful Control contribute to children's mathematics achievement?

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    Sánchez-Pérez, Noelia; Fuentes, Luis J; Pina, Violeta; López-López, Jose A; González-Salinas, Carmen

    2015-01-01

    This work sought to investigate the specific contribution of two different components of Effortful Control (EC) -attentional focusing (AF) and inhibitory control- to children's mathematics achievement. The sample was composed of 142 children aged 9-12 year-old. EC components were measured through the Temperament in Middle Childhood Questionnaire (TMCQ; parent's report); math achievement was measured via teacher's report and through the standard Woodcock-Johnson test. Additionally, the contribution of other cognitive and socio-emotional processes was taken into account. Our results showed that only AF significantly contributed to the variance of children's mathematics achievement; interestingly, mediational models showed that the relationship between effortful attentional self-regulation and mathematics achievement was mediated by academic peer popularity, as well as by intelligence and study skills. Results are discussed in the light of the current theories on the role of children's self-regulation abilities in the context of school.

  15. Time-independent and time-dependent contributions to the unavailability of standby safety system components

    Energy Technology Data Exchange (ETDEWEB)

    Lofgren, E.V. [Science Applications International Corp., Fairfax Station, VA (United States); Uryasev, S.; Samanta, P. [Brookhaven National Lab., Upton, NY (United States)

    1997-02-01

    The unavailability of standby safety system components due to failures in nuclear power plants is considered to involve a time-independent and a time-dependent part. The former relates to the component`s unavailability from demand stresses due to usage, and the latter represents the component`s unavailability due to standby-time stresses related to the environment. In this paper, data from the nuclear plant reliability data system (NPRDS) were used to partition the component`s unavailability into the contributions from standby-time stress (i.e., due to environmental factors) and demand stress (i.e., due to usage). Analyses are presented of motor-operated valves (MOVs), motor-driven pumps (MDPs), and turbine-driven pumps (TDPs). MOVs fail predominantly (approx. 78 %) from environmental factors (standby-time stress failures). MDPs fail slightly more frequently from demand stresses (approx. 63 %) than standby-time stresses, while TDPs fail predominantly from standby-time stresses (approx. 78 %). Such partitions of component unavailability have many uses in risk-informed and performance-based regulation relating to modifications to Technical Specification, in-service testing, precise determination of dominant accident sequences, and implementation of maintenance rules.

  16. Time-independent and time-dependent contributions to the unavailability of standby safety system components

    Energy Technology Data Exchange (ETDEWEB)

    Lofgren, E.V. [Science Applications International Corp., Fairfax Station, VA (United States); Uryasev, S.; Samanta, P. [Brookhaven National Lab., Upton, NY (United States)

    1997-03-01

    The unavailability of standby safety system components due to failures in nuclear power plants is considered to involve a time independent and a time dependent part. The former relates to the component`s unavailability from demand stresses due to usage, and the latter represents the component`s unavailability due to standby time stresses related to the environment. In this paper, data from the nuclear plant reliability data system (NPRDS) were used to partition the component`s unavailability into the contributions from standby time stress (i.e., due to environmental factors) and demand stress (i.e., due to usage). Analyses are presented of motor operated valves (MOVs), motor driven pumps (MDPs), and turbine driven pumps (FDPs). MOVs fail predominantly (approx. 78%) from environmental factors (standby time stress failures). MDPs fail slightly more frequently from demand stresses (approx. 63%) than standby time stresses, while TDPs fail predominantly from standby time stresses (approx. 78%). Such partitions of component unavailability have many uses in risk informed and performance based regulation relating to modifications to Technical Specification, in-service testing, precise determination of dominant accident sequences, and implementation of maintenance rules.

  17. The contribution of the diffuse light component to the topographic effect on remotely sensed data

    Science.gov (United States)

    Justice, C.; Holben, B.

    1980-01-01

    The topographic effect is measured by the difference between the global radiance from inclined surfaces as a function of their orientation relative to the sensor position and light source. The short wave radiant energy incident on a surface is composed of direct sunlight, scattered skylight, and light reflected from surrounding terrain. The latter two components are commonly known as the diffuse component. The contribution of the diffuse light component to the topographic effect was examined and the significance of this diffuse component with respect to two direct radiance models was assessed. Diffuse and global spectral radiances were measured for a series of slopes and aspects of a uniform and surface in the red and photographic infrared parts of the spectrum, using a nadir pointing two channel handheld radiometer. The diffuse light was found to produce a topographic effect which varied from the topographic effect for direct light. The topographic effect caused by diffuse light was found to increase slightly with solar elevation and wavelength for the channels examined. The correlations between data derived from two simple direct radiance simulation models and the field data were not significantly affected when the diffuse component was removed from the radiances. Radiances from a 60 percent reflective surface, assuming no atmospheric path radiance, the diffuse light topographic effect contributed a maximum range of 3 pixel values in simulated LANDSAT data from all aspects with slopes up to 30 degrees.

  18. Mild MPP(+) exposure impairs autophagic degradation through a novel lysosomal acidity-independent mechanism.

    Science.gov (United States)

    Miyara, Masatsugu; Kotake, Yaichiro; Tokunaga, Wataru; Sanoh, Seigo; Ohta, Shigeru

    2016-10-01

    Parkinson's disease (PD) is the second most common neurodegenerative disorder, but its underlying cause remains unknown. Although recent studies using PD-related neurotoxin MPP(+) suggest autophagy involvement in the pathogenesis of PD, the effect of MPP(+) on autophagic processes under mild exposure, which mimics the slow progressive nature of PD, remains largely unclear. We examined the effect of mild MPP(+) exposure (10 and 200 μM for 48 h), which induces a more slowly developing cell death, on autophagic processes and the mechanistic differences with acute MPP(+) toxicity (2.5 and 5 mM for 24 h). In SH-SY5Y cells, mild MPP(+) exposure predominantly inhibited autophagosome degradation, whereas acute MPP(+) exposure inhibited both autophagosome degradation and basal autophagy. Mild MPP(+) exposure reduced lysosomal hydrolase cathepsin D activity without changing lysosomal acidity, whereas acute exposure decreased lysosomal density. Lysosome biogenesis enhancers trehalose and rapamycin partially alleviated mild MPP(+) exposure induced impaired autophagosome degradation and cell death, but did not prevent the pathogenic response to acute MPP(+) exposure, suggesting irreversible lysosomal damage. We demonstrated impaired autophagic degradation by MPP(+) exposure and mechanistic differences between mild and acute MPP(+) toxicities. Mild MPP(+) toxicity impaired autophagosome degradation through novel lysosomal acidity-independent mechanisms. Sustained mild lysosomal damage may contribute to PD. We examined the effects of MPP(+) on autophagic processes under mild exposure, which mimics the slow progressive nature of Parkinson's disease, in SH-SY5Y cells. This study demonstrated impaired autophagic degradation through a reduction in lysosomal cathepsin D activity without altering lysosomal acidity by mild MPP(+) exposure. Mechanistic differences between acute and mild MPP(+) toxicity were also observed. Sustained mild damage of lysosome may be an underlying cause

  19. Contribution to the edaphic components definition in the desertification susceptibility index

    Energy Technology Data Exchange (ETDEWEB)

    Sampaio, E. P.; Corte-Real, J. A.

    2009-07-01

    Many of the biophysical processes involved in the scope of desertification depend on the hydric characteristics of the soils the impact on vegetation cover. To protect soils against desertification, it is necessary to understand how some of these characteristics (such as water storage) interact in a complex and integrated chain of degradation processes. Several works have been developed to contribute to the definition of a Index of Desertification Susceptibility (DSI) expressed as a function of several components, climatic, edaphic, vegetative and slope. However, the various built-in edaphic components already defined, leave aside the water retention in soil. Furthermore, these components only focus on the characteristics of the uppermost surface soil layer (A-layer). In fact, desertification is simultaneously cause and consequence of the depleted soil water retention with a positive feedback of the plant life and on the hydrological cycle. (Author) 10 refs.

  20. Glucagon-like Peptide-1 Protects Pancreatic Beta-cells from Death by Increasing Autophagic Flux and Restoring Lysosomal Function.

    Science.gov (United States)

    Zummo, Francesco P; Cullen, Kirsty S; Honkanen-Scott, Minna; Shaw, James Am; Lovat, Penny E; Arden, Catherine

    2017-02-23

    Studies in animal models of type 2 diabetes have shown that glucagon-like peptide-1 (GLP-1) receptor agonists prevent β-cell loss. Whether GLP-1 mediates β-cell survival via the key lysosomal-mediated process of autophagy is unknown.Here we report that treatment of INS-1E β-cells and primary islets with glucolipotoxicity (0.5mmol/l palmitate, 25mmol/l glucose) increases LC3 II, a marker of autophagy. Further analysis indicates a blockage in autophagic flux associated with lysosomal dysfunction. Accumulation of defective lysosomes leads to lysosomal membrane permeabilisation (LMP) and release of Cathepsin D, which contributes to cell death. Our data further demonstrated defects in autophagic flux and lysosomal staining in human samples of type 2 diabetes. Co-treatment with the GLP-1 receptor agonist exendin-4 reversed the lysosomal dysfunction, relieving the impairment in autophagic flux and further stimulated autophagy. siRNA knockdown showed the restoration of autophagic flux is also essential for the protective effects of exendin-4.Collectively, our data highlights lysosomal dysfunction as a critical mediator of β-cell loss and shows that exendin-4 improves cell survival via restoration of lysosomal function and autophagic flux. Modulation of autophagy / lysosomal homeostasis may thus define a novel therapeutic strategy for type 2 diabetes, with the GLP-1 signalling pathway as a potential focus.

  1. How do different components of Effortful Control contribute to children's mathematics achievement?

    Directory of Open Access Journals (Sweden)

    Noelia eSánchez-Pérez

    2015-09-01

    Full Text Available This work sought to investigate the specific contribution of two different components of Effortful Control -attentional focusing and inhibitory control- to children’s mathematics achievement. The sample was composed of 142 children aged 9 to 12 years old. Effortful Control components were measured through the Temperament in Middle Childhood Questionnaire (TMCQ; parent´s report; math achievement was measured via teacher’s report and through the standard Woodcock-Johnson test. Additionally, the contribution of other cognitive and socio-emotional processes was taken into account. Our results showed that only attentional focusing significantly contributed to the variance of children’s mathematics achievement; interestingly, mediational models showed that the relationship between effortful attentional self-regulation and mathematics achievement was mediated by academic peer popularity, as well as by intelligence and study skills. Results are discussed in the light of the current theories on the role of children’ self-regulation abilities in the context of school.

  2. M1 contributes to the intrinsic but not the extrinsic components of motor-skills.

    Science.gov (United States)

    Romei, Vincenzo; Thut, Gregor; Ramos-Estebanez, Ciro; Pascual-Leone, Alvaro

    2009-10-01

    Procedural skills consist of several components that can be simultaneously acquired. During a motor-learning task we can distinguish between how a "movement" is performed (intrinsic component) and the spatial-related (extrinsic) component of this movement. The intrinsic movement component is thought to be supported by motor loops, including primary motor cortex (M1) as assessed with neuroimaging studies. Here we want to test further whether M1 makes a critical contribution to the movement rather than spatial-related component of skill-learning. To this purpose, we used repetitive Transcranial Magnetic Stimulation (rTMS) and the serial reaction time (SRT) task. Twenty right-handed participants performed the SRT-task starting with their left or right hand. After this learning session, participants switched to the untrained hand by performing original (spatial-related) and mirror-ordered (movement-based) sequences. rTMS was applied to M1 ipsi- or contralateral to the transfer-hand and both sequences were retested. Results revealed rTMS-interference with motor-skill transfer of mirror-ordered but not original sequences, showing that M1 is critically involved in the retrieval/transformation of the intrinsic but not the extrinsic movement coordinates. rTMS-interference in the mirror-condition consisted of both (i) disruption and (ii) release of motor-skill transfer depending on the stimulated hemisphere and on transfer-hand. The pattern of results suggests (i) contralateral (right) M1 involvement in retrieval/transformation of motor information during left-hand reproduction of previously acquired right-hand motor-skills; and (ii) modulatory interactions of inhibitory nature from the dominant (left) to the non-dominant (right) M1 in the same transfer-condition. These results provide further evidence that M1 is essential to intrinsic movement-based skill-learning and novel insight on models of motor-learning and hemispheric specialization, suggesting the involvement of

  3. Utilization of contribution margin in the costing system in production of components for wood working machines

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    Marek Potkány

    2009-06-01

    Full Text Available The aim of this paper is to propose optimization of costing method for planning a production-sales programme of the chosen engineering enterprise dealing with the production of components for wood working machines. This engineering company uses the calculation pattern methodology in the comprehensive cost accounting system. All costs components are absorbed by individual outputs in this cost calculation. The results of this calculation are not available for decision-making tasks. In order to solve the decision tasks relating to output assortment optimization, it is necessary to show separately variable costs influenced by changes in production volume and fixed costs not influenced by changes in production volume. For these reasons we propose a specific application of retrograde costing as a necessary condition for effective system of decision-making on the basis of contribution margin calculation. The contribution margin/standard hour is the criteria for the calculation in a critical place of production and this is very important information for developing an optimal production-sales programme.

  4. Methods for assessing autophagy and autophagic cell death.

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    Tasdemir, Ezgi; Galluzzi, Lorenzo; Maiuri, M Chiara; Criollo, Alfredo; Vitale, Ilio; Hangen, Emilie; Modjtahedi, Nazanine; Kroemer, Guido

    2008-01-01

    Autophagic (or type 2) cell death is characterized by the massive accumulation of autophagic vacuoles (autophagosomes) in the cytoplasm of cells that lack signs of apoptosis (type 1 cell death). Here we detail and critically assess a series of methods to promote and inhibit autophagy via pharmacological and genetic manipulations. We also review the techniques currently available to detect autophagy, including transmission electron microscopy, half-life assessments of long-lived proteins, detection of LC3 maturation/aggregation, fluorescence microscopy, and colocalization of mitochondrion- or endoplasmic reticulum-specific markers with lysosomal proteins. Massive autophagic vacuolization may cause cellular stress and represent a frustrated attempt of adaptation. In this case, cell death occurs with (or in spite of) autophagy. When cell death occurs through autophagy, on the contrary, the inhibition of the autophagic process should prevent cellular demise. Accordingly, we describe a strategy for discriminating cell death with autophagy from cell death through autophagy.

  5. Autophagic flux promotes cisplatin resistance in human ovarian carcinoma cells through ATP-mediated lysosomal function.

    Science.gov (United States)

    Ma, Liwei; Xu, Ye; Su, Jing; Yu, Huimei; Kang, Jinsong; Li, Hongyan; Li, Xiaoning; Xie, Qi; Yu, Chunyan; Sun, Liankun; Li, Yang

    2015-11-01

    Lysosomes are involved in promoting resistance of cancer cells to chemotherapeutic agents. However, the mechanisms underlying lysosomal influence of cisplatin resistance in ovarian cancer remain incompletely understood. We report that, compared with cisplatin-sensitive SKOV3 cells, autophagy increases in cisplatin-resistant SKOV3/DDP cells treated with cisplatin. Inhibition of early-stage autophagy enhanced cisplatin-mediated cytotoxicity in SKOV3/DDP cells, but autophagy inhibition at a later stage by disturbing autophagosome-lysosome fusion is more effective. Notably, SKOV3/DDP cells contained more lysosomes than cisplatin-sensitive SKOV3 cells. Abundant lysosomes and lysosomal cathepsin D activity were required for continued autolysosomal degradation and maintenance of autophagic flux in SKOV3/DDP cells. Furthermore, SKOV3/DDP cells contain abundant lysosomal ATP required for lysosomal function, and inhibition of lysosomal ATP accumulation impaired lysosomal function and blocked autophagic flux. Therefore, our findings suggest that lysosomes at least partially contribute to cisplatin resistance in ovarian cancer cells through their role in cisplatin-induced autophagic processes, and provide insight into the mechanism of cisplatin resistance in tumors.

  6. Evaluation of the contributions of four components of gross domestic product in various regions in China.

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    Sanmang Wu

    Full Text Available Four major components influence the growth of the gross domestic product in Chinese provinces: consumption, investment, transnational exports, and inter-provincial exports. By splitting a competitive input-output table into a non-competitive input-output table, this study used an input-output model to measure the contributions of the four components of gross domestic product in various regions in China. We found that international exports drove the growth of the gross domestic product more strongly in the eastern region than in other regions. Investment and inter-provincial exports were the major impetus for gross domestic product growth in the central and western regions. We also found that consumption played a minimal role in driving the growth of the gross domestic product in all regions in China. According to these findings, although various regions can share much in terms of policies to transform the impetus for economic growth, there should be different foci for different regions. Their shared policy is to increase the role of final consumption in stimulating economic growth. Region-specific policies mandate that the eastern region should strengthen the driving force provided by international exports and that the central and western regions should strengthen indigenous growth capabilities by improving scientific innovation, industrial support, and institutional innovation.

  7. Soil CO2 efflux in a sand grassland: contribution by root, mycorrhizal and basal respiration components

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    Papp, Marianna; Balogh, János; Pintér, Krisztina; Cserhalmi, Dóra; Nagy, Zoltán

    2014-05-01

    Grasslands play an important role in global carbon cycle because of their remarkable extension and carbon storage capacity. Soil respiration takes a major part in the carbon cycle of the ecosystems; ratio of its autotrophic and heterotrophic components is important also when considering their sensitivity to environmental drivers. The aim of the study was to estimate the contribution by root, mycorrhizal and basal components to total soil CO2 efflux. The study was carried out in the semi-arid sandy grassland dominated by Festuca pseudovina at the Kiskunság National Park in Hungary (Bugac site) where C-flux measurements have been going on since 2002. The soil CO2 effluxes were measured in the following treatments: a./ control, b./ root-exclusion, c./ root and mycorrhiza exclusion by using 80 cm long 15 cm inner diameter PVC tubes and micro-pore inox meshes. Inox mesh was used to exclude roots, but let the mycorrhiza filaments to grow into the tubes. 10 soil cores were excavated, sieved, then root-free soil was packed back layer by layer into the cores giving 6 and 4 repetitions in b and c treatments respectively. Basal respiration is referred to as the heterotrophic respiration without influence of roots or mycorrhiza. Difference between root-exclusion and root and mycorrhiza exclusion treatment gave the value of mycorrhizal respiration and control (non-disturbed) plots the total soil CO2 efflux. The contribution by the above components was evaluated. Soil CO2 efflux was measured continuously by using an automated open system of 10 soil respiration chambers. Data was collected in every two hours from each treatment (one of the chambers recorded basal respiration, 3 chambers were settled on root-excluded treatments and 6 chambers measured control plots). Chambers were moved in every 2 weeks between the repetitions of the treatments. Soil CO2 efflux (mycorrhiza-free, root free, control) data were fitted using a soil respiration model, where soil temperature, soil

  8. Enhancing lysosomal biogenesis and autophagic flux by activating the transcription factor EB protects against cadmium-induced neurotoxicity

    Science.gov (United States)

    Pi, Huifeng; Li, Min; Tian, Li; Yang, Zhiqi; Yu, Zhengping; Zhou, Zhou

    2017-01-01

    Cadmium (Cd), a highly ubiquitous heavy metal, is a well-known inducer of neurotoxicity. However, the mechanism underlying cadmium-induced neurotoxicity remains unclear. In this study, we found that Cd inhibits autophagosome-lysosome fusion and impairs lysosomal function by reducing the levels of lysosomal-associated membrane proteins, inhibiting lysosomal proteolysis and altering lysosomal pH, contributing to defects in autophagic clearance and subsequently leading to nerve cell death. In addition, Cd decreases transcription factor EB (TFEB) expression at both the mRNA and protein levels. Furthermore, Cd induces the nuclear translocation of TFEB and TFEB target-gene expression, associated with compromised lysosomal function or a compensatory effect after the impairment of the autophagic flux. Notably, restoration of the levels of lysosomal-associated membrane protein, lysosomal proteolysis, lysosomal pH and autophagic flux through Tfeb overexpression protects against Cd-induced neurotoxicity, and this protective effect is incompletely dependent on TFEB nuclear translocation. Moreover, gene transfer of the master autophagy regulator TFEB results in the clearance of toxic proteins and the correction of Cd-induced neurotoxicity in vivo. Our study is the first to demonstrate that Cd disrupts lysosomal function and autophagic flux and manipulation of TFEB signalling may be a therapeutic approach for antagonizing Cd-induced neurotoxicity. PMID:28240313

  9. Deoxycholate, an Endogenous Cytotoxin/Genotoxin, Induces the Autophagic Stress-Survival Pathway: Implications for Colon Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Claire M. Payne

    2009-01-01

    Full Text Available We report that deoxycholate (DOC, a hydrophobic bile acid associated with a high-fat diet, activates the autophagic pathway in non-cancer colon epithelial cells (NCM-460, and that this activation contributes to cell survival. The DOC-induced increase in autophagy was documented by an increase in autophagic vacuoles (detected using transmission electron microscopy, increased levels of LC3-I and LC3-II (western blotting, an increase in acidic vesicles (fluorescence spectroscopy of monodansycadaverine and lysotracker red probes, and increased expression of the autophagic protein, beclin-1 (immunohistochemistry/western blotting. The DOC-induced increase in beclin-1 expression was ROS-dependent. Rapamycin (activator of autophagy pre-treatment of NCM-460 cells significantly (P<.05 decreased, and 3-MA (inhibitor of autophagy significantly (P<.05 increased the cell loss caused by DOC treatment, alone. Rapamycin pre-treatment of the apoptosis-resistant colon cancer cell line, HCT-116RC (developed in our laboratory, resulted in a significant decrease in DOC-induced cell death. Bafilomycin A1 and hydroxychloroquine (inhibitors of the autophagic process increased the DOC-induced percentage of apoptotic cells in HCT-116RC cells. It was concluded that the activation of autophagy by DOC has important implications for colon carcinogenesis and for the treatment of colon cancer in conjunction with commonly used chemotherapeutic agents.

  10. Conditioned place preference for social interaction in rats: contribution of sensory components

    Directory of Open Access Journals (Sweden)

    Kai eKummer

    2011-11-01

    Full Text Available A main challenge in the therapy of drug dependent individuals is to help them reactivate interest in non-drug-associated activities. We previously developed a rat experimental model based on the conditioned place preference (CPP paradigm in which only four 15-min episodes of social interaction with a gender- and weight-matched male Sprague Dawley rat (i reversed CPP from cocaine to social interaction despite continuing cocaine training and (ii prevented the reinstatement of cocaine CPP. In the present study, we investigated which of the sensory modalities of the composite stimulus 'social interaction' contributes most to the rats’ preference for it. If touch was limited by steel bars spaced at a distance of 2 cm and running across the whole length of a partitioning, CPP was still acquired, albeit to a lesser degree. If both rats were placed on the same side of a partitioning, rats did not develop CPP for social interaction. Thus, decreasing the available area for social interaction from 750 to 375 cm² prevented the acquisition of CPP to social interaction despite the fact that animals could touch each other more intensely than through the bars of the partitioning. When touch was fully restricted by a glass screen dividing the conditioning chambers, and the only sensory modalities left were visual and olfactory cues, place preference shifted to place aversion. Overall, our findings indicate that the major rewarding sensory component of the composite stimulus 'social interaction' is touch (tactition.

  11. Decoupling the contribution of dispersive and acid-base components of surface energy on the cohesion of pharmaceutical powders.

    Science.gov (United States)

    Shah, Umang V; Olusanmi, Dolapo; Narang, Ajit S; Hussain, Munir A; Tobyn, Michael J; Heng, Jerry Y Y

    2014-11-20

    This study reports an experimental approach to determine the contribution from two different components of surface energy on cohesion. A method to tailor the surface chemistry of mefenamic acid via silanization is established and the role of surface energy on cohesion is investigated. Silanization was used as a method to functionalize mefenamic acid surfaces with four different functional end groups resulting in an ascending order of the dispersive component of surface energy. Furthermore, four haloalkane functional end groups were grafted on to the surface of mefenamic acid, resulting in varying levels of acid-base component of surface energy, while maintaining constant dispersive component of surface energy. A proportional increase in cohesion was observed with increases in both dispersive as well as acid-base components of surface energy. Contributions from dispersive and acid-base surface energy on cohesion were determined using an iterative approach. Due to the contribution from acid-base surface energy, cohesion was found to increase ∼11.7× compared to the contribution from dispersive surface energy. Here, we provide an approach to deconvolute the contribution from two different components of surface energy on cohesion, which has the potential of predicting powder flow behavior and ultimately controlling powder cohesion.

  12. Can assessing for potential contribution of soil organic and inorganic components for butachlor sorption be improved?

    Science.gov (United States)

    He, Yan; Liu, Zhongzhen; Zhang, Jian; Wang, Haizhen; Shi, Jiachun; Xu, Jianming

    2011-01-01

    Sorption of butachlor to various types of common soil components was investigated. Six pure minerals (montmorillonite [Mont], kaolinite [Kaol], Ca homoionic montmorillonite [Ca-Mont] and kaolinite [Ca-Kaol], amorphous hydrated Al and Fe oxides [AHOs-Al, AHOs-Fe]), four soil alkali-extractable pure humic acids (HAs), and the four corresponding HAs originated real unmodified and HO-treated soils were selected as the representative sorbents. Results showed that the HAs played a crucial role, and clay minerals (especially Mont) also showed an important effect in butachlor sorption. The AHOs may likely influence only in a mediator way by enhancing the availability of sorption domains of HAs. By removing 78% (on average) of the total organic carbon (TOC) from the soils with HO, the content ratio of clay to TOC (RCO) increased by an average of 367% and became >60. This change simultaneously decreased the sorption capacity of soils (40%, on average). Considering that the surface sorption domain on clay minerals may be highly exposed and more competitive after the partial removal of soil organic matter (SOM), this reaffirmed the potential contribution from clay minerals. It can thus be inferred that in the real soil where SOM and clay minerals are associated, the coating of clay minerals may have weakened the partition function of SOM or blocked some sorption domain within SOM, resulting in a decreased sorption of butachlor. Therefore, clay minerals, especially 2:1 type expanding minerals, may play a dual function vs. SOM content for the sorption of butachlor in soil.

  13. Left dorsal speech stream components and their contribution to phonological processing.

    Science.gov (United States)

    Murakami, Takenobu; Kell, Christian A; Restle, Julia; Ugawa, Yoshikazu; Ziemann, Ulf

    2015-01-28

    Models propose an auditory-motor mapping via a left-hemispheric dorsal speech-processing stream, yet its detailed contributions to speech perception and production are unclear. Using fMRI-navigated repetitive transcranial magnetic stimulation (rTMS), we virtually lesioned left dorsal stream components in healthy human subjects and probed the consequences on speech-related facilitation of articulatory motor cortex (M1) excitability, as indexed by increases in motor-evoked potential (MEP) amplitude of a lip muscle, and on speech processing performance in phonological tests. Speech-related MEP facilitation was disrupted by rTMS of the posterior superior temporal sulcus (pSTS), the sylvian parieto-temporal region (SPT), and by double-knock-out but not individual lesioning of pars opercularis of the inferior frontal gyrus (pIFG) and the dorsal premotor cortex (dPMC), and not by rTMS of the ventral speech-processing stream or an occipital control site. RTMS of the dorsal stream but not of the ventral stream or the occipital control site caused deficits specifically in the processing of fast transients of the acoustic speech signal. Performance of syllable and pseudoword repetition correlated with speech-related MEP facilitation, and this relation was abolished with rTMS of pSTS, SPT, and pIFG. Findings provide direct evidence that auditory-motor mapping in the left dorsal stream causes reliable and specific speech-related MEP facilitation in left articulatory M1. The left dorsal stream targets the articulatory M1 through pSTS and SPT constituting essential posterior input regions and parallel via frontal pathways through pIFG and dPMC. Finally, engagement of the left dorsal stream is necessary for processing of fast transients in the auditory signal.

  14. Research program Integrity of Components (FKS). A substantial contribution to component safety; Forschungsvorhaben Komponentensicherheit (FKS). Ein wesentlicher Beitrag zur Komponentensicherheit

    Energy Technology Data Exchange (ETDEWEB)

    Kussmaul, K.; Roos, E.; Foehl, J.

    1998-11-01

    The main objectives pursued are: (a) verify the quality of reactor pressure vessels in existing LWR-type reactors, and (b) quantify the safety margin using both specified and non-specified materials and welds. On the basis of knowledge obtained through earlier programmes, the research project was to examine in particular deviations from the specified materials properties, for more exact quantification of the safety margin before RPV failure. There are three major factors influencing the component performance until failure, which are aggregate material fatigue, flaws, loading conditions, and the research work was to focus on the materials properties. An item of main interest was to assess the impact of long service life on the materials properties, assuming particularly unfavourable boundary conditions for materials properties and operational loads. (orig./CB) [Deutsch] Die Hauptziele des Forschungsvorhabens Komponentensicherheit waren (a) die Qualitaet bestehender Reaktordruckbehaelter von Leichtwasserreaktoren zu verifizieren, und (b) den Sicherheitsabstand zu quantifizieren unter Verwendung von Werkstoffen und Schweissverbindungen, die innerhalb und ausserhalb der Spezifikation liegen. Gestuetzt auf Erkenntnisse aus frueheren Programmen sollten zur quantitativen Erfassung des Sicherheitsabstandes gegen Versagen des RDB`s insbesondere auch Abweichungen vom spezifikationsgemaessen Werkstoffzustand betrachtet werden. Von den drei Haupteinflussgroessen Werkstoffzustand, Fehlerzustand, Beanspruchungszustand, die das Versagensverhalten bestimmen, lag der Schwerpunkt des FKS auf der Untersuchung des Werkstoffeinflusses. Insbesondere sollte geprueft werden, wie sich der Langzeitbetrieb auf die Aenderung der Werkstoffeigenschaften auswirkt, wenn besonders unguenstige Randbedingungen von Werkstoffzustand und Betriebsbedingungen zugrunde gelegt werden. (orig./MM)

  15. The implicit contribution of slab modes to the perpendicular diffusion coefficient of particles interacting with two-component turbulence

    CERN Document Server

    Shalchi, Andreas

    2016-01-01

    We explore the transport of energetic particles in two-component turbulence in which the stochastic magnetic field is assumed to be a superposition of slab and two-dimensional modes. It is known that in magnetostatic slab turbulence, the motion of particles across the mean magnetic field is subdiffusive. If a two-dimensional component is added, diffusion is recovered. It was also shown before that in two-component turbulence, the slab modes do not explicitly contribute to the perpendicular diffusion coefficient. In the current paper the implicit contribution of slab modes is explored and it is shown that this contribution leads to a reduction of the perpendicular diffusion coefficient. This effect improves the agreement between simulations and analytical theory. Furthermore, the obtained results are relevant for investigations of diffusive shock acceleration.

  16. Routine Western blot to check autophagic flux : Cautions and recommendations

    NARCIS (Netherlands)

    Gomez-Sanchez, Ruben; Pizarro-Estrella, Elisa; Yakhine-Diop, Sokhna M. S.; Rodriguez-Arribas, Mario; Bravo-San Pedro, Jose M.; Fuentes, Jose M.; Gonzalez-Polo, Rosa A.

    2015-01-01

    At present, the analysis of autophagic flux by Western blotting (WB), which measures two of the most important markers of autophagy, i.e., microtubule-associated protein 1 light chain 3 (LC3) and p62, is widely accepted in the scientific community. In this study, we addressed the possible disadvanta

  17. Group-contribution+ (GC+) based estimation of properties of pure components: Improved property estimation and uncertainty analysis

    DEFF Research Database (Denmark)

    Hukkerikar, Amol; Sarup, Bent; Ten Kate, Antoon

    2012-01-01

    The aim of this work is to present revised and improved model parameters for group-contribution+ (GC+) models (combined group-contribution (GC) method and atom connectivity index (CI) method) employed for the estimation of pure component properties, together with covariance matrices to quantify.......g. prediction errors in terms of 95% confidence intervals) in the estimated property values. This feature allows one to evaluate the effects of these uncertainties on product-process design, simulation and optimization calculations, contributing to better-informed and more reliable engineering solutions. (C...

  18. Age-related disruption of autophagy in dermal fibroblasts modulates extracellular matrix components

    Energy Technology Data Exchange (ETDEWEB)

    Tashiro, Kanae [Skin Research Department, POLA Chemical Industries, Inc., Yokohama (Japan); Division of Pharmaceutical Cell Biology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka (Japan); Shishido, Mayumi [Skin Research Department, POLA Chemical Industries, Inc., Yokohama (Japan); Fujimoto, Keiko [Division of Pharmaceutical Cell Biology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka (Japan); Organelle Homeostasis Research Center, Kyushu University, Fukuoka (Japan); Hirota, Yuko [Division of Pharmaceutical Cell Biology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka (Japan); Yo, Kazuyuki; Gomi, Takamasa [Skin Research Department, POLA Chemical Industries, Inc., Yokohama (Japan); Tanaka, Yoshitaka, E-mail: tanakay@bioc.phar.kyushu-u.ac.jp [Division of Pharmaceutical Cell Biology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka (Japan); Organelle Homeostasis Research Center, Kyushu University, Fukuoka (Japan)

    2014-01-03

    Highlights: •Autophagosomes accumulate in aged dermal fibroblasts. •Autophagic degradation is impaired in aged dermal fibroblasts. •Autophagy disruption affects extracellular matrix components in dermal fibroblasts. -- Abstract: Autophagy is an intracellular degradative system that is believed to be involved in the aging process. The contribution of autophagy to age-related changes in the human skin is unclear. In this study, we examined the relationship between autophagy and skin aging. Transmission electron microscopy and immunofluorescence microscopy analyses of skin tissue and cultured dermal fibroblasts derived from women of different ages revealed an increase in the number of nascent double-membrane autophagosomes with age. Western blot analysis showed that the amount of LC3-II, a form associated with autophagic vacuolar membranes, was significantly increased in aged dermal fibroblasts compared with that in young dermal fibroblasts. Aged dermal fibroblasts were minimally affected by inhibition of autophagic activity. Although lipofuscin autofluorescence was elevated in aged dermal fibroblasts, the expression of Beclin-1 and Atg5—genes essential for autophagosome formation—was similar between young and aged dermal fibroblasts, suggesting that the increase of autophagosomes in aged dermal fibroblasts was due to impaired autophagic flux rather than an increase in autophagosome formation. Treatment of young dermal fibroblasts with lysosomal protease inhibitors, which mimic the condition of aged dermal fibroblasts with reduced autophagic activity, altered the fibroblast content of type I procollagen, hyaluronan and elastin, and caused a breakdown of collagen fibrils. Collectively, these findings suggest that the autophagy pathway is impaired in aged dermal fibroblasts, which leads to deterioration of dermal integrity and skin fragility.

  19. [Evaluation on contribution rate of each component total salvianolic acids and characterization of apparent oil/water partition coefficient].

    Science.gov (United States)

    Yan, Hong-mei; Chen, Xiao-yun; Xia, Hai-jian; Liu, Dan; Jia, Xiao-bin; Zhang, Zhen-hai

    2015-02-01

    The difference between three representative components of total salvianolic acids in pharmacodynamic activity were compared by three different pharmacological experiments: HUVECs oxidative damage experiment, 4 items of blood coagulation in vitro experiment in rabbits and experimental myocardial ischemia in rats. And the effects of contribution rate of each component were calculated by multi index comprehensive evaluation method based on CRITIC weights. The contribution rates of salvianolic acid B, rosmarinic acid and Danshensu were 28.85%, 30.11%, 41.04%. Apparent oil/water partition coefficient of each representative components of total salvianolic acids in n-octyl alcohol-buffer was tested and the total salvianolic acid components were characterized based on a combination of the approach of self-defined weighting coefficient with effects of contribution rate. Apparent oil/water partition coefficient of total salvianolic acids was 0.32, 1.06, 0.89, 0.98, 0.90, 0.13, 0.02, 0.20, 0.56 when in octanol-water/pH 1.2 dilute hydrochloric acid solution/ pH 2.0, 2.5, 5.0, 5.8, 6.8, 7.4, 7.8 phosphate buffer solution. It provides a certain reference for the characterization of components.

  20. Component

    Directory of Open Access Journals (Sweden)

    Tibor Tot

    2011-01-01

    Full Text Available A unique case of metaplastic breast carcinoma with an epithelial component showing tumoral necrosis and neuroectodermal stromal component is described. The tumor grew rapidly and measured 9 cm at the time of diagnosis. No lymph node metastases were present. The disease progressed rapidly and the patient died two years after the diagnosis from a hemorrhage caused by brain metastases. The morphology and phenotype of the tumor are described in detail and the differential diagnostic options are discussed.

  1. Analysis of near-field components of a plasmonic optical antenna and their contribution to quantum dot infrared photodetector enhancement.

    Science.gov (United States)

    Gu, Guiru; Vaillancourt, Jarrod; Lu, Xuejun

    2014-10-20

    In this paper, we analyze near-field vector components of a metallic circular disk array (MCDA) plasmonic optical antenna and their contribution to quantum dot infrared photodetector (QDIP) enhancement. The near-field vector components of the MCDA optical antenna and their distribution in the QD active region are simulated. The near-field overlap integral with the QD active region is calculated at different wavelengths and compared with the QDIP enhancement spectrum. The x-component (E(x)) of the near-field vector shows a larger intensity overlap integral and stronger correlation with the QDIP enhancement than E(z) and thus is determined to be the major near-field component to the QDIP enhancement.

  2. Identifying the damping contribution of building components based on measured top vibration

    NARCIS (Netherlands)

    Berg, R.L.J. van den; Steenbergen, R.D.J.M.

    2013-01-01

    In this paper, a damping model for a high-rise building is introduced. This model is used to investigate the possibilities to identify the relative damping contribution of the internal material damping in building elements, energy loss at element interfaces and energy outflow at the interface with t

  3. The role of autophagic and lysosomal pathways in ischemic brain injury******

    Institute of Scientific and Technical Information of China (English)

    Zhaohua Gu; Nan Shi; Qian Zhang; Wei Zhang; Meizhen Zhao; Xiaojiang Sun; Yinyi Sun; Kangyong Liu; Fen Wang; Ting Zhang; Qiang Li; Liwei Shen; Ling Zhou; Liang Dong

    2013-01-01

    Autophagy is involved in neural cel death after cerebral ischemia. Our previous studies showed that rapamycin-induced autophagy decreased the rate of apoptosis, but the rate of apoptosis was creased after the autophagy inhibitor, 3-methyladenine, was used. In this study, a suture-occluded method was performed to generate a rat model of brain ischemia. Under a transmission electron microscope, autophagic bodies and autophagy lysosomes were markedly accumulated in neurons at 4 hours post brain ischemic injury, with their numbers gradual y reducing over time. Western blotting demonstrated that protein levels of light chain 3-II and cathepsin B were significantly in-creased within 4 hours of ischemic injury, but these levels were not persistently upregulated over time. Confocal microscopy showed that autophagy was mainly found in neurons with positive light chain 3 signal. Injection of rapamycin via tail vein promoted the occurrence of autophagy in rat brain tissue after cerebral ischemia and elevated light chain 3 and cathepsin B expression. However, in-jection of 3-methyladenine significantly diminished light chain 3-II and cathepsin B expression. Results verified that autophagic and lysosomal activity is increased in ischemic neurons. Abnormal components in cel s can be eliminated through upregulating cel autophagy or inhibiting autophagy after ischemic brain injury, resulting in a dynamic balance of substances in cel s. Moreover, drugs that interfere with autophagy may be potential therapies for the treatment of brain injury.

  4. Apigenin induces autophagic cell death in human papillary thyroid carcinoma BCPAP cells.

    Science.gov (United States)

    Zhang, Li; Cheng, Xian; Gao, Yanyan; Zheng, Jie; Xu, Qiang; Sun, Yang; Guan, Haixia; Yu, Huixin; Sun, Zhen

    2015-11-01

    Apigenin, abundantly present in fruits and vegetables, is recognized as a flavonoid with anti-inflammatory, antioxidant and anticancer properties. In this study, we first investigated the anti-neoplastic effects of apigenin on papillary thyroid carcinoma (PTC) cell line BCPAP cells. Our results show that apigenin inhibited the viability of BCPAP cells in a dose-dependent manner. A large body of evidence demonstrates that autophagy contributes to cell death in certain contexts. In the present study, autophagy was induced by apigenin treatment in BCPAP cells, as evidenced by Beclin-1 accumulation, conversion of LC3 protein, p62 degradation as well as the significantly increased formation of acidic vesicular organelles (AVOs) compared to the control group. 3-MA, an autophagy inhibitor, rescued the cells from apigenin-induced cell death. Notably, apigenin enhanced production of reactive oxygen species (ROS), and subsequent induction of significant DNA damage as monitored by the TUNEL assay. In addition, apigenin treatment caused a significant accumulation of cells in the G2/M phase via down-regulation of Cdc25C expression. Our findings reveal that apigenin inhibits papillary thyroid cancer cell viability by the stimulation of reactive oxygen species (ROS) production, induction of DNA damage, leading to G2/M cell cycle arrest followed by autophagic cell death. Thus, our results provide new insights into the molecular mechanisms underlying apigenin-mediated autophagic cell death and suggest apigenin as a potential chemotherapeutic agent which is able to fight against papillary thyroid cancer.

  5. What component of executive functions contributes to normal and impaired reading comprehension in young adults?

    Science.gov (United States)

    Georgiou, George K; Das, J P

    2016-01-01

    The purpose of this study was two-fold: (a) to examine what component of executive functions (EF) - planning and working memory - predicts reading comprehension in young adults (Study 1), and (b) to examine if less skilled comprehenders experience deficits in the EF components (Study 2). In Study 1, we assessed 178 university students (120 females; mean age=21.82 years) on planning (Planned Connections, Planned Codes, and Planned Patterns), working memory (Listening Span, Digit Span Backward, and Digit Memory), and reading comprehension (Nelson-Denny Reading Test). The results of structural equation modeling indicated that only planning was a significant predictor of reading comprehension. In Study 2, we assessed 30 university students with a specific reading comprehension deficit (19 females; mean age=23.01 years) and 30 controls (18 females; mean age=22.77 years) on planning (Planned Connections and Crack the Code) and working memory (Listening Span and Digit Span Backward). The results showed that less skilled comprehenders performed significantly poorer than controls only in planning. Taken together, the findings of both studies suggest that planning is the preeminent component of EF that is driving its relationship with reading comprehension in young adults.

  6. The contribution of yield components in determining the productivity of winter wheat (Triticum aestivum L.

    Directory of Open Access Journals (Sweden)

    Elżbieta Harasim

    2016-09-01

    Full Text Available The aim of the present study was to determine the effect of different growth regulator rates and nitrogen fertilization levels on yield components and to evaluate their influence on winter wheat productivity. A field experiment with winter wheat ‘Muza’ was conducted at the Czesławice Experimental Farm, belonging to the University of Life Sciences in Lublin, Poland over the period 2004–2007. In this experiment, the effect of the studied factors on yield and its components was primarily dependent on weather conditions during the study period. An increase in nitrogen rate from 100 to 150 kg ha−1 in 2005 and 2007 had a significant effect on the increase in grain yield per unit area. In 2005, the grain yield rose through increased spike density (by 6.3% and a higher number of grains per spike (by 1.6%. The 1000-grain weight decreased the grain yield per unit area (by 0.04 t ha−1. In 2007, the higher yield of wheat fertilized with nitrogen at a rate of 150 kg N ha−1 was positively affected by all the three yield components. The statistical analysis of the results showed that the winter wheat grain yields were also significantly affected by the retardant rates applied depending on the year.

  7. The Contribution of Cell Surface Components to the Neutrophil Mechanosensitivity to Shear Stresses

    Directory of Open Access Journals (Sweden)

    Michael L. Akenhead

    2015-08-01

    Full Text Available This review discusses the regulation of neutrophils by fluid shear stress in the context of factors that may govern cell mechanosensitivity and its influence on cell functions. There is substantial evidence that mechanoreceptors located on the peripheral membrane contribute to the ability of shear stress to regulate cell activity. In the case of neutrophils, the formyl peptide receptor (FPR and the CD18 integrins on the cell membrane have been shown to provide neutrophils with the ability to sense shear stresses in their local environment and alter their physiological state, accordingly. This configuration is also found for other types of cells, although they involve different cell-specific mechanoreceptors. Moreover, from an examination of the neutrophil mechanotransducing capacity, it is apparent that cellular mechanosensitivity depends on a number of factors that, if altered, contribute to dysregulation and ultimately pathophysiology. To exemplify this, we first describe the neutrophil responses to shear exposure. We then review two neutrophil mechanoreceptors, specifically FPR and CD18 integrins, which participate in controlling cell activity levels under physiological conditions. Next, we discuss the various factors that may alter neutrophil mechanosensitivity to shear stress and how these may underlie the circulatory pathobiology of two cardiovascular disease states: hypertension and hypercholesterolemia. Based on the material presented, it is conceivable that cell mechanosensitivity is a powerful global metric that permits a more efficient approach to understanding the contribution of mechanobiology to physiology and to disease processes.

  8. Comparison of the relative contributions of intra-abdominal and liver fat to components of the metabolic syndrome

    DEFF Research Database (Denmark)

    Kotronen, Anna; Yki-Järvinen, Hannele; Sevastianova, Ksenia

    2011-01-01

    Abdominally obese individuals with the metabolic syndrome often have excess fat deposition both intra-abdominally (IA) and in the liver, but the relative contribution of these two deposits to variation in components of the metabolic syndrome remains unclear. We determined the mutually independent...... quantitative contributions of IA and liver fat to components of the syndrome, fasting serum (fS) insulin, and liver enzymes and measures of hepatic insulin sensitivity in 356 subjects (mean age 42 years, mean BMI 29.7 kg/m²) in whom liver fat and abdominal fat volumes were measured. IA and liver fat contents...... were correlated (r = 0.65, P fat, liver fat or IA fat explained variation in fS-triglyceride (TG) and high-density lipoprotein (HDL) cholesterol, plasma glucose, insulin and liver enzyme concentrations, and hepatic...

  9. OMIP contribution to CMIP6: experimental and diagnostic protocol for the physical component of the Ocean Model Intercomparison Project

    OpenAIRE

    Griffies, Stephen M.; Danabasoglu, Gokhan; Durack, Paul J.; Adcroft, Alistair J.; Balaji, V.; Böning, Claus W.; Chassignet, Eric P.; Curchitser, Enrique; Deshayes, Julie; Drange, Helge; Fox-kemper, Baylor; Gleckler, Peter J.; Gregory, Jonathan M; Haak, Helmuth; Hallberg, Robert W.

    2016-01-01

    The Ocean Model Intercomparison Project (OMIP) is an endorsed project in the Coupled Model Intercomparison Project Phase 6 (CMIP6). OMIP addresses CMIP6 science questions, investigating the origins and consequences of systematic model biases. It does so by providing a framework for evaluating (including assessment of systematic biases), understanding, and improving ocean, sea-ice, tracer, and biogeochemical components of climate and earth system models contributing to CMIP6....

  10. BH3 mimetics activate multiple pro-autophagic pathways.

    Science.gov (United States)

    Malik, S A; Orhon, I; Morselli, E; Criollo, A; Shen, S; Mariño, G; BenYounes, A; Bénit, P; Rustin, P; Maiuri, M C; Kroemer, G

    2011-09-15

    The BH3 mimetic ABT737 induces autophagy by competitively disrupting the inhibitory interaction between the BH3 domain of Beclin 1 and the anti-apoptotic proteins Bcl-2 and Bcl-X(L), thereby stimulating the Beclin 1-dependent allosteric activation of the pro-autophagic lipid kinase VPS34. Here, we examined whether ABT737 stimulates other pro-autophagic signal-transduction pathways. ABT737 caused the activating phosphorylation of AMP-dependent kinase (AMPK) and of the AMPK substrate acetyl CoA carboxylase, the activating phosphorylation of several subunits of the inhibitor of NF-κB (IκB) kinase (IKK) and the hyperphosphorylation of the IKK substrate IκB, inhibition of the activity of mammalian target of rapamycin (mTOR) and consequent dephosphorylation of the mTOR substrate S6 kinase. In addition, ABT737 treatment dephosphorylates (and hence likewise inhibits) p53, glycogen synthase kinase-3 and Akt. All these effects were shared by ABT737 and another structurally unrelated BH3 mimetic, HA14-1. Functional experiments revealed that pharmacological or genetic inhibition of IKK, Sirtuin and the p53-depleting ubiquitin ligase MDM2 prevented ABT737-induced autophagy. These results point to unexpected and pleiotropic pro-autophagic effects of BH3 mimetics involving the modulation of multiple signalling pathways.

  11. The contribution of inflammasome components on macrophage response to surface nanotopography and chemistry

    Science.gov (United States)

    Christo, Susan; Bachhuka, Akash; Diener, Kerrilyn R.; Vasilev, Krasimir; Hayball, John D.

    2016-05-01

    Implantable devices have become an established part of medical practice. However, often a negative inflammatory host response can impede the integration and functionality of the device. In this paper, we interrogate the role of surface nanotopography and chemistry on the potential molecular role of the inflammasome in controlling macrophage responses. To achieve this goal we engineered model substrata having precisely controlled nanotopography of predetermined height and tailored outermost surface chemistry. Bone marrow derived macrophages (BMDM) were harvested from genetically engineered mice deficient in the inflammasome components ASC, NLRP3 and AIM2. These cells were then cultured on these nanoengineered substrata and assessed for their capacity to attach and express pro-inflammatory cytokines. Our data provide evidence that the inflammasome components ASC, NLRP3 and AIM2 play a role in regulating macrophage adhesion and activation in response to surface nanotopography and chemistry. The findings of this paper are important for understanding the inflammatory consequences caused by biomaterials and pave the way to the rational design of future implantable devices having controlled and predictable inflammatory outcomes.

  12. The contribution of inflammasome components on macrophage response to surface nanotopography and chemistry

    Science.gov (United States)

    Christo, Susan; Bachhuka, Akash; Diener, Kerrilyn R.; Vasilev, Krasimir; Hayball, John D.

    2016-01-01

    Implantable devices have become an established part of medical practice. However, often a negative inflammatory host response can impede the integration and functionality of the device. In this paper, we interrogate the role of surface nanotopography and chemistry on the potential molecular role of the inflammasome in controlling macrophage responses. To achieve this goal we engineered model substrata having precisely controlled nanotopography of predetermined height and tailored outermost surface chemistry. Bone marrow derived macrophages (BMDM) were harvested from genetically engineered mice deficient in the inflammasome components ASC, NLRP3 and AIM2. These cells were then cultured on these nanoengineered substrata and assessed for their capacity to attach and express pro-inflammatory cytokines. Our data provide evidence that the inflammasome components ASC, NLRP3 and AIM2 play a role in regulating macrophage adhesion and activation in response to surface nanotopography and chemistry. The findings of this paper are important for understanding the inflammatory consequences caused by biomaterials and pave the way to the rational design of future implantable devices having controlled and predictable inflammatory outcomes. PMID:27188492

  13. How do neural responses to eyes contribute to face-sensitive ERP components in young infants? A rapid repetition study.

    Science.gov (United States)

    Hoehl, Stefanie

    2015-04-01

    Several face-sensitive components of the event-related potential (ERP) have been identified in infants, such as the posterior N290 and P400 components. The contribution of eye-sensitive neurons to these components is still unclear, however. A rapid repetition ERP paradigm was used to test 4-month-olds' responses to faces with and without eyes (preceded by houses, i.e., unprimed) and faces with eyes that were preceded by faces with or without eyes (i.e., primed). N290 latency was reduced and P400 amplitude was increased for unprimed faces without eyes compared to intact faces. In addition, N290 latency was reduced for faces preceded by intact faces compared to faces preceded by faces without eyes. Thus, processing speed at the level of the N290 and amplitude of the P400 are affected by the absence of eyes in a face supporting the notion that eye-sensitive neurons contribute to these components in infancy. Findings are discussed in relation to the early development of face processing and infant and adult ERP responses to faces and eyes.

  14. Quantification of frequency-components contributions to the discharge of a karst spring

    Science.gov (United States)

    Taver, V.; Johannet, A.; Vinches, M.; Borrell, V.; Pistre, S.; Bertin, D.

    2013-12-01

    Karst aquifers represent important underground resources for water supplies, providing it to 25% of the population. Nevertheless such systems are currently underexploited because of their heterogeneity and complexity, which make work fields and physical measurements expensive, and frequently not representative of the whole aquifer. The systemic paradigm appears thus at a complementary approach to study and model karst aquifers in the framework of non-linear system analysis. Its input and output signals, namely rainfalls and discharge contain information about the function performed by the physical process. Therefore, improvement of knowledge about the karst system can be provided using time series analysis, for example Fourier analysis or orthogonal decomposition [1]. Another level of analysis consists in building non-linear models to identify rainfall/discharge relation, component by component [2]. In this context, this communication proposes to use neural networks to first model the rainfall-runoff relation using frequency components, and second to analyze the models, using the KnoX method [3], in order to quantify the importance of each component. Two different neural models were designed: (i) the recurrent model which implements a non-linear recurrent model fed by rainfalls, ETP and previous estimated discharge, (ii) the feed-forward model which implements a non-linear static model fed by rainfalls, ETP and previous observed discharges. The first model is known to better represent the rainfall-runoff relation; the second one to better predict the discharge based on previous discharge observations. KnoX method is based on a variable selection method, which simply considers values of parameters after the training without taking into account the non-linear behavior of the model during functioning. An amelioration of the KnoX method, is thus proposed in order to overcome this inadequacy. The proposed method, leads thus to both a hierarchization and a quantification

  15. Contributions and Challenges of Non-Professional Patient Care: A Key Component of Contemporary Canadian Healthcare.

    Science.gov (United States)

    Montague, Terrence; Gogovor, Amédé; Ahmed, Sara; Torr, Emily; Aylen, John; Marshall, Lucas; Henningsen, Nadine; Nemis-White, Joanna

    2015-01-01

    The Canadian public is aging. Population levels of excellent, or very good, health are decreasing, and the prevalence of chronic diseases is increasing. Timely access to caring and respectful care from health professionals, with supporting information transfer, are key qualities in patients' sense of centricity and hope for best outcomes. Data from the 2013-2014 Health Care in Canada (HCIC) survey reveal, however, that 38% of such patients do not always, or often, access this support. The lack of timely access may be one underlying driver for non-professional caregivers to contribute to the care, as well as the personal and financial management, of family members or friends with chronic disease. Previous HCIC surveys, in 2005, 2006 and 2007, reported non-professional caregivers' prevalence in the adult public at 21, 23 and 26%, respectively, compared with 19% in the 2013-2014 survey. In all the surveys, a notable feature of non-professional care providers has been their universality of contribution, across age, sex, geography and time. Caregivers pay, however, a price. They have a lower level of self-related health, a higher incidence of chronic illness and net-negative impacts on relationships, career and finances, including use of personal savings (53%) and necessity of quitting their job (12%). Conversely, they infrequently claim available tax (12%) or compassionate care (11%) benefits. Interestingly, non-professional caregivers work in team-care settings with health professionals more frequently (29%) than patients in the general population with chronic illnesses (18%). Nonetheless, their current levels of always, or often, receiving assisting support (46%) and information (53%) from health professionals are lower than the respective results reported by the general public (65% and 68%). In conclusion, non-professional patient care in Canada is a common, longstanding and not-for-profit enterprise. It is more likely driven by altruistic caring or sense of duty

  16. Evaluation of the Doppler component contribution in the total backscattered flux for noninvasive medical spectroscopy

    Science.gov (United States)

    Lapitan, Denis; Rogatkin, Dmitry

    2014-05-01

    The widespread introduction of laser noninvasive diagnostic techniques in medicine gave rise interest to theoretical description of light propagation in turbid media. One of the purposes for that is a preliminary simulation of incoming radiation for diagnostic spectrophotometry equipment. For complex diagnostic devices combining the Laser Doppler Flowmetry (LDF) and the tissue reflectance oximetry (TRO) it is necessary to know a ratio of signals in each diagnostic channel for a proper choice of the radiation power of laser sources, sensitivity of photodetectors, etc. In LDF the lightbeating backscattered signal mixed from moving red blood cells and static inhomogeneities inside the tissue is the useful signal, while in TRO both signals from static and moving scatterers are registered in the sum. The aim of our study was an estimation of the ratio between flux with the Doppler shifted signal and the total backscattered flux. For this purpose the simple analytical model describing the backscattered radiation for a two-layered tissue with different levels of blood volume in the second layer was under consideration. The physical model was based on the improved Kubelka-Munk approach. This approach involves an additional parameter of the density of scatterers, so it is useful for the Doppler signal intensity calculation as well. To assess the intensity of the Doppler component the single-scattering approximation inside the tissue's second layer was used. It was found that the fraction of the Doppler component in the total backscattered flux can vary in the range of 1-10% for the blood volume of 1-20%.

  17. Inferring ultraviolet anatomical exposure patterns while distinguishing the relative contribution of radiation components

    Energy Technology Data Exchange (ETDEWEB)

    Vuilleumier, Laurent [Federal Office of Meteorology and Climatology, MeteoSwiss, Payerne (Switzerland); Milon, Antoine; Vernez, David [Institute of Work and Health, University of Lausanne and Geneva, Lausanne (Switzerland); Bulliard, Jean-Luc [Cancer Epidemiology Unit, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne (Switzerland); Moccozet, Laurent [Institute of Services Science, University of Geneva (Switzerland)

    2013-05-10

    Exposure to solar ultraviolet (UV) radiation is the main causative factor for skin cancer. UV exposure depends on environmental and individual factors, but individual exposure data remain scarce. While ground UV irradiance is monitored via different techniques, it is difficult to translate such observations into human UV exposure or dose because of confounding factors. A multi-disciplinary collaboration developed a model predicting the dose and distribution of UV exposure on the basis of ground irradiation and morphological data. Standard 3D computer graphics techniques were adapted to develop a simulation tool that estimates solar exposure of a virtual manikin depicted as a triangle mesh surface. The amount of solar energy received by various body locations is computed for direct, diffuse and reflected radiation separately. Dosimetric measurements obtained in field conditions were used to assess the model performance. The model predicted exposure to solar UV adequately with a symmetric mean absolute percentage error of 13% and half of the predictions within 17% range of the measurements. Using this tool, solar UV exposure patterns were investigated with respect to the relative contribution of the direct, diffuse and reflected radiation. Exposure doses for various body parts and exposure scenarios of a standing individual were assessed using erythemally-weighted UV ground irradiance data measured in 2009 at Payerne, Switzerland as input. For most anatomical sites, mean daily doses were high (typically 6.2-14.6 Standard Erythemal Dose, SED) and exceeded recommended exposure values. Direct exposure was important during specific periods (e.g. midday during summer), but contributed moderately to the annual dose, ranging from 15 to 24% for vertical and horizontal body parts, respectively. Diffuse irradiation explained about 80% of the cumulative annual exposure dose.

  18. RNA is an integral component of chromatin that contributes to its structural organization.

    Directory of Open Access Journals (Sweden)

    Antonio Rodríguez-Campos

    Full Text Available Chromatin structure is influenced by multiples factors, such as pH, temperature, nature and concentration of counterions, post-translational modifications of histones and binding of structural non-histone proteins. RNA is also known to contribute to the regulation of chromatin structure as chromatin-induced gene silencing was shown to depend on the RNAi machinery in S. pombe, plants and Drosophila. Moreover, both in Drosophila and mammals, dosage compensation requires the contribution of specific non-coding RNAs. However, whether RNA itself plays a direct structural role in chromatin is not known. Here, we report results that indicate a general structural role for RNA in eukaryotic chromatin. RNA is found associated to purified chromatin prepared from chicken liver, or cultured Drosophila S2 cells, and treatment with RNase A alters the structural properties of chromatin. Our results indicate that chromatin-associated RNAs, which account for 2%-5% of total chromatin-associated nucleic acids, are polyA(- and show a size similar to that of the DNA contained in the corresponding chromatin fragments. Chromatin-associated RNA(s are not likely to correspond to nascent transcripts as they are also found bound to chromatin when cells are treated with alpha-amanitin. After treatment with RNase A, chromatin fragments of molecular weight >3.000 bp of DNA showed reduced sedimentation through sucrose gradients and increased sensitivity to micrococcal nuclease digestion. This structural transition, which is observed both at euchromatic and heterochromatic regions, proceeds without loss of histone H1 or any significant change in core-histone composition and integrity.

  19. A Systematic Methodology for Uncertainty Analysis of Group Contribution Based and Atom Connectivity Index Based Models for Estimation of Properties of Pure Components

    OpenAIRE

    Hukkerikar, Amol; Sarup, Bent; Sin, Gürkan; Gani, Rafiqul

    2011-01-01

    One of the most widely employed group contribution method for estimation of properties of pure components is the Marrero and Gani (MG) method. For the given component whose molecular structure is not completely described by any of the available groups, group contribution+ method (combined MG method and atomic connectivity index method) has been employed to create the missing groups and predict their contributions through the regressed contributions of connectivity indices. The objective of th...

  20. Working memory contributions to reading comprehension components in middle childhood children.

    Science.gov (United States)

    Chrysochoou, Elisavet; Bablekou, Zoe; Tsigilis, Nikolaos

    2011-01-01

    This study examined working memory contributions to reading comprehension subskills in Greek children (mean age 9 years, 1 month). The phonological loop of the Baddeley and Hitch working memory model was assessed with 3 recall tasks (words, nonwords, and digits) and a word list matching task. The central executive (CE) was assessed with 3 tasks (listening, counting, and backward digit recall). Participants were also given a receptive vocabulary task, a reading fluency task, and written stories accompanied by comprehension questions. Canonical correlation analyses showed that the comprehension variables were related to the CE rather than the phonological loop measures. CE functions were more strongly associated with elaborative inference generation (involving significant offline processing) and comprehension control (involving metacognitive monitoring). Smaller yet significant associations were observed between the CE and the necessary inference and literal comprehension measures, whereas a moderate relationship was found in the case of the simile comprehension variable. Among the CE variables, listening recall demonstrated the highest loading on the canonical function, followed by moderate yet significant counting and backward digit recall loadings. Vocabulary was found to fully mediate several associations between working memory and comprehension measures; however, the relationship between listening recall and elaborative inferences was partly mediated. Reading fluency and, on several occasions, Greek vocabulary knowledge did not mediate the relationships between CE measures and comprehension skills assessed. This study demonstrates the usefulness of CE measures for identifying young children's possible difficulties in carrying out specific reading comprehension processes.

  1. Hydraulic Performance Modifications of a Zeolite Membrane after an Alkaline Treatment: Contribution of Polar and Apolar Surface Tension Components

    Directory of Open Access Journals (Sweden)

    Patrick Dutournié

    2015-01-01

    Full Text Available Hydraulic permeability measurements are performed on low cut-off Na-mordenite (MOR-type zeolites membranes after a mild alkaline treatment. A decrease of the hydraulic permeability is systematically observed. Contact angle measurements are carried out (with three polar liquids on Na-mordenite films seeded onto alumina plates (flat membranes. A decrease of the contact angles is observed after the alkaline treatment for the three liquids. According to the theory of Lifshitz-van der Waals interactions in condensated state, surface modifications are investigated and a variation of the polar component of the material surface tension is observed. After the alkaline treatment, the electron-donor contribution (mainly due to the two remaining lone electron pairs of the oxygen atoms present in the zeolite extra frameworks decreases and an increase of the electron-receptor contribution is observed and quantified. The contribution of the polar component to the surface tension is attributed to the presence of surface defaults, which increase the surface hydrophilicity. The estimated modifications of the surface interaction energy between the solvent (water and the Na-mordenite active layer are in good agreement with the decrease of the hydraulic permeability observed after a mild alkaline treatment.

  2. Do different components of terrestrial sources contribute to the riverine suspended load?

    Science.gov (United States)

    Voss, B. M.; Peucker-Ehrenbrink, B.; Eglinton, T. I.; Galy, V.

    2012-04-01

    Establishing the relationship between source (bedrock, soil, floodplain sediments, vegetation) and mobilized materials (bedload and suspended load) within a river drainage network is critical to understanding the fate of particulate matter exported to the coastal ocean. First, linking material carried in river channels to its terrestrial sources aides in predicting the reactivity of organic matter associated with mineral particles and understanding which portions of a watershed contribute substantially to organic carbon fluxes and transformations in these systems. Second, identifying terrestrial reservoirs of future riverine suspended material can enhance our ability to comprehensively characterize the chemical and physical nature of fluvial sediments. We present a study of sedimentological and bulk organic carbon properties of sediments from across the Fraser River watershed in southwestern British Columbia, Canada. Bulk samples and size fractions from surface soils and riverbank sediments, as well as vegetation, are analyzed for metrics including carbon and nitrogen content, 13C and 14C composition, and specific surface area. These are compared with measurements of riverine suspended sediments and size fractions of sediments deposited in the Fraser estuary. The correspondence of suspended sediment properties with different portions of soil, alluvial, and vegetation pools from different sites suggests a complex link between source materials and exported material. Such variability may stem from the heterogeneous nature of soil types, hillslope morphology, and runoff regimes in different portions of the drainage basin; settling/resuspension processes during river transit; and/or modification of particle structure and organic matter between mobilization of terrestrial material and arrival at distant downstream sites. The preferential loss/preservation of different size fractions within mineral source materials highlights the unequal importance of different mineral

  3. YAP enhances autophagic flux to promote breast cancer cell survival in response to nutrient deprivation.

    Directory of Open Access Journals (Sweden)

    Qinghe Song

    Full Text Available The Yes-associated protein (YAP, a transcriptional coactivator inactivated by the Hippo tumor suppressor pathway, functions as an oncoprotein in a variety of cancers. However, its contribution to breast cancer remains controversial. This study investigated the role of YAP in breast cancer cells under nutrient deprivation (ND. Here, we show that YAP knockdown sensitized MCF7 breast cancer cells to nutrient deprivation-induced apoptosis. Furthermore, in response to ND, YAP increased the autolysosome degradation, thereby enhancing the cellular autophagic flux in breast cancer cells. Of note, autophagy is crucial for YAP to protect MCF7 cells from apoptosis under ND conditions. In addition, the TEA domain (TEAD family of growth-promoting transcription factors was indispensable for YAP-mediated regulation of autophagy. Collectively, our data reveal a role for YAP in promoting breast cancer cell survival upon ND stress and uncover an unappreciated function of YAP/TEAD in the regulation of autophagy.

  4. OMIP contribution to CMIP6: experimental and diagnostic protocol for the physical component of the Ocean Model Intercomparison Project

    Science.gov (United States)

    Griffies, Stephen M.; Danabasoglu, Gokhan; Durack, Paul J.; Adcroft, Alistair J.; Balaji, V.; Böning, Claus W.; Chassignet, Eric P.; Curchitser, Enrique; Deshayes, Julie; Drange, Helge; Fox-Kemper, Baylor; Gleckler, Peter J.; Gregory, Jonathan M.; Haak, Helmuth; Hallberg, Robert W.; Heimbach, Patrick; Hewitt, Helene T.; Holland, David M.; Ilyina, Tatiana; Jungclaus, Johann H.; Komuro, Yoshiki; Krasting, John P.; Large, William G.; Marsland, Simon J.; Masina, Simona; McDougall, Trevor J.; Nurser, A. J. George; Orr, James C.; Pirani, Anna; Qiao, Fangli; Stouffer, Ronald J.; Taylor, Karl E.; Treguier, Anne Marie; Tsujino, Hiroyuki; Uotila, Petteri; Valdivieso, Maria; Wang, Qiang; Winton, Michael; Yeager, Stephen G.

    2016-09-01

    The Ocean Model Intercomparison Project (OMIP) is an endorsed project in the Coupled Model Intercomparison Project Phase 6 (CMIP6). OMIP addresses CMIP6 science questions, investigating the origins and consequences of systematic model biases. It does so by providing a framework for evaluating (including assessment of systematic biases), understanding, and improving ocean, sea-ice, tracer, and biogeochemical components of climate and earth system models contributing to CMIP6. Among the WCRP Grand Challenges in climate science (GCs), OMIP primarily contributes to the regional sea level change and near-term (climate/decadal) prediction GCs.OMIP provides (a) an experimental protocol for global ocean/sea-ice models run with a prescribed atmospheric forcing; and (b) a protocol for ocean diagnostics to be saved as part of CMIP6. We focus here on the physical component of OMIP, with a companion paper (Orr et al., 2016) detailing methods for the inert chemistry and interactive biogeochemistry. The physical portion of the OMIP experimental protocol follows the interannual Coordinated Ocean-ice Reference Experiments (CORE-II). Since 2009, CORE-I (Normal Year Forcing) and CORE-II (Interannual Forcing) have become the standard methods to evaluate global ocean/sea-ice simulations and to examine mechanisms for forced ocean climate variability. The OMIP diagnostic protocol is relevant for any ocean model component of CMIP6, including the DECK (Diagnostic, Evaluation and Characterization of Klima experiments), historical simulations, FAFMIP (Flux Anomaly Forced MIP), C4MIP (Coupled Carbon Cycle Climate MIP), DAMIP (Detection and Attribution MIP), DCPP (Decadal Climate Prediction Project), ScenarioMIP, HighResMIP (High Resolution MIP), as well as the ocean/sea-ice OMIP simulations.

  5. Contribution of NMDA receptor-mediated component to the EPSP in mouse Schaffer collateral synapses under single pulse stimulation protocol.

    Science.gov (United States)

    Neagu, Bogdan; Strominger, Norman L; Carpenter, David O

    2008-11-13

    The degree to which NMDA receptors contribute to hippocampal CA(1) stratum radiatum excitatory postsynaptic potentials (EPSP) is a matter of debate. This experiment was designed to resolve the issue by documenting and positively identifying the elements of the NMDA dependent component in the extracellularly recorded stratum radiatum CA(1) field potential under low stimulation conditions and in the presence of physiologic levels of Mg(2+). We show that EPSP generation consists of activation of both AMPA and NMDA receptor channels, which mediate distinct components of the recorded field potential. We propose that the EPSP is a combination of two waves rather than one, which sometimes has been attributed to the exclusive activation of AMPA channels. Our data suggest that the three recorded peaks signify different events. The first peak reflects the presynaptic volley while the other two represent the actual EPSP. The first peak of the EPSP is determined mainly by flow of ions through AMPA channels. The second peak most likely is determined by the concurrence of two phenomena: ionic flow through NMDA channels and the source corresponding to the sink generated at the cell bodies in the pyramidal layer. The NMDA dependent component was recorded when Mg(2+) was present in physiological concentrations. The presynaptic volley and second peak do not saturate over a 10-fold increase of the stimulation charge and their amplitudes are highly correlated. The first peak amplitude rapidly saturates. The sensitivity of the recorded signals is different, the first peak being the most sensitive (1.25-0.26 mV/nC). Isolation of NMDA dependent components under physiological conditions when using a single pulse low stimulation protocol would allow more precise investigations of the NMDA dependent forms of synaptic plasticity.

  6. HAMLET (human alpha-lactalbumin made lethal to tumor cells) triggers autophagic tumor cell death.

    Science.gov (United States)

    Aits, Sonja; Gustafsson, Lotta; Hallgren, Oskar; Brest, Patrick; Gustafsson, Mattias; Trulsson, Maria; Mossberg, Ann-Kristin; Simon, Hans-Uwe; Mograbi, Baharia; Svanborg, Catharina

    2009-03-01

    HAMLET, a complex of partially unfolded alpha-lactalbumin and oleic acid, kills a wide range of tumor cells. Here we propose that HAMLET causes macroautophagy in tumor cells and that this contributes to their death. Cell death was accompanied by mitochondrial damage and a reduction in the level of active mTOR and HAMLET triggered extensive cytoplasmic vacuolization and the formation of double-membrane-enclosed vesicles typical of macroautophagy. In addition, HAMLET caused a change from uniform (LC3-I) to granular (LC3-II) staining in LC3-GFP-transfected cells reflecting LC3 translocation during macroautophagy, and this was blocked by the macroautophagy inhibitor 3-methyladenine. HAMLET also caused accumulation of LC3-II detected by Western blot when lysosomal degradation was inhibited suggesting that HAMLET caused an increase in autophagic flux. To determine if macroautophagy contributed to cell death, we used RNA interference against Beclin-1 and Atg5. Suppression of Beclin-1 and Atg5 improved the survival of HAMLET-treated tumor cells and inhibited the increase in granular LC3-GFP staining. The results show that HAMLET triggers macroautophagy in tumor cells and suggest that macroautophagy contributes to HAMLET-induced tumor cell death.

  7. Cellular metabolic and autophagic pathways: traffic control by redox signaling.

    Science.gov (United States)

    Dodson, Matthew; Darley-Usmar, Victor; Zhang, Jianhua

    2013-10-01

    It has been established that the key metabolic pathways of glycolysis and oxidative phosphorylation are intimately related to redox biology through control of cell signaling. Under physiological conditions glucose metabolism is linked to control of the NADH/NAD redox couple, as well as providing the major reductant, NADPH, for thiol-dependent antioxidant defenses. Retrograde signaling from the mitochondrion to the nucleus or cytosol controls cell growth and differentiation. Under pathological conditions mitochondria are targets for reactive oxygen and nitrogen species and are critical in controlling apoptotic cell death. At the interface of these metabolic pathways, the autophagy-lysosomal pathway functions to maintain mitochondrial quality and generally serves an important cytoprotective function. In this review we will discuss the autophagic response to reactive oxygen and nitrogen species that are generated from perturbations of cellular glucose metabolism and bioenergetic function.

