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Sample records for mediate random switching

  1. Phasevarions mediate random switching of gene expression in pathogenic Neisseria.

    PubMed

    Srikhanta, Yogitha N; Dowideit, Stefanie J; Edwards, Jennifer L; Falsetta, Megan L; Wu, Hsing-Ju; Harrison, Odile B; Fox, Kate L; Seib, Kate L; Maguire, Tina L; Wang, Andrew H-J; Maiden, Martin C; Grimmond, Sean M; Apicella, Michael A; Jennings, Michael P

    2009-04-01

    Many host-adapted bacterial pathogens contain DNA methyltransferases (mod genes) that are subject to phase-variable expression (high-frequency reversible ON/OFF switching of gene expression). In Haemophilus influenzae, the random switching of the modA gene controls expression of a phase-variable regulon of genes (a "phasevarion"), via differential methylation of the genome in the modA ON and OFF states. Phase-variable mod genes are also present in Neisseria meningitidis and Neisseria gonorrhoeae, suggesting that phasevarions may occur in these important human pathogens. Phylogenetic studies on phase-variable mod genes associated with type III restriction modification (R-M) systems revealed that these organisms have two distinct mod genes--modA and modB. There are also distinct alleles of modA (abundant: modA11, 12, 13; minor: modA4, 15, 18) and modB (modB1, 2). These alleles differ only in their DNA recognition domain. ModA11 was only found in N. meningitidis and modA13 only in N. gonorrhoeae. The recognition site for the modA13 methyltransferase in N. gonorrhoeae strain FA1090 was identified as 5'-AGAAA-3'. Mutant strains lacking the modA11, 12 or 13 genes were made in N. meningitidis and N. gonorrhoeae and their phenotype analyzed in comparison to a corresponding mod ON wild-type strain. Microarray analysis revealed that in all three modA alleles multiple genes were either upregulated or downregulated, some of which were virulence-associated. For example, in N. meningitidis MC58 (modA11), differentially expressed genes included those encoding the candidate vaccine antigens lactoferrin binding proteins A and B. Functional studies using N. gonorrhoeae FA1090 and the clinical isolate O1G1370 confirmed that modA13 ON and OFF strains have distinct phenotypes in antimicrobial resistance, in a primary human cervical epithelial cell model of infection, and in biofilm formation. This study, in conjunction with our previous work in H. influenzae, indicates that

  2. Correlated randomness and switching phenomena

    NASA Astrophysics Data System (ADS)

    Stanley, H. E.; Buldyrev, S. V.; Franzese, G.; Havlin, S.; Mallamace, F.; Kumar, P.; Plerou, V.; Preis, T.

    2010-08-01

    One challenge of biology, medicine, and economics is that the systems treated by these serious scientific disciplines have no perfect metronome in time and no perfect spatial architecture-crystalline or otherwise. Nonetheless, as if by magic, out of nothing but randomness one finds remarkably fine-tuned processes in time and remarkably fine-tuned structures in space. Further, many of these processes and structures have the remarkable feature of “switching” from one behavior to another as if by magic. The past century has, philosophically, been concerned with placing aside the human tendency to see the universe as a fine-tuned machine. Here we will address the challenge of uncovering how, through randomness (albeit, as we shall see, strongly correlated randomness), one can arrive at some of the many spatial and temporal patterns in biology, medicine, and economics and even begin to characterize the switching phenomena that enables a system to pass from one state to another. Inspired by principles developed by A. Nihat Berker and scores of other statistical physicists in recent years, we discuss some applications of correlated randomness to understand switching phenomena in various fields. Specifically, we present evidence from experiments and from computer simulations supporting the hypothesis that water’s anomalies are related to a switching point (which is not unlike the “tipping point” immortalized by Malcolm Gladwell), and that the bubbles in economic phenomena that occur on all scales are not “outliers” (another Gladwell immortalization). Though more speculative, we support the idea of disease as arising from some kind of yet-to-be-understood complex switching phenomenon, by discussing data on selected examples, including heart disease and Alzheimer disease.

  3. Subthalamic nucleus gamma oscillations mediate a switch from automatic to controlled processing: a study of random number generation in Parkinson's disease.

    PubMed

    Anzak, Anam; Gaynor, Louise; Beigi, Mazda; Foltynie, Thomas; Limousin, Patricia; Zrinzo, Ludvic; Brown, Peter; Jahanshahi, Marjan

    2013-01-01

    In paced random number generation (RNG) participants are asked to generate numbers between 1 and 9 in a random fashion, in synchrony with a pacing stimulus. Successful task performance can be achieved through control of the main biases known to exist in human RNG compared to a computer generated series: seriation, cycling through a set of available numbers, and repetition avoidance. A role in response inhibition and switching from automatic to controlled processing has previously been ascribed to the subthalamic nucleus (STN). We sought evidence of frequency-specific changes in STN oscillatory activity which could be directly related to use of such strategies during RNG. Local field potentials (LFPs) were recorded from depth electrodes implanted in the STN of 7 patients (14 sides) with Parkinson's disease (PD), when patients were on dopaminergic medication. Patients were instructed to (1) generate a series of 100 numbers between 1 and 9 in a random fashion, and (2) undertake a control serial counting task, both in synchrony with a 0.5 Hz pacing stimulus. Significant increases in LFP power (p ≤ 0.05) across a narrow gamma frequency band (45-60 Hz) during RNG, compared to the control counting task, were observed. Further, the number of 'repeated pairs' (a decline in which reflects repetition avoidance bias in human RNG) was positively correlated with these gamma increases. We therefore suggest that STN gamma activity is relevant for controlled processing, in particular the active selection and repetition of the same number on successive trials. These results are consistent with a frequency-specific role of the STN in executive processes such as suppression of habitual responses and 'switching-on' of more controlled processing strategies. Copyright © 2012 Elsevier Inc. All rights reserved.