  8. A Systematic Methodology for Uncertainty Analysis of Group Contribution Based and Atom Connectivity Index Based Models for Estimation of Properties of Pure Components

    DEFF Research Database (Denmark)

    Hukkerikar, Amol; Sarup, Bent; Sin, Gürkan

    One of the most widely employed group contribution method for estimation of properties of pure components is the Marrero and Gani (MG) method. For the given component whose molecular structure is not completely described by any of the available groups, group contribution+ method (combined MG method...... and atomic connectivity index method) has been employed to create the missing groups and predict their contributions through the regressed contributions of connectivity indices. The objective of this work is to develop a systematic methodology to carry out uncertainty analysis of group contribution based...... and atom connectivity index based property prediction models. This includes: (i) parameter estimation using available MG based property prediction models and large training sets to determine improved group and atom contributions; and (ii) uncertainty analysis to establish statistical information...

  9. THE CONTRIBUTION OF 'RESTING' BODY MUSCLES TO THE SLOW COMPONENT OF PULMONARY OXYGEN UPTAKE DURING HIGH-INTENSITY CYCLING

    Directory of Open Access Journals (Sweden)

    Susan A. Ward

    2012-12-01

    Full Text Available Oxygen uptake (VO2 kinetics during moderate constant- workrate (WR exercise (>lactate-threshold (ӨL are well described as exponential. AboveӨL, these kinetics are more complex, consequent to the development of a delayed slow component (VO2sc, whose aetiology remains controversial. To assess the extent of the contribution to the VO2sc from arm muscles involved in postural stability during cycling, six healthy subjects completed an incremental cycle-ergometer test to the tolerable limit for estimation of ӨL and determination of peak VO2. They then completed two constant-WR tests at 90% of ӨL and two at 80% of ∆ (difference between ӨL and VO2peak. Gas exchange variables were derived breath-by-breath. Local oxygenation profiles of the vastus lateralis and biceps brachii muscles were assessed by near-infrared spectroscopy, with maximal voluntary contractions (MVC of the relevant muscles being performed post-exercise to provide a frame of reference for normalising the exercise-related oxygenation responses across subjects. Above supra-ӨL, VO2 rose in an exponential-like fashion ("phase 2, with a delayed VO2sc subsequently developing. This was accompanied by an increase in [reduced haemoglobin] relative to baseline (∆[Hb], which attained 79 ± 13 % (mean, SD of MVC maximum in vastus lateralis at end-exercise and 52 ± 27 % in biceps brachii. Biceps brachii ∆[Hb] was significantly correlated with VO2 throughout the slow phase. In contrast, for sub- L exercise, VO2 rose exponentially to reach a steady state with a more modest increase in vastus lateralis ∆[Hb] (30 ± 11 %; biceps brachii ∆[Hb] was minimally affected (8 ± 2 %. That the intramuscular O2 desaturation profile in biceps brachii was proportional to that for VO2sc during supra-ӨL cycle ergometry is consistent with additional stabilizing arm work contributing to the VO2sc

  10. Autophagic flux is highly active in early mitosis and differentially regulated throughout the cell cycle

    OpenAIRE

    Li, Zhiyuan; Ji, Xinmiao; Wang, Dongmei; Liu, Juanjuan; Zhang, Xin

    2016-01-01

    Mitosis is a fast process that involves dramatic cellular remodeling and has a high energy demand. Whether autophagy is active or inactive during the early stages of mitosis in a naturally dividing cell is still debated. Here we aimed to use multiple assays to resolve this apparent discrepancy. Although the LC3 puncta number was reduced in mitosis, the four different cell lines we tested all have active autophagic flux in both interphase and mitosis. In addition, the autophagic flux was highl...

  11. Perceptual Correlates of Turkish Word Stress and Their Contribution to Automatic Lexical Access: Evidence from Early ERP Components

    Science.gov (United States)

    Zora, Hatice; Heldner, Mattias; Schwarz, Iris-Corinna

    2016-01-01

    Perceptual correlates of Turkish word stress and their contribution to lexical access were studied using the mismatch negativity (MMN) component in event-related potentials (ERPs). The MMN was expected to indicate if segmentally identical Turkish words were distinguished on the sole basis of prosodic features such as fundamental frequency (f0), spectral emphasis (SE), and duration. The salience of these features in lexical access was expected to be reflected in the amplitude of MMN responses. In a multi-deviant oddball paradigm, neural responses to changes in f0, SE, and duration individually, as well as to all three features combined, were recorded for words and pseudowords presented to 14 native speakers of Turkish. The word and pseudoword contrast was used to differentiate language-related effects from acoustic-change effects on the neural responses. First and in line with previous findings, the overall MMN was maximal over frontal and central scalp locations. Second, changes in prosodic features elicited neural responses both in words and pseudowords, confirming the brain's automatic response to any change in auditory input. However, there were processing differences between the prosodic features, most significantly in f0: While f0 manipulation elicited a slightly right-lateralized frontally-maximal MMN in words, it elicited a frontal P3a in pseudowords. Considering that P3a is associated with involuntary allocation of attention to salient changes, the manipulations of f0 in the absence of lexical processing lead to an intentional evaluation of pitch change. f0 is therefore claimed to be lexically specified in Turkish. Rather than combined features, individual prosodic features differentiate language-related effects from acoustic-change effects. The present study confirms that segmentally identical words can be distinguished on the basis of prosodic information alone, and establishes the salience of f0 in lexical access. PMID:26834534

  12. Two components of delayed rectifier K+ current in heart:molecular basis,functional diversity,and contribution to repolarization

    Institute of Scientific and Technical Information of China (English)

    Jian-hua CHENG; Itsuo KODAMA

    2004-01-01

    Delayed rectifier K+ current (IK) is the major outward current responsible for ventricular repolarization. Two components of IK (IKr and IKs) have been identified in many mammalian species including humans. IKr. plays a pivotal role in normal ventricular repolarization. A prolongation of action potential duration (APD) under a variety of conditions would favor the activation of IKs so that to prevent excessive repolarization delay causing early afterdepolarization. The pore-forming α subunits of IKr and IKs are composed of HERG (KCNH2) and KvLQT l (KCNQ l), respectively. KvLQT l is associated with a function-altering β subunit, minK to form IKs. HERG may be associated with minK (KCNE1) and/or minK-related protein (MiRP1) to form IKr, but the issue remains to be established. IKs is enhanced, whereas IKr is usually attenuated by β-adrenergic stimulation via cyclic adenosine 31,51-monophosphate (cAMP)/protein kinase A-dependent pathways. There exist regional differences in the density of IKr and IKs transmurally (endo-epicardial) and along the apico-basal axis, contributing to the spatial heterogeneity of ventricular repolarization. A decrease of IKr or IKs by mutations in either HERG, KvLQTl, or KCNE family results in inherited long QT syndrome (LQTS) with high risk for Torsades de pointes (TdP)-type polymorphic ventricular tachycardia and ventricular fibrillation. As to the pharmacological treatment and prevention of ventricular tachyarrhythmias, selectively block of IKs is expected to be more beneficial than selectively block of IKr in terms of homogeneous prolongation of refractoriness at high heart rates especially in diseased hearts including myocardial ischemia.

  13. Bortezomib induces autophagic death in proliferating human endothelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Belloni, Daniela; Veschini, Lorenzo [Myeloma Unit, Department of Oncology, IRCCS H San Raffaele, Milan (Italy); Foglieni, Chiara [Department of Cardiology, IRCCS H San Raffaele, Milan (Italy); Dell' Antonio, Giacomo [Department of Pathology, IRCCS H San Raffaele, Milan (Italy); Caligaris-Cappio, Federico [Myeloma Unit, Department of Oncology, IRCCS H San Raffaele, Milan (Italy); Universita Vita-Salute IRCCS H San Raffaele, Milan (Italy); Ferrarini, Marina [Myeloma Unit, Department of Oncology, IRCCS H San Raffaele, Milan (Italy); Ferrero, Elisabetta, E-mail: elisabetta.ferrero@hsr.it [Myeloma Unit, Department of Oncology, IRCCS H San Raffaele, Milan (Italy)

    2010-04-01

    The proteasome inhibitor Bortezomib has been approved for the treatment of relapsed/refractory multiple myeloma (MM), thanks to its ability to induce MM cell apoptosis. Moreover, Bortezomib has antiangiogenic properties. We report that endothelial cells (EC) exposed to Bortezomib undergo death to an extent that depends strictly on their activation state. Indeed, while quiescent EC are resistant to Bortezomib, the drug results maximally toxic in EC switched toward angiogenesis with FGF, and exerts a moderate effect on subconfluent HUVEC. Moreover, EC activation state deeply influences the death pathway elicited by Bortezomib: after treatment, angiogenesis-triggered EC display typical features of apoptosis. Conversely, death of subconfluent EC is preceded by ROS generation and signs typical of autophagy, including intense cytoplasmic vacuolization with evidence of autophagosomes at electron microscopy, and conversion of the cytosolic MAP LC3 I form toward the autophagosome-associated LC3 II form. Treatment with the specific autophagy inhibitor 3-MA prevents both LC3 I/LC3 II conversion and HUVEC cell death. Finally, early removal of Bortezomib is accompanied by the recovery of cell shape and viability. These findings strongly suggest that Bortezomib induces either apoptosis or autophagy in EC; interfering with the autophagic response may potentiate the antiangiogenic effect of the drug.

  14. Reserve autophagic capacity in alveolar epithelia provides a replicative niche for influenza A virus.

    Science.gov (United States)

    Hahn, David R; Na, Cheng-Lun; Weaver, Timothy E

    2014-09-01

    Autophagy contributes to cellular homeostasis through metabolite recycling and degradation of cytotoxic protein aggregates and damaged organelles. Although recent studies have established that the requirement for basal autophagy is largely tissue specific, the importance of autophagy for alveolar epithelial cell homeostasis remains an important knowledge gap. In the present study we generated two mouse models, with > 90% or > 50% recombination at the Atg5 locus in the distal respiratory epithelium, to assess the effect of dose-dependent decreases in autophagy on alveolar homeostasis. A 90% decrease in autophagy was well tolerated in young adult mice but resulted in alveolar septal thickening and altered lung mechanics in aged animals, consistent with accumulation of damage over time. By comparison, a 50% decrease in autophagy had no effect on alveolar structure or function throughout the murine life span, indicating that basal autophagy in this compartment exceeds that required for homeostasis. A 50% decrease in autophagy in the bronchoalveolar epithelium significantly attenuated influenza A/H3N2 viral replication, leading to improved lung structure and function and reduced morbidity and mortality after infection. The reserve of autophagic capacity in the alveolar epithelium may provide a niche for replication of influenza A virus.

  15. Clozapine Induces Autophagic Cell Death in Non-Small Cell Lung Cancer Cells

    Directory of Open Access Journals (Sweden)

    Yu-Chun Yin

    2015-02-01

    Full Text Available Background/Aims: Previous studies have shown that patients with schizophrenia have a lower incidence of cancer than the general population, and several antipsychotics have been demonstrated to have cytotoxic effects on cancer cells. However, the mechanisms underlying these results remain unclear. The present study aimed to investigate the effect of clozapine, which is often used to treat patients with refractory schizophrenia, on the growth of non-small cell lung carcinoma cell lines and to examine whether autophagy contributes to its effects. Methods: A549 and H1299 cells were treated with clozapine, and cell cytotoxicity, cell cycle and autophagy were then assessed. The autophagy inhibitor bafilomycin A1 and siRNA-targeted Atg7 were used to determine the role of autophagy in the effect of clozapine. Results: Clozapine inhibited A549 and H1299 proliferation and increased p21 and p27 expression levels, leading to cell cycle arrest. Clozapine also induced a high level of autophagy, but not apoptosis, in both cell lines, and the growth inhibitory effect of clozapine was blunted by treatment with the autophagy inhibitor bafilomycin A1 or with an siRNA targeting atg7. Conclusions: Clozapine inhibits cell proliferation by inducing autophagic cell death in two non-small cell lung carcinoma cell lines. These findings may provide insights into the relationship between clozapine use and the lower incidence of lung cancer among patients with schizophrenia.

  16. Lipid rafts participate in aberrant degradative autophagic-lysosomal pathway of amyloid-beta peptide in Alzheimer’s disease

    Institute of Scientific and Technical Information of China (English)

    Xin Zhou; Chun Yang; Yufeng Liu; Peng Li; Huiying Yang; Jingxing Dai; Rongmei Qu; Lin Yuan

    2014-01-01

    Amyloid-beta peptide is the main component of amyloid plaques, which are found in Alzhei-mer’s disease. The generation and deposition of amyloid-beta is one of the crucial factors for the onset and progression of Alzheimer’s disease. Lipid rafts are glycolipid-rich liquid domains of the plasma membrane, where certain types of protein tend to aggregate and intercalate. Lipid rafts are involved in the generation of amyloid-beta oligomers and the formation of amyloid-beta peptides. In this paper, we review the mechanism by which lipid rafts disturb the aberrant deg-radative autophagic-lysosomal pathway of amyloid-beta, which plays an important role in the pathological process of Alzheimer’s disease. Moreover, we describe this mechanism from the view of the Two-system Theory of fasciology and thus, suggest that lipid rafts may be a new target of Alzheimer’s disease treatment.

  17. Estimation of Properties of Pure Components Using Improved Group-Contribution+ (GC+) Based Models and Uncertainty Analysis

    DEFF Research Database (Denmark)

    Hukkerikar, Amol; Sarup, Bent; Abildskov, Jens

    they must be estimated. Predictive methods such as the group-contribution+ (GC+) method (combined group-contribution (GC) method and atom connectivity index (CI) method) are generally suitable to estimate the needed property values. For assessing the quality and reliability of the selected property...... the estimated property values using the GC+ approach, but also the uncertainties in the estimated property values. This feature allows one to evaluate the effects of these uncertainties on the product-process design calculations thereby contributing to better-informed and reliable engineering solutions....

  18. Rapid screening of potential autophagic inductor agents using mammalian cell lines.

    Science.gov (United States)

    Martins, Waleska K; Severino, Divinomar; Souza, Cleidiane; Stolf, Beatriz S; Baptista, Maurício S

    2013-06-01

    Recent progress in understanding the molecular basis of autophagy has demonstrated its importance in several areas of human health. Affordable screening techniques with higher sensitivity and specificity to identify autophagy are, however, needed to move the field forward. In fact, only laborious and/or expensive methodologies such as electron microscopy, dye-staining of autophagic vesicles, and LC3-II immunoblotting or immunoassaying are available for autophagy identification. Aiming to fulfill this technical gap, we describe here the association of three widely used assays to determine cell viability - Crystal Violet staining (CVS), 3-[4, 5-dimethylthiaolyl]-2, 5-diphenyl-tetrazolium bromide (MTT) reduction, and neutral red uptake (NRU) - to predict autophagic cell death in vitro. The conceptual framework of the method is the superior uptake of NR in cells engaging in autophagy. NRU was then weighted by the average of MTT reduction and CVS allowing the calculation of autophagic arbitrary units (AAU), a numeric variable that correlated specifically with the autophagic cell death. The proposed strategy is very useful for drug discovery, allowing the investigation of potential autophagic inductor agents through a rapid screening using mammalian cell lines B16-F10, HaCaT, HeLa, MES-SA, and MES-SA/Dx5 in a unique single microplate.

  19. The natural product peiminine represses colorectal carcinoma tumor growth by inducing autophagic cell death

    Energy Technology Data Exchange (ETDEWEB)

    Lyu, Qing [School of Life Sciences, Tsinghua University, Beijing, 100084 (China); Key Lab in Healthy Science and Technology, Division of Life Science, Graduate School at Shenzhen, Tsinghua University, Shenzhen, 518055 (China); Tou, Fangfang [Jiangxi Provincial Key Lab of Oncology Translation Medicine, Jiangxi Cancer Hospital, Nanchang, 330029 (China); Su, Hong; Wu, Xiaoyong [First Affiliated Hospital, Guiyang College of Traditional Chinese Medicine, Guiyang, 550002 (China); Chen, Xinyi [Department of Hematology and Oncology, Beijing University of Chinese Medicine, Beijing, 100029 (China); Zheng, Zhi, E-mail: zheng_sheva@hotmail.com [Jiangxi Provincial Key Lab of Oncology Translation Medicine, Jiangxi Cancer Hospital, Nanchang, 330029 (China)

    2015-06-19

    Autophagy is evolutionarily conservative in eukaryotic cells that engulf cellular long-lived proteins and organelles, and it degrades the contents through fusion with lysosomes, via which the cell acquires recycled building blocks for the synthesis of new molecules. In this study, we revealed that peiminine induces cell death and enhances autophagic flux in colorectal carcinoma HCT-116 cells. We determined that peiminine enhances the autophagic flux by repressing the phosphorylation of mTOR through inhibiting upstream signals. Knocking down ATG5 greatly reduced the peiminine-induced cell death in wild-type HCT-116 cells, while treating Bax/Bak-deficient cells with peiminine resulted in significant cell death. In summary, our discoveries demonstrated that peiminine represses colorectal carcinoma cell proliferation and cell growth by inducing autophagic cell death. - Highlights: • Peiminine induces autophagy and upregulates autophagic flux. • Peiminine represses colorectal carcinoma tumor growth. • Peiminine induces autophagic cell death. • Peiminine represses mTOR phosphorylation by influencing PI3K/Akt and AMPK pathway.

  20. Autophagy prevents autophagic cell death in Tetrahymena in response to oxidative stress.

    Science.gov (United States)

    Zhang, Si-Wei; Feng, Jiang-Nan; Cao, Yi; Meng, Li-Ping; Wang, Shu-Lin

    2015-05-18

    Autophagy is a major cellular pathway used to degrade long-lived proteins or organelles that may be damaged due to increased reactive oxygen species (ROS) generated by cellular stress. Autophagy typically enhances cell survival, but it may also act to promote cell death under certain conditions. The mechanism underlying this paradox, however, remains unclear. We showed that Tetrahymena cells exerted increased membrane-bound vacuoles characteristic of autophagy followed by autophagic cell death (referred to as cell death with autophagy) after exposure to hydrogen peroxide. Inhibition of autophagy by chloroquine or 3-methyladenine significantly augmented autophagic cell death induced by hydrogen peroxide. Blockage of the mitochondrial electron transport chain or starvation triggered activation of autophagy followed by cell death by inducing the production of ROS due to the loss of mitochondrial membrane potential. This indicated a regulatory role of mitochondrial ROS in programming autophagy and autophagic cell death in Tetrahymena. Importantly, suppression of autophagy enhanced autophagic cell death in Tetrahymena in response to elevated ROS production from starvation, and this was reversed by antioxidants. Therefore, our results suggest that autophagy was activated upon oxidative stress to prevent the initiation of autophagic cell death in Tetrahymena until the accumulation of ROS passed the point of no return, leading to delayed cell death in Tetrahymena.

  1. Identification and quantification of aroma-active components that contribute to the distinct malty flavor of buckwheat honey.

    Science.gov (United States)

    Zhou, Qiaoxuan; Wintersteen, Carol L; Cadwallader, Keith R

    2002-03-27

    Characteristic aroma components of buckwheat honey were studied by combined sensory and instrumental techniques. Relative aroma intensity of individual volatile components was evaluated by aroma extract dilution analysis (AEDA) of solvent extracts and by gas chromatography-olfactometry (GCO) of decreasing headspace samples (GCO-H). Results indicated that 3-methylbutanal, 3-hydroxy-4,5-dimethyl-2(5H)-furanone (sotolon), and (E)-beta-damascenone were the most potent odorants in buckwheat honey, with 3-methylbutanal being primarily responsible for the distinct malty aroma. Other important aroma-active compounds included methylpropanal, 2,3-butanedione, phenylacetaldehyde, 3-methylbutyric acid, maltol, vanillin, methional, coumarin, and p-cresol.

  2. Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins.

    Science.gov (United States)

    Matsumoto, Gen; Wada, Koji; Okuno, Misako; Kurosawa, Masaru; Nukina, Nobuyuki

    2011-10-21

    Selective macroautophagy (autophagy) of ubiquitinated protein is implicated as a compensatory mechanism of the ubiquitin-proteasome system. p62/SQSTM1 is a key molecule managing autophagic clearance of polyubiquitinated proteins. However, little is known about mechanisms controlling autophagic degradation of polyubiquitinated proteins. Here, we show that the specific phosphorylation of p62 at serine 403 (S403) in its ubiquitin-associated (UBA) domain increases the affinity between UBA and polyubiquitin chain, resulting in efficiently targeting polyubiquitinated proteins in "sequestosomes" and stabilizing sequestosome structure as a cargo of ubiquitinated proteins for autophagosome entry. Casein kinase 2 (CK2) phosphorylates S403 of p62 directly. Furthermore, CK2 overexpression or phosphatase inhibition reduces the formation of inclusion bodies of the polyglutamine-expanded huntingtin exon1 fragment in a p62-dependent manner. We propose that phosphorylation of p62 at S403 regulates autophagic clearance of ubiquitinated proteins and protein aggregates that are poorly degraded by proteasomes.

  3. Lung autophagic response following exposure of mice to whole body irradiation, with and without amifostine

    Energy Technology Data Exchange (ETDEWEB)

    Zois, Christos E. [Department of Radiotherapy - Oncology, Democritus University of Thrace, Alexandroupolis 68100 (Greece); Giatromanolaki, Alexandra [Department of Pathology, Democritus University of Thrace, Alexandroupolis (Greece); Kainulainen, Heikki [Department of Biology of Physical Activity, University of Jyvaeskylae (Finland); Botaitis, Sotirios [Department of Experimental Surgery, Democritus University of Thrace, Alexandroupolis (Greece); Torvinen, Sira [Department of Biology of Physical Activity, University of Jyvaeskylae (Finland); Simopoulos, Constantinos [Department of Experimental Surgery, Democritus University of Thrace, Alexandroupolis (Greece); Kortsaris, Alexandros [Department of Biochemistry, Democritus University of Thrace, Alexandroupolis (Greece); Sivridis, Efthimios [Department of Pathology, Democritus University of Thrace, Alexandroupolis (Greece); Koukourakis, Michael I., E-mail: targ@her.forthnet.gr [Department of Radiotherapy - Oncology, Democritus University of Thrace, Alexandroupolis 68100 (Greece)

    2011-01-07

    Research highlights: {yields} We investigated the effect 6 Gy of WBI on the autophagic machinery of normal mouse lung. {yields} Irradiation induces dysfunction of the autophagic machinery in normal lung, characterized by decreased transcription of the LC3A/Beclin-1 mRNA and accumulation of the LC3A, and p62 proteins. {yields} The membrane bound LC3A-II protein levels increased in the cytosolic fraction (not in the pellet), contrasting the patterns noted after starvation-induced autophagy. {yields} Administration of amifostine, reversed all the LC3A and p62 findings, suggesting protection of the normal autophagic function. -- Abstract: Purpose: The effect of ionizing irradiation on the autophagic response of normal tissues is largely unexplored. Abnormal autophagic function may interfere the protein quality control leading to cell degeneration and dysfunction. This study investigates its effect on the autophagic machinery of normal mouse lung. Methods and materials: Mice were exposed to 6 Gy of whole body {gamma}-radiation and sacrificed at various time points. The expression of MAP1LC3A/LC3A/Atg8, beclin-1, p62/sequestosome-1 and of the Bnip3 proteins was analyzed. Results: Following irradiation, the LC3A-I and LC3A-II protein levels increased significantly at 72 h and 7 days. Strikingly, LC3A-II protein was increased (5.6-fold at 7 days; p < 0.001) only in the cytosolic fraction, but remained unchanged in the membrane fraction. The p62 protein, was significantly increased in both supernatant and pellet fraction (p < 0.001), suggesting an autophagosome turnover deregulation. These findings contrast the patterns of starvation-induced autophagy up-regulation. Beclin-1 levels remained unchanged. The Bnip3 protein was significantly increased at 8 h, but it sharply decreased at 72 h (p < 0.05). Administration of amifostine (200 mg/kg), 30 min before irradiation, reversed all the LC3A and p62 findings on blots, suggesting restoration of the normal autophagic function

  4. HDAC1 inactivation induces mitotic defect and caspase-independent autophagic cell death in liver cancer.

    Directory of Open Access Journals (Sweden)

    Hong Jian Xie

    Full Text Available Histone deacetylases (HDACs are known to play a central role in the regulation of several cellular properties interlinked with the development and progression of cancer. Recently, HDAC1 has been reported to be overexpressed in hepatocellular carcinoma (HCC, but its biological roles in hepatocarcinogenesis remain to be elucidated. In this study, we demonstrated overexpression of HDAC1 in a subset of human HCCs and liver cancer cell lines. HDAC1 inactivation resulted in regression of tumor cell growth and activation of caspase-independent autophagic cell death, via LC3B-II activation pathway in Hep3B cells. In cell cycle regulation, HDAC1 inactivation selectively induced both p21(WAF1/Cip1 and p27(Kip1 expressions, and simultaneously suppressed the expression of cyclin D1 and CDK2. Consequently, HDAC1 inactivation led to the hypophosphorylation of pRb in G1/S transition, and thereby inactivated E2F/DP1 transcription activity. In addition, we demonstrated that HDAC1 suppresses p21(WAF1/Cip1 transcriptional activity through Sp1-binding sites in the p21(WAF1/Cip1 promoter. Furthermore, sustained suppression of HDAC1 attenuated in vitro colony formation and in vivo tumor growth in a mouse xenograft model. Taken together, we suggest the aberrant regulation of HDAC1 in HCC and its epigenetic regulation of gene transcription of autophagy and cell cycle components. Overexpression of HDAC1 may play a pivotal role through the systemic regulation of mitotic effectors in the development of HCC, providing a particularly relevant potential target in cancer therapy.

  5. A Founder Mutation in VPS11 Causes an Autosomal Recessive Leukoencephalopathy Linked to Autophagic Defects.

    Science.gov (United States)

    Zhang, Jinglan; Lachance, Véronik; Schaffner, Adam; Li, Xianting; Fedick, Anastasia; Kaye, Lauren E; Liao, Jun; Rosenfeld, Jill; Yachelevich, Naomi; Chu, Mary-Lynn; Mitchell, Wendy G; Boles, Richard G; Moran, Ellen; Tokita, Mari; Gorman, Elizabeth; Bagley, Kaytee; Zhang, Wei; Xia, Fan; Leduc, Magalie; Yang, Yaping; Eng, Christine; Wong, Lee-Jun; Schiffmann, Raphael; Diaz, George A; Kornreich, Ruth; Thummel, Ryan; Wasserstein, Melissa; Yue, Zhenyu; Edelmann, Lisa

    2016-04-01

    Genetic leukoencephalopathies (gLEs) are a group of heterogeneous disorders with white matter abnormalities affecting the central nervous system (CNS). The causative mutation in ~50% of gLEs is unknown. Using whole exome sequencing (WES), we identified homozygosity for a missense variant, VPS11: c.2536T>G (p.C846G), as the genetic cause of a leukoencephalopathy syndrome in five individuals from three unrelated Ashkenazi Jewish (AJ) families. All five patients exhibited highly concordant disease progression characterized by infantile onset leukoencephalopathy with brain white matter abnormalities, severe motor impairment, cortical blindness, intellectual disability, and seizures. The carrier frequency of the VPS11: c.2536T>G variant is 1:250 in the AJ population (n = 2,026). VPS11 protein is a core component of HOPS (homotypic fusion and protein sorting) and CORVET (class C core vacuole/endosome tethering) protein complexes involved in membrane trafficking and fusion of the lysosomes and endosomes. The cysteine 846 resides in an evolutionarily conserved cysteine-rich RING-H2 domain in carboxyl terminal regions of VPS11 proteins. Our data shows that the C846G mutation causes aberrant ubiquitination and accelerated turnover of VPS11 protein as well as compromised VPS11-VPS18 complex assembly, suggesting a loss of function in the mutant protein. Reduced VPS11 expression leads to an impaired autophagic activity in human cells. Importantly, zebrafish harboring a vps11 mutation with truncated RING-H2 domain demonstrated a significant reduction in CNS myelination following extensive neuronal death in the hindbrain and midbrain. Thus, our study reveals a defect in VPS11 as the underlying etiology for an autosomal recessive leukoencephalopathy disorder associated with a dysfunctional autophagy-lysosome trafficking pathway.

  6. A Founder Mutation in VPS11 Causes an Autosomal Recessive Leukoencephalopathy Linked to Autophagic Defects.

    Directory of Open Access Journals (Sweden)

    Jinglan Zhang

    2016-04-01

    Full Text Available Genetic leukoencephalopathies (gLEs are a group of heterogeneous disorders with white matter abnormalities affecting the central nervous system (CNS. The causative mutation in ~50% of gLEs is unknown. Using whole exome sequencing (WES, we identified homozygosity for a missense variant, VPS11: c.2536T>G (p.C846G, as the genetic cause of a leukoencephalopathy syndrome in five individuals from three unrelated Ashkenazi Jewish (AJ families. All five patients exhibited highly concordant disease progression characterized by infantile onset leukoencephalopathy with brain white matter abnormalities, severe motor impairment, cortical blindness, intellectual disability, and seizures. The carrier frequency of the VPS11: c.2536T>G variant is 1:250 in the AJ population (n = 2,026. VPS11 protein is a core component of HOPS (homotypic fusion and protein sorting and CORVET (class C core vacuole/endosome tethering protein complexes involved in membrane trafficking and fusion of the lysosomes and endosomes. The cysteine 846 resides in an evolutionarily conserved cysteine-rich RING-H2 domain in carboxyl terminal regions of VPS11 proteins. Our data shows that the C846G mutation causes aberrant ubiquitination and accelerated turnover of VPS11 protein as well as compromised VPS11-VPS18 complex assembly, suggesting a loss of function in the mutant protein. Reduced VPS11 expression leads to an impaired autophagic activity in human cells. Importantly, zebrafish harboring a vps11 mutation with truncated RING-H2 domain demonstrated a significant reduction in CNS myelination following extensive neuronal death in the hindbrain and midbrain. Thus, our study reveals a defect in VPS11 as the underlying etiology for an autosomal recessive leukoencephalopathy disorder associated with a dysfunctional autophagy-lysosome trafficking pathway.

  7. A Founder Mutation in VPS11 Causes an Autosomal Recessive Leukoencephalopathy Linked to Autophagic Defects

    Science.gov (United States)

    Schaffner, Adam; Fedick, Anastasia; Kaye, Lauren E.; Liao, Jun; Yachelevich, Naomi; Chu, Mary-Lynn; Boles, Richard G.; Moran, Ellen; Tokita, Mari; Gorman, Elizabeth; Zhang, Wei; Xia, Fan; Leduc, Magalie; Yang, Yaping; Eng, Christine; Wong, Lee-Jun; Schiffmann, Raphael; Diaz, George A.; Kornreich, Ruth; Thummel, Ryan; Wasserstein, Melissa; Yue, Zhenyu; Edelmann, Lisa

    2016-01-01

    Genetic leukoencephalopathies (gLEs) are a group of heterogeneous disorders with white matter abnormalities affecting the central nervous system (CNS). The causative mutation in ~50% of gLEs is unknown. Using whole exome sequencing (WES), we identified homozygosity for a missense variant, VPS11: c.2536T>G (p.C846G), as the genetic cause of a leukoencephalopathy syndrome in five individuals from three unrelated Ashkenazi Jewish (AJ) families. All five patients exhibited highly concordant disease progression characterized by infantile onset leukoencephalopathy with brain white matter abnormalities, severe motor impairment, cortical blindness, intellectual disability, and seizures. The carrier frequency of the VPS11: c.2536T>G variant is 1:250 in the AJ population (n = 2,026). VPS11 protein is a core component of HOPS (homotypic fusion and protein sorting) and CORVET (class C core vacuole/endosome tethering) protein complexes involved in membrane trafficking and fusion of the lysosomes and endosomes. The cysteine 846 resides in an evolutionarily conserved cysteine-rich RING-H2 domain in carboxyl terminal regions of VPS11 proteins. Our data shows that the C846G mutation causes aberrant ubiquitination and accelerated turnover of VPS11 protein as well as compromised VPS11-VPS18 complex assembly, suggesting a loss of function in the mutant protein. Reduced VPS11 expression leads to an impaired autophagic activity in human cells. Importantly, zebrafish harboring a vps11 mutation with truncated RING-H2 domain demonstrated a significant reduction in CNS myelination following extensive neuronal death in the hindbrain and midbrain. Thus, our study reveals a defect in VPS11 as the underlying etiology for an autosomal recessive leukoencephalopathy disorder associated with a dysfunctional autophagy-lysosome trafficking pathway. PMID:27120463

  8. Conessine Interferes with Oxidative Stress-Induced C2C12 Myoblast Cell Death through Inhibition of Autophagic Flux.

    Directory of Open Access Journals (Sweden)

    Hyunju Kim

    Full Text Available Conessine, a steroidal alkaloid isolated from Holarrhena floribunda, has anti-malarial activity and interacts with the histamine H3 receptor. However, the cellular effects of conessine are poorly understood. Accordingly, we evaluated the involvement of conessine in the regulation of autophagy. We searched natural compounds that modulate autophagy, and conessine was identified as an inhibitor of autophagic flux. Conessine treatment induced the formation of autophagosomes, and p62, an autophagic adapter, accumulated in the autophagosomes. Reactive oxygen species such as hydrogen peroxide (H2O2 result in muscle cell death by inducing excessive autophagic flux. Treatment with conessine inhibited H2O2-induced autophagic flux in C2C12 myoblast cells and also interfered with cell death. Our results indicate that conessine has the potential effect to inhibit muscle cell death by interfering with autophagic flux.

  9. Conessine Interferes with Oxidative Stress-Induced C2C12 Myoblast Cell Death through Inhibition of Autophagic Flux

    Science.gov (United States)

    Kim, Hyunju; Lee, Kang Il; Jang, Minsu; Namkoong, Sim; Park, Rackhyun; Ju, Hyunwoo; Choi, Inho; Oh, Won Keun

    2016-01-01

    Conessine, a steroidal alkaloid isolated from Holarrhena floribunda, has anti-malarial activity and interacts with the histamine H3 receptor. However, the cellular effects of conessine are poorly understood. Accordingly, we evaluated the involvement of conessine in the regulation of autophagy. We searched natural compounds that modulate autophagy, and conessine was identified as an inhibitor of autophagic flux. Conessine treatment induced the formation of autophagosomes, and p62, an autophagic adapter, accumulated in the autophagosomes. Reactive oxygen species such as hydrogen peroxide (H2O2) result in muscle cell death by inducing excessive autophagic flux. Treatment with conessine inhibited H2O2-induced autophagic flux in C2C12 myoblast cells and also interfered with cell death. Our results indicate that conessine has the potential effect to inhibit muscle cell death by interfering with autophagic flux. PMID:27257813

  10. Autophagic Cell Death and Apoptosis Jointly Mediate Cisatracurium Besylate-Induced Cell Injury

    Directory of Open Access Journals (Sweden)

    Haixia Zhuang

    2016-04-01

    Full Text Available Cisatracurium besylate is an ideal non-depolarizing muscle relaxant which is widely used in clinical application. However, some studies have suggested that cisatracurium besylate can affect cell proliferation. Moreover, its specific mechanism of action remains unclear. Here, we found that the number of GFP-LC3 (green fluoresent protein-light chain 3 positive autophagosomes and the rate of mitochondria fracture both increased significantly in drug-treated GFP-LC3 and MitoDsRed stable HeLa cells. Moreover, cisatracurium promoted the co-localization of LC3 and mitochondria and induced formation of autolysosomes. Levels of mitochondrial proteins decreased, which were reversed by the lysosome inhibitor Bafinomycin A1. Similar results with evidence of dose-dependent effects were found in both HeLa and Human Umbilical Vein Endothelial Cells (HUVECs. Cisatracurium lowered HUVEC viability to 0.16 (OD490 at 100 µM and to 0.05 (OD490 after 48 h in vitro; it increased the cell death rate to 56% at 100 µM and to 60% after 24 h in a concentration- and time-dependent manner (p < 0.01. Cell proliferation decreased significantly by four fold in Atg5 WT (wildtype MEF (mouse embryonic fibroblast (p < 0.01 but was unaffected in Atg5 KO (Knockout MEF, even upon treatment with a high dose of cisatracurium. Cisatracurium induced significant increase in cell death of wild-type MEFs even in the presence of the apoptosis inhibitor zVAD. Thus, we conclude that activation of both the autophagic cell death and cell apoptosis pathways contributes to cisatracurium-mediated cell injury.

  11. Autophagic clearance of mitochondria in the kidney copes with metabolic acidosis.

    Science.gov (United States)

    Namba, Tomoko; Takabatake, Yoshitsugu; Kimura, Tomonori; Takahashi, Atsushi; Yamamoto, Takeshi; Matsuda, Jun; Kitamura, Harumi; Niimura, Fumio; Matsusaka, Taiji; Iwatani, Hirotsugu; Matsui, Isao; Kaimori, Junya; Kioka, Hidetaka; Isaka, Yoshitaka; Rakugi, Hiromi

    2014-10-01

    Metabolic acidosis, a common complication of CKD, causes mitochondrial stress by undefined mechanisms. Selective autophagy of impaired mitochondria, called mitophagy, contributes toward maintaining cellular homeostasis in various settings. We hypothesized that mitophagy is involved in proximal tubular cell adaptations to chronic metabolic acidosis. In transgenic mice expressing green fluorescent protein-tagged microtubule-associated protein 1 light chain 3 (GFP-LC3), NH4Cl loading increased the number of GFP puncta exclusively in the proximal tubule. In vitro, culture in acidic medium produced similar results in proximal tubular cell lines stably expressing GFP-LC3 and facilitated the degradation of SQSTM1/p62 in wild-type cells, indicating enhanced autophagic flux. Upon acid loading, proximal tubule-specific autophagy-deficient (Atg5-deficient) mice displayed significantly reduced ammonium production and severe metabolic acidosis compared with wild-type mice. In vitro and in vivo, acid loading caused Atg5-deficient proximal tubular cells to exhibit reduced mitochondrial respiratory chain activity, reduced mitochondrial membrane potential, and fragmented morphology with marked swelling in mitochondria. GFP-LC3-tagged autophagosomes colocalized with ubiquitinated mitochondria in proximal tubular cells cultured in acidic medium, suggesting that metabolic acidosis induces mitophagy. Furthermore, restoration of Atg5-intact nuclei in Atg5-deficient proximal tubular cells increased mitochondrial membrane potential and ammoniagenesis. In conclusion, metabolic acidosis induces autophagy in proximal tubular cells, which is indispensable for maintaining proper mitochondrial functions including ammoniagenesis, and thus for adapted urinary acid excretion. Our results provide a rationale for the beneficial effect of alkali supplementation in CKD, a condition in which autophagy may be reduced, and suggest a new therapeutic option for acidosis by modulating autophagy.

  12. Aging and Autophagic Function Influences the Progressive Decline of Adult Drosophila Behaviors.

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    Eric P Ratliff

    Full Text Available Multiple neurological disorders are characterized by the abnormal accumulation of protein aggregates and the progressive impairment of complex behaviors. Our Drosophila studies demonstrate that middle-aged wild-type flies (WT, ~4-weeks exhibit a marked accumulation of neural aggregates that is commensurate with the decline of the autophagy pathway. However, enhancing autophagy via neuronal over-expression of Atg8a (Atg8a-OE reduces the age-dependent accumulation of aggregates. Here we assess basal locomotor activity profiles for single- and group-housed male and female WT flies and observed that only modest behavioral changes occurred by 4-weeks of age, with the noted exception of group-housed male flies. Male flies in same-sex social groups exhibit a progressive increase in nighttime activity. Infrared videos show aged group-housed males (4-weeks are engaged in extensive bouts of courtship during periods of darkness, which is partly repressed during lighted conditions. Together, these nighttime courtship behaviors were nearly absent in young WT flies and aged Atg8a-OE flies. Previous studies have indicated a regulatory role for olfaction in male courtship partner choice. Coincidently, the mRNA expression profiles of several olfactory genes decline with age in WT flies; however, they are maintained in age-matched Atg8a-OE flies. Together, these results suggest that middle-aged male flies develop impairments in olfaction, which could contribute to the dysregulation of courtship behaviors during dark time periods. Combined, our results demonstrate that as Drosophila age, they develop early behavior defects that are coordinate with protein aggregate accumulation in the nervous system. In addition, the nighttime activity behavior is preserved when neuronal autophagy is maintained (Atg8a-OE flies. Thus, environmental or genetic factors that modify autophagic capacity could have a positive impact on neuronal aging and complex behaviors.

  13. The Drosophila effector caspase Dcp-1 regulates mitochondrial dynamics and autophagic flux via SesB.

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    DeVorkin, Lindsay; Go, Nancy Erro; Hou, Ying-Chen Claire; Moradian, Annie; Morin, Gregg B; Gorski, Sharon M

    2014-05-26

    Increasing evidence reveals that a subset of proteins participates in both the autophagy and apoptosis pathways, and this intersection is important in normal physiological contexts and in pathological settings. In this paper, we show that the Drosophila effector caspase, Drosophila caspase 1 (Dcp-1), localizes within mitochondria and regulates mitochondrial morphology and autophagic flux. Loss of Dcp-1 led to mitochondrial elongation, increased levels of the mitochondrial adenine nucleotide translocase stress-sensitive B (SesB), increased adenosine triphosphate (ATP), and a reduction in autophagic flux. Moreover, we find that SesB suppresses autophagic flux during midoogenesis, identifying a novel negative regulator of autophagy. Reduced SesB activity or depletion of ATP by oligomycin A could rescue the autophagic defect in Dcp-1 loss-of-function flies, demonstrating that Dcp-1 promotes autophagy by negatively regulating SesB and ATP levels. Furthermore, we find that pro-Dcp-1 interacts with SesB in a nonproteolytic manner to regulate its stability. These data reveal a new mitochondrial-associated molecular link between nonapoptotic caspase function and autophagy regulation in vivo.

  14. Autophagic vesicles on mature human reticulocytes explain phosphatidylserine-positive red cells in sickle cell disease.

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    Mankelow, Tosti J; Griffiths, Rebecca E; Trompeter, Sara; Flatt, Joanna F; Cogan, Nicola M; Massey, Edwin J; Anstee, David J

    2015-10-08

    During maturation to an erythrocyte, a reticulocyte must eliminate any residual organelles and reduce its surface area and volume. Here we show this involves a novel process whereby large, intact, inside-out phosphatidylserine (PS)-exposed autophagic vesicles are extruded. Cell surface PS is a well-characterized apoptotic signal initiating phagocytosis. In peripheral blood from patients after splenectomy or in patients with sickle cell disease (SCD), the number of circulating red cells exposing PS on their surface is elevated. We show that in these patients PS is present on the cell surface of red cells in large (∼1.4 µm) discrete areas corresponding to autophagic vesicles. The autophagic vesicles found on reticulocytes are identical to those observed on red cells from splenectomized individuals and patients with SCD. Our data suggest the increased thrombotic risk associated with splenectomy, and patients with hemoglobinopathies is a possible consequence of increased levels of circulating mature reticulocytes expressing inside-out PS-exposed autophagic vesicles because of asplenia.

  15. Contribution of fibrinolysis to the physical component summary of the SF-36 after acute submassive pulmonary embolism

    Science.gov (United States)

    Stewart, Lauren K.; Peitz, Geoffrey W.; Nordenholz, Kristen E.; Courtney, D. Mark; Kabrhel, Christopher; Jones, Alan E.; Rondina, Matthew T.; Diercks, Deborah B.; Klinger, James R.

    2015-01-01

    Acute pulmonary embolism (PE) can diminish patient quality of life (QoL). The objective was to test whether treatment with tenecteplase has an independent effect on a measurement that reflects QoL in patients with submassive PE. This was a secondary analysis of an 8-center, prospective randomized controlled trial, utilizing multivariate regression to control for predefined predictors of worsened QoL including: age, active malignancy, history of PE or deep venous thrombosis (DVT), recurrent PE or DVT, chronic obstructive pulmonary disease and heart failure. QoL was measured with the physical component summary (PCS) of the SF-36. Analysis included 76 patients (37 randomized to tenecteplase, 39 to placebo). Multivariate regression yielded an equation f(8, 67), Ptenecteplase second (β = 4.73, P = 0.056). After controlling for all interactions, tenecteplase increased the PCS by +5.37 points (P = 0.027). In patients without any of the defined comorbidities, the coefficient on the tenecteplase variable was not significant (−0.835, P = 0.777). In patients with submassive PE, obesity had the greatest influence on QoL, followed by use of fibrinolysis. Fibrinolysis had a marginal independent effect on patient QoL after controlling for comorbidities, but was not significant in patients without comorbid conditions. PMID:25433511

  16. Lysine suppresses protein degradation through autophagic-lysosomal system in C2C12 myotubes.

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    Sato, Tomonori; Ito, Yoshiaki; Nedachi, Taku; Nagasawa, Takashi

    2014-06-01

    Muscle mass is determined between protein synthesis and protein degradation. Reduction of muscle mass leads to bedridden condition and attenuation of resistance to diseases. Moreover, bedridden condition leads to additional muscle loss due to disuse muscle atrophy. In our previous study (Sato et al. 2013), we showed that administered lysine (Lys), one of essential amino acid, suppressed protein degradation in skeletal muscle. In this study, we investigated that the mechanism of the suppressive effects of Lys on skeletal muscle proteolysis in C2C12 cell line. C2C12 myotubes were incubated in the serum-free medium containing 10 mM Lys or 20 mM Lys, and myofibrillar protein degradation was determined by the rates of 3-methylhistidine (MeHis) release from the cells. The mammalian target of rapamycin (mTOR) activity from the phosphorylation levels of p70-ribosormal protein S6 kinase 1 and eIF4E-binding protein 1 and the autophagic-lysosomal system activity from the ratio of LC3-II/I in C2C12 myotubes stimulated by 10 mM Lys for 0-3 h were measured. The rates of MeHis release were markedly reduced by addition of Lys. The autophagic-lysosomal system activity was inhibited upon 30 min of Lys supplementation. The activity of mTOR was significantly increased upon 30 min of Lys supplementation. The suppressive effect of Lys on the proteolysis by the autophagic-lysosomal system was maintained partially when mTOR activity was inhibited by 100 nM rapamycin, suggesting that some regulator other than mTOR signaling, for example, Akt, might also suppress the autophagic-lysosomal system. From these results, we suggested that Lys suppressed the activity of the autophagic-lysosomal system in part through activation of mTOR and reduced myofibrillar protein degradation in C2C12 myotubes.

  17. Investigation of endogenous blood lipids components that contribute to matrix effects in dried blood spot samples by liquid chromatography-tandem mass spectrometry.

    Science.gov (United States)

    Ismaiel, Omnia A; Jenkins, Rand G; Karnes, H Thomas

    2013-08-01

    Dried blood spot (DBS) sampling coupled to liquid chromatography-tandem mass spectrometry (LC-MS/MS) is a rapidly developing approach in the field of biopharmaceutical analysis. DBS sampling enables analysis of small sample volumes with high sensitivity and selectivity while providing a convenient easy to store and ship format. Lipid components that may be extracted during biological sample processing may result in matrix ionization effects and can significantly affect the precision and accuracy of the results. Glycerophosphocholines (GPChos), cholesterols and triacylglycerols (TAG) are the main lipid components that contribute to matrix effects in LC-MS/MS. Various organic solvents such as methanol, acetonitrile, methyl tertiary butyl ether, ethyl ether, dichloromethane and n-hexane were investigated for elution of these lipid components from DBS samples. Methanol extracts demonstrated the highest levels of GPChos whereas ethyl ether and n-hexane extracts contained less than 1.0 % of the GPChos levels in the methanol extracts. Ethyl ether extracts contained the highest levels of cholesterols and TAG in comparison to other investigated organic solvents. Acetonitrile is recommended as an elution solvent due to low lipid recoveries. Matrix effects resulted from different extracted lipid components should be studied and assessed carefully in DBS samples.

  18. Response curves of the surface modules of the Pierre Auger Observatory and the contribution of the hadronic component to the total signal of extensive showers

    Energy Technology Data Exchange (ETDEWEB)

    Mueller, Marcio Ap.; Chinellato, J.A. [Universidade Estadual de Campinas (UNICAMP), SP (Brazil). Inst. de Fisica

    2011-07-01

    Full text: At large distances from the shower's core, is generally said that the electromagnetic and muonic components are responsible for most of the signal detected and the contribution of hadrons is irrelevant. In fact, looking at the events generated by the simulations of showers, we see an average number of hadrons which is small compared to other components. On the other hand, the important factor to be considered is the fraction of energy they carry. Geant4 full simulations of shower particles interacting in the surface module are very time consuming. To overcome this difficulty, we produced a set of response curves that can replace the corresponding full simulations. To include albedo phenomena, we include a soil layer as a new target for hadronic interactions, with the detailed treatment of hadron interactions available in Geant4 tool kit. The response curves for each particle type were obtained with full runs of Geant4 in the new setup. We will present this parametrization, which reduce the processing time by factors larger than 1000 times. These response curves were implemented in the tool kit Offline, developed by the collaboration to simulate/reconstruct the development of air showers. The Geant4 class corresponding to the surface module was replaced by our parametrization, while the rest of the simulation chain remained unchanged. The main focus of this work are the interactions of the hadronic component, in the tank and in the soil target below the tank. Those were obtained with the new setup and compared to the results from the original version of Offline. To assess the contribution of hadrons, we also studied the contribution of other components under the same conditions, so we can to obtain always the effect of hadronic interactions compared with the other components. We make a comparison between the energy reconstructed by the original Offline (with no changes) and the Offline with the implementation of our parameterization. We can infer the

  19. Serotype- and strain- dependent contribution of the sensor kinase CovS of the CovRS two-component system to Streptococcus pyogenes pathogenesis

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    Podbielski Andreas

    2010-02-01

    Full Text Available Abstract Background The Streptococcus pyogenes (group A streptococci, GAS two-component signal transduction system CovRS has been described to be important for pathogenesis of this exclusively human bacterial species. If this system acts uniquely in all serotypes is currently unclear. Presence of serotype- or strain-dependent regulatory circuits and polarity is an emerging scheme in Streptococcus pyogenes pathogenesis. Thus, the contribution of the sensor kinase (CovS of the global regulatory two-component signal transduction system CovRS on pathogenesis of several M serotypes was investigated. Results CovS mutation uniformly repressed capsule expression and hampered keratinocyte adherence in all tested serotypes. However, a serotype- and even strain-dependent contribution on survival in whole human blood and biofilm formation was noted, respectively. Conclusions These data provide new information on the action of the CovS sensor kinase and revealed that its activity on capsule expression and keratinocyte adherence is uniform across serotypes, whereas the influence on biofilm formation and blood survival is serotype or even strain dependent. This adds the CovRS system to a growing list of serotype-specific acting regulatory loci in S. pyogenes.

  20. Autophagic induction of amyotrophic lateral sclerosis-linked Cu/Zn superoxide dismutase 1 G93A mutant in NSC34 cells

    Institute of Scientific and Technical Information of China (English)

    Yanming Wei

    2014-01-01

    Previous studies have conifrmed that the beclin 1 complex plays a key role in the initial stage of autophagy and deregulated autophagy might involve in amyotrophic lateral sclerosis. However, the mechanism underlying altered autophagy associated with the beclin 1 complex remains un-clear. In this study, we transfected the Cu/Zn superoxide dismutase 1 G93A mutant protein into the motor neuron-like cell line NSC34 cultured in vitro. Western blotting and co-immunopre-cipitation showed that the Cu/Zn superoxide dismutase 1 G93A mutant enhanced the turnover of autophagic marker microtubule-associated protein light chain 3II (LC3II) and stimulated the conversion of EGFP-LC3I to EGFP-LC3II, but had little inlfuence on the binding capacity of the autophagy modulators ATG14L, rubicon, UVRAG, and hVps34 to beclin 1 during auto-phagosome formation. These results suggest that the amyotrophic lateral sclerosis-linked Cu/Zn superoxide dismutase 1 G93A mutant can upregulate autophagic activity in NSC34 cells, but that this does not markedly affect beclin 1 complex components.

  1. Acute NMDA toxicity in cultured rat cerebellar granule neurons is accompanied by autophagy induction and late onset autophagic cell death phenotype

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    Kobeissy Firas H

    2010-02-01

    Full Text Available Abstract Background Autophagy, an intracellular response to stress, is characterized by double membrane cytosolic vesicles called autophagosomes. Prolonged autophagy is known to result in autophagic (Type II cell death. This study examined the potential role of an autophagic response in cultured cerebellar granule neurons challenged with excitotoxin N-methyl-D-aspartate (NMDA. Results NMDA exposure induced light chain-3 (LC-3-immunopositive and monodansylcadaverine (MDC fluorescent dye-labeled autophagosome formation in both cell bodies and neurites as early as 3 hours post-treatment. Elevated levels of Beclin-1 and the autophagosome-targeting LC3-II were also observed following NMDA exposure. Prolonged exposure of the cultures to NMDA (8-24 h generated MDC-, LC3-positive autophagosomal bodies, concomitant with the neurodegenerative phase of NMDA challenge. Lysosomal inhibition studies also suggest that NMDA-treatment diverted the autophagosome-associated LC3-II from the normal lysosomal degradation pathway. Autophagy inhibitor 3-methyladenine significantly reduced NMDA-induced LC3-II/LC3-I ratio increase, accumulation of autophagosomes, and suppressed NMDA-mediated neuronal death. ATG7 siRNA studies also showed neuroprotective effects following NMDA treatment. Conclusions Collectively, this study shows that autophagy machinery is robustly induced in cultured neurons subjected to prolonged exposure to excitotoxin, while autophagosome clearance by lysosomal pathway might be impaired. Our data further show that prolonged autophagy contributes to cell death in NMDA-mediated excitotoxicity.

  2. Normal autophagic activity in macrophages from mice lacking Gαi3, AGS3, or RGS19.

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    Ali Vural

    Full Text Available In macrophages autophagy assists antigen presentation, affects cytokine release, and promotes intracellular pathogen elimination. In some cells autophagy is modulated by a signaling pathway that employs Gαi3, Activator of G-protein Signaling-3 (AGS3/GPSM1, and Regulator of G-protein Signaling 19 (RGS19. As macrophages express each of these proteins, we tested their importance in regulating macrophage autophagy. We assessed LC3 processing and the formation of LC3 puncta in bone marrow derived macrophages prepared from wild type, Gnai3(-/-, Gpsm1(-/-, or Rgs19(-/- mice following amino acid starvation or Nigericin treatment. In addition, we evaluated rapamycin-induced autophagic proteolysis rates by long-lived protein degradation assays and anti-autophagic action after rapamycin induction in wild type, Gnai3(-/-, and Gpsm1(-/- macrophages. In similar assays we compared macrophages treated or not with pertussis toxin, an inhibitor of GPCR (G-protein couple receptor triggered Gαi nucleotide exchange. Despite previous findings, the level of basal autophagy, autophagic induction, autophagic flux, autophagic degradation and the anti-autophagic action in macrophages that lacked Gαi3, AGS3, or RGS19; or had been treated with pertussis toxin, were similar to controls. These results indicate that while Gαi signaling may impact autophagy in some cell types it does not in macrophages.

  3. Autophagic deficiency is related to steroidogenic decline in aged rat Leydig cells

    Institute of Scientific and Technical Information of China (English)

    Wei-Ren Li; Zhe-Zhu Gao; Zhong-Cheng Xin; Liang Chen; Zhi-Jie Chang; Hua Xin; Tao Liu; Yan-Quan Zhang; Guang-Yong Li; Feng Zhou; Yan-Qing Gong

    2011-01-01

    Late-onset hypogonadism (LOH) is closely related to secondary androgen deficiency in aged males,but the mechanism remains unclear.In this study,we found that reduced testosterone production in aged rat Leydig cells is associated with decreased autophagic activity.Primary rat Leydig cells and the TM3 mouse Leydig cell line were used to study the effect of autophagic deficiency on Leydig cell testosterone production.In Leydig cells from young and aged rats,treatment with wortmannin,an autophagy inhibitor,inhibited luteinising hormone (LH)-stimulated steroidogenic acute regulatory (StAR) protein expression and decreased testosterone production.In contrast,treatment with rapamycin,an autophagy activator,enhanced LH-stimulated steroidogenesis in Leydig cells from aged,but not young,rats.Intracellular reactive oxygen species (ROS) levels were increased in both young and aged Leydig cells treated with wortmannin but decreased only in aged Leydig cells treated with rapamycin.Furthermore,an increased level of ROS,induced by H2O2,resulted in LH-stimulated steroidogenic inhibition.Finally,knockdown of Beclin 1 decreased LH-stimulated StAR expression and testosterone production in TM3 mouse Leydig cells,which were associated with increased intracellular ROS level.These results suggested that autophagic deficiency is related to steroidogenic decline in aged rat Leydig cells,which might be influenced by intracellular ROS levels.

  4. MP Resulting in Autophagic Cell Death of Microglia through Zinc Changes against Spinal Cord Injury

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    Dingding Li

    2016-01-01

    Full Text Available Methylprednisolone pulse therapy (MPPT, as a public recognized therapy of spinal cord injury (SCI, is doubted recently, and the exact mechanism of MP on SCI is unclear. This study sought to investigate the exact effect of MP on SCI. We examined the effect of MP in a model of SCI in vivo and an LPS induced model in vitro. We found that administration of MP produced an increase in the Basso, Beattie, and Bresnahan scores and motor neurons counts of injured rats. Besides the number of activated microglia was apparently reduced by MP in vivo, and Beclin-1 dependent autophagic cell death of microglia was induced by MP in LPS induced model. At the same time, MP increases cellular zinc concentration and level of ZIP8, and TPEN could revert effect of MP on autophagic cell death of microglia. Finally, we have found that MP could inhibit NF-κβ in LPS induced model. These results show that the MP could result in autophagic cell death of microglia, which mainly depends on increasing cellular labile zinc, and may be associated with inhibition of NF-κβ, and that MP can produce neuroprotective effect in SCI.

  5. HTLV-1 Tax deregulates autophagy by recruiting autophagic molecules into lipid raft microdomains.

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    Ren, T; Takahashi, Y; Liu, X; Loughran, T P; Sun, S-C; Wang, H-G; Cheng, H

    2015-01-15

    The retroviral oncoprotein Tax from human T-cell leukemia virus type 1 (HTLV-1), an etiological factor that causes adult T-cell leukemia and lymphoma, has a crucial role in initiating T-lymphocyte transformation by inducing oncogenic signaling activation. We here report that Tax is a determining factor for dysregulation of autophagy in HTLV-1-transformed T cells and Tax-immortalized CD4 memory T cells. Tax facilitated autophagic process by activating inhibitor of κB (IκB) kinase (IKK) complex, which subsequently recruited an autophagy molecular complex containing Beclin1 and Bif-1 to the lipid raft microdomains. Tax engaged a crosstalk between IKK complex and autophagic molecule complex by directly interacting with both complexes, promoting assembly of LC3+ autophagosomes. Moreover, expression of lipid raft-targeted Bif-1 or Beclin1 was sufficient to induce formation of LC3+ autophagosomes, suggesting that Tax recruitment of autophagic molecules to lipid rafts is a dominant strategy to deregulate autophagy in the context of HTLV-1 transformation of T cells. Furthermore, depletion of autophagy molecules such as Beclin1 and PI3 kinase class III resulted in impaired growth of HTLV-1-transformed T cells, indicating a critical role of Tax-deregulated autophagy in promoting survival and transformation of virally infected T cells.

  6. Changes in chemical components of aerosol particles in different haze regions in China from 2006 to 2013 and contribution of meteorological factors

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    X. Y. Zhang

    2015-07-01

    Full Text Available Since individuals experienced persistent haze-fog events in January 2013 in central-eastern China, questions on factors causing differences in drastic changes in 2013 from those in adjacent years have been raised. Changes in major chemical components of aerosol particles over the years also remain unclear. The extent of meteorological factors contributed to such changes is yet to be determined. The study intends to present the changes in daily-based major water-soluble constituents, carbonaceous species and mineral aerosol in PM10 at 13 stations within different haze regions in China from 2006 to 2013, associated with specific meteorological conditions that are highly related with aerosol pollution (parameterized as an index called "PLAM". No obvious changes were found in annual mean concentrations of these various chemical components and PM10 in 2013, relative to 2012. By contrast, wintertime mass of these components were quite different, in Hua Bei Plain (HBP, sulfate, OC, nitrate, ammonium, EC, and mineral dust concentrations in winter were approximately 43, 55, 28, 23, 21 and 130 μg m−3, respectively; these masses were approximately two to four times higher than those in background mass, also exhibiting a decline during 2006 to 2010, and then a rise till 2013. The mass of these concentrations and PM10, except mineral, respectively increased by approximately 28 to 117 and 25 % in January 2013 compared with that in January 2012. Thus, persistent haze-fog events occurred in January 2013, and approximately 60 % of this increase in component concentrations from 2012 to 2013 can be attributed to severe meteorological conditions in the winter of 2013. In Yangtzi River Delta (YRD area, winter masses of these components, unlike HBP, did not significantly increase since 2010; PLAM was also maintained at a similar level without significant changes. In the Pearl River Delta (PRD area, the regional background concentrations of the major chemical

  7. Changes in chemical components of aerosol particles in different haze regions in China from 2006 to 2013 and contribution of meteorological factors

    Science.gov (United States)

    Zhang, X. Y.; Wang, J. Z.; Wang, Y. Q.; Liu, H. L.; Sun, J. Y.; Zhang, Y. M.

    2015-11-01

    Since there have been individual reports of persistent haze-fog events in January 2013 in central-eastern China, questions on factors causing the drastic differences in changes in 2013 from changes in adjacent years have been raised. Changes in major chemical components of aerosol particles over the years also remain unclear. The extent of meteorological factors contributing to such changes is yet to be determined. The study intends to present the changes in daily based major water-soluble constituents, carbonaceous species, and mineral aerosol in PM10 at 13 stations within different haze regions in China from 2006 to 2013, which are associated with specific meteorological conditions that are highly related to aerosol pollution (parameterized as an index called Parameter Linking Aerosol Pollution and Meteorological Elements - PLAM). No obvious changes were found in annual mean concentrations of these various chemical components and PM10 in 2013, relative to 2012. By contrast, wintertime mass of these components was quite different. In Hua Bei Plain (HBP), sulfate, organic carbon (OC), nitrate, ammonium, element carbon (EC), and mineral dust concentrations in winter were approximately 43, 55, 28, 23, 21, and 130 μg m-3, respectively; these masses were approximately 2 to 4 times higher than those in background mass, which also exhibited a decline during 2006 to 2010 and then a rise till 2013. The mass of these concentrations and PM10, except minerals, respectively, increased by approximately 28 to 117 % and 25 % in January 2013 compared with that in January 2012. Thus, persistent haze-fog events occurred in January 2013, and approximately 60 % of this increase in component concentrations from 2012 to 2013 can be attributed to severe meteorological conditions in the winter of 2013. In the Yangtze River Delta (YRD) area, winter masses of these components, unlike HBP, have not significantly increase since 2010; PLAM were also maintained at a similar level without

  8. CORRELATION AND PATH ANALYSIS OF SEED YIELD AND YIELD CONTRIBUTING COMPONENTS OF BLACKGRAM ( VIGNA MUNGO L. HEPPER UNDER RAINFED CONDITION FROM ANDHRA PRADESH, INDIA

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    G. Vijay Kumar

    2014-09-01

    Full Text Available Correlation coefficient and path analysis studies werecarried out with seventeen parents (fourteen lines and three testers resulting 42 F1crosses for fifteen yield contributing component characters. The phenotypic and genotypic correlation analysis revealed that seed yield was highly significantly and positively correlated with number of branches, number of clusters, number of pods per plant, number of seeds per plant pod weight, total biomass and also highly significantly and positively correlated among themselves. Path coefficient analysis for seed yield revealed that significant phenotypic and genotypic direct effect with seeds per plant, 100 seed weight, harvest index, pod weight and number of clusters per plant. Hence selection for these characters may be carried out in the field and lab for overall yield improvement in blackgram.

  9. Contributions of Two-Component Regulatory Systems, Alternative σ Factors, and Negative Regulators to Listeria monocytogenes Cold Adaptation and Cold Growth

    Science.gov (United States)

    Chan, Yvonne C.; Hu, Yuewei; Chaturongakul, Soraya; Files, Kali D.; Bowen, Barbara M.; Boor, Kathryn J.; Wiedmann, Martin

    2011-01-01

    The ability of Listeria monocytogenes to grow at refrigeration temperatures is critical for transmission of this foodborne pathogen. We evaluated the contributions of different transcriptional regulators and two-component regulatory systems to L. monocytogenes cold adaptation and cold growth. L. monocytogenes parent strain 10403S and selected isogenic null mutants in genes encoding four alternative σ factors (sigB, sigH, sigC, and sigL), two regulators of σB (rsbT and rsbV), two negative regulators (ctsR and hrcA), and 15 two-component response regulators were grown in brain heart infusion broth at 4°C with (i) a high-concentration starting inoculum (108 CFU/ml), (ii) a low-concentration starting inoculum (102 CFU/ml), and (iii) a high-concentration starting inoculum of cold-adapted cells. With a starting inoculum of 108 CFU/ml, null mutants in genes encoding selected alternative σ factors (ΔsigH, ΔsigC, and ΔsigL), a negative regulator (ΔctsR), regulators of σB (ΔrsbT and ΔrsbV), and selected two-component response regulators (ΔlisR, Δlmo1172, and Δlmo1060) had significantly reduced growth (P < 0.05) compared with the parent strain after 12 days at 4°C. The growth defect for ΔsigL was limited and was not confirmed by optical density (OD600) measurement data. With a starting inoculum of 102 CFU/ml and after monitoring growth at 4°C over 84 days, only the ΔctsR strain had a consistent but limited growth defect; the other mutant strains had either no growth defects or limited growth defects apparent at only one or two of the nine sampling points evaluated during the 84-day growth period (ΔsigB, ΔsigC, and Δlmo1172). With a 108 CFU/ml starting inoculum of cold-adapted cells, none of the mutant strains that had a growth defect when inoculation was performed with cells pregrown at 37°C had reduced growth as compared with the parent strain after 12 days at 4°C, suggesting a specific defect in the ability of these mutant strains to adapt to 4

  10. Protective effect of N-acetylcysteine against nicardipine hydrochloride-induced autophagic cell death of human vascular endothelial cells.

    Science.gov (United States)

    Ochi, Masanori; Tanaka, Yoshiyuki; Toyoda, Hiromu

    2015-01-01

    Nicardipine hydrochloride (NIC) injection has been widely used for emergency treatment of abnormally high blood pressure. However, NIC injection often causes severe peripheral vascular injury. The purpose of the present study was to reduce the NIC-induced cell injury in human vascular endothelial cells by use of clinical agents. The mechanism of NIC-induced cell injury was evaluated by time-lapse microscopic imaging, autophagosome staining with monodansylcadaverine, immunostaining of light chain 3 isoform B (LC-3B) and assessment of cell viability after exposure to NIC with or without an inhibitor of autophagosome formation (3-methyladenine, 3-MA). Results from autophagosome labeling and immunostaining of LC-3B revealed an increase of autophagosomes and LC-3B in NIC-treated cells. NIC-mediated reduction of cell viability was inhibited by 3-methyladenine. Moreover, we found that N-acetylcysteine (NAC) reduced NIC-induced cell injury in human vascular endothelial cells. These findings suggest that NIC causes severe peripheral venous irritation via induction of autophagic cell death and that inhibition of autophagy with NAC could contribute to the reduction of NIC-induced vascular injury.

  11. Dopaminergic Neuronal Loss, Reduced Neurite Complexity and Autophagic Abnormalities in Transgenic Mice Expressing G2019S Mutant LRRK2

    Science.gov (United States)

    Lin, Brian M.; Stafa, Klodjan; Kim, Jaekwang; Banerjee, Rebecca; Westerlund, Marie; Pletnikova, Olga; Glauser, Liliane; Yang, Lichuan; Liu, Ying; Swing, Deborah A.; Beal, M. Flint; Troncoso, Juan C.; McCaffery, J. Michael; Jenkins, Nancy A.; Copeland, Neal G.; Galter, Dagmar; Thomas, Bobby; Lee, Michael K.; Dawson, Ted M.; Dawson, Valina L.; Moore, Darren J.

    2011-01-01

    Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset, autosomal dominant familial Parkinson's disease (PD) and also contribute to idiopathic PD. LRRK2 mutations represent the most common cause of PD with clinical and neurochemical features that are largely indistinguishable from idiopathic disease. Currently, transgenic mice expressing wild-type or disease-causing mutants of LRRK2 have failed to produce overt neurodegeneration, although abnormalities in nigrostriatal dopaminergic neurotransmission have been observed. Here, we describe the development and characterization of transgenic mice expressing human LRRK2 bearing the familial PD mutations, R1441C and G2019S. Our study demonstrates that expression of G2019S mutant LRRK2 induces the degeneration of nigrostriatal pathway dopaminergic neurons in an age-dependent manner. In addition, we observe autophagic and mitochondrial abnormalities in the brains of aged G2019S LRRK2 mice and markedly reduced neurite complexity of cultured dopaminergic neurons. These new LRRK2 transgenic mice will provide important tools for understanding the mechanism(s) through which familial mutations precipitate neuronal degeneration and PD. PMID:21494637

  12. Dopaminergic neuronal loss, reduced neurite complexity and autophagic abnormalities in transgenic mice expressing G2019S mutant LRRK2.

    Directory of Open Access Journals (Sweden)

    David Ramonet

    Full Text Available Mutations in the leucine-rich repeat kinase 2 (LRRK2 gene cause late-onset, autosomal dominant familial Parkinson's disease (PD and also contribute to idiopathic PD. LRRK2 mutations represent the most common cause of PD with clinical and neurochemical features that are largely indistinguishable from idiopathic disease. Currently, transgenic mice expressing wild-type or disease-causing mutants of LRRK2 have failed to produce overt neurodegeneration, although abnormalities in nigrostriatal dopaminergic neurotransmission have been observed. Here, we describe the development and characterization of transgenic mice expressing human LRRK2 bearing the familial PD mutations, R1441C and G2019S. Our study demonstrates that expression of G2019S mutant LRRK2 induces the degeneration of nigrostriatal pathway dopaminergic neurons in an age-dependent manner. In addition, we observe autophagic and mitochondrial abnormalities in the brains of aged G2019S LRRK2 mice and markedly reduced neurite complexity of cultured dopaminergic neurons. These new LRRK2 transgenic mice will provide important tools for understanding the mechanism(s through which familial mutations precipitate neuronal degeneration and PD.

  13. Differential autophagic responses to nano-sized materials.

    Science.gov (United States)

    Popp, Lauren; Segatori, Laura

    2015-12-01

    Autophagy is a complex catabolic pathway that mediates degradation of excess or unwanted cytoplasmic components through the lysosome. Activated by environmental factors, such as nutrient depletion, and intracellular stimuli, such as proteotoxic stress, it provides a highly dynamic quality control mechanism to recycle cellular components, eliminate aberrant materials, and, ultimately, maintain cellular homeostasis. A growing body of evidence suggests that autophagy is also activated upon internalization of engineered nanomaterials, most likely as a protective response to what is perceived as foreign or toxic. This review describes the mechanisms of autophagy activation in response to naturally occurring and engineered nanomaterials. We provide a comprehensive analysis of the impact of nanomaterials on the lysosome-autophagy system, with particular emphasis on cellular markers associated with biocompatible and bioadverse outcomes of autophagy activation, such as clearance of toxic material and autophagy-associated cell death. Potential applications of the next-generation nanomaterials designed to interface with cellular clearance mechanisms with precisely tunable properties are also discussed.

  14. Contribution of water-soluble and insoluble components and their hydrophobic/hydrophilic subfractions to the reactive oxygen species-generating potential of fine ambient aerosols.

    Science.gov (United States)

    Verma, Vishal; Rico-Martinez, Roberto; Kotra, Neel; King, Laura; Liu, Jiumeng; Snell, Terry W; Weber, Rodney J

    2012-10-16

    Relative contributions of water- and methanol-soluble compounds and their hydrophobic/hydrophilic subfractions to the ROS (reactive oxygen species)-generating potential of ambient fine aerosols (D(p) Hydrophobic and hydrophilic fractions were then subsequently segregated via a C-18 solid phase extraction column. The DTT assay response was significantly higher for the methanol extract, and for both extracts a substantial fraction of PM oxidative potential was associated with the hydrophobic compounds as evident from a substantial attenuation in DTT response after passing PM extracts through the C-18 column (64% for water and 83% for methanol extract; both median values). The DTT activities of water and methanol extracts were correlated with the water-soluble (R = 0.86) and water-insoluble organic carbon (R = 0.94) contents of the PM, respectively. Brown carbon (BrC), which predominantly represents the hydrophobic organic fraction (referred to as humic-like substances, HULIS), was also correlated with DTT activity in both the water (R = 0.78) and methanol extracts (R = 0.83). Oxidative potential was not correlated with any metals measured in the extracts. These findings suggest that the hydrophobic components of both water-soluble and insoluble organic aerosols substantially contribute to the oxidative properties of ambient PM. Further investigation of these hydrophobic organic compounds could help identify sources of a significant fraction of ambient aerosol toxicity.