  4. Instability in time-delayed switched systems induced by fast and random switching

    NASA Astrophysics Data System (ADS)

    Guo, Yao; Lin, Wei; Chen, Yuming; Wu, Jianhong

    2017-07-01

    In this paper, we consider a switched system comprising finitely or infinitely many subsystems described by linear time-delayed differential equations and a rule that orchestrates the system switching randomly among these subsystems, where the switching times are also randomly chosen. We first construct a counterintuitive example where even though all the time-delayed subsystems are exponentially stable, the behaviors of the randomly switched system change from stable dynamics to unstable dynamics with a decrease of the dwell time. Then by using the theories of stochastic processes and delay differential equations, we present a general result on when this fast and random switching induced instability should occur and we extend this to the case of nonlinear time-delayed switched systems as well.

  5. DNA-mediated excitonic upconversion FRET switching

    SciTech Connect

    Kellis, Donald L.; Rehn, Sarah M.; Cannon, Brittany L.; Davis, Paul H.; Graugnard, Elton; Lee, Jeunghoon; Yurke, Bernard; Knowlton, William B.

    2015-11-17

    Excitonics is a rapidly expanding field of nanophotonics in which the harvesting of photons, ensuing creation and transport of excitons via Förster resonant energy transfer (FRET), and subsequent charge separation or photon emission has led to the demonstration of excitonic wires, switches, Boolean logic and light harvesting antennas for many applications. FRET funnels excitons down an energy gradient resulting in energy loss with each step along the pathway. Conversely, excitonic energy up conversion via up conversion nanoparticles (UCNPs), although currently inefficient, serves as an energy ratchet to boost the exciton energy. Although FRET-based up conversion has been demonstrated, it suffers from low FRET efficiency and lacks the ability to modulate the FRET. We have engineered an up conversion FRET-based switch by combining lanthanide-doped UCNPs and fluorophores that demonstrates excitonic energy up conversion by nearly a factor of 2, an excited state donor to acceptor FRET efficiency of nearly 25%, and an acceptor fluorophore quantum efficiency that is close to unity. These findings offer a promising path for energy up conversion in nanophotonic applications including artificial light harvesting, excitonic circuits, photovoltaics, nanomedicine, and optoelectronics.

  6. DNA-mediated excitonic upconversion FRET switching

    DOE PAGES

    Kellis, Donald L.; Rehn, Sarah M.; Cannon, Brittany L.; ...

    2015-11-17

    Excitonics is a rapidly expanding field of nanophotonics in which the harvesting of photons, ensuing creation and transport of excitons via Förster resonant energy transfer (FRET), and subsequent charge separation or photon emission has led to the demonstration of excitonic wires, switches, Boolean logic and light harvesting antennas for many applications. FRET funnels excitons down an energy gradient resulting in energy loss with each step along the pathway. Conversely, excitonic energy up conversion via up conversion nanoparticles (UCNPs), although currently inefficient, serves as an energy ratchet to boost the exciton energy. Although FRET-based up conversion has been demonstrated, it suffersmore » from low FRET efficiency and lacks the ability to modulate the FRET. We have engineered an up conversion FRET-based switch by combining lanthanide-doped UCNPs and fluorophores that demonstrates excitonic energy up conversion by nearly a factor of 2, an excited state donor to acceptor FRET efficiency of nearly 25%, and an acceptor fluorophore quantum efficiency that is close to unity. These findings offer a promising path for energy up conversion in nanophotonic applications including artificial light harvesting, excitonic circuits, photovoltaics, nanomedicine, and optoelectronics.« less

  7. Effect of arousal increase in predictable and random task switching: evidence for the involvement of the anterior attentional network in random but not in predictable task switching.

    PubMed

    Solano Galvis, César Augusto; Tornay Mejías, Francisco; Gómez Milán, Emilio

    2010-11-01

    Switch cost does not disappear as more preparation time for the next task is allowed. Tornay and Milán showed that the residual cost is smaller when tasks switch randomly than when they alternate in predictable sequences. They proposed that the difference was due to control mechanisms (anterior attentional network) being activated in the random condition because of its overall difficulty. Besides, it has been shown that increasing arousal levels inhibits the anterior attentional network. Therefore, Tornay and Milán's account predicts that high arousal should result in switch cost for the random condition increasing to the levels of predictable switching. In this work, this prediction was tested by assessing the interaction between increased arousal and switch cost with both predictable and random-task switching. The results may help to solve the ongoing controversy about the causes of switch cost.

  8. Extracellular Adenosine Mediates a Systemic Metabolic Switch during Immune Response

    PubMed Central

    Bajgar, Adam; Kucerova, Katerina; Jonatova, Lucie; Tomcala, Ales; Schneedorferova, Ivana; Okrouhlik, Jan; Dolezal, Tomas

    2015-01-01

    Immune defense is energetically costly, and thus an effective response requires metabolic adaptation of the organism to reallocate energy from storage, growth, and development towards the immune system. We employ the natural infection of Drosophila with a parasitoid wasp to study energy regulation during immune response. To combat the invasion, the host must produce specialized immune cells (lamellocytes) that destroy the parasitoid egg. We show that a significant portion of nutrients are allocated to differentiating lamellocytes when they would otherwise be used for development. This systemic metabolic switch is mediated by extracellular adenosine released from immune cells. The switch is crucial for an effective immune response. Preventing adenosine transport from immune cells or blocking adenosine receptor precludes the metabolic switch and the deceleration of development, dramatically reducing host resistance. Adenosine thus serves as a signal that the “selfish” immune cells send during infection to secure more energy at the expense of other tissues. PMID:25915062

  9. Field assisted spin switching in magnetic random access memory

    NASA Astrophysics Data System (ADS)

    Jeong, W. C.; Park, J. H.; Oh, J. H.; Koh, G. H.; Jeong, G. T.; Jeong, H. S.; Kim, Kinam

    2006-04-01

    A switching method called by field assisted spin switching has been investigated. A field assisted spin switching consists of a metal line induced magnetic field and a spin switching through a magnetic tunnel junction. It is a variation of a current induced switching and assisted by the magnetic field induced by the current-carrying metal line. Various current paths have been tested to investigate how and how much the spin switching contributes to the overall switching and the results will be explained. A computer simulation has been complemented to measure the degree of the thermal effect in the switching.

  10. Rosuvastatin vs. protease inhibitor switching for hypercholesterolaemia: a randomized trial.

    PubMed

    Lee, F J; Monteiro, P; Baker, D; Bloch, M; Roth, N; Finlayson, R; Moore, R; Hoy, J; Martinez, E; Carr, A

    2016-09-01

    The aim of the study was to compare the efficacy and safety of rosuvastatin initiation with those of switching of ritonavir-boosted protease inhibitors (PI/rs) in HIV-1-infected adults with hypercholesterolaemia and increased cardiovascular risk scores. In this open-label, multicentre study, HIV-1-infected adults on PI/r-based therapy with viral load < 50 HIV-1 RNA copies/mL, fasting total cholesterol ≥ 5.5 mmol/L (both for ≥ 6 months) and elevated cardiovascular risk (Framingham score ≥ 8% or diabetes or family history), and not on lipid-lowering therapy, were randomized to open-label rosuvastatin 10 mg/day or to PI/r switching, both with standardized diet/exercise advice. The primary endpoint was change in total cholesterol at week 12 (intention to treat). There were 43 participants (23 on rosuvastatin). Baseline characteristics were: mean [± standard deviation (SD)] age 55 (8.5) years, 42 (98%) male, 41 (95%) white race, and mean (± SD) total cholesterol 6.2 (1.2) mmol/L. At enrolment, PI/rs were lopinavir/ritonavir (n = 22; 51%), atazanavir/ritonavir (n = 12; 28%) and darunavir/ritonavir (n = 9; 21%). The commonest PI/r substitutes were raltegravir (n = 9; 45%) and rilpivirine (n = 4; 20%). All participants were adherent through to week 12. Rosuvastatin yielded greater declines than PI/r switching in total (- 21.4% vs. - 8.7%, respectively; P = 0.003) and low-density lipoprotein (- 29.9% vs. - 1.0%, respectively; P < 0.001) cholesterol, but smaller declines in very low-density lipoprotein cholesterol and triglycerides (P < 0.01). Cholesterol lowering was greater in participants on atazanavir/ritonavir or once-daily darunavir/ritonavir (vs. lopinavir/ritonavir). More study drug-related adverse events (mostly grade 1 nausea/diarrhoea; 10 vs. one, respectively; P = 0.001) occurred with PI/r switching than with rosuvastatin. In adults receiving a PI/r, rosuvastatin 10 mg/day for 12 weeks yielded larger decreases in total and low-density lipoprotein

  11. Interfacial chemical bonding-mediated ionic resistive switching.

    PubMed

    Moon, Hyeongjoo; Zade, Vishal; Kang, Hung-Sen; Han, Jin-Woo; Lee, Eunseok; Hwang, Cheol Seong; Lee, Min Hwan

    2017-04-28

    In this paper, we present a unique resistive switching (RS) mechanism study of Pt/TiO2/Pt cell, one of the most widely studied RS system, by focusing on the role of interfacial bonding at the active TiO2-Pt interface, as opposed to a physico-chemical change within the RS film. This study was enabled by the use of a non-conventional scanning probe-based setup. The nanoscale cell is formed by bringing a Pt/TiO2-coated atomic force microscope tip into contact with a flat substrate coated with Pt. The study reveals that electrical resistance and interfacial bonding status are highly coupled together. An oxygen-mediated chemical bonding at the active interface between TiO2 and Pt is a necessary condition for a non-polar low-resistance state, and a reset switching process disconnects the chemical bonding. Bipolar switching mode did not involve the chemical bonding. The nature of chemical bonding at the TiO2-metal interface is further studied by density functional theory calculations.

  12. Switch junction sequences in PMS2-deficient mice reveal a microhomology-mediated mechanism of Ig class switch recombination

    PubMed Central

    Ehrenstein, Michael R.; Rada, Cristina; Jones, Anne-Marie; Milstein, César; Neuberger, Michael S.

    2001-01-01

    Isotype switching involves a region-specific, nonhomologous recombinational deletion that has been suggested to occur by nonhomologous joining of broken DNA ends. Here, we find increased donor/acceptor homology at switch junctions from PMS2-deficient mice and propose that class switching can occur by microhomology-mediated end-joining. Interestingly, although isotype switching and somatic hypermutation show many parallels, we confirm that PMS2 deficiency has no major effect on the pattern of nucleotide substitutions generated during somatic hypermutation. This finding is in contrast to MSH2 deficiency. With MSH2, the altered pattern of switch recombination and hypermutation suggests parallels in the mechanics of the two processes, whereas the fact that PMS2 deficiency affects only switch recombination may reflect differences in the pathways of break resolution. PMID:11717399

  13. Towards developing a compact model for magnetization switching in straintronics magnetic random access memory devices

    NASA Astrophysics Data System (ADS)

    Barangi, Mahmood; Erementchouk, Mikhail; Mazumder, Pinaki

    2016-08-01

    Strain-mediated magnetization switching in a magnetic tunneling junction (MTJ) by exploiting a combination of piezoelectricity and magnetostriction has been proposed as an energy efficient alternative to spin transfer torque (STT) and field induced magnetization switching methods in MTJ-based magnetic random access memories (MRAM). Theoretical studies have shown the inherent advantages of strain-assisted switching, and the dynamic response of the magnetization has been modeled using the Landau-Lifshitz-Gilbert (LLG) equation. However, an attempt to use LLG for simulating dynamics of individual elements in large-scale simulations of multi-megabyte straintronics MRAM leads to extremely time-consuming calculations. Hence, a compact analytical solution, predicting the flipping delay of the magnetization vector in the nanomagnet under stress, combined with a liberal approximation of the LLG dynamics in the straintronics MTJ, can lead to a simplified model of the device suited for fast large-scale simulations of multi-megabyte straintronics MRAMs. In this work, a tensor-based approach is developed to study the dynamic behavior of the stressed nanomagnet. First, using the developed method, the effect of stress on the switching behavior of the magnetization is investigated to realize the margins between the underdamped and overdamped regimes. The latter helps the designer realize the oscillatory behavior of the magnetization when settling along the minor axis, and the dependency of oscillations on the stress level and the damping factor. Next, a theoretical model to predict the flipping delay of the magnetization vector is developed and tested against LLG-based numerical simulations to confirm the accuracy of findings. Lastly, the obtained delay is incorporated into the approximate solutions of the LLG dynamics, in order to create a compact model to liberally and quickly simulate the magnetization dynamics of the MTJ under stress. Using the developed delay equation, the