  15. Potential contribution of planktonic components to ammonium cycling in the coastal area off central-southern Chile during non-upwelling conditions

    Science.gov (United States)

    Molina, Veronica; Morales, Carmen E.; Farías, Laura; Cornejo, Marcela; Graco, Michelle; Eissler, Yoanna; Cuevas, Luis A.

    2012-01-01

    The potential contributions of different microbial components (consumption and production, and carbon assimilation associated with photolithotrophic and chemolithoautotrophic (nitrification) metabolisms in the water column were performed. Despite low water column concentrations of ammonium in wintertime, intense ammonium transformations were registered. Prokaryotes (or bacterioplankton) contributed most to ammonium generation rates over the entire water column; these rates increased with depth (0.4-3.1 μM d -1). In surface waters (10 m depth), aerobic ammonium oxidation (potentially by Bacteria and Archaea) was the dominant consumption process (average 0.7 μM d -1) whereas in the subsurface layer (20 and 50 m depth), unexpectedly, eukaryotes accounted for most of its consumption (average 2.1 μM d -1). Nitrification oxidized an important proportion of the ammonium in both layers (from 25% to 100%) and provided regenerated nitrate. The integrated water column rates of chemosynthesis (0.005 g C m -2 d -1) represented a large proportion (51%) of the total dark carbon fixation during the non-upwelling season when integrated rates of photosynthesis are relatively low (0.42 g C m -2 d -1) and microbial food webs dominate the transfer of carbon within this coastal system.

  16. The autophagic- lysosomal pathway determines the fate of glial cells under manganese- induced oxidative stress conditions.

    Science.gov (United States)

    Gorojod, R M; Alaimo, A; Porte Alcon, S; Pomilio, C; Saravia, F; Kotler, M L

    2015-10-01

    Manganese (Mn) overexposure is frequently associated with the development of a neurodegenerative disorder known as Manganism. The Mn-mediated generation of reactive oxygen species (ROS) promotes cellular damage, finally leading to apoptotic cell death in rat astrocytoma C6 cells. In this scenario, the autophagic pathway could play an important role in preventing cytotoxicity. In the present study, we found that Mn induced an increase in the amount and total volume of acidic vesicular organelles (AVOs), a process usually related to the activation of the autophagic pathway. Particularly, the generation of enlarged AVOs was a ROS- dependent event. In this report we demonstrated for the first time that Mn induces autophagy in glial cells. This conclusion emerged from the results obtained employing a battery of autophagy markers: a) the increase in LC3-II expression levels, b) the formation of autophagic vesicles labeled with monodansylcadaverine (MDC) or LC3 and, c) the increase in Beclin 1/ Bcl-2 and Beclin 1/ Bcl-X(L) ratio. Autophagy inhibition employing 3-MA and mAtg5(K130R) resulted in decreased cell viability indicating that this event plays a protective role in Mn- induced cell death. In addition, mitophagy was demonstrated by an increase in LC3 and TOM-20 colocalization. On the other hand, we proposed the occurrence of lysosomal membrane permeabilization (LMP) based in the fact that cathepsins B and D activities are essential for cell death. Both cathepsin B inhibitor (Ca-074 Me) or cathepsin D inhibitor (Pepstatin A) completely prevented Mn- induced cytotoxicity. In addition, low dose of Bafilomycin A1 showed a similar effect, a finding that adds evidence about the lysosomal role in Mn cytotoxicity. Finally, in vivo experiments demonstrated that Mn induces injury and alters LC3 expression levels in rat striatal astrocytes. In summary, our results demonstrated that autophagy is activated to counteract the harmful effect caused by Mn. These data is valuable to

  17. Interactions between autophagic and endo-lysosomal markers in endothelial cells.

    Science.gov (United States)

    Oeste, Clara L; Seco, Esther; Patton, Wayne F; Boya, Patricia; Pérez-Sala, Dolores

    2013-05-01

    Autophagic and endo-lysosomal degradative pathways are essential for cell homeostasis. Availability of reliable tools to interrogate these pathways is critical to unveil their involvement in physiology and pathophysiology. Although several probes have been recently developed to monitor autophagic or lysosomal compartments, their specificity has not been validated through co-localization studies with well-known markers. Here, we evaluate the selectivity and interactions between one lysosomal (Lyso-ID) and one autophagosomal (Cyto-ID) probe under conditions modulating autophagy and/or endo-lysosomal function in live cells. The probe for acidic compartments Lyso-ID was fully localized inside vesicles positive for markers of late endosome-lysosomes, including Lamp1-GFP and GFP-CINCCKVL. Induction of autophagy by amino acid deprivation in bovine aortic endothelial cells caused an early and potent increase in the fluorescence of the proposed autophagy dye Cyto-ID. Cyto-ID-positive compartments extensively co-localized with the autophagosomal fluorescent reporter RFP-LC3, although the time and/or threshold for organelle detection was different for each probe. Interestingly, use of Cyto-ID in combination with Lysotracker Red or Lyso-ID allowed the observation of structures labeled with either one or both probes, the extent of co-localization increasing upon treatment with protease inhibitors. Inhibition of the endo-lysosomal pathway with chloroquine or U18666A resulted in the formation of large Cyto-ID and Lyso-ID-positive compartments. These results constitute the first assessment of the selectivity of Cyto-ID and Lyso-ID as probes for the autophagic and lysosomal pathways, respectively. Our observations show that these probes can be used in combination with protein-based markers for monitoring the interactions of both pathways in live cells.

  18. Developmental changes in polyamines and autophagic marker levels in normal and growth-restricted fetal pigs.

    Science.gov (United States)

    Zhu, Y H; Lin, G; Dai, Z L; Zhou, T J; Yuan, T L; Feng, C P; Chen, F; Wu, G Y; Wang, J J

    2015-07-01

    Polyamines are essential for embryonic and fetal survival, growth, and development. Additionally, polyamines may induce autophagy in mammalian cells. However, little is known about the availability of polyamines or autophagy in the porcine conceptus with intrauterine growth restriction (IUGR). The present study was performed to evaluate the developmental changes of polyamine concentrations in IUGR and normal porcine fetuses as well as autophagic marker levels in the fetal intestinal mucosa during the second half of gestation when most fetal growth occurs. Allantoic fluid (ALF), amniotic fluid (AMF), umbilical vein, and the small-intestinal mucosa were obtained from both IUGR and normal fetal pigs at d 60, 90, and 110 of gestation. Concentrations of polyamines in fetal fluids as well as protein abundances of microtubule-associated protein light chain 3B (LC3B), an autophagic marker, in the fetal small-intestinal mucosa were determined. Concentrations of polyamines varied greatly in different fetal compartments and changed substantially with advancing gestation. Concentrations of polyamines in IUGR fetal fluids and the small-intestinal mucosa were markedly different from those in their normal counterparts at d 60 and 90 of gestation, whereas most of the differences were not detected by late (d 110) gestation. Specifically, polyamine levels were lower in the umbilical vein plasma but higher in ALF and AMF from IUGR fetuses. Furthermore, enhanced levels of an autophagic marker were observed in the small-intestinal mucosa of IUGR fetuses throughout mid and late gestation in association with abnormal spermidine levels in fetal plasma. These findings support the notion that enhanced autophagy may be an important survival mechanism in IUGR fetuses. Collectively, our findings provide a new framework for future studies to define the roles for polyamines in the prevention and treatment of IUGR in both human medicine and animal production.

  19. Cyclic Mechanical Stretching Induces Autophagic Cell Death in Tenofibroblasts Through Activation of Prostaglandin E2 Production

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    Hua Chen

    2015-04-01

    Full Text Available Background/Aims: Autophagic cell death has recently been implicated in the pathophysiology of tendinopathy. Prostaglandin E2 (PGE2, a known inflammatory mediator of tendinitis, inhibits tenofibroblast proliferation in vitro; however, the underlying mechanism is unclear. The present study investigated the relationship between PGE2 production and autophagic cell death in mechanically loaded human patellar tendon fibroblasts (HPTFs in vitro. Methods: Cultured HPTFs were subjected to exogenous PGE2 treatment or repetitive cyclic mechanical stretching. Cell death was determined by flow cytometry with acridine orange/ethidium bromide staining. Induction of autophagy was assessed by autophagy markers including the formation of autophagosomes and autolysosomes (by electron microscopy, AO staining, and formation of GPF-LC3-labeled vacuoles and the expression of LC3-II and BECN1 (by western blot. Stretching-induced PGE2 release was determined by ELISA. Results: Exogenous PGE2 significantly induced cell death and autophagy in HPTFs in a dose-dependent manner. Blocking autophagy using inhibitors 3-methyladenine and chloroquine, or small interfering RNAs against autophagy genes Becn-1 and Atg-5 prevented PGE2-induced cell death. Cyclic mechanical stretching at 8% and 12% magnitudes for 24 h significantly stimulated PGE2 release by HPTFs in a magnitude-dependent manner. In addition, mechanical stretching induced autophagy and cell death. Blocking PGE2 production using COX inhibitors indomethacin and celecoxib significantly reduced stretching-induced autophagy and cell death. Conclusion: Taken together, cyclic mechanical stretching induces autophagic cell death in tenofibroblasts through activation of PGE2 production.

  20. Contribution of β-phenethylamine, a component of chocolate and wine, to dopaminergic neurodegeneration: implications for the pathogenesis of Parkinson's disease.

    Science.gov (United States)

    Borah, Anupom; Paul, Rajib; Mazumder, Muhammed Khairujjaman; Bhattacharjee, Nivedita

    2013-10-01

    While the cause of dopaminergic neuronal cell death in Parkinson's disease (PD) is not yet understood, many endogenous molecules have been implicated in its pathogenesis. β-phenethylamine (β-PEA), a component of various food items including chocolate and wine, is an endogenous molecule produced from phenylalanine in the brain. It has been reported recently that long-term administration of β-PEA in rodents causes neurochemical and behavioral alterations similar to that produced by parkinsonian neurotoxins. The toxicity of β-PEA has been linked to the production of hydroxyl radical ((·)OH) and the generation of oxidative stress in dopaminergic areas of the brain, and this may be mediated by inhibition of mitochondrial complex-I. Another significant observation is that administration of β-PEA to rodents reduces striatal dopamine content and induces movement disorders similar to those of parkinsonian rodents. However, no reports are available on the extent of dopaminergic neuronal cell death after administration of β-PEA. Based on the literature, we set out to establish β-PEA as an endogenous molecule that potentially contributes to the progressive development of PD. The sequence of molecular events that could be responsible for dopaminergic neuronal cell death in PD by consumption of β-PEA-containing foods is proposed here. Thus, long-term over-consumption of food items containing β-PEA could be a neurological risk factor having significant pathological consequences.

  1. Blocking autophagic flux enhances matrine-induced apoptosis in human hepatoma cells.

    Science.gov (United States)

    Wang, Li; Gao, Chun; Yao, Shukun; Xie, Bushan

    2013-11-25

    Autophagy, a self-defense mechanism, has been found to be associated with drug resistance in hepatocellular carcinoma (HCC). Our study was designed to investigate the role and related mechanisms of autophagy in matrine-induced apoptosis in hepatoma cells of HepG2 and Bel7402. Cell apoptosis was detected by flow cytometry analysis (Annexin V-FITC/PI double-staining assay), the activity and activating cleavages of caspase-3, -8, and -9. MTT assay and colony forming assay were used to assess the effect of matrine on growth and proliferation of HCC cells. Autophagic flux in HCC cells was analyzed using the expression of LC3BI/II and p62/SQSTM1, GFP-LC3 transfection, and transmission electron microscopy. Moreover, regarding to the associated mechanisms, the effects of matrine on the phosphoinositide 3-kinase/AKT/mTOR pathway and beclin-1 were studied. Our results showed that: (1) both autophagy and apoptosis could be induced by treatment with matrine; (2) using the autophagic inhibitor chloroquine and beclin-1 small-interfering RNA, cell apoptosis induced by matrine could be enhanced in a caspase-dependent manner; and (3) autophagy was induced via inhibition of PI3K/AKT/mTOR pathway and up-regulation of beclin-1. In conclusion, inhibition of autophagy could enhance matrine-induced apoptosis in human hepatoma cells.

  2. Blocking Autophagic Flux Enhances Matrine-Induced Apoptosis in Human Hepatoma Cells

    Directory of Open Access Journals (Sweden)

    Li Wang

    2013-11-01

    Full Text Available Autophagy, a self-defense mechanism, has been found to be associated with drug resistance in hepatocellular carcinoma (HCC. Our study was designed to investigate the role and related mechanisms of autophagy in matrine-induced apoptosis in hepatoma cells of HepG2 and Bel7402. Cell apoptosis was detected by flow cytometry analysis (Annexin V–FITC/PI double-staining assay, the activity and activating cleavages of caspase-3, -8, and -9. MTT assay and colony forming assay were used to assess the effect of matrine on growth and proliferation of HCC cells. Autophagic flux in HCC cells was analyzed using the expression of LC3BI/II and p62/SQSTM1, GFP-LC3 transfection, and transmission electron microscopy. Moreover, regarding to the associated mechanisms, the effects of matrine on the phosphoinositide 3-kinase/AKT/mTOR pathway and beclin-1 were studied. Our results showed that: (1 both autophagy and apoptosis could be induced by treatment with matrine; (2 using the autophagic inhibitor chloroquine and beclin-1 small-interfering RNA, cell apoptosis induced by matrine could be enhanced in a caspase-dependent manner; and (3 autophagy was induced via inhibition of PI3K/AKT/mTOR pathway and up-regulation of beclin-1. In conclusion, inhibition of autophagy could enhance matrine-induced apoptosis in human hepatoma cells.

  3. Monitoring autophagic flux using Ref(2)P, the Drosophila p62 ortholog.

    Science.gov (United States)

    DeVorkin, Lindsay; Gorski, Sharon M

    2014-09-02

    Human p62, also known as Sequestome-1 (SQSTM1), is a multifunctional scaffold protein that contains many domains, including a Phox/Bem1P (PB1) multimerization domain, an ubiquitin-associated (UBA) domain, and a light chain 3 (LC3) recognition sequence. p62 binds ubiquitinated proteins and targets them for degradation by the proteasome. In addition, p62 directly binds LC3; this may serve as a mechanism to deliver ubiquitinated proteins for degradation by autophagy. During this process, p62 itself is degraded. The inhibition of autophagy leads to the accumulation of p62, indicating that it can be used as a marker of autophagic flux. Ref(2)P (refractory to sigma P), the Drosophila ortholog of p62, is also required for the formation of ubiquitinated protein aggregates. Ref(2)P contains a putative LC3-interacting region, and genetic inhibition of autophagy in Drosophila leads to the accumulation of Ref(2)P protein levels. Thus, like p62, Ref(2)P may serve as a marker of autophagic flux. Here we provide two procedures to examine Ref(2)P protein levels in Drosophila ovaries.

  4. Precise temporal regulation of roughest is required for correct salivary gland autophagic cell death in Drosophila.

    Science.gov (United States)

    Simon, Claudio R; Moda, Livia M R; Octacilio-Silva, Shirlei; Anhezini, Lucas; Machado-Gitai, Luciana C H; Ramos, Ricardo Guelerman P

    2009-07-01

    The Drosophila roughest (rst) locus encodes an immunoglobulin superfamily transmembrane glycoprotein implicated in a variety of embryonic and postembryonic developmental processes. Here we demonstrate a previously unnoticed role for this gene in the autophagic elimination of larval salivary glands during early pupal stages by showing that overexpression of the Rst protein ectodomain in early pupa leads to persistence of salivary glands up to at least 12 hours after head eversion, although with variable penetrance. The same phenotype is observed in individuals carrying the dominant regulatory allele rst(D), but not in loss of function alleles. Analysis of persistent glands at the ultrastructural level showed that programmed cell death starts at the right time but is arrested at an early stage of the process. Finally we describe the expression pattern and intracellular distribution of Rst in wild type and rst(D) mutants, showing that its downregulation in salivary glands at the beginning of pupal stage is an important factor in the correct implementation of the autophagic program of this tissue in space and time.

  5. 5-ALA mediated photodynamic therapy induces autophagic cell death via AMP-activated protein kinase

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    Lin Yu-Hsin

    2010-04-01

    Full Text Available Abstract Photodynamic therapy (PDT has been developed as an anticancer treatment, which is based on the tumor-specific accumulation of a photosensitizer that induces cell death after irradiation of light with a specific wavelength. Depending on the subcellular localization of the photosensitizer, PDT could trigger various signal transduction cascades and induce cell death such as apoptosis, autophagy, and necrosis. In this study, we report that both AMP-activated protein kinase (AMPK and mitogen-activated protein kinase (MAPK signaling cascades are activated following 5-aminolevulinic acid (ALA-mediated PDT in both PC12 and CL1-0 cells. Although the activities of caspase-9 and -3 are elevated, the caspase inhibitor zVAD-fmk did not protect cells against ALA-PDT-induced cell death. Instead, autophagic cell death was found in PC12 and CL1-0 cells treated with ALA-PDT. Most importantly, we report here for the first time that it is the activation of AMPK, but not MAPKs that plays a crucial role in mediating autophagic cell death induced by ALA-PDT. This novel observation indicates that the AMPK pathway play an important role in ALA-PDT-induced autophagy.

  6. Naringin Attenuates Autophagic Stress and Neuroinflammation in Kainic Acid-Treated Hippocampus In Vivo

    Directory of Open Access Journals (Sweden)

    Kyoung Hoon Jeong

    2015-01-01

    Full Text Available Kainic acid (KA is well known as a chemical compound to study epileptic seizures and neuronal excitotoxicity. KA-induced excitotoxicity causes neuronal death by induction of autophagic stress and microglia-derived neuroinflammation, suggesting that the control of KA-induced effects may be important to inhibit epileptic seizures with neuroprotection. Naringin, a flavonoid in grapefruit and citrus fruits, has anti-inflammatory and antioxidative activities, resulting in neuroprotection in animal models from neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease. In the present study, we examined its beneficial effects involved in antiautophagic stress and antineuroinflammation in the KA-treated hippocampus. Our results showed that naringin treatment delayed the onset of KA-induced seizures and decreased the occurrence of chronic spontaneous recurrent seizures (SRS in KA-treated mice. Moreover, naringin treatment protected hippocampal CA1 neurons in the KA-treated hippocampus, ameliorated KA-induced autophagic stress, confirmed by the expression of microtubule-associated protein light chain 3 (LC3, and attenuated an increase in tumor necrosis factor-α (TNFα in activated microglia. These results suggest that naringin may have beneficial effects of preventing epileptic events and neuronal death through antiautophagic stress and antineuroinflammation in the hippocampus in vivo.

  7. Hydrogen peroxide impairs autophagic flux in a cell model of nonalcoholic fatty liver disease

    Energy Technology Data Exchange (ETDEWEB)

    Jiang, Pengtao [National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101 (China); University of Chinese Academy of Sciences, 19 Yuquan Road, Shijingshan District, Beijing 100049 (China); Huang, Zhen [Department of Abdominal Surgical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences, 17 Panjiayuan Nanli, Chaoyang District, Beijing 100021 (China); Zhao, Hong, E-mail: zhaohong9@sina.com [Department of Abdominal Surgical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences, 17 Panjiayuan Nanli, Chaoyang District, Beijing 100021 (China); Wei, Taotao, E-mail: weitt@moon.ibp.ac.cn [National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101 (China)

    2013-04-19

    Highlights: •Free fatty acids exposure induces elevated autophagy. •H{sub 2}O{sub 2} inhibits autophagic flux through impairing the fusion between autophagosomes and lysosomes. •Inhibition of autophagy potentiates H{sub 2}O{sub 2}-induced cell death. -- Abstract: Nonalcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease, but the pathogenesis of NAFLD is not fully clear. The aim of this study was to determine whether autophagy plays a role in the pathogenesis of NAFLD. We found that the levels of autophagy were elevated in hepatoma cells upon exposure to free fatty acids, as confirmed by the increase in the number of autophagosomes. However, exposure of hepatoma cells to H{sub 2}O{sub 2} and TNF-α, two typical “second hit” factors, increased the initiation of autophagy but inhibited the autophagic flux. The inhibition of autophagy sensitized cells to pro-apoptotic stimuli. Taken together, our results suggest that autophagy acts as a protective mechanism in the pathogenesis of NAFLD and that impairment of autophagy might induce more severe lesions of the liver. These findings will be a benefit to the understanding of the pathogenesis of NAFLD and might suggest a strategy for the prevention and cure of NAFLD.

  8. Staphylococcal lipoteichoic acid promotes osteogenic differentiation of mouse mesenchymal stem cells by increasing autophagic activity.

    Science.gov (United States)

    Liu, Xin; Wang, Yuan; Cao, Zhen; Dou, Ce; Bai, Yun; Liu, Chuan; Dong, Shiwu; Fei, Jun

    2017-02-16

    This study sought to explore the effect of staphylococcal lipoteichoic acid (LTA) on autophagy in mouse mesenchymal stem cells (MSCs), and then influence osteogenesis through the change of autophagy. C3H10T1/2 cells were induced by osteogenic medium with the treatment of LTA at different concentrations (1, 5, 10 μg/mL); 3-methyladenine (3-MA) were used as the autophagy inhibitor, and rapamycin (rapamycin, Rap) were used to activate autophagy; the effects on osteogenesis were detected by alkaline phosphatase staining, alizarin red staining, real-time quantitative PCR, and western blotting; autophagic activity was investigated by the expression of LC3-Ⅱand p62 proteins. Compared with control group, the expression of osteogenesis markers was significantly up-regulated with the LTA treatment on the mRNA and protein level; the positive rate of alkaline phosphatase was enhanced in the LTA groups; and the formation of calcium nodules was increased simultaneously. The expression of LC3-Ⅱ protein was increased in LTA groups, while the expression of p62 protein was decreased. Inhibition of autophagy significantly reduced the effect of LTA on osteogenesis of MSCs; the promotion of LTA on osteogenic differentiation was further enhanced when adding rapamycin to activate autophagic activity. It provides new insight of prevention and treatment for bone infection.

  9. Features of autophagic cell death in Plasmodium liver-stage parasites.

    Science.gov (United States)

    Eickel, Nina; Kaiser, Gesine; Prado, Monica; Burda, Paul-Christian; Roelli, Matthias; Stanway, Rebecca R; Heussler, Volker T

    2013-04-01

    Analyzing molecular determinants of Plasmodium parasite cell death is a promising approach for exploring new avenues in the fight against malaria. Three major forms of cell death (apoptosis, necrosis and autophagic cell death) have been described in multicellular organisms but which cell death processes exist in protozoa is still a matter of debate. Here we suggest that all three types of cell death occur in Plasmodium liver-stage parasites. Whereas typical molecular markers for apoptosis and necrosis have not been found in the genome of Plasmodium parasites, we identified genes coding for putative autophagy-marker proteins and thus concentrated on autophagic cell death. We characterized the Plasmodium berghei homolog of the prominent autophagy marker protein Atg8/LC3 and found that it localized to the apicoplast. A relocalization of PbAtg8 to autophagosome-like vesicles or vacuoles that appear in dying parasites was not, however, observed. This strongly suggests that the function of this protein in liver-stage parasites is restricted to apicoplast biology.

  10. Isogambogenic acid induces apoptosis-independent autophagic cell death in human non-small-cell lung carcinoma cells.

    Science.gov (United States)

    Yang, Jianhong; Zhou, Yongzhao; Cheng, Xia; Fan, Yi; He, Shichao; Li, Shucai; Ye, Haoyu; Xie, Caifeng; Wu, Wenshuang; Li, Chunyan; Pei, Heying; Li, Luyuan; Wei, Zhe; Peng, Aihua; Wei, Yuquan; Li, Weimin; Chen, Lijuan

    2015-01-09

    To overcome drug resistance caused by apoptosis deficiency in patients with non-small cell lung carcinoma (NSCLC), there is a need to identify other means of triggering apoptosis-independent cancer cell death. We are the first to report that isogambogenic acid (iso-GNA) can induce apoptosis-independent autophagic cell death in human NSCLC cells. Several features of the iso-GNA-treated NSCLC cells indicated that iso-GNA induced autophagic cell death. First, there was no evidence of apoptosis or cleaved caspase 3 accumulation and activation. Second, iso-GNA treatment induced the formation of autophagic vacuoles, increased LC3 conversion, caused the appearance of autophagosomes and increased the expression of autophagy-related proteins. These findings provide evidence that iso-GNA induces autophagy in NSCLC cells. Third, iso-GNA-induced cell death was inhibited by autophagic inhibitors or by selective ablation of Atg7 and Beclin 1 genes. Furthermore, the mTOR inhibitor rapamycin increased iso-GNA-induced cell death by enhancing autophagy. Finally, a xenograft model provided additional evidence that iso-GNA exhibited anticancer effect through inducing autophagy-dependent cell death in NSCLC cells. Taken together, our results demonstrated that iso-GNA exhibited an anticancer effect by inducing autophagy-dependent cell death in NSCLC cells, which may be an effective chemotherapeutic agent that can be used against NSCLC in a clinical setting.

  11. Silencing of MicroRNA-21 confers the sensitivity to tamoxifen and fulvestrant by enhancing autophagic cell death through inhibition of the PI3K-AKT-mTOR pathway in breast cancer cells.

    Science.gov (United States)

    Yu, Xinfeng; Li, Ruilian; Shi, Wenna; Jiang, Tao; Wang, Yufei; Li, Cong; Qu, Xianjun

    2016-02-01

    Tamoxifen (TAM) and fulvestrant (FUL) represent the major adjuvant therapy to estrogen receptor-alpha positive (ER(+)) breast cancer patients. However, endocrine resistance to TAM and FUL is a great impediment for successful treatment. We hypothesized that miR-21 might alter the sensitivity of breast cancer cells to TAM or FUL by regulating cell autophagy. Using the ER(+) breast cancer cells, we knockdown miR-21.by transfection with miR-21 inhibitor, then the cells were exposed to TAM or FUL and the percentages of apoptosis and autophagy were determined. Knockdown of miR-21 significantly increased the TAM or FUL-induced apoptosis in ER(+) breast cancer cells. Further, silencing of miR-21 in MCF-7 cells enhanced cell autophagy at both basal and TAM or FUL-induced level. The increase of autophagy in miR-21-knockdown MCF-7 cells was also indicated by increase of beclin-1, LC3-II and increased GFP-LC3 dots. Importantly, knockdown of miR-21 contributed to autophagic cell death, which is responsible for part of TAM induced cell death in miR-21 inhibitor-transfected cells. Further analysis suggested that miR-21 inhibitor enhance autophagic cell death through inhibition of PI3K-AKT-mTOR pathway. MiR-21 coordinated the function of autophagy and apoptosis by targeting Phosphatase and tensin homolog (PTEN) through inhibition of PI3K-AKT-mTOR pathway. In conclusion, silencing of miR-21 increased the sensitivity of ER(+) breast cancer cells to TAM or FUL by increasing autophagic cell death. Targeting autophagy-related miRNAs is a potential strategy for overcoming endocrine resistance to TAM and FUL.

  12. The convergent point of the endocytic and autophagic pathways in leydig cells

    Institute of Scientific and Technical Information of China (English)

    YIJING; XUEMINGTANG

    1999-01-01

    Endocytic tracers and marker enzyme of lysosomes were used in the present study to analyze the processes of autophagocytosis and endocytosis,and the convergent point of these two pathways in Leydig cells.The endocytic and autophagic compartments can be easily identified in Leydig cells,which makes easier to difine the stages of two pathways than was possible before.The evidences indicated that late endosomes (dense MVBs) deliver their endocytosed gold tracers together with lysosomal enzymes to the early autophagosomes and they are the convergent point of the two pathways.During this convergent process,the early autophadosomes transform into late autophagosomes and the late endosomes transform into mature lysosomes.

  13. The tricyclic antidepressant imipramine induces autophagic cell death in U-87MG glioma cells.

    Science.gov (United States)

    Jeon, Seung-Hyun; Kim, Se Hyun; Kim, Yeni; Kim, Yong Sik; Lim, Yoongho; Lee, Young Han; Shin, Soon Young

    2011-09-23

    In this study, we investigated the antitumor effects of the tricyclic antidepressant 3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N-dimethylpropan-1-amine (imipramine) on glioma cells. We found that exposure of U-87MG cells to imipramine resulted in the inhibition of PI3K/Akt/mTOR signaling, reduction of clonogenicity, and induction of cell death. Imipramine stimulated the formation of acidic vesicular organelles, the conversion of LC3-I to LC3-II, and the redistribution of LC3 to autophagosomes, suggesting that it stimulates the progression of autophagy. It did not, however, induce apoptosis. We further showed that knockdown of Beclin-1 using siRNA abrogated imipramine-induced cell death. These results suggest that imipramine exerts antitumor effects on PTEN-null U-87MG human glioma cells by inhibiting PI3K/Akt/mTOR signaling and by inducing autophagic cell death.

  14. Inhibition of autophagic flux by salinomycin results in anti-cancer effect in hepatocellular carcinoma cells.

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    Johannes Klose

    Full Text Available Salinomycin raised hope to be effective in anti-cancer therapies due to its capability to overcome apoptosis-resistance in several types of cancer cells. Recently, its effectiveness against human hepatocellular carcinoma (HCC cells both in vitro and in vivo was demonstrated. However, the mechanism of action remained unclear. Latest studies implicated interference with the degradation pathway of autophagy. This study aimed to determine the impact of Salinomycin on HCC-autophagy and whether primary human hepatocytes (PHH likewise are affected. Following exposure of HCC cell lines HepG2 and Huh7 to varying concentrations of Salinomycin (0-10 µM, comprehensive analysis of autophagic activity using western-blotting and flow-cytometry was performed. Drug effects were analyzed in the settings of autophagy stimulation by starvation or PP242-treatment and correlated with cell viability, proliferation, apoptosis induction, mitochondrial mass accumulation and reactive oxygen species (ROS formation. Impact on apoptosis induction and cell function of PHH was analyzed. Constitutive and stimulated autophagic activities both were effectively suppressed in HCC by Salinomycin. This inhibition was associated with dysfunctional mitochondria accumulation, increased apoptosis and decreased proliferation and cell viability. Effects of Salinomycin were dose and time dependent and could readily be replicated by pharmacological and genetic inhibition of HCC-autophagy alone. Salinomycin exposure to PHH resulted in transient impairment of synthesis function and cell viability without apoptosis induction. In conclusion, our data suggest that Salinomycin suppresses late stages of HCC-autophagy, leading to impaired recycling and accumulation of dysfunctional mitochondria with increased ROS-production all of which are associated with induction of apoptosis.

  15. Inhibition of autophagic flux by salinomycin results in anti-cancer effect in hepatocellular carcinoma cells.

    Science.gov (United States)

    Klose, Johannes; Stankov, Metodi V; Kleine, Moritz; Ramackers, Wolf; Panayotova-Dimitrova, Diana; Jäger, Mark D; Klempnauer, Jürgen; Winkler, Michael; Bektas, Hüseyin; Behrens, Georg M N; Vondran, Florian W R

    2014-01-01

    Salinomycin raised hope to be effective in anti-cancer therapies due to its capability to overcome apoptosis-resistance in several types of cancer cells. Recently, its effectiveness against human hepatocellular carcinoma (HCC) cells both in vitro and in vivo was demonstrated. However, the mechanism of action remained unclear. Latest studies implicated interference with the degradation pathway of autophagy. This study aimed to determine the impact of Salinomycin on HCC-autophagy and whether primary human hepatocytes (PHH) likewise are affected. Following exposure of HCC cell lines HepG2 and Huh7 to varying concentrations of Salinomycin (0-10 µM), comprehensive analysis of autophagic activity using western-blotting and flow-cytometry was performed. Drug effects were analyzed in the settings of autophagy stimulation by starvation or PP242-treatment and correlated with cell viability, proliferation, apoptosis induction, mitochondrial mass accumulation and reactive oxygen species (ROS) formation. Impact on apoptosis induction and cell function of PHH was analyzed. Constitutive and stimulated autophagic activities both were effectively suppressed in HCC by Salinomycin. This inhibition was associated with dysfunctional mitochondria accumulation, increased apoptosis and decreased proliferation and cell viability. Effects of Salinomycin were dose and time dependent and could readily be replicated by pharmacological and genetic inhibition of HCC-autophagy alone. Salinomycin exposure to PHH resulted in transient impairment of synthesis function and cell viability without apoptosis induction. In conclusion, our data suggest that Salinomycin suppresses late stages of HCC-autophagy, leading to impaired recycling and accumulation of dysfunctional mitochondria with increased ROS-production all of which are associated with induction of apoptosis.

  16. Contribution to the determination of priority constructive influences on the hot crack initiation of welded components; Beitrag zur Ermittlung vorrangig konstruktiver Einflussgroessen auf die Heissrissinitiierung an geschweissten Bauteilen

    Energy Technology Data Exchange (ETDEWEB)

    Gollnow, Christian

    2015-07-01

    The previous research results do not allow a general hot crack characterisation although a variety of experimental and numerical knowledge is available. The reason for this is mainly the large number of influencing factors that complicate a complete description of the hot cracking phenomenon and especially solidification cracking. The hot crack formation and thus the solidification crack initiation can be described by the interaction of process, metallurgy and design. However, the literature examination shows that in the solidifaction crack characterisation the influence of the design aspect is often underestimated. The pre-stresses of the structural components is up to now not considered as an essential cause for the formation of solidification cracks. The evaluation of the influence of the various parameters is presented partly inconsistent. In addition, the targeted presentation of the design influence with respect to the solidification cracks in the weld is because the limited transferability of the various component-specific stresses on a laboratory scale and thus to the respective hot cracking tests restricted. Hence, the difficulty to transfer the results between laboratory specimen and component as well as the general hot crack characterisation is given. In this work the different types of stresses from the component welding in the laboratory and to quantify experimentally the solidification crack critical values, displacements and displacement rates were detected. In this regard external loaded hot cracking tests were carried out by using the advantages of contactless measurement techniques close to the weld and to analyse the welding process with respect to various local and global design-specific factors influencing the formation of solidification cracks in high alloyed steel. These investigations were performed on austenitic (1.4828) and ferritic (1.4509) materials with different mechanical and technological properties. To reflect the praxis relevant

  17. CRF receptor 1 antagonism and brain distribution of active components contribute to the ameliorative effect of rikkunshito on stress-induced anorexia.

    Science.gov (United States)

    Mogami, Sachiko; Sadakane, Chiharu; Nahata, Miwa; Mizuhara, Yasuharu; Yamada, Chihiro; Hattori, Tomohisa; Takeda, Hiroshi

    2016-06-08

    Rikkunshito (RKT), a Kampo medicine, has been reported to show an ameliorative effect on sustained hypophagia after novelty stress exposure in aged mice through serotonin 2C receptor (5-HT2CR) antagonism. We aimed to determine (1) whether the activation of anorexigenic neurons, corticotropin-releasing factor (CRF), and pro-opiomelanocortin (POMC) neurons, is involved in the initiation of hypophagia induced by novelty stress in aged mice; (2) whether the ameliorative effect of RKT is associated with CRF and POMC neurons and downstream signal transduction; and (3) the plasma and brain distribution of the active components of RKT. The administration of RKT or 5-HT2CR, CRF receptor 1 (CRFR1), and melanocortin-4 receptor antagonists significantly restored the decreased food intake observed in aged male C57BL/6 mice in the early stage after novelty stress exposure. Seven components of RKT exhibited antagonistic activity against CRFR1. Hesperetin and isoliquiritigenin, which showed antagonistic effects against both CRFR1 and 5-HT2CR, were distributed in the plasma and brain of male Sprague-Dawley rats after a single oral administration of RKT. In conclusion, the ameliorative effect of RKT in this model is assumed to be at least partly due to brain-distributed active components possessing 5-HT2CR and CRFR1 antagonistic activities.

  18. Lapatinib induces autophagic cell death and differentiation in acute myeloblastic leukemia

    Directory of Open Access Journals (Sweden)

    Chen YJ

    2016-07-01

    Full Text Available Yu-Jen Chen,1–4 Li-Wen Fang,5 Wen-Chi Su,6,7 Wen-Yi Hsu,1 Kai-Chien Yang,1 Huey-Lan Huang8 1Department of Medical Research, 2Department of Radiation Oncology, Mackay Memorial Hospital, 3Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, 4Institute of Pharmacology, Taipei Medical University, Taipei, 5Department of Nutrition, I-Shou University, Kaohsiung, 6Research Center for Emerging Viruses, China Medical University Hospital, 7Graduate Institute of Clinical Medical Science, China Medical University, Taichung, 8Department of Bioscience Technology, College of Health Science, Chang Jung Christian University, Tainan, Taiwan, Republic of China Abstract: Lapatinib is an oral-form dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR or ErbB/Her superfamily members with anticancer activity. In this study, we examined the effects and mechanism of action of lapatinib on several human leukemia cells lines, including acute myeloid leukemia (AML, chronic myeloid leukemia (CML, and acute lymphoblastic leukemia (ALL cells. We found that lapatinib inhibited the growth of human AML U937, HL-60, NB4, CML KU812, MEG-01, and ALL Jurkat T cells. Among these leukemia cell lines, lapatinib induced apoptosis in HL-60, NB4, and Jurkat cells, but induced nonapoptotic cell death in U937, K562, and MEG-01 cells. Moreover, lapatinib treatment caused autophagic cell death as shown by positive acridine orange staining, the massive formation of vacuoles as seen by electronic microscopy, and the upregulation of LC3-II, ATG5, and ATG7 in AML U937 cells. Furthermore, autophagy inhibitor 3-methyladenine and knockdown of ATG5, ATG7, and Beclin-1 using short hairpin RNA (shRNA partially rescued lapatinib-induced cell death. In addition, the induction of phagocytosis and ROS production as well as the upregulation of surface markers CD14 and CD68 was detected in lapatinib-treated U937 cells, suggesting the induction of

  19. Combined aerobic exercise and enzyme replacement therapy rejuvenates the mitochondrial-lysosomal axis and alleviates autophagic blockage in Pompe disease.

    Science.gov (United States)

    Nilsson, M I; MacNeil, L G; Kitaoka, Y; Suri, R; Young, S P; Kaczor, J J; Nates, N J; Ansari, M U; Wong, T; Ahktar, M; Brandt, L; Hettinga, B P; Tarnopolsky, M A

    2015-10-01

    A unifying feature in the pathogenesis of aging, neurodegenerative disease, and lysosomal storage disorders is the progressive deposition of macromolecular debris impervious to enzyme catalysis by cellular waste disposal mechanisms (e.g., lipofuscin). Aerobic exercise training (AET) has pleiotropic effects and stimulates mitochondrial biogenesis, antioxidant defense systems, and autophagic flux in multiple organs and tissues. Our aim was to explore the therapeutic potential of AET as an ancillary therapy to mitigate autophagic buildup and oxidative damage and rejuvenate the mitochondrial-lysosomal axis in Pompe disease (GSD II/PD). Fourteen weeks of combined recombinant acid α-glucosidase (rhGAA) and AET polytherapy attenuated mitochondrial swelling, fortified antioxidant defense systems, reduced oxidative damage, and augmented glycogen clearance and removal of autophagic debris/lipofuscin in fast-twitch skeletal muscle of GAA-KO mice. Ancillary AET potently augmented the pool of PI4KA transcripts and exerted a mild restorative effect on Syt VII and VAMP-5/myobrevin, collectively suggesting improved endosomal transport and Ca(2+)- mediated lysosomal exocytosis. Compared with traditional rhGAA monotherapy, AET and rhGAA polytherapy effectively mitigated buildup of protein carbonyls, autophagic debris/lipofuscin, and P62/SQSTM1, while enhancing MnSOD expression, nuclear translocation of Nrf-2, muscle mass, and motor function in GAA-KO mice. Combined AET and rhGAA therapy reactivates cellular clearance pathways, mitigates mitochondrial senescence, and strengthens antioxidant defense systems in GSD II/PD. Aerobic exercise training (or pharmacologic targeting of contractile-activity-induced pathways) may have therapeutic potential for mitochondrial-lysosomal axis rejuvenation in lysosomal storage disorders and related conditions (e.g., aging and neurodegenerative disease).

  20. Dismantling the autophagic arsenal when it is time to die: concerted AMBRA1 degradation by caspases and calpains.

    Science.gov (United States)

    Corazzari, Marco; Fimia, Gian Maria; Piacentini, Mauro

    2012-08-01

    Under stress conditions cells activate different response pathways which result in cell survival or apoptosis depending on: (1) the nature of the insults, (2) the type, if acute or chronic stress, and (3) how long the stress persists. Generally, autophagy is induced early to sustain cell survival and inhibit cell death. However, adverse conditions are able to overcome autophagy to promote cell death. Increasing evidence suggests that the inhibition of autophagy by the apoptotic machinery has been proposed as one of the crucial events responsible for the irreversible switch from survival to death. The mechanism seems to be related to the selective apoptotic protease-mediated degradation of key autophagic proteins. We recently found that AMBRA1, an important regulator of the autophagic process mediating the initial steps of autophagosome formation, is also irreversibly degraded by the combined activity of caspases and calpains. This phenomenon is not merely a consequence of apoptosis execution but represents a key step required to efficiently promote the autophagic vs apoptosis switch.

  1. Mediation of autophagic cell death by type 3 ryanodine receptor (RyR3 in adult hippocampal neural stem cells

    Directory of Open Access Journals (Sweden)

    Kyung Min eChung

    2016-05-01

    Full Text Available Cytoplasmic Ca2+ actively engages in diverse intracellular processes from protein synthesis, folding and trafficking to cell survival and death. Dysregulation of intracellular Ca2+ levels is observed in various neuropathological states including Alzheimer’s and Parkinson’s diseases. Ryanodine receptors (RyRs and IP3 receptors (IP3Rs, the main Ca2+ release channels located in endoplasmic reticulum (ER membranes, are known to direct various cellular events such as autophagy and apoptosis. Here we investigated the intracellular Ca2+-mediated regulation of survival and death of adult hippocampal neural stem (HCN cells utilizing an insulin withdrawal model of autophagic cell death. Despite comparable expression levels of RyR and IP3R transcripts in HCN cells at normal state, the expression levels of RyRs — especially RyR3 — were markedly upregulated upon insulin withdrawal. While treatment with the RyR agonist caffeine significantly promoted the autophagic death of insulin-deficient HCN cells, treatment with its inhibitor dantrolene prevented the induction of autophagy following insulin withdrawal. Furthermore, CRISPR/Cas9-mediated knockout of the RyR3 gene abolished autophagic cell death of HCN cells. This study delineates a distinct, RyR3-mediated ER Ca2+ regulation of autophagy and programmed cell death in neural stem cells. Our findings provide novel insights into the critical, yet understudied mechanisms underlying the regulatory function of ER Ca2+ in neural stem cell biology.

  2. Aberrant Autophagic Response in The Muscle of A Knock-in Mouse Model of Spinal and Bulbar Muscular Atrophy

    Science.gov (United States)

    Rusmini, Paola; Polanco, Maria Josefa; Cristofani, Riccardo; Cicardi, Maria Elena; Meroni, Marco; Galbiati, Mariarita; Piccolella, Margherita; Messi, Elio; Giorgetti, Elisa; Lieberman, Andrew P.; Milioto, Carmelo; Rocchi, Anna; Aggarwal, Tanya; Pennuto, Maria; Crippa, Valeria; Poletti, Angelo

    2015-01-01

    Spinal and bulbar muscular atrophy (SBMA) is characterized by loss of motoneurons and sensory neurons, accompanied by atrophy of muscle cells. SBMA is due to an androgen receptor containing a polyglutamine tract (ARpolyQ) that misfolds and aggregates, thereby perturbing the protein quality control (PQC) system. Using SBMA AR113Q mice we analyzed proteotoxic stress-induced alterations of HSPB8-mediated PQC machinery promoting clearance of misfolded proteins by autophagy. In muscle of symptomatic AR113Q male mice, we found expression upregulation of Pax-7, myogenin, E2-ubiquitin ligase UBE2Q1 and acetylcholine receptor (AchR), but not of MyoD, and of two E3-ligases (MuRF-1 and Cullin3). TGFβ1 and PGC-1α were also robustly upregulated. We also found a dramatic perturbation of the autophagic response, with upregulation of most autophagic markers (Beclin-1, ATG10, p62/SQSTM1, LC3) and of the HSPB8-mediated PQC response. Both HSPB8 and its co-chaperone BAG3 were robustly upregulated together with other specific HSPB8 interactors (HSPB2 and HSPB3). Notably, the BAG3:BAG1 ratio increased in muscle suggesting preferential misfolded proteins routing to autophagy rather than to proteasome. Thus, mutant ARpolyQ induces a potent autophagic response in muscle cells. Alteration in HSPB8-based PQC machinery may represent muscle-specific biomarkers useful to assess SBMA progression in mice and patients in response to pharmacological treatments. PMID:26490709

  3. Autophagic degradation of farnesylated prelamin A as a therapeutic approach to lamin-linked progeria

    Science.gov (United States)

    Cenni, V.; Capanni, C.; Columbaro, M.; Ortolani, M.; D'Apice, M.R.; Novelli, G.; Fini, M.; Marmiroli, S.; Scarano, E.; Maraldi, N.M.; Squarzoni, S.; Prencipe, S.; Lattanzi, G.

    2011-01-01

    Farnesylated prelamin A is a processing intermediate produced in the lamin A maturation pathway. Accumulation of a truncated farnesylated prelamin A form, called progerin, is a hallmark of the severe premature ageing syndrome, Hutchinson-Gilford progeria. Progerin elicits toxic effects in cells, leading to chromatin damage and cellular senescence and ultimately causes skin and endothelial defects, bone resorption, lipodystrophy and accelerated ageing. Knowledge of the mechanism underlying prelamin A turnover is critical for the development of clinically effective protein inhibitors that can avoid accumulation to toxic levels without impairing lamin A/C expression, which is essential for normal biological functions. Little is known about specific molecules that may target farnesylated prelamin A to elicit protein degradation. Here, we report the discovery of rapamycin as a novel inhibitor of progerin, which dramatically and selectively decreases protein levels through a mechanism involving autophagic degradation. Rapamycin treatment of progeria cells lowers progerin, as well as wild-type prelamin A levels, and rescues the chromatin phenotype of cultured fibroblasts, including histone methylation status and BAF and LAP2α distribution patterns. Importantly, rapamycin treatment does not affect lamin C protein levels, but increases the relative expression of the prelamin A endoprotease ZMPSTE24. Thus, rapamycin, an antibiotic belonging to the class of macrolides, previously found to increase longevity in mouse models, can serve as a therapeutic tool, to eliminate progerin, avoid farnesylated prelamin A accumulation, and restore chromatin dynamics in progeroid laminopathies. PMID:22297442

  4. Resveratrol attenuated hydrogen peroxide-induced myocardial apoptosis by autophagic flux

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    Chih-Yang Huang

    2016-05-01

    Full Text Available Background: Resveratrol is a Sirt-1-specific activator, which also exerts cardioprotective effects that regulate redox signalling during oxidative stress and autophagy during cardiovascular disease (CVD. Objective: This study investigated the protective effects of resveratrol against hydrogen peroxide-induced damage in cardiomyocytes. Design: In this article, hydrogen peroxide-induced autophagy and apoptosis in H9c2 cardiomyoblasts were studied at an increasing concentration from 0 to 100 µM. Results: Resveratrol pretreatment with concentrations of 10, 20, and 50 µM inhibits autophagic apoptosis by increasing p-Akt and Bcl-2 protein levels in H9c2 cells. Interestingly, resveratrol treatment activates the Beclin-1, LC3, p62, and the lysosome-associated protein LAMP2a within 24 h of administration. Conclusions: These results suggest that resveratrol-regulated autophagy may play a role in degrading damaged organelles in H9c2 cells rather than causing apoptosis, and this may be a possible mechanism by which resveratrol protects the heart during CVD.

  5. Involvement of Autophagic Pathway in the Progression of Retinal Degeneration in a Mouse Model of Diabetes.

    Science.gov (United States)

    Piano, Ilaria; Novelli, Elena; Della Santina, Luca; Strettoi, Enrica; Cervetto, Luigi; Gargini, Claudia

    2016-01-01

    The notion that diabetic retinopathy (DR) is essentially a micro-vascular disease has been recently challenged by studies reporting that vascular changes are preceded by signs of damage and loss of retinal neurons. As to the mode by which neuronal death occurs, the evidence that apoptosis is the main cause of neuronal loss is far from compelling. The objective of this study was to investigate these controversies in a mouse model of streptozotocin (STZ) induced diabetes. Starting from 8 weeks after diabetes induction there was loss of rod but not of cone photoreceptors, together with reduced thickness of the outer and inner synaptic layers. Correspondingly, rhodopsin expression was downregulated and the scotopic electroretinogram (ERG) is suppressed. In contrast, cone opsin expression and photopic ERG response were not affected. Suppression of the scotopic ERG preceded morphological changes as well as any detectable sign of vascular alteration. Only sparse apoptotic figures were detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and glia was not activated. The physiological autophagy flow was altered instead, as seen by increased LC3 immunostaining at the level of outer plexiform layer (OPL) and upregulation of the autophagic proteins Beclin-1 and Atg5. Collectively, our results show that the streptozotocin induced DR in mouse initiates with a functional loss of the rod visual pathway. The pathogenic pathways leading to cell death develop with the initial dysregulation of autophagy well before the appearance of signs of vascular damage and without strong involvement of apoptosis.

  6. Endothelial cells are damaged by autophagic induction before hepatocytes in Con A-induced acute hepatitis.

    Science.gov (United States)

    Yang, Ming-Chen; Chang, Chih-Peng; Lei, Huan-Yao

    2010-08-01

    We have reported both T-cell-dependent and -independent hepatitis in immunocompetent and immunodeficiency mice, respectively, after intravenous injection of Con A in mice. The mode of hepatocyte cell death is different: autophagy for T-cell-independent hepatitis in contrast to apoptosis for T-cell-dependent one. In this study, we further demonstrate that liver blood vessels are the first target in both modes. The infused Con A bond to the hepatic vascular endothelial cells and cause its damage with autophagy. Before the elevation of the serum alanine aminotransferase at 6 h post-injection, the plasma leakage and hemorrhage occur at 1-3 h without inflammation. Con A induces autophagy of endothelial cells and hemorrhage that is enhanced by IFN-gamma. Using the endothelial cell line HMEC-1, a dose- and time-dependent cell death with autophagic LC3-II (microtubule-associated protein light chain 3) conversion was induced by Con A and was enhanced by IFN-gamma. In conclusion, Con A induced autophagy on hepatic endothelial cells; the damage of liver blood vessel occurs before the induction of T-cell-dependent hepatitis via apoptosis or T-cell-independent hepatitis via autophagy.

  7. TNFα Impairs Rhabdoviral Clearance by Inhibiting the Host Autophagic Antiviral Response.

    Science.gov (United States)

    Espín-Palazón, Raquel; Martínez-López, Alicia; Roca, Francisco J; López-Muñoz, Azucena; Tyrkalska, Sylwia D; Candel, Sergio; García-Moreno, Diana; Falco, Alberto; Meseguer, José; Estepa, Amparo; Mulero, Victoriano

    2016-06-01

    TNFα is a pleiotropic pro-inflammatory cytokine with a key role in the activation of the immune system to fight viral infections. Despite its antiviral role, a few viruses might utilize the host produced TNFα to their benefit. Some recent reports have shown that anti-TNFα therapies could be utilized to treat certain viral infections. However, the underlying mechanisms by which TNFα can favor virus replication have not been identified. Here, a rhabdoviral infection model in zebrafish allowed us to identify the mechanism of action by which Tnfa has a deleterious role for the host to combat certain viral infections. Our results demonstrate that Tnfa signals through its receptor Tnfr2 to enhance viral replication. Mechanistically, Tnfa does not affect viral adhesion and delivery from endosomes to the cytosol. In addition, the host interferon response was also unaffected by Tnfa levels. However, Tnfa blocks the host autophagic response, which is required for viral clearance. This mechanism of action provides new therapeutic targets for the treatment of SVCV-infected fish, and advances our understanding of the previously enigmatic deleterious role of TNFα in certain viral infections.

  8. Autophagic degradation of aquaporin-2 is an early event in hypokalemia-induced nephrogenic diabetes insipidus.

    Science.gov (United States)

    Khositseth, Sookkasem; Uawithya, Panapat; Somparn, Poorichaya; Charngkaew, Komgrid; Thippamom, Nattakan; Hoffert, Jason D; Saeed, Fahad; Michael Payne, D; Chen, Shu-Hui; Fenton, Robert A; Pisitkun, Trairak

    2015-12-17

    Hypokalemia (low serum potassium level) is a common electrolyte imbalance that can cause a defect in urinary concentrating ability, i.e., nephrogenic diabetes insipidus (NDI), but the molecular mechanism is unknown. We employed proteomic analysis of inner medullary collecting ducts (IMCD) from rats fed with a potassium-free diet for 1 day. IMCD protein quantification was performed by mass spectrometry using a label-free methodology. A total of 131 proteins, including the water channel AQP2, exhibited significant changes in abundance, most of which were decreased. Bioinformatic analysis revealed that many of the down-regulated proteins were associated with the biological processes of generation of precursor metabolites and energy, actin cytoskeleton organization, and cell-cell adhesion. Targeted LC-MS/MS and immunoblotting studies further confirmed the down regulation of 18 selected proteins. Electron microscopy showed autophagosomes/autophagolysosomes in the IMCD cells of rats deprived of potassium for only 1 day. An increased number of autophagosomes was also confirmed by immunofluorescence, demonstrating co-localization of LC3 and Lamp1 with AQP2 and several other down-regulated proteins in IMCD cells. AQP2 was also detected in autophagosomes in IMCD cells of potassium-deprived rats by immunogold electron microscopy. Thus, enhanced autophagic degradation of proteins, most notably including AQP2, is an early event in hypokalemia-induced NDI.

  9. Acupuncture promotes mTOR-independent autophagic clearance of aggregation-prone proteins in mouse brain.

    Science.gov (United States)

    Tian, Tian; Sun, Yanhong; Wu, Huangan; Pei, Jian; Zhang, Jing; Zhang, Yi; Wang, Lu; Li, Bin; Wang, Lihua; Shi, Jiye; Hu, Jun; Fan, Chunhai

    2016-01-21

    Acupuncture has historically been practiced to treat medical disorders by mechanically stimulating specific acupoints with fine needles. Despite its well-documented efficacy, its biological basis remains largely elusive. In this study, we found that mechanical stimulation at the acupoint of Yanglingquan (GB34) promoted the autophagic clearance of α-synuclein (α-syn), a well known aggregation-prone protein closely related to Parkinson's disease (PD), in the substantia nigra par compacta (SNpc) of the brain in a PD mouse model. We found the protein clearance arose from the activation of the autophagy-lysosome pathway (ALP) in a mammalian target of rapamycin (mTOR)-independent approach. Further, we observed the recovery in the activity of dopaminergic neurons in SNpc, and improvement in the motor function at the behavior level of PD mice. Whereas acupuncture and rapamycin, a chemical mTOR inhibitor, show comparable α-syn clearance and therapeutic effects in the PD mouse model, the latter adopts a distinctly different, mTOR-dependent, autophagy induction process. Due to this fundamental difference, acupuncture may circumvent adverse effects of the rapamycin treatment. The newly discovered connection between acupuncture and autophagy not only provides a new route to understanding the molecular mechanism of acupuncture but also sheds new light on cost-effective and safe therapy of neurodegenerative diseases.

  10. TNFα Impairs Rhabdoviral Clearance by Inhibiting the Host Autophagic Antiviral Response.

    Directory of Open Access Journals (Sweden)

    Raquel Espín-Palazón

    2016-06-01

    Full Text Available TNFα is a pleiotropic pro-inflammatory cytokine with a key role in the activation of the immune system to fight viral infections. Despite its antiviral role, a few viruses might utilize the host produced TNFα to their benefit. Some recent reports have shown that anti-TNFα therapies could be utilized to treat certain viral infections. However, the underlying mechanisms by which TNFα can favor virus replication have not been identified. Here, a rhabdoviral infection model in zebrafish allowed us to identify the mechanism of action by which Tnfa has a deleterious role for the host to combat certain viral infections. Our results demonstrate that Tnfa signals through its receptor Tnfr2 to enhance viral replication. Mechanistically, Tnfa does not affect viral adhesion and delivery from endosomes to the cytosol. In addition, the host interferon response was also unaffected by Tnfa levels. However, Tnfa blocks the host autophagic response, which is required for viral clearance. This mechanism of action provides new therapeutic targets for the treatment of SVCV-infected fish, and advances our understanding of the previously enigmatic deleterious role of TNFα in certain viral infections.

  11. Autophagic degradation of farnesylated prelamin A as a therapeutic approach to lamin-linked progeria

    Directory of Open Access Journals (Sweden)

    V. Cenni

    2011-10-01

    Full Text Available Farnesylated prelamin A is a processing intermediate produced in the lamin A maturation pathway. Accumulation of a truncated farnesylated prelamin A form, called progerin, is a hallmark of the severe premature ageing syndrome, Hutchinson-Gilford progeria. Progerin elicits toxic effects in cells, leading to chromatin damage and cellular senescence and ultimately causes skin and endothelial defects, bone resorption, lipodystrophy and accelerated ageing. Knowledge of the mechanism underlying prelamin A turnover is critical for the development of clinically effective protein inhibitors that can avoid accumulation to toxic levels without impairing lamin A/C expression, which is essential for normal biological functions. Little is known about specific molecules that may target farnesylated prelamin A to elicit protein degradation. Here, we report the discovery of rapamycin as a novel inhibitor of progerin, which dramatically and selectively decreases protein levels through a mechanism involving autophagic degradation. Rapamycin treatment of progeria cells lowers progerin, as well as wild-type prelamin A levels, and rescues the chromatin phenotype of cultured fibroblasts, including histone methylation status and BAF and LAP2alpha distribution patterns. Importantly, rapamycin treatment does not affect lamin C protein levels, but increases the relative expression of the prelamin A endoprotease ZMPSTE24. Thus, rapamycin, an antibiotic belonging to the class of macrolides, previously found to increase longevity in mouse models, can serve as a therapeutic tool, to eliminate progerin, avoid farnesylated prelamin A accumulation, and restore chromatin dynamics in progeroid laminopathies.

  12. BH3 Mimetics Reactivate Autophagic Cell Death in Anoxia-Resistant Malignant Glioma Cells

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    Holger Hetschko

    2008-08-01

    Full Text Available Here, we investigated the specific roles of Bcl-2 family members in anoxia tolerance of malignant glioma. Flow cytometry analysis of cell death in 17 glioma cell lines revealed drastic differences in their sensitivity to oxygen withdrawal (<0.1% O2. Cell death correlated with mitochondrial depolarization, cytochrome C release, and translocation of green fluorescent protein (GFP-tagged light chain 3 to autophagosomes but occurred in the absence of caspase activation or phosphatidylserine exposure. In both sensitive and tolerant glioma cell lines, anoxia caused a significant up-regulation of BH3-only genes previously implicated in mediating anoxic cell death in other cell types (BNIP3, NIX, PUMA, and Noxa. In contrast, we detected a strong correlation between anoxia resistance and high expression levels of antiapoptotic Bcl-2 family proteins Bcl-xL, Bcl-2, and Mcl-1 that function to neutralize the proapoptotic activity of BH3-only proteins. Importantly, inhibition of both Bcl-2 and Bcl-xL with the small-molecule BH3 mimetics HA14-1 and BH3I-2′ and by RNA interference reactivated anoxia-induced autophagic cell death in previously resistant glioma cells. Our data suggest that endogenous BH3-only protein induction may not be able to compensate for the high expression of antiapoptotic Bcl-2 family proteins in anoxia-resistant astrocytomas. They also support the conjecture that BH3 mimetics may represent an exciting new approach for the treatment of malignant glioma.

  13. Dealcoholated red wine induces autophagic and apoptotic cell death in an osteosarcoma cell line.

    Science.gov (United States)

    Tedesco, I; Russo, M; Bilotto, S; Spagnuolo, C; Scognamiglio, A; Palumbo, R; Nappo, A; Iacomino, G; Moio, L; Russo, G L

    2013-10-01

    Until recently, the supposed preventive effects of red wine against cardiovascular diseases, the so-called "French Paradox", has been associated to its antioxidant properties. The interest in the anticancer capacity of polyphenols present in red wine strongly increased consequently to the enormous number of studies on resveratrol. In this study, using lyophilized red wine, we present evidence that its anticancer effect in a cellular model is mediated by apoptotic and autophagic cell death. Using a human osteosarcoma cell line, U2Os, we found that the lyophilized red wine was cytotoxic in a dose-dependent manner with a maximum effect in the range of 100-200 μg/ml equivalents of gallic acid. A mixed phenotype of types I/II cell death was evidenced by means of specific assays following treatment of U2Os with lyophilized red wine, e.g., autophagy and apoptosis. We found that cell death induced by lyophilized red wine proceeded through a mechanism independent from its anti-oxidant activity and involving the inhibition of PI3K/Akt kinase signaling. Considering the relative low concentration of each single bioactive compound in lyophilized red wine, our study suggests the activation of synergistic mechanism able to inhibit growth in malignant cells.

  14. Relative contribution of combined kinetic and exchange energy terms vs the electronic component of molecular electrostatic potential in hardness potential derivatives.

    Science.gov (United States)

    Bhattacharjee, Rituparna; Roy, Ram Kinkar

    2013-11-14

    The relative contribution of the sum of kinetic [(10/9)CFρ(r)2/3] and exchange energy [(4/9)CXρ(r)1/3] terms to that of the electronic part of the molecular electrostatic potential [Vel(r)] in the variants of hardness potential is investigated to assess the proposed definition of Δ+h(k) = −[VelN+1(k) – VelN(k)] and Δ–h(k) = −[VelN(k) – VelN–1(k)] (Saha; et al. J. Comput. Chem. 2013, 34, 662). Some substituted benzenes and polycyclic aromatic hydrocarbons (PAHs) (undergoing electrophilic aromatic substitution), carboxylic acids, and their derivatives are chosen to carry out the theoretical investigation as stated above. Intra- and intermolecular reactivity trends generated by Δ+h(k) and Δ–h(k) are found to be satisfactory and are correlated reasonably well with experimental results.

  15. Interaction of NANOS2 and NANOS3 with different components of the CNOT complex may contribute to the functional differences in mouse male germ cells

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    Atsushi Suzuki

    2014-11-01

    Full Text Available NANOS2 and NANOS3 belong to the Nanos family of proteins that contain a conserved zinc finger domain, which consists of two consecutive CCHC-type zinc finger motifs, and contribute to germ cell development in mice. Previous studies indicate that there are redundant and distinct functions of these two proteins. NANOS2 rescues NANOS3 functions in the maintenance of primordial germ cells, whereas NANOS3 fails to replace NANOS2 functions in the male germ cell pathway. However, the lack of a conditional allele of Nanos3 has hampered delineation of each contribution of NANOS2 and NANOS3 to the male germ cell pathway. In addition, the molecular mechanism underlying the distinct functions of these proteins remains unexplored. Here, we report an unexpected observation of a transgenic mouse line expressing a NANOS2 variant harboring mutations in the zinc finger domain. Transcription of Nanos2 and Nanos3 was strongly compromised in the presence of this transgene, which resulted in the mimicking of the Nanos2/Nanos3 double-null condition in the male gonad. In these transgenic mice, P-bodies involved in RNA metabolism had disappeared and germ cell differentiation was more severely affected than that in Nanos2-null mice, indicating that NANOS3 partially substitutes for NANOS2 functions. In addition, similar to NANOS2, we found that NANOS3 associated with the CCR4-NOT deadenylation complex but via a direct interaction with CNOT8, unlike CNOT1 in the case of NANOS2. This alternate interaction might account for the molecular basis of the functional redundancy and differences in NANOS2 and NANOS3 functions.

  16. The fluvial geochemistry, contributions of silicate, carbonate and saline-alkaline components to chemical weathering flux and controlling parameters: Narmada River (Deccan Traps), India

    Science.gov (United States)

    Gupta, Harish; Chakrapani, Govind J.; Selvaraj, Kandasamy; Kao, Shuh-Ji

    2011-02-01

    The Narmada River in India is the largest west-flowing river into the Arabian Sea, draining through the Deccan Traps, one of the largest flood basalt provinces in the world. The fluvial geochemical characteristics and chemical weathering rates (CWR) for the mainstream and its major tributaries were determined using a composite dataset, which includes four phases of seasonal field (spot) samples (during 2003 and 2004) and a decade-long (1990-2000) fortnight time series (multiannual) data. Here, we demonstrate the influence of minor lithologies (carbonates and saline-alkaline soils) on basaltic signature, as reflected in sudden increases of Ca 2+-Mg 2+ and Na + contents at many locations along the mainstream and in tributaries. Both spot and multiannual data corrected for non-geological contributions were used to calculate the CWR. The CWR for spot samples (CWR spot) vary between 25 and 63 ton km -2 year -1, showing a reasonable correspondence with the CWR estimated for multiannual data (CWR multi) at most study locations. The weathering rates of silicate ( SilWR), carbonate ( CarbWR) and evaporite ( Sal-AlkWR) have contributed ˜38-58, 28-45 and 8-23%, respectively to the CWR spot at different locations. The estimated SilWR (11-36 ton km -2 year -1) for the Narmada basin indicates that the previous studies on the North Deccan Rivers (Narmada-Tapti-Godavari) overestimated the silicate weathering rates and associated CO 2 consumption rates. The average annual CO 2 drawdown via silicate weathering calculated for the Narmada basin is ˜0.032 × 10 12 moles year -1, suggesting that chemical weathering of the entire Deccan Trap basalts consumes approximately 2% (˜0.24 × 10 12 moles) of the annual global CO 2 drawdown. The present study also evaluates the influence of meteorological parameters (runoff and temperature) and physical weathering rates (PWR) in controlling the CWR at annual scale across the basin. The CWR and the SilWR show significant correlation with runoff

  17. New insights into the interactions between cork chemical components and pesticides. The contribution of π-π interactions, hydrogen bonding and hydrophobic effect.

    Science.gov (United States)

    Olivella, M À; Bazzicalupi, C; Bianchi, A; Fiol, N; Villaescusa, I

    2015-01-01

    The role of chemical components of cork in the sorption of several pesticides has been investigated. For this purpose raw cork and three cork extracted fractions (i.e. cork free of aliphatic extractives, cork free of all extractives and cork free of all extractives and suberin) were used as sorbent of three ionic pesticides (propazine, 2,4-dichlorophenoxy acetic acid (2,4-D) and alachlor) and five non-ionic pesticides (chlorpyrifos, isoproturon, metamitron, methomyl and oxamyl) with a logKow within the range -0.47 to 4.92. The effect of cations on the ionic pesticides, propazine and 2,4-D sorption was also analyzed. Results indicated that the highest yields were obtained for chlorpyrifos and alachlor sorption onto raw cork (>55%). After removal of aliphatic extractives sorption of all pesticides increased that ranged from 3% for propazine to 31% for alachlor. In contrast, removal of phenolic extractives caused a sorption decrease. Low sorption yields were obtained for hydrophobic pesticides such as metamitron, oxamyl and methomyl (cork fractions and extremely low when using raw cork (cork toward aromatic pesticides. Results presented in this paper gain insights into the cork affinities for pesticides and the interactions involved in the sorption process and also enables to envisage sorption affinity of cork for other organic pollutants.

  18. Formation and excretion of autophagic plastids (plastolysomes in Brassica napus embryogenic microspores

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    Veronica eParra-Vega

    2015-02-01

    Full Text Available The change in developmental fate of microspores reprogrammed towards embryogenesis is a complex but fascinating experimental system where microspores undergo dramatic changes derived from the developmental switch. After 40 years of study of the ultrastructural changes undergone by the induced microspores, many questions are still open. In this work, we analyzed the architecture of DNA-containing organelles such as plastids and mitochondria in samples of B. napus isolated microspore cultures covering the different stages before, during and after the developmental switch. Mitochondria presented a conventional oval or sausage-like morphology for all cell types studied, similar to that found in vivo in other cell types from vegetative parts. Similarly, plastids of microspores before induction and of non-induced cells showed conventional architectures. However, approximately 40% of the plastids of embryogenic microspores presented atypical features such as curved profiles, protrusions, and internal compartments filled with cytoplasm. Three-dimensional reconstructions confirmed that these plastids actually engulf cytoplasm regions, isolating them from the rest of the cell. Acid phosphatase activity was found in them, confirming the lytic activity of these organelles. In addition, digested plastid-like structures were found excreted to the apoplast. All these phenomena seemed transient, since microspore-derived embryos showed conventional plastids. Together, these results strongly suggested that under special circumstances, such as those of the androgenic switch, plastids of embryogenic microspores behave as autophagic plastids (plastolysomes, engulfing cytoplasm for digestion, and then are excreted out of the cytoplasm as part of a cleaning program necessary for microspores to become embryos.

  19. The Root Hair Specific SYP123 Regulates the Localization of Cell Wall Components and Contributes to Rizhobacterial Priming of Induced Systemic Resistance

    Science.gov (United States)

    Rodriguez-Furlán, Cecilia; Salinas-Grenet, Hernán; Sandoval, Omar; Recabarren, Camilo; Arraño-Salinas, Paulina; Soto-Alvear, Sylvana; Orellana, Ariel; Blanco-Herrera, Francisca

    2016-01-01

    Root hairs are important for nutrient and water uptake and are also critically involved the interaction with soil inhabiting microbiota. Root hairs are tubular-shaped outgrowths that emerge from trichoblasts. This polarized elongation is maintained and regulated by a robust mechanism involving the endomembrane secretory and endocytic system. Members of the syntaxin family of SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) in plants (SYP), have been implicated in regulation of the fusion of vesicles with the target membranes in both exocytic and endocytic pathways. One member of this family, SYP123, is expressed specifically in the root hairs and accumulated in the growing tip region. This study shows evidence of the SYP123 role in polarized trafficking using knockout insertional mutant plants. We were able to observe defects in the deposition of cell wall proline rich protein PRP3 and cell wall polysaccharides. In a complementary strategy, similar results were obtained using a plant expressing a dominant negative soluble version of SYP123 (SP2 fragment) lacking the transmembrane domain. The evidence presented indicates that SYP123 is also regulating PRP3 protein distribution by recycling by endocytosis. We also present evidence that indicates that SYP123 is necessary for the response of roots to plant growth promoting rhizobacterium (PGPR) in order to trigger trigger induced systemic response (ISR). Plants with a defective SYP123 function were unable to mount a systemic acquired resistance in response to bacterial pathogen infection and ISR upon interaction with rhizobacteria. These results indicated that SYP123 was involved in the polarized localization of protein and polysaccharides in growing root hairs and that this activity also contributed to the establishment of effective plant defense responses. Root hairs represent very plastic structures were many biotic and abiotic factors can affect the number, anatomy and physiology of

  20. The Root Hair Specific SYP123 Regulates the Localization of Cell Wall Components and Contributes to Rizhobacterial Priming of Induced Systemic Resistance

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    Cecilia Rodriguez-Furlán

    2016-07-01

    Full Text Available Root hairs are important for nutrient and water uptake and are also critically involved the interaction with soil inhabiting microbiota. Root hairs are tubular-shaped outgrowths that emerge from trichoblasts. This polarized elongation is maintained and regulated by a robust mechanism involving the endomembrane secretory and endocytic system. Members of the syntaxin family of SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptor in plants (SYP, have been implicated in regulation of the fusion of vesicles with the target membranes in both exocytic and endocytic pathways. One member of this family, SYP123, is expressed specifically in the root hairs and accumulated in the growing tip region. This study shows evidence of the SYP123 role in polarized trafficking using knockout insertional mutant plants. We were able to observe defects in the deposition of cell wall proline rich protein PRP3 and cell wall polysaccharides. In a complementary strategy, similar results were obtained using a plant expressing a dominant negative soluble version of SYP123 (SP2 fragment lacking the transmembrane domain. The evidence presented indicates that SYP123 is also regulating PRP3 protein distribution by recycling by endocytosis. We also present evidence that indicates that SYP123 is necessary for the response of roots to plant growth promoting rhizobacterium (PGPR in order to trigger trigger induced systemic response (ISR. Plants with a defective SYP123 function were unable to mount a systemic acquired resistance (SAR in response to bacterial pathogen infection and induced systemic resistance (ISR upon interaction with rhizobacteria. These results indicated that SYP123 was involved in the polarized localization of protein and polysaccharides in growing root hairs and that this activity also contributed to the establishment of effective plant defense responses. Root hairs represent very plastic structures were many biotic and abiotic factors

  1. The Root Hair Specific SYP123 Regulates the Localization of Cell Wall Components and Contributes to Rizhobacterial Priming of Induced Systemic Resistance.