  14. Towards developing a compact model for magnetization switching in straintronics magnetic random access memory devices

    SciTech Connect

    Barangi, Mahmood Erementchouk, Mikhail; Mazumder, Pinaki

    2016-08-21

    Strain-mediated magnetization switching in a magnetic tunneling junction (MTJ) by exploiting a combination of piezoelectricity and magnetostriction has been proposed as an energy efficient alternative to spin transfer torque (STT) and field induced magnetization switching methods in MTJ-based magnetic random access memories (MRAM). Theoretical studies have shown the inherent advantages of strain-assisted switching, and the dynamic response of the magnetization has been modeled using the Landau-Lifshitz-Gilbert (LLG) equation. However, an attempt to use LLG for simulating dynamics of individual elements in large-scale simulations of multi-megabyte straintronics MRAM leads to extremely time-consuming calculations. Hence, a compact analytical solution, predicting the flipping delay of the magnetization vector in the nanomagnet under stress, combined with a liberal approximation of the LLG dynamics in the straintronics MTJ, can lead to a simplified model of the device suited for fast large-scale simulations of multi-megabyte straintronics MRAMs. In this work, a tensor-based approach is developed to study the dynamic behavior of the stressed nanomagnet. First, using the developed method, the effect of stress on the switching behavior of the magnetization is investigated to realize the margins between the underdamped and overdamped regimes. The latter helps the designer realize the oscillatory behavior of the magnetization when settling along the minor axis, and the dependency of oscillations on the stress level and the damping factor. Next, a theoretical model to predict the flipping delay of the magnetization vector is developed and tested against LLG-based numerical simulations to confirm the accuracy of findings. Lastly, the obtained delay is incorporated into the approximate solutions of the LLG dynamics, in order to create a compact model to liberally and quickly simulate the magnetization dynamics of the MTJ under stress. Using the developed delay equation, the

  15. Interpreting Instructional Cues in Task Switching Procedures: The Role of Mediator Retrieval

    ERIC Educational Resources Information Center

    Logan, Gordon D.; Schneider, Darryl W.

    2006-01-01

    In 3 experiments the role of mediators in task switching with transparent and nontransparent cues was examined. Subjects switched between magnitude (greater or less than 5) and parity (odd or even) judgments of single digits. A cue-target congruency effect indicated mediator use: subjects responded faster to congruent cue-target combinations…

  16. Interpreting Instructional Cues in Task Switching Procedures: The Role of Mediator Retrieval

    ERIC Educational Resources Information Center

    Logan, Gordon D.; Schneider, Darryl W.

    2006-01-01

    In 3 experiments the role of mediators in task switching with transparent and nontransparent cues was examined. Subjects switched between magnitude (greater or less than 5) and parity (odd or even) judgments of single digits. A cue-target congruency effect indicated mediator use: subjects responded faster to congruent cue-target combinations…

  17. A more complete task-set reconfiguration in random than in predictable task switch.

    PubMed

    Tornay, F J; Milán, E G

    2001-08-01

    Three experiments are presented that compare the cost found when switching from one task to another in two different conditions. In one of them, the tasks switch in predictable sequences. In the other condition, the tasks alternate at random. A smaller time cost is found in the random-switch condition when enough preparation time is allowed. Such an effect is due to the random-switch cost continuing to decrease with preparation time after the predictable-switch cost has reached an asymptote. Although the relationship between number of repetitions of one task and time cost is different in the random- and the predictable-switch conditions, only the latter shows the presence of an "exogenous" component of cost. The implications of this finding are discussed in relationship with the usual distinction between an endogenous component of switch cost that is affected by preparation time and another exogenous, residual component (e.g., Rogers & Monsell, 1995). It is proposed that a different kind of task-set preparation is at work when tasks alternate at random.

  18. Recovery of failed resistive switching random access memory devices by a low-temperature supercritical treatment

    NASA Astrophysics Data System (ADS)

    Du, Xiaoqin; Wu, Xiaojing; Chang, Ting-Chang; Chang, Kuan-Chang; Pan, Chih-Hung; Wu, Cheng-Hsien; Lin, Yu-Shuo; Chen, Po-Hsun; Zhang, Shengdong; Sze, Simon M.

    2017-06-01

    The successful recovery of resistive switching random access memory (RRAM) devices that have undergone switching failure is achieved by introducing a low-temperature supercritical-fluid process that passivates the switching layer. These failed RRAM devices, which are incapable of switching between high- and low-resistance states, were treated with supercritical carbon dioxide with pure water at 120 °C for 1 h. After the treatment, the devices became operational again and showed excellent current-voltage (I-V) characteristics and reliability as before. On the basis of the current conduction mechanism fitting results, we propose a model to explain the phenomenon.

  19. TiO2 thin film based transparent flexible resistive switching random access memory

    NASA Astrophysics Data System (ADS)

    Pham, Kim Ngoc; Dung Hoang, Van; Tran, Cao Vinh; Thang Phan, Bach

    2016-03-01

    In our work we have fabricated TiO2 based resistive switching devices both on transparent substrates (ITO, IGZO/glass) and transparent flexible substrate (ITO/PET). All devices demonstrate the reproducibility of forming free bipolar resistive switching with high transparency in the visible light range (∼80% at the wavelength of 550 nm). Particularly, transparent and flexible device exhibits stable resistive switching performance at the initial state (flat) and even after bending state up to 500 times with curvature radius of 10% compared to flat state. The achieved characteristics of resistive switching of TiO2 thin films seem to be promising for transparent flexible random access memory.