    Science.gov (United States)

    Rodriguez-Furlán, Cecilia; Salinas-Grenet, Hernán; Sandoval, Omar; Recabarren, Camilo; Arraño-Salinas, Paulina; Soto-Alvear, Sylvana; Orellana, Ariel; Blanco-Herrera, Francisca

    2016-01-01

    Root hairs are important for nutrient and water uptake and are also critically involved the interaction with soil inhabiting microbiota. Root hairs are tubular-shaped outgrowths that emerge from trichoblasts. This polarized elongation is maintained and regulated by a robust mechanism involving the endomembrane secretory and endocytic system. Members of the syntaxin family of SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) in plants (SYP), have been implicated in regulation of the fusion of vesicles with the target membranes in both exocytic and endocytic pathways. One member of this family, SYP123, is expressed specifically in the root hairs and accumulated in the growing tip region. This study shows evidence of the SYP123 role in polarized trafficking using knockout insertional mutant plants. We were able to observe defects in the deposition of cell wall proline rich protein PRP3 and cell wall polysaccharides. In a complementary strategy, similar results were obtained using a plant expressing a dominant negative soluble version of SYP123 (SP2 fragment) lacking the transmembrane domain. The evidence presented indicates that SYP123 is also regulating PRP3 protein distribution by recycling by endocytosis. We also present evidence that indicates that SYP123 is necessary for the response of roots to plant growth promoting rhizobacterium (PGPR) in order to trigger trigger induced systemic response (ISR). Plants with a defective SYP123 function were unable to mount a systemic acquired resistance in response to bacterial pathogen infection and ISR upon interaction with rhizobacteria. These results indicated that SYP123 was involved in the polarized localization of protein and polysaccharides in growing root hairs and that this activity also contributed to the establishment of effective plant defense responses. Root hairs represent very plastic structures were many biotic and abiotic factors can affect the number, anatomy and physiology of

  2. Thymoquinone induces caspase-independent, autophagic cell death in CPT-11-resistant lovo colon cancer via mitochondrial dysfunction and activation of JNK and p38.

    Science.gov (United States)

    Chen, Ming-Cheng; Lee, Nien-Hung; Hsu, Hsi-Hsien; Ho, Tsung-Jung; Tu, Chuan-Chou; Hsieh, Dennis Jine-Yuan; Lin, Yueh-Min; Chen, Li-Mien; Kuo, Wei-Wen; Huang, Chih-Yang

    2015-02-11

    Chemotherapy causes unwanted side effects and chemoresistance, limiting its effectiveness. Therefore, phytochemicals are now used as alternative treatments. Thymoquinone (TQ) is used to treat different cancers, including colon cancer. The irinotecan-resistant (CPT-11-R) LoVo colon cancer cell line was previously constructed by stepwise CPT-11 challenges to untreated parental LoVo cells. TQ dose-dependently increased the total cell death index and activated apoptosis at 2 μM, which then diminished at increasing doses. The possibility of autophagic cell death was then investigated. TQ caused mitochondrial outer membrane permeability (MOMP) and activated autophagic cell death. JNK and p38 inhibitors (SP600125 and SB203580, respectively) reversed TQ autophagic cell death. TQ was also found to activate apoptosis before autophagy, and the direction of cell death was switched toward autophagic cell death at initiation of autophagosome formation. Therefore, TQ resulted in caspase-independent, autophagic cell death via MOMP and activation of JNK and p38 in CPT-11-R LoVo colon cancer cells.

  3. Carbazole alkaloids from Murraya koenigii trigger apoptosis and autophagic flux inhibition in human oral squamous cell carcinoma cells.

    Science.gov (United States)

    Utaipan, Tanyarath; Athipornchai, Anan; Suksamrarn, Apichart; Jirachotikoon, Canussanun; Yuan, Xiaohong; Lertcanawanichakul, Monthon; Chunglok, Warangkana

    2017-01-01

    Carbazole alkaloids, a major constituent of Murraya koenigii (L.) Sprengel (Rutaceae), exhibit biological effects such as anticancer activity via the induction of apoptosis, and they represent candidate chemotherapeutic agents. Oral squamous cell carcinoma (OSCC) is the most prevalent cancer of the oral cavity and a growing and serious health problem worldwide. In this study, we investigated the anticancer properties and mechanisms of action of two carbazole alkaloids derived from M. koenigii leaves, mahanine and isomahanine, in the OSCC cell line CLS-354. At 15 μM, mahanine and isomahanine were cytotoxic to CLS-354 cells, triggering apoptosis via caspase-dependent and -independent mechanisms. Autophagosomes, visualised using monodansylcadaverine (MDC) labelling, were numerous in carbazole alkaloid-treated cells. Mahanine and isomahanine markedly induced the expression of the autophagosome marker microtubule-associated protein 1 light chain 3, type II (LC3B-II). Genetic and chemical inhibition of autophagy via silencing of the Autophagy protein 5 gene and exposure to bafilomycin A1 (BafA1), respectively, did not arrest carbazole alkaloid-induced apoptosis, indicating that it occurs independently of autophagic activation. Surprisingly, both carbazole alkaloids caused increased accumulation of p62/sequestosome1 (p62/SQSTM1), with coordinated expression of LC3B-II and cleaved caspase-3, suggesting inhibition of autophagic flux. Our results suggest that inhibition of autophagic flux is associated with carbazole alkaloid-induced apoptosis. Our findings provide evidence of a novel cytotoxic action of natural carbazole alkaloids and support their use as candidate chemotherapeutic agents for the treatment of OSCC.

  4. Ceria nanoparticles stabilized by organic surface coatings activate the lysosome-autophagy system and enhance autophagic clearance.

    Science.gov (United States)

    Song, Wensi; Soo Lee, Seung; Savini, Marzia; Popp, Lauren; Colvin, Vicki L; Segatori, Laura

    2014-10-28

    Cerium oxide nanoparticles (nanoceria) are widely used in a variety of industrial applications including UV filters and catalysts. The expanding commercial scale production and use of ceria nanoparticles have inevitably increased the risk of release of nanoceria into the environment as well as the risk of human exposure. The use of nanoceria in biomedical applications is also being currently investigated because of its recently characterized antioxidative properties. In this study, we investigated the impact of ceria nanoparticles on the lysosome-autophagy system, the main catabolic pathway that is activated in mammalian cells upon internalization of exogenous material. We tested a battery of ceria nanoparticles functionalized with different types of biocompatible coatings (N-acetylglucosamine, polyethylene glycol and polyvinylpyrrolidone) expected to have minimal effect on lysosomal integrity and function. We found that ceria nanoparticles promote activation of the transcription factor EB, a master regulator of lysosomal function and autophagy, and induce upregulation of genes of the lysosome-autophagy system. We further show that the array of differently functionalized ceria nanoparticles tested in this study enhance autophagic clearance of proteolipid aggregates that accumulate as a result of inefficient function of the lysosome-autophagy system. This study provides a mechanistic understanding of the interaction of ceria nanoparticles with the lysosome-autophagy system and demonstrates that ceria nanoparticles are activators of autophagy and promote clearance of autophagic cargo. These results provide insights for the use of nanoceria in biomedical applications, including drug delivery. These findings will also inform the design of engineered nanoparticles with safe and precisely controlled impact on the environment and the design of nanotherapeutics for the treatment of diseases with defective autophagic function and accumulation of lysosomal storage material.

  5. Interference with the Autophagic Process as a Viral Strategy to Escape from the Immune Control: Lesson from Gamma Herpesviruses

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    Roberta Santarelli

    2015-01-01

    Full Text Available We summarized the most recent findings on the role of autophagy in antiviral immune response. We described how viruses have developed strategies to subvert the autophagic process. A particular attention has been given to Epstein-Barr and Kaposi’s sarcoma associated Herpesvirus, viruses studied for many years in our laboratory. These two viruses belong to γ-Herpesvirus subfamily and are associated with several human cancers. Besides the effects on the immune response, we have described how autophagy subversion by viruses may also concur to the enhancement of their replication and to viral tumorigenesis.

  6. Contribution of the autophagy-lysosomal and ubiquitin-proteasomal proteolytic systems to total proteolysis in rainbow trout (Oncorhynchus mykiss) myotubes

    Science.gov (United States)

    Two major proteolytic systems are thought to (co-) operate in the skeletal muscle of vertebrates, the ubiquitin-proteasomal system (UPS) and the autophagic/lysosomal system (ALS). While their relative contribution to muscle loss has been already well documented in mammals, little is known in fish sp...

  7. Benzyl isothiocyanate causes FoxO1-mediated autophagic death in human breast cancer cells.

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    Dong Xiao

    Full Text Available Benzyl isothiocyanate (BITC, a constituent of edible cruciferous vegetables, inhibits growth of breast cancer cells but the mechanisms underlying growth inhibitory effect of BITC are not fully understood. Here, we demonstrate that BITC treatment causes FoxO1-mediated autophagic death in cultured human breast cancer cells. The BITC-treated breast cancer cells (MDA-MB-231, MCF-7, MDA-MB-468, BT-474, and BRI-JM04 and MDA-MB-231 xenografts from BITC-treated mice exhibited several features characteristic of autophagy, including appearance of double-membrane vacuoles (transmission electron microscopy and acidic vesicular organelles (acridine orange staining, cleavage of microtubule-associated protein 1 light chain 3 (LC3, and/or suppression of p62 (p62/SQSTM1 or sequestosome 1 expression. On the other hand, a normal human mammary epithelial cell line (MCF-10A was resistant to BITC-induced autophagy. BITC-mediated inhibition of MDA-MB-231 and MCF-7 cell viability was partially but statistically significantly attenuated in the presence of autophagy inhibitors 3-methyl adenine and bafilomycin A1. Stable overexpression of Mn-superoxide dismutase, which was fully protective against apoptosis, conferred only partial protection against BITC-induced autophagy. BITC treatment decreased phosphorylation of mTOR and its downstream targets (P70s6k and 4E-BP1 in cultured MDA-MB-231 and MCF-7 cells and MDA-MB-231 xenografts, but activation of mTOR by transient overexpression of its positive regulator Rheb failed to confer protection against BITC-induced autophagy. Autophagy induction by BITC was associated with increased expression and acetylation of FoxO1. Furthermore, autophagy induction and cell growth inhibition resulting from BITC exposure were significantly attenuated by small interfering RNA knockdown of FoxO1. In conclusion, the present study provides novel insights into the molecular circuitry of BITC-induced cell death involving FoxO1-mediated autophagy.

  8. Reserve Component Contribution to Imagery Intelligence

    Science.gov (United States)

    2006-05-31

    Richard K. Betts writes, “After the Cold War, intelligence resources went down as requirements went up.”2 By the later part of the 20th Century...the nation’s security needs. As Richard Betts writes, it is easy to “throw money at the problem” by attaining more resources, but as he suggests, this...Staff Study. 40Ted Davis, LTC (USA (Ret), Robert H. Dorf , and Robert D. Walz, LTC (Ret), “A Brief Introduction to Concepts and Approaches in the

  9. Effects of contaminant exposure and food restriction on hepatic autophagic lysosomal parameters in Herring Gull (Larus argentatus) chicks.

    Science.gov (United States)

    Hegseth, Marit Nøst; Gorbi, Stephania; Bocchetti, Raffaella; Camus, Lionel; Gabrielsen, Geir Wing; Regoli, Francesco

    2014-08-01

    Lysosomal autophagic responses, such as lysosomal membrane stability, neutral lipids (NL), lipofuscin (LF), and malondialdehyde (MDA) levels, are valuable measures of cellular early-onset effects induced by environmental stress factors, such as contaminant exposure and fasting. In this study, these parameters were analysed and related to levels of halogenated organic contaminants (HOCs) in 40 Herring Gull (Larus argentatus) chicks. Chicks were experimentally exposed to HOCs through diet and went through a period of nutrient deprivation at the end of the experiment. HOC exposure and fasting were conducted separately and in combination. NL storages were depleted, and lysosomal membranes were destabilised after HOC exposure and nutrient deprivation. These responses were not related specifically to one type of stress or the extent of the treatment. No synergistic or additive effects from the combination of HOC exposure and fasting were observed. LF accumulated, and MDA levels increased as a result of fasting, but were unaffected by HOC exposure. LF accumulation was strongly associated with the percent weight change in the chicks. Large weight loss was associated with high LF levels, and slight weight gain was associated with low LF levels. Hence, food deprivation affected all the measured parameters, and HOC exposure decreased NL levels and lysosomal membrane stability in HG chick liver. Furthermore, autophagic lysosomal parameters have frequently been applied as biomarkers of cellular health status in previous studies of marine and terrestrial invertebrates, and this study suggests that these parameters may be good candidates for biomarkers of cellular health status in seabirds as well.

  10. SET overexpression in HEK293 cells regulates mitochondrial uncoupling proteins levels within a mitochondrial fission/reduced autophagic flux scenario.

    Science.gov (United States)

    Almeida, Luciana O; Goto, Renata N; Neto, Marinaldo P C; Sousa, Lucas O; Curti, Carlos; Leopoldino, Andréia M

    2015-03-01

    We hypothesized that SET, a protein accumulated in some cancer types and Alzheimer disease, is involved in cell death through mitochondrial mechanisms. We addressed the mRNA and protein levels of the mitochondrial uncoupling proteins UCP1, UCP2 and UCP3 (S and L isoforms) by quantitative real-time PCR and immunofluorescence as well as other mitochondrial involvements, in HEK293 cells overexpressing the SET protein (HEK293/SET), either in the presence or absence of oxidative stress induced by the pro-oxidant t-butyl hydroperoxide (t-BHP). SET overexpression in HEK293 cells decreased UCP1 and increased UCP2 and UCP3 (S/L) mRNA and protein levels, whilst also preventing lipid peroxidation and decreasing the content of cellular ATP. SET overexpression also (i) decreased the area of mitochondria and increased the number of organelles and lysosomes, (ii) increased mitochondrial fission, as demonstrated by increased FIS1 mRNA and FIS-1 protein levels, an apparent accumulation of DRP-1 protein, and an increase in the VDAC protein level, and (iii) reduced autophagic flux, as demonstrated by a decrease in LC3B lipidation (LC3B-II) in the presence of chloroquine. Therefore, SET overexpression in HEK293 cells promotes mitochondrial fission and reduces autophagic flux in apparent association with up-regulation of UCP2 and UCP3; this implies a potential involvement in cellular processes that are deregulated such as in Alzheimer's disease and cancer.

  11. UCP2 inhibition triggers ROS-dependent nuclear translocation of GAPDH and autophagic cell death in pancreatic adenocarcinoma cells.

    Science.gov (United States)

    Dando, Ilaria; Fiorini, Claudia; Pozza, Elisa Dalla; Padroni, Chiara; Costanzo, Chiara; Palmieri, Marta; Donadelli, Massimo

    2013-03-01

    Mitochondrial uncoupling protein 2 (UCP2) can moderate oxidative stress by favoring the influx of protons into the mitochondrial matrix, thus reducing electron leakage from respiratory chain and mitochondrial superoxide production. Here, we demonstrate that UCP2 inhibition by genipin or UCP2 siRNA strongly increases reactive oxygen species (ROS) production inhibiting pancreatic adenocarcinoma cell growth. We also show that UCP2 inhibition triggers ROS-dependent nuclear translocation of the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH), formation of autophagosomes, and the expression of the autophagy marker LC3-II. Consistently, UCP2 over-expression significantly reduces basal autophagy confirming the anti-autophagic role of UCP2. Furthermore, we demonstrate that autophagy induced by UCP2 inhibition determines a ROS-dependent cell death, as indicated by the apoptosis decrease in the presence of the autophagy inhibitors chloroquine (CQ) or 3-methyladenine (3-MA), or the radical scavenger NAC. Intriguingly, the autophagy induced by genipin is able to potentiate the autophagic cell death triggered by gemcitabine, the standard chemotherapeutic drug for pancreatic adenocarcinoma, supporting the development of an anti-cancer therapy based on UCP2 inhibition associated to standard chemotherapy. Our results demonstrate for the first time that UCP2 plays a role in autophagy regulation bringing new insights into mitochondrial uncoupling protein field.

  12. Phospholipase C-related catalytically inactive protein participates in the autophagic elimination of Staphylococcus aureus infecting mouse embryonic fibroblasts.

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    Kae Harada-Hada

    Full Text Available Autophagy is an intrinsic host defense system that recognizes and eliminates invading bacterial pathogens. We have identified microtubule-associated protein 1 light chain 3 (LC3, a hallmark of autophagy, as a binding partner of phospholipase C-related catalytically inactive protein (PRIP that was originally identified as an inositol trisphosphate-binding protein. Here, we investigated the involvement of PRIP in the autophagic elimination of Staphylococcus aureus in infected mouse embryonic fibroblasts (MEFs. We observed significantly more LC3-positive autophagosome-like vacuoles enclosing an increased number of S. aureus cells in PRIP-deficient MEFs than control MEFs, 3 h and 4.5 h post infection, suggesting that S. aureus proliferates in LC3-positive autophagosome-like vacuoles in PRIP-deficient MEFs. We performed autophagic flux analysis using an mRFP-GFP-tagged LC3 plasmid and found that autophagosome maturation is significantly inhibited in PRIP-deficient MEFs. Furthermore, acidification of autophagosomes was significantly inhibited in PRIP-deficient MEFs compared to the wild-type MEFs, as determined by LysoTracker staining and time-lapse image analysis performed using mRFP-GFP-tagged LC3. Taken together, our data show that PRIP is required for the fusion of S. aureus-containing autophagosome-like vacuoles with lysosomes, indicating that PRIP is a novel modulator in the regulation of the innate immune system in non-professional phagocytic host cells.

  13. The ATG autophagic conjugation system in maize: ATG transcripts and abundance of the ATG8-lipid adduct are regulated by development and nutrient availability.

    Science.gov (United States)

    Chung, Taijoon; Suttangkakul, Anongpat; Vierstra, Richard D

    2009-01-01

    Plants employ sophisticated mechanisms to recycle intracellular constituents needed for growth, development, and survival under nutrient-limiting conditions. Autophagy is one important route in which cytoplasm and organelles are sequestered in bulk into vesicles and subsequently delivered to the vacuole for breakdown by resident hydrolases. The formation and trafficking of autophagic vesicles are directed in part by associated conjugation cascades that couple the AUTOPHAGY-RELATED8 (ATG8) and ATG12 proteins to their respective targets, phosphatidylethanolamine and the ATG5 protein. To help understand the importance of autophagy to nutrient remobilization in cereals, we describe here the ATG8/12 conjugation cascades in maize (Zea mays) and examine their dynamics during development, leaf senescence, and nitrogen and fixed-carbon starvation. From searches of the maize genomic sequence using Arabidopsis (Arabidopsis thaliana) and rice (Oryza sativa) counterparts as queries, we identified orthologous loci encoding all components necessary for ATG8/12 conjugation, including a five-member gene family expressing ATG8. Alternative splicing was evident for almost all Atg transcripts, which could have important regulatory consequences. In addition to free ATG8, its membrane-associated, lipidated form was detected in many maize tissues, suggesting that its conjugation cascade is active throughout the plant at most, if not all, developmental stages. Levels of Atg transcripts and/or the ATG8-phosphatidylethanolamine adduct increase during leaf senescence and nitrogen and fixed-carbon limitations, indicating that autophagy plays a key role in nutrient remobilization. The description of the maize ATG system now provides a battery of molecular and biochemical tools to study autophagy in this crop under field conditions.

  14. Using isotope, hydrochemical methods and energy-balance modelling to estimate contribution of different components to flow forming process in a high-altitude catchment (Dzhancuat river basin case study)

    Science.gov (United States)

    Rets, Ekaterina; Loshakova, Nadezhda; Chizhova, Julia; Kireeva, Maria; Frolova, Natalia; Tokarev, Igor; Budantseva, Nadine; Vasilchuk, Yurij

    2016-04-01

    A multicomponent structure of sources of river runoff formation is characteristic of high-altitude territories: ice and firn melting; seasonal snow melting on glacier covered and non-glacier area of a watershed; liquid precipitation; underground waters. In addition, each of these components can run off the watershed surface in different ways. Use of isotopic, hydrochemical methods and energy balance modelling provides possibility to estimate contribution of different components to river runoff that is an essential to understand the mechanism of flow formation in mountainious areas. A study was carried out for Dzhancuat river basin that was chosen as representative for North Caucasus in course of the International Hydrological Decade. Complex glaciological, hydrological and meteorological observation have been carried in the basin since 1965. In years 2013-2015 the program also included daily collecting of water samples on natural stable isotopes on the Dzhancuat river gauging station, and sampling water nourishment sources (ice, snow, firn, liquid precipitation) within the study area. More then 800 water samples were collected. Application of an energy balance model of snow and ice melt with distributed parameters provided an opportunity to identify Dzhancuat river runoff respond to glaciers melt regime and seasonal redistribution of melt water. The diurnal amplitude of oscillation of the Dzhakuat river runoff in the days without precipitation is formed by melting at almost snow-free areas of the Dzhancuat glacier tongues. Snowmelt water from the non-glacierized part contributes to the formation of the next day runoff. A wave of snow and firn melt in upper zones of glacier flattens considerably during filtration through snow and run-off over the surface and in the body of the glacier. This determines a general significant inertia of the Dzhacuat river runoff. Some part of melt water is stored into natural regulating reservoirs of the watershed that supply the

  15. Effect of the pituitary adenylate cyclase-activating polypeptide on the autophagic activation observed in in vitro and in vivo models of Parkinson's disease.

    Science.gov (United States)

    Lamine-Ajili, Asma; Fahmy, Ahmed M; Létourneau, Myriam; Chatenet, David; Labonté, Patrick; Vaudry, David; Fournier, Alain

    2016-04-01

    Parkinson's disease (PD) is a neurodegenerative disorder that leads to destruction of the midbrain dopaminergic (DA) neurons. This phenomenon is related to apoptosis and its activation can be blocked by the pituitary adenylate cyclase-activating polypeptide (PACAP). Growing evidence indicates that autophagy, a self-degradation activity that cleans up the cell, is induced during the course of neurodegenerative diseases. However, the role of autophagy in the pathogenesis of neuronal disorders is yet poorly understood and the potential ability of PACAP to modulate the related autophagic activation has never been significantly investigated. Hence, we explored the putative autophagy-modulating properties of PACAP in in vitro and in vivo models of PD, using the neurotoxic agents 1-methyl-4-phenylpyridinium (MPP(+)) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), respectively, to trigger alterations of DA neurons. In both models, following the toxin exposure, PACAP reduced the autophagic activity as evaluated by the production of LC3 II, the modulation of the p62 protein levels, and the formation of autophagic vacuoles. The ability of PACAP to inhibit autophagy was also observed in an in vitro cell assay by the blocking of the p62-sequestration activity produced with the autophagy inducer rapamycin. Thus, the results demonstrated that autophagy is induced in PD experimental models and that PACAP exhibits not only anti-apoptotic but also anti-autophagic properties.

  16. The antimalarial amodiaquine causes autophagic-lysosomal and proliferative blockade sensitizing human melanoma cells to starvation- and chemotherapy-induced cell death.

    Science.gov (United States)

    Qiao, Shuxi; Tao, Shasha; Rojo de la Vega, Montserrat; Park, Sophia L; Vonderfecht, Amanda A; Jacobs, Suesan L; Zhang, Donna D; Wondrak, Georg T

    2013-12-01

    Pharmacological inhibition of autophagic-lysosomal function has recently emerged as a promising strategy for chemotherapeutic intervention targeting cancer cells. Repurposing approved and abandoned non-oncological drugs is an alternative approach to the identification and development of anticancer therapeutics, and antimalarials that target autophagic-lysosomal functions have recently attracted considerable attention as candidates for oncological repurposing. Since cumulative research suggests that dependence on autophagy represents a specific vulnerability of malignant melanoma cells, we screened a focused compound library of antimalarials for antimelanoma activity. Here we report for the first time that amodiaquine (AQ), a clinical 4-aminoquinoline antimalarial with unexplored cancer-directed chemotherapeutic potential, causes autophagic-lysosomal and proliferative blockade in melanoma cells that surpasses that of its parent compound chloroquine. Monitoring an established set of protein markers (LAMP1, LC3-II, SQSTM1) and cell ultrastructural changes detected by electron microscopy, we observed that AQ treatment caused autophagic-lysosomal blockade in malignant A375 melanoma cells, a finding substantiated by detection of rapid inactivation of lysosomal cathepsins (CTSB, CTSL, CTSD). AQ-treatment was associated with early induction of energy crisis (ATP depletion) and sensitized melanoma cells to either starvation- or chemotherapeutic agent-induced cell death. AQ displayed potent antiproliferative effects, and gene expression array analysis revealed changes at the mRNA (CDKN1A, E2F1) and protein level (TP53, CDKN1A, CCND1, phospho-RB1 [Ser 780]/[Ser 807/811], E2F1) consistent with the observed proliferative blockade in S-phase. Taken together, our data suggest that the clinical antimalarial AQ is a promising candidate for repurposing efforts that aim at targeting autophagic-lysosomal function and proliferative control in malignant melanoma cells.

  17. Sulindac sulfide induces autophagic death in gastric epithelial cells via survivin down-regulation: a mechanism of NSAIDs-induced gastric injury.

    Science.gov (United States)

    Chiou, Shiun-Kwei; Hoa, Neil; Hodges, Amy

    2011-06-01

    Sulindac sulfide, a nonsteroidal anti-inflammatory drug (NSAID), has anti-tumorigenic and anti-inflammatory activities, but causes gastric mucosal damage. NSAIDs cause gastric injury in part by down-regulation of Survivin, an apoptosis inhibitor, resulting in apoptosis induction. Autophagy is a process that promotes cellular health by destroying unwanted cellular materials. Excessive autophagy induction could lead to a non-apoptotic cell death (autophagic cell death). The present study showed that sulindac sulfide at a physiological concentration also induces autophagic death in human gastric epithelial AGS and rat gastric epithelial RGM-1 cells, and that Survivin down-regulation is a mechanism involved: Sulindac sulfide treatment increased LC3b-II and APG7 levels and cytosolic vacuole formation, indications of autophagy induction, in AGS and RGM-1 cells. Sulindac sulfide treatment induced AGS and RGM-1 cell death, which was significantly reduced by pretreatment with the autophagy inhibitors 3-methyladenine and chloroquine, indicating that sulindac sulfide induced autophagic cell death. Stable overexpression of Survivin in RGM-1 cells did not inhibit the induction of LC3b-II levels or vacuole formation by sulindac sulfide, but significantly reduced the resulting cell death, suggesting that Survivin may inhibit autophagic cell death downstream of LC3b-II induction and vacuole formation. Indeed, siRNA depletion of LC3b in AGS cells inhibited the down-regulation of Survivin levels and the induction of cell death by sulindac sulfide, confirming that down-regulation of Survivin occurs in the autophagy pathway downstream of LC3b-II induction by sulindac sulfide. Induction of Survivin-dependent autophagic cell death is a novel mechanism by which sulindac sulfide induces gastric mucosal injury.

  18. The autophagic tumor stroma model of cancer or "battery-operated tumor growth": A simple solution to the autophagy paradox.

    Science.gov (United States)

    Martinez-Outschoorn, Ubaldo E; Whitaker-Menezes, Diana; Pavlides, Stephanos; Chiavarina, Barbara; Bonuccelli, Gloria; Casey, Trimmer; Tsirigos, Aristotelis; Migneco, Gemma; Witkiewicz, Agnieszka; Balliet, Renee; Mercier, Isabelle; Wang, Chengwang; Flomenberg, Neal; Howell, Anthony; Lin, Zhao; Caro, Jaime; Pestell, Richard G; Sotgia, Federica; Lisanti, Michael P

    2010-11-01

    The role of autophagy in tumorigenesis is controversial. Both autophagy inhibitors (chloroquine) and autophagy promoters (rapamycin) block tumorigenesis by unknown mechanism(s). This is called the "Autophagy Paradox". We have recently reported a simple solution to this paradox. We demonstrated that epithelial cancer cells use oxidative stress to induce autophagy in the tumor microenvironment. As a consequence, the autophagic tumor stroma generates recycled nutrients that can then be used as chemical building blocks by anabolic epithelial cancer cells. This model results in a net energy transfer from the tumor stroma to epithelial cancer cells (an energy imbalance), thereby promoting tumor growth. This net energy transfer is both unilateral and vectorial, from the tumor stroma to the epithelial cancer cells, representing a true host-parasite relationship. We have termed this new paradigm "The Autophagic Tumor Stroma Model of Cancer Cell Metabolism" or "Battery-Operated Tumor Growth". In this sense, autophagy in the tumor stroma serves as a "battery" to fuel tumor growth, progression and metastasis, independently of angiogenesis. Using this model, the systemic induction of autophagy will prevent epithelial cancer cells from using recycled nutrients, while the systemic inhibiton of autophagy will prevent stromal cells from producing recycled nutrients-both effectively "starving" cancer cells. We discuss the idea that tumor cells could become resistant to the systemic induction of autophagy, by the upregulation of natural endogenous autophagy inhibitors in cancer cells. Alternatively, tumor cells could also become resistant to the systemic induction of autophagy, by the genetic silencing/deletion of pro-autophagic molecules, such as Beclin1. If autophagy resistance develops in cancer cells, then the systemic inhibition of autophagy would provide a therapeutic solution to this type of drug resistance, as it would still target autophagy in the tumor stroma. As such, an

  19. Staurosporine-induced cell death in Tetrahymena thermophila has mixed characteristics of both apoptotic and autophagic degeneration

    DEFF Research Database (Denmark)

    Christensen, S T; Chemnitz, J; Straarup, E M;

    1998-01-01

    phosphorylation of the PKC-specific substrate, myelin basic protein fragment 4-14. Our results show that cell death in the presence of staurosporine is associated with morphological and ultrastructural changes similar to both apoptosis and autophagic degeneration, but these in turn can be postponed or prevented......Staurosporine blocks signal transduction associated with cell survival, proliferation and chemosensory behaviour in the ciliated protozoan, Tetrahymena thermophila. Staurosporine inhibits cell proliferation and in vivo protein phosphorylation induced by phorbol ester. It also reduces the in vitro...... by 8-bromo-cyclic GMP, protoporphyrin IX, hemin or actinomycin D, although phorbol ester and insulin were ineffective. The results support the notion that staurosporine-induced cell death is an active process, associated with and/or requiring de novo RNA synthesis....

  20. Toll-like receptor 8 ligands activate a vitamin D mediated autophagic response that inhibits human immunodeficiency virus type 1.

    Science.gov (United States)

    Campbell, Grant R; Spector, Stephen A

    2012-01-01

    Toll-like receptors (TLR) are important in recognizing microbial pathogens and triggering host innate immune responses, including autophagy, and in the mediation of immune activation during human immunodeficiency virus type-1 (HIV) infection. We report here that TLR8 activation in human macrophages induces the expression of the human cathelicidin microbial peptide (CAMP), the vitamin D receptor (VDR) and cytochrome P450, family 27, subfamily B, polypeptide 1 (CYP27B1), which 1α-hydroxylates the inactive form of vitamin D, 25-hydroxycholecalciferol, into its biologically active metabolite. Moreover, we demonstrate using RNA interference, chemical inhibitors and vitamin D deficient media that TLR8 agonists inhibit HIV through a vitamin D and CAMP dependent autophagic mechanism. These data support an important role for vitamin D in the control of HIV infection, and provide a biological explanation for the benefits of vitamin D. These findings also provide new insights into potential novel targets to prevent and treat HIV infection.

  1. In Vivo Evidence for Lysosome Depletion and Impaired Autophagic Clearance in Hereditary Spastic Paraplegia Type SPG11.

    Directory of Open Access Journals (Sweden)

    Rita-Eva Varga

    2015-08-01

    Full Text Available Hereditary spastic paraplegia (HSP is characterized by a dying back degeneration of corticospinal axons which leads to progressive weakness and spasticity of the legs. SPG11 is the most common autosomal-recessive form of HSPs and is caused by mutations in SPG11. A recent in vitro study suggested that Spatacsin, the respective gene product, is needed for the recycling of lysosomes from autolysosomes, a process known as autophagic lysosome reformation. The relevance of this observation for hereditary spastic paraplegia, however, has remained unclear. Here, we report that disruption of Spatacsin in mice indeed causes hereditary spastic paraplegia-like phenotypes with loss of cortical neurons and Purkinje cells. Degenerating neurons accumulate autofluorescent material, which stains for the lysosomal protein Lamp1 and for p62, a marker of substrate destined to be degraded by autophagy, and hence appears to be related to autolysosomes. Supporting a more generalized defect of autophagy, levels of lipidated LC3 are increased in Spatacsin knockout mouse embryonic fibrobasts (MEFs. Though distinct parameters of lysosomal function like processing of cathepsin D and lysosomal pH are preserved, lysosome numbers are reduced in knockout MEFs and the recovery of lysosomes during sustained starvation impaired consistent with a defect of autophagic lysosome reformation. Because lysosomes are reduced in cortical neurons and Purkinje cells in vivo, we propose that the decreased number of lysosomes available for fusion with autophagosomes impairs autolysosomal clearance, results in the accumulation of undegraded material and finally causes death of particularly sensitive neurons like cortical motoneurons and Purkinje cells in knockout mice.

  2. In Vivo Evidence for Lysosome Depletion and Impaired Autophagic Clearance in Hereditary Spastic Paraplegia Type SPG11.

    Science.gov (United States)

    Varga, Rita-Eva; Khundadze, Mukhran; Damme, Markus; Nietzsche, Sandor; Hoffmann, Birgit; Stauber, Tobias; Koch, Nicole; Hennings, J Christopher; Franzka, Patricia; Huebner, Antje K; Kessels, Michael M; Biskup, Christoph; Jentsch, Thomas J; Qualmann, Britta; Braulke, Thomas; Kurth, Ingo; Beetz, Christian; Hübner, Christian A

    2015-08-01

    Hereditary spastic paraplegia (HSP) is characterized by a dying back degeneration of corticospinal axons which leads to progressive weakness and spasticity of the legs. SPG11 is the most common autosomal-recessive form of HSPs and is caused by mutations in SPG11. A recent in vitro study suggested that Spatacsin, the respective gene product, is needed for the recycling of lysosomes from autolysosomes, a process known as autophagic lysosome reformation. The relevance of this observation for hereditary spastic paraplegia, however, has remained unclear. Here, we report that disruption of Spatacsin in mice indeed causes hereditary spastic paraplegia-like phenotypes with loss of cortical neurons and Purkinje cells. Degenerating neurons accumulate autofluorescent material, which stains for the lysosomal protein Lamp1 and for p62, a marker of substrate destined to be degraded by autophagy, and hence appears to be related to autolysosomes. Supporting a more generalized defect of autophagy, levels of lipidated LC3 are increased in Spatacsin knockout mouse embryonic fibrobasts (MEFs). Though distinct parameters of lysosomal function like processing of cathepsin D and lysosomal pH are preserved, lysosome numbers are reduced in knockout MEFs and the recovery of lysosomes during sustained starvation impaired consistent with a defect of autophagic lysosome reformation. Because lysosomes are reduced in cortical neurons and Purkinje cells in vivo, we propose that the decreased number of lysosomes available for fusion with autophagosomes impairs autolysosomal clearance, results in the accumulation of undegraded material and finally causes death of particularly sensitive neurons like cortical motoneurons and Purkinje cells in knockout mice.

  3. SET overexpression in HEK293 cells regulates mitochondrial uncoupling proteins levels within a mitochondrial fission/reduced autophagic flux scenario

    Energy Technology Data Exchange (ETDEWEB)

    Almeida, Luciana O.; Goto, Renata N. [Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP (Brazil); Neto, Marinaldo P.C. [Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP (Brazil); Sousa, Lucas O. [Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP (Brazil); Curti, Carlos [Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP (Brazil); Leopoldino, Andréia M., E-mail: andreiaml@usp.br [Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP (Brazil)

    2015-03-06

    We hypothesized that SET, a protein accumulated in some cancer types and Alzheimer disease, is involved in cell death through mitochondrial mechanisms. We addressed the mRNA and protein levels of the mitochondrial uncoupling proteins UCP1, UCP2 and UCP3 (S and L isoforms) by quantitative real-time PCR and immunofluorescence as well as other mitochondrial involvements, in HEK293 cells overexpressing the SET protein (HEK293/SET), either in the presence or absence of oxidative stress induced by the pro-oxidant t-butyl hydroperoxide (t-BHP). SET overexpression in HEK293 cells decreased UCP1 and increased UCP2 and UCP3 (S/L) mRNA and protein levels, whilst also preventing lipid peroxidation and decreasing the content of cellular ATP. SET overexpression also (i) decreased the area of mitochondria and increased the number of organelles and lysosomes, (ii) increased mitochondrial fission, as demonstrated by increased FIS1 mRNA and FIS-1 protein levels, an apparent accumulation of DRP-1 protein, and an increase in the VDAC protein level, and (iii) reduced autophagic flux, as demonstrated by a decrease in LC3B lipidation (LC3B-II) in the presence of chloroquine. Therefore, SET overexpression in HEK293 cells promotes mitochondrial fission and reduces autophagic flux in apparent association with up-regulation of UCP2 and UCP3; this implies a potential involvement in cellular processes that are deregulated such as in Alzheimer's disease and cancer. - Highlights: • SET, UCPs and autophagy prevention are correlated. • SET action has mitochondrial involvement. • UCP2/3 may reduce ROS and prevent autophagy. • SET protects cell from ROS via UCP2/3.

  4. Andrographolide alleviates imiquimod-induced psoriasis in mice via inducing autophagic proteolysis of MyD88.

    Science.gov (United States)

    Shao, Fenli; Tan, Tao; Tan, Yang; Sun, Yang; Wu, Xingxin; Xu, Qiang

    2016-09-01

    Psoriasis is a chronic inflammatory skin disease with excessive activation of toll-like receptors (TLRs), which play important roles in developing psoriasis. Targeting TLR signaling remains a challenge for treating psoriasis. Here, we found that andrographolide (Andro), a small-molecule natural product, alleviated imiquimod- but not interleukin 23 (IL-23)-induced psoriasis in mice with reducing expressions of IL-23 and IL-1β in the skin. The improvement in imiquimod-induced psoriasis by Andro was not observed in microtubule-associated protein 1 light chain 3 beta (MAP1LC3B) knockout mice. Furthermore, Andro inhibited mRNA expressions of IL-23, IL-6 and IL-1β but not CD80 and CD86 in bone-marrow derived dendritic cells (BMDCs) treated with lipopolysaccharide (LPS) in a MAP1LC3B-dependent manner. In addition, Andro inhibited imiquimod-induced mRNA expressions of IL-23, IL-6, IL-1β, CD80 and CD86 in BMDCs from mice. Interestingly, Andro induced a degradation of myeloid differentiation factor 88 (MyD88) and blocked the recruitment of TNF receptor-associated factor 6 (TRAF6) to MyD88 upon LPS stimulation in BMDCs from mice. Blockade of autophagic proteolysis using NH4Cl or MAP1LC3B(-/-) BMDCs abolished the Andro-induced MyD88 degradation. In conclusion, Andro controls activation of MyD88-dependent cytokines and alleviates psoriasis in mice via inducing autophagic proteolysis of MyD88, which could be a novel strategy to treat psoriasis.

  5. In Vivo Evidence for Lysosome Depletion and Impaired Autophagic Clearance in Hereditary Spastic Paraplegia Type SPG11

    Science.gov (United States)

    Varga, Rita-Eva; Khundadze, Mukhran; Damme, Markus; Nietzsche, Sandor; Hoffmann, Birgit; Stauber, Tobias; Koch, Nicole; Hennings, J. Christopher; Franzka, Patricia; Huebner, Antje K.; Kessels, Michael M.; Biskup, Christoph; Jentsch, Thomas J.; Qualmann, Britta; Braulke, Thomas; Kurth, Ingo; Beetz, Christian; Hübner, Christian A.

    2015-01-01

    Hereditary spastic paraplegia (HSP) is characterized by a dying back degeneration of corticospinal axons which leads to progressive weakness and spasticity of the legs. SPG11 is the most common autosomal-recessive form of HSPs and is caused by mutations in SPG11. A recent in vitro study suggested that Spatacsin, the respective gene product, is needed for the recycling of lysosomes from autolysosomes, a process known as autophagic lysosome reformation. The relevance of this observation for hereditary spastic paraplegia, however, has remained unclear. Here, we report that disruption of Spatacsin in mice indeed causes hereditary spastic paraplegia-like phenotypes with loss of cortical neurons and Purkinje cells. Degenerating neurons accumulate autofluorescent material, which stains for the lysosomal protein Lamp1 and for p62, a marker of substrate destined to be degraded by autophagy, and hence appears to be related to autolysosomes. Supporting a more generalized defect of autophagy, levels of lipidated LC3 are increased in Spatacsin knockout mouse embryonic fibrobasts (MEFs). Though distinct parameters of lysosomal function like processing of cathepsin D and lysosomal pH are preserved, lysosome numbers are reduced in knockout MEFs and the recovery of lysosomes during sustained starvation impaired consistent with a defect of autophagic lysosome reformation. Because lysosomes are reduced in cortical neurons and Purkinje cells in vivo, we propose that the decreased number of lysosomes available for fusion with autophagosomes impairs autolysosomal clearance, results in the accumulation of undegraded material and finally causes death of particularly sensitive neurons like cortical motoneurons and Purkinje cells in knockout mice. PMID:26284655

  6. Novel pure component contribution, mean centering of ratio spectra and factor based algorithms for simultaneous resolution and quantification of overlapped spectral signals: An application to recently co-formulated tablets of chlorzoxazone, aceclofenac and paracetamol

    Science.gov (United States)

    Toubar, Safaa S.; Hegazy, Maha A.; Elshahed, Mona S.; Helmy, Marwa I.

    2016-06-01

    In this work, resolution and quantitation of spectral signals are achieved by several univariate and multivariate techniques. The novel pure component contribution algorithm (PCCA) along with mean centering of ratio spectra (MCR) and the factor based partial least squares (PLS) algorithms were developed for simultaneous determination of chlorzoxazone (CXZ), aceclofenac (ACF) and paracetamol (PAR) in their pure form and recently co-formulated tablets. The PCCA method allows the determination of each drug at its λmax. While, the mean centered values at 230, 302 and 253 nm, were used for quantification of CXZ, ACF and PAR, respectively, by MCR method. Partial least-squares (PLS) algorithm was applied as a multivariate calibration method. The three methods were successfully applied for determination of CXZ, ACF and PAR in pure form and tablets. Good linear relationships were obtained in the ranges of 2-50, 2-40 and 2-30 μg mL- 1 for CXZ, ACF and PAR, in order, by both PCCA and MCR, while the PLS model was built for the three compounds each in the range of 2-10 μg mL- 1. The results obtained from the proposed methods were statistically compared with a reported one. PCCA and MCR methods were validated according to ICH guidelines, while PLS method was validated by both cross validation and an independent data set. They are found suitable for the determination of the studied drugs in bulk powder and tablets.

  7. Changes in biodiversity and trade-offs among ecosystem services, stakeholders, and components of well-being: the contribution of the International Long-Term Ecological Research network (ILTER to Programme on Ecosystem Change and Society (PECS

    Directory of Open Access Journals (Sweden)

    Manuel Maass

    2016-09-01

    Full Text Available The International Long-Term Ecological Research (ILTER network comprises > 600 scientific groups conducting site-based research within 40 countries. Its mission includes improving the understanding of global ecosystems and informs solutions to current and future environmental problems at the global scales. The ILTER network covers a wide range of social-ecological conditions and is aligned with the Programme on Ecosystem Change and Society (PECS goals and approach. Our aim is to examine and develop the conceptual basis for proposed collaboration between ILTER and PECS. We describe how a coordinated effort of several contrasting LTER site-based research groups contributes to the understanding of how policies and technologies drive either toward or away from the sustainable delivery of ecosystem services. This effort is based on three tenets: transdisciplinary research; cross-scale interactions and subsequent dynamics; and an ecological stewardship orientation. The overarching goal is to design management practices taking into account trade-offs between using and conserving ecosystems toward more sustainable solutions. To that end, we propose a conceptual approach linking ecosystem integrity, ecosystem services, and stakeholder well-being, and as a way to analyze trade-offs among ecosystem services inherent in diverse management options. We also outline our methodological approach that includes: (i monitoring and synthesis activities following spatial and temporal trends and changes on each site and by documenting cross-scale interactions; (ii developing analytical tools for integration; (iii promoting trans-site comparison; and (iv developing conceptual tools to design adequate policies and management interventions to deal with trade-offs. Finally, we highlight the heterogeneity in the social-ecological setting encountered in a subset of 15 ILTER sites. These study cases are diverse enough to provide a broad cross-section of contrasting

  8. Beyond starvation: An update on the autophagic machinery and its functions.

    Science.gov (United States)

    Kawabata, Tsuyoshi; Yoshimori, Tamotsu

    2016-06-01

    Autophagy was originally identified as a cytoprotective system that provides emergency backup energy and basic building blocks under starvation condition by digesting self components. Recent advances in the field unveiled that this system also protects cells against multiple types of stress, as well as invasion by pathogens. Consistent with these findings, autophagy has been redefined as a safeguard system that plays a vital role in human pathology, and this realization has led to exponential progress in autophagy research. In this review, we introduce the basic mechanisms of canonical autophagy and also discuss selective autophagy, a set of pathways that target specific cellular components for digestion; in particular, we focus on lysophagy, a recently identified mechanism required for lysosomal homeostasis.

  9. Novel monofunctional platinum (II) complex Mono-Pt induces apoptosis-independent autophagic cell death in human ovarian carcinoma cells, distinct from cisplatin.

    Science.gov (United States)

    Guo, Wen-Jie; Zhang, Yang-Miao; Zhang, Li; Huang, Bin; Tao, Fei-Fei; Chen, Wei; Guo, Zi-Jian; Xu, Qiang; Sun, Yang

    2013-07-01

    Failure to engage apoptosis appears to be a leading mechanism of resistance to traditional platinum drugs in patients with ovarian cancer. Therefore, an alternative strategy to induce cell death is needed for the chemotherapy of this apoptosis-resistant cancer. Here we report that autophagic cell death, distinct from cisplatin-induced apoptosis, is triggered by a novel monofunctional platinum (II) complex named Mono-Pt in human ovarian carcinoma cells. Mono-Pt-induced cell death has the following features: cytoplasmic vacuolation, caspase-independent, no nuclear fragmentation or chromatin condensation, and no apoptotic bodies. These characteristics integrally indicated that Mono-Pt, rather than cisplatin, initiated a nonapoptotic cell death in Caov-3 ovarian carcinoma cells. Furthermore, incubation of the cells with Mono-Pt but not with cisplatin produced an increasing punctate distribution of microtubule-associated protein 1 light chain 3 (LC3), and an increasing ratio of LC3-II to LC3-I. Mono-Pt also caused the formation of autophagic vacuoles as revealed by monodansylcadaverine staining and transmission electron microscopy. In addition, Mono-Pt-induced cell death was significantly inhibited by the knockdown of either BECN1 or ATG7 gene expression, or by autophagy inhibitors 3-methyladenine, chloroquine and bafilomycin A 1. Moreover, the effect of Mono-Pt involved the AKT1-MTOR-RPS6KB1 pathway and MAPK1 (ERK2)/MAPK3 (ERK1) signaling, since the MTOR inhibitor rapamycin increased, while the MAPK1/3 inhibitor U0126 decreased Mono-Pt-induced autophagic cell death. Taken together, our results suggest that Mono-Pt exerts anticancer effect via autophagic cell death in apoptosis-resistant ovarian cancer. These findings lead to increased options for anticancer platinum drugs to induce cell death in cancer.

  10. Asparagine slows down the breakdown of storage lipid and degradation of autophagic bodies in sugar-starved embryo axes of germinating lupin seeds.

    Science.gov (United States)

    Borek, Sławomir; Paluch-Lubawa, Ewelina; Pukacka, Stanisława; Pietrowska-Borek, Małgorzata; Ratajczak, Lech

    2017-02-01

    The research was conducted on embryo axes of yellow lupin (Lupinus luteus L.), white lupin (Lupinus albus L.) and Andean lupin (Lupinus mutabilis Sweet), which were isolated from imbibed seeds and cultured for 96h in vitro under different conditions of carbon and nitrogen nutrition. Isolated embryo axes were fed with 60mM sucrose or were sugar-starved. The effect of 35mM asparagine (a central amino acid in the metabolism of germinating lupin seeds) and 35mM nitrate (used as an inorganic kind of nitrogen) on growth, storage lipid breakdown and autophagy was investigated. The sugar-starved isolated embryo axes contained more total lipid than axes fed with sucrose, and the content of this storage compound was even higher in sugar-starved isolated embryo axes fed with asparagine. Ultrastructural observations showed that asparagine significantly slowed down decomposition of autophagic bodies, and this allowed detailed analysis of their content. We found peroxisomes inside autophagic bodies in cells of sugar-starved Andean lupin embryo axes fed with asparagine, which led us to conclude that peroxisomes may be degraded during autophagy in sugar-starved isolated lupin embryo axes. One reason for the slower degradation of autophagic bodies was the markedly lower lipolytic activity in axes fed with asparagine.

  11. Graveoline isolated from ethanolic extract of Ruta graveolens triggers apoptosis and autophagy in skin melanoma cells: a novel apoptosis-independent autophagic signaling pathway.

    Science.gov (United States)

    Ghosh, Samrat; Bishayee, Kausik; Khuda-Bukhsh, Anisur Rahman

    2014-08-01

    Anti-cancer drugs generally kill cancer cells by apoptosis but fail to do so when they become resistant and escape apoptosis signals. But these resistant cells can still be killed by autophagy. Therefore, drugs having both apoptotic and autophagic abilities are solicited in effective cancer management. In search of such a drug, we examined the efficacy of graveoline, a bioactive compound isolated from Ruta graveolens on skin melanoma A375 cells through the use of specific signaling cascades and their inhibitors. Cytotoxicity of graveoline was tested by conducting MTT assay. Induction of autophagy and apoptosis was checked. Expression of related proteins and their localization were studied by conducting immunoblot assay and through confocal microscopy, respectively. We found graveoline-induced Beclin-1 associated autophagy in A375 cells and 3-methyladenine, an inhibitor of autophagy did not affect apoptosis. Conversely, caspase inhibitor that blocked apoptosis did not affect autophagic cell death, suggesting thereby that these two were independent events. Use of reactive oxygen species (ROS) scavengers inhibited cell death, but blocking autophagy did not affect graveoline-induced ROS generation, suggesting that ROS generation ensued autophagy. Thus, graveoline-induced both apoptotic and autophagic cell death in skin melanoma cells, a desirable quality in effective anti-cancer drug design.

  12. Reduced cathepsins B and D cause impaired autophagic degradation that can be almost completely restored by overexpression of these two proteases in Sap C-deficient fibroblasts.

    Science.gov (United States)

    Tatti, Massimo; Motta, Marialetizia; Di Bartolomeo, Sabrina; Scarpa, Susanna; Cianfanelli, Valentina; Cecconi, Francesco; Salvioli, Rosa

    2012-12-01

    Saposin (Sap) C deficiency, a rare variant form of Gaucher disease, is due to mutations in the Sap C coding region of the prosaposin (PSAP) gene. Sap C is required as an activator of the lysosomal enzyme glucosylceramidase (GCase), which catalyzes glucosylceramide (GC) degradation. Deficit of either GCase or Sap C leads to the accumulation of undegraded GC and other lipids in lysosomes of monocyte/macrophage lineage. Recently, we reported that Sap C mutations affecting a cysteine residue result in increased autophagy. Here, we characterized the basis for the autophagic dysfunction. We analyzed Sap C-deficient and GCase-deficient fibroblasts and observed that autophagic disturbance was only associated with lack of Sap C. By a combined fluorescence microscopy and biochemical studies, we demonstrated that the accumulation of autophagosomes in Sap C-deficient fibroblasts is not due to enhanced autophagosome formation but to delayed degradation of autolysosomes caused, in part, to decreased amount and reduced enzymatic activity of cathepsins B and D. On the contrary, in GCase-deficient fibroblasts, the protein level and enzymatic activity of cathepsin D were comparable with control fibroblasts, whereas those of cathepsin B were almost doubled. Moreover, the enhanced expression of both these lysosomal proteases in Sap C-deficient fibroblasts resulted in close to functional autophagic degradation. Our data provide a novel example of altered autophagy as secondary event resulting from insufficient lysosomal function.

  13. Autophagic Turnover of Inactive 26S Proteasomes in Yeast Is Directed by the Ubiquitin Receptor Cue5 and the Hsp42 Chaperone

    Directory of Open Access Journals (Sweden)

    Richard S. Marshall

    2016-08-01

    Full Text Available The autophagic clearance of 26S proteasomes (proteaphagy is an important homeostatic mechanism within the ubiquitin system that modulates proteolytic capacity and eliminates damaged particles. Here, we define two proteaphagy routes in yeast that respond to either nitrogen starvation or particle inactivation. Whereas the core autophagic machineries required for Atg8 lipidation and vesiculation are essential for both routes, the upstream Atg1 kinase participates only in starvation-induced proteaphagy. Following inactivation, 26S proteasomes become extensively modified with ubiquitin. Although prior studies with Arabidopsis implicated RPN10 in tethering ubiquitylated proteasomes to ATG8 lining the autophagic membranes, yeast proteaphagy employs the evolutionarily distinct receptor Cue5, which simultaneously binds ubiquitin and Atg8. Proteaphagy of inactivated proteasomes also requires the oligomeric Hsp42 chaperone, suggesting that ubiquitylated proteasomes are directed by Hsp42 to insoluble protein deposit (IPOD-type structures before encapsulation. Together, Cue5 and Hsp42 provide a quality control checkpoint in yeast directed at recycling dysfunctional 26S proteasomes.

  14. Functional drug screening reveals anticonvulsants as enhancers of mTOR-independent autophagic killing of Mycobacterium tuberculosis through inositol depletion.

    Science.gov (United States)

    Schiebler, Mark; Brown, Karen; Hegyi, Krisztina; Newton, Sandra M; Renna, Maurizio; Hepburn, Lucy; Klapholz, Catherine; Coulter, Sarah; Obregón-Henao, Andres; Henao Tamayo, Marcela; Basaraba, Randall; Kampmann, Beate; Henry, Katherine M; Burgon, Joseph; Renshaw, Stephen A; Fleming, Angeleen; Kay, Robert R; Anderson, Karen E; Hawkins, Phillip T; Ordway, Diane J; Rubinsztein, David C; Floto, Rodrigo Andres

    2015-02-01

    Mycobacterium tuberculosis (MTB) remains a major challenge to global health made worse by the spread of multidrug resistance. We therefore examined whether stimulating intracellular killing of mycobacteria through pharmacological enhancement of macroautophagy might provide a novel therapeutic strategy. Despite the resistance of MTB to killing by basal autophagy, cell-based screening of FDA-approved drugs revealed two anticonvulsants, carbamazepine and valproic acid, that were able to stimulate autophagic killing of intracellular M. tuberculosis within primary human macrophages at concentrations achievable in humans. Using a zebrafish model, we show that carbamazepine can stimulate autophagy in vivo and enhance clearance of M. marinum, while in mice infected with a highly virulent multidrug-resistant MTB strain, carbamazepine treatment reduced bacterial burden, improved lung pathology and stimulated adaptive immunity. We show that carbamazepine induces antimicrobial autophagy through a novel, evolutionarily conserved, mTOR-independent pathway controlled by cellular depletion of myo-inositol. While strain-specific differences in susceptibility to in vivo carbamazepine treatment may exist, autophagy enhancement by repurposed drugs provides an easily implementable potential therapy for the treatment of multidrug-resistant mycobacterial infection.

  15. Paeoniflorin protects HUVECs from AGE-BSA-induced injury via an autophagic pathway by acting on the RAGE.

    Science.gov (United States)

    Chen, Yufang; Du, Xing; Zhou, Yande; Zhang, Yanlin; Yang, Yaping; Liu, Zhihua; Liu, Chunfeng; Xie, Ying

    2015-01-01

    The aim of our study was to investigate the protective effects of Paeoniflorin (PF) against injury induced by AGE-modified bovine serum albumin (AGE-BSA) in human umbilical vein endothelial cells (HUVECs), and to examine the underlying mechanisms of these effects. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was used to determine cell viability. Protein expression levels were determined by western blotting. For function-blocking experiments, we used small interfering RNA molecules (siRNA) for function-blocking experiments. At 6 h, we found that 100 μg/mL AGE-BSA reduced the viability of HUVECs. However, pretreatment with PF restored cell viability in a dose-dependent manner. AGE-BSA increased the levels of microtubule-associated protein light chain 3-II (LC3-II) and the receptor for advanced glycation end products (RAGE). Expression of p62 protein was also increased, but not at a statistically significant level. Pretreatment with PF further increased levels of LC3-II and RAGE, but reduced the expression of p62. In cells transfected with Atg5 and RAGE siRNA, cell viability and expression of LC3-II decreased in both the AGE-BSA and PF + AGE-BSA treatments. PF can protect HUVECs from AGE-BSA-induced injury by upregulating autophagy and promoting the completion of autophagy flux. RAGE plays an important role in this autophagic protection effect.

  16. Electronic components

    CERN Document Server

    Colwell, Morris A

    1976-01-01

    Electronic Components provides a basic grounding in the practical aspects of using and selecting electronics components. The book describes the basic requirements needed to start practical work on electronic equipment, resistors and potentiometers, capacitance, and inductors and transformers. The text discusses semiconductor devices such as diodes, thyristors and triacs, transistors and heat sinks, logic and linear integrated circuits (I.C.s) and electromechanical devices. Common abbreviations applied to components are provided. Constructors and electronics engineers will find the book useful

  17. p53-mediated autophagic regulation: A prospective strategy for cancer therapy.

    Science.gov (United States)

    Tang, Juanjuan; Di, Jiehui; Cao, Huan; Bai, Jin; Zheng, Junnian

    2015-07-28

    Autophagy is a major catabolic process that degrades and recycles cytosolic components in autophagosomes, which fuse with lysosomes. This process enables starving cells to sustain their energy requirements and metabolic states, thus facilitating their survival, especially in cancer pathogenesis. The regulation of autophagy is quite intricate. It involves a series of signaling cascades including p53, known as the best-characterized tumor suppressor protein. Recent reports have indicated that p53 plays dual roles in regulating autophagy depending on its subcellular localization. Nuclear p53 facilitates autophagy by transactivating its target genes, whereas cytoplasmic p53 mainly inhibits autophagy through extranuclear, transcription-independent mechanisms. The relationship between autophagy and neoplasia is complicated. It may be intrinsically associated with the functional status of p53, but this is not clearly elucidated. This review focuses on the role of p53 as a master regulator of autophagy. We conclude that the contextual role of autophagy in cancer, which could be switched by p53 status, is expected to be developed into a new anticancer therapeutic approach.

  18. FLCN, a novel autophagy component, interacts with GABARAP and is regulated by ULK1 phosphorylation.

    Science.gov (United States)

    Dunlop, Elaine A; Seifan, Sara; Claessens, Tijs; Behrends, Christian; Kamps, Miriam Af; Rozycka, Ewelina; Kemp, Alain J; Nookala, Ravi K; Blenis, John; Coull, Barry J; Murray, James T; van Steensel, Maurice Am; Wilkinson, Simon; Tee, Andrew R

    2014-10-01

    Birt-Hogg-Dubé (BHD) syndrome is a rare autosomal dominant condition caused by mutations in the FLCN gene and characterized by benign hair follicle tumors, pneumothorax, and renal cancer. Folliculin (FLCN), the protein product of the FLCN gene, is a poorly characterized tumor suppressor protein, currently linked to multiple cellular pathways. Autophagy maintains cellular homeostasis by removing damaged organelles and macromolecules. Although the autophagy kinase ULK1 drives autophagy, the underlying mechanisms are still being unraveled and few ULK1 substrates have been identified to date. Here, we identify that loss of FLCN moderately impairs basal autophagic flux, while re-expression of FLCN rescues autophagy. We reveal that the FLCN complex is regulated by ULK1 and elucidate 3 novel phosphorylation sites (Ser406, Ser537, and Ser542) within FLCN, which are induced by ULK1 overexpression. In addition, our findings demonstrate that FLCN interacts with a second integral component of the autophagy machinery, GABA(A) receptor-associated protein (GABARAP). The FLCN-GABARAP association is modulated by the presence of either folliculin-interacting protein (FNIP)-1 or FNIP2 and further regulated by ULK1. As observed by elevation of GABARAP, sequestome 1 (SQSTM1) and microtubule-associated protein 1 light chain 3 (MAP1LC3B) in chromophobe and clear cell tumors from a BHD patient, we found that autophagy is impaired in BHD-associated renal tumors. Consequently, this work reveals a novel facet of autophagy regulation by ULK1 and substantially contributes to our understanding of FLCN function by linking it directly to autophagy through GABARAP and ULK1.

  19. The novel pterostilbene derivative ANK-199 induces autophagic cell death through regulating PI3 kinase class III/beclin 1/Atg‑related proteins in cisplatin‑resistant CAR human oral cancer cells.

    Science.gov (United States)

    Hsieh, Min-Tsang; Chen, Hao-Ping; Lu, Chi-Cheng; Chiang, Jo-Hua; Wu, Tian-Shung; Kuo, Daih-Huang; Huang, Li-Jiau; Kuo, Sheng-Chu; Yang, Jai-Sing

    2014-08-01

    Pterostilbene is an effective chemopreventive agent against multiple types of cancer cells. A novel pterostilbene derivative, ANK-199, was designed and synthesized by our group. Its antitumor activity and mechanism in cisplatin-resistant CAR human oral cancer cells were investigated in this study. Our results show that ANK-199 has an extremely low toxicity in normal oral cell lines. The formation of autophagic vacuoles and acidic vesicular organelles (AVOs) was observed in the ANK-199-treated CAR cells by monodansylcadaverine (MDC) and acridine orange (AO) staining, suggesting that ANK-199 is able to induce autophagic cell death in CAR cells. Neither DNA fragmentation nor DNA condensation was observed, which means that ANK-199-induced cell death is not triggered by apoptosis. In accordance with morphological observation, 3-MA, a specific inhibitor of PI3K kinase class III, can inhibit the autophagic vesicle formation induced by ANK-199. In addition, ANK-199 is also able to enhance the protein levels of autophagic proteins, Atg complex, beclin 1, PI3K class III and LC3-II, and mRNA expression of autophagic genes Atg7, Atg12, beclin 1 and LC3-II in the ANK-199-treated CAR cells. A molecular signaling pathway induced by ANK-199 was therefore summarized. Results presented in this study show that ANK-199 may become a novel therapeutic reagent for the treatment of oral cancer in the near future (patent pending).

  20. Multilevel Contracts for Trusted Components

    CERN Document Server

    Messabihi, Mohamed; Attiogbé, Christian; 10.4204/EPTCS.37.6

    2010-01-01

    This article contributes to the design and the verification of trusted components and services. The contracts are declined at several levels to cover then different facets, such as component consistency, compatibility or correctness. The article introduces multilevel contracts and a design+verification process for handling and analysing these contracts in component models. The approach is implemented with the COSTO platform that supports the Kmelia component model. A case study illustrates the overall approach.

  1. Propofol prevents autophagic cell death following oxygen and glucose deprivation in PC12 cells and cerebral ischemia-reperfusion injury in rats.

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    Derong Cui

    Full Text Available BACKGROUND: Propofol exerts protective effects on neuronal cells, in part through the inhibition of programmed cell death. Autophagic cell death is a type of programmed cell death that plays elusive roles in controlling neuronal damage and metabolic homeostasis. We therefore studied whether propofol could attenuate the formation of autophagosomes, and if so, whether the inhibition of autophagic cell death mediates the neuroprotective effects observed with propofol. METHODOLOGY/PRINCIPAL FINDINGS: The cell model was established by depriving the cells of oxygen and glucose (OGD for 6 hours, and the rat model of ischemia was introduced by a transient two-vessel occlusion for 10 minutes. Transmission electron microscopy (TEM revealed that the formation of autophagosomes and autolysosomes in both neuronal PC12 cells and pyramidal rat hippocampal neurons after respective OGD and ischemia/reperfusion (I/R insults. A western blot analysis revealed that the autophagy-related proteins, such as microtubule-associated protein 1 light chain 3 (LC3-II, Beclin-1 and class III PI3K, were also increased accordingly, but cytoprotective Bcl-2 protein was decreased. The negative effects of OGD and I/R, including the formation of autophagosomes and autolysosomes, the increase in LC3-II, Beclin-1 and class III PI3K expression and the decline in Bcl-2 production were all inhibited by propofol and specific inhibitors of autophagy, such as 3-methyladenine (3-MA, LY294002 and Bafilomycin A1 (Baf,. Furthermore, in vitro OGD cultures and in vivo I/R rats showed an increase in cell survival following the administration of propofol, as assessed by an MTT assay or histochemical analyses. CONCLUSIONS/SIGNIFICANCE: Our data suggest that propofol can markedly attenuate autophagic processes via the decreased expression of autophagy-related proteins in vitro and in vivo. This inhibition improves cell survival, which provides a novel explanation for the pleiotropic effects of

  2. Physiological response of Pichia pastoris GS115 to methanol-induced high level production of the Hepatitis B surface antigen: catabolic adaptation, stress responses, and autophagic processes

    Directory of Open Access Journals (Sweden)

    Vanz Ana Leticia

    2012-08-01

    degradation of HBsAg could proceed via the ERAD pathway and through the proteasome. However, the amount of HBsAg did not show any significant decline during the cultivation revealing its general protection from proteolytic degradation. During the methanol fed-batch phase, induction of vacuolar proteases (e.g. strong increase of APR1 and constitutive autophagic processes were observed. Vacuolar enclosures were mainly found around peroxisomes and not close to HBsAg deposits and, thus, were most likely provoked by peroxisomal components damaged by reactive oxygen species generated by methanol oxidation. Conclusions In the methanol fed-batch phase P. pastoris is exposed to dual stress; stress resulting from methanol degradation and stress resulting from the production of the recombinant protein leading to the induction of oxidative stress and unfolded protein response pathways, respectively. Finally, the modest increase of methanol assimilatory enzymes compared to the strong increase of methanol dissimilatory enzymes suggests here a potential to increase methanol incorporation into biomass/product through metabolic enhancement of the methanol assimilatory pathway.

  3. Studying p53 family proteins in yeast: Induction of autophagic cell death and modulation by interactors and small molecules

    Energy Technology Data Exchange (ETDEWEB)

    Leão, Mariana; Gomes, Sara; Bessa, Cláudia; Soares, Joana; Raimundo, Liliana [REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira n. 164, 4050-313 Porto (Portugal); Monti, Paola; Fronza, Gilberto [Mutagenesis Unit, Istituto di Ricerca e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria San Martino-IST-Istituto Nazionale per la Ricerca sul Cancro, 16132 Genoa (Italy); Pereira, Clara [REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira n. 164, 4050-313 Porto (Portugal); Saraiva, Lucília, E-mail: lucilia.saraiva@ff.up.pt [REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira n. 164, 4050-313 Porto (Portugal)

    2015-01-01

    In this work, the yeast Saccharomyces cerevisiae was used to individually study human p53, p63 (full length and truncated forms) and p73. Using this cell system, the effect of these proteins on cell proliferation and death, and the influence of MDM2 and MDMX on their activities were analyzed. When expressed in yeast, wild-type p53, TAp63, ΔNp63 and TAp73 induced growth inhibition associated with S-phase cell cycle arrest. This growth inhibition was accompanied by reactive oxygen species production and autophagic cell death. Furthermore, they stimulated rapamycin-induced autophagy. On the contrary, none of the tested p53 family members induced apoptosis either per se or after apoptotic stimuli. As previously reported for p53, also TAp63, ΔNp63 and TAp73 increased actin expression levels and its depolarization, suggesting that ACT1 is also a p63 and p73 putative yeast target gene. Additionally, MDM2 and MDMX inhibited the activity of all tested p53 family members in yeast, although the effect was weaker on TAp63. Moreover, Nutlin-3a and SJ-172550 were identified as potential inhibitors of the p73 interaction with MDM2 and MDMX, respectively. Altogether, the yeast-based assays herein developed can be envisaged as a simplified cell system to study the involvement of p53 family members in autophagy, the modulation of their activities by specific interactors (MDM2 and MDMX), and the potential of new small molecules to modulate these interactions. - Highlights: • p53, p63 and p73 are individually studied in the yeast S. cerevisiae. • p53 family members induce ROS production, cell cycle arrest and autophagy in yeast. • p53 family members increase actin depolarization and expression levels in yeast. • MDM2 and MDMX inhibit the activity of p53 family members in yeast. • Yeast can be a useful tool to study the biology and drugability of p53, p63 and p73.

  4. [Contributions of the Council of Europe's Blood Transfusion Steering Committee to the determination of rules for the selection of donors of blood and blood components and the study of sexual behaviors having an impact on blood safety].

    Science.gov (United States)

    Behr-Gross, M-E; Heiden, M; Norda, R

    2013-05-01

    In November 2009, the Council of Europe's Blood Transfusion Steering Committee created a group of experts to explore the problem of behaviors having an impact on the management of donors of blood and blood components and on blood transfusion safety in Europe. This ad hoc group sought a harmonised interpretation of temporary exclusion (or temporary deferral), as opposed to permanent exclusion (or permanent deferral), in the context of the selection of donors of blood and blood components. It was also given the mandate to assess, on the basis of available data, the possibility of differentiating "at risk" behaviours from behaviours "at high risk" of contamination by serious infectious diseases transmitted by blood, blood components or derived therapeutic products. The primary objective of this work was to ensure the safety of blood, blood components and derived therapeutic products for future recipients by promoting a risk analysis-based approach, given that some countries envisaged amending their provisions for donor selection. However, a risk analysis can only be performed on groups, not individuals, which may give the impression of a discriminatory approach, so it needed to be justified in the context of transfusion safety. A collaborative project, which included an investigation phase, led to the drafting of a technical memorandum that summarised the data collected in ten Council of Europe member states on the selection criteria for blood donors and the epidemiology of infectious diseases (with a focus on human immunodeficiency virus) in the general population and among blood donors. The technical memorandum was published in 2011 on the European Directorate for the Quality of Medicines and Healthcare website dedicated to this project. A draft resolution of the Committee of Ministers of the Council of Europe was then developed by the Council of Europe's Blood Transfusion Steering Committee. This text was circulated among member and observer states of the Council

  5. Multi-component modelling of human brain tissue: a contribution to the constitutive and computational description of deformation, flow and diffusion processes with application to the invasive drug-delivery problem.

    Science.gov (United States)

    Ehlers, Wolfgang; Wagner, Arndt

    2015-01-01

    Human brain tissue is complex and multi-component in nature. It consists of an anisotropic hyperelastic solid material composed of tissue cells and blood vessel walls. Brain tissue is permeated by two viscous pore liquids, the interstitial fluid and the blood. Both liquids are mobile within the tissue and exhibit a significant anisotropic perfusion behaviour. To model this complex aggregate, the well-founded Theory of Porous Media, a continuum-mechanical approach for the description of multi-component aggregates, is used. To include microscopic information, the model is enhanced by tissue characteristics obtained from medical imaging techniques. Moreover, the model is applied to invasive drug-delivery strategies, i.e. the direct extra-vascular infusion of therapeutic agents. For this purpose, the overall interstitial fluid is treated as a real two-component mixture of a liquid solvent and a dissolved therapeutic solute. Finally, the continuum-mechanical model results in a set of strongly coupled partial differential equations which are spatially discretised using mixed finite elements and solved in a monolithic manner with an implicit Euler time-integration scheme. Numerical examples demonstrate the applicability of the presented model.

  6. Study of the contribution of the different components of atmospheric cosmic radiation in dose received by the aircraft crew; Avaliacao da contribuicao dos diferentes componentes da radiacao cosmica atmosferica na dose em tripulacoes de aeronaves

    Energy Technology Data Exchange (ETDEWEB)

    Pereira, Marlon A.; Prado, Adriane C.M., E-mail: adriane.acm@hotmail.com, E-mail: marlon@ieav.cta.br [Instituto Tecnologico de Aeronautica (ITA/DCTA), Sao Jose dos Campos, SP (Brazil); Federico, Claudio A.; Goncalez, Odair L., E-mail: claudiofederico@ieav.cta.br, E-mail: odairl@ieav.cta.br [Instituto de Estudos Avancados (IEAv/DCTA), Sao Jose dos Campos, SP (Brazil)

    2014-07-01

    The crews and aircraft passengers are exposed to atmospheric cosmic radiation. The flow of this radiation is modulated by the solar cycle and space weather, varying with the geomagnetic latitude and altitude. This paper presents a study of the contributions of radiation in total ambient dose equivalent of the crews depending on flight altitude up to 20 km, during maximum and minimum solar and in equatorial and polar regions. The results of calculations of the particle flows generated by the EXPACS and QARM codes are used. The particles evaluated that contributing significantly in the ambient dose equivalent are neutrons, protons, electrons, positrons, alphas, photons, muons and charged pions. This review allows us to characterize the origin of the dose received by crews and also support a project of a dosimetric system suitable for this ionizing radiation field in aircraft and on the ground.

  7. ER Stress and Autophagic Perturbations Lead to Elevated Extracellular α-Synuclein in GBA-N370S Parkinson's iPSC-Derived Dopamine Neurons

    Directory of Open Access Journals (Sweden)

    Hugo J.R. Fernandes

    2016-03-01

    Full Text Available Heterozygous mutations in the glucocerebrosidase gene (GBA represent the strongest common genetic risk factor for Parkinson's disease (PD, the second most common neurodegenerative disorder. However, the molecular mechanisms underlying this association are still poorly understood. Here, we have analyzed ten independent induced pluripotent stem cell (iPSC lines from three controls and three unrelated PD patients heterozygous for the GBA-N370S mutation, and identified relevant disease mechanisms. After differentiation into dopaminergic neurons, we observed misprocessing of mutant glucocerebrosidase protein in the ER, associated with activation of ER stress and abnormal cellular lipid profiles. Furthermore, we observed autophagic perturbations and an enlargement of the lysosomal compartment specifically in dopamine neurons. Finally, we found increased extracellular α-synuclein in patient-derived neuronal culture medium, which was not associated with exosomes. Overall, ER stress, autophagic/lysosomal perturbations, and elevated extracellular α-synuclein likely represent critical early cellular phenotypes of PD, which might offer multiple therapeutic targets.

  8. Aqueous Extract of Solanum nigrum Leaf Activates Autophagic Cell Death and Enhances Docetaxel-Induced Cytotoxicity in Human Endometrial Carcinoma Cells

    Directory of Open Access Journals (Sweden)

    Cheng-Jeng Tai

    2012-01-01

    Full Text Available Chemotherapy is the main approach in dealing with advanced and recurrent endometrial cancer. An effective complementary ingredient can be helpful in improving the clinical outcome. Aqueous extract of Solanum nigrum leaf (AE-SN is a principal ingredient for treating cancer patients in traditional Chinese medicinal practice but lacks sufficient evidence to verify its tumor suppression efficacy. This study evaluated the antitumor effects of AE-SN and also assessed the synergistic effects of AE-SN with docetaxel On the human endometrial cancer cell lines, HEC1A, HEC1B, and KLE. The activation of apoptotic markers, caspase-3 and poly-ADP-ribose polymerase, and autophagic marker, microtubule-associated protein 1 light chain 3 A/B, wAS determined to clarify the cell death pathways responsible for AE-SN induced tumor cell death. Results indicated that AE-SN-treatment has significant cytotoxicity on the tested endometrial cancer cells with accumulation of LC3 A/B II and demonstrated a synergistic effect of AE-SN and docetaxel in HEC1A and HEC1B cells, but not KLE cells. In conclusion, AE-SN treatment was effective in suppressing endometrial cancer cells via the autophagic pathway and was also capable of enhancing the cytotoxicity of docetaxel in human endometrial cancer cells. Our results provide meaningful evidence for integrative cancer therapy in the future.

  9. Bioinert Anodic Alumina Nanotubes for Targeting of Endoplasmic Reticulum Stress and Autophagic Signaling: A Combinatorial Nanotube-Based Drug Delivery System for Enhancing Cancer Therapy.

    Science.gov (United States)

    Wang, Ye; Kaur, Gagandeep; Chen, Yuting; Santos, Abel; Losic, Dusan; Evdokiou, Andreas

    2015-12-16

    Although nanoparticle-based targeted delivery systems have gained promising achievements for cancer therapy, the development of sophisticated strategies with effective combinatorial therapies remains an enduring challenge. Herein, we report the fabrication of a novel nanomaterial, so-called anodic alumina nanotubes (AANTs) for proof-of-concept cancer therapy by targeting cell signaling networks. This strategy is to target autophagic and endoplasmic reticulum (ER) stress signaling by using thapsigargin (TG)-loaded AANTs cotreated with an autophagy inhibitor 3-methyladenine (3-MA). We first show that AANTs are nontoxic and can activate autophagy in different cell types including human fibroblast cells (HFF), human monocyte cells (THP-1), and human breast cancer cells (MDA-MB 231-TXSA). Treatment with 3-MA at a nontoxic dose reduced the level of autophagy induced by AANTs, and consequently sensitized breast cancer cells to AANTs-induced cellular stresses. To target autophagic and ER stress signaling networking, breast cancer cells were treated with 3-MA together with AANTs loaded with the prototype ER stress inducer TG. We demonstrated that 3-MA enhanced the cancer cell killing effect of AANTs loaded with TG. This effect was associated with enhanced ER stress signaling due to the combination effect of TG and 3-MA. These findings not only demonstrate the excellent biocompatibility of AANTs as novel biomaterials but also provide new opportunities for developing ER- and autophagy-targeted delivery systems for future clinical cancer therapy.

  10. The Ketone Body, β-Hydroxybutyrate Stimulates the Autophagic Flux and Prevents Neuronal Death Induced by Glucose Deprivation in Cortical Cultured Neurons.

    Science.gov (United States)

    Camberos-Luna, Lucy; Gerónimo-Olvera, Cristian; Montiel, Teresa; Rincon-Heredia, Ruth; Massieu, Lourdes

    2016-03-01

    Glucose is the major energy substrate in brain, however, during ketogenesis induced by starvation or prolonged hypoglycemia, the ketone bodies (KB), acetoacetate and β-hydroxybutyrate (BHB) can substitute for glucose. KB improve neuronal survival in diverse injury models, but the mechanisms by which KB prevent neuronal damage are still not well understood. In the present study we have investigated whether protection by the D isomer of BHB (D-BHB) against neuronal death induced by glucose deprivation (GD), is related to autophagy. Autophagy is a lysosomal-dependent degradation process activated during nutritional stress, which leads to the digestion of damaged proteins and organelles providing energy for cell survival. Results show that autophagy is activated in cortical cultured neurons during GD, as indicated by the increase in the levels of the lipidated form of the microtubule associated protein light chain 3 (LC3-II), and the number of autophagic vesicles. At early phases of glucose reintroduction (GR), the levels of p62 declined suggesting that the degradation of the autophagolysosomal content takes place at this time. In cultures exposed to GD and GR in the presence of D-BHB, the levels of LC3-II and p62 rapidly declined and remained low during GR, suggesting that the KB stimulates the autophagic flux preventing autophagosome accumulation and improving neuronal survival.

  11. cAMP and EPAC are key players in the regulation of the signal transduction pathway involved in the α-hemolysin autophagic response.

    Directory of Open Access Journals (Sweden)

    María Belén Mestre

    Full Text Available Staphylococcus aureus is a microorganism that causes serious diseases in the human being. This microorganism is able to escape the phagolysosomal pathway, increasing intracellular bacterial survival and killing the eukaryotic host cell to spread the infection. One of the key features of S. aureus infection is the production of a series of virulence factors, including secreted enzymes and toxins. We have shown that the pore-forming toxin α-hemolysin (Hla is the S. aureus-secreted factor responsible for the activation of the autophagic pathway and that this response occurs through a PI3K/Beclin1-independent form. In the present report we demonstrate that cAMP has a key role in the regulation of this autophagic response. Our results indicate that cAMP is able to inhibit the autophagy induced by Hla and that PKA, the classical cAMP effector, does not participate in this regulation. We present evidence that EPAC and Rap2b, through calpain activation, are the proteins involved in the regulation of Hla-induced autophagy. Similar results were obtained in cells infected with different S. aureus strains. Interestingly, in this report we show, for the first time to our knowledge, that both EPAC and Rap2b are recruited to the S. aureus-containing phagosome. We believe that our findings have important implications in understanding innate immune processes involved in intracellular pathogen invasion of the host cell.

  12. Micromechanical modelling of heterogeneous materials in transient conditions: contributions for the study of the ageing of structural components under service; Modelisation micromecanique des materiaux heterogenes en regimes transitoires: contributions en vue de l'etude du vieillissement des structures en service

    Energy Technology Data Exchange (ETDEWEB)

    Masson, R.

    2010-12-20

    considering the particular situation where regions of the representative volume element have ill-defined mechanical properties. In the linear elastic case, new bounds for the effective behaviour are derived by marrying the structural analysis and a variational approach. This last work opens on important prospects for further works: more tightened bounds, nonlinear behaviours,... Considering homogenisation methods, further works are precisely defined, in particular for polycrystalline materials. In that situation, the field of investigation widens clearly (Fatigue, Large strains,...) thanks to the internal variables formulation proposed. Lastly, the simulation of irradiation effects constitutes the third topic of interest for the years to come, the general objective being to better predict the effects of the swelling strains induced by irradiation on the behaviour of structural components under service. (author) [French] La modelisation du comportement mecanique des materiaux de structure se nourrit de plus en plus de parametres microstructuraux. Dans ce cadre, les methodes d'homogeneisation presentent l'avantage de fournir des methodes deductives qui, a partir des proprietes et de la repartition spatiale des heterogeneites, deduisent les proprietes effectives du materiau considere. Neanmoins de nombreuses applications soulevent encore des difficultes. C'est en particulier le cas des materiaux de structure presentant un comportement elasto-viscoplastique et soumis a un trajet de chargement non monotone et non isotherme. Progresser sur le traitement par homogeneisation de ces situations concretes constitue precisement le fil conducteur des differentes contributions presentees dans ce memoire d'HDR. Dans le cas elastique lineaire, de nouvelles expressions pour le calcul du tenseur d'Eshelby sont tout d'abord etablies afin d'ameliorer l'efficacite des methodes d'homogeneisation habituellement proposees. Toujours pour des comportements

  13. Poster contributions; Contributions par affiches

    Energy Technology Data Exchange (ETDEWEB)

    Allegraud, K.; Gatilova, I.; Guaitella, O.; Ionikh, Y.; Roepcke, J.; Rousseau, A.; Aranchuk, L.E.; Larour, J.; Asad, S.; Tendero, C.; Tixier, C.; Jaoul, C.; Tristant, P.; Boisse-Laporte, C.; Leprince, P.; Leniniven, C.; Assouar, M.B.; Jimenez Rioboo, R.J.; Aubert, X.; Rousseau, A.; Sadeghi, N.; Bekstein, A.; Benhenni, M.; Yousfi, M.; Bousquet, A.; Granier, A.; Cartry, G.; Calafat, M.; Escaich, D.; Raynaud, P.; Clergereaux, R.; Cardoso, R.P.; Belmonte, T.; Henrion, G.; Sadeghi, N.; Cavarroc, M.; Mikikian, M.; Tessier, Y.; Boufendi, I.; Celestin, S.; Guaitella, O.; Bourdon, A.; Rousseau, A.; Cernogora, G.; Szopa, C.; Cavarroc, M.; Boufendi, I.; Commaux, N.; Geraud, A.; Pegourie, B.; Clairet, F.; Gil, C.; Gros, G.; Gunn, J.; Joffrin, E.; Hertout, P.; Costin, C.; Choimet, J.B.; Minea, T.; Couedel, L.; Mikikian, M.; Tessier, Y.; Boufendi, I.; Samarian, A.A.; Cousin, R.; Larour, J.; Gouard, P.; Raymond, P.; Curley, G.A.; Booth, J.P.; Corr, C.S.; Foldes, T.; Guillon, J.; Czarny, O.; Huysmans, G.; Daniel, A.; Belmonte, T.; Poucques, L. de; Imbert, J.C.; Teule-Gay, L.; Boisse-Laporte, C.; Devaux, S.; Manfredi, G.; Dif-Pradalier, G.; Grandgirard, V.; Sarazin, Y.; Garbet, X.; Ghendrih, Ph.; Dong, B.; Bauchire, J.M.; Pouvesle, J.M.; Magnier, P.; Hong, D.; Duluard, C.; Tillocher, T.; Mekkakia Maaza, N.; Dussart, R.; Mellhaoui, X.; Lefaucheux, P.; Puech, M.; Ranson, P.; Faudot, E.; Heuraux, S.; Colas, L.; Fubiani, G.; Boilson, D.; Hemsworth, R.S.; Gatilova, L.; Allegraud, K.; Ionikh, Y.; Roepcke, J.; Cartry, G.; Rousseau, A.; Gauthier, J.C.; Fourment, C.; Schurtz, G.; Nicolai, Ph.; Peyrusse, O.; Feugeas, J.L

    2006-07-01

    This document gathers the poster contributions among which 11 are relevant for fusion plasmas or particle acceleration: 1) the spectral study of a micro plasma from an X-pinch explosion; 2) experiments with a plasma density greater than the Greenwald value via the injection of icicles in Tore-Supra; 3) Bezier's surfaces and finite elements method for non-linear MHD; 4) 2-dimensional simulation of the RF casings before the ICRF antennas in tokamaks; 5) negative ion sources for ITER; 6) experimental characterization of electron heat transport on the laser integration line; 7) comparison of fluctuation measurement methods of plasma density via reflectometry in mode-o and mode-x in Tore-Supra; 8) water-bag model applied to kinetics equations of magnetic fusion plasmas; 9) computerized simulation of electron acceleration in plasma waves generated in a capillary pipe through laser wakefield; 10) the slowing-down of an alpha particle in a strongly magnetized dense plasma; and 11) stochastic processes of particle trapping by a wave in a magnetized plasma. (A.C.)

  14. PAMAM Nanoparticles Promote Acute Lung Injury by Inducing Autophagic Cell Death through the Akt-TSC2-mTOR Signaling Pathway

    Institute of Scientific and Technical Information of China (English)

    Chenggang Li; Haolin Liu; Yang Sun; Hongliang Wang; Feng Guo; Shuan Rao; Jiejie Deng; Yanli Zhang; Yufa Miao; Chenying Guo; Jie Meng; Xiping Chen; Limin Li; Dangsheng Li; Haiyan Xu; Heng Wang; Bo Li; Chengyu Jiang

    2009-01-01

    Nanotechnology is an important and emerging industry with a projected annual market of around one trillion US dollars by 2011–2015. Concerns about the toxicity of nanomaterials in humans, however, have recently been raised. Although studies of nanoparticle toxicity have focused on lung disease the molecular link between nanoparticle exposure and lung injury remained unclear. In this report, we show that cationic Starburst polyamidoamine dendrimer (PAMAM), a class of nanomaterials that are being widely developed for clinical applications can induce acute lung injury in vivo. PAMAM triggers autophagic cell death by deregulating the Akt-TSC2-mTOR signaling pathway. The autophagy inhibitor 3-methyladenine rescued PAMAM dendrimer-induced cell death and ameliorated acute lung injury caused by PAMAM in mice. Our data provide a molecular explanation for nanoparticle-induced lung injury, and suggest potential remedies to address the growing concerns of nanotechnology safety.

  15. The Autophagic Process Occurs in Human Bone Metastasis and Implicates Molecular Mechanisms Differently Affected by Rab5a in the Early and Late Stages

    Directory of Open Access Journals (Sweden)

    Paola Maroni

    2016-03-01

    Full Text Available Autophagy favours metastatic growth through fuelling energy and nutrients and resistance to anoikis, typical of disseminated-tumour cells. The autophagic process, mediated by a unique organelle, the autophagosome, which fuses with lysosomes, is divided into three steps. Several stages, especially early omegasome formation and isolation-membrane initiation, remain controversial; molecular mechanisms involve the small-GTPase Rab5a, which regulates vesicle traffic for autophagosome formation. We examined Rab5a involvement in the function of key members of ubiquitin-conjugation systems, Atg7 and LC3-lipidated, interacting with the scaffold-protein p62. Immunohistochemistry of Rab5a was performed in human specimens of bone metastasis and pair-matched breast carcinoma; the autophagic-molecular mechanisms affected by Rab5a were evaluated in human 1833 bone metastatic cells, derived from breast-carcinoma MDA-MB231 cells. To clarify the role of Rab5a, 1833 cells were transfected transiently with Rab5a-dominant negative, and/or stably with the short-hairpin RNA Atg7, were exposed to two inhibitors of autolysosome function, and LC3II and p62 expression was measured. We showed basal autophagy in bone-metastatic cells and the pivotal role of Rab5a together with Beclin 1 between the early stages, elongation of isolation membrane/closed autophagosome mediated by Atg7, and the late-degradative stages. This regulatory network might occur in bone-metastasis and in high-grade dysplastic lesions, preceding invasive-breast carcinoma and conferring phenotypic characteristics for dissemination.

  16. The Autophagic Process Occurs in Human Bone Metastasis and Implicates Molecular Mechanisms Differently Affected by Rab5a in the Early and Late Stages

    Science.gov (United States)

    Maroni, Paola; Bendinelli, Paola; Resnati, Massimo; Matteucci, Emanuela; Milan, Enrico; Desiderio, Maria Alfonsina

    2016-01-01

    Autophagy favours metastatic growth through fuelling energy and nutrients and resistance to anoikis, typical of disseminated-tumour cells. The autophagic process, mediated by a unique organelle, the autophagosome, which fuses with lysosomes, is divided into three steps. Several stages, especially early omegasome formation and isolation-membrane initiation, remain controversial; molecular mechanisms involve the small-GTPase Rab5a, which regulates vesicle traffic for autophagosome formation. We examined Rab5a involvement in the function of key members of ubiquitin-conjugation systems, Atg7 and LC3-lipidated, interacting with the scaffold-protein p62. Immunohistochemistry of Rab5a was performed in human specimens of bone metastasis and pair-matched breast carcinoma; the autophagic-molecular mechanisms affected by Rab5a were evaluated in human 1833 bone metastatic cells, derived from breast-carcinoma MDA-MB231 cells. To clarify the role of Rab5a, 1833 cells were transfected transiently with Rab5a-dominant negative, and/or stably with the short-hairpin RNA Atg7, were exposed to two inhibitors of autolysosome function, and LC3II and p62 expression was measured. We showed basal autophagy in bone-metastatic cells and the pivotal role of Rab5a together with Beclin 1 between the early stages, elongation of isolation membrane/closed autophagosome mediated by Atg7, and the late-degradative stages. This regulatory network might occur in bone-metastasis and in high-grade dysplastic lesions, preceding invasive-breast carcinoma and conferring phenotypic characteristics for dissemination. PMID:27023526

  17. Impairment of Atg5-dependent autophagic flux promotes paraquat- and MPP⁺-induced apoptosis but not rotenone or 6-hydroxydopamine toxicity.

    Science.gov (United States)

    Garcia-Garcia, Aracely; Anandhan, Annandurai; Burns, Michaela; Chen, Han; Zhou, You; Franco, Rodrigo

    2013-11-01

    Controversial reports on the role of autophagy as a survival or cell death mechanism in dopaminergic cell death induced by parkinsonian toxins exist. We investigated the alterations in autophagic flux and the role of autophagy protein 5 (Atg5)-dependent autophagy in dopaminergic cell death induced by parkinsonian toxins. Dopaminergic cell death induced by the mitochondrial complex I inhibitors 1-methyl-4-phenylpyridinium (MPP⁺) and rotenone, the pesticide paraquat, and the dopamine analog 6-hydroxydopamine (6-OHDA) was paralleled by increased autophagosome accumulation. However, when compared with basal autophagy levels using chloroquine, autophagosome accumulation was a result of impaired autophagic flux. Only 6-OHDA induced an increase in autophagosome formation. Overexpression of a dominant negative form of Atg5 increased paraquat- and MPP⁺-induced cell death. Stimulation of mammalian target of rapamycin (mTOR)-dependent signaling protected against cell death induced by paraquat, whereas MPP⁺-induced toxicity was enhanced by wortmannin, a phosphoinositide 3-kinase class III inhibitor, rapamycin, and trehalose, an mTOR-independent autophagy activator. Modulation of autophagy by either pharmacological or genetic approaches had no effect on rotenone or 6-OHDA toxicity. Cell death induced by parkinsonian neurotoxins was inhibited by the pan caspase inhibitor (Z-VAD), but only caspase-3 inhibition was able to decrease MPP⁺-induced cell death. Finally, inhibition of the lysosomal hydrolases, cathepsins, increased the toxicity by paraquat and MPP⁺, supporting a protective role of Atg5-dependent autophagy and lysosomes degradation pathways on dopaminegic cell death. These results demonstrate that in dopaminergic cells, Atg5-dependent autophagy acts as a protective mechanism during apoptotic cell death induced by paraquat and MPP⁺ but not during rotenone or 6-OHDA toxicity.

  18. Contribution of Water-soluble Components in Lipids to Flavor of Cooked Rongchang Pork%荣昌猪脂质中水溶性成分对肉品风味的作用

    Institute of Scientific and Technical Information of China (English)

    王庭; 李洪军; 贺稚非; 黄业传; 秦刚

    2011-01-01

    Chloroform-methanol(2:1,V/V) extracts from longissimus dorsi muscle and subcutaneous fat of Rongchang pig with and without water-soluble fraction were compared for their differences in odor and volatile composition,measured by electronic nose,sensory evaluation and headspace solid-phase microextraction(HS-SPME) coupled with GC-MS.Lipid differences before and after secondary aqueous extraction of chloroform-methanol extract from the lean meat of Rongchang pig were effectively detected by electronic nose and sensory evaluation.Thus,water-soluble lipids greatly contribute the flavor of lean pork.In addition,various volatile compounds including furans,alcohols,esters,sulphur-containing compounds and aldehydes derived from Maillard reaction revealed an obviously higher level before econdary aqueous extraction.However,electronic nose and sensory evaluation could not clearly differentiate lipid differences between chloroform-methanol extracts from the fat meat of Rongchang pig with and without secondary aqueous extraction.As a result,there was no significant difference in volatile compounds,which is due to a smaller amount of water-soluble lipids in the fat meat of Rongchang pig.%以荣昌猪瘦肉和肥肉为原料,采用电子鼻、感官实验、气相-质谱联用仪(GC-MS)分别对比经氯仿甲醇萃取的脂质以及其水洗后的脂质。感官实验和电子鼻可以将氯仿甲醇萃取瘦肉中的脂质(对照瘦肉中脂质)以及其水洗后的瘦肉中脂质很好的区分,表明瘦肉脂质中的水溶性成分对肉香有显著贡献,且各类挥发性成分含量前者都显著大于后者,呋喃类、醇类、酯类、含硫化合物以及美拉德反应衍生的醛类比例也大于后者;感官实验和电子鼻不能将氯仿甲醇萃取肥肉中的脂质(对照肥肉中脂质)以及其水洗后的肥肉中的脂质很好的区分,各类挥发性成分含量差异也不显著,原因是肥肉脂质中本身水溶性成分含量就比较少。

  19. Transglutaminase 2 contributes to a TP53-induced autophagy program to prevent oncogenic transformation.

    Science.gov (United States)

    Yeo, Shi Yun; Itahana, Yoko; Guo, Alvin Kunyao; Han, Rachel; Iwamoto, Kozue; Nguyen, Hung Thanh; Bao, Yi; Kleiber, Kai; Wu, Ya Jun; Bay, Boon Huat; Voorhoeve, Mathijs; Itahana, Koji

    2016-03-09

    Genetic alterations which impair the function of the TP53 signaling pathway in TP53 wild-type human tumors remain elusive. To identify new components of this pathway, we performed a screen for genes whose loss-of-function debilitated TP53 signaling and enabled oncogenic transformation of human mammary epithelial cells. We identified transglutaminase 2 (TGM2) as a putative tumor suppressor in the TP53 pathway. TGM2 suppressed colony formation in soft agar and tumor formation in a xenograft mouse model. The depletion of growth supplements induced both TGM2 expression and autophagy in a TP53-dependent manner, and TGM2 promoted autophagic flux by enhancing autophagic protein degradation and autolysosome clearance. Reduced expression of both CDKN1A, which regulates the cell cycle downstream of TP53, and TGM2 synergized to promote oncogenic transformation. Our findings suggest that TGM2-mediated autophagy and CDKN1A-mediated cell cycle arrest are two important barriers in the TP53 pathway that prevent oncogenic transformation.

  20. Contribution to the study of recovery mechanisms to be considered in the selection of MOS-type components used in radiative environments; Contribution a l'etude des mecanismes de guerison intervenant dans la selection des composants de type MOS utilises en environnements radiatifs

    Energy Technology Data Exchange (ETDEWEB)

    Quittard, O

    1999-12-01

    The generalized use of commercial devices in a radiative environment (nuclear power plant, spatial) raises the problem of the sensitivity of electronic equipment to the radiation induced dose effect. Irradiation of electronic devices has varying impact on their electrical characteristics, according to the concomitant bias scenario. Under bias, there is a process of continuous degradation; but recovery will occur if subsequent irradiation is performed without bias voltage. This phenomenon is known as RICN (Radiation-Induced Charge Neutralization). On the other hand, increasingly widespread use of radiation-sensitive commercial off-the-shelf components (COTS) has raised interest in exploring the degradation and recovery phenomena encountered during the irradiation as a function of bias. In this work, a general method for selecting MOS devices is presented which takes into account their operating conditions (temperature, bias). After a description of the physical phenomena responsible for the oxide-trapped charge evolution, we present the RICN annealing and their implications on devices selection in a radiative environment. The tests describes in this study were performed on SRAMs and on a set of CMOS inverts from three manufacturers. In the last section, we compare our analytical model of RICN annealing with experimental data. (authors)

  1. The contribution of fat component to gestational weight gain

    Directory of Open Access Journals (Sweden)

    V N Pokusaeva

    2013-12-01

    Full Text Available Objective: to estimate the role of adipose tissue in gestational weight gain (GWG and preferential fat deposition among normal-weight women. Subjects and methods: prospective cohort study of 84 pregnancies: maternal body mass index 18,5–24,9 kg/m2, singleton term pregnancy, nondiabetic women, somatically well. GWG and skinfold thickness were evaluated in the 1st, 2nd, 3d trimesters, on the 3d day after delivery. Results: fat mass gain in low GWG was similar to recommended GWG and in the high-GWG group was greater one. Women with recommended and low GWG returned to their initial fat level on the 3d day after delivery, in excessive weight gain fat significantly increased (р=0,025. Compared to initial recommended GWG resulted in triceps skinfold thicknesses loss (р=0,001, in abdominal skinfold gained nothing and in thighs skinfold thicknesses increasing (р=0,021. Inadequate GWG leads to fat loss in arms (р=0,017, fat of abdominal area and thighs return to initial level. In excessive GWG fat in the upper trunk and arms not changed, in the lower area (thighs significantly increased compared to initial level (р=0,001 or other groups (р=0,001. Conclusion: excessive GWG was associated with greater adipose tissue cumulation and its deposition preferentially over the thighs. Inadequate GWG was clearly linked to low fat-free mass gain.

  2. Protective Effect of Sevoflurane Postconditioning against Cardiac Ischemia/Reperfusion Injury via Ameliorating Mitochondrial Impairment, Oxidative Stress and Rescuing Autophagic Clearance.

    Directory of Open Access Journals (Sweden)

    Peng Yu

    Full Text Available Myocardial infarction leads to heart failure. Autophagy is excessively activated in myocardial ischemia/reperfusion (I/R in rats. The aim of this study is to investigate whether the protection of sevoflurane postconditioning (SPC in myocardial I/R is through restored impaired autophagic flux.Except for the sham control (SHAM group, each rat underwent 30 min occlusion of the left anterior descending coronary (LAD followed by 2 h reperfusion. Cardiac infarction was determined by 2,3,5-triphenyltetrazolium chloride triazole (TTC staining. Cardiac function was examined by hemodynamics and echocardiography. The activation of autophagy was evaluated by autophagosome accumulation, LC3 conversion and p62 degradation. Potential molecular mechanisms were investigated by immunoblotting, real-time PCR and immunofluorescence staining.SPC improved the hemodynamic parameters, cardiac dysfunction, histopathological and ultrastructural damages, and decreased myocardial infarction size after myocardial I/R injury (P < 0.05 vs. I/R group. Compared with the cases in I/R group, myocardial ATP and NAD+ content, mitochondrial function related genes and proteins, and the expressions of SOD2 and HO-1 were increased, while the expressions of ROS and Vimentin were decreased in the SPC group (P < 0.05 vs. I/R group. SPC significantly activated Akt/mTOR signaling, and inhibited the formation of Vps34/Beclin1 complex via increasing expression of Bcl2 protein (P < 0.05 vs. I/R group. SPC suppressed elevated expressions of LC3 II/I ratio, Beclin1, Atg5 and Atg7 in I/R rat, which indicated that SPC inhibited over-activation of autophagy, and promoted autophagosome clearance. Meanwhile, SPC significantly suppressed the decline of Opa1 and increases of Drp1 and Parkin induced by I/R injury (P < 0.05 vs. I/R group. Moreover, SPC maintained the contents of ATP by reducing impaired mitochondria.SPC protects rat hearts against I/R injury via ameliorating mitochondrial impairment

  3. Fucosylation of LAMP-1 and LAMP-2 by FUT1 correlates with lysosomal positioning and autophagic flux of breast cancer cells.

    Science.gov (United States)

    Tan, Keng-Poo; Ho, Ming-Yi; Cho, Huan-Chieh; Yu, John; Hung, Jung-Tung; Yu, Alice Lin-Tsing

    2016-08-25

    Alpha1,2-fucosyltransferases, FUT1 and FUT2, which transfer fucoses onto the terminal galactose of N-acetyl-lactosamine via α1,2-linkage have been shown to be highly expressed in various types of cancers. A few studies have shown the involvement of FUT1 substrates in tumor cell proliferation and migration. Lysosome-associated membrane protein 1, LAMP-1, has been reported to carry alpha1,2-fucosylated Lewis Y (LeY) antigens in breast cancer cells, however, the biological functions of LeY on LAMP-1 remain largely unknown. Whether or not its family member, LAMP-2, displays similar modifications and functions as LAMP-1 has not yet been addressed. In this study, we have presented evidence supporting that both LAMP-1 and 2 are substrates for FUT1, but not FUT2. We have also demonstrated the presence of H2 and LeY antigens on LAMP-1 by a targeted nanoLC-MS(3) and the decreased levels of fucosylation on LAMP-2 by MALDI-TOF analysis upon FUT1 knockdown. In addition, we found that the expression of LeY was substantial in less invasive ER+/PR+/HER- breast cancer cells (MCF-7 and T47D) but negligible in highly invasive triple-negative MDA-MB-231 cells, of which LeY levels were correlated with the levels of LeY carried by LAMP-1 and 2. Intriguingly, we also observed a striking change in the subcellular localization of lysosomes upon FUT1 knockdown from peripheral distribution of LAMP-1 and 2 to a preferential perinuclear accumulation. Besides that, knockdown of FUT1 led to an increased rate of autophagic flux along with diminished activity of mammalian target of rapamycin complex 1 (mTORC1) and enhanced autophagosome-lysosome fusion. This may be associated with the predominantly perinuclear distribution of lysosomes mediated by FUT1 knockdown as lysosomal positioning has been reported to regulate mTOR activity and autophagy. Taken together, our results suggest that downregulation of FUT1, which leads to the perinuclear localization of LAMP-1 and 2, is correlated with increased

  4. Nucleolin antagonist triggers autophagic cell death in human glioblastoma primary cells and decreased in vivo tumor growth in orthotopic brain tumor model.

    Science.gov (United States)

    Benedetti, Elisabetta; Antonosante, Andrea; d'Angelo, Michele; Cristiano, Loredana; Galzio, Renato; Destouches, Damien; Florio, Tiziana Marilena; Dhez, Anne Chloé; Astarita, Carlo; Cinque, Benedetta; Fidoamore, Alessia; Rosati, Floriana; Cifone, Maria Grazia; Ippoliti, Rodolfo; Giordano, Antonio; Courty, José; Cimini, Annamaria

    2015-12-01

    Nucleolin (NCL) is highly expressed in several types of cancer and represents an interesting therapeutic target. It is expressed at the plasma membrane of tumor cells, a property which is being used as a marker for several human cancer including glioblastoma. In this study we investigated targeting NCL as a new therapeutic strategy for the treatment of this pathology. To explore this possibility, we studied the effect of an antagonist of NCL, the multivalent pseudopeptide N6L using primary culture of human glioblastoma cells. In this system, N6L inhibits cell growth with different sensitivity depending to NCL localization. Cell cycle analysis indicated that N6L-induced growth reduction was due to a block of the G1/S transition with down-regulation of the expression of cyclin D1 and B2. By monitoring autophagy markers such as p62 and LC3II, we demonstrate that autophagy is enhanced after N6L treatment. In addition, N6L-treatment of mice bearing tumor decreased in vivo tumor growth in orthotopic brain tumor model and increase mice survival. The results obtained indicated an anti-proliferative and pro-autophagic effect of N6L and point towards its possible use as adjuvant agent to the standard therapeutic protocols presently utilized for glioblastoma.

  5. Formal Component-Based Semantics

    CERN Document Server

    Madlener, Ken; van Eekelen, Marko; 10.4204/EPTCS.62.2

    2011-01-01

    One of the proposed solutions for improving the scalability of semantics of programming languages is Component-Based Semantics, introduced by Peter D. Mosses. It is expected that this framework can also be used effectively for modular meta theoretic reasoning. This paper presents a formalization of Component-Based Semantics in the theorem prover Coq. It is based on Modular SOS, a variant of SOS, and makes essential use of dependent types, while profiting from type classes. This formalization constitutes a contribution towards modular meta theoretic formalizations in theorem provers. As a small example, a modular proof of determinism of a mini-language is developed.

  6. 6-Shogaol Inhibits Breast Cancer Cells and Stem Cell-Like Spheroids by Modulation of Notch Signaling Pathway and Induction of Autophagic Cell Death.

    Science.gov (United States)

    Ray, Anasuya; Vasudevan, Smreti; Sengupta, Suparna

    2015-01-01

    Cancer stem cells (CSCs) pose a serious obstacle to cancer therapy as they can be responsible for poor prognosis and tumour relapse. In this study, we have investigated inhibitory activity of the ginger-derived compound 6-shogaol against breast cancer cells both in monolayer and in cancer-stem cell-like spheroid culture. The spheroids were generated from adherent breast cancer cells. 6-shogaol was effective in killing both breast cancer monolayer cells and spheroids at doses that were not toxic to noncancerous cells. The percentages of CD44+CD24-/low cells and the secondary sphere content were reduced drastically upon treatment with 6-shogaol confirming its action on CSCs. Treatment with 6-shogaol caused cytoplasmic vacuole formation and cleavage of microtubule associated protein Light Chain3 (LC3) in both monolayer and spheroid culture indicating that it induced autophagy. Kinetic analysis of the LC3 expression and a combination treatment with chloroquine revealed that the autophagic flux instigated cell death in 6-shogaol treated breast cancer cells in contrast to the autophagy inhibitor chloroquine. Furthermore, 6-shogaol-induced cell death got suppressed in the presence of chloroquine and a very low level of apoptosis was exhibited even after prolonged treatment of the compound, suggesting that autophagy is the major mode of cell death induced by 6-shogaol in breast cancer cells. 6-shogaol reduced the expression levels of Cleaved Notch1 and its target proteins Hes1 and Cyclin D1 in spheroids, and the reduction was further pronounced in the presence of a γ-secretase inhibitor. Secondary sphere formation in the presence of the inhibitor was also further reduced by 6-shogaol. Together, these results indicate that the inhibitory action of 6-shogaol on spheroid growth and sustainability is conferred through γ-secretase mediated down-regulation of Notch signaling. The efficacy of 6-shogaol in monolayer and cancer stem cell-like spheroids raise hope for its

  7. Effects of interval and continuous exercise training on CD4 lymphocyte apoptotic and autophagic responses to hypoxic stress in sedentary men.

    Directory of Open Access Journals (Sweden)

    Tzu-Pin Weng

    Full Text Available Exercise is linked with the type/intensity-dependent adaptive immune responses, whereas hypoxic stress facilitates the programmed death of CD4 lymphocytes. This study investigated how high intensity-interval (HIT and moderate intensity-continuous (MCT exercise training influence hypoxia-induced apoptosis and autophagy of CD4 lymphocytes in sedentary men. Thirty healthy sedentary males were randomized to engage either HIT (3-minute intervals at 40% and 80%VO2max, n=10 or MCT (sustained 60%VO2max, n=10 for 30 minutes/day, 5 days/week for 5 weeks, or to a control group that did not received exercise intervention (CTL, n=10. CD4 lymphocyte apoptotic and autophagic responses to hypoxic exercise (HE, 100 W under 12%O2 for 30 minutes were determined before and after various regimens. The results demonstrated that HIT exhibited higher enhancements of pulmonary ventilation, cardiac output, and VO2 at ventilatory threshold and peak performance than MCT did. Before the intervention, HE significantly down-regulated autophagy by decreased beclin-1, Atg-1, LC3-II, Atg-12, and LAMP-2 expressions and acridine orange staining, and simultaneously enhanced apoptosis by increased phospho-Bcl-2 and active caspase-9/-3 levels and phosphotidylserine exposure in CD4 lymphocytes. However, five weeks of HIT and MCT, but not CTL, reduced the extents of declined autophagy and potentiated apoptosis in CD4 lymphocytes caused by HE. Furthermore, both HIT and MCT regimens manifestly lowered plasma myeloperoxidase and interleukin-4 levels and elevated the ratio of interleukin-4 to interferon-γ at rest and following HE. Therefore, we conclude that HIT is superior to MCT for enhancing aerobic fitness. Moreover, either HIT or MCT effectively depresses apoptosis and promotes autophagy in CD4 lymphocytes and is accompanied by increased interleukin-4/interferon-γ ratio and decreased peroxide production during HE.

  8. Variability and component composition

    NARCIS (Netherlands)

    Storm, T. van der

    2004-01-01

    In component-based product populations, feature models have to be described at the component level to be able to benefit from a product family approach. As a consequence, composition of components becomes very complex. We describe how component-level variability can be managed in the face of compone

  9. NAC1 modulates sensitivity of ovarian cancer cells to cisplatin by altering the HMGB1-mediated autophagic response.

    Science.gov (United States)

    Zhang, Y; Cheng, Y; Ren, X; Zhang, L; Yap, K L; Wu, H; Patel, R; Liu, D; Qin, Z-H; Shih, I-M; Yang, J-M

    2012-02-23

    Nucleus accumbens-1 (NAC1), a nuclear factor belonging to the BTB/POZ gene family, is known to have important roles in proliferation and growth of tumor cells and in chemotherapy resistance. Yet, the mechanisms underlying how NAC1 contributes to drug resistance remain largely unclear. We report here that autophagy was involved in NAC1-mediated resistance to cisplatin, a commonly used chemotherapeutic drug in the treatment of ovarian cancer. We found that treatment with cisplatin caused an activation of autophagy in ovarian cancer cell lines, A2780, OVCAR3 and SKOV3. We further demonstrated that knockdown of NAC1 by RNA interference or inactivation of NAC1 by inducing the expression of a NAC1 deletion mutant that contains only the BTB/POZ domain significantly inhibited the cisplatin-induced autophagy, resulting in increased cisplatin cytotoxicity. Moreover, inhibition of autophagy and sensitization to cisplatin by NAC1 knockdown or inactivation were accompanied by induction of apoptosis. To confirm that the sensitizing effect of NAC1 inhibition on the cytotoxicity of cisplatin was attributed to suppression of autophagy, we assessed the effects of the autophagy inhibitors 3-methyladenosine and chloroquine, and small interfering RNAs (siRNAs) targeting beclin 1 or Atg5 on the cytotoxicity of cisplatin. Treatment with 3-methyladenosine, chloroquine or beclin 1 and Atg5-targeted siRNA also enhanced the sensitivity of SKOV3, A2780 and OVCAR3 cells to cisplatin, indicating that suppression of autophagy indeed renders tumor cells more sensitive to cisplatin. Regulation of autophagy by NAC1 was mediated by the high-mobility group box 1 (HMGB1), as the functional status of NAC1 was associated with the expression, translocation and release of HMGB1. The results of our study not only revealed a new mechanism determining cisplatin sensitivity but also identified NAC1 as a novel regulator of autophagy. Thus, the NAC1-mediated autophagy may be exploited as a new target for

  10. [Blood components and good practices in transfusion].

    Science.gov (United States)

    Andreu, Georges

    2015-02-01

    Each year, more than three millions of blood components are transfused to more than five hundred thousand patients in France. The optimal use of blood components requires that physicians prescribing blood components master the clinical indications of red blood cells concentrates, platelet concentrates and fresh frozen plasma. In addition, physicians in charge of blood component prescription should provide adequate pre- and post-transfusion information to their patients. Compliance of blood components administration in patients with safety guidelines contributes as well to their optimal use. In addition, for each blood component transfused, a proper evaluation of its safety and its efficacy should be done. Finally, a regular evaluation of transfusion practice in hospital services were blood components are used, through audits made in cooperation with their blood component provider, either blood transfusion centre or the hospital blood bank, enables to appreciate the level of compliance with safety and clinical guidelines, and more globally how the transfusion process is mastered.

  11. 6-Shogaol Inhibits Breast Cancer Cells and Stem Cell-Like Spheroids by Modulation of Notch Signaling Pathway and Induction of Autophagic Cell Death.

    Directory of Open Access Journals (Sweden)

    Anasuya Ray

    Full Text Available Cancer stem cells (CSCs pose a serious obstacle to cancer therapy as they can be responsible for poor prognosis and tumour relapse. In this study, we have investigated inhibitory activity of the ginger-derived compound 6-shogaol against breast cancer cells both in monolayer and in cancer-stem cell-like spheroid culture. The spheroids were generated from adherent breast cancer cells. 6-shogaol was effective in killing both breast cancer monolayer cells and spheroids at doses that were not toxic to noncancerous cells. The percentages of CD44+CD24-/low cells and the secondary sphere content were reduced drastically upon treatment with 6-shogaol confirming its action on CSCs. Treatment with 6-shogaol caused cytoplasmic vacuole formation and cleavage of microtubule associated protein Light Chain3 (LC3 in both monolayer and spheroid culture indicating that it induced autophagy. Kinetic analysis of the LC3 expression and a combination treatment with chloroquine revealed that the autophagic flux instigated cell death in 6-shogaol treated breast cancer cells in contrast to the autophagy inhibitor chloroquine. Furthermore, 6-shogaol-induced cell death got suppressed in the presence of chloroquine and a very low level of apoptosis was exhibited even after prolonged treatment of the compound, suggesting that autophagy is the major mode of cell death induced by 6-shogaol in breast cancer cells. 6-shogaol reduced the expression levels of Cleaved Notch1 and its target proteins Hes1 and Cyclin D1 in spheroids, and the reduction was further pronounced in the presence of a γ-secretase inhibitor. Secondary sphere formation in the presence of the inhibitor was also further reduced by 6-shogaol. Together, these results indicate that the inhibitory action of 6-shogaol on spheroid growth and sustainability is conferred through γ-secretase mediated down-regulation of Notch signaling. The efficacy of 6-shogaol in monolayer and cancer stem cell-like spheroids raise

  12. A novel herbal medicine, KIOM-C, induces autophagic and apoptotic cell death mediated by activation of JNK and reactive oxygen species in HT1080 human fibrosarcoma cells.

    Directory of Open Access Journals (Sweden)

    Aeyung Kim

    Full Text Available KIOM-C was recently demonstrated to have anti-metastatic activity in highly malignant cancer cells via suppression of NF-κB-mediated MMP-9 activity. In addition, it was reported to be effective for clearance of the influenza virus by increasing production of anti-viral cytokines, such as TNF-α and IFN-γ, and efficacious in the treatment of pigs suffering from porcine circovirus-associated disease (PCVAD. In this study, we investigated whether KIOM-C induces cancer cell death and elucidated the underlying anti-cancer mechanisms. In addition, we examined whether KIOM-C oral administration suppresses in vivo tumor growth of HT1080 cells in athymic nude mice. We initially found that KIOM-C at concentrations of 500 and 1000 µg/ml caused dose- and time-dependent cell death in cancer cells, but not normal hepatocytes, to approximately 50% of control levels. At the early stage of KIOM-C treatment (12 h, cells were arrested in G1 phase, which was accompanied by up-regulation of p21 and p27, down-regulation of cyclin D1, and subsequent increases in apoptotic and autophagic cells. Following KIOM-C treatment, the extent of caspase-3 activation, PARP cleavage, Beclin-1 expression, and LC3-II conversion was remarkably up-regulated, but p62 expression was down-regulated. Phosphorylation of AMPK, ULK, JNK, c-jun, and p53 was increased significantly in response to KIOM-C treatment. The levels of intracellular ROS and CHOP expression were also increased. In particular, the JNK-specific inhibitor SP600125 blocked KIOM-C-induced ROS generation and CHOP expression almost completely, which consequently almost completely rescued cell death, indicating that JNK activation plays a critical role in KIOM-C-induced cell death. Furthermore, daily oral administration of 85 and 170 mg/kg KIOM-C efficiently suppressed the tumorigenic growth of HT1080 cells, without systemic toxicity. These results collectively suggest that KIOM-C efficiently induces cancer cell death by

  13. A Drosophila Model of Neuronopathic Gaucher Disease Demonstrates Lysosomal-Autophagic Defects and Altered mTOR Signalling and Is Functionally Rescued by Rapamycin

    Science.gov (United States)

    Grönke, Sebastian; Castillo-Quan, Jorge Iván; Woodling, Nathaniel S.; Li, Li; Sirka, Ernestas; Gegg, Matthew; Mills, Kevin; Hardy, John; Bjedov, Ivana

    2016-01-01

    Glucocerebrosidase (GBA1) mutations are associated with Gaucher disease (GD), an autosomal recessive disorder caused by functional deficiency of glucocerebrosidase (GBA), a lysosomal enzyme that hydrolyzes glucosylceramide to ceramide and glucose. Neuronopathic forms of GD can be associated with rapid neurological decline (Type II) or manifest as a chronic form (Type III) with a wide spectrum of neurological signs. Furthermore, there is now a well-established link between GBA1 mutations and Parkinson's disease (PD), with heterozygote mutations in GBA1 considered the commonest genetic defect in PD. Here we describe a novel Drosophila model of GD that lacks the two fly GBA1 orthologs. This knock-out model recapitulates the main features of GD at the cellular level with severe lysosomal defects and accumulation of glucosylceramide in the fly brain. We also demonstrate a block in autophagy flux in association with reduced lifespan, age-dependent locomotor deficits and accumulation of autophagy substrates in dGBA-deficient fly brains. Furthermore, mechanistic target of rapamycin (mTOR) signaling is downregulated in dGBA knock-out flies, with a concomitant upregulation of Mitf gene expression, the fly ortholog of mammalian TFEB, likely as a compensatory response to the autophagy block. Moreover, the mTOR inhibitor rapamycin is able to partially ameliorate the lifespan, locomotor, and oxidative stress phenotypes. Together, our results demonstrate that this dGBA1-deficient fly model is a useful platform for the further study of the role of lysosomal-autophagic impairment and the potential therapeutic benefits of rapamycin in neuronopathic GD. These results also have important implications for the role of autophagy and mTOR signaling in GBA1-associated PD. SIGNIFICANCE STATEMENT We developed a Drosophila model of neuronopathic GD by knocking-out the fly orthologs of the GBA1 gene, demonstrating abnormal lysosomal pathology in the fly brain. Functioning lysosomes are

  14. A role for the membrane Golgi protein Ema in autophagy.

    Science.gov (United States)

    Kim, Sungsu; DiAntonio, Aaron

    2012-08-01

    Autophagy is a cellular homeostatic response that involves degradation of self-components by the double-membraned autophagosome. The biogenesis of autophagosomes has been well described, but the ensuing processes after autophagosome formation are not clear. In our recent study, we proposed a model in which the Golgi complex contributes to the growth of autophagic structures, and that the Drosophila melanogaster membrane protein Ema promotes this process. In fat body cells of the D. melanogaster ema mutant, the recruitment of the Golgi complex protein Lava lamp (Lva) to autophagic structures is impaired and autophagic structures are very small. In addition, in the ema mutant autophagic turnover of SQSTM1/p62 and mitophagy are impaired. Our study not only identifies a role for Ema in autophagy, but also supports the hypothesis that the Golgi complex may be a potential membrane source for the biogenesis and development of autophagic structures.

  15. Reusable Component Services

    Data.gov (United States)

    U.S. Environmental Protection Agency — The Reusable Component Services (RCS) is a super-catalog of components, services, solutions and technologies that facilitates search, discovery and collaboration in...

  16. Sparse Principal Component Analysis with missing observations

    CERN Document Server

    Lounici, Karim

    2012-01-01

    In this paper, we study the problem of sparse Principal Component Analysis (PCA) in the high-dimensional setting with missing observations. Our goal is to estimate the first principal component when we only have access to partial observations. Existing estimation techniques are usually derived for fully observed data sets and require a prior knowledge of the sparsity of the first principal component in order to achieve good statistical guarantees. Our contributions is threefold. First, we establish the first information-theoretic lower bound for the sparse PCA problem with missing observations. Second, we propose a simple procedure that does not require any prior knowledge on the sparsity of the unknown first principal component or any imputation of the missing observations, adapts to the unknown sparsity of the first principal component and achieves the optimal rate of estimation up to a logarithmic factor. Third, if the covariance matrix of interest admits a sparse first principal component and is in additi...

  17. Supply chain components

    Directory of Open Access Journals (Sweden)

    Vieraşu, T.

    2011-01-01

    Full Text Available In this article I will go through three main logistics components, which are represented by: transportation, inventory and facilities, and the three secondary logistical components: information, production location, price and how they determine performance of any supply chain. I will discuss then how these components are used in the design, planning and operation of a supply chain. I will also talk about some obstacles a supply chain manager may encounter.

  18. Psychological Component of Infertility

    Science.gov (United States)

    ... Home FAQs Frequently Asked Questions Quick Facts About Infertility FAQs About Infertility FAQs About the Psychological Component of Infertility FAQs About Cloning and Stem Cell Research SART's ...

  19. Design of Critical Components

    Science.gov (United States)

    Hendricks, Robert C.; Zaretsky, Erwin V.

    2001-01-01

    Critical component design is based on minimizing product failures that results in loss of life. Potential catastrophic failures are reduced to secondary failures where components removed for cause or operating time in the system. Issues of liability and cost of component removal become of paramount importance. Deterministic design with factors of safety and probabilistic design address but lack the essential characteristics for the design of critical components. In deterministic design and fabrication there are heuristic rules and safety factors developed over time for large sets of structural/material components. These factors did not come without cost. Many designs failed and many rules (codes) have standing committees to oversee their proper usage and enforcement. In probabilistic design, not only are failures a given, the failures are calculated; an element of risk is assumed based on empirical failure data for large classes of component operations. Failure of a class of components can be predicted, yet one can not predict when a specific component will fail. The analogy is to the life insurance industry where very careful statistics are book-kept on classes of individuals. For a specific class, life span can be predicted within statistical limits, yet life-span of a specific element of that class can not be predicted.

  20. Multilevel component analysis

    NARCIS (Netherlands)

    Timmerman, M.E.

    2006-01-01

    A general framework for the exploratory component analysis of multilevel data (MLCA) is proposed. In this framework, a separate component model is specified for each group of objects at a certain level. The similarities between the groups of objects at a given level can be expressed by imposing cons

  1. Aligning component upgrades

    Directory of Open Access Journals (Sweden)

    Roberto Di Cosmo

    2011-08-01

    Full Text Available Modern software systems, like GNU/Linux distributions or Eclipse-based development environment, are often deployed by selecting components out of large component repositories. Maintaining such software systems by performing component upgrades is a complex task, and the users need to have an expressive preferences language at their disposal to specify the kind of upgrades they are interested in. Recent research has shown that it is possible to develop solvers that handle preferences expressed as a combination of a few basic criteria used in the MISC competition, ranging from the number of new components to the freshness of the final configuration. In this work we introduce a set of new criteria that allow the users to specify their preferences for solutions with components aligned to the same upstream sources, provide an efficient encoding and report on the experimental results that prove that optimising these alignment criteria is a tractable problem in practice.

  2. The Significance of Common Molecular Biomarkers of Autophay Pathway in Reflecting Autophagic Activity%自噬途径常用分子生物学指标在反映自噬活性上的意义

    Institute of Scientific and Technical Information of China (English)

    潘明娇; 王小丹(综述); 喻陆(审校)

    2015-01-01

    As a self-degradative cell pathway in eukaryotic cells,autophagy is evolutionarily conserved and mainly responsible for the degradation of long-lived proteins and damaged organelles.Autophagy is alsoconducive to maintaining the normal cellular homeostasis.The past decades have witnessed a remarkable progressof research on autophagy.A great number of studies obtain their conclusions through observing thechange of autophagic activity,therefore it is important to correctly explain the results from the autophagy activity test.Among the test methods,the molecular biological methods are widely used,and through clarifying the molecular mechanisms of autophagy and the relationship between autophagy and ubiquitin proteasome system,we could make better use of the common molecular biomarkers to reflect the change of autophagic activity.%自噬是一种真核细胞自我降解、维持自稳态的细胞途径,在进化过程中高度保守,主要负责降解长寿蛋白和损伤细胞器。近年来,关于自噬的研究较多,其中许多研究需要通过观察自噬活性的变化来得出结论,因此准确解释自噬活性检测结果十分重要。在众多自噬活性检测方法中,分子生物学检测技术应用较为广泛,通过了解自噬的分子机制及其与泛素蛋白酶体系的关系,可以更好地利用自噬途径常用分子生物学指标来反映自噬活性变化。

  3. How Many Separable Sources? Model Selection In Independent Components Analysis

    DEFF Research Database (Denmark)

    Woods, Roger P.; Hansen, Lars Kai; Strother, Stephen

    2015-01-01

    Unlike mixtures consisting solely of non-Gaussian sources, mixtures including two or more Gaussian components cannot be separated using standard independent components analysis methods that are based on higher order statistics and independent observations. The mixed Independent Components Analysi...... might otherwise be questionable. Failure of the Akaike Information Criterion in model selection also has relevance in traditional independent components analysis where all sources are assumed non-Gaussian.......Unlike mixtures consisting solely of non-Gaussian sources, mixtures including two or more Gaussian components cannot be separated using standard independent components analysis methods that are based on higher order statistics and independent observations. The mixed Independent Components Analysis....../Principal Components Analysis (mixed ICA/PCA) model described here accommodates one or more Gaussian components in the independent components analysis model and uses principal components analysis to characterize contributions from this inseparable Gaussian subspace. Information theory can then be used to select from...

  4. Contributions to industrial statistics

    OpenAIRE

    2015-01-01

    This thesis is about statistics' contributions to industry. It is an article compendium comprising four articles divided in two blocks: (i) two contributions for a water supply company, and (ii) significance of the effects in Design of Experiments. In the first block, great emphasis is placed on how the research design and statistics can be applied to various real problems that a water company raises and it aims to convince water management companies that statistics can be very useful to impr...

  5. Discriminant Incoherent Component Analysis.

    Science.gov (United States)

    Georgakis, Christos; Panagakis, Yannis; Pantic, Maja

    2016-05-01

    Face images convey rich information which can be perceived as a superposition of low-complexity components associated with attributes, such as facial identity, expressions, and activation of facial action units (AUs). For instance, low-rank components characterizing neutral facial images are associated with identity, while sparse components capturing non-rigid deformations occurring in certain face regions reveal expressions and AU activations. In this paper, the discriminant incoherent component analysis (DICA) is proposed in order to extract low-complexity components, corresponding to facial attributes, which are mutually incoherent among different classes (e.g., identity, expression, and AU activation) from training data, even in the presence of gross sparse errors. To this end, a suitable optimization problem, involving the minimization of nuclear-and l1 -norm, is solved. Having found an ensemble of class-specific incoherent components by the DICA, an unseen (test) image is expressed as a group-sparse linear combination of these components, where the non-zero coefficients reveal the class(es) of the respective facial attribute(s) that it belongs to. The performance of the DICA is experimentally assessed on both synthetic and real-world data. Emphasis is placed on face analysis tasks, namely, joint face and expression recognition, face recognition under varying percentages of training data corruption, subject-independent expression recognition, and AU detection by conducting experiments on four data sets. The proposed method outperforms all the methods that are compared with all the tasks and experimental settings.

  6. Robust Principal Component Analysis?

    CERN Document Server

    Candes, Emmanuel J; Ma, Yi; Wright, John

    2009-01-01

    This paper is about a curious phenomenon. Suppose we have a data matrix, which is the superposition of a low-rank component and a sparse component. Can we recover each component individually? We prove that under some suitable assumptions, it is possible to recover both the low-rank and the sparse components exactly by solving a very convenient convex program called Principal Component Pursuit; among all feasible decompositions, simply minimize a weighted combination of the nuclear norm and of the L1 norm. This suggests the possibility of a principled approach to robust principal component analysis since our methodology and results assert that one can recover the principal components of a data matrix even though a positive fraction of its entries are arbitrarily corrupted. This extends to the situation where a fraction of the entries are missing as well. We discuss an algorithm for solving this optimization problem, and present applications in the area of video surveillance, where our methodology allows for th...

  7. GCS component development cycle

    Science.gov (United States)

    Rodríguez, Jose A.; Macias, Rosa; Molgo, Jordi; Guerra, Dailos; Pi, Marti

    2012-09-01

    The GTC1 is an optical-infrared 10-meter segmented mirror telescope at the ORM observatory in Canary Islands (Spain). First light was at 13/07/2007 and since them it is in the operation phase. The GTC control system (GCS) is a distributed object & component oriented system based on RT-CORBA8 and it is responsible for the management and operation of the telescope, including its instrumentation. GCS has used the Rational Unified process (RUP9) in its development. RUP is an iterative software development process framework. After analysing (use cases) and designing (UML10) any of GCS subsystems, an initial component description of its interface is obtained and from that information a component specification is written. In order to improve the code productivity, GCS has adopted the code generation to transform this component specification into the skeleton of component classes based on a software framework, called Device Component Framework. Using the GCS development tools, based on javadoc and gcc, in only one step, the component is generated, compiled and deployed to be tested for the first time through our GUI inspector. The main advantages of this approach are the following: It reduces the learning curve of new developers and the development error rate, allows a systematic use of design patterns in the development and software reuse, speeds up the deliverables of the software product and massively increase the timescale, design consistency and design quality, and eliminates the future refactoring process required for the code.

  8. Scientific Software Component Technology

    Energy Technology Data Exchange (ETDEWEB)

    Kohn, S.; Dykman, N.; Kumfert, G.; Smolinski, B.

    2000-02-16

    We are developing new software component technology for high-performance parallel scientific computing to address issues of complexity, re-use, and interoperability for laboratory software. Component technology enables cross-project code re-use, reduces software development costs, and provides additional simulation capabilities for massively parallel laboratory application codes. The success of our approach will be measured by its impact on DOE mathematical and scientific software efforts. Thus, we are collaborating closely with library developers and application scientists in the Common Component Architecture forum, the Equation Solver Interface forum, and other DOE mathematical software groups to gather requirements, write and adopt a variety of design specifications, and develop demonstration projects to validate our approach. Numerical simulation is essential to the science mission at the laboratory. However, it is becoming increasingly difficult to manage the complexity of modern simulation software. Computational scientists develop complex, three-dimensional, massively parallel, full-physics simulations that require the integration of diverse software packages written by outside development teams. Currently, the integration of a new software package, such as a new linear solver library, can require several months of effort. Current industry component technologies such as CORBA, JavaBeans, and COM have all been used successfully in the business domain to reduce software development costs and increase software quality. However, these existing industry component infrastructures will not scale to support massively parallel applications in science and engineering. In particular, they do not address issues related to high-performance parallel computing on ASCI-class machines, such as fast in-process connections between components, language interoperability for scientific languages such as Fortran, parallel data redistribution between components, and massively

  9. Emotional Components of Pain

    Directory of Open Access Journals (Sweden)

    Carla J Hale

    1997-01-01

    Full Text Available BACKGROUND: Current definitions of pain suggest that emotion is an essential component of pain, however, the presumed relationship between emotion and pain, and the specific emotions that are involved in pain experiences have yet to be clarified.

  10. Explosive Components Facility

    Data.gov (United States)

    Federal Laboratory Consortium — The 98,000 square foot Explosive Components Facility (ECF) is a state-of-the-art facility that provides a full-range of chemical, material, and performance analysis...

  11. Component fragility research program

    Energy Technology Data Exchange (ETDEWEB)

    Tsai, N.C.; Mochizuki, G.L.; Holman, G.S. (NCT Engineering, Inc., Lafayette, CA (USA); Lawrence Livermore National Lab., CA (USA))

    1989-11-01

    To demonstrate how high-level'' qualification test data can be used to estimate the ultimate seismic capacity of nuclear power plant equipment, we assessed in detail various electrical components tested by the Pacific Gas Electric Company for its Diablo Canyon plant. As part of our Phase I Component Fragility Research Program, we evaluated seismic fragility for five Diablo Canyon components: medium-voltage (4kV) switchgear; safeguard relay board; emergency light battery pack; potential transformer; and station battery and racks. This report discusses our Phase II fragility evaluation of a single Westinghouse Type W motor control center column, a fan cooler motor controller, and three local starters at the Diablo Canyon nuclear power plant. These components were seismically qualified by means of biaxial random motion tests on a shaker table, and the test response spectra formed the basis for the estimate of the seismic capacity of the components. The seismic capacity of each component is referenced to the zero period acceleration (ZPA) and, in our Phase II study only, to the average spectral acceleration (ASA) of the motion at its base. For the motor control center, the seismic capacity was compared to the capacity of a Westinghouse Five-Star MCC subjected to actual fragility tests by LLNL during the Phase I Component Fragility Research Program, and to generic capacities developed by the Brookhaven National Laboratory for motor control center. Except for the medium-voltage switchgear, all of the components considered in both our Phase I and Phase II evaluations were qualified in their standard commercial configurations or with only relatively minor modifications such as top bracing of cabinets. 8 refs., 67 figs., 7 tabs.

  12. Develop a Model Component

    Science.gov (United States)

    Ensey, Tyler S.

    2013-01-01

    During my internship at NASA, I was a model developer for Ground Support Equipment (GSE). The purpose of a model developer is to develop and unit test model component libraries (fluid, electrical, gas, etc.). The models are designed to simulate software for GSE (Ground Special Power, Crew Access Arm, Cryo, Fire and Leak Detection System, Environmental Control System (ECS), etc. .) before they are implemented into hardware. These models support verifying local control and remote software for End-Item Software Under Test (SUT). The model simulates the physical behavior (function, state, limits and 110) of each end-item and it's dependencies as defined in the Subsystem Interface Table, Software Requirements & Design Specification (SRDS), Ground Integrated Schematic (GIS), and System Mechanical Schematic.(SMS). The software of each specific model component is simulated through MATLAB's Simulink program. The intensiv model development life cycle is a.s follows: Identify source documents; identify model scope; update schedule; preliminary design review; develop model requirements; update model.. scope; update schedule; detailed design review; create/modify library component; implement library components reference; implement subsystem components; develop a test script; run the test script; develop users guide; send model out for peer review; the model is sent out for verifictionlvalidation; if there is empirical data, a validation data package is generated; if there is not empirical data, a verification package is generated; the test results are then reviewed; and finally, the user. requests accreditation, and a statement of accreditation is prepared. Once each component model is reviewed and approved, they are intertwined together into one integrated model. This integrated model is then tested itself, through a test script and autotest, so that it can be concluded that all models work conjointly, for a single purpose. The component I was assigned, specifically, was a

  13. Bioactivity of Minor Milk Components

    DEFF Research Database (Denmark)

    Nguyen, Duc Ninh

    . In particular, 3-15% of very low birth weight preterm infants suffer from the most servere form of intestinal inflammation, known as necrotizing enterocolitis (NEC). This disease is incurable with a high mortality rate of 15-30%. Mother’s breast milk consists of different bioactive constituents...... several steps of thermal processing, which are known to decrease/abolish bioactivity of milk constituents. This may explain for high NEC incidence in formula-fed preterm infants. We therefore in this PhD project investigated whether gentle thermal processing conditions increase the bioavailability...... of infant formula. Thereafter, bioactive milk components which were preserved in gently-processed infant formula were selected for further investigation of their immunomodulatory activity in cell and preterm pig models. We hope this project will contribute to the research on the development of new...

  14. Scientific Component Technology Initiative

    Energy Technology Data Exchange (ETDEWEB)

    Kohn, S; Bosl, B; Dahlgren, T; Kumfert, G; Smith, S

    2003-02-07

    The laboratory has invested a significant amount of resources towards the development of high-performance scientific simulation software, including numerical libraries, visualization, steering, software frameworks, and physics packages. Unfortunately, because this software was not designed for interoperability and re-use, it is often difficult to share these sophisticated software packages among applications due to differences in implementation language, programming style, or calling interfaces. This LDRD Strategic Initiative investigated and developed software component technology for high-performance parallel scientific computing to address problems of complexity, re-use, and interoperability for laboratory software. Component technology is an extension of scripting and object-oriented software development techniques that specifically focuses on the needs of software interoperability. Component approaches based on CORBA, COM, and Java technologies are widely used in industry; however, they do not support massively parallel applications in science and engineering. Our research focused on the unique requirements of scientific computing on ASCI-class machines, such as fast in-process connections among components, language interoperability for scientific languages, and data distribution support for massively parallel SPMD components.

  15. Adaptable component frameworks

    DEFF Research Database (Denmark)

    Katajainen, Jyrki; Simonsen, Bo

    2009-01-01

    The CPH STL is a special edition of the STL, the containers and algorithms part of the C++ standard library. The specification of the generic components of the STL is given in the C++ standard. Any implementation of the STL, e.g. the one that ships with your standard-compliant C++ compiler, shoul...... the development of component frameworks which we hope to be of benefit to persons engaged in the design and implementation of generic software libraries.......The CPH STL is a special edition of the STL, the containers and algorithms part of the C++ standard library. The specification of the generic components of the STL is given in the C++ standard. Any implementation of the STL, e.g. the one that ships with your standard-compliant C++ compiler, should...... of balanced search tree. Also, we do provide safe and compact versions of each container. To ease the maintenance of this large collection of implementations, we have developed component frameworks for the STL containers. In this paper, we describe the design and implementation of a component framework...

  16. 腹主动脉缩窄20周大鼠心肌细胞的自噬通量%Autophagic flux of cardiomyocytes from 20-week transverse abdominal aortic constriction rats

    Institute of Scientific and Technical Information of China (English)

    崔龙彪; 圣娟娟; 王云英; 余志斌

    2013-01-01

    Cardiac autophagy dramatically increases in heart failure induced by sustained pressure overload.However,it has not yet been addressed if enhanced autophagy plays a role in protecting myocardium or mediating progression from compensative hypertrophy to heart failure.The aim of the present study was to detect autophagic flux of cardiomyocytes from 20-week transverse abdominal aortic constriction (TAC) rats.Fasting rats were used as the positive control for detecting cardiac autophagy.Echocardiography was applied to find the changes of cardiac structure and function.Immunofluorescent histochemistry and Western blot were used to analyze the related biomolecular indexes reflecting cardiac autophagic flux.After the previous methods for detecting cardiac autophagy were confirmed,the autophagic flux in cardiomyocytes of rats subjected to 20-week TAC was examined.The results showed that fasting had no obvious influence on parameters of cardiac structure in rats,including interventricular septal wall thickness and left ventricle posterior wall thickness,but heart rate,diastolic left ventricle internal dimension,fractional shortening of left ventricle dimension,ejection fraction and mitral inflow velocity decreased in rats after fasting for 3 d.Meanwhile,positively stained particles of LC3 and cathepsin D,but not ubiquitin and complement 9,distributed within cardiomyocytes of 3-day fasting rats,indicating augmented autophagic flux.Compared with sham rats,20-week TAC rats did not show any changes ofLC3,cathepsin D,ubiquitin and complement 9 in myocardium detected by immunofluorescent histochemistry.In addition,protein levels of LC3,cathepsin D and p62 in myocardium of TAC rats did not changed.These results reveal the unchanged autophagic flux in cardiomyocytes at middle or late phase of cardiac hypertrophy in TAC rats,implying a balance between inhibition of hypertrophy and activation of pressure load stress on autophagy.%长期心脏压力超负荷致心衰心肌的自噬

  17. Electronic components and systems

    CERN Document Server

    Dennis, W H

    2013-01-01

    Electronic Components and Systems focuses on the principles and processes in the field of electronics and the integrated circuit. Covered in the book are basic aspects and physical fundamentals; different types of materials involved in the field; and passive and active electronic components such as capacitors, inductors, diodes, and transistors. Also covered in the book are topics such as the fabrication of semiconductors and integrated circuits; analog circuitry; digital logic technology; and microprocessors. The monograph is recommended for beginning electrical engineers who would like to kn

  18. Towards Cognitive Component Analysis

    DEFF Research Database (Denmark)

    Hansen, Lars Kai; Ahrendt, Peter; Larsen, Jan

    2005-01-01

    Cognitive component analysis (COCA) is here defined as the process of unsupervised grouping of data such that the ensuing group structure is well-aligned with that resulting from human cognitive activity. We have earlier demonstrated that independent components analysis is relevant for representi...... semantics, not only in text, but also in dynamic text (chat), images, and combinations of text and images. Here we further expand on the relevance of the ICA model for representing context, including two new analyzes of abstract data: social networks and musical features....

  19. IVS contribution to ITRF2014

    Science.gov (United States)

    Bachmann, Sabine; Thaller, Daniela; Roggenbuck, Ole; Lösler, Michael; Messerschmitt, Linda

    2016-07-01

    Every few years the International Terrestrial Reference System (ITRS) Center of the International Earth Rotation and Reference Systems Service (IERS) decides to generate a new version of the International Terrestrial Reference Frame (ITRF). For the upcoming ITRF2014 the official contribution of the International VLBI Service for Geodesy and Astrometry (IVS) comprises 5796 combined sessions in SINEX file format from 1979.6 to 2015.0 containing 158 stations, overall. Nine AC contributions were included in the combination process, using five different software packages. Station coordinate time series of the combined solution show an overall repeatability of 3.3 mm for the north, 4.3 mm for the east and 7.5 mm for the height component over all stations. The minimum repeatabilities are 1.5 mm for north, 2.1 mm for east and 2.9 mm for height. One of the important differences between the IVS contribution to the ITRF2014 and the routine IVS combination is the omission of the correction for non-tidal atmospheric pressure loading (NTAL). Comparisons between the amplitudes of the annual signals derived by the VLBI observations and the annual signals from an NTAL model show that for some stations, NTAL has a high impact on station height variation. For other stations, the effect of NTAL is low. Occasionally other loading effects have a higher influence (e.g. continental water storage loading). External comparisons of the scale parameter between the VTRF2014 (a TRF based on combined VLBI solutions), DTRF2008 (DGFI-TUM realization of ITRS) and ITRF2008 revealed a significant difference in the scale. A scale difference of 0.11 ppb (i.e. 0.7 mm on the Earth's surface) has been detected between the VTRF2014 and the DTRF2008, and a scale difference of 0.44 ppb (i.e. 2.8 mm on the Earth's surface) between the VTRF2014 and ITRF2008. Internal comparisons between the EOP of the combined solution and the individual solutions from the AC contributions show a WRMS in X- and Y-Pole between

  20. Abstracts of contributed papers

    Energy Technology Data Exchange (ETDEWEB)

    1994-08-01

    This volume contains 571 abstracts of contributed papers to be presented during the Twelfth US National Congress of Applied Mechanics. Abstracts are arranged in the order in which they fall in the program -- the main sessions are listed chronologically in the Table of Contents. The Author Index is in alphabetical order and lists each paper number (matching the schedule in the Final Program) with its corresponding page number in the book.

  1. Contributions to statistics

    CERN Document Server

    Mahalanobis, P C

    1965-01-01

    Contributions to Statistics focuses on the processes, methodologies, and approaches involved in statistics. The book is presented to Professor P. C. Mahalanobis on the occasion of his 70th birthday. The selection first offers information on the recovery of ancillary information and combinatorial properties of partially balanced designs and association schemes. Discussions focus on combinatorial applications of the algebra of association matrices, sample size analogy, association matrices and the algebra of association schemes, and conceptual statistical experiments. The book then examines latt

  2. Contributions to sampling statistics

    CERN Document Server

    Conti, Pier; Ranalli, Maria

    2014-01-01

    This book contains a selection of the papers presented at the ITACOSM 2013 Conference, held in Milan in June 2013. ITACOSM is the bi-annual meeting of the Survey Sampling Group S2G of the Italian Statistical Society, intended as an international  forum of scientific discussion on the developments of theory and application of survey sampling methodologies and applications in human and natural sciences. The book gathers research papers carefully selected from both invited and contributed sessions of the conference. The whole book appears to be a relevant contribution to various key aspects of sampling methodology and techniques; it deals with some hot topics in sampling theory, such as calibration, quantile-regression and multiple frame surveys, and with innovative methodologies in important topics of both sampling theory and applications. Contributions cut across current sampling methodologies such as interval estimation for complex samples, randomized responses, bootstrap, weighting, modeling, imputati...

  3. Component School Construction Program.

    Science.gov (United States)

    New Brunswick Dept. of Economic Growth, Fredericton.

    In 1968, the Province of New Brunswick initiated a three-phase program to provide for elementary school facilities, employing a component systems approach to their construction. This booklet describes briefly the planning and construction of these schools, and provides graphic and photographic records of the construction in progress as well as of…

  4. Multimode geodesic branching components

    Science.gov (United States)

    Schulz, D.; Voges, E.

    1983-01-01

    Geodesic branching components are investigated for multimode guided wave optics. Geodesic structures with particular properties, e.g. focussing star couplers, are derived by a synthesis technique based on a theorem of Toraldo di Francia. Experimentally, the geodesic surfaces are printed on acrylic glass and are spin-coated with organic film waveguides.

  5. Autonomous component carrier selection

    DEFF Research Database (Denmark)

    Garcia, Luis Guilherme Uzeda; Pedersen, Klaus; Mogensen, Preben

    2009-01-01

    in local areas, basing our study case on LTE-Advanced. We present extensive network simulation results to demonstrate that a simple and robust interference management scheme, called autonomous component carrier selection allows each cell to select the most attractive frequency configuration; improving...

  6. Developing a Model Component

    Science.gov (United States)

    Fields, Christina M.