  20. Regulation of a pulsed random fiber laser in the Q-switched regime

    NASA Astrophysics Data System (ADS)

    Zeng, X. P.; Zhang, W. L.; Ma, R.; Yang, Z. J.; Zeng, X.; Dong, X.; Rao, Y. J.

    2016-11-01

    A random fiber laser with regulated Q-switched pulses has been proposed and realized through a half-open cavity, which is formed between a compound fiber-based optic ring resonator (ORR) and a segment of 500 m dispersion compensation fiber (DCF). The compound fiber-based ORR provides frequency filtered feedback, which together with Brillouin scattering of the DCF forms a Q-switched mechanism. As a result, Q-switched pulses are generated randomly. Nevertheless, each Q-switched event typically consists of several ordered sub-pulses with the same pulse interval thanks to resonant interferences of the compound fiber-based ORR. Compared with former reports, the shape and the interval of pulses in each Q-switch event are regulated greatly.

  1. Microstructural transitions in resistive random access memory composed of molybdenum oxide with copper during switching cycles.

    PubMed

    Arita, Masashi; Ohno, Yuuki; Murakami, Yosuke; Takamizawa, Keisuke; Tsurumaki-Fukuchi, Atsushi; Takahashi, Yasuo

    2016-08-21

    The switching operation of a Cu/MoOx/TiN resistive random access memory (ReRAM) device was investigated using in situ transmission electron microscopy (TEM), where the TiN surface was slightly oxidized (ox-TiN). The relationship between the switching properties and the dynamics of the ReRAM microstructure was confirmed experimentally. The growth and/or shrinkage of the conductive filament (CF) can be classified into two set modes and two reset modes. These switching modes depend on the device's switching history, factors such as the amount of Cu inclusions in the MoOx layer and the CF geometry. High currents are needed to produce an observable change in the CF. However, sharp and stable switching behaviour can be achieved without requiring such a major change. The local region around the CF is thought to contribute to the ReRAM switching process.

  2. Microstructural transitions in resistive random access memory composed of molybdenum oxide with copper during switching cycles

    NASA Astrophysics Data System (ADS)

    Arita, Masashi; Ohno, Yuuki; Murakami, Yosuke; Takamizawa, Keisuke; Tsurumaki-Fukuchi, Atsushi; Takahashi, Yasuo

    2016-08-01

    The switching operation of a Cu/MoOx/TiN resistive random access memory (ReRAM) device was investigated using in situ transmission electron microscopy (TEM), where the TiN surface was slightly oxidized (ox-TiN). The relationship between the switching properties and the dynamics of the ReRAM microstructure was confirmed experimentally. The growth and/or shrinkage of the conductive filament (CF) can be classified into two set modes and two reset modes. These switching modes depend on the device's switching history, factors such as the amount of Cu inclusions in the MoOx layer and the CF geometry. High currents are needed to produce an observable change in the CF. However, sharp and stable switching behaviour can be achieved without requiring such a major change. The local region around the CF is thought to contribute to the ReRAM switching process.The switching operation of a Cu/MoOx/TiN resistive random access memory (ReRAM) device was investigated using in situ transmission electron microscopy (TEM), where the TiN surface was slightly oxidized (ox-TiN). The relationship between the switching properties and the dynamics of the ReRAM microstructure was confirmed experimentally. The growth and/or shrinkage of the conductive filament (CF) can be classified into two set modes and two reset modes. These switching modes depend on the device's switching history, factors such as the amount of Cu inclusions in the MoOx layer and the CF geometry. High currents are needed to produce an observable change in the CF. However, sharp and stable switching behaviour can be achieved without requiring such a major change. The local region around the CF is thought to contribute to the ReRAM switching process. Electronic supplementary information (ESI) available. See DOI: 10.1039/c6nr02602h

  3. Bile acid profiles over 5 years after gastric bypass and duodenal switch: results from a randomized clinical trial.

    PubMed

    Risstad, Hilde; Kristinsson, Jon A; Fagerland, Morten W; le Roux, Carel W; Birkeland, Kåre I; Gulseth, Hanne L; Thorsby, Per M; Vincent, Royce P; Engström, My; Olbers, Torsten; Mala, Tom

    2017-05-25

    Bile acids have been proposed as key mediators of the metabolic effects after bariatric surgery. Currently no reports on bile acid profiles after duodenal switch exist, and long-term data after gastric bypass are lacking. To investigate bile acid profiles up to 5 years after Roux-en-Y gastric bypass and biliopancreatic diversion with duodenal switch and to explore the relationship among bile acids and weight loss, lipid profile, and glucose metabolism. Two Scandinavian University Hospitals. We present data from a randomized clinical trial of 60 patients with body mass index 50-60 kg/m(2) operated with gastric bypass or duodenal switch. Repeated measurements of total and individual bile acids from fasting serum during 5 years after surgery were performed. Mean concentrations of total bile acids increased from 2.3 µmol/L (95% confidence interval [CI], -.1 to 4.7) at baseline to 5.9 µmol/L (3.5-8.3) 5 years after gastric bypass and from 1.0 µmol/L (95% CI, -1.4 to 3.5) to 9.5 µmol/L (95% CI, 7.1-11.9) after duodenal switch; mean between-group difference was -4.8 µmol/L (95% CI, -9.3 to -.3), P = .036. Mean concentrations of primary bile acids increased more after duodenal switch, whereas secondary bile acids increased proportionally across the groups. Higher levels of total bile acids at 5 years were associated with lower body mass index, greater weight loss, and lower total cholesterol. Total bile acid concentrations increased substantially over 5 years after both gastric bypass and duodenal switch, with greater increases in total and primary bile acids after duodenal switch. (Surg Obes Relat Dis 2017;0:000-000.) © 2017 American Society for Metabolic and Bariatric Surgery. All rights reserved. Copyright © 2017 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.