    2013-01-01

    The Spaceport Command and Control System (SCCS) Simulation Computer Software Configuration Item (CSCI) is responsible for providing simulations to support test and verification of SCCS hardware and software. The Universal Coolant Transporter System (UCTS) was a Space Shuttle Orbiter support piece of the Ground Servicing Equipment (GSE). The initial purpose of the UCTS was to provide two support services to the Space Shuttle Orbiter immediately after landing at the Shuttle Landing Facility. The UCTS is designed with the capability of servicing future space vehicles; including all Space Station Requirements necessary for the MPLM Modules. The Simulation uses GSE Models to stand in for the actual systems to support testing of SCCS systems during their development. As an intern at Kennedy Space Center (KSC), my assignment was to develop a model component for the UCTS. I was given a fluid component (dryer) to model in Simulink. I completed training for UNIX and Simulink. The dryer is a Catch All replaceable core type filter-dryer. The filter-dryer provides maximum protection for the thermostatic expansion valve and solenoid valve from dirt that may be in the system. The filter-dryer also protects the valves from freezing up. I researched fluid dynamics to understand the function of my component. The filter-dryer was modeled by determining affects it has on the pressure and velocity of the system. I used Bernoulli's Equation to calculate the pressure and velocity differential through the dryer. I created my filter-dryer model in Simulink and wrote the test script to test the component. I completed component testing and captured test data. The finalized model was sent for peer review for any improvements. I participated in Simulation meetings and was involved in the subsystem design process and team collaborations. I gained valuable work experience and insight into a career path as an engineer.

  7. Attenuation of Aβ{sub 25–35}-induced parallel autophagic and apoptotic cell death by gypenoside XVII through the estrogen receptor-dependent activation of Nrf2/ARE pathways

    Energy Technology Data Exchange (ETDEWEB)

    Meng, Xiangbao; Wang, Min [Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193 (China); Sun, Guibo, E-mail: sunguibo@126.com [Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193 (China); Ye, Jingxue [Jilin Agricultural University, Changchun, Jilin 130021 (China); Zhou, Yanhui [Center of Cardiology, People' s Hospital of Jilin Province, Changchun, 130021, Jilin (China); Dong, Xi [Wenzhou Medical University, Wenzhou, Zhejiang 325035 (China); Wang, Tingting; Lu, Shan [Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193 (China); Sun, Xiaobo, E-mail: sun_xiaobo163@163.com [Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193 (China)

    2014-08-15

    Amyloid-beta (Aβ) has a pivotal function in the pathogenesis of Alzheimer's disease. To investigate Aβ neurotoxicity, we used an in vitro model that involves Aβ{sub 25–35}-induced cell death in the nerve growth factor-induced differentiation of PC12 cells. Aβ{sub 25–35} (20 μM) treatment for 24 h caused apoptotic cell death, as evidenced by significant cell viability reduction, LDH release, phosphatidylserine externalization, mitochondrial membrane potential disruption, cytochrome c release, caspase-3 activation, PARP cleavage, and DNA fragmentation in PC12 cells. Aβ{sub 25–35} treatment led to autophagic cell death, as evidenced by augmented GFP-LC3 puncta, conversion of LC3-I to LC3-II, and increased LC3-II/LC3-I ratio. Aβ{sub 25–35} treatment induced oxidative stress, as evidenced by intracellular ROS accumulation and increased production of mitochondrial superoxide, malondialdehyde, protein carbonyl, and 8-OHdG. Phytoestrogens have been proved to be protective against Aβ-induced neurotoxicity and regarded as relatively safe targets for AD drug development. Gypenoside XVII (GP-17) is a novel phytoestrogen isolated from Gynostemma pentaphyllum or Panax notoginseng. Pretreatment with GP-17 (10 μM) for 12 h increased estrogen response element reporter activity, activated PI3K/Akt pathways, inhibited GSK-3β, induced Nrf2 nuclear translocation, augmented antioxidant responsive element enhancer activity, upregulated heme oxygenase 1 (HO-1) expression and activity, and provided protective effects against Aβ{sub 25–35}-induced neurotoxicity, including oxidative stress, apoptosis, and autophagic cell death. In conclusion, GP-17 conferred protection against Aβ{sub 25–35}-induced neurotoxicity through estrogen receptor-dependent activation of PI3K/Akt pathways, inactivation of GSK-3β and activation of Nrf2/ARE/HO-1 pathways. This finding might provide novel insights into understanding the mechanism for neuroprotective effects of phytoestrogens

  8. Durability of building materials and components

    CERN Document Server

    Delgado, JMPQ

    2013-01-01

    Durability of Building Materials and Components provides a collection of recent research works to contribute to the systematization and dissemination of knowledge related to the long-term performance and durability of construction and, simultaneously, to show the most recent advances in this domain. It includes a set of new developments in the field of durability, service life prediction methodologies, the durability approach for historical and old buildings, asset and maintenance management and on the durability of materials, systems and components. The book is divided in several chapters that intend to be a resume of the current state of knowledge for benefit of professional colleagues.

  9. Cognitive Component Analysis

    DEFF Research Database (Denmark)

    Feng, Ling

    2008-01-01

    of audio contexts along with pattern recognition methods to map components to known contexts. It also involves looking for the right representations for auditory inputs, i.e. the data analytic processing pipelines invoked by human brains. The main ideas refer to Cognitive Component Analysis, defined...... as the process of unsupervised grouping of generic data such that the ensuing group structure is well-aligned with that resulting from human cognitive activity. Its hypothesis runs ecologically: features which are essentially independent in a context defined ensemble, can be efficiently coded as sparse......-documented that unsupervised learning discovers statistical regularities. However human cognition is too complicated and not yet fully understood. Nevertheless, in our approach we represent human cognitive processes as a classification rule in supervised learning. Thus we have devised a testable protocol to test...

  10. Food Components and Supplements

    DEFF Research Database (Denmark)

    Parlesak, Alexandr

    2012-01-01

    The major part of food consists of chemical compounds that can be used for energy production, biological synthesis, or maintenance of metabolic processes by the host. These components are defined as nutrients, and can be categorized into macronutrients (proteins, carbohydrates, triglycerides.......g., secondary plant metabolites such as flavonoids), or as contaminants that enter the food chain at different stages or during the food production process. For these components, a wide spectrum of biological effects was observed that ranges from health-threatening impacts (e.g., polycyclic aromatic amines......, and alcohol), minerals, and micronutrients. The latter category comprises 13 vitamins and a hand full of trace elements. Many micronutrients are used as food supplements and are ingested at doses exceeding the amounts that can be consumed along with food by a factor of 10–100. Both macro- and micronutrients...

  11. Compressive Principal Component Pursuit

    CERN Document Server

    Wright, John; Min, Kerui; Ma, Yi

    2012-01-01

    We consider the problem of recovering a target matrix that is a superposition of low-rank and sparse components, from a small set of linear measurements. This problem arises in compressed sensing of structured high-dimensional signals such as videos and hyperspectral images, as well as in the analysis of transformation invariant low-rank recovery. We analyze the performance of the natural convex heuristic for solving this problem, under the assumption that measurements are chosen uniformly at random. We prove that this heuristic exactly recovers low-rank and sparse terms, provided the number of observations exceeds the number of intrinsic degrees of freedom of the component signals by a polylogarithmic factor. Our analysis introduces several ideas that may be of independent interest for the more general problem of compressed sensing and decomposing superpositions of multiple structured signals.

  12. Food Components and Supplements

    DEFF Research Database (Denmark)

    Parlesak, Alexandr

    2012-01-01

    .g., secondary plant metabolites such as flavonoids), or as contaminants that enter the food chain at different stages or during the food production process. For these components, a wide spectrum of biological effects was observed that ranges from health-threatening impacts (e.g., polycyclic aromatic amines...... the growth of these bacteria (prebiotics) are added to food to achieve health effects exceeding its pure nutritional function. Several of these effects are mediated by enzyme systems involved in xenobiotic and drug metabolism, and in some cases this might lead to undesired interactions with medication...... cases, nutrients, food contaminants, and secondary plant metabolites can themselves become substrates for xenobiotic-metabolizing enzymes, resulting in health-promoting or health-threatening products. This chapter focuses on how important components of our daily nutrition and supplements can interfere...

  13. Bayesian Independent Component Analysis

    DEFF Research Database (Denmark)

    Winther, Ole; Petersen, Kaare Brandt

    2007-01-01

    In this paper we present an empirical Bayesian framework for independent component analysis. The framework provides estimates of the sources, the mixing matrix and the noise parameters, and is flexible with respect to choice of source prior and the number of sources and sensors. Inside the engine...... in a Matlab toolbox, is demonstrated for non-negative decompositions and compared with non-negative matrix factorization....

  14. Stable Principal Component Pursuit

    CERN Document Server

    Zhou, Zihan; Wright, John; Candes, Emmanuel; Ma, Yi

    2010-01-01

    In this paper, we study the problem of recovering a low-rank matrix (the principal components) from a high-dimensional data matrix despite both small entry-wise noise and gross sparse errors. Recently, it has been shown that a convex program, named Principal Component Pursuit (PCP), can recover the low-rank matrix when the data matrix is corrupted by gross sparse errors. We further prove that the solution to a related convex program (a relaxed PCP) gives an estimate of the low-rank matrix that is simultaneously stable to small entrywise noise and robust to gross sparse errors. More precisely, our result shows that the proposed convex program recovers the low-rank matrix even though a positive fraction of its entries are arbitrarily corrupted, with an error bound proportional to the noise level. We present simulation results to support our result and demonstrate that the new convex program accurately recovers the principal components (the low-rank matrix) under quite broad conditions. To our knowledge, this is...

  15. Inkjet deposited circuit components

    Science.gov (United States)

    Bidoki, S. M.; Nouri, J.; Heidari, A. A.

    2010-05-01

    All-printed electronics as a means of achieving ultra-low-cost electronic circuits has attracted great interest in recent years. Inkjet printing is one of the most promising techniques by which the circuit components can be ultimately drawn (i.e. printed) onto the substrate in one step. Here, the inkjet printing technique was used to chemically deposit silver nanoparticles (10-200 nm) simply by ejection of silver nitrate and reducing solutions onto different substrates such as paper, PET plastic film and textile fabrics. The silver patterns were tested for their functionality to work as circuit components like conductor, resistor, capacitor and inductor. Different levels of conductivity were achieved simply by changing the printing sequence, inks ratio and concentration. The highest level of conductivity achieved by an office thermal inkjet printer (300 dpi) was 5.54 × 105 S m-1 on paper. Inkjet deposited capacitors could exhibit a capacitance of more than 1.5 nF (parallel plate 45 × 45 mm2) and induction coils displayed an inductance of around 400 µH (planar coil 10 cm in diameter). Comparison of electronic performance of inkjet deposited components to the performance of conventionally etched items makes the technique highly promising for fabricating different printed electronic devices.

  16. Optimized Kernel Entropy Components.

    Science.gov (United States)

    Izquierdo-Verdiguier, Emma; Laparra, Valero; Jenssen, Robert; Gomez-Chova, Luis; Camps-Valls, Gustau

    2016-02-25

    This brief addresses two main issues of the standard kernel entropy component analysis (KECA) algorithm: the optimization of the kernel decomposition and the optimization of the Gaussian kernel parameter. KECA roughly reduces to a sorting of the importance of kernel eigenvectors by entropy instead of variance, as in the kernel principal components analysis. In this brief, we propose an extension of the KECA method, named optimized KECA (OKECA), that directly extracts the optimal features retaining most of the data entropy by means of compacting the information in very few features (often in just one or two). The proposed method produces features which have higher expressive power. In particular, it is based on the independent component analysis framework, and introduces an extra rotation to the eigen decomposition, which is optimized via gradient-ascent search. This maximum entropy preservation suggests that OKECA features are more efficient than KECA features for density estimation. In addition, a critical issue in both the methods is the selection of the kernel parameter, since it critically affects the resulting performance. Here, we analyze the most common kernel length-scale selection criteria. The results of both the methods are illustrated in different synthetic and real problems. Results show that OKECA returns projections with more expressive power than KECA, the most successful rule for estimating the kernel parameter is based on maximum likelihood, and OKECA is more robust to the selection of the length-scale parameter in kernel density estimation.

  17. Fundamental plane: dark matter and dissipation contributions

    CERN Document Server

    Ribeiro, Andre L B

    2010-01-01

    Stellar and galactic systems are objects in dynamical equilibrium that are composed of ordinary baryonic matter hypothetically embedded in extended dominant dark matter halos. Our aim is to investigate the scaling relations and dissipational features of these objects over a wide range of their properties, taking the dynamical influence of the dark matter component into account. We study the physical properties of these self-gravitating systems using the two-component virial theorem in conjunction with data that embrace a wide range of astrophysical systems. We find that the scaling relations defined by the properties of these objects admit a dark-to-luminous density ratio parameter as a natural requirement in this framework. We also probe dissipational effects on the fundamental surface defined by the two-component virial theorem and discuss their relations with respect to the region devoid of objects in the data distribution. Our results indicate complementary contributions of dissipation and dark matter to ...

  18. Composing simulations using persistent software components

    Energy Technology Data Exchange (ETDEWEB)

    Holland, J.V.; Michelsen, R.E.; Powell, D.R.; Upton, S.C.; Thompson, D.R.

    1999-03-01

    The traditional process for developing large-scale simulations is cumbersome, time consuming, costly, and in some cases, inadequate. The topics of software components and component-based software engineering are being explored by software professionals in academic and industrial settings. A component is a well-delineated, relatively independent, and replaceable part of a software system that performs a specific function. Many researchers have addressed the potential to derive a component-based approach to simulations in general, and a few have focused on military simulations in particular. In a component-based approach, functional or logical blocks of the simulation entities are represented as coherent collections of components satisfying explicitly defined interface requirements. A simulation is a top-level aggregate comprised of a collection of components that interact with each other in the context of a simulated environment. A component may represent a simulation artifact, an agent, or any entity that can generated events affecting itself, other simulated entities, or the state of the system. The component-based approach promotes code reuse, contributes to reducing time spent validating or verifying models, and promises to reduce the cost of development while still delivering tailored simulations specific to analysis questions. The Integrated Virtual Environment for Simulation (IVES) is a composition-centered framework to achieve this potential. IVES is a Java implementation of simulation composition concepts developed at Los Alamos National Laboratory for use in several application domains. In this paper, its use in the military domain is demonstrated via the simulation of dismounted infantry in an urban environment.

  19. Variation in Hsp70-1A Expression Contributes to Skin Color Diversity.

    Science.gov (United States)

    Murase, Daiki; Hachiya, Akira; Fullenkamp, Rachel; Beck, Anita; Moriwaki, Shigeru; Hase, Tadashi; Takema, Yoshinori; Manga, Prashiela

    2016-08-01

    The wide range in human skin color results from varying levels of the pigment melanin. Genetic mechanisms underlying coloration differences have been explored, but identified genes do not account for all variation seen in the skin color spectrum. Post-transcriptional and post-translational regulation of factors that determine skin color, including melanin synthesis in epidermal melanocytes, melanosome transfer to keratinocytes, and melanosome degradation, is also critical for pigmentation. We therefore investigated proteins that are differentially expressed in melanocytes derived from either white or African American skin. Two-dimensional gel electrophoresis and mass spectrometry demonstrated that heat shock protein 70-1A (Hsp70-1A) protein levels were significantly higher in African American melanocytes compared with white melanocytes. Hsp70-1A expression significantly correlated with levels of tyrosinase, the rate-limiting melanogenic enzyme, consistent with a proposed role for Hsp70 family members in tyrosinase post-translational modification. In addition, pharmacologic inhibition and small interfering RNA-mediated downregulation of Hsp70-1A correlated with pigmentation changes in cultured melanocytes, modified human skin substitutes, and ex vivo skin. Furthermore, Hsp70-1A inhibition led to increased autophagy-mediated melanosome degradation in keratinocytes. Our data thus reveal that epidermal Hsp70-1A contributes to the diversity of skin color by regulating the amount of melanin synthesized in melanocytes and modulating autophagic melanosome degradation in keratinocytes.

  20. Folliculin contributes to VHL tumor suppressing activity in renal cancer through regulation of autophagy.

    Directory of Open Access Journals (Sweden)

    Prabhat Bastola

    Full Text Available Von Hippel-Lindau tumor suppressor (VHL is lost in the majority of clear cell renal cell carcinomas (ccRCC. Folliculin (FLCN is a tumor suppressor whose function is lost in Birt-Hogg-Dubé syndrome (BHD, a disorder characterized by renal cancer of multiple histological types including clear cell carcinoma, cutaneous fibrofolliculoma, and pneumothorax. Here we explored whether there is connection between VHL and FLCN in clear cell renal carcinoma cell lines and tumors. We demonstrate that VHL regulates expression of FLCN at the mRNA and protein levels in RCC cell lines, and that FLCN protein expression is decreased in human ccRCC tumors with VHL loss, as compared with matched normal kidney tissue. Knockdown of FLCN results in increased formation of tumors by RCC cells with wild-type VHL in orthotopic xenografts in nude mice, an indication that FLCN plays a role in the tumor-suppressing activity of VHL. Interestingly, FLCN, similarly to VHL, is necessary for the activity of LC3C-mediated autophagic program that we have previously characterized as contributing to the tumor suppressing activity of VHL. The results show the existence of functional crosstalk between two major tumor suppressors in renal cancer, VHL and FLCN, converging on regulation of autophagy.

  1. Overexpression of smooth muscle myosin heavy chain leads to activation of the unfolded protein response and autophagic turnover of thick filament-associated proteins in vascular smooth muscle cells.

    Science.gov (United States)

    Kwartler, Callie S; Chen, Jiyuan; Thakur, Dhananjay; Li, Shumin; Baskin, Kedryn; Wang, Shanzhi; Wang, Zhao V; Walker, Lori; Hill, Joseph A; Epstein, Henry F; Taegtmeyer, Heinrich; Milewicz, Dianna M

    2014-05-16

    Duplications spanning nine genes at the genomic locus 16p13.1 predispose individuals to acute aortic dissections. The most likely candidate gene in this region leading to the predisposition for dissection is MYH11, which encodes smooth muscle myosin heavy chain (SM-MHC). The effects of increased expression of MYH11 on smooth muscle cell (SMC) phenotypes were explored using mouse aortic SMCs with transgenic overexpression of one isoform of SM-MHC. We found that these cells show increased expression of Myh11 and myosin filament-associated contractile genes at the message level when compared with control SMCs, but not at the protein level due to increased protein degradation. Increased expression of Myh11 resulted in endoplasmic reticulum (ER) stress in SMCs, which led to a paradoxical decrease of protein levels through increased autophagic degradation. An additional consequence of ER stress in SMCs was increased intracellular calcium ion concentration, resulting in increased contractile signaling and contraction. The increased signals for contraction further promote transcription of contractile genes, leading to a feedback loop of metabolic abnormalities in these SMCs. We suggest that overexpression of MYH11 can lead to increased ER stress and autophagy, findings that may be globally implicated in disease processes associated with genomic duplications.

  2. Overexpression of Smooth Muscle Myosin Heavy Chain Leads to Activation of the Unfolded Protein Response and Autophagic Turnover of Thick Filament-associated Proteins in Vascular Smooth Muscle Cells*

    Science.gov (United States)

    Kwartler, Callie S.; Chen, Jiyuan; Thakur, Dhananjay; Li, Shumin; Baskin, Kedryn; Wang, Shanzhi; Wang, Zhao V.; Walker, Lori; Hill, Joseph A.; Epstein, Henry F.; Taegtmeyer, Heinrich; Milewicz, Dianna M.

    2014-01-01

    Duplications spanning nine genes at the genomic locus 16p13.1 predispose individuals to acute aortic dissections. The most likely candidate gene in this region leading to the predisposition for dissection is MYH11, which encodes smooth muscle myosin heavy chain (SM-MHC). The effects of increased expression of MYH11 on smooth muscle cell (SMC) phenotypes were explored using mouse aortic SMCs with transgenic overexpression of one isoform of SM-MHC. We found that these cells show increased expression of Myh11 and myosin filament-associated contractile genes at the message level when compared with control SMCs, but not at the protein level due to increased protein degradation. Increased expression of Myh11 resulted in endoplasmic reticulum (ER) stress in SMCs, which led to a paradoxical decrease of protein levels through increased autophagic degradation. An additional consequence of ER stress in SMCs was increased intracellular calcium ion concentration, resulting in increased contractile signaling and contraction. The increased signals for contraction further promote transcription of contractile genes, leading to a feedback loop of metabolic abnormalities in these SMCs. We suggest that overexpression of MYH11 can lead to increased ER stress and autophagy, findings that may be globally implicated in disease processes associated with genomic duplications. PMID:24711452

  3. An Introductory Idea for Teaching Two-Component Phase Diagrams

    Science.gov (United States)

    Peckham, Gavin D.; McNaught, Ian J.

    2011-01-01

    The teaching of two-component phase diagrams has attracted little attention in this "Journal," and it is hoped that this article will make a useful contribution. Current physical chemistry textbooks describe two-component phase diagrams adequately, but do so in a piecemeal fashion one section at a time; first solid-liquid equilibria, then…

  4. Characterization of sorbed oil components on clays and quartz grains in oil sand. A contribution to the wettability of reservoir rocks in petroleum deposits. Charakterisierung sorbierter Oelkomponenten auf Tonmineralien und Quarzkoernern in Oelsanden. Ein Beitrag zur Benetzbarkeit von Reservoirgesteinen in Oellagerstaetten

    Energy Technology Data Exchange (ETDEWEB)

    Fendel, A.

    1989-02-01

    The wettability of an oil reservoir strongly influences the recovery rate during primary production and the feasibility of Enhanced Oil Recovery. In order to achieve an insight into the chemical nature of the oil components sorbed onto mineral surfaces, unconsolidated Canadian (Athabasca, Cold Lake) and U.S. oilsands (Tar Sand Triangle) were exhaustively extracted with dichloromethane by Soxhlet to remove the non-sorbed, so called free oil. The sorbed oil on the clays were investigated in situ by spectroscopy and pyrolysis. Clays and quartz were extensively extracted with polar solvent mixtures to release the sorbed oil. The extractable sorbed oil and the corresponding free oil were fractionated in chemically defined compound classes by adsorption chromatography. The fractions were characterized by means of GC, GC//MS and IR-spectroscopy. The sorbed oil is highly enriched in oxygen functions bearing components, which partly show a polyfunctional character. The surprising existence of n-alkanes in the sorbed oil, which are not detected in the free oil, is explained by occlusion in the sorbed organic layer. The existence of sterols could be shown in the free and the sorbed oil though not being reported in literature to date. Clays and quartz show a different behavior of sorption. Opposite to the general accepted idea, of smectites showing the highest capacity to sorb organics, the highest amount of sorbed oil was found in the kaolinite-/illite-rich samples. Different mechanisms of oil sorption onto the mineral surfaces, possibly driven by entropy, are discussed. (orig./RB).

  5. Contributing from the margins

    DEFF Research Database (Denmark)

    Chimirri, Niklas Alexander

    /herself as a contributor to an investigated practice, as inextricably entangled with the conducts of life of the others in relation to the conditions in practice. Doing research in the kindergarten thus becomes a mutual and collective endeavor, to which pedagogues, parents, children, and the researcher contribute. Even......To engage in practice research implies taking a range of ethical-political decisions. One of the most critical decisions is to set the analytical focus, which encompasses the questions of who to collaborate with and on what grounds, as well as with which concepts to interpret the findings. In my...... empirical study, I focused on kindergarten children’s first-person perspectives on the electronic media technologies they deemed subjectively relevant for conducting everyday life in the practice of their kindergarten. The concept of the children’s perspectives opens possibilities for transcending...

  6. Computational Support for the Selection of Energy Saving Building Components

    NARCIS (Netherlands)

    De Wilde, P.J.C.J.

    2004-01-01

    Buildings use energy for heating, cooling and lighting, contributing to the problems of exhaustion of fossil fuel supplies and environmental pollution. In order to make buildings more energy-efficient an extensive set of âenergy saving building componentsâ has been developed that contributes to mini

  7. A Profile of Corporate Contributions.

    Science.gov (United States)

    Smith, Hayden W.

    The extent and distribution of charitable contributions by corporations were studied. In addition to a history of giving from 1936 to 1981, information is presented on corporate contributions in 1977 in terms of the distribution of companies (1) by size of contributions, (2) by contributions as percentage of net income, (3) by industry, and (4) by…

  8. Pollen tube reuses intracellular components of nucellar cells undergoing programmed cell death in Pinus densiflora.

    Science.gov (United States)

    Hiratsuka, Rie; Terasaka, Osamu

    2011-04-01

    Through the process known as programmed cell death (PCD), nucelli of Pinus densiflora serve as the transmitting tissue for growth of the pollen tube. We sought to clarify the processes of degradation of nucellar cell components and their transport to the pollen tube during PCD in response to pollen tube penetration of such nucelli. Stimulated by pollination, synthesis of large amounts of starch grains occurred in cells in a wide region of the nucellus, but as the pollen tube penetrated the nucellus, starch grains were degraded in amyloplasts of nucellar cells. In cells undergoing PCD, electron-dense vacuoles with high membrane contrast appeared, assumed a variety of autophagic structures, expanded, and ultimately collapsed and disappeared. Vesicles and electron-dense amorphous materials were released inside the thickened walls of cells undergoing PCD, and those vesicles and materials reaching the pollen tube after passing through the extracellular matrix were taken into the tube by endocytosis. These results show that in PCD of nucellar cells, intracellular materials are degraded in amyloplasts and vacuoles, and some of the degraded material is supplied to the pollen tube by vesicular transport to support tube growth.

  9. Electronic components and technology

    CERN Document Server

    Sangwine, Stephen

    2007-01-01

    Most introductory textbooks in electronics focus on the theory while leaving the practical aspects to be covered in laboratory courses. However, the sooner such matters are introduced, the better able students will be to include such important concerns as parasitic effects and reliability at the very earliest stages of design. This philosophy has kept Electronic Components and Technology thriving for two decades, and this completely updated third edition continues the approach with a more international outlook.Not only does this textbook introduce the properties, behavior, fabrication, and use

  10. Analysis Components Investigation Report

    Science.gov (United States)

    2014-10-01

    value is t ds each te rms presen t, and !()*+) PREVIOUS WRI open sour a training , tagged -1 t or... measure tion and Analys 2 is Component THIS DOCU The mis pro inte cou For sele con The use as solu ran .3 Prot In t be A G and wh and sec Wh info Thi...ASSIFIED December 2 LOSED TO ANY P d to specif c. The valu , the user c keywords p as relevan ument’s me system cou the docum iterion and/ e

  11. Recursive principal components analysis.

    Science.gov (United States)

    Voegtlin, Thomas

    2005-10-01

    A recurrent linear network can be trained with Oja's constrained Hebbian learning rule. As a result, the network learns to represent the temporal context associated to its input sequence. The operation performed by the network is a generalization of Principal Components Analysis (PCA) to time-series, called Recursive PCA. The representations learned by the network are adapted to the temporal statistics of the input. Moreover, sequences stored in the network may be retrieved explicitly, in the reverse order of presentation, thus providing a straight-forward neural implementation of a logical stack.

  12. Similar component analysis

    Institute of Scientific and Technical Information of China (English)

    ZHANG Hong; WANG Xin; LI Junwei; CAO Xianguang

    2006-01-01

    A new unsupervised feature extraction method called similar component analysis (SCA) is proposed in this paper. SCA method has a self-aggregation property that the data objects will move towards each other to form clusters through SCA theoretically,which can reveal the inherent pattern of similarity hidden in the dataset. The inputs of SCA are just the pairwise similarities of the dataset,which makes it easier for time series analysis due to the variable length of the time series. Our experimental results on many problems have verified the effectiveness of SCA on some engineering application.

  13. The solvent component of macromolecular crystals

    Energy Technology Data Exchange (ETDEWEB)

    Weichenberger, Christian X. [European Academy of Bozen/Bolzano (EURAC), Viale Druso 1, Bozen/Bolzano, I-39100 Südtirol/Alto Adige (Italy); Afonine, Pavel V. [Lawrence Berkeley National Laboratory (LBNL), 1 Cyclotron Road, Mail Stop 64R0121, Berkeley, CA 94720 (United States); Kantardjieff, Katherine [California State University, San Marcos, CA 92078 (United States); Rupp, Bernhard, E-mail: br@hofkristallamt.org [k.-k. Hofkristallamt, 991 Audrey Place, Vista, CA 92084 (United States); Medical University of Innsbruck, Schöpfstrasse 41, A-6020 Innsbruck (Austria)

    2015-04-30

    On average, the mother liquor or solvent and its constituents occupy about 50% of a macromolecular crystal. Ordered as well as disordered solvent components need to be accurately accounted for in modelling and refinement, often with considerable complexity. The mother liquor from which a biomolecular crystal is grown will contain water, buffer molecules, native ligands and cofactors, crystallization precipitants and additives, various metal ions, and often small-molecule ligands or inhibitors. On average, about half the volume of a biomolecular crystal consists of this mother liquor, whose components form the disordered bulk solvent. Its scattering contributions can be exploited in initial phasing and must be included in crystal structure refinement as a bulk-solvent model. Concomitantly, distinct electron density originating from ordered solvent components must be correctly identified and represented as part of the atomic crystal structure model. Herein, are reviewed (i) probabilistic bulk-solvent content estimates, (ii) the use of bulk-solvent density modification in phase improvement, (iii) bulk-solvent models and refinement of bulk-solvent contributions and (iv) modelling and validation of ordered solvent constituents. A brief summary is provided of current tools for bulk-solvent analysis and refinement, as well as of modelling, refinement and analysis of ordered solvent components, including small-molecule ligands.

  14. Interactions between photodegradation components

    Directory of Open Access Journals (Sweden)

    Abdollahi Yadollah

    2012-09-01

    Full Text Available Abstract Background The interactions of p-cresol photocatalytic degradation components were studied by response surface methodology. The study was designed by central composite design using the irradiation time, pH, the amount of photocatalyst and the p-cresol concentration as variables. The design was performed to obtain photodegradation % as actual responses. The actual responses were fitted with linear, two factor interactions, cubic and quadratic model to select an appropriate model. The selected model was validated by analysis of variance which provided evidences such as high F-value (845.09, very low P-value (2 = 0.999, adjusted R-squared (Radj2 = 0.998, predicted R-squared (Rpred2 = 0.994 and the adequate precision (95.94. Results From the validated model demonstrated that the component had interaction with irradiation time under 180 min of the time while the interaction with pH was above pH 9. Moreover, photocatalyst and p-cresol had interaction at minimal amount of photocatalyst (p-cresol. Conclusion These variables are interdependent and should be simultaneously considered during the photodegradation process, which is one of the advantages of the response surface methodology over the traditional laboratory method.

  15. Advanced Power Electronics Components

    Science.gov (United States)

    Schwarze, Gene E.

    2004-01-01

    This paper will give a description and status of the Advanced Power Electronics Materials and Components Technology program being conducted by the NASA Glenn Research Center for future aerospace power applications. The focus of this research program is on the following: 1) New and/or significantly improved dielectric materials for the development of power capacitors with increased volumetric efficiency, energy density, and operating temperature. Materials being investigated include nanocrystalline and composite ceramic dielectrics and diamond-like carbon films; 2) New and/or significantly improved high frequency, high temperature, low loss soft magnetic materials for the development of transformers/inductors with increased power/energy density, electrical efficiency, and operating temperature. Materials being investigated include nanocrystalline and nanocomposite soft magnetic materials; 3) Packaged high temperature, high power density, high voltage, and low loss SiC diodes and switches. Development of high quality 4H- and 6H- SiC atomically smooth substrates to significantly improve device performance is a major emphasis of the SiC materials program; 4) Demonstration of high temperature (> 200 C) circuits using the components developed above.

  16. Laser generating metallic components

    Science.gov (United States)

    McLean, Marc A.; Shannon, G. J.; Steen, William M.

    1997-04-01

    Recent developments in rapid prototyping have led to the concept of laser generating, the first additive manufacturing technology. This paper presents an innovative process of depositing multi-layer tracks, by fusing successive powder tracks, to generate three dimensional components, thereby offering an alternative to casting for small metal component manufacture. A coaxial nozzle assembly has been designed and manufactured enabling consistent omni-directional multi-layer deposition. In conjunction with this the software route from a CAD drawing to machine code generation has been established. The part is manufactured on a six axes machining center incorporating a 1.8 kW carbon-dioxide laser, providing an integrated opto-mechanical workstation. The part build-up program is controlled by a P150 host computer, linked directly to the DNC machining center. The direct manufacturing route is shown, including initial examples of simple objects (primitives -- cube, cylinder, cone) leading to more complex turbine blade generation, incorporating build-up techniques and the associated mechanical properties.

  17. One-component nanomedicine.

    Science.gov (United States)

    Su, Hao; Koo, Jin Mo; Cui, Honggang

    2015-12-10

    One-component nanomedicine (OCN) represents an emerging class of therapeutic nanostructures that contain only one type of chemical substance. This one-component feature allows for fine-tuning and optimization of the drug loading and physicochemical properties of nanomedicine in a precise manner through molecular engineering of the underlying building blocks. Using a precipitation procedure or effective molecular assembly strategies, molecularly crafted therapeutic agents (e.g. polymer-drug conjugates, small molecule prodrugs, or drug amphiphiles) could involuntarily aggregate, or self-assemble into nanoscale objects of well-defined sizes and shapes. Unlike traditional carrier-based nanomedicines that are inherently multicomponent systems, an OCN does not require the use of additional carriers and could itself possess desired physicochemical features for preferential accumulation at target sites. We review here recent progress in the molecular design, conjugation methods, and fabrication strategies of OCN, and analyze the opportunities that this emerging platform could open for the new and improved treatment of devastating diseases such as cancer.

  18. Prognostics for Microgrid Components

    Science.gov (United States)

    Saxena, Abhinav

    2012-01-01

    Prognostics is the science of predicting future performance and potential failures based on targeted condition monitoring. Moving away from the traditional reliability centric view, prognostics aims at detecting and quantifying the time to impending failures. This advance warning provides the opportunity to take actions that can preserve uptime, reduce cost of damage, or extend the life of the component. The talk will focus on the concepts and basics of prognostics from the viewpoint of condition-based systems health management. Differences with other techniques used in systems health management and philosophies of prognostics used in other domains will be shown. Examples relevant to micro grid systems and subsystems will be used to illustrate various types of prediction scenarios and the resources it take to set up a desired prognostic system. Specifically, the implementation results for power storage and power semiconductor components will demonstrate specific solution approaches of prognostics. The role of constituent elements of prognostics, such as model, prediction algorithms, failure threshold, run-to-failure data, requirements and specifications, and post-prognostic reasoning will be explained. A discussion on performance evaluation and performance metrics will conclude the technical discussion followed by general comments on open research problems and challenges in prognostics.

  19. Contribution to postnonclassical psychopathology.

    Directory of Open Access Journals (Sweden)

    Quintino-Aires J.

    2014-09-01

    Full Text Available Any psychological paradigm needs a psychopathological system that helps professionals to describe and explain the behavioral expressions that deviate from “normal” (whether this term is used with the semantic property of statistical or ideal adaptations. In this work, I seek to present the system that I have been developing since 1998 among the psychologists at the Instituto Vegotsky de Lisboa (Vygotsky Institute of Lisbon, Portugal, to understand psychopathology with regard to the vygotskian approach. It was conceived and designed according to the work of Rita Mendes Leal and her contribution to socioemotional development theory, AR Luria’s systemic and dynamic theory of the human brain, the theory of Activity (dyatel’nost of AN Leont’ev, and the psychopathological German school of E Kraepelin, presented and disseminated in Portugal in the early twentieth century by Professor Sobral Cid. It is intended to be a proposal to colleagues who are interested in postnonclassical psychology and a request for arguments.

  20. Sensitivity Analysis of Component Reliability

    Institute of Scientific and Technical Information of China (English)

    ZhenhuaGe

    2004-01-01

    In a system, Every component has its unique position within system and its unique failure characteristics. When a component's reliability is changed, its effect on system reliability is not equal. Component reliability sensitivity is a measure of effect on system reliability while a component's reliability is changed. In this paper, the definition and relative matrix of component reliability sensitivity is proposed, and some of their characteristics are analyzed. All these will help us to analyse or improve the system reliability.

  1. Distributed and Parallel Component Library

    Institute of Scientific and Technical Information of China (English)

    XU Zheng-quan; XU Yang; YAN Ai-ping

    2005-01-01

    Software component library is the essential part of reuse-based software development. It is shown that making use of a single component library to store all kinds of components and from which components are searched is very inefficient. We construct multi-libraries to support software reuse and use PVM as development environments to imitate largescale computer, which is expected to fulfill distributed storage and parallel search of components efficiently and improve software reuse.

  2. Impedance and component heating

    CERN Document Server

    Métral, E; Mounet, N; Pieloni, T; Salvant, B

    2015-01-01

    The impedance is a complex function of frequency, which represents, for the plane under consideration (longitudinal, horizontal or vertical), the force integrated over the length of an element, from a “source” to a “test” wave, normalized by their charges. In general, the impedance in a given plane is a nonlinear function of the test and source transverse coordinates, but it is most of the time sufficient to consider only the first few linear terms. Impedances can influence the motion of trailing particles, in the longitudinal and in one or both transverse directions, leading to energy loss, beam instabilities, or producing undesirable secondary effects such as excessive heating of sensitive components at or near the chamber wall, called beam-induced RF heating. The LHC performance limitations linked to impedances encountered during the 2010-2012 run are reviewed and the currently expected situation during the HL-LHC era is discussed.

  3. Sprayed skin turbine component

    Science.gov (United States)

    Allen, David B

    2013-06-04

    Fabricating a turbine component (50) by casting a core structure (30), forming an array of pits (24) in an outer surface (32) of the core structure, depositing a transient liquid phase (TLP) material (40) on the outer surface of the core structure, the TLP containing a melting-point depressant, depositing a skin (42) on the outer surface of the core structure over the TLP material, and heating the assembly, thus forming both a diffusion bond and a mechanical interlock between the skin and the core structure. The heating diffuses the melting-point depressant away from the interface. Subsurface cooling channels (35) may be formed by forming grooves (34) in the outer surface of the core structure, filling the grooves with a fugitive filler (36), depositing and bonding the skin (42), then removing the fugitive material.

  4. EMSL Contribution Plan

    Energy Technology Data Exchange (ETDEWEB)

    Campbell, Allison A.

    2008-12-01

    This Contribution Plan is EMSL’s template for achieving our vision of simultaneous excellence in all aspects of our mission as a national scientific user facility. It reflects our understanding of the long-term stewardship we must work toward to meet the scientific challenges faced by the Department of Energy (DOE) and the nation. During the next decade, we will implement the strategies contained in this Plan, working closely with the scientific community, our advisory committees, DOE’s Office of Biological and Environmental Research, and other key stakeholders. This Plan is fully aligned with the strategic plans of DOE, its Office of Science, and the Pacific Northwest National Laboratory (PNNL). We recognize that shifts in science and technology, national priorities, and resources made available through the Federal budget process create planning uncertainties and, ultimately, a highly dynamic planning environment. Accordingly, this Plan should be viewed as a living document and we continually evaluate the changing needs and opportunities posed by our stakeholders (i.e., DOE, users, staff, advisory committees), work closely with them to understand and respond to those changes, and align our strategy accordingly. This Plan is organized around two sections. Section 1 describes our vision and four strategic outcomes: 1) Scientific Innovation, 2) Capabilities that Transform Science, 3) Outstanding Management and Operations, and Engaged and Proactive Users. These outcomes provide the framework for seven critical actions we must take during the next 3 to 5 years: 1) Establishing leadership in EMSL science themes, 2) building and deploying transformational capabilities, 3) integrating computation with experiment, 4) ensuring EMSL’s workforce meets the scientific challenges of the future, 5) creating partnerships, 6) attracting and engaging users in EMSL’s long-term strategy, and 7) building a research infrastructure that meets emerging scientific needs. Section 2

  5. Group Contribution Methods for Phase Equilibrium Calculations.

    Science.gov (United States)

    Gmehling, Jürgen; Constantinescu, Dana; Schmid, Bastian

    2015-01-01

    The development and design of chemical processes are carried out by solving the balance equations of a mathematical model for sections of or the whole chemical plant with the help of process simulators. For process simulation, besides kinetic data for the chemical reaction, various pure component and mixture properties are required. Because of the great importance of separation processes for a chemical plant in particular, a reliable knowledge of the phase equilibrium behavior is required. The phase equilibrium behavior can be calculated with the help of modern equations of state or g(E)-models using only binary parameters. But unfortunately, only a very small part of the experimental data for fitting the required binary model parameters is available, so very often these models cannot be applied directly. To solve this problem, powerful predictive thermodynamic models have been developed. Group contribution methods allow the prediction of the required phase equilibrium data using only a limited number of group interaction parameters. A prerequisite for fitting the required group interaction parameters is a comprehensive database. That is why for the development of powerful group contribution methods almost all published pure component properties, phase equilibrium data, excess properties, etc., were stored in computerized form in the Dortmund Data Bank. In this review, the present status, weaknesses, advantages and disadvantages, possible applications, and typical results of the different group contribution methods for the calculation of phase equilibria are presented.

  6. Component Composition Using Feature Models

    DEFF Research Database (Denmark)

    Eichberg, Michael; Klose, Karl; Mitschke, Ralf;

    2010-01-01

    In general, components provide and require services and two components are bound if the first component provides a service required by the second component. However, certain variability in services - w.r.t. how and which functionality is provided or required - cannot be described using standard...... interface description languages. If this variability is relevant when selecting a matching component then human interaction is required to decide which components can be bound. We propose to use feature models for making this variability explicit and (re-)enabling automatic component binding. In our...... approach, feature models are one part of service specifications. This enables to declaratively specify which service variant is provided by a component. By referring to a service's variation points, a component that requires a specific service can list the requirements on the desired variant. Using...

  7. Turmeric toxicity in A431 epidermoid cancer cells associates with autophagy degradation of anti-apoptotic and anti-autophagic p53 mutant.

    Science.gov (United States)

    Thongrakard, Visa; Titone, Rossella; Follo, Carlo; Morani, Federica; Suksamrarn, Apichart; Tencomnao, Tewin; Isidoro, Ciro

    2014-12-01

    The keratinocyte-derived A431 Squamous Cell Carcinoma cells express the p53R273H mutant, which has been reported to inhibit apoptosis and autophagy. Here, we show that the crude extract of turmeric (Curcuma longa), similarly to its bioactive component Curcumin, could induce both apoptosis and autophagy in A431 cells, and these effects were concomitant with degradation of p53. Turmeric and curcumin also stimulated the activity of mTOR, which notoriously promotes cell growth and acts negatively on basal autophagy. Rapamycin-mediated inhibition of mTOR synergized with turmeric and curcumin in causing p53 degradation, increased the production of autophagosomes and exacerbated cell toxicity leading to cell necrosis. Small-interference mediated silencing of the autophagy proteins BECLIN 1 or ATG7 abrogated the induction of autophagy and largely rescued p53 stability in Turmeric-treated or Curcumin-treated cells, indicating that macroautophagy was mainly responsible for mutant p53 degradation. These data uncover a novel mechanism of turmeric and curcumin toxicity in chemoresistant cancer cells bearing mutant p53.

  8. Crystalline Nickel Sulfide Induced Malignant Transformation of 16HBE Cells through Autophagic Pathway%结晶型硫化镍通过自噬途径诱导16HBE细胞恶性转化癌变

    Institute of Scientific and Technical Information of China (English)

    张岚; 杨磊; 吕嘉春

    2012-01-01

    Nickel compounds, which widely exist in the environment of human occupation, are the major risk factor for human lung cancer. Our previous studies had confirmed that exposure to toxic,metallic crystalline nickel sulfide (NiS) was an important cause of lung cancer, but the concrete carcinogenic mechanism is still unclear. In this study, we used the previouslyestablished human bronchial epithelial (16HBE-T) cells malignant transformation model, which was induced by crystalline NiS. For the first time, fluorescence intensity and position of the GFP-LC3 protein in malignant transformed (16HBE-T) cells and normal cell (16HBE-N), were real-time monitored with the technique of confocal laser scanning microscopy imaging without damaging the condition. Moreover, we used Western Blotting to detect the intracellular autophagic signal which is expressed by key effective molecule pathway. Confocal experimental results showed that: Compared with that of 16HBE-N-cells, the GFP-LC3 protein punctate aggregation of 16HBE-T cells significantly reduced to the merely 1/3 amount of 16HBE-N-cells, suggesting that autophagy levels declined. At the same time, it was found that the mTOR kinase activity increased, and that Beclin 1 expression decreased. The above research result demonstrated that the mechanism of crystalline NiS induced 16HBE cell malignant transformation was through multiple autophagic pathway and it will provide an important message in the prevention and treatment of lung cancer.%镍化合物广泛存在于人类职业环境中,是人类发生肺癌的主要危险因素.我们前期研究已证实金属毒物结晶型硫化镍(NiS)的暴露是发生肺癌的重要病因,但具体的致癌机制仍未明了.本研究利用前期建立的结晶型NiS恶性转化人支气管上皮细胞的细胞模型,首次采用激光共聚焦扫描显微镜成像技术,在无损伤状态下,实时观测恶性转化细胞(16HBE-T)和正常细胞(16HBE-N)中自噬体标记蛋白GFP-LC3

  9. Local Component Analysis

    CERN Document Server

    Roux, Nicolas Le

    2011-01-01

    Kernel density estimation, a.k.a. Parzen windows, is a popular density estimation method, which can be used for outlier detection or clustering. With multivariate data, its performance is heavily reliant on the metric used within the kernel. Most earlier work has focused on learning only the bandwidth of the kernel (i.e., a scalar multiplicative factor). In this paper, we propose to learn a full Euclidean metric through an expectation-minimization (EM) procedure, which can be seen as an unsupervised counterpart to neighbourhood component analysis (NCA). In order to avoid overfitting with a fully nonparametric density estimator in high dimensions, we also consider a semi-parametric Gaussian-Parzen density model, where some of the variables are modelled through a jointly Gaussian density, while others are modelled through Parzen windows. For these two models, EM leads to simple closed-form updates based on matrix inversions and eigenvalue decompositions. We show empirically that our method leads to density esti...

  10. Surface Active Components: Review

    Directory of Open Access Journals (Sweden)

    Z. Shafiei

    2014-03-01

    Full Text Available Biosurfactant or surface active components are produced by many different microorganisms. Biosurfactants are amphiphilic molecules with both hydrophilic and hydrophobic (generally hydrocarbon moieties that partition preferentially a within the interface between fluid phases with some other degrees of polarity and hydrogen bonding including oil/water or air/water interfaces. These properties render surfactants able to reducing surface and interfacial tension and forming microemulsion where hydrocarbons can solubilize in water or where water can solubilize in hydrocarbons, the majority of surfactants have gained importance in the fields of enhanced oil recovery, environmental bioremediation, food processing and pharmaceuticals. However, large-scale production of these molecules has not been realized as a result of low yields in production processes and high recovery and purification costs. This review article represents a classification of biosurfactant in addition to their microbial origin and effect of some nutrition and environmental factor for high production of biosurfactant. The nitrogen, carbon sources and environmental factors can make a difference key to the regulating biosurfactants synthesis Fascination with microbial surfactants have been steadily increasing recently because of advantages over the chemical surfactants for example environmentally friendly nature, lower toxicity, higher biodegradability, higher selectivity and specific gravity at extreme temperature, pH and salinity. For this reason the demand of biosurfactant are increasing day by day.

  11. Security Components of Globalization

    Directory of Open Access Journals (Sweden)

    Florin Iftode

    2015-05-01

    Full Text Available The objective of this paper is our intention to present what are the main connections between globalization and international security. In terms of global security we can perceive the globalization as a process by which global state is represented by the UN, with a single world system, represented by major security organizations and with global effects. We will present from the beginning the main theoretical aspects that define the phenomenon of globalization, and then our contribution in assessing the implications of this phenomenon on the regional and global security. The results of our research are materialized in the last part of the paper. They emphasize the personal assessments on how the phenomenon of globalization has direct effect on global security. When talking about government, we think of norms, rules and decisionmaking procedures in the management of international life. The value that we add to the new scientific interpretation of the definition of globalization is represented, primarily, by the valuable bibliographic used resources and the original approach on the concept that refers to the links between globalization and security. This article may be, at any time, a starting point in an interesting research direction in the field of global security.

  12. Contribuição dos componentes e composição química de pastagens em sistemas forrageiros constituídos por diferentes leguminosas Components contribution and chemical composition of pastures in forage systems with different legumes

    Directory of Open Access Journals (Sweden)

    Clair Jorge Olivo

    2010-12-01

    Full Text Available Realizou-se o presente trabalho com o objetivo de avaliar a composição química de dois sistemas forrageiros, tendo como componentes comuns o capim-elefante, o azevém e as espécies de crescimento espontâneo, variando em um sistema o consórcio com o trevo branco, e, em outro, com o amendoim forrageiro. Para avaliação, foram usados quatro piquetes com 0,25ha cada um. Como animais experimentais, foram utilizadas vacas em lactação da raça Holandesa. O delineamento experimental utilizado foi o inteiramente casualizado, com dois tratamentos (sistemas forrageiros e duas repetições (piquetes. Para análise de proteína bruta (PB, fibra em detergente neutro (FDN e fibra em detergente ácido (FDA, foram retiradas amostras através de simulação de pastejo. A participação dos componentes dos sistemas forrageiros variou segundo as leguminosas componentes. O sistema composto por amendoim forrageiro permitiu suportar maior carga no período estival. Os valores médios (pré e pós-pastejo para PB, FDN e FDA foram de 18,76; 71,46; 34,87% para o sistema forrageiro constituído com o trevo branco e de 19,31; 71,19 e 35,40%. Os resultados foram similares entre os sistemas forrageiros.The aim of this research was to evaluate the chemical composition of two pasture-based systems having as common components the elephantgrass, ryegrass and spontaneous growth species, in one system the white clover and, in another system, the forage peanut. Four paddocks, each one with 0.25ha, were used in the evaluation. Holstein cows were used in the evaluation. The experimental design was completely randomized, with two treatments (pasture-based systems, two replications (paddocks. To analyze the crude protein (CP, neutral detergent fiber (NDF and acid detergent fiber (ADF, hand-plucked samples were collected. Composition of forage systems changes according to its legumes compounds. Forage peanut system allowed a greater stocking rate in hot season. The mean values

  13. Application of fuzzy-MOORA method: Ranking of components for reliability estimation of component-based software systems

    Directory of Open Access Journals (Sweden)

    Zeeshan Ali Siddiqui

    2016-01-01

    Full Text Available Component-based software system (CBSS development technique is an emerging discipline that promises to take software development into a new era. As hardware systems are presently being constructed from kits of parts, software systems may also be assembled from components. It is more reliable to reuse software than to create. It is the glue code and individual components reliability that contribute to the reliability of the overall system. Every component contributes to overall system reliability according to the number of times it is being used, some components are of critical usage, known as usage frequency of component. The usage frequency decides the weight of each component. According to their weights, each component contributes to the overall reliability of the system. Therefore, ranking of components may be obtained by analyzing their reliability impacts on overall application. In this paper, we propose the application of fuzzy multi-objective optimization on the basis of ratio analysis, Fuzzy-MOORA. The method helps us find the best suitable alternative, software component, from a set of available feasible alternatives named software components. It is an accurate and easy to understand tool for solving multi-criteria decision making problems that have imprecise and vague evaluation data. By the use of ratio analysis, the proposed method determines the most suitable alternative among all possible alternatives, and dimensionless measurement will realize the job of ranking of components for estimating CBSS reliability in a non-subjective way. Finally, three case studies are shown to illustrate the use of the proposed technique.

  14. Performance Engineering Technology for Scientific Component Software

    Energy Technology Data Exchange (ETDEWEB)

    Malony, Allen D.

    2007-05-08

    Large-scale, complex scientific applications are beginning to benefit from the use of component software design methodology and technology for software development. Integral to the success of component-based applications is the ability to achieve high-performing code solutions through the use of performance engineering tools for both intra-component and inter-component analysis and optimization. Our work on this project aimed to develop performance engineering technology for scientific component software in association with the DOE CCTTSS SciDAC project (active during the contract period) and the broader Common Component Architecture (CCA) community. Our specific implementation objectives were to extend the TAU performance system and Program Database Toolkit (PDT) to support performance instrumentation, measurement, and analysis of CCA components and frameworks, and to develop performance measurement and monitoring infrastructure that could be integrated in CCA applications. These objectives have been met in the completion of all project milestones and in the transfer of the technology into the continuing CCA activities as part of the DOE TASCS SciDAC2 effort. In addition to these achievements, over the past three years, we have been an active member of the CCA Forum, attending all meetings and serving in several working groups, such as the CCA Toolkit working group, the CQoS working group, and the Tutorial working group. We have contributed significantly to CCA tutorials since SC'04, hosted two CCA meetings, participated in the annual ACTS workshops, and were co-authors on the recent CCA journal paper [24]. There are four main areas where our project has delivered results: component performance instrumentation and measurement, component performance modeling and optimization, performance database and data mining, and online performance monitoring. This final report outlines the achievements in these areas for the entire project period. The submitted progress

  15. Towards Prognostics for Electronics Components

    Data.gov (United States)

    National Aeronautics and Space Administration — Electronics components have an increasingly critical role in avionics systems and in the development of future aircraft systems. Prognostics of such components is...

  16. Thermal Degradation of Lignocellulosic Fuels: Biopolymers Contribution

    OpenAIRE

    Leroy, Valérie; Leoni, Eric; Cancellieri, Dominique

    2010-01-01

    In wildland fire modelling and forest fuel hazard studies, the thermal degradation of the solid is a fundamental stage. Two ways are suitable: the first one considers the thermal degradation of the whole fuel giving a complex mixture of gas, tars and chars; the second one considers the thermal degradation as the sum of the contributions from the principal components of the fuel. Our aim was to verify the validity of the second approach. DSC analyses were performed in order to get the enthalpy...

  17. 化肥施用对中国粮食产量的贡献率分析--基于主成分回归C-D生产函数模型的实证研究%Application of Chemical Fertilizer on Grain Yield in China Analysis of Contribution Rate:Based on Principal Component Regression C-D Production Function Model and Its Empirical Study

    Institute of Scientific and Technical Information of China (English)

    房丽萍; 孟军

    2013-01-01

    Fertilizer was an important measure for sustainable development of agriculture, fertilizers role in guarding the safety of our food is put into the other factors of production are not a substitute for, grasp the stimulation effect of chemical fertilizers from the guidance of agricultural production and to determine the scientific and effective fertilization programs have important theoretical and practical significance. This paper analyzed the chemical fertilizer use and food production relationship, selected the sown area of grain crops, the total power of agricultural machinery, the effective irrigation area, the amount of chemical fertilizer and agricultural workers for China's grain yield affecting factors. By using the principal component regression C-D production function model, calculated the input of chemical fertilizer on grain output elasticity and contribution rate. The results showed that: the use of chemical fertilizer and grain yield between strong positive correlation;1978 to 2010 years of fertilizer on grain yield growth elasticity value was 0.18, the contribution rate was 20.79%, chemical fertilizer on increasing grain output elasticity and contribution and the results of previous studied phase decreased slightly, per unit mass of chemical fertilizer input to bring the actual grain yield increase the quantity decreases somewhat, but chemical fertilizer input was still an important factor in the increase of grain yield.%  施肥是农业持续发展的重要措施,施用化肥对中国粮食安全的保障作用是投入其他生产要素所不能替代的,掌握化肥的增产效应从指导农业生产及确定科学有效的施肥方案方面来说,都具有重要的理论与实践意义。分析了化肥施用量与粮食产量之间的关系,选取粮食作物播种面积、农用机械总动力、有效灌溉面积、化肥施用量和农业从业人员为中国粮食产量的影响因素,采用主成分回归C-D生产函数模

  18. Cooling system for electronic components

    Energy Technology Data Exchange (ETDEWEB)

    Anderl, William James; Colgan, Evan George; Gerken, James Dorance; Marroquin, Christopher Michael; Tian, Shurong

    2016-05-17

    Embodiments of the present invention provide for non interruptive fluid cooling of an electronic enclosure. One or more electronic component packages may be removable from a circuit card having a fluid flow system. When installed, the electronic component packages are coincident to and in a thermal relationship with the fluid flow system. If a particular electronic component package becomes non-functional, it may be removed from the electronic enclosure without affecting either the fluid flow system or other neighboring electronic component packages.

  19. Cooling system for electronic components

    Energy Technology Data Exchange (ETDEWEB)

    Anderl, William James; Colgan, Evan George; Gerken, James Dorance; Marroquin, Christopher Michael; Tian, Shurong

    2015-12-15

    Embodiments of the present invention provide for non interruptive fluid cooling of an electronic enclosure. One or more electronic component packages may be removable from a circuit card having a fluid flow system. When installed, the electronic component packages are coincident to and in a thermal relationship with the fluid flow system. If a particular electronic component package becomes non-functional, it may be removed from the electronic enclosure without affecting either the fluid flow system or other neighboring electronic component packages.

  20. Formalization in Component Based Development

    DEFF Research Database (Denmark)

    Holmegaard, Jens Peter; Knudsen, John; Makowski, Piotr;

    2006-01-01

    We present a unifying conceptual framework for components, component interfaces, contracts and composition of components by focusing on the collection of properties or qualities that they must share. A specific property, such as signature, functionality behaviour or timing is an aspect. Each aspe...... by small examples, using UML as concrete syntax for various aspects, and is illustrated by one larger case study based on an industrial prototype of a complex component based system....

  1. Biometric relationships of ocular components in esotropic amblyopia

    Directory of Open Access Journals (Sweden)

    Iara Debert

    2012-02-01

    Full Text Available PURPOSE: To investigate the contribution of the individual ocular components, i.e. anterior chamber depth, lens thickness and vitreous chamber depth, to total axial length in patients with esotropic amblyopia. METHODS: The study population consisted of 74 children, aged between 5 and 8 years: thirty-seven patients with esotropic amblyopia and 37 healthy volunteers (control group. The participants underwent a comprehensive ophthalmological examination, including cycloplegic refraction and A-scan ultrasonography. Anterior chamber depth, lens thickness, vitreous chamber depth and total axial length were recorded. Paired Student's t-tests were used to compare biometric measurements between amblyopic eyes and their fellow eyes and between right and left eyes in the control group. To evaluate the contribution of the ocular components to the total axial length, we report the individual components as a percentage of total axial length. RESULTS: The comparison between amblyopic and fellow eyes regarding the individual contribution from ocular components to the total axial length revealed greater contribution from lens thickness (P=0.001 and smaller contribution from vitreous chamber depth (P=0.001 in amblyopic eyes, despite similar contribution from anterior chamber depth (P=0.434. The comparison between right and left eyes in the control group showed similar contributions from anterior chamber depth (P=0.620, lens thickness (P=0.721, and vitreous chamber depth (P=0.483. CONCLUSIONS: This study shows differences between amblyopic and non-amblyopic eyes when the total axial length is broken down into the individual contribution from the ocular components.

  2. Actual service life prediction of building components

    DEFF Research Database (Denmark)

    Aagaard, Niels-Jørgen; Brandt, Erik; Hansen, Ernst Jan de Place

    2014-01-01

    a condensed method for assessment of life cycle costs for buildings. Estimation of life cycle costs has traditionally been based on predicted service life for building components in terms of technical performance. This paper suggests a method for taking into account other contributing factors...... such as economics, aesthetics and use of the building. Each of these factors is regarded as a stochastic variable and can be seen as competing causes of bringing service life to an end. A model is proposed for combining such variables resulting in the actual service life of building components. Furthermore......, the paper presents an analysis of service life of buildings as such with respect to the use of the building partially based on analysis of data from the nationwide Danish register of buildings and housing as well as turnover in the Danish construction industry from refurbishment and demolition activities...

  3. How Pure Components Control Polymer Blend Miscibility

    Science.gov (United States)

    White, Ronald; Lipson, Jane; Higgins, Julia

    2012-02-01

    We present insight into some intriguing relationships revealed by our recent studies of polymer mixture miscibility. Applying our simple lattice-based equation of state, we discuss some of the patterns observed over a sample of experimental blends. We focus on the question of how much key information can one determine from a knowledge of just the pure components only, and further, on the role of separate enthalpic and entropic contributions to the miscibility behavior. One interesting correlation connects the value of the difference in pure component energetic parameters with that of the mixed segment interactions, suggesting new possibilities for predictive modeling. We also show how in some cases these two parameter groupings act as separate controls determining the entropy and enthalpy of mixing. Also discussed are the different patterns exhibited for UCST-type and LCST-type blends, these being revealed in some cases by simple examination of the underlying microscopic parameters.

  4. A potent dauer pheromone component in Caenorhabditis elegans that acts synergistically with other components.

    Science.gov (United States)

    Butcher, Rebecca A; Ragains, Justin R; Kim, Edward; Clardy, Jon

    2008-09-23

    In the model organism Caenorhabditis elegans, the dauer pheromone is the primary cue for entry into the developmentally arrested, dauer larval stage. The dauer is specialized for survival under harsh environmental conditions and is considered "nonaging" because larvae that exit dauer have a normal life span. C. elegans constitutively secretes the dauer pheromone into its environment, enabling it to sense its population density. Several components of the dauer pheromone have been identified as derivatives of the dideoxy sugar ascarylose, but additional unidentified components of the dauer pheromone contribute to its activity. Here, we show that an ascaroside with a 3-hydroxypropionate side chain is a highly potent component of the dauer pheromone that acts synergistically with previously identified components. Furthermore, we show that the active dauer pheromone components that are produced by C. elegans vary depending on cultivation conditions. Identifying the active components of the dauer pheromone, the conditions under which they are produced, and their mechanisms of action will greatly extend our understanding of how chemosensory cues from the environment can influence such fundamental processes as development, metabolism, and aging in nematodes and in higher organisms.

  5. 75 FR 43799 - Employee Contribution Elections and Contribution Allocations

    Science.gov (United States)

    2010-07-27

    ... Part 1600 Employee Contribution Elections and Contribution Allocations AGENCY: Federal Retirement...), which was established by the Federal Employees' Retirement System Act of 1986 (FERSA), Public Law 99-335...-79. The TSP is a tax-deferred retirement savings plan for Federal civilian employees and members...

  6. Magnetic field contribution to the last electron-photon scattering

    OpenAIRE

    Giovannini, Massimo

    2010-01-01

    When the cosmic microwave photons scatter electrons just prior to the decoupling of matter and radiation, magnetic fields do contribute to the Stokes matrix as well as to the scalar, vector and tensor components of the transport equations for the brightness perturbations. The magnetized electron-photon scattering is hereby discussed in general terms by including, for the first time, the contribution of magnetic fields with arbitrary direction and in the presence of the scalar, vector and tens...

  7. Component-specific modeling. [jet engine hot section components

    Science.gov (United States)

    Mcknight, R. L.; Maffeo, R. J.; Tipton, M. T.; Weber, G.

    1992-01-01

    Accomplishments are described for a 3 year program to develop methodology for component-specific modeling of aircraft hot section components (turbine blades, turbine vanes, and burner liners). These accomplishments include: (1) engine thermodynamic and mission models, (2) geometry model generators, (3) remeshing, (4) specialty three-dimensional inelastic structural analysis, (5) computationally efficient solvers, (6) adaptive solution strategies, (7) engine performance parameters/component response variables decomposition and synthesis, (8) integrated software architecture and development, and (9) validation cases for software developed.

  8. 75 FR 32659 - Contributed Property

    Science.gov (United States)

    2010-06-09

    ... Internal Revenue Service 26 CFR Part 1 RIN 1545-BF28 Contributed Property AGENCY: Internal Revenue Service... property to the partnership. In that regard, the anti- abuse rule of Sec. 1.701-2(b) provides that, if a... contribution of property to a partnership should be recast to avoid results that are inconsistent...

  9. Notes on the Components for Intelligent Tutoring Systems

    Directory of Open Access Journals (Sweden)

    Ladislav Samuelis

    2007-08-01

    Full Text Available The aim of this contribution is to present briefly several views on the componentsfor the intelligent tutoring systems (ITSs and to analyze the concepts behind them. We willbriefly analyze the concepts provided by the classical machine learning (ML approachesand then we discuss the role of the components in distributed environment. Finally wesynthesize the converging trends of the ITSs technologies and try to outline further possibleresearch directions in building ITS from components.

  10. Assessment and control of tonal components in electric vehicles

    OpenAIRE

    Lennström, David

    2015-01-01

    New challenges arise for noise, vibration and harshness (NVH) engineers when electric motors are introduced into cars traditionally powered by internal combustion engines (ICE). The noise signature from an electric traction motor is characterized by speed-dependent high frequency tonal components due to electro-magnetic excitation. Despite the relatively low overall levels, those tonal components can be prominent and contribute to perceived annoyance for the occupants inside the car. With the...

  11. SBA Network Components & Software Inventory

    Data.gov (United States)

    Small Business Administration — SBA’s Network Components & Software Inventory contains a complete inventory of all devices connected to SBA’s network including workstations, servers, routers,...

  12. A novel contribution of spvB to pathogenesis of Salmonella Typhimurium by inhibiting autophagy in host cells.

    Science.gov (United States)

    Chu, Yuanyuan; Gao, Song; Wang, Ting; Yan, Jing; Xu, Guangmei; Li, Yuanyuan; Niu, Hua; Huang, Rui; Wu, Shuyan

    2016-02-16

    Salmonella plasmid virulence genes (spv) are highly conserved in strains of clinically important Salmonella serovars. It is essential for Salmonella plasmid-correlated virulence, although the exact mechanism remains to be elucidated. Autophagy has been reported to play an important role in host immune responses limiting Salmonella infection. Our previous studies demonstrated that Salmonella conjugative plasmid harboring spv genes could enhance bacterial cytotoxicity by inhibiting autophagy. In the present study, we investigated whether spvB, which is one of the most important constituents of spv ORF could intervene in autophagy pathway. Murine macrophage-like cells J774A.1, human epithelial HeLa cells, and BALB/c mice infected with Salmonella Typhimurium wild type, mutant and complementary strains (carrying or free spvB or complemented only with ADP-ribosyltransferase activity of SpvB) were used in vitro and in vivo assay, respectively. To further explore the molecular mechanisms, both SpvB ectopic eukaryotic expression system and cells deficient in essential autophagy components by siRNA were generated. Results indicated that spvB could suppress autophagosome formation through its function in depolymerizing actin, and aggravate inflammatory injury of the host in response to S. Typhimurium infection. Our studies demonstrated virulence of spvB involving in inhibition of autophagic flux for the first time, which could provide novel insights into Salmonella pathogenesis, and have potential application to develop new antibacterial strategies for Salmonellosis.

  13. Active and passive contributions to spatial learning.

    Science.gov (United States)

    Chrastil, Elizabeth R; Warren, William H

    2012-02-01

    It seems intuitively obvious that active exploration of a new environment will lead to better spatial learning than will passive exposure. However, the literature on this issue is decidedly mixed-in part, because the concept itself is not well defined. We identify five potential components of active spatial learning and review the evidence regarding their role in the acquisition of landmark, route, and survey knowledge. We find that (1) idiothetic information in walking contributes to metric survey knowledge, (2) there is little evidence as yet that decision making during exploration contributes to route or survey knowledge, (3) attention to place-action associations and relevant spatial relations contributes to route and survey knowledge, although landmarks and boundaries appear to be learned without effort, (4) route and survey information are differentially encoded in subunits of working memory, and (5) there is preliminary evidence that mental manipulation of such properties facilitates spatial learning. Idiothetic information appears to be necessary to reveal the influence of attention and, possibly, decision making in survey learning, which may explain the mixed results in desktop virtual reality. Thus, there is indeed an active advantage in spatial learning, which manifests itself in the task-dependent acquisition of route and survey knowledge.

  14. Connected Component Labeling Using Components Neighbors-Scan Labeling Approach

    Directory of Open Access Journals (Sweden)

    Akmal Rakhmadi

    2010-01-01

    Full Text Available Problem statement: Many approaches have been proposed in previous such as the classic sequential connected components labeling algorithm which is relies on two subsequent raster-scans of a binary image. This method produced good performance in terms of accuracy, but because of the implementation of the image processing systems now requires faster process of the computer, the speed of this technique’s process has become an important issue. Approach: A computational approach, called components neighbors-scan labeling algorithm for connected component labeling was presented in this study. This algorithm required scanning through an image only once to label connected components. The algorithm started by scanning from the head of the component’s group, before tracing all the components neighbors by using the main component’s information. This algorithm had desirable characteristics, it is simple while promoted accuracy and low time consuming. By using a table of components, this approach also gave other advantages as the information for the next higher process. Results: The approach had been tested with a collection of binary images. In practically all cases, the technique had successfully given the desired result. Averagely, from the results the algorithm increased the speed around 67.4% from the two times scanning method. Conclusion: Conclusion from the comparison with the previous method, the approach of components neighbors-scan for connected component labeling promoted speed, accuracy and simplicity. The results showed that the approach has a good performance in terms of accuracy, the time consumed and the simplicity of the algorithm.

  15. Introducing and modeling inefficiency contributions

    DEFF Research Database (Denmark)

    Asmild, Mette; Kronborg, Dorte; Matthews, Kent

    2016-01-01

    Whilst Data Envelopment Analysis (DEA) is the most commonly used non-parametric benchmarking approach, the interpretation and application of DEA results can be limited by the fact that radial improvement potentials are identified across variables. In contrast, Multi-directional Efficiency Analysis......-called inefficiency contributions, which are defined as the relative contributions from specific variables to the overall levels of inefficiencies. A statistical model for distinguishing the inefficiency contributions between subgroups is proposed and the method is illustrated on a data set on Chinese banks....

  16. Semantic Annotation of Computational Components

    Science.gov (United States)

    Vanderbilt, Peter; Mehrotra, Piyush

    2004-01-01

    This paper describes a methodology to specify machine-processable semantic descriptions of computational components to enable them to be shared and reused. A particular focus of this scheme is to enable automatic compositon of such components into simple work-flows.

  17. Components of Successful Magnet Schools.

    Science.gov (United States)

    Bryant, Faye B.

    This paper identifies and discusses components of successful magnet programs. It is based on a review of existing research literature and information gathered directly from school districts. First, the paper discusses separately the following elements, which are considered "core components": (1) leadership; (2) organizational structure; (3)…

  18. Active components in food supplements

    NARCIS (Netherlands)

    Siemelink M; Jansen EHJM; Piersma AH; Opperhuizen A; LEO

    2000-01-01

    The growing food supplement market, where supplements are both more diverse and more easily available (e.g. through Internet) formed the backdrop to the inventory of the active components in food supplements. The safety of an increased intake of food components via supplements was also at issue her

  19. Secure coupling of hardware components

    NARCIS (Netherlands)

    Knobbe, J.W.; Hoepman, J.H.; Joosten, H.J.M.

    2011-01-01

    A method and a system for securing communication between at least a first and a second hardware components of a mobile device is described. The method includes establishing a first shared secret between the first and the second hardware components during an initialization of the mobile device and, f

  20. Diverse Multilingual Researchers Contribute Language Acquisition Components to an Integrated Model of Education

    Science.gov (United States)

    Hobbs, Robert Dean

    2012-01-01

    Evidence-based outcomes in the literature have caused adjustments in neuro-psycholinguistic and sociolinguistic perspectives that indicate a need for a current model of education. Implications from research suggest the new model of education should use a multilingual framework: L3 enhances and reinforces L2 and L1, if L2 and L1 are supported. The…

  1. National Guard Special Forces: Enhancing the Contributions of Reserve Component Army Special Operations Forces

    Science.gov (United States)

    2012-01-01

    See Lolita C. Baldor, “US Special Forces Show Strain, Says Admiral,” Boston Globe, February 9, 2011, p. 8. 13 The “Playbook” is the USASOC management...46thsfca.org/ Baldor, Lolita C., “US Special Forces Show Strain, Says Admiral,” Boston Globe, February 9, 2011, p. 8. Blalock, MG Abner C., Alabama Adjutant

  2. Diesel fuel component contribution to engine emissions and performance. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Erwin, J.; Ryan, T.W. III; Moulton, D.S. [Southwest Research Institute, San Antonio, TX (United States)

    1994-11-01

    Contemporary diesel fuel is a blend of several refinery streams chosen to meet specifications. The need to increase yield of transportation fuel from crude oil has resulted in converting increased proportions of residual oil to lighter products. This conversion is accomplished by thermal, catalytic, and hydrocracking of high molecular weight materials rich in aromatic compounds. The current efforts to reformulate California diesel fuel for reduced emissions from existing engines is an example of another driving force affecting refining practice: regulations designed to reduce exhaust emissions. Although derived from petroleum crude oil, reformulated diesel fuel is an alternative to current specification-grade diesel fuel, and this alternative presents opportunities and questions to be resolved by fuel and engine research. Various concerned parties have argued that regulations for fuel reformulation have not been based on an adequate data base. Despite numerous studies, much ambiguity remains about the relationship of exhaust parameters to fuel composition, particularly for diesel fuel. In an effort to gather pertinent data, the automobile industry and the oil refiners have joined forces in the Air Quality Improvement Research Program (AUTO/OIL) to address this question for gasoline. The objective of that work is to define the relationship between gasoline composition and the magnitude and composition of the exhaust emissions. The results of the AUTO/OEL program will also be used, along with other data bases, to define the EPA {open_quotes}complex model{close_quotes} for reformulated gasolines. Valuable insights have been gained for compression ignition engines in the Coordinating Research Council`s VE-1 program, but no program similar to AUTO/OIL has been started for diesel fuel reformulation. A more detailed understanding of the fuel/performance relationship is a readily apparent need.

  3. Novel Structural Components Contribute to the High Thermal Stability of Acyl Carrier Protein from Enterococcus faecalis.

    Science.gov (United States)

    Park, Young-Guen; Jung, Min-Cheol; Song, Heesang; Jeong, Ki-Woong; Bang, Eunjung; Hwang, Geum-Sook; Kim, Yangmee

    2016-01-22

    Enterococcus faecalis is a Gram-positive, commensal bacterium that lives in the gastrointestinal tracts of humans and other mammals. It causes severe infections because of high antibiotic resistance. E. faecalis can endure extremes of temperature and pH. Acyl carrier protein (ACP) is a key element in the biosynthesis of fatty acids responsible for acyl group shuttling and delivery. In this study, to understand the origin of high thermal stabilities of E. faecalis ACP (Ef-ACP), its solution structure was investigated for the first time. CD experiments showed that the melting temperature of Ef-ACP is 78.8 °C, which is much higher than that of Escherichia coli ACP (67.2 °C). The overall structure of Ef-ACP shows the common ACP folding pattern consisting of four α-helices (helix I (residues 3-17), helix II (residues 39-53), helix III (residues 60-64), and helix IV (residues 68-78)) connected by three loops. Unique Ef-ACP structural features include a hydrophobic interaction between Phe(45) in helix II and Phe(18) in the α1α2 loop and a hydrogen bonding between Ser(15) in helix I and Ile(20) in the α1α2 loop, resulting in its high thermal stability. Phe(45)-mediated hydrophobic packing may block acyl chain binding subpocket II entry. Furthermore, Ser(58) in the α2α3 loop in Ef-ACP, which usually constitutes a proline in other ACPs, exhibited slow conformational exchanges, resulting in the movement of the helix III outside the structure to accommodate a longer acyl chain in the acyl binding cavity. These results might provide insights into the development of antibiotics against pathogenic drug-resistant E. faecalis strains.

  4. Pb isotope evidence for contributions from different Iceland mantle components to Palaeogene East Greenland flood basalts

    DEFF Research Database (Denmark)

    Peate, David; Stecher, Ole

    2003-01-01

    We present new Pb isotope data on 21 samples of break-up-related flood basalts (56–54 Ma) from the Blosseville Kyst region of East Greenland. These samples show a considerable range in isotopic composition (206Pb/204Pb 17.6 to 19.3) that broadly correlates with compositional type. The ‘low-Ti’ type...

  5. Contribution analysis of a Bolivian innovation grant fund

    NARCIS (Netherlands)

    Ton, Giel

    2016-01-01

    We used contribution analysis to verify the key assumption in the intervention logic of an innovation fund in Bolivia directed to economic farmer organisations to develop value-added activities. We focussed the research on three sub-components of the intervention logic: relevance of the farmer gr

  6. The Contribution of Visualization to Learning Computer Architecture

    Science.gov (United States)

    Yehezkel, Cecile; Ben-Ari, Mordechai; Dreyfus, Tommy

    2007-01-01

    This paper describes a visualization environment and associated learning activities designed to improve learning of computer architecture. The environment, EasyCPU, displays a model of the components of a computer and the dynamic processes involved in program execution. We present the results of a research program that analysed the contribution of…

  7. Multiview Bayesian Correlated Component Analysis

    DEFF Research Database (Denmark)

    Kamronn, Simon Due; Poulsen, Andreas Trier; Hansen, Lars Kai

    2015-01-01

    Correlated component analysis as proposed by Dmochowski, Sajda, Dias, and Parra (2012) is a tool for investigating brain process similarity in the responses to multiple views of a given stimulus. Correlated components are identified under the assumption that the involved spatial networks are iden......Correlated component analysis as proposed by Dmochowski, Sajda, Dias, and Parra (2012) is a tool for investigating brain process similarity in the responses to multiple views of a given stimulus. Correlated components are identified under the assumption that the involved spatial networks...... we denote Bayesian correlated component analysis, evaluates favorably against three relevant algorithms in simulated data. A well-established benchmark EEG data set is used to further validate the new model and infer the variability of spatial representations across multiple subjects....

  8. Component reliability for electronic systems

    CERN Document Server

    Bajenescu, Titu-Marius I

    2010-01-01

    The main reason for the premature breakdown of today's electronic products (computers, cars, tools, appliances, etc.) is the failure of the components used to build these products. Today professionals are looking for effective ways to minimize the degradation of electronic components to help ensure longer-lasting, more technically sound products and systems. This practical book offers engineers specific guidance on how to design more reliable components and build more reliable electronic systems. Professionals learn how to optimize a virtual component prototype, accurately monitor product reliability during the entire production process, and add the burn-in and selection procedures that are the most appropriate for the intended applications. Moreover, the book helps system designers ensure that all components are correctly applied, margins are adequate, wear-out failure modes are prevented during the expected duration of life, and system interfaces cannot lead to failure.

  9. Autophagic effect on tumor and its potential applicationsin non-small cell lung cancer molecular targeted therapy%肿瘤自噬效应及其在非小细胞肺癌分子靶向治疗中的潜在应用

    Institute of Scientific and Technical Information of China (English)

    陈美娟; 詹瑧; 张旭

    2012-01-01

    目前针对非小细胞肺癌(NSCLC)的手术、放化疗等治疗手段临床疗效仍很不足,相应的分子靶向治疗药物随着临床抗药性的产生疗效也明显下降.自噬对肿瘤进展具有双重影响作用.在NSCLC临床治疗的各个阶段都应充分考虑自噬效应所起的作用,对其进行合理调节和利用,从而提高各种治疗手段的临床疗效.%Now clinical treatments for non-small cell lung cancer ( NSCLC ) such as surgery, radiotherapy, and chemotherapy are still insufficient, and the efficacy of some molecular targeted therapy is also limited because of natural and acquired resistance in clinics. Autophagy exhibited the effects of a double-blade sword on tumor progression. On the one hand, autophagic can induce the death of tumor cells, and on the other hand, it alsoprotects the tumor in stress such as nutritional deficiency. Clinical treatment of NSCLC at various stages should take full account of autophagic effect on its progression, which can improve the clinical efficacy of various treatments by reasonable combination.

  10. Inhibition of autophagy contributes to ischemic postconditioning-induced neuroprotection against focal cerebral ischemia in rats.

    Directory of Open Access Journals (Sweden)

    Li Gao

    Full Text Available BACKGROUND: Ischemic postconditioning (IPOC, or relief of ischemia in a stuttered manner, has emerged as an innovative treatment strategy to reduce programmed cell death, attenuate ischemic injuries, and improve neurological outcomes. However, the mechanisms involved have not been completely elucidated. Recent studies indicate that autophagy is a type of programmed cell death that plays elusive roles in controlling neuronal damage and metabolic homeostasis. This study aims to determine the role of autophagy in IPOC-induced neuroprotection against focal cerebral ischemia in rats. METHODOLOGY/PRINCIPAL FINDINGS: A focal cerebral ischemic model with permanent middle cerebral artery (MCA occlusion plus transient common carotid artery (CCA occlusion was established. The autophagosomes and the expressions of LC3/Beclin 1/p62 were evaluated for their contribution to the activation of autophagy. We found that autophagy was markedly induced with the upregulation of LC3/Beclin 1 and downregulation of p62 in the penumbra at various time intervals following ischemia. IPOC, performed at the onset of reperfusion, reduced infarct size, mitigated brain edema, inhibited the induction of LC3/Beclin 1 and reversed the reduction of p62 simultaneously. Rapamycin, an inducer of autophagy, partially reversed all the aforementioned effects induced by IPOC. Conversely, autophagy inhibitor 3-methyladenine (3-MA attenuated the ischemic insults, inhibited the activation of autophagy, and elevated the expression of anti-apoptotic protein Bcl-2, to an extent comparable to IPOC. CONCLUSIONS/SIGNIFICANCE: The present study suggests that inhibition of the autophagic pathway plays a key role in IPOC-induced neuroprotection against focal cerebral ischemia. Thus, pharmacological inhibition of autophagy may provide a novel therapeutic strategy for the treatment of stroke.

  11. DFB component production at IHEP complete

    CERN Multimedia

    2007-01-01

    The last of the components for the 42 DFBs (electrical distribution boxes feeding the strings of superconducting magnets in the LHC) produced for CERN by IHEP Protvino (Russia) were delivered to CERN in January 2007. The DFBs will provide the electrical supply for the superconducting magnets for the LHC, making possible the transition from room temperature down to -268ºC (4.5 K) (see Bulletin No. 37/2006). This important achievement was celebrated on the 14th February 2007 at the IHEP House of Scientists in Protvino in the presence of all the IHEP personnel who contributed to the DFB components production, and with the participation of eight delegates from CERN Management and CERN engineers involved in DFB production. Lyn Evans handed over a present symbolizing the IHEP-CERN collaboration to Nikolaj Tyurin, who offered to Lyn Evans a model of a DFB. Since August 2005, when the components for the first two boxes arrived at CERN, a total of 360 tonnes of raw materials were transported to IHEP on 19 lorries...

  12. ECN contributions to GLOBAL `95

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1995-06-01

    This report contains the 9 contributions of the Netherlands Energy Research Foundation ECN to the international conference on evaluation of emerging nuclear fuel cycle systems, GLOBAL `95, held in Versailles, France, on September 11-14, 1995. (orig./GL).

  13. Uncapacitated facility location problems: contributions

    Directory of Open Access Journals (Sweden)

    Galvão Roberto Diéguez

    2004-01-01

    Full Text Available The objective of the present paper is to review my personal contributions in the field of uncapacitated facility location problems. These contributions took place throughout my academic career, from the time I was a Ph.D. student at Imperial College to the present day. They cover approximately 30 years, from 1973 to 2003; they address: algorithms developed for the p-median problem and for a general formulation of uncapacitated location problems; the study of dynamic location models; covering and hierarchical location problems; queuing-based probabilistic location models. The contributions encompass theoretical developments, computational algorithms and practical applications. All work took place in an academic environment, with the invaluable collaboration of colleagues (both in Brazil and abroad and research students at COPPE. Each section in the paper is dedicated to a topic that involves a personal contribution. Every one of them is placed within the context of the existing literature.

  14. Protection against neurotoxicity by an autophagic mechanism

    Directory of Open Access Journals (Sweden)

    Kangyong Liu

    2012-05-01

    Full Text Available The objective of the present study was to investigate the effects of 3-n-butylphthalide (NBP on a 1-methyl-4-phenylpyridinium (MPP+-induced cellular model of Parkinson’s disease (PD and to illustrate the potential mechanism of autophagy in this process. For this purpose, rat PC12 pheochromocytoma cells were treated with MPP+ (1 mM for 24 h following pretreatment with NBP (0.1 mM. Cell metabolic viability was determined by the MTT assay and cell ultrastructure was examined by transmission electron microscopy. The intracellular distribution and expression of α-synuclein and microtubule-associated protein light chain 3 (LC3 were detected by immunocytochemistry and Western blotting. Our results demonstrated that: 1 NBP prevented MPP+-induced cytotoxicity in PC12 cells by promoting metabolic viability. 2 NBP induced the accumulation of autophagosomes in MPP+-treated PC12 cells. 3 Further study of the molecular mechanism demonstrated that NBP enhanced the colocalization of α-synuclein and LC3 and up-regulated the protein level of LC3-II. These results demonstrate that NBP protects PC12 cells against MPP+-induced neurotoxicity by activating autophagy-mediated α-synuclein degradation, implying that it may be a potential effective therapeutic agent for the treatment of PD.

  15. Protection against neurotoxicity by an autophagic mechanism

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Kangyong; Huang, Jiankang; Chen, Rongfu; Zhang, Ting [Department of Neurology, Affiliated Sixth People' s Hospital, Shanghai Jiaotong University, Shanghai (China); Shen, Liwei [Department of Neurology, Fifth People' s Hospital, Fudan University, Shanghai (China); Yang, Jiajun; Sun, Xiaojiang [Department of Neurology, Affiliated Sixth People' s Hospital, Shanghai Jiaotong University, Shanghai (China)

    2012-03-23

    The objective of the present study was to investigate the effects of 3-n-butylphthalide (NBP) on a 1-methyl-4-phenylpyridinium (MPP{sup +})-induced cellular model of Parkinson's disease (PD) and to illustrate the potential mechanism of autophagy in this process. For this purpose, rat PC12 pheochromocytoma cells were treated with MPP{sup +} (1 mM) for 24 h following pretreatment with NBP (0.1 mM). Cell metabolic viability was determined by the MTT assay and cell ultrastructure was examined by transmission electron microscopy. The intracellular distribution and expression of α-synuclein and microtubule-associated protein light chain 3 (LC3) were detected by immunocytochemistry and Western blotting. Our results demonstrated that: 1) NBP prevented MPP{sup +}-induced cytotoxicity in PC12 cells by promoting metabolic viability. 2) NBP induced the accumulation of autophagosomes in MPP{sup +}-treated PC12 cells. 3) Further study of the molecular mechanism demonstrated that NBP enhanced the colocalization of α-synuclein and LC3 and up-regulated the protein level of LC3-II. These results demonstrate that NBP protects PC12 cells against MPP{sup +}-induced neurotoxicity by activating autophagy-mediated α-synuclein degradation, implying that it may be a potential effective therapeutic agent for the treatment of PD.

  16. The autophagic paradox in cancer therapy.

    Science.gov (United States)

    Wu, W K K; Coffelt, S B; Cho, C H; Wang, X J; Lee, C W; Chan, F K L; Yu, J; Sung, J J Y

    2012-02-23

    Autophagy, hallmarked by the formation of double-membrane bound organelles known as autophagosomes, is a lysosome-dependent pathway for protein degradation. The role of autophagy in carcinogenesis is context dependent. As a tumor-suppressing mechanism in early-stage carcinogenesis, autophagy inhibits inflammation and promotes genomic stability. Moreover, disruption of autophagy-related genes accelerates tumorigenesis in animals. However, autophagy may also act as a pro-survival mechanism to protect cancer cells from various forms of cellular stress. In cancer therapy, adaptive autophagy in cancer cells sustains tumor growth and survival in face of the toxicity of cancer therapy. To this end, inhibition of autophagy may sensitize cancer cells to chemotherapeutic agents and ionizing radiation. Nevertheless, in certain circumstances, autophagy mediates the therapeutic effects of some anticancer agents. Data from recent studies are beginning to unveil the apparently paradoxical nature of autophagy as a cell-fate decision machinery. Taken together, modulation of autophagy is a novel approach for enhancing the efficacy of existing cancer therapy, but its Janus-faced nature may complicate the clinical development of autophagy modulators as anticancer therapeutics.

  17. Stuart Hall’ Contributions to CCCS

    Institute of Scientific and Technical Information of China (English)

    涂艳

    2014-01-01

    Hall is the most prominent master of Birmingham school. To some extent, Hall just represents CCCS and makes outstanding contributions to establishment of this school. Hall’s cultural theory is characterized by the interdisciplinary ideology, cultural gaze of race diaspora, collective creation, academic openness, cultural politics, civilization of the talent and so on, so that displays his value and significance as a cultural theorists and critic, in addition demonstrates his contribution to the whole world.

  18. Vacuum Brazing of Accelerator Components

    Science.gov (United States)

    Singh, Rajvir; Pant, K. K.; Lal, Shankar; Yadav, D. P.; Garg, S. R.; Raghuvanshi, V. K.; Mundra, G.

    2012-11-01

    Commonly used materials for accelerator components are those which are vacuum compatible and thermally conductive. Stainless steel, aluminum and copper are common among them. Stainless steel is a poor heat conductor and not very common in use where good thermal conductivity is required. Aluminum and copper and their alloys meet the above requirements and are frequently used for the above purpose. The accelerator components made of aluminum and its alloys using welding process have become a common practice now a days. It is mandatory to use copper and its other grades in RF devices required for accelerators. Beam line and Front End components of the accelerators are fabricated from stainless steel and OFHC copper. Fabrication of components made of copper using welding process is very difficult and in most of the cases it is impossible. Fabrication and joining in such cases is possible using brazing process especially under vacuum and inert gas atmosphere. Several accelerator components have been vacuum brazed for Indus projects at Raja Ramanna Centre for Advanced Technology (RRCAT), Indore using vacuum brazing facility available at RRCAT, Indore. This paper presents details regarding development of the above mentioned high value and strategic components/assemblies. It will include basics required for vacuum brazing, details of vacuum brazing facility, joint design, fixturing of the jobs, selection of filler alloys, optimization of brazing parameters so as to obtain high quality brazed joints, brief description of vacuum brazed accelerator components etc.

  19. Component Fragility Research Program: Phase 1 component prioritization

    Energy Technology Data Exchange (ETDEWEB)

    Holman, G.S.; Chou, C.K.

    1987-06-01

    Current probabilistic risk assessment (PRA) methods for nuclear power plants utilize seismic ''fragilities'' - probabilities of failure conditioned on the severity of seismic input motion - that are based largely on limited test data and on engineering judgment. Under the NRC Component Fragility Research Program (CFRP), the Lawrence Livermore National Laboratory (LLNL) has developed and demonstrated procedures for using test data to derive probabilistic fragility descriptions for mechanical and electrical components. As part of its CFRP activities, LLNL systematically identified and categorized components influencing plant safety in order to identify ''candidate'' components for future NRC testing. Plant systems relevant to safety were first identified; within each system components were then ranked according to their importance to overall system function and their anticipated seismic capacity. Highest priority for future testing was assigned to those ''very important'' components having ''low'' seismic capacity. This report describes the LLNL prioritization effort, which also included application of ''high-level'' qualification data as an alternate means of developing probabilistic fragility descriptions for PRA applications.

  20. How many separable sources? Model selection in independent components analysis.

    Science.gov (United States)

    Woods, Roger P; Hansen, Lars Kai; Strother, Stephen

    2015-01-01

    Unlike mixtures consisting solely of non-Gaussian sources, mixtures including two or more Gaussian components cannot be separated using standard independent components analysis methods that are based on higher order statistics and independent observations. The mixed Independent Components Analysis/Principal Components Analysis (mixed ICA/PCA) model described here accommodates one or more Gaussian components in the independent components analysis model and uses principal components analysis to characterize contributions from this inseparable Gaussian subspace. Information theory can then be used to select from among potential model categories with differing numbers of Gaussian components. Based on simulation studies, the assumptions and approximations underlying the Akaike Information Criterion do not hold in this setting, even with a very large number of observations. Cross-validation is a suitable, though computationally intensive alternative for model selection. Application of the algorithm is illustrated using Fisher's iris data set and Howells' craniometric data set. Mixed ICA/PCA is of potential interest in any field of scientific investigation where the authenticity of blindly separated non-Gaussian sources might otherwise be questionable. Failure of the Akaike Information Criterion in model selection also has relevance in traditional independent components analysis where all sources are assumed non-Gaussian.

  1. Component Based Electronic Voting Systems

    Science.gov (United States)

    Lundin, David

    An electronic voting system may be said to be composed of a number of components, each of which has a number of properties. One of the most attractive effects of this way of thinking is that each component may have an attached in-depth threat analysis and verification strategy. Furthermore, the need to include the full system when making changes to a component is minimised and a model at this level can be turned into a lower-level implementation model where changes can cascade to as few parts of the implementation as possible.

  2. Electronic components, tubes and transistors

    CERN Document Server

    Dummer, G W A

    1965-01-01

    Electronic Components, Tubes and Transistors aims to bridge the gap between the basic measurement theory of resistance, capacitance, and inductance and the practical application of electronic components in equipments. The more practical or usage aspect of electron tubes and semiconductors is given emphasis over theory. The essential characteristics of each main type of component, tube, and transistor are summarized. This book is comprised of six chapters and begins with a discussion on the essential characteristics in terms of the parameters usually required in choosing a resistor, including s

  3. Components of School Engagement among African American Adolescents

    Science.gov (United States)

    Sirin, Selcuk R.; Rogers-Sirin, Lauren

    2005-01-01

    This study examined how various components of school engagement contribute to the academic performance of African American adolescents. The sample consisted of 499 African American adolescents in Grades 9 to 11. We investigated how adolescents' gender, grade, cognitive functioning, and parental education affect their school engagement and whether…

  4. Sparse principal component analysis in hyperspectral change detection

    DEFF Research Database (Denmark)

    Nielsen, Allan Aasbjerg; Larsen, Rasmus; Vestergaard, Jacob Schack

    2011-01-01

    This contribution deals with change detection by means of sparse principal component analysis (PCA) of simple differences of calibrated, bi-temporal HyMap data. Results show that if we retain only 15 nonzero loadings (out of 126) in the sparse PCA the resulting change scores appear visually very ...

  5. Contributions of nuclear architecture to transcriptional control.

    Science.gov (United States)

    Stein, G S; van Wijnen, A J; Stein, J; Lian, J B; Montecino, M

    1995-01-01

    Three parameters of nuclear structure contribute to transcriptional control. The linear representation of promoter elements provides competency for physiological responsiveness within the contexts of development as well as cycle- and phenotype-dependent regulation. Chromatin structure and nucleosome organization reduce distances between independent regulatory elements providing a basis for integrating components of transcriptional control. The nuclear matrix supports gene expression by imposing physical constraints on chromatin related to three-dimensional genomic organization. In addition, the nuclear matrix facilitates gene localization as well as the concentration and targeting of transcription factors. Several lines of evidence are presented that are consistent with involvement of multiple levels of nuclear architecture in cell growth and tissue-specific gene expression during differentiation. Growth factor and steroid hormone responsive modifications in chromatin structure, nucleosome organization, and the nuclear matrix that influence transcription of the cell cycle-regulated histone gene and the bone tissue-specific osteocalcin gene during progressive expression of the osteoblast phenotype are considered.

  6. Plasmonic components fabrication via nanoimprint

    DEFF Research Database (Denmark)

    Boltasseva, Alexandra

    2009-01-01

    A review report on nanoimprinted plasmonic components is given. The fabrication of different metal–dielectric geometries and nanostructured surfaces that support either propagating or localized surface plasmon modes is discussed. The main characteristics and advantages of the nanoimprint technolo...

  7. Metallurgical Laboratory and Components Testing

    Data.gov (United States)

    Federal Laboratory Consortium — In the field of metallurgy, TTC is equipped to run laboratory tests on track and rolling stock components and materials. The testing lab contains scanning-electron,...

  8. Passive Microwave Components and Antennas

    DEFF Research Database (Denmark)

    State-of-the-art microwave systems always require higher performance and lower cost microwave components. Constantly growing demands and performance requirements of industrial and scientific applications often make employing traditionally designed components impractical. For that reason, the design...... and development process remains a great challenge today. This problem motivated intensive research efforts in microwave design and technology, which is responsible for a great number of recently appeared alternative approaches to analysis and design of microwave components and antennas. This book highlights...... techniques. Modelling and computations in electromagnetics is a quite fast-growing research area. The recent interest in this field is caused by the increased demand for designing complex microwave components, modeling electromagnetic materials, and rapid increase in computational power for calculation...

  9. Component Reliability Assessment of Offshore Jacket Platforms

    Directory of Open Access Journals (Sweden)

    V.J. Kurian

    2015-01-01

    Full Text Available Oil and gas industry is one of the most important industries contributing to the Malaysian economy. To extract hydrocarbons, various types of production platforms have been developed. Fixed jacket platform is the earliest type of production structure, widely installed in Malaysia’s shallow and intermediate waters. To date, more than 60% of these jacket platforms have operated exceeding their initial design life, thus making the re-evaluation and reassessment necessary for these platforms to continue to be put in service. In normal engineering practice, system reliability of a structure is evaluated as its safety parameter. This method is however, much complicated and time consuming. Assessing component's reliability can be an alternative approach to provide assurance about a structure’s condition in an early stage. Design codes such as the Working Stress Design (WSD and the Load and Resistance Factor Design (LRFD are well established for the component-level assessment. In reliability analysis, failure function, which consists of strength and load, is used to define the failure event. If the load acting exceeds the capacity of a structure, the structure will fail. Calculation of stress utilization ratio as given in the design codes is able to predict the reliability of a member and to estimate the extent to which a member is being utilised. The basic idea of this ratio is that if it is more than one, the member has failed and vice versa. Stress utilization ratio is a ratio of applied stress, which is the output reaction of environmental loadings acting on the structural member, to the design strength that comes from the member’s geometric and material properties. Adopting this ratio as the failure event, the reliability of each component is found. This study reviews and discusses the reliability for selected members of three Malaysian offshore jacket platforms. First Order Reliability Method (FORM was used to generate reliability index and

  10. Formal aspects of component software

    OpenAIRE

    Sun, Meng; Schatz, B.

    2014-01-01

    This issue includes extended versions of selected best papers from the 7th International Workshop on Formal Aspects of Component Software (FACS 2010) held in Guimarães, Portugal on October 14–16, 2010. The component-based software development approach has emerged as a promising paradigm to cope with an ever increasing complexity of present-day software solutions by bringing sound production and engineering principles into software engineering. However, many conceptual and technological iss...

  11. 75 FR 34388 - Employee Contribution Elections and Contribution Allocations

    Science.gov (United States)

    2010-06-17

    ...; ] FEDERAL RETIREMENT THRIFT INVESTMENT BOARD 5 CFR Part 1600 Employee Contribution Elections and... Employees' Retirement System Act of 1986 (FERSA), Public Law 99-335, 100 Stat. 514. The TSP provisions of... retirement savings plan for Federal civilian employees and members of the uniformed services. The TSP...

  12. Components in models of learning: Different operationalisations and relations between components

    Directory of Open Access Journals (Sweden)

    Mirkov Snežana

    2013-01-01

    Full Text Available This paper provides the presentation of different operationalisations of components in different models of learning. Special emphasis is on the empirical verifications of relations between components. Starting from the research of congruence between learning motives and strategies, underlying the general model of school learning that comprises different approaches to learning, we have analyzed the empirical verifications of factor structure of instruments containing the scales of motives and learning strategies corresponding to these motives. Considering the problems in the conceptualization of the achievement approach to learning, we have discussed the ways of operational sing the goal orientations and exploring their role in using learning strategies, especially within the model of the regulation of constructive learning processes. This model has served as the basis for researching learning styles that are the combination of a large number of components. Complex relations between the components point to the need for further investigation of the constructs involved in various models. We have discussed the findings and implications of the studies of relations between the components involved in different models, especially between learning motives/goals and learning strategies. We have analyzed the role of regulation in the learning process, whose elaboration, as indicated by empirical findings, can contribute to a more precise operationalisation of certain learning components. [Projekat Ministarstva nauke Republike Srbije, br. 47008: Unapređivanje kvaliteta i dostupnosti obrazovanja u procesima modernizacije Srbije i br. 179034: Od podsticanja inicijative, saradnje i stvaralaštva u obrazovanju do novih uloga i identiteta u društvu

  13. Stuart Hall’ Contributions to CCCS

    Institute of Scientific and Technical Information of China (English)

    涂艳

    2014-01-01

    Hall is the most prominent master of Birmingham school.To some extent,Hall just represents CCCS and makes outstanding contributions to establishment of this school.Hall’s cultural theory is characterized by the interdisciplinary ideology,cultural gaze of race diaspora,collective creation,academic openness,cultural politics,civilization of the talent and so on,so that displays his value and significance as a cultural theorists and critic,in addition demonstrates his contribution to the whole world.

  14. Unknown components of the plastidial permeome

    Directory of Open Access Journals (Sweden)

    Thea Renate Pick

    2014-08-01

    Full Text Available Beyond their role in photosynthesis plastids provide a plethora of additional metabolic functions to plant cells. For example, they harbor complete biosynthetic pathways for the de novo synthesis of carotenoids, fatty acids, and amino acids. Furthermore plastids contribute important reactions to multi-compartmentalized pathways, such as photorespiration or plant hormone syntheses, and they depend on the import essential molecules that they cannot synthesize themselves, such as ascorbic acid. This causes a high traffic of metabolites across the plastid envelope. Although it was recently shown that nonpolar substrates could be exchanged between the plastid and the ER without involving transporters, various essential transport processes are mediated by highly selective but still unknown metabolite transporters. This review focuses on selected components of the plastidial permeome that are predicted to exist but that have not yet been identified as molecular entities, such as the transporter for isopentenyl diphosphate (IPP or ascorbic acid.

  15. Diesel engine management systems and components

    CERN Document Server

    2014-01-01

    This reference book provides a comprehensive insight into todays diesel injection systems and electronic control. It focusses on minimizing emissions and exhaust-gas treatment. Innovations by Bosch in the field of diesel-injection technology have made a significant contribution to the diesel boom. Calls for lower fuel consumption, reduced exhaust-gas emissions and quiet engines are making greater demands on the engine and fuel-injection systems. Contents History of the diesel engine.- Areas of use for diesel engines.- Basic principles of the diesel engine.- Fuels: Diesel fuel.- Fuels: Alternative fuels.- Cylinder-charge control systems.- Basic principles of diesel fuel-injection.- Overview of diesel fuel-injection systems.- Fuel supply to the low pressure stage.- Overview of discrete cylinder systems.- Unit injector system.- Unit pump system.- Overview of common-rail systems.- High pressure components of the common-rail system.- Injection nozzles.- Nozzle holders.- High pressure lines.- Start assist systems.-...

  16. Gravitational contribution to fermion masses

    Energy Technology Data Exchange (ETDEWEB)

    Tiemblo, A.; Tresguerres, R. [Consejo Superior de Investigaciones Cientificas, Instituto de Matematicas y Fisica Fundamental, Madrid (Spain)

    2005-08-01

    In the context of a non-linear gauge theory of the Poincare group, we show that covariant derivatives of Dirac fields include a coupling to the translational connections, manifesting itself in the matter action as a universal background mass contribution to fermions. (orig.)

  17. Gravitational contribution to fermion masses

    CERN Document Server

    Tiemblo, A; Tiemblo, Alfredo; Tresguerres, Romualdo

    2005-01-01

    In the context of a nonlinear gauge theory of the Poincar\\'e group, we show that covariant derivatives of Dirac fields include a coupling to the translational connections, manifesting itself in the matter action as a universal background mass contribution to fermions.

  18. Assessing Contributions to Group Assignments

    Science.gov (United States)

    Johnston, Lucy; Miles, Lynden

    2004-01-01

    We report the use of a combination of self- and peer-assessment in an undergraduate social psychology laboratory course. Students worked in small groups on a self-directed empirical project that they each wrote up independently as a laboratory report. Marks for the written assignment were moderated by a contribution index measure based on the…

  19. Processed foods: contributions to nutrition.

    Science.gov (United States)

    Weaver, Connie M; Dwyer, Johanna; Fulgoni, Victor L; King, Janet C; Leveille, Gilbert A; MacDonald, Ruth S; Ordovas, Jose; Schnakenberg, David

    2014-06-01

    Both fresh and processed foods make up vital parts of the food supply. Processed food contributes to both food security (ensuring that sufficient food is available) and nutrition security (ensuring that food quality meets human nutrient needs). This ASN scientific statement focuses on one aspect of processed foods: their nutritional impacts. Specifically, this scientific statement 1) provides an introduction to how processed foods contribute to the health of populations, 2) analyzes the contribution of processed foods to "nutrients to encourage" and "constituents to limit" in the American diet as recommended by the Dietary Guidelines for Americans, 3) identifies the responsibilities of various stakeholders in improving the American diet, and 4) reviews emerging technologies and the research needed for a better understanding of the role of processed foods in a healthy diet. Analyses of the NHANES 2003-2008 show that processed foods provide both nutrients to encourage and constituents to limit as specified in the 2010 Dietary Guidelines for Americans. Of the nutrients to encourage, processed foods contributed 55% of dietary fiber, 48% of calcium, 43% of potassium, 34% of vitamin D, 64% of iron, 65% of folate, and 46% of vitamin B-12. Of the constituents to limit, processed foods contributed 57% of energy, 52% of saturated fat, 75% of added sugars, and 57% of sodium. Diets are more likely to meet food guidance recommendations if nutrient-dense foods, either processed or not, are selected. Nutrition and food science professionals, the food industry, and other stakeholders can help to improve the diets of Americans by providing a nutritious food supply that is safe, enjoyable, affordable, and sustainable by communicating effectively and accurately with each other and by working together to improve the overall knowledge of consumers.

  20. Towards Prognostics for Electronics Components

    Science.gov (United States)

    Saha, Bhaskar; Celaya, Jose R.; Wysocki, Philip F.; Goebel, Kai F.

    2013-01-01

    Electronics components have an increasingly critical role in avionics systems and in the development of future aircraft systems. Prognostics of such components is becoming a very important research field as a result of the need to provide aircraft systems with system level health management information. This paper focuses on a prognostics application for electronics components within avionics systems, and in particular its application to an Isolated Gate Bipolar Transistor (IGBT). This application utilizes the remaining useful life prediction, accomplished by employing the particle filter framework, leveraging data from accelerated aging tests on IGBTs. These tests induced thermal-electrical overstresses by applying thermal cycling to the IGBT devices. In-situ state monitoring, including measurements of steady-state voltages and currents, electrical transients, and thermal transients are recorded and used as potential precursors of failure.

  1. Two component systems: physiological effect of a third component.

    Directory of Open Access Journals (Sweden)

    Baldiri Salvado

    Full Text Available Signal transduction systems mediate the response and adaptation of organisms to environmental changes. In prokaryotes, this signal transduction is often done through Two Component Systems (TCS. These TCS are phosphotransfer protein cascades, and in their prototypical form they are composed by a kinase that senses the environmental signals (SK and by a response regulator (RR that regulates the cellular response. This basic motif can be modified by the addition of a third protein that interacts either with the SK or the RR in a way that could change the dynamic response of the TCS module. In this work we aim at understanding the effect of such an additional protein (which we call "third component" on the functional properties of a prototypical TCS. To do so we build mathematical models of TCS with alternative designs for their interaction with that third component. These mathematical models are analyzed in order to identify the differences in dynamic behavior inherent to each design, with respect to functionally relevant properties such as sensitivity to changes in either the parameter values or the molecular concentrations, temporal responsiveness, possibility of multiple steady states, or stochastic fluctuations in the system. The differences are then correlated to the physiological requirements that impinge on the functioning of the TCS. This analysis sheds light on both, the dynamic behavior of synthetically designed TCS, and the conditions under which natural selection might favor each of the designs. We find that a third component that modulates SK activity increases the parameter space where a bistable response of the TCS module to signals is possible, if SK is monofunctional, but decreases it when the SK is bifunctional. The presence of a third component that modulates RR activity decreases the parameter space where a bistable response of the TCS module to signals is possible.

  2. BRAF associated autophagy exploitation: BRAF and autophagy inhibitors synergise to efficiently overcome resistance of BRAF mutant colorectal cancer cells

    Science.gov (United States)

    Goulielmaki, Maria; Koustas, Evangelos; Moysidou, Eirini; Vlassi, Margarita; Sasazuki, Takehiko; Shirasawa, Senji; Zografos, George; Oikonomou, Eftychia; Pintzas, Alexander

    2016-01-01

    Autophagy is the basic catabolic mechanism that involves cell degradation of unnecessary or dysfunctional cellular components. Autophagy has a controversial role in cancer – both in protecting against tumor progression by isolation of damaged organelles, or by potentially contributing to cancer growth. The impact of autophagy in RAS induced transformation still remains to be further analyzed based on the differential effect of RAS isoforms and tumor cell context. In the present study, the effect of KRAS/BRAF/PIK3CA oncogenic pathways on the autophagic cell properties and on main components of the autophagic machinery like p62 (SQSTM1), Beclin-1 (BECN1) and MAP1LC3 (LC3) in colon cancer cells was investigated. This study provides evidence that BRAF oncogene induces the expression of key autophagic markers, like LC3 and BECN1 in colorectal tumor cells. Herein, PI3K/AKT/MTOR inhibitors induce autophagic tumor properties, whereas RAF/MEK/ERK signalling inhibitors reduce expression of autophagic markers. Based on the ineffectiveness of BRAFV600E inhibitors in BRAFV600E bearing colorectal tumors, the BRAF related autophagic properties in colorectal cancer cells are further exploited, by novel combinatorial anti-cancer protocols. Strong evidence is provided here that pre-treatment of autophagy inhibitor 3-MA followed by its combination with BRAFV600E targeting drug PLX4720 can synergistically sensitize resistant colorectal tumors. Notably, colorectal cancer cells are very sensitive to mono-treatments of another autophagy inhibitor, Bafilomycin A1. The findings of this study are expected to provide novel efficient protocols for treatment of otherwise resistant colorectal tumors bearing BRAFV600E, by exploiting the autophagic properties induced by BRAF oncogene. PMID:26802026

  3. BRAF associated autophagy exploitation: BRAF and autophagy inhibitors synergise to efficiently overcome resistance of BRAF mutant colorectal cancer cells.

    Science.gov (United States)

    Goulielmaki, Maria; Koustas, Evangelos; Moysidou, Eirini; Vlassi, Margarita; Sasazuki, Takehiko; Shirasawa, Senji; Zografos, George; Oikonomou, Eftychia; Pintzas, Alexander

    2016-02-23

    Autophagy is the basic catabolic mechanism that involves cell degradation of unnecessary or dysfunctional cellular components. Autophagy has a controversial role in cancer--both in protecting against tumor progression by isolation of damaged organelles, or by potentially contributing to cancer growth. The impact of autophagy in RAS induced transformation still remains to be further analyzed based on the differential effect of RAS isoforms and tumor cell context. In the present study, the effect of KRAS/BRAF/PIK3CA oncogenic pathways on the autophagic cell properties and on main components of the autophagic machinery like p62 (SQSTM1), Beclin-1 (BECN1) and MAP1LC3 (LC3) in colon cancer cells was investigated. This study provides evidence that BRAF oncogene induces the expression of key autophagic markers, like LC3 and BECN1 in colorectal tumor cells. Herein, PI3K/AKT/MTOR inhibitors induce autophagic tumor properties, whereas RAF/MEK/ERK signalling inhibitors reduce expression of autophagic markers. Based on the ineffectiveness of BRAFV600E inhibitors in BRAFV600E bearing colorectal tumors, the BRAF related autophagic properties in colorectal cancer cells are further exploited, by novel combinatorial anti-cancer protocols. Strong evidence is provided here that pre-treatment of autophagy inhibitor 3-MA followed by its combination with BRAFV600E targeting drug PLX4720 can synergistically sensitize resistant colorectal tumors. Notably, colorectal cancer cells are very sensitive to mono-treatments of another autophagy inhibitor, Bafilomycin A1. The findings of this study are expected to provide novel efficient protocols for treatment of otherwise resistant colorectal tumors bearing BRAFV600E, by exploiting the autophagic properties induced by BRAF oncogene.

  4. Principal Component Analysis In Radar Polarimetry

    Directory of Open Access Journals (Sweden)

    A. Danklmayer

    2005-01-01

    Full Text Available Second order moments of multivariate (often Gaussian joint probability density functions can be described by the covariance or normalised correlation matrices or by the Kennaugh matrix (Kronecker matrix. In Radar Polarimetry the application of the covariance matrix is known as target decomposition theory, which is a special application of the extremely versatile Principle Component Analysis (PCA. The basic idea of PCA is to convert a data set, consisting of correlated random variables into a new set of uncorrelated variables and order the new variables according to the value of their variances. It is important to stress that uncorrelatedness does not necessarily mean independent which is used in the much stronger concept of Independent Component Analysis (ICA. Both concepts agree for multivariate Gaussian distribution functions, representing the most random and least structured distribution. In this contribution, we propose a new approach in applying the concept of PCA to Radar Polarimetry. Therefore, new uncorrelated random variables will be introduced by means of linear transformations with well determined loading coefficients. This in turn, will allow the decomposition of the original random backscattering target variables into three point targets with new random uncorrelated variables whose variances agree with the eigenvalues of the covariance matrix. This allows a new interpretation of existing decomposition theorems.

  5. Intelligent Component Monitoring for Nuclear Power Plants

    Energy Technology Data Exchange (ETDEWEB)

    Lefteri Tsoukalas

    2010-07-30

    Reliability and economy are two major concerns for a nuclear power generation system. Next generation nuclear power reactors are being developed to be more reliable and economic. An effective and efficient surveillance system can generously contribute toward this goal. Recent progress in computer systems and computational tools has made it necessary and possible to upgrade current surveillance/monitoring strategy for better performance. For example, intelligent computing techniques can be applied to develop algorithm that help people better understand the information collected from sensors and thus reduce human error to a new low level. Incidents incurred from human error in nuclear industry are not rare and have been proven costly. The goal of this project is to develop and test an intelligent prognostics methodology for predicting aging effects impacting long-term performance of nuclear components and systems. The approach is particularly suitable for predicting the performance of nuclear reactor systems which have low failure probabilities (e.g., less than 10-6 year-). Such components and systems are often perceived as peripheral to the reactor and are left somewhat unattended. That is, even when inspected, if they are not perceived to be causing some immediate problem, they may not be paid due attention. Attention to such systems normally involves long term monitoring and possibly reasoning with multiple features and evidence, requirements that are not best suited for humans.

  6. Latent semantics as cognitive components

    DEFF Research Database (Denmark)

    Petersen, Michael Kai; Mørup, Morten; Hansen, Lars Kai

    2010-01-01

    Cognitive component analysis, defined as an unsupervised learning of features resembling human comprehension, suggests that the sensory structures we perceive might often be modeled by reducing dimensionality and treating objects in space and time as linear mixtures incorporating sparsity...... emotional responses can be encoded in words, we propose a simplified cognitive approach to model how we perceive media. Representing song lyrics in a vector space of reduced dimensionality using LSA, we combine bottom-up defined term distances with affective adjectives, that top-down constrain the latent......, which we suggest might function as cognitive components for perceiving the underlying structure in lyrics....

  7. Sustainable Development in Indian Automotive Component Clusters

    Science.gov (United States)

    Bhaskaran, E.

    2013-01-01

    India is the world's second fastest growing auto market and boasts of the sixth largest automobile industry after China, the US, Germany, Japan and Brazil. The Indian auto component industry recorded its highest year-on-year growth of 34.2 % in 2010-2011, raking in revenue of US 39.9 billion; major contribution coming from exports at US five billion and fresh investment from the US at around US two billion. For inclusive growth and sustainable development most of the auto components manufacturers has adopted the cluster development approach. The objective is to study the technical efficiency (θ), peer weights (λ i ), input slacks (S-) and output slacks (S+) of four Auto Component Clusters (ACC) in India. The methodology adopted is using Data Envelopment Analysis of Input Oriented Banker Charnes Cooper Model by taking number of units and number of employments as inputs and sales and exports in crores as an outputs. The non-zero λ i 's represents the weights for efficient clusters. The S > 0 obtained for one ACC reveals the excess no. of units (S-) and employment (S-) and shortage in sales (S+) and exports (S+). However the variable returns to scale are increasing for three clusters, constant for one more cluster and with nil decrease. To conclude, for inclusive growth and sustainable development, the inefficient ACC should increase their turnover and exports, as decrease in no. of enterprises and employment is practically not possible. Moreover for sustainable development, the ACC should strengthen infrastructure interrelationships, technology interrelationships, procurement interrelationships, production interrelationships and marketing interrelationships to increase productivity and efficiency to compete in the world market.

  8. Does Impaired Gallbladder Function Contribute to the Development of Barrett's Esophagus and Esophageal Adenocarcinoma?

    LENUS (Irish Health Repository)

    Nassr, Ayman O

    2011-06-01

    Esophageal adenocarcinoma is aetiologically associated with gastro-esophageal reflux, but the mechanisms responsible for the metaplasia-dysplasia sequence are unknown. Bile components are implicated. Impaired gallbladder function may contribute to duodenogastric reflux (DGR) and harmful GERD.

  9. Contribution of Oceanic Circulation to the Poleward Heat Flux

    Institute of Scientific and Technical Information of China (English)

    HUANG Ruixin

    2005-01-01

    Oceanic contribution to the poleward heat flux in the climate system includes two components: the sensible heat flux and the latent heat flux. Although the latent heat flux has been classified as atmospheric heat flux exclusively, it is argued that oceanic control over this component of poleward heat flux should play a critically important role. The so-called swamp ocean model practice is analyzed in detail, and the critical role of oceanic circulation in the establishment of the meridional moisture transport is emphasized.

  10. Feller's Contributions to Mathematical Biology

    OpenAIRE

    Baake, Ellen; Wakolbinger, Anton

    2015-01-01

    This is a review of William Feller's important contributions to mathematical biology. The seminal paper [Feller1951] "Diffusion processes in genetics" was particularly influential on the development of stochastic processes at the interface to evolutionary biology, and interesting ideas in this direction (including a first characterization of what is nowadays known as "Feller's branching diffusion") already shaped up in the paper [Feller 1939] (written in German) "The foundations of a probabis...

  11. Changes in accounting for contributions.

    Science.gov (United States)

    Pelfrey, S

    1992-03-01

    A proposed accounting change in the timing of income recognition for restricted contributions and pledges can greatly impact a hospital's excess of revenue over expenses (net income). The author addresses steps that administrators can take to lessen its impact. With this knowledge, nurse administrators and other hospital executives can plan alternatives to reduce the income recognition and prepare themselves to answer questions posed by patients and members of the community regarding increased hospital profits.

  12. COMPONENT ELEMENTS OF MARKETING COMMUNICATIONS

    Directory of Open Access Journals (Sweden)

    G. I. Tamoshina

    2012-01-01

    Full Text Available Marketing communications are the specific communication program of the company. It consists of: advertising, which is intended for informing about commodity and accommodations (services; encouragement of marketing- sales augmentation for acceleration of marketing; straight marketing, that provide with personal contacts, flexibility and ability to make a bargain; public relations - all that components are promoting and uphold the image of the firm.

  13. Carcinogenicity of hair dye components.

    Science.gov (United States)

    Van Duuren, B L

    1980-03-01

    The available animal carcinogenicity data on hair dye components was reviewed. From this review it became clear that certain hair dye components, some of which are still in hair dye formulations now on the market, are animal carcinogens. The compounds of concern that are still in use are: 3-amino-4-methoxyaniline, 2-nitro-4-aminoaniline and 3-nitro-4-hydroxyaniline. Certain azo dyes formerly used, and related compounds still in use, contain the benzidine moiety. Two of these compounds, Direct Blue 6 and Direct Black 38, have been shown to be metabolized in animals to the human carcinogen benzidine. Furthermore, skin absorption studies carried out with radiolabeled hair dye components applied to animal or human skin have conclusively shown that these compounds are systemically absorbed and excreted. Known cocarcinogens such as catechol and pyrogallol, which enhance benzo(a)pyrene carcinogenicity on mouse skin, are used as hair dye components. It is not known whether such compounds will enhance the carcinogenicity of substituted aniline hair dye chemicals. The available epidemiologic data are not sufficient to link hair dye use with an increased incidence in human cancer.

  14. Opinions about Component Energetic Security

    OpenAIRE

    Elena GOLUMBEANU (GEORGESCU)

    2012-01-01

    Collective security (international) represent the morphological expression of individual security components. According to the Report presented at the United Nations Development Programme, collective security (international) as well as national security, is the expression of seven synergistic dimensions as follows: economic security, food security, environmental security, personal security, community security, political security and individual security. As part of economic security, energy an...

  15. Components of dynamic digital maps

    Science.gov (United States)

    Condit, Christopher D.

    1999-05-01

    The core of a dynamic digital map (DDM) is a program created to display a digital geologic map and its associated data set as a single integrated package. This DDM program core is authored using a high-level object oriented graphical programming environment, SuperCard, a Macintosh `xTalk' language. Some of the major philosophical underpinnings relevant to the job of creating DDMs in this programming environment include taking advantage of specific object's attributes, how to organize data structure effectively for this job and keeping applicable code as transportable (generalized) as possible between objects. The core components of DDMs are parts of a SuperCard `template' or map display `container' into which the various externally created digital pieces (e.g. CAD produced geologic maps, spread sheet data, digital images, text files, movies) can be inserted for integrated display and digital publication. Components of DDMs consist of windows, cards within these windows, card fields (text and data containers) and a menu structure. The paper discusses each of these major components and how they fit into a DDM and gives examples of each topic in programs whose components demonstrate the concept. These programs are available from Web (see Appendix A); readers can refer to them as they examine these examples.

  16. Black Component of Dark Matter

    Directory of Open Access Journals (Sweden)

    A. V. Grobov

    2014-01-01

    Full Text Available A mechanism of primordial black hole formation with specific mass spectrum is discussed. It is shown that these black holes could contribute to the energy density of dark matter. Our approach is elaborated in the framework of universal extra dimensions.

  17. Principal component analysis of minimal excitatory postsynaptic potentials.

    Science.gov (United States)

    Astrelin, A V; Sokolov, M V; Behnisch, T; Reymann, K G; Voronin, L L

    1998-02-20

    'Minimal' excitatory postsynaptic potentials (EPSPs) are often recorded from central neurones, specifically for quantal analysis. However the EPSPs may emerge from activation of several fibres or transmission sites so that formal quantal analysis may give false results. Here we extended application of the principal component analysis (PCA) to minimal EPSPs. We tested a PCA algorithm and a new graphical 'alignment' procedure against both simulated data and hippocampal EPSPs. Minimal EPSPs were recorded before and up to 3.5 h following induction of long-term potentiation (LTP) in CA1 neurones. In 29 out of 45 EPSPs, two (N=22) or three (N=7) components were detected which differed in latencies, rise time (Trise) or both. The detected differences ranged from 0.6 to 7.8 ms for the latency and from 1.6-9 ms for Trise. Different components behaved differently following LTP induction. Cases were found when one component was potentiated immediately after tetanus whereas the other with a delay of 15-60 min. The immediately potentiated component could decline in 1-2 h so that the two components contributed differently into early (reflections of synchronized quantal releases. In general, the results demonstrate PCA applicability to separate EPSPs into different components and its usefulness for precise analysis of synaptic transmission.

  18. Possible solar noble-gas component in Hawaiian basalts

    Energy Technology Data Exchange (ETDEWEB)

    Honda, Masahiko; McDougall, I.; Patterson, D.B.; Doulgeris, A. (Australian National Univ., Canberra (Australia). Research School of Earth Sciences); Clague, D.A. (Geological Survey, Menlo Park, CA (USA))

    1991-01-10

    The noble-gas elemental and isotopic composition in the Earth is significantly different from that of the present atmosphere, and provides an important clue to the origin and history of the Earth and its atmosphere. Possible candidates for the noble-gas composition of the primordial Earth include a solar-like component, a planetary-like component (as observed in primitive meteorites) and a component similar in composition to the present atmosphere. In an attempt to identify the contributions of such components, we have measured isotope ratios of helium and neon in fresh basaltic glasses dredged from Loihi seamount and the East Rift Zone of Kilauea. We find a systematic enrichment in {sup 20}Ne and {sup 21}Ne relative to {sup 22}Ne, compared with atmospheric neon. The helium and neon isotope signatures observed in our samples can be explained by mixing of solar, present atmospheric, radiogenic and nucleogenic components. These data suggest that the noble-gas isotopic composition of the mantle source of the Hawaiian plume is different from that of the present atmosphere, and that it includes a significant solar-like component. We infer that this component was acquired during the formation of the Earth. (author).

  19. Component-based Systems Reconfigurations Using Graph Grammars

    Directory of Open Access Journals (Sweden)

    O. Kouchnarenko

    2016-01-01

    Full Text Available Dynamic reconfigurations can modify the architecture of component-based systems without incurring any system downtime. In this context, the main contribution of the present article is the establishment of correctness results proving component-based systems reconfigurations using graph grammars. New guarded reconfigurations allow us to build reconfigurations based on primitive reconfiguration operations using sequences of reconfigurations and the alternative and the repetitive constructs, while preserving configuration consistency. A practical contribution consists of the implementation of a component-based model using the GROOVE graph transformation tool. Then, after enriching the model with interpreted configurations and reconfigurations in a consistency compatible manner, a simulation relation is exploited to validate component systems’ implementations. This sound implementation is illustrated on a cloud-based multitier application hosting environment managed as a component-based system.

  20. Evaluation of cutting force uncertainty components in turning

    DEFF Research Database (Denmark)

    Axinte, Dragos Aurelian; Belluco, Walter; De Chiffre, Leonardo

    2000-01-01

    A procedure is proposed for the evaluation of those uncertainty components of a single cutting force measurement in turning that are related to the contributions of the dynamometer calibration and the cutting process itself. Based on an empirical model including errors form both sources......, the uncertainty for a single measurement of cutting force is presented, and expressions for the expected uncertainty vs. cutting parameters are proposed. This approach gives the possibility of evaluating cutting force uncertainty components in turning, for a defined range of cutting parameters, based on few...

  1. Component Dependency in object-Oriented Software

    Institute of Scientific and Technical Information of China (English)

    Li-Guo Yu; Srini Ramaswamy

    2007-01-01

    Component dependency is an important software measure. It is directly related to software understandability,maintainability, and reusability. Two important parameters in describing component dependency are the type of couplingbetween two components and the type of the dependent component. Depending upon the different types of coupling and thetype of the dependent components, there can be different effects on component maintenance and component reuse. In thispaper, we divide dependent components into three types. We then classify various component dependencies and analyzetheir effects on maintenance and reuse. Based on the classification, we present a dependency metric and validate it on 11open-source Java components. Our study shows that a strong correlation exists between the measurement of the dependencyof the component and the effort to reuse the component. This indicates that the classification of component dependencyand the suggested metric could be further used to represent other external software quality factors.

  2. The role of event water, a rapid shallow flow component, and catchment size in summer stormflow

    Science.gov (United States)

    Brown, V.A.; McDonnell, Jeffery J.; Burns, Douglas A.; Kendall, C.

    1999-01-01

    Seven nested headwater catchments (8 to 161 ha) were monitored during five summer rain events to evaluate storm runoff components and the effect of catchment size on water sources. Two-component isotopic hydrograph separation showed that event-water contributions near the time of peakflow ranged from 49% to 62% in the 7 catchments during the highest intensity event. The proportion of event water in stormflow was greater than could be accounted for by direct precipitation onto saturated areas. DOC concentrations in stormflow were strongly correlated with stream 18O composition. Bivariate mixing diagrams indicated that the large event water contributions were likely derived from flow through the soil O-horizon. Results from two-tracer, three-component hydrograph separations showed that the throughfall and O-horizon soil-water components together could account for the estimated contributions of event water to stormflow. End-member mixing analysis confirmed these results. Estimated event-water contributions were inversely related to catchment size, but the relation was significant for only the event with greatest rainfall intensity. Our results suggest that perched, shallow subsurface flow provides a substantial contribution to summer stormflow in these small catchments, but the relative contribution of this component decreases with catchment size.Seven nested headwater catchments (8 to 161 ha) were monitored during five summer rain events to evaluate storm runoff components and the effect of catchment size on water sources. Two-component isotopic hydrograph separation showed that event-water contributions near the time of peakflow ranged from 49% to 62% in the 7 catchments during the highest intensity event. The proportion of event water in stormflow was greater than could be accounted for by direct precipitation onto saturated areas. DOC concentrations in stormflow were strongly correlated with stream 18O composition. Bivariate mixing diagrams indicated that the

  3. The ILRS Contribution to ITRF2013

    Science.gov (United States)

    Pavlis, Erricos C.; Luceri, Cinzia; Sciarretta, Cecilia; Evans, Keith

    2014-05-01

    Satellite Laser Ranging (SLR) data have contributed to the definition of the International Terrestrial Reference Frame (ITRF) over the past three decades. The development of ITRF2005 ushered a new era with the use of weekly or session contributions, allowing greater flexibility in the editing, relative weighting and the combination of information from the four contributing techniques. The new approach allows each Service to generate a solution based on the rigorous combination of the individual Analysis Centers' contributions that provides an opportunity to verify the intra-technique consistency and a comparison of internal procedures and adopted models. The intra- and inter-technique comparisons that the time series approach facilitates are an extremely powerful diagnostic that highlights differences and inconsistencies at the single station level. Over the past year the ILRS Analysis Working Group (AWG) worked on designing an improved ILRS contribution for the development of ITRF2013. The ILRS approach is based on the current IERS Conventions 2010 and our internal ILRS standards, with a few deviations that are documented. Since the Global Geodetic Observing System - GGOS identified the ITRF as its key project, the ILRS has taken a two-pronged approach in order to meet its stringent goals: modernizing the engineering components (ground and space segments), and revising the modeling standards taking advantage of recent improvements in system Earth modeling. The main concern in the case of SLR is monitoring systematic errors at individual stations, accounting for undocumented discontinuities, and improving the target signature models. The latter has been addressed with the adoption of mm-level models for all of our targets. As far as the station systematics, the AWG had already embarked on a major effort to improve the handling of such errors prior to the development of ITRF2008. The results of that effort formed the foundation for the re-examination of the

  4. Methanotrophs Contribute to Peatland Nitrogen

    Science.gov (United States)

    Larmola, Tuula; Leppänen, Sanna M.; Tuittila, Eeva-Stiina; Aarva, Maija; Merilä, Päivi; Fritze, Hannu; Tiirola, Marja

    2016-04-01

    Atmospheric nitrogen (N2) fixation is potentially an important N input mechanism to peatland ecosystems, but the extent of this process may have been underestimated because of the methods traditionally used inhibit the activity of methanothrophs. We examined the linkage of methane (CH4) oxidation and N2 fixation using 15N2 technique. Dominant flark and hummock Sphagnum species were collected from twelve pristine peatlands in Siikajoki, Finland, which varied in age from 200 to 2,500 y due to the postglacial rebound. The mosses were incubated in a two-day field 15N2 and 13CH4 pulse labelling experiment and the incorporation of 15N2 and 13CH4 in biomass was measured with Isotope Ratio Mass Spectrometer. The rates of Sphagnum-associated N2 fixation (0.1-2.9 g N m-2 y-1) were up to 10 times the current N deposition rates. Methane-induced N2 fixation contributed to over 1/3 of moss-associated N2 fixation in younger stages, but was switched off in old successional stages, despite active CH4 oxidation in these stages. Both the N2 fixation rates and the methanotrophic contribution to N2 fixation during peatland succession were primarily constrained by phosphorus availability. Previously overlooked methanotrophic N contribution may explain rapid peat and N accumulation during fen stages of peatland development. Reference. Larmola T., Leppänen S.M., Tuittila E.-S, Aarva M., Merilä P., Fritze H., Tiirola M. (2014) Methanotrophy induces nitrogen fixation during peatland development. Proceedings of the National Academy of Sciences USA 111 (2): 734-739.

  5. Cylinder components properties, applications, materials

    CERN Document Server

    2016-01-01

    Owing to the ever-increasing requirements to be met by gasoline and diesel engines in terms of CO2 reduction, emission behavior, weight, and service life, a comprehensive understanding of combustion engine components is essential today. It is no longer possible for professionals in automotive engineering to manage without the corresponding expertise, whether they work in the field of design, development, testing, or maintenance. This technical book provides in-depth answers to questions about design, production, and machining of cylinder components. In this second edition, every section has been revised and expanded to include the latest developments in the combustion engine. Content Piston rings Piston pins and piston pin circlips Bearings Connecting rods Crankcase and cylinder liners Target audience Engineers in the field of engine development and maintenanceLecturers and students in the areas of mechanical engineering, engine technology, and vehicle constructionAnyone interested in technology Publisher MAH...

  6. Components of Attention in Synesthesia

    DEFF Research Database (Denmark)

    Sørensen, Thomas Alrik; Nordfang, Maria; Pedersen, Michael Nygaard

    2013-01-01

    One of the most common forms of synesthesia is between colors and graphemes (Colizoli, Murre, & Rouw, 2012). Numerous studies have investigated different aspects of attention and synesthesia, e.g. effects of Stroop-like interference by colors that are incongruent with the synesthetic experience....... Here we attempt to isolate how speci¿ c components of attention are affected by grapheme-color synesthesia. Eight carefully screened healthy participants with synesthesia reported the letters in brie¿ y presented, post-masked arrays of letters and digits. On half the trials, the letters and digits were...... presented in colors congruent with the synesthetic experience. On the other half of the trials, the letters and digits were presented in colors that were incongruent with the synesthetic experience. Components of attention were estimated separately for congruent and incongruent trials by ¿ tting the data...

  7. Genes contributing to prion pathogenesis

    DEFF Research Database (Denmark)

    Tamgüney, Gültekin; Giles, Kurt; Glidden, David V;

    2008-01-01

    incubation times, indicating that the conversion reaction may be influenced by other gene products. To identify genes that contribute to prion pathogenesis, we analysed incubation times of prions in mice in which the gene product was inactivated, knocked out or overexpressed. We tested 20 candidate genes...... show that many genes previously implicated in prion replication have no discernible effect on the pathogenesis of prion disease. While most genes tested did not significantly affect survival times, ablation of the amyloid beta (A4) precursor protein (App) or interleukin-1 receptor, type I (Il1r1...

  8. Ethnographic Contributions to Method Development

    DEFF Research Database (Denmark)

    Leander, Anna

    2016-01-01

    of IR—Critical Security Studies. Ethnographic research works with what has been termed a “strong” understanding of objectivity. When this understanding is taken seriously, it must lead to a refashioning of the processes of gathering, analyzing, and presenting data in ways that reverse many standard......Contrary to common assumptions, there is much to be learned about methods from constructivist/post-structuralist approaches to International Relations (IR) broadly speaking. This article develops this point by unpacking the contributions of one specific method—ethnography—as used in one subfield...

  9. Information component of hybrid war

    OpenAIRE

    Bohdanov, Aleksander

    2015-01-01

    A hybrid warfare in the three-dimensional coordinate system «Matter-Information-measure» is considering. In particular, the information component is highlighted and analyzed. The factors of preparation of information operations is defined, which are disclosed as an example of experience of volunteer group information warfare of Institute of special communication and information security of NTUU «KPI».Keywords: coordinate system «Matter-Information-Measure» hybrid warfare, information componen...

  10. The Risk Components of Liquidity

    OpenAIRE

    Chollete, Lorán; Næs, Randi; Johannes A. Skjeltorp

    2008-01-01

    Does liquidity risk differ depending on our choice of liquidity proxy? Unlike literature that considers common liquidity variation, we focus on identifying different components of liquidity, statistically and economically, using more than a decade of US transaction data. We identify three main statistical liquidity factors which are utilized in a linear asset pricing framework. We motivate a correspondence of the statistical factors to traditional dimensions of liquidity as well as the notion...

  11. Optimization of structures and components

    CERN Document Server

    Muñoz-Rojas, Pablo Andrés

    2013-01-01

    Written by an international group of active researchers in the field, this volume presents innovative formulations and applied procedures for sensitivity analysis and structural design optimization. Eight chapters discuss subjects ranging from recent developments in the determination and application of topological gradients, to the use of evolutionary algorithms and meta-models to solve practical engineering problems. With such a comprehensive set of contributions, the book is a valuable source of information for graduate students and researchers entering or working in the matter.

  12. Nobel Prizes: Contributions to Cardiology

    Science.gov (United States)

    Mesquita, Evandro Tinoco; Marchese, Luana de Decco; Dias, Danielle Warol; Barbeito, Andressa Brasil; Gomes, Jonathan Costa; Muradas, Maria Clara Soares; Lanzieri, Pedro Gemal; Gismondi, Ronaldo Altenburg

    2015-01-01

    The Nobel Prize was created by Alfred Nobel. The first prize was awarded in 1901 and Emil Adolf von Behring was the first laureate in medicine due to his research in diphtheria serum. Regarding cardiology, Nobel Prize’s history permits a global comprehension of progress in pathophysiology, diagnosis and therapeutics of various cardiac diseases in last 120 years. The objective of this study was to review the major scientific discoveries contemplated by Nobel Prizes that contributed to cardiology. In addition, we also hypothesized why Carlos Chagas, one of our most important scientists, did not win the prize in two occasions. We carried out a non-systematic review of Nobel Prize winners, selecting the main studies relevant to heart diseaseamong the laureates. In the period between 1901 and 2013, 204 researches and 104 prizes were awarded in Nobel Prize, of which 16 (15%) studies were important for cardiovascular area. There were 33 (16%) laureates, and two (6%) were women. Fourteen (42%) were American, 15 (45%) Europeans and four (13%) were from other countries. There was only one winner born in Brazil, Peter Medawar, whose career was all in England. Reviewing the history of the Nobel Prize in physiology or medicine area made possible to identify which researchers and studies had contributed to advances in the diagnosis, prevention and treatment of cardiovascular diseases. Most winners were North Americans and Europeans, and male. PMID:25945466

  13. Nobel Prizes: Contributions to Cardiology

    Directory of Open Access Journals (Sweden)

    Evandro Tinoco Mesquita

    2015-01-01

    Full Text Available The Nobel Prize was created by Alfred Nobel. The first prize was awarded in 1901 and Emil Adolf von Behring was the first laureate in medicine due to his research in diphtheria serum. Regarding cardiology, Nobel Prize’s history permits a global comprehension of progress in pathophysiology, diagnosis and therapeutics of various cardiac diseases in last 120 years. The objective of this study was to review the major scientific discoveries contemplated by Nobel Prizes that contributed to cardiology. In addition, we also hypothesized why Carlos Chagas, one of our most important scientists, did not win the prize in two occasions. We carried out a non-systematic review of Nobel Prize winners, selecting the main studies relevant to heart diseaseamong the laureates. In the period between 1901 and 2013, 204 researches and 104 prizes were awarded in Nobel Prize, of which 16 (15% studies were important for cardiovascular area. There were 33 (16% laureates, and two (6% were women. Fourteen (42% were American, 15 (45% Europeans and four (13% were from other countries. There was only one winner born in Brazil, Peter Medawar, whose career was all in England. Reviewing the history of the Nobel Prize in physiology or medicine area made possible to identify which researchers and studies had contributed to advances in the diagnosis, prevention and treatment of cardiovascular diseases. Most winners were North Americans and Europeans, and male.

  14. Nobel prizes: contributions to cardiology.

    Science.gov (United States)

    Mesquita, Evandro Tinoco; Marchese, Luana de Decco; Dias, Danielle Warol; Barbeito, Andressa Brasil; Gomes, Jonathan Costa; Muradas, Maria Clara Soares; Lanzieri, Pedro Gemal; Gismondi, Ronaldo Altenburg

    2015-08-01

    The Nobel Prize was created by Alfred Nobel. The first prize was awarded in 1901 and Emil Adolf von Behring was the first laureate in medicine due to his research in diphtheria serum. Regarding cardiology, Nobel Prize's history permits a global comprehension of progress in pathophysiology, diagnosis and therapeutics of various cardiac diseases in last 120 years. The objective of this study was to review the major scientific discoveries contemplated by Nobel Prizes that contributed to cardiology. In addition, we also hypothesized why Carlos Chagas, one of our most important scientists, did not win the prize in two occasions. We carried out a non-systematic review of Nobel Prize winners, selecting the main studies relevant to heart diseaseamong the laureates. In the period between 1901 and 2013, 204 researches and 104 prizes were awarded in Nobel Prize, of which 16 (15%) studies were important for cardiovascular area. There were 33 (16%) laureates, and two (6%) were women. Fourteen (42%) were American, 15 (45%) Europeans and four (13%) were from other countries. There was only one winner born in Brazil, Peter Medawar, whose career was all in England. Reviewing the history of the Nobel Prize in physiology or medicine area made possible to identify which researchers and studies had contributed to advances in the diagnosis, prevention and treatment of cardiovascular diseases. Most winners were North Americans and Europeans, and male.

  15. Nobel Prizes: Contributions to Cardiology

    Directory of Open Access Journals (Sweden)

    Evandro Tinoco Mesquita

    2015-08-01

    Full Text Available The Nobel Prize was created by Alfred Nobel. The first prize was awarded in 1901 and Emil Adolf von Behring was the first laureate in medicine due to his research in diphtheria serum. Regarding cardiology, Nobel Prize’s history permits a global comprehension of progress in pathophysiology, diagnosis and therapeutics of various cardiac diseases in last 120 years. The objective of this study was to review the major scientific discoveries contemplated by Nobel Prizes that contributed to cardiology. In addition, we also hypothesized why Carlos Chagas, one of our most important scientists, did not win the prize in two occasions. We carried out a non-systematic review of Nobel Prize winners, selecting the main studies relevant to heart diseaseamong the laureates. In the period between 1901 and 2013, 204 researches and 104 prizes were awarded in Nobel Prize, of which 16 (15% studies were important for cardiovascular area. There were 33 (16% laureates, and two (6% were women. Fourteen (42% were American, 15 (45% Europeans and four (13% were from other countries. There was only one winner born in Brazil, Peter Medawar, whose career was all in England. Reviewing the history of the Nobel Prize in physiology or medicine area made possible to identify which researchers and studies had contributed to advances in the diagnosis, prevention and treatment of cardiovascular diseases. Most winners were North Americans and Europeans, and male.

  16. Nobel Prizes: Contributions to Cardiology

    Energy Technology Data Exchange (ETDEWEB)

    Mesquita, Evandro Tinoco; Marchese, Luana de Decco; Dias, Danielle Warol; Barbeito, Andressa Brasil; Gomes, Jonathan Costa; Muradas, Maria Clara Soares; Lanzieri, Pedro Gemal; Gismondi, Ronaldo Altenburg, E-mail: ronaldo@floralia.com.br [Universidade Federal Fluminense, Niterói, RJ (Brazil)

    2015-08-15

    The Nobel Prize was created by Alfred Nobel. The first prize was awarded in 1901 and Emil Adolf von Behring was the first laureate in medicine due to his research in diphtheria serum. Regarding cardiology, Nobel Prize’s history permits a global comprehension of progress in pathophysiology, diagnosis and therapeutics of various cardiac diseases in last 120 years. The objective of this study was to review the major scientific discoveries contemplated by Nobel Prizes that contributed to cardiology. In addition, we also hypothesized why Carlos Chagas, one of our most important scientists, did not win the prize in two occasions. We carried out a non-systematic review of Nobel Prize winners, selecting the main studies relevant to heart diseaseamong the laureates. In the period between 1901 and 2013, 204 researches and 104 prizes were awarded in Nobel Prize, of which 16 (15%) studies were important for cardiovascular area. There were 33 (16%) laureates, and two (6%) were women. Fourteen (42%) were American, 15 (45%) Europeans and four (13%) were from other countries. There was only one winner born in Brazil, Peter Medawar, whose career was all in England. Reviewing the history of the Nobel Prize in physiology or medicine area made possible to identify which researchers and studies had contributed to advances in the diagnosis, prevention and treatment of cardiovascular diseases. Most winners were North Americans and Europeans, and male.

  17. Soil Organic Nitrogen and Its Contribution to Crop Production

    Institute of Scientific and Technical Information of China (English)

    LI Sheng-xiu; WANG Zhao-hui; MIAO Yan-fang; LI Shi-qing

    2014-01-01

    Plant growth and crop production depend to a large extent on soil N supplying capacity (SNSC):The higher the SNSC, the higher the dependence of crops on soil and the lower the N fertilizer recovery. Of the SNSC, soil organic N (ON) played a key role in supplying N nutrient to crop production and still does in many subsistence and low-input farming systems. In this paper, soil ON contents, types, chemical components and its contribution to plant production are reviewed up to date in details, the characteristics of ON in dryland soils discussed together with its chemical components, and the mineralization and availability to plants of some important chemical components are emphasized at the last part for practical considerations.

  18. Mechanisms of mitochondria and autophagy crosstalk.

    Science.gov (United States)

    Rambold, Angelika S; Lippincott-Schwartz, Jennifer

    2011-12-01

    Autophagy is a cellular survival pathway that recycles intracellular components to compensate for nutrient depletion and ensures the appropriate degradation of organelles. Mitochondrial number and health are regulated by mitophagy, a process by which excessive or damaged mitochondria are subjected to autophagic degradation. Autophagy is thus a key determinant for mitochondrial health and proper cell function. Mitophagic malfunction has been recently proposed to contribute to progressive neuronal loss in Parkinson's disease. In addition to autophagy's significance in mitochondrial integrity, several lines of evidence suggest that mitochondria can also substantially influence the autophagic process. The mitochondria's ability to influence and be influenced by autophagy places both elements (mitochondria and autophagy) in a unique position where defects in one or the other system could increase the risk to various metabolic and autophagic related diseases.

  19. Components of the costs of controlling quality: a transaction cost economics approach.

    Science.gov (United States)

    Stiles, R A; Mick, S S

    1997-01-01

    This article identifies the components that contribute to a healthcare organization's costs in controlling quality. A central tenet of our argument is that at its core, quality is the result of a series of transactions among members of a diverse network. Transaction cost economics is applied internally to analyze intraorganizational transactions that contribute to quality control, and questions for future research are posed.