  4. Transcription mediated insulation and interference direct gene cluster expression switches

    PubMed Central

    Nguyen, Tania; Brown, David; Murray, Struan C; Haenni, Simon; Halstead, James M; O'Connor, Leigh; Shipkovenska, Gergana; Steinmetz, Lars M; Mellor, Jane

    2014-01-01

    In yeast, many tandemly arranged genes show peak expression in different phases of the metabolic cycle (YMC) or in different carbon sources, indicative of regulation by a bi-modal switch, but it is not clear how these switches are controlled. Using native elongating transcript analysis (NET-seq), we show that transcription itself is a component of bi-modal switches, facilitating reciprocal expression in gene clusters. HMS2, encoding a growth-regulated transcription factor, switches between sense- or antisense-dominant states that also coordinate up- and down-regulation of transcription at neighbouring genes. Engineering HMS2 reveals alternative mono-, di- or tri-cistronic and antisense transcription units (TUs), using different promoter and terminator combinations, that underlie state-switching. Promoters or terminators are excluded from functional TUs by read-through transcriptional interference, while antisense TUs insulate downstream genes from interference. We propose that the balance of transcriptional insulation and interference at gene clusters facilitates gene expression switches during intracellular and extracellular environmental change. DOI: http://dx.doi.org/10.7554/eLife.03635.001 PMID:25407679

  5. Transcription mediated insulation and interference direct gene cluster expression switches.

    PubMed

    Nguyen, Tania; Fischl, Harry; Howe, Françoise S; Woloszczuk, Ronja; Serra Barros, Ana; Xu, Zhenyu; Brown, David; Murray, Struan C; Haenni, Simon; Halstead, James M; O'Connor, Leigh; Shipkovenska, Gergana; Steinmetz, Lars M; Mellor, Jane

    2014-11-19

    In yeast, many tandemly arranged genes show peak expression in different phases of the metabolic cycle (YMC) or in different carbon sources, indicative of regulation by a bi-modal switch, but it is not clear how these switches are controlled. Using native elongating transcript analysis (NET-seq), we show that transcription itself is a component of bi-modal switches, facilitating reciprocal expression in gene clusters. HMS2, encoding a growth-regulated transcription factor, switches between sense- or antisense-dominant states that also coordinate up- and down-regulation of transcription at neighbouring genes. Engineering HMS2 reveals alternative mono-, di- or tri-cistronic and antisense transcription units (TUs), using different promoter and terminator combinations, that underlie state-switching. Promoters or terminators are excluded from functional TUs by read-through transcriptional interference, while antisense TUs insulate downstream genes from interference. We propose that the balance of transcriptional insulation and interference at gene clusters facilitates gene expression switches during intracellular and extracellular environmental change.

  6. Switching methods in magnetic random access memory for low power applications

    NASA Astrophysics Data System (ADS)

    Guchang, Han; Jiancheng, Huang; Cheow Hin, Sim; Tran, Michael; Sze Ter, Lim

    2015-06-01

    Effect of saturation magnetization (Ms) of the free layer (FL) on the switching current is analyzed for spin transfer torque (STT) magnetic random access memory (MRAM). For in-plane FL, critical switching current (Ic0) decreases as Ms decreases. However, reduction in Ms also results in a low thermal stability factor (Δ), which must be compensated through increasing shape anisotropy, thus limiting scalability. For perpendicular FL, Ic0 reduction by using low-Ms materials is actually at the expense of data retention. To save energy consumed by STT current, two electric field (EF) controlled switching methods are proposed. Our simulation results show that elliptical FL can be switched by an EF pulse with a suitable width. However, it is difficult to implement this type of switching in real MRAM devices due to the distribution of the required switching pulse widths. A reliable switching method is to use an Oersted field guided switching. Our simulation and experimental results show that the bi-directional magnetization switching could be realized by an EF with an external field as low as  ±5 Oe if the offset field could be removed.

  7. Alcohol-Mediated Resistance-Switching Behavior in Metal-Organic Framework-Based Electronic Devices.

    PubMed

    Liu, Yaqing; Wang, Hong; Shi, Wenxiong; Zhang, Weina; Yu, Jiancan; Chandran, Bevita K; Cui, Chenlong; Zhu, Bowen; Liu, Zhiyuan; Li, Bin; Xu, Cai; Xu, Zhiling; Li, Shuzhou; Huang, Wei; Huo, Fengwei; Chen, Xiaodong

    2016-07-25

    Metal-organic frameworks (MOFs) have drawn increasing attentions as promising candidates for functional devices. Herein, we present MOF films in constructing memory devices with alcohol mediated resistance switching property, where the resistance state is controlled by applying alcohol vapors to achieve multilevel information storage. The ordered packing mode and the hydrogen bonding system of the guest molecules adsorbed in MOF crystals are shown to be the reason for the alcohol mediated electrical switching. This chemically mediated memory device can be a candidate in achieving environment-responsive devices and exhibits potential applications in wearable information storage systems. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. Discrete-time systems with random switches: From systems stability to networks synchronization

    NASA Astrophysics Data System (ADS)

    Guo, Yao; Lin, Wei; Ho, Daniel W. C.

    2016-03-01

    In this article, we develop some approaches, which enable us to more accurately and analytically identify the essential patterns that guarantee the almost sure stability of discrete-time systems with random switches. We allow for the case that the elements in the switching connection matrix even obey some unbounded and continuous-valued distributions. In addition to the almost sure stability, we further investigate the almost sure synchronization in complex dynamical networks consisting of randomly connected nodes. Numerical examples illustrate that a chaotic dynamics in the synchronization manifold is preserved when statistical parameters enter some almost sure synchronization region established by the developed approach. Moreover, some delicate configurations are considered on probability space for ensuring synchronization in networks whose nodes are described by nonlinear maps. Both theoretical and numerical results on synchronization are presented by setting only a few random connections in each switch duration. More interestingly, we analytically find it possible to achieve almost sure synchronization in the randomly switching complex networks even with very large population sizes, which cannot be easily realized in non-switching but deterministically connected networks.

  9. Discrete-time systems with random switches: From systems stability to networks synchronization

    SciTech Connect

    Guo, Yao; Lin, Wei; Ho, Daniel W. C.

    2016-03-15

    In this article, we develop some approaches, which enable us to more accurately and analytically identify the essential patterns that guarantee the almost sure stability of discrete-time systems with random switches. We allow for the case that the elements in the switching connection matrix even obey some unbounded and continuous-valued distributions. In addition to the almost sure stability, we further investigate the almost sure synchronization in complex dynamical networks consisting of randomly connected nodes. Numerical examples illustrate that a chaotic dynamics in the synchronization manifold is preserved when statistical parameters enter some almost sure synchronization region established by the developed approach. Moreover, some delicate configurations are considered on probability space for ensuring synchronization in networks whose nodes are described by nonlinear maps. Both theoretical and numerical results on synchronization are presented by setting only a few random connections in each switch duration. More interestingly, we analytically find it possible to achieve almost sure synchronization in the randomly switching complex networks even with very large population sizes, which cannot be easily realized in non-switching but deterministically connected networks.

  10. The repetitive portion of the Xenopus IgH Mu switch region mediates orientation-dependent class switch recombination.

    PubMed

    Zhang, Zheng Z; Pannunzio, Nicholas R; Lu, Zhengfei; Hsu, Ellen; Yu, Kefei; Lieber, Michael R

    2015-10-01

    Vertebrates developed immunoglobulin heavy chain (IgH) class switch recombination (CSR) to express different IgH constant regions. Most double-strand breaks for Ig CSR occur within the repetitive portion of the switch regions located upstream of each set of constant domain exons for the Igγ, Igα or Igϵ heavy chain. Unlike mammalian switch regions, Xenopus switch regions do not have a high G-density on the non-template DNA strand. In previous studies, when Xenopus Sμ DNA was moved to the genome of mice, it is able to support substantial CSR when it is used to replace the murine Sγ1 region. Here, we tested both the 2kb repetitive portion and the 4.6 kb full-length portions of the Xenopus Sμ in both their natural (forward) orientation relative to the constant domain exons, as well as the opposite (reverse) orientation. Consistent with previous work, we find that the 4.6 kb full-length Sμ mediates similar levels of CSR in both the forward and reverse orientations. Whereas, the forward orientation of the 2kb portion can restore the majority of the CSR level of the 4.6 kb full-length Sμ, the reverse orientation poorly supports R-looping and no CSR. The forward orientation of the 2kb repetitive portion has more GG dinucleotides on the non-template strand than the reverse orientation. The correlation of R-loop formation with CSR efficiency, as demonstrated in the 2kb repetitive fragment of the Xenopus switch region, confirms a role played by R-looping in CSR that appears to be conserved through evolution.

  11. Fast 180° magnetization switching in a strain-mediated multiferroic heterostructure driven by a voltage

    PubMed Central

    Peng, Ren-Ci; Hu, Jia-Mian; Momeni, Kasra; Wang, Jian-Jun; Chen, Long-Qing; Nan, Ce-Wen

    2016-01-01

    Voltage-driven 180° magnetization switching provides a low-power alternative to current-driven magnetization switching widely used in spintronic devices. Here we computationally demonstrate a promising route to achieve voltage-driven in-plane 180° magnetization switching in a strain-mediated multiferroic heterostructure (e.g., a heterostructure consisting of an amorphous, slightly elliptical Co40Fe40B20 nanomagnet on top of a Pb(Zr,Ti)O3 film as an example). This 180° switching follows a unique precessional path all in the film plane, and is enabled by manipulating magnetization dynamics with fast, local piezostrains (rise/release time <0.1 ns) on the Pb(Zr,Ti)O3 film surface. Our analyses predict ultralow area energy consumption per switching (~0.03 J/m2), approximately three orders of magnitude smaller than that dissipated by current-driven magnetization switching. A fast overall switching time of about 2.3 ns is also demonstrated. Further reduction of energy consumption and switching time can be achieved by optimizing the structure and material selection. The present design provides an additional viable route to realizing low-power and high-speed spintronics. PMID:27272678

  12. Fast 180° magnetization switching in a strain-mediated multiferroic heterostructure driven by a voltage

    NASA Astrophysics Data System (ADS)

    Peng, Ren-Ci; Hu, Jia-Mian; Momeni, Kasra; Wang, Jian-Jun; Chen, Long-Qing; Nan, Ce-Wen

    2016-06-01

    Voltage-driven 180° magnetization switching provides a low-power alternative to current-driven magnetization switching widely used in spintronic devices. Here we computationally demonstrate a promising route to achieve voltage-driven in-plane 180° magnetization switching in a strain-mediated multiferroic heterostructure (e.g., a heterostructure consisting of an amorphous, slightly elliptical Co40Fe40B20 nanomagnet on top of a Pb(Zr,Ti)O3 film as an example). This 180° switching follows a unique precessional path all in the film plane, and is enabled by manipulating magnetization dynamics with fast, local piezostrains (rise/release time <0.1 ns) on the Pb(Zr,Ti)O3 film surface. Our analyses predict ultralow area energy consumption per switching (~0.03 J/m2), approximately three orders of magnitude smaller than that dissipated by current-driven magnetization switching. A fast overall switching time of about 2.3 ns is also demonstrated. Further reduction of energy consumption and switching time can be achieved by optimizing the structure and material selection. The present design provides an additional viable route to realizing low-power and high-speed spintronics.

  13. A chemical-induced pH-mediated molecular switch

    PubMed Central

    Jayawardhana, Dilani A.; Sengupta, Mrinal K.; Krishantha, D.M. Milan; Gupta, Jyoti; Armstrong, Daniel W.; Guan, Xiyun

    2011-01-01

    The transmembrane protein α-hemolysin pore has been used to develop ultrasensitive biosensors, study biomolecular folding and unfolding, investigate covalent and non-covalent bonding interactions, and probe enzyme kinetics. Here, we report that by addition of ionic liquid tetrakis(hydroxymethyl)phosphonium chloride solution to the α-hemolysin pore, the α-hemolysin channel can be controlled open or closed by adjusting the pH of the solution. This approach can be employed to develop a novel molecular switch to regulate molecular transport, and should find potential applications as a ‘smart’ drug delivery method. PMID:21919492

  14. Chemical-induced pH-mediated molecular switch.

    PubMed

    Jayawardhana, Dilani A; Sengupta, Mrinal K; Krishantha, D M Milan; Gupta, Jyoti; Armstrong, Daniel W; Guan, Xiyun

    2011-10-15

    The transmembrane protein α-hemolysin pore has been used to develop ultrasensitive biosensors, study biomolecular folding and unfolding, investigate covalent and noncovalent bonding interactions, and probe enzyme kinetics. Here, we report that, by addition of ionic liquid tetrakis(hydroxymethyl)phosphonium chloride solution to the α-hemolysin pore, the α-hemolysin channel can be controlled open or closed by adjusting the pH of the solution. This approach can be employed to develop a novel molecular switch to regulate molecular transport and should find potential applications as a "smart" drug delivery method.

  15. Development of Curie point switching for thin film, random access, memory device

    NASA Technical Reports Server (NTRS)

    Lewicki, G. W.; Tchernev, D. I.

    1967-01-01

    Managanese bismuthide films are used in the development of a random access memory device of high packing density and nondestructive readout capability. Memory entry is by Curie point switching using a laser beam. Readout is accomplished by microoptical or micromagnetic scanning.

  16. Regulating infidelity: RNA-mediated recruitment of AID to DNA during class switch recombination

    PubMed Central

    DiMenna, Lauren; Chaudhuri, Jayanta

    2016-01-01

    The mechanism by which the DNA deaminase AID is specifically recruited to repetitive switch region DNA during class switch recombination is still poorly understood. Work over the past decade has revealed a strong link between transcription and RNA polymerase-associated factors in AID recruitment, yet none of these processes satisfactorily explain how AID specificity is effected. Here we review a recent finding wherein AID is guided to switch regions not by a protein factor but by an RNA moiety, and especially one associated with a non-coding RNA that has been long thought of as being inert. This work explains the long-standing requirement of splicing of non-coding transcripts during class switching, and has implications in both B-cell-mediated immunity as well as the underlying pathological syndromes associated with the recombination reaction. PMID:26799454

  17. Regulating infidelity: RNA-mediated recruitment of AID to DNA during class switch recombination.

    PubMed

    DiMenna, Lauren J; Chaudhuri, Jayanta

    2016-03-01

    The mechanism by which the DNA deaminase activation-induced cytidine deaminase (AID) is specifically recruited to repetitive switch region DNA during class switch recombination is still poorly understood. Work over the past decade has revealed a strong link between transcription and RNA polymerase-associated factors in AID recruitment, yet none of these processes satisfactorily explain how AID specificity is affected. Here, we review a recent finding wherein AID is guided to switch regions not by a protein factor but by an RNA moiety, and especially one associated with a noncoding RNA that has been long thought of as being inert. This work explains the long-standing requirement of splicing of noncoding transcripts during class switching, and has implications in both B cell-mediated immunity as well as the underlying pathological syndromes associated with the recombination reaction.

  18. Social Interaction, Noise and Antibiotic-Mediated Switches in the Intestinal Microbiota

    PubMed Central

    Bucci, Vanni; Bradde, Serena; Biroli, Giulio; Xavier, Joao B.

    2012-01-01

    The intestinal microbiota plays important roles in digestion and resistance against entero-pathogens. As with other ecosystems, its species composition is resilient against small disturbances but strong perturbations such as antibiotics can affect the consortium dramatically. Antibiotic cessation does not necessarily restore pre-treatment conditions and disturbed microbiota are often susceptible to pathogen invasion. Here we propose a mathematical model to explain how antibiotic-mediated switches in the microbiota composition can result from simple social interactions between antibiotic-tolerant and antibiotic-sensitive bacterial groups. We build a two-species (e.g. two functional-groups) model and identify regions of domination by antibiotic-sensitive or antibiotic-tolerant bacteria, as well as a region of multistability where domination by either group is possible. Using a new framework that we derived from statistical physics, we calculate the duration of each microbiota composition state. This is shown to depend on the balance between random fluctuations in the bacterial densities and the strength of microbial interactions. The singular value decomposition of recent metagenomic data confirms our assumption of grouping microbes as antibiotic-tolerant or antibiotic-sensitive in response to a single antibiotic. Our methodology can be extended to multiple bacterial groups and thus it provides an ecological formalism to help interpret the present surge in microbiome data. PMID:22577356

  19. Identification of Causal Parameters in Randomized Studies with Mediating Variables

    ERIC Educational Resources Information Center

    Sobel, Michael E.

    2008-01-01

    Treatments in randomized studies are often targeted to key mediating variables. Researchers want to know if the treatment is effective and how the mediators affect the outcome. The data are often analyzed using structural equation models (SEMs), and model coefficients are interpreted as effects. However, only assignment to treatment groups is…

  20. Isolating a Mediated Route for Response Congruency Effects in Task Switching

    ERIC Educational Resources Information Center

    Schneider, Darryl W.

    2015-01-01

    Response congruency effects in task switching reflect worse performance for incongruent targets associated with different responses across tasks than for congruent targets associated with the same response. In the present study, the author investigated whether the effects can be produced solely by a mediated route for response selection, whereby…

  1. Thermodynamics of Phase Transitions and Bipolar Filamentary Switching in Resistive Random-Access Memory

    NASA Astrophysics Data System (ADS)

    Karpov, V. G.; Niraula, D.; Karpov, I. V.; Kotlyar, R.

    2017-08-01

    We present a phenomenological theory of bipolar filamentary resistive random-access memory describing the commonly observed features of their current-voltage