  20. Making High-Tensile-Strength Amalgam Components

    Science.gov (United States)

    Grugel, Richard

    2008-01-01

    Structural components made of amalgams can be made to have tensile strengths much greater than previously known to be possible. Amalgams, perhaps best known for their use in dental fillings, have several useful attributes, including room-temperature fabrication, corrosion resistance, dimensional stability, and high compressive strength. However, the range of applications of amalgams has been limited by their very small tensile strengths. Now, it has been discovered that the tensile strength of an amalgam depends critically on the sizes and shapes of the particles from which it is made and, consequently, the tensile strength can be greatly increased through suitable choice of the particles. Heretofore, the powder particles used to make amalgams have been, variously, in the form of micron-sized spheroids or flakes. The tensile reinforcement contributed by the spheroids and flakes is minimal because fracture paths simply go around these particles. However, if spheroids or flakes are replaced by strands having greater lengths, then tensile reinforcement can be increased significantly. The feasibility of this concept was shown in an experiment in which electrical copper wires, serving as demonstration substitutes for copper powder particles, were triturated with gallium by use of a mortar and pestle and the resulting amalgam was compressed into a mold. The tensile strength of the amalgam specimen was then measured and found to be greater than 10(exp 4) psi (greater than about 69 MPa). Much remains to be done to optimize the properties of amalgams for various applications through suitable choice of starting constituents and modification of the trituration and molding processes. The choice of wire size and composition are expected to be especially important. Perusal of phase diagrams of metal mixtures could give insight that would enable choices of solid and liquid metal constituents. Finally, whereas heretofore, only binary alloys have been considered for amalgams

  1. Minisuperspace models as infrared contributions

    CERN Document Server

    Bojowald, Martin

    2015-01-01

    A direct correspondence of quantum mechanics as a minisuperspace model for a self-interacting scalar quantum-field theory is established by computing, in several models, the infrared contributions to 1-loop effective potentials of Coleman--Weinberg type. A minisuperspace approximation rather than truncation is thereby obtained. By this approximation, the spatial averaging scale of minisuperspace models is identified with an infrared scale (but not a regulator or cut-off) delimiting the modes included in the minisuperspace model. Some versions of the models studied here have discrete space or modifications of the Hamiltonian expected from proposals of loop quantum gravity. They shed light on the question of how minisuperspace models of quantum cosmology can capture features of full quantum gravity. While it is shown that modifications of the Hamiltonian can well be described by minisuperspace truncations, some related phenomena such as signature change, confirmed and clarified here for modified scalar field th...

  2. Hadron Contribution to Vacuum Polarisation

    Science.gov (United States)

    Davier, M.; Hoecker, A.; Malaescu, B.; Zhang, Z.

    2016-10-01

    Precision tests of the Standard Theory require theoretical predictions taking into account higher-order quantum corrections. Among these vacuum polarisation plays a predominant role. Vacuum polarisation originates from creation and annihilation of virtual particle-antiparticle states. Leptonic vacuum polarisation can be computed from quantum electrodynamics. Hadronic vacuum polarisation cannot because of the non-perturbative nature of QCD at low energy. The problem is remedied by establishing dispersion relations involving experimental data on the cross section for e+ e- annihilation into hadrons. This chapter sets the theoretical and experimental scene and reviews the progress achieved in the last decades thanks to more precise and complete data sets. Among the various applications of hadronic vacuum polarisation calculations, two are emphasised: the contribution to the anomalous magnetic moment of the muon, and the running of the fine structure constant α to the Z mass scale. They are fundamental ingredients to high precision tests of the Standard Theory.

  3. Hadron Contribution to Vacuum Polarisation

    CERN Document Server

    Davier, M; Malaescu, B; Zhang, Z

    2016-01-01

    Precision tests of the Standard Theory require theoretical predictions taking into account higher-order quantum corrections. Among these vacuum polarisation plays a predominant role. Vacuum polarisation originates from creation and annihilation of virtual particle–antiparticle states. Leptonic vacuum polarisation can be computed from quantum electrodynamics. Hadronic vacuum polarisation cannot because of the non-perturbative nature of QCD at low energy. The problem is remedied by establishing dispersion relations involving experimental data on the cross section for e+ e− annihilation into hadrons. This chapter sets the theoretical and experimental scene and reviews the progress achieved in the last decades thanks to more precise and complete data sets. Among the various applications of hadronic vacuum polarisation calculations, two are emphasised: the contribution to the anomalous magnetic moment of the muon, and the running of the fine structure constant α to the Z mass scale. They are fundamental ingre...

  4. Factors contributing to adolescent obesity.

    Science.gov (United States)

    Al-Kloub, Manal I; Froelicher, Erika S

    2009-06-01

    Obesity in children is a significant public health concern. The prevalence of overweight and obesity in Jordanian children, and adolescents has increased in the last decade. The consequences of obesity to health in childhood and adulthood have both medical, and economic cost to individuals and society. This paper reviews the factors that contribute to adolescent obesity and emphasizes behavioral and environmental factors. An individual's behaviors such as increased consumption of high caloric foods, increased sedentary activity while decreasing physical activity has been identified as key issues in the development of obesity. Additionally, the current environment in homes, schools, and neighborhoods tend to discourage a healthy lifestyle. A comprehensive approach that involves the whole community is the best strategy for preventing adolescent obesity. Nurses are in a unique position to provide leadership in developing programs for healthier lifestyle choices for adolescents' and adoption of these goals into their daily lives.

  5. The search for putative unifying genetic factors for components of the metabolic syndrome

    DEFF Research Database (Denmark)

    Sjögren, M; Lyssenko, V; Jonsson, Anna Elisabet

    2008-01-01

    The metabolic syndrome is a cluster of factors contributing to increased risk of cardiovascular disease and type 2 diabetes but unifying mechanisms have not been identified. Our aim was to study whether common variations in 17 genes previously associated with type 2 diabetes or components...... of the metabolic syndrome and variants in nine genes with inconsistent association with at least two components of the metabolic syndrome would also predict future development of components of the metabolic syndrome, individually or in combination....

  6. High-frequency magnetic components

    CERN Document Server

    Kazimierczuk, Marian K

    2009-01-01

    If you are looking for a complete study of the fundamental concepts in magnetic theory, read this book. No other textbook covers magnetic components of inductors and transformers for high-frequency applications in detail. This unique text examines design techniques of the major types of inductors and transformers used for a wide variety of high-frequency applications including switching-mode power supplies (SMPS) and resonant circuits. It describes skin effect and proximity effect in detail to provide you with a sound understanding of high-frequency phenomena. As well as this, you will disco

  7. Parallel Assembly of LIGA Components

    Energy Technology Data Exchange (ETDEWEB)

    Christenson, T.R.; Feddema, J.T.

    1999-03-04

    In this paper, a prototype robotic workcell for the parallel assembly of LIGA components is described. A Cartesian robot is used to press 386 and 485 micron diameter pins into a LIGA substrate and then place a 3-inch diameter wafer with LIGA gears onto the pins. Upward and downward looking microscopes are used to locate holes in the LIGA substrate, pins to be pressed in the holes, and gears to be placed on the pins. This vision system can locate parts within 3 microns, while the Cartesian manipulator can place the parts within 0.4 microns.

  8. Components of Co-creation

    DEFF Research Database (Denmark)

    Tanev, Stoyan

    2009-01-01

    . However, these typically focus on the study, discussion and analysis of a small number of cases using deep, ethnographic description of their practices aiming at conceptualization and categorization of the different types of interactions between end users, the firm and the value network. Although useful...... and end customers based on the application of web search and Principal Component Analysis (PCA) techniques. The analysis of these preliminary results is then used as an opportunity to identify a number of research questions to be addressed in future research. The emerging research questions follow...

  9. Anthropological Component of Descartes’ Ontology

    Directory of Open Access Journals (Sweden)

    Anatolii M. Malivskyi

    2014-06-01

    Full Text Available The purpose of the article is to outline and comprehend the Descartes’ theory about anthropological component of ontology as the most important part of his philosophy. The accomplishment of this purpose covers the successive solution of the following tasks: 1 review of the research literature concerning the problem of human’s presence and the individual nature of truth; 2 emphasize the ambivalence of the basic intention of his legacy; 3 justify the thesis about constitutivity of human’s presence and comprehend passions as the form of disclosure of ontology’s anthropological component. Methodology. The use of the euristic potential of phenomenology, postpositivism and postmodernism makes it possible to emphasize the multiple-layer and multiple-meaning classical philosophy works, to comprehend the limitation and scarcity of the naïve-enlightening vision of human nature and to look for a new reception of European classics that provides the overcoming of established nihilism and pessimism concerning the interpretation of human nature. Scientific novelty. It is the first time that anthropological component of Descartes’ ontology became an object of particular attention. It previously lacked attention because of following main reasons: 1 traditional underestimating of the fact of Descartes’ legacy incompleteness as an unrealized anthropological project and 2 lack of proper attention to the individual nature of truth. The premise for its constructive overcoming is the attention to ambivalence of the basic intention and the significance of ethics in the philosopher’s legacy. His texts and research literature allow confirming the constitutive nature of human’s presence and passions as the key form of disclosure of the ontology anthropological component. Conclusions. The established tradition of interpretation the Descartes’ philosophizing nature as the filiation process of impersonal knowledge loses its cogency these days. The

  10. Astrophysical components from Planck maps

    CERN Document Server

    Burigana, Carlo; Paoletti, Daniela; Mandolesi, Nazzareno; Natoli, Paolo

    2016-01-01

    The Planck Collaboration has recently released maps of the microwave sky in both temperature and polarization. Diffuse astrophysical components (including Galactic emissions, cosmic far infrared (IR) background, y-maps of the thermal Sunyaev-Zeldovich (SZ) effect) and catalogs of many thousands of Galactic and extragalactic radio and far-IR sources, and galaxy clusters detected through the SZ effect are the main astrophysical products of the mission. A concise overview of these results and of astrophysical studies based on Planck data is presented.

  11. Fast Steerable Principal Component Analysis

    OpenAIRE

    Zhao, Zhizhen; Shkolnisky, Yoel; Singer, Amit

    2016-01-01

    Cryo-electron microscopy nowadays often requires the analysis of hundreds of thousands of 2D images as large as a few hundred pixels in each direction. Here we introduce an algorithm that efficiently and accurately performs principal component analysis (PCA) for a large set of two-dimensional images, and, for each image, the set of its uniform rotations in the plane and their reflections. For a dataset consisting of $n$ images of size $L \\times L$ pixels, the computational complexity of our a...

  12. Induced radioactivity in LDEF components

    Science.gov (United States)

    Harmon, B. A.; Fishman, G. J.; Parnell, T. A.; Laird, C. E.

    1992-01-01

    A systematic study of the induced radioactivity of the Long Duration Exposure Facility (LDEF) is being carried out in order to gather information about the low earth orbit radiation environment and its effects on materials. The large mass of the LDEF spacecraft, its stabilized configuration, and long mission duration have presented an opportunity to determine space radiation-induced radioactivities with a precision not possible before. Data presented include preliminary activities for steel and aluminum structural samples, and activation subexperiment foils. Effects seen in the data show a clear indication of the trapped proton anisotropy in the South Atlantic Anomaly and suggest contributions from different sources of external radiation fluxes.

  13. Comparison of conforming and nonconforming retrieved glenoid components.

    Science.gov (United States)

    Nho, Shane J; Ala, Owen L; Dodson, Christopher C; Figgie, Mark P; Wright, Timothy M; Craig, Edward V; Warren, Russell F

    2008-01-01

    The purpose of this study was to compare differences in wear performance of conforming and nonconforming glenoid designs, using clinical, radiographic, and retrieved polyethylene glenoid component outcome Sixty-three glenoids met the study criteria, and each glenoid was assigned to the conforming group (if the radii of curvature of the humeral and glenoid components were identical) or the nonconforming group (if a mismatch existed between the radii of curvature). The mean length of implantation was 5.6 +/- 5.5 years in the conforming group and 3.1 +/- 3.1 years for the nonconforming group (P conforming group and 2.4 +/- 1.2 in the nonconforming one (P conforming group had greater abrasion and delamination scores (P conformity contributes to differences observed from retrieved polyethylene glenoid components, which are consistent with differences in performance that may influence loosening.

  14. A probabilistic model for component-based shape synthesis

    KAUST Repository

    Kalogerakis, Evangelos

    2012-07-01

    We present an approach to synthesizing shapes from complex domains, by identifying new plausible combinations of components from existing shapes. Our primary contribution is a new generative model of component-based shape structure. The model represents probabilistic relationships between properties of shape components, and relates them to learned underlying causes of structural variability within the domain. These causes are treated as latent variables, leading to a compact representation that can be effectively learned without supervision from a set of compatibly segmented shapes. We evaluate the model on a number of shape datasets with complex structural variability and demonstrate its application to amplification of shape databases and to interactive shape synthesis. © 2012 ACM 0730-0301/2012/08-ART55.

  15. Cosmic Ray Excesses from Multi-component Dark Matter Decays

    CERN Document Server

    Geng, Chao-Qiang; Tsai, Lu-Hsing

    2014-01-01

    We use multi-component decaying dark matter (DM) scenario to explain the possible cosmic ray excesses in the positron fraction recently confirmed by AMS-02 and the total $e^+ +e^-$ flux observed by Fermi-LAT. In the two-component DM models, we find an interesting variation of the flavor structure along with the cutoff of the heavy DM. For the three-component DM case, we focus on a particular parameter range in which the best fits prefer to open only 2 DM decay channels with a third DM contributing nothing to the electron and positron spectra. We show that all models give the reasonable fits to both the AMS-02 positron fraction and the Fermi-LAT total $e^++e^-$ flux, which are also consistent with the measured diffuse $\\gamma$-ray flux by Fermi-LAT.

  16. Harmonic component detection: Optimized Spectral Kurtosis for operational modal analysis

    Science.gov (United States)

    Dion, J.-L.; Tawfiq, I.; Chevallier, G.

    2012-01-01

    This work is a contribution in the field of Operational Modal Analysis to identify the modal parameters of mechanical structures using only measured responses. The study deals with structural responses coupled with harmonic components amplitude and frequency modulated in a short range, a common combination for mechanical systems with engines and other rotating machines in operation. These harmonic components generate misleading data interpreted erroneously by the classical methods used in OMA. The present work attempts to differentiate maxima in spectra stemming from harmonic components and structural modes. The detection method proposed is based on the so-called Optimized Spectral Kurtosis and compared with others definitions of Spectral Kurtosis described in the literature. After a parametric study of the method, a critical study is performed on numerical simulations and then on an experimental structure in operation in order to assess the method's performance.

  17. Cabazitaxel-induced autophagy via the PI3K/Akt/mTOR pathway contributes to A549 cell death

    Science.gov (United States)

    Huo, Ruichao; Wang, Lili; Liu, Peijuan; Zhao, Yong; Zhang, Caiqin; Bai, Bing; Liu, Xueying; Shi, Changhong; Wei, Sanhua; Zhang, Hai

    2016-01-01

    Cabazitaxel has been used to treat castration-resistant prostate cancer since its approval by the US Food and Drug Administration in 2010. However, whether cabazitaxel may inhibit the proliferation of other tissue-derived cancer cells, and its underlying mechanism, remains unknown. In the present study, the A549 lung adenocarcinoma cancer cell line was exposed to cabazitaxel, in order to investigate its cytotoxic effect and determine the underlying mechanism. The results demonstrated that cabazitaxel was able to induce autophagy in A549 cells, as evidenced by the formation of autophagosomes, upregulated LC3-II expression and increased LC3 puncta. Cabazitaxel-induced autophagy had a cytotoxic effect on A549 cells, as evidenced by the induction of cell death and cell cycle arrest at G2/M phase, which was independent of the apoptotic pathway. Furthermore, transfection with Beclin1 small interfering RNA and treatment with the autophagy inhibitor 3-methyladenine protected cells from cabazitaxel-induced cell death, thus confirming that cabazitaxel-induced autophagy contributed to A549 cell death. In addition, cabazitaxel targeted the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway to induce autophagy, as indicated by reduced phosphorylation of Akt and mTOR. In conclusion, the present study demonstrated that cabazitaxel exerts a cytotoxic effect on A549 cells by acting on the PI3K/Akt/mTOR pathway to promote autophagic cell death. This result supports the potential use of cabazitaxel as a chemotherapeutic agent for the treatment of lung cancer. PMID:27572899

  18. Cabazitaxel-induced autophagy via the PI3K/Akt/mTOR pathway contributes to A549 cell death.

    Science.gov (United States)

    Huo, Ruichao; Wang, Lili; Liu, Peijuan; Zhao, Yong; Zhang, Caiqin; Bai, Bing; Liu, Xueying; Shi, Changhong; Wei, Sanhua; Zhang, Hai

    2016-10-01

    Cabazitaxel has been used to treat castration-resistant prostate cancer since its approval by the US Food and Drug Administration in 2010. However, whether cabazitaxel may inhibit the proliferation of other tissue‑derived cancer cells, and its underlying mechanism, remains unknown. In the present study, the A549 lung adenocarcinoma cancer cell line was exposed to cabazitaxel, in order to investigate its cytotoxic effect and determine the underlying mechanism. The results demonstrated that cabazitaxel was able to induce autophagy in A549 cells, as evidenced by the formation of autophagosomes, upregulated LC3‑II expression and increased LC3 puncta. Cabazitaxel‑induced autophagy had a cytotoxic effect on A549 cells, as evidenced by the induction of cell death and cell cycle arrest at G2/M phase, which was independent of the apoptotic pathway. Furthermore, transfection with Beclin1 small interfering RNA and treatment with the autophagy inhibitor 3‑methyladenine protected cells from cabazitaxel‑induced cell death, thus confirming that cabazitaxel‑induced autophagy contributed to A549 cell death. In addition, cabazitaxel targeted the phosphoinositide 3‑kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway to induce autophagy, as indicated by reduced phosphorylation of Akt and mTOR. In conclusion, the present study demonstrated that cabazitaxel exerts a cytotoxic effect on A549 cells by acting on the PI3K/Akt/mTOR pathway to promote autophagic cell death. This result supports the potential use of cabazitaxel as a chemotherapeutic agent for the treatment of lung cancer.

  19. Interpretable functional principal component analysis.

    Science.gov (United States)

    Lin, Zhenhua; Wang, Liangliang; Cao, Jiguo

    2016-09-01

    Functional principal component analysis (FPCA) is a popular approach to explore major sources of variation in a sample of random curves. These major sources of variation are represented by functional principal components (FPCs). The intervals where the values of FPCs are significant are interpreted as where sample curves have major variations. However, these intervals are often hard for naïve users to identify, because of the vague definition of "significant values". In this article, we develop a novel penalty-based method to derive FPCs that are only nonzero precisely in the intervals where the values of FPCs are significant, whence the derived FPCs possess better interpretability than the FPCs derived from existing methods. To compute the proposed FPCs, we devise an efficient algorithm based on projection deflation techniques. We show that the proposed interpretable FPCs are strongly consistent and asymptotically normal under mild conditions. Simulation studies confirm that with a competitive performance in explaining variations of sample curves, the proposed FPCs are more interpretable than the traditional counterparts. This advantage is demonstrated by analyzing two real datasets, namely, electroencephalography data and Canadian weather data.

  20. The components of paraphrase evaluations.

    Science.gov (United States)

    McCarthy, Philip M; Guess, Rebekah H; McNamara, Danielle S

    2009-08-01

    Two sentences are paraphrases if their meanings are equivalent but their words and syntax are different. Paraphrasing can be used to aid comprehension, stimulate prior knowledge, and assist in writing-skills development. As such, paraphrasing is a feature of fields as diverse as discourse psychology, composition, and computer science. Although automated paraphrase assessment is both commonplace and useful, research has centered solely on artificial, edited paraphrases and has used only binary dimensions (i.e., is or is not a paraphrase). In this study, we use an extensive database (N=1,998) of natural paraphrases generated by high school students that have been assessed along 10 dimensions (e.g., semantic completeness, lexical similarity, syntactical similarity). This study investigates the components of paraphrase quality emerging from these dimensions and examines whether computational approaches can simulate those human evaluations. The results suggest that semantic and syntactic evaluations are the primary components of paraphrase quality, and that computationally light systems such as latent semantic analysis (semantics) and minimal edit distances (syntax) present promising approaches to simulating human evaluations of paraphrases.

  1. Components of Adenovirus Genome Packaging

    Science.gov (United States)

    Ahi, Yadvinder S.; Mittal, Suresh K.

    2016-01-01

    Adenoviruses (AdVs) are icosahedral viruses with double-stranded DNA (dsDNA) genomes. Genome packaging in AdV is thought to be similar to that seen in dsDNA containing icosahedral bacteriophages and herpesviruses. Specific recognition of the AdV genome is mediated by a packaging domain located close to the left end of the viral genome and is mediated by the viral packaging machinery. Our understanding of the role of various components of the viral packaging machinery in AdV genome packaging has greatly advanced in recent years. Characterization of empty capsids assembled in the absence of one or more components involved in packaging, identification of the unique vertex, and demonstration of the role of IVa2, the putative packaging ATPase, in genome packaging have provided compelling evidence that AdVs follow a sequential assembly pathway. This review provides a detailed discussion on the functions of the various viral and cellular factors involved in AdV genome packaging. We conclude by briefly discussing the roles of the empty capsids, assembly intermediates, scaffolding proteins, portal vertex and DNA encapsidating enzymes in AdV assembly and packaging. PMID:27721809

  2. Measurement, analysis and modification of the fifth-order fringe field components of magnetic quadrupole lenses

    Energy Technology Data Exchange (ETDEWEB)

    Moloney, G.R.; Jamieson, D.N.; Legge, G.J.F. (School of Physics, Univ. of Melbourne, Parkville (Australia))

    1991-03-01

    Extensive, quantitative measurements of magnetic quadrupole lens fringe fields have been conducted. The fringe field region of magnetic quadrupole lenses has been shown to contain significant contamination by higher-order multipole fields. These multipole components will contribute to the aberration coefficients of the lens. One of the largest components is the duodecapole component, which contributes to the fifth-order geometric aberrations of the lens. The measured multipole profiles in the fringe field region of the Melbourne quadrupoles are presented. We also present the results of an investigation into the effect of modifying the quadrupole pole tip profile at the pole ends. (orig.).

  3. Stochastic Modeling Of Wind Turbine Drivetrain Components

    DEFF Research Database (Denmark)

    Rafsanjani, Hesam Mirzaei; Sørensen, John Dalsgaard

    2014-01-01

    reliable components are needed for wind turbine. In this paper focus is on reliability of critical components in drivetrain such as bearings and shafts. High failure rates of these components imply a need for more reliable components. To estimate the reliability of these components, stochastic models...... are needed for initial defects and damage accumulation. In this paper, stochastic models are formulated considering some of the failure modes observed in these components. The models are based on theoretical considerations, manufacturing uncertainties, size effects of different scales. It is illustrated how...... the stochastic models can be used to obtain estimates of failure rates for wind turbine components....

  4. Understanding symmetrical components for power system modeling

    CERN Document Server

    Das, J C

    2017-01-01

    This book utilizes symmetrical components for analyzing unbalanced three-phase electrical systems, by applying single-phase analysis tools. The author covers two approaches for studying symmetrical components; the physical approach, avoiding many mathematical matrix algebra equations, and a mathematical approach, using matrix theory. Divided into seven sections, topics include: symmetrical components using matrix methods, fundamental concepts of symmetrical components, symmetrical components –transmission lines and cables, sequence components of rotating equipment and static load, three-phase models of transformers and conductors, unsymmetrical fault calculations, and some limitations of symmetrical components.

  5. Components of executive functioning in metamemory.

    Science.gov (United States)

    Mäntylä, Timo; Rönnlund, Michael; Kliegel, Matthias

    2010-10-01

    This study examined metamemory in relation to three basic executive functions (set shifting, working memory updating, and response inhibition) measured as latent variables. Young adults (Experiment 1) and middle-aged adults (Experiment 2) completed a set of executive functioning tasks and the Prospective and Retrospective Memory Questionnaire (PRMQ). In Experiment 1, source recall and face recognition tasks were included as indicators of objective memory performance. In both experiments, analyses of the executive functioning data yielded a two-factor solution, with the updating and inhibition tasks constituting a common factor and the shifting tasks a separate factor. Self-reported memory problems showed low predictive validity, but subjective and objective memory performance were related to different components of executive functioning. In both experiments, set shifting, but not updating and inhibition, was related to PRMQ, whereas source recall showed the opposite pattern of correlations in Experiment 1. These findings suggest that metamemorial judgments reflect selective effects of executive functioning and that individual differences in mental flexibility contribute to self-beliefs of efficacy.

  6. Metabolic syndrome components in murine models.

    Science.gov (United States)

    Lawson, Heather A; Cheverud, James M

    2010-03-01

    Animal models have enriched understanding of the physiological basis of metabolic disorders and advanced identification of genetic risk factors underlying the metabolic syndrome (MetS). Murine models are especially appropriate for this type of research, and are an excellent resource not only for identifying candidate genomic regions, but also for illuminating the possible molecular mechanisms or pathways affected in individual components of MetS. In this review, we briefly discuss findings from mouse models of metabolic disorders, particularly in light of issues raised by the recent flood of human genome-wide association studies (GWAS) results. We describe how mouse models are revealing that genotype interacts with environment in important ways, indicating that the underlying genetics of MetS is highly context dependant. Further we show that epistasis, imprinting and maternal effects each contribute to the genetic architecture underlying variation in metabolic traits, and mouse models provide an opportunity to dissect these aspects of the genetic architecture that are difficult if not impossible to ascertain in humans. Finally we discuss how knowledge gained from mouse models can be used in conjunction with comparative genomic methods and bioinformatic resources to inform human MetS research.

  7. Minisuperspace models as infrared contributions

    Science.gov (United States)

    Bojowald, Martin; Brahma, Suddhasattwa

    2016-06-01

    A direct correspondence of quantum mechanics as a minisuperspace model for a self-interacting scalar quantum-field theory is established by computing, in several models, the infrared contributions to 1-loop effective potentials of Coleman-Weinberg type. A minisuperspace approximation rather than truncation is thereby obtained. By this approximation, the spatial averaging scale of minisuperspace models is identified with an infrared scale (but not a regulator or cutoff) delimiting the modes included in the minisuperspace model. Some versions of the models studied here have discrete space or modifications of the Hamiltonian expected from proposals of loop quantum gravity. They shed light on the question of how minisuperspace models of quantum cosmology can capture features of full quantum gravity. While it is shown that modifications of the Hamiltonian can be well described by minisuperspace truncations, some related phenomena such as signature change, confirmed and clarified here for modified scalar field theories, require at least a perturbative treatment of inhomogeneity beyond a strict minisuperspace model. The new methods suggest a systematic extension of minisuperspace models by a canonical effective formulation of perturbative inhomogeneity.

  8. Quarkonium Contribution to Meson Molecules

    CERN Document Server

    Cincioglu, E; Ozpineci, A; Yilmazer, A U

    2016-01-01

    Starting from a molecular picture for the X(3872) resonance, this state and its J^{PC}=2++ HQSS partner [X2(4012)] are analyzed within a model which incorporates possible mixings with 2P charmonium states. Since it is reasonable to expect the bare chi_{c1}(2P) to be located above the D\\bar D* threshold, but relatively close to it, the presence of the charmonium state provides an effective attraction that will contribute to bind the X(3872), but it will not appear in the 2++ sector. Indeed in this latter sector, the chi_{c2}(2P) should provide an effective small repulsion, because it is placed well below the D*\\bar D* threshold. We show how the 1++ and 2++ bare charmonium poles are modified due to the D(*)\\bar D(*) loop effects, and the first one is moved to the complex plane. The meson loops produce, besides some shifts in the masses of the charmonia, a finite width for the 1++ dressed charmonium state. On the other hand, the X(3872) and X2(4012) start developing some charmonium content, which is estimated by...

  9. The magnet components database system

    Energy Technology Data Exchange (ETDEWEB)

    Baggett, M.J. (Brookhaven National Lab., Upton, NY (USA)); Leedy, R.; Saltmarsh, C.; Tompkins, J.C. (Superconducting Supercollider Lab., Dallas, TX (USA))

    1990-01-01

    The philosophy, structure, and usage MagCom, the SSC magnet components database, are described. The database has been implemented in Sybase (a powerful relational database management system) on a UNIX-based workstation at the Superconducting Super Collider Laboratory (SSCL); magnet project collaborators can access the database via network connections. The database was designed to contain the specifications and measured values of important properties for major materials, plus configuration information (specifying which individual items were used in each cable, coil, and magnet) and the test results on completed magnets. These data will facilitate the tracking and control of the production process as well as the correlation of magnet performance with the properties of its constituents. 3 refs., 10 figs.

  10. Fast Steerable Principal Component Analysis.

    Science.gov (United States)

    Zhao, Zhizhen; Shkolnisky, Yoel; Singer, Amit

    2016-03-01

    Cryo-electron microscopy nowadays often requires the analysis of hundreds of thousands of 2-D images as large as a few hundred pixels in each direction. Here, we introduce an algorithm that efficiently and accurately performs principal component analysis (PCA) for a large set of 2-D images, and, for each image, the set of its uniform rotations in the plane and their reflections. For a dataset consisting of n images of size L × L pixels, the computational complexity of our algorithm is O(nL(3) + L(4)), while existing algorithms take O(nL(4)). The new algorithm computes the expansion coefficients of the images in a Fourier-Bessel basis efficiently using the nonuniform fast Fourier transform. We compare the accuracy and efficiency of the new algorithm with traditional PCA and existing algorithms for steerable PCA.

  11. Rosin components identified in diapers.

    Science.gov (United States)

    Karlberg, A T; Magnusson, K

    1996-03-01

    As part of the investigation of sources of exposure to rosin allergens, disposable diapers (napkins) common on the Swedish market were analyzed, using gas chromatography, to detect the main rosin compounds. Rosin components were detected in all diapers, the highest amounts in those from the 2 major producers. In these diapers, more rosin was found in the top layer, which is in close contact with the skin than in the fluff. Despite the possibly minimal risk of induction of sensitization to rosin allergens in diapers, there is a real risk of elicitation of dermatitis in sensitive individuals, especially since penetration is enhanced by occlusion and irritation. Such material is not only used for infant diapers, but also for adult incontinence products and feminine hygiene products.

  12. Neural components of altruistic punishment

    Directory of Open Access Journals (Sweden)

    Emily eDu

    2015-02-01

    Full Text Available Altruistic punishment, which occurs when an individual incurs a cost to punish in response to unfairness or a norm violation, may play a role in perpetuating cooperation. The neural correlates underlying costly punishment have only recently begun to be explored. Here we review the current state of research on the neural basis of altruism from the perspectives of costly punishment, emphasizing the importance of characterizing elementary neural processes underlying a decision to punish. In particular, we emphasize three cognitive processes that contribute to the decision to altruistically punish in most scenarios: inequity aversion, cost-benefit calculation, and social reference frame to distinguish self from others. Overall, we argue for the importance of understanding the neural correlates of altruistic punishment with respect to the core computations necessary to achieve a decision to punish.

  13. Peripheral contributions to visceral hyperalgesia.

    Science.gov (United States)

    Gebhart, G F

    1999-03-01

    and, along with activated mechanically insensitive receptors, increase the afferent barrage into the spinal cord, contributing to the development of visceral hyperalgesia.

  14. Ascribing soil erosion of hillslope components to river sediment yield.

    Science.gov (United States)

    Nosrati, Kazem

    2016-10-11

    In recent decades, soil erosion has increased in catchments of Iran. It is, therefore, necessary to understand soil erosion processes and sources in order to mitigate this problem. Geomorphic landforms play an important role in influencing water erosion. Therefore, ascribing hillslope components soil erosion to river sediment yield could be useful for soil and sediment management in order to decrease the off-site effects related to downstream sedimentation areas. The main objectives of this study were to apply radionuclide tracers and soil organic carbon to determine relative contributions of hillslope component sediment sources in two land use types (forest and crop field) by using a Bayesian-mixing model, as well as to estimate the uncertainty in sediment fingerprinting in a mountainous catchment of western Iran. In this analysis, (137)Cs, (40)K, (238)U, (226)Ra, (232)Th and soil organic carbon tracers were measured in 32 different sampling sites from four hillslope component sediment sources (summit, shoulder, backslope, and toeslope) in forested and crop fields along with six bed sediment samples at the downstream reach of the catchment. To quantify the sediment source proportions, the Bayesian mixing model was based on (1) primary sediment sources and (2) combined primary and secondary sediment sources. The results of both approaches indicated that erosion from crop field shoulder dominated the sources of river sediments. The estimated contribution of crop field shoulder for all river samples was 63.7% (32.4-79.8%) for primary sediment sources approach, and 67% (15.3%-81.7%) for the combined primary and secondary sources approach. The Bayesian mixing model, based on an optimum set of tracers, estimated that the highest contribution of soil erosion in crop field land use and shoulder-component landforms constituted the most important land-use factor. This technique could, therefore, be a useful tool for soil and sediment control management strategies.

  15. Age-related differences in working memory updating components.

    Science.gov (United States)

    Linares, Rocío; Bajo, M Teresa; Pelegrina, Santiago

    2016-07-01

    The aim of this study was to investigate possible age-related changes throughout childhood and adolescence in different component processes of working memory updating (WMU): retrieval, transformation, and substitution. A set of numerical WMU tasks was administered to four age groups (8-, 11-, 14-, and 21-year-olds). To isolate the effect of each of the WMU components, participants performed different versions of a task that included different combinations of the WMU components. The results showed an expected overall decrease in response times and an increase in accuracy performance with age. Most important, specific age-related changes in the retrieval component were found, demonstrating that the effect of retrieval on accuracy was larger in children than in adolescents or young adults. These findings indicate that the availability of representations from outside the focus of attention may change with age. Thus, the retrieval component of updating could contribute to the age-related changes observed in the performance of many updating tasks.

  16. Additive genetic contribution to symptom dimensions in major depressive disorder.

    Science.gov (United States)

    Pearson, Rahel; Palmer, Rohan H C; Brick, Leslie A; McGeary, John E; Knopik, Valerie S; Beevers, Christopher G

    2016-05-01

    Major depressive disorder (MDD) is a phenotypically heterogeneous disorder with a complex genetic architecture. In this study, genomic-relatedness-matrix restricted maximum-likelihood analysis (GREML) was used to investigate the extent to which variance in depression symptoms/symptom dimensions can be explained by variation in common single nucleotide polymorphisms (SNPs) in a sample of individuals with MDD (N = 1,558) who participated in the National Institute of Mental Health Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. A principal components analysis of items from the Hamilton Rating Scale for Depression (HRSD) obtained prior to treatment revealed 4 depression symptom components: (a) appetite, (b) core depression symptoms (e.g., depressed mood, anhedonia), (c) insomnia, and (d) anxiety. These symptom dimensions were associated with SNP-based heritability (hSNP2) estimates of 30%, 14%, 30%, and 5%, respectively. Results indicated that the genetic contribution of common SNPs to depression symptom dimensions were not uniform. Appetite and insomnia symptoms in MDD had a relatively strong genetic contribution whereas the genetic contribution was relatively small for core depression and anxiety symptoms. While in need of replication, these results suggest that future gene discovery efforts may strongly benefit from parsing depression into its constituent parts. (PsycINFO Database Record

  17. A Component Based Heuristic Search method with Adaptive Perturbations for Hospital Personnel Scheduling

    CERN Document Server

    Li, Jingpeng; Burke, Edmund

    2008-01-01

    Nurse rostering is a complex scheduling problem that affects hospital personnel on a daily basis all over the world. This paper presents a new component-based approach with adaptive perturbations, for a nurse scheduling problem arising at a major UK hospital. The main idea behind this technique is to decompose a schedule into its components (i.e. the allocated shift pattern of each nurse), and then mimic a natural evolutionary process on these components to iteratively deliver better schedules. The worthiness of all components in the schedule has to be continuously demonstrated in order for them to remain there. This demonstration employs a dynamic evaluation function which evaluates how well each component contributes towards the final objective. Two perturbation steps are then applied: the first perturbation eliminates a number of components that are deemed not worthy to stay in the current schedule; the second perturbation may also throw out, with a low level of probability, some worthy components. The eli...

  18. Analysis 6. Component requirements, competition and export. A survey of innovation related to building components; Analyse 6. Komponentkrav, konkurrence og eksport. En kortlaegning af innovation i byggekomponenter

    Energy Technology Data Exchange (ETDEWEB)

    Svendsen, Svend

    2011-02-15

    The report collates several sub-analyses about feasible developments in relation to improved energy requirements for the most important building parts, components and installations for low-energy buildings. The aim is to achieve 75% reduction of energy consumption in the future building class 2020. The findings will contribute to the plans of introducing new building component requirements to force Danish manufacturers to use innovative solutions and to force manufacturers from other countries to market the best products only. (LN)

  19. 12 CFR 1291.2 - Required annual AHP contributions; allocation of contributions.

    Science.gov (United States)

    2010-01-01

    ... 12 Banks and Banking 7 2010-01-01 2010-01-01 false Required annual AHP contributions; allocation... GOALS AND MISSION FEDERAL HOME LOAN BANKS' AFFORDABLE HOUSING PROGRAM § 1291.2 Required annual AHP contributions; allocation of contributions. (a) Annual AHP contributions. Each Bank shall contribute annually...

  20. The GMOS contributions to GEOSS

    Directory of Open Access Journals (Sweden)

    Pirrone N.

    2013-04-01

    oceans, and in the UTLS will support the validation of regional and global atmospheric mercury models for use in evaluating different policy options for reducing mercury pollution and its impacts on human health and ecosystems. The data sets, the validated models, and the interoperable system that is produced within this program, will support the policymaking process in the framework of UNEP Governing Council activities, and in the UNECE-LRTAP convention. The task builds upon contributions from, among others, the Global Mercury Observation System (GMOS project, the UNEP Mercury Programme, the Hemispheric Transport of Air Pollutants Task Force (TF HTAP, the European Monitoring and Evaluation Program (EMEP, the MercNet/AMNet initiative in the USA, the CAMNet in Canada, and other international monitoring and modelling efforts.

  1. Quarkonium Contribution to Meson Molecules

    Energy Technology Data Exchange (ETDEWEB)

    Cincioglu, E.; Yilmazer, A.U. [Ankara University, Department of Physics Engineering, Ankara (Turkey); Nieves, J. [Instituto de Fisica Corpuscular (IFIC) Centro Mixto CSIC-Universidad de Valencia, Institutos de Investigacion de Paterna, Valencia (Spain); Ozpineci, A. [Middle East Technical University, Department of Physics, Ankara (Turkey)

    2016-10-15

    Starting from a molecular picture for the X(3872) resonance, this state and its J{sup PC} = 2{sup ++} heavy-quark spin symmetry partner [X{sub 2}(4012)] are analyzed within a model which incorporates possible mixings with 2P charmonium (c anti c) states. Since it is reasonable to expect the bare χ{sub c1}(2P) to be located above the D anti D{sup *} threshold, but relatively close to it, the presence of the charmonium state provides an effective attraction that will contribute to binding the X(3872), but it will not appear in the 2{sup ++} sector. Indeed in the latter sector, the χ{sub c2}(2P) should provide an effective small repulsion, because it is placed well below the D{sup *} anti D{sup *} threshold. We show how the 1{sup ++} and 2{sup ++} bare charmonium poles are modified due to the D{sup (*)} anti D{sup (*)} loop effects, and the first one is moved to the complex plane. The meson loops produce, besides some shifts in the masses of the charmonia, a finite width for the 1{sup ++} dressed charmonium state. On the other hand, X(3872) and X{sub 2}(4012) start developing some charmonium content, which is estimated by means of the compositeness Weinberg sum rule. It turns out that in the heavy-quark limit, there is only one coupling between the 2P charmonia and the D{sup (*)} anti D{sup (*)} pairs. We also show that, for reasonable values of this coupling, leading to X(3872) molecular probabilities of around 70-90 %, the X{sub 2} resonance destabilizes and disappears from the spectrum, becoming either a virtual state or one being located deep into the complex plane, with decreasing influence in the D{sup *} anti D{sup *} scattering line. Moreover, we also discuss how around 10-30 % charmonium probability in the X(3872) might explain the ratio of radiative decays of this resonance into ψ(2S)γ and J/ψγ. Finally, we qualitatively discuss within this scheme, the hidden bottom flavor sector, paying a special attention to the implications for the X{sub b} and X

  2. Molecular Components of Catalytic Selectivity

    Energy Technology Data Exchange (ETDEWEB)

    Somorjai, Gabor A.; Park, Jeong Y.

    2008-07-02

    Selectivity, that is, to produce one molecule out of many other thermodynamically feasible product molecules, is the key concept to develop 'clean manufacturing' processes that do not produce byproducts (green chemistry). Small differences in potential energy barriers for elementary reaction steps control which reaction channel is more likely to yield the desired product molecule (selectivity), instead of the overall activation energy for the reaction that controls turnover rates (activity). Recent studies have demonstrated the atomic- or molecular-level tailoring of parameters such as the surface structures of active sites that give rise to nanoparticle size and shape dependence of turnover rates and reaction selectivities. Here, we highlight seven molecular components that influence reaction selectivities. These include: surface structure, adsorbate-induced restructuring, adsorbate mobility, reaction intermediates, surface composition, charge transport, and oxidation states for model metal single crystal and colloid nanoparticle catalysts. We show examples of their functioning and describe in-situ instruments that permit us to investigate their roles in surface reactions.

  3. Memory Systems, Processing Modes, and Components: Functional Neuroimaging Evidence

    Science.gov (United States)

    Cabeza, Roberto; Moscovitch, Morris

    2013-01-01

    In the 1980s and 1990s, there was a major theoretical debate in the memory domain regarding the multiple memory systems and processing modes frameworks. The components of processing framework argued for a middle ground: Instead of neatly divided memory systems or processing modes, this framework proposed the existence of numerous processing components that are recruited in different combinations by memory tasks and yield complex patterns of associations and dissociations. Because behavioral evidence was not sufficient to decide among these three frameworks, the debate was largely abandoned. However, functional neuroimaging evidence accumulated during the last two decades resolves the stalemate, because this evidence is more consistent with the components framework than with the other two frameworks. For example, functional neuroimaging evidence shows that brain regions attributed to one memory system can contribute to tasks associated with other memory systems and that brain regions attributed to the same processing mode (perceptual or conceptual) can be dissociated from each other. Functional neuroimaging evidence suggests that memory processes are supported by transient interactions between a few regions called process-specific alliances. These conceptual developments are an example of how functional neuroimaging can contribute to theoretical debates in cognitive psychology. PMID:24163702

  4. Efficient speaker verification using Gaussian mixture model component clustering.

    Energy Technology Data Exchange (ETDEWEB)

    De Leon, Phillip L. (New Mexico State University, Las Cruces, NM); McClanahan, Richard D.

    2012-04-01

    In speaker verification (SV) systems that employ a support vector machine (SVM) classifier to make decisions on a supervector derived from Gaussian mixture model (GMM) component mean vectors, a significant portion of the computational load is involved in the calculation of the a posteriori probability of the feature vectors of the speaker under test with respect to the individual component densities of the universal background model (UBM). Further, the calculation of the sufficient statistics for the weight, mean, and covariance parameters derived from these same feature vectors also contribute a substantial amount of processing load to the SV system. In this paper, we propose a method that utilizes clusters of GMM-UBM mixture component densities in order to reduce the computational load required. In the adaptation step we score the feature vectors against the clusters and calculate the a posteriori probabilities and update the statistics exclusively for mixture components belonging to appropriate clusters. Each cluster is a grouping of multivariate normal distributions and is modeled by a single multivariate distribution. As such, the set of multivariate normal distributions representing the different clusters also form a GMM. This GMM is referred to as a hash GMM which can be considered to a lower resolution representation of the GMM-UBM. The mapping that associates the components of the hash GMM with components of the original GMM-UBM is referred to as a shortlist. This research investigates various methods of clustering the components of the GMM-UBM and forming hash GMMs. Of five different methods that are presented one method, Gaussian mixture reduction as proposed by Runnall's, easily outperformed the other methods. This method of Gaussian reduction iteratively reduces the size of a GMM by successively merging pairs of component densities. Pairs are selected for merger by using a Kullback-Leibler based metric. Using Runnal's method of reduction, we

  5. Quality control in digital mammography: the noise components

    Energy Technology Data Exchange (ETDEWEB)

    Leyton, Fernando [Universidade de Tarapaca, Arica (Chile). Centro de Estudios en Ciencias Radiologicas; Centro de Desenvolvimento da Tecnologia Nuclear (CDTN/CNEN-MG), Belo Horizonte, MG (Brazil); Nogueira, Maria do Socorro, E-mail: mnogue@cdtn.b [Centro de Desenvolvimento da Tecnologia Nuclear (CDTN/CNEN-MG), Belo Horizonte, MG (Brazil); Duran, Maria Paz [Clinica Alemana, Santiago (Chile). Dept. de Radiologia; Dantas, Marcelino, E-mail: marcelino@inb.gov.b [Industrias Nucleares do Brasil (INB), Caldas, MG (Brazil). Unidade de Tratamento de Minerios; Ubeda, Carlos, E-mail: cubeda@uta.c [Universidade de Tarapaca, Arica (Chile). Fac. de Ciencias de la Salud

    2011-07-01

    To measure the linearity of the detector and determine the noise components (quantum, electronic and structural noise) that contributed to losing image quality and to determine the signal noise ratio (SNR) and contrast noise ratio (CNR). This paper describes the results of the implementation of a protocol for quality control in digital mammography performed in two direct digital mammography equipment (Hologic, Selenia) in Santiago of Chile. Shows the results of linearity and noise analysis of the images which establishes the main cause of noise in the image of the mammogram to ensure the quality and optimize procedures. The study evaluated two digital mammography's Selenia, Hologic (DR) from Santiago, Chile. We conducted the assessment of linearity of the detector, the signal noise ratio, contrast noise ratio and was determined the contribution of different noise components (quantum, electronics and structural noise). Used different thicknesses used in clinical practice according to the protocol for quality control in digital mammography of Spanish society of medical physics and NHSBSP Equipment Report 0604 Version 3. The Selenia mammography software was used for the analysis of images and Unfors Xi detector for measuring doses. The mammography detector has a linear performance, the CNR and SNR did not comply with the Protocol for the thicknesses of 60 and 70 mm. The main contribution of the noise corresponds to the quantum noise, therefore it is necessary to adjust and optimize the mammography system. (author)

  6. Seasonal contributions of vegetation types to suburban evapotranspiration

    Science.gov (United States)

    Peters, Emily B.; Hiller, Rebecca V.; McFadden, Joseph P.

    2011-03-01

    Evapotranspiration is an important term of energy and water budgets in urban areas and is responsible for multiple ecosystem services provided by urban vegetation. The spatial heterogeneity of urban surface types with different seasonal water use patterns (e.g., trees and turfgrass lawns) complicates efforts to predict and manage urban evapotranspiration rates, necessitating a surface type, or component-based, approach. In a suburban neighborhood of Minneapolis-Saint Paul, Minnesota, United States, we simultaneously measured ecosystem evapotranspiration and its main component fluxes using eddy covariance and heat dissipation sap flux techniques to assess the relative contribution of plant functional types (evergreen needleleaf tree, deciduous broadleaf tree, cool season turfgrass) to seasonal and spatial variations in evapotranspiration. Component-based evapotranspiration estimates agreed well with measured water vapor fluxes, although the imbalance between methods varied seasonally from a 20% overestimate in spring to an 11% underestimate in summer. Turfgrasses represented the largest contribution to annual evapotranspiration in recreational and residential land use types (87% and 64%, respectively), followed by trees (10% and 31%, respectively), with the relative contribution of plant functional types dependent on their fractional cover and daily water use. Recreational areas had higher annual evapotranspiration than residential areas (467 versus 324 mm yr-1, respectively) and altered seasonal patterns of evapotranspiration due to greater turfgrass cover (74% versus 34%, respectively). Our results suggest that plant functional types capture much of the variability required to predict the seasonal patterns of evapotranspiration among cities, as well as differences in evapotranspiration that could result from changes in climate, land use, or vegetation composition.

  7. Semiautomatic device tests components with biaxial leads

    Science.gov (United States)

    Marshall, T. C.

    1966-01-01

    Semiautomatic device with a four-terminal network tests quantities of components having biaxial leads. The four-terminal network permits the testing of components in different environments. This device is easily modified for completely automatic operation.

  8. Additive Manufacturing of Aerospace Propulsion Components

    Science.gov (United States)

    Misra, Ajay K.; Grady, Joseph E.; Carter, Robert

    2015-01-01

    The presentation will provide an overview of ongoing activities on additive manufacturing of aerospace propulsion components, which included rocket propulsion and gas turbine engines. Future opportunities on additive manufacturing of hybrid electric propulsion components will be discussed.

  9. Tengi Interfaces for Tracing between Heterogeneous Components

    DEFF Research Database (Denmark)

    Pfeiffer, Rolf-Helge; Wasowski, Andrzej

    2012-01-01

    for the definition of software components containing heterogeneous artifacts. Tengi interfaces link components containing different textual and visual software development artifacts ranging from high-level specification documents to low-level implementation documents. We formally define and implement Tengi...

  10. CoC Awards by Program Component

    Data.gov (United States)

    Department of Housing and Urban Development — CoC Awards by Program Component reports provide snapshots of award data broken down by eligible program component types for the year selected. The reports, which can...

  11. Magnetic field contribution to the last electron-photon scattering

    CERN Document Server

    Giovannini, Massimo

    2010-01-01

    When the cosmic microwave photons scatter electrons just prior to the decoupling of matter and radiation, magnetic fields do contribute to the Stokes matrix as well as to the scalar, vector and tensor components of the transport equations for the brightness perturbations. The magnetized electron-photon scattering is hereby discussed in general terms by including, for the first time, the contribution of magnetic fields with arbitrary direction and in the presence of the scalar, vector and tensor modes of the geometry. The propagation of relic vectors and relic gravitons is discussed for a varying magnetic field orientation and for different photon directions. The source terms of the transport equations in the presence of the relativistic fluctuations of the geometry are also explicitly averaged over the magnetic field orientations and the problem of a consistent account of the small-scale and large-scale magnetic field is briefly outlined.

  12. Magnetic field contribution to the last electron-photon scattering

    Energy Technology Data Exchange (ETDEWEB)

    Giovannini, Massimo, E-mail: massimo.giovannini@cern.c [Department of Physics, Theory Division, CERN, 1211 Geneva 23 (Switzerland); INFN, Section of Milan-Bicocca, 20126 Milan (Italy)

    2010-11-21

    When the cosmic microwave photons scatter electrons just prior to the decoupling of matter and radiation, magnetic fields do contribute to the Stokes matrix as well as to the scalar, vector and tensor components of the transport equations for the brightness perturbations. The magnetized electron-photon scattering is hereby discussed in general terms by including, for the first time, the contribution of magnetic fields with arbitrary direction and in the presence of the scalar, vector and tensor modes of the geometry. The propagation of relic vectors and relic gravitons is discussed for a varying magnetic field orientation and for different photon directions. The source terms of the transport equations in the presence of the relativistic fluctuations of the geometry are also explicitly averaged over the magnetic field orientations and the problem of a consistent account of the small-scale and large-scale magnetic field is briefly outlined.

  13. Magnetic field contribution to the last electron-photon scattering

    Science.gov (United States)

    Giovannini, Massimo

    2010-11-01

    When the cosmic microwave photons scatter electrons just prior to the decoupling of matter and radiation, magnetic fields do contribute to the Stokes matrix as well as to the scalar, vector and tensor components of the transport equations for the brightness perturbations. The magnetized electron-photon scattering is hereby discussed in general terms by including, for the first time, the contribution of magnetic fields with arbitrary direction and in the presence of the scalar, vector and tensor modes of the geometry. The propagation of relic vectors and relic gravitons is discussed for a varying magnetic field orientation and for different photon directions. The source terms of the transport equations in the presence of the relativistic fluctuations of the geometry are also explicitly averaged over the magnetic field orientations and the problem of a consistent account of the small-scale and large-scale magnetic field is briefly outlined.

  14. The nursing contribution to nutritional care in cancer cachexia.

    Science.gov (United States)

    Hopkinson, Jane B

    2015-11-01

    Cancer cachexia is a complex syndrome. Its defining feature is involuntary weight loss, which arises, in part, because of muscle atrophy and is accompanied by functional decline. International expert consensus recommends that nutritional support and counselling is a component of multimodal therapy for cancer cachexia, as poor nutritional intake can contribute to progression of the syndrome. The present paper focuses on what is presently known about the nursing contribution to nutritional care in cancer cachexia. There is potential for nurses to play an important role. However, obstacles to this include lack of a robust evidence base to support their nutritional care practices and unmet need for education about nutrition in cancer. The nursing role's boundaries and the outcomes of nurse-delivered nutritional care in cancer cachexia are both uncertain and should be investigated.

  15. Contribution of pertussis toxin to the pathogenesis of pertussis disease.

    Science.gov (United States)

    Carbonetti, Nicholas H

    2015-11-01

    Pertussis toxin (PT) is a multisubunit protein toxin secreted by Bordetella pertussis, the bacterial agent of the disease pertussis or whooping cough. PT in detoxified form is a component of all licensed acellular pertussis vaccines, since it is considered to be an important virulence factor for this pathogen. PT inhibits G protein-coupled receptor signaling through Gi proteins in mammalian cells, an activity that has led to its widespread use as a cell biology tool. But how does this activity of PT contribute to pertussis, including the severe respiratory symptoms of this disease? In this minireview, the contribution of PT to the pathogenesis of pertussis disease will be considered based on evidence from both human infections and animal model studies. Although definitive proof of the role of PT in humans is lacking, substantial evidence supports the idea that PT is a major contributor to pertussis pathology, including the severe respiratory symptoms associated with this disease.

  16. Group Contribution Based Process Flowsheet Synthesis, Design and Modelling

    DEFF Research Database (Denmark)

    d'Anterroches, Loïc; Gani, Rafiqul

    2005-01-01

    In a group contribution method for pure component property prediction, a molecule is described as a set of groups linked together to form a molecular structure. In the same way, for flowsheet "property" prediction, a flowsheet can be described as a set of process-groups linked together to represent...... provides a contribution to the "property" of the flowsheet, which can be performance in terms of energy consumption, thereby allowing a flowsheet "property" to be calculated, once it is described by the groups. Another feature of this approach is that the process-group attachments provide automatically...... the flowsheet structure. Just as a functional group is a collection of atoms, a process-group is a collection of operations forming an "unit" operation or a set of "unit" operations. The link between the process-groups are the streams similar to the bonds that are attachments to atoms/groups. Each process-group...

  17. Electric Vehicle based on standard industrial components

    OpenAIRE

    Fernández Ramos, José; Aghili Kathir, Foroohar

    2013-01-01

    The aim of this paper is to presents the complete design of an electric vehicle by using standard industrial components as VRLA batteries, AC induction motors and standard frequency converters. In comparison with dedicated components, the use of standard components has the following advantages: higher reliability, low price, broad range of products and suppliers, and high availability and technological independence. Besides this, we show that these components allow to ...

  18. Indexing Mount For Rotation Of Optical Component

    Science.gov (United States)

    Reichle, Donald J., Jr.; Barnes, Norman P.

    1993-01-01

    Indexing mount for polarizer, wave plate, birefringent plate, or other optical component facilitates rotation of component to one or more preset angles. Includes hexagonal nut holding polarizer or other optical component. Ball bearing loaded by screw engages notch on cylindrical extension of nut engaging bracket. Time-consuming and tedious angular adjustment unnecessary: component turned quickly and easily, by hand or by use of wrench, to preset angular positions maintained by simple ball-detent mechanism.

  19. Direct UV-written integrated optical components

    DEFF Research Database (Denmark)

    Svalgaard, Mikael

    2004-01-01

    Direct UV writing is an emerging method for flexible, low cost fabrication of integrated optical waveguides and components. The performance of UV written components can be similar to that achieved with more elaborate fabrication techniques.......Direct UV writing is an emerging method for flexible, low cost fabrication of integrated optical waveguides and components. The performance of UV written components can be similar to that achieved with more elaborate fabrication techniques....

  20. The infrared excess of cool giant stars - A chromospheric contribution

    Science.gov (United States)

    Lambert, D. L.; Snell, R. L.

    1975-01-01

    The idea that the infrared excesses of evolved M stars may contain a contribution from a chromosphere is explored using alpha Ori and W Hya as test cases. The spectrum of alpha Ori between 8 and 30 millimicrons can be interpreted satisfactorily in terms of three components: a photosphere, a silicate dust cloud, and a cool chromosphere (temperature about 5000 K), which is optically thick at 14 millimicrons. A similar modelling for W Hya suggests a hotter chromosphere (temperature about 8000 K), with unit optical depth at 30 millimicrons. Some consequences of these chromospheres are briefly discussed.

  1. 21 CFR 890.3920 - Wheelchair component.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Wheelchair component. 890.3920 Section 890.3920...) MEDICAL DEVICES PHYSICAL MEDICINE DEVICES Physical Medicine Prosthetic Devices § 890.3920 Wheelchair component. (a) Identification. A wheelchair component is a device intended for medical purposes that...

  2. Blind Detection of Independent Dynamic Components

    DEFF Research Database (Denmark)

    Hansen, Lars Kai; Larsen, Jan; Kolenda, Thomas

    2001-01-01

    In certain applications of independent component analysis (ICA) it is of interest to test hypotheses concerning the number of components or simply to test whether a given number of components is significant relative to a "white noise" null hypothesis. We estimate probabilities of such competing h...

  3. An Architectural Model for Component Groupware

    NARCIS (Netherlands)

    Farias, de Clever R.G.; Goncalves, Carlos E.; Rosatelli, Marta C.; Ferreira Pires, Luis; Sinderen, van Marten; Fuks, Hugo; Lukosch, Stephan; Salgado, Ana Carolina

    2005-01-01

    This paper proposes an architectural model to facilitate the design of component-based groupware systems. This architectural model has been defined based on (1) three pre-defined component types, (2) a refinement strategy that relies on these component types, (3) the identification of layers of coll

  4. Manufacturing complex silica aerogel target components

    Energy Technology Data Exchange (ETDEWEB)

    Defriend Obrey, Kimberly Ann [Los Alamos National Laboratory; Day, Robert D [Los Alamos National Laboratory; Espinoza, Brent F [Los Alamos National Laboratory; Hatch, Doug [Los Alamos National Laboratory; Patterson, Brian M [Los Alamos National Laboratory; Feng, Shihai [Los Alamos National Laboratory

    2008-01-01

    Aerogel is a material used in numerous components in High Energy Density Physics targets. In the past these components were molded into the proper shapes. Artifacts left in the parts from the molding process, such as contour irregularities from shrinkage and density gradients caused by the skin, have caused LANL to pursue machining as a way to make the components.

  5. Two component theory and electron magnetic moment

    NARCIS (Netherlands)

    Veltman, M.J.G.

    1998-01-01

    The two-component formulation of quantum electrodynamics is studied. The relation with the usual Dirac formulation is exhibited, and the Feynman rules for the two-component form of the theory are presented in terms of familiar objects. The transformation from the Dirac theory to the two-component th

  6. Unmodelled magnetic contributions in satellite-based models

    Science.gov (United States)

    Tozzi, Roberta; Mandea, Mioara; De Michelis, Paola

    2016-06-01

    A complex system of electric currents flowing in the ionosphere and magnetosphere originates from the interaction of the solar wind and the Interplanetary Magnetic Field (IMF) with the Earth's magnetic field. These electric currents generate magnetic fields contributing themselves to those measured by both ground observatories and satellites. Here, low-resolution (1 Hz) magnetic vector data recorded between 1 March 2014 and 31 May 2015 by the recently launched Swarm constellation are considered. The core and crustal magnetic fields and part of that originating in the magnetosphere are removed from Swarm measurements using CHAOS-5 model. Low- and mid-latitude residuals of the geomagnetic field representing the ionospheric and the unmodelled magnetospheric contributions are investigated, in the Solar Magnetic frame, according to the polarity of IMF B y (azimuthal) and B z (north-south) components and to different geomagnetic activity levels. The proposed approach makes it possible to investigate the features of unmodelled contributions due to the external sources of the geomagnetic field. Results show, on one side, the existence of a relation between the analysed residuals and IMF components B y and B z , possibly due to the long distance effect of high-latitude field-aligned currents. On the other side, they suggest the presence of a contribution due to the partial ring current that is activated during the main phase of geomagnetic storms. The perturbation observed on residuals is also compatible with the effect of the net field-aligned currents. Moreover, we have quantitatively estimated the effect of these current systems on computed residuals.

  7. NF-κB p65 repression by the sesquiterpene lactone, Helenalin, contributes to the induction of autophagy cell death

    Directory of Open Access Journals (Sweden)

    Lim Chuan

    2012-07-01

    Full Text Available Abstract Background Numerous studies have demonstrated that autophagy plays a vital role in maintaining cellular homeostasis. Interestingly, several anticancer agents were found to exert their anticancer effects by triggering autophagy. Emerging data suggest that autophagy represents a novel mechanism that can be exploited for therapeutic benefit. Pharmacologically active natural compounds such as those from marine, terrestrial plants and animals represent a promising resource for novel anticancer drugs. There are several prominent examples from the past proving the success of natural products and derivatives exhibiting anticancer activity. Helenalin, a sesquiterpene lactone has been demonstrated to have potent anti-inflammatory and antitumor activity. Albeit previous studies demonstrating helenalin’s multi modal action on cellular proliferative and apoptosis, the mechanisms underlying its action are largely unexplained. Methods To deduce the mechanistic action of helenalin, cancer cells were treated with the drug at various concentrations and time intervals. Using western blot, FACS analysis, overexpression and knockdown studies, cellular signaling pathways were interrogated focusing on apoptosis and autophagy markers. Results We show here that helenalin induces sub-G1 arrest, apoptosis, caspase cleavage and increases the levels of the autophagic markers. Suppression of caspase cleavage by the pan caspase inhibitor, Z-VAD-fmk, suppressed induction of LC3-B and Atg12 and reduced autophagic cell death, indicating caspase activity was essential for autophagic cell death induced by helenalin. Additionally, helenalin suppressed NF-κB p65 expression in a dose and time dependent manner. Exogenous overexpression of p65 was accompanied by reduced levels of cell death whereas siRNA mediated suppression led to augmented levels of caspase cleavage, autophagic cell death markers and increased cell death. Conclusions Taken together, these results show

  8. Method of using infrared radiation for assembling a first component with a second component

    Energy Technology Data Exchange (ETDEWEB)

    Sikka, V.K.; Whitson, B.G.; Blue, C.A.

    1999-12-14

    A method of assembling a first component for assembly with a second component involves a heating device which includes an enclosure having a cavity for inserting a first component. An array of infrared energy generators is disposed within the enclosure. At least a portion of the first component is inserted into the cavity, exposed to infrared energy and thereby heated to a temperature wherein the portion of the first component is sufficiently softened and/or expanded for assembly with a second component.

  9. Method of using infrared radiation for assembling a first component with a second component

    Energy Technology Data Exchange (ETDEWEB)

    Sikka, Vinod K. (Oak Ridge, TN); Whitson, Barry G. (Corryton, TN); Blue, Craig A. (Knoxville, TN)

    1999-01-01

    A method of assembling a first component for assembly with a second component involves a heating device which includes an enclosure having a cavity for inserting a first component. An array of infrared energy generators is disposed within the enclosure. At least a portion of the first component is inserted into the cavity, exposed to infrared energy and thereby heated to a temperature wherein the portion of the first component is sufficiently softened and/or expanded for assembly with a second component.

  10. Processing, testing and selecting blood components.

    Science.gov (United States)

    Jones, Alister; Heyes, Jennifer

    Transfusion of blood components can be an essential and lifesaving treatment for many patients. However, components must comply with a number of national requirements to ensure they are safe and fit for use. Transfusion of incorrect blood components can lead to mortality and morbidity in patients, which is why patient testing and blood selection are important. This second article in our five-part series on blood transfusion outlines the requirements for different blood components, the importance of the ABO and RhD blood group systems and the processes that ensure the correct blood component is issued to each patient.

  11. Principal component regression analysis with SPSS.

    Science.gov (United States)

    Liu, R X; Kuang, J; Gong, Q; Hou, X L

    2003-06-01

    The paper introduces all indices of multicollinearity diagnoses, the basic principle of principal component regression and determination of 'best' equation method. The paper uses an example to describe how to do principal component regression analysis with SPSS 10.0: including all calculating processes of the principal component regression and all operations of linear regression, factor analysis, descriptives, compute variable and bivariate correlations procedures in SPSS 10.0. The principal component regression analysis can be used to overcome disturbance of the multicollinearity. The simplified, speeded up and accurate statistical effect is reached through the principal component regression analysis with SPSS.

  12. FUSE Spectroscopy of the Accreting Hot Components in Symbiotic Variables

    Science.gov (United States)

    Sion, Edward M.; Godon, Patrick; Mikolajewska, Joanna; Sabra, Bassem; Kolobow, Craig

    2017-04-01

    We have conducted a spectroscopic analysis of the far-ultraviolet archival spectra of four symbiotic variables, EG And, AE Ara, CQ Dra, and RW Hya. RW Hya and EG And have never had a recorded outburst, while CQ Dra and AE Ara have outburst histories. We analyze these systems while they are in quiescence in order to help reveal the physical properties of their hot components via comparisons of the observations with optically thick accretion disk models and non-LTE model white dwarf photospheres. We have extended the wavelength coverage down to the Lyman limit with Far Ultraviolet Spectroscopic Explorer (FUSE) spectra. We find that the hot component in RW Hya is a low-mass white dwarf with a surface temperature of 160,000 K. We reexamine whether or not the symbiotic system CQ Dra is a triple system with a red giant transferring matter to a hot component made up of a cataclysmic variable in which the white dwarf has a surface temperature as low as ∼20,000 K. The very small size of the hot component contributing to the shortest wavelengths of the FUSE spectrum of CQ Dra agrees with an optically thick and geometrically thin (∼4% of the WD surface) hot (∼120,000 K) boundary layer. Our analysis of EG And reveals that its hot component is a hot, bare, low-mass white dwarf with a surface temperature of 80,000–95,000 K, with a surface gravity {log}(g)=7.5. For AE Ara, we also find that a low-gravity ({log}(g)∼ 6), hot (T∼ {{130,000}} K) WD accounts for the hot component.

  13. Diagnosis Aerobic Component of Operational Preparedness Skill Players

    Directory of Open Access Journals (Sweden)

    Vasylyuk Vasyl

    2017-01-01

    Full Text Available Considerable importance for the control system, selection and orientation of the players on the stage long-term preparation plays a selection of effective methods of testing the various components of functional fitness athlete for timely, objective information about the players. The use of reliable scientific methods of effective monitoring of the athlete contributes to the further improvement of skills, increase athletic achievements. The purpose of this article is to describe and summarize modern methods of diagnosis and development of aerobic component of operational preparedness players qualifications. This article describes methods that actively and effectively used in leading European football teams. Specifically Yo-Yo test, test Shuttle (beep-test, Bangsbo test, test Hoff-Helgerud, test Conconi, Wingate-test. These tests have a high level of reliability and security mechanisms for assessing aerobic power players.

  14. Budding Transition of Asymmetric Two-component Lipid Domains

    CERN Document Server

    Wolff, Jean; Andelman, David

    2016-01-01

    We propose a model that accounts for the budding transition of asymmetric two-component lipid domains, where the two monolayers (leaflets) have different average compositions controlled by independent chemical potentials. Assuming a coupling between the local curvature and local lipid composition in each of the leaflets, we discuss the morphology and thermodynamic behavior of asymmetric lipid domains. The membrane free-energy contains three contributions: the bending energy, the line tension, and a Landau free-energy for a lateral phase separation. Within a mean-field treatment, we obtain various phase diagrams containing fully budded, dimpled, and flat states as a function of the two leaflet compositions. The global phase behavior is analyzed, and depending on system parameters, the phase diagrams include one-phase, two-phase and three-phase regions. In particular, we predict various phase coexistence regions between different morphologies of domains, which may be observed in multi-component membranes or ves...

  15. GRB-081029: A Step Towards Understanding Multiple Afterglow Components

    Science.gov (United States)

    Holland Stephen T.

    2010-01-01

    We present an analysis of the unusual optical light curve of the gamma-ray burst-081029 at a redshift of z = 3.8474. We combine X-ray and optical observations from (Swift) with optical and infrared data from REM to obtain a detailed data set extending from approx 10(exp 2)s to approx 10(exp 5)s after the BAT trigger, and from approx.10 keV to 16,000 AA. The X-ray afterglow showed a shallow initial decay followed by u rapid decay after about 18,000 s. The optical afterglow, however, shows an uncharecteristic rise at about 5000 s that has no corresponding feature in the X-ray light curve. The data are not consistent with a single-component jet. It is possible that there are multiple physical components contributing to the afterglow of GRB-081029.

  16. Polarized CMB recovery with sparse component separation

    CERN Document Server

    Bobin, Jerome; Starck, Jean-Luc

    2015-01-01

    The polarization modes of the cosmological microwave background are an invaluable source of information for cosmology, and a unique window to probe the energy scale of inflation. Extracting such information from microwave surveys requires disentangling between foreground emissions and the cosmological signal, which boils down to solving a component separation problem. Component separation techniques have been widely studied for the recovery of CMB temperature anisotropies but quite rarely for the polarization modes. In this case, most component separation techniques make use of second-order statistics to discriminate between the various components. More recent methods, which rather emphasize on the sparsity of the components in the wavelet domain, have been shown to provide low-foreground, full-sky estimate of the CMB temperature anisotropies. Building on sparsity, the present paper introduces a new component separation technique dubbed PolGMCA (Polarized Generalized Morphological Component Analysis), which r...

  17. The artifacts of component-based development

    CERN Document Server

    Qureshi, M Rizwan Jameel

    2012-01-01

    Component based development idea was floated in a conference name "Mass Produced Software Components" in 1968 [1]. Since then engineering and scientific libraries are developed to reuse the previously developed functions. This concept is now widely used in SW development as component based development (CBD). Component-based software engineering (CBSE) is used to develop/ assemble software from existing components [2]. Software developed using components is called component ware [3]. This paper presents different architectures of CBD such as ActiveX, common object request broker architecture (CORBA), remote method invocation (RMI) and simple object access protocol (SOAP). The overall objective of this paper is to support the practice of CBD by comparing its advantages and disadvantages. This paper also evaluates object oriented process model to adapt it for CBD.

  18. VIRTUAL ELECTRONIC COMPONENTS OF THE ELECTRONIC EQUIPMENT

    Directory of Open Access Journals (Sweden)

    E. Lazarevich

    2013-01-01

    Full Text Available The article is present new idea of the creation, developments and improvements of the electronic equipment of complex systems by means of the virtual electronic components. The idea of the virtual electronic components is a presentation and perception of the creation and developments of the equipment on two forming: real – in the manner of standard marketed block of the intellectual property and image – in the manner of virtual component. The real component in most cases slows the development of the electronic equipment. The imaginary component is the «locomotive» of development of the electronic equipment. The Imaginary component contains the scientific has brushed against developer. The scientific has brushed against developer reveals of itself in the manner of virtual component on the modern level of the design rates of microelectronics.

  19. Polynomial analysis of canopy spectra and biochemical component content inversion

    Institute of Scientific and Technical Information of China (English)

    YAN Chunyan; LIU Qiang; NIU Zheng; WANG Jihua; HUANG Wenjiang; LIU Liangyun

    2005-01-01

    A polynomial expression model was developed in this paper to describe directional canopy spectra, and the decomposition of the polynomial expression was used as a tool for retrieving biochemical component content from canopy multi-angle spectra. First, the basic formula of the polynomial expression was introduced and the physical meaning of its terms and coefficients was discussed. Based on this analysis, a complete polynomial expression model and its decomposition method were given. By decomposing the canopy spectra simulated with SAILH model, it shows that the polynomial expression can not only fit well the canopy spectra, but also show the contribution of every order scattering to the whole reflectance. Taking the first scattering coefficients a10 and a01 for example, the test results show that the polynomial coefficients reflect very well the hot spot phenomenon and the effects of viewing angles, LAI and leaf inclination angle on canopy spectra. By coupling the polynomial expression with leaf model PROSPECT, a canopy biochemical component content inversion model was given. In the simulated test, the canopy multi-angle spectra were simulated by two different models, SAILH and 4-SCALE respectively, then the biochemical component content was retrieved by inverting the coupled polynomial expression + PROSPECT model. Results of the simulated test are promising, and when applying the algorithm to measured corn canopy multi-angle spectra, we also get relatively accurate chlorophyll content. It shows that the polynomial analysis provides a new method to get biochemical component content independent of any specific canopy model.

  20. Mapping UML Component Specifications to JEE Implementations

    Directory of Open Access Journals (Sweden)

    Jyhjong Lin

    2007-01-01

    Full Text Available Component-based Software Engineering (CbSE has become a well-accepted approach for developing complex software systems due to its significant advantages on composition and reuse. In practice, however, its use still requires the conjunction of a component specification method that describes how system requirements are satisfied in terms of software components. Such a component specification is then implemented in a variety of software component models (e.g., COM+, CORBA, EJB. To achieve this, a sound mapping from the specification to a designated component model is critical. In addition, for rapid advances on Internet technologies, software systems have gradually been architected as processing in distributed environments. Since a distributed environment involves often synchronous/asynchronous messages communicating among various processes, this paper focuses therefore on the mapping issue from a component specification to a component model that particularly takes into consideration of the communicating of synchronous/asynchronous messages. To illustrate, an on-line e-Learning curriculum order system is modeled for demonstrating the mapping idea. In completing the component specification, we adopt the well-known UML Components method, while in the component model we use the Enterprise Java Beans (EJB standard in that EJB is the core component model of the JEE (J2EE platform which supports well distributed operations/services. With such a practical mapping, software systems can be developed in a more effective way by specifying requirements in UML Components and implementing software components in EJB with the communicating of synchronous/asynchronous messages among various processes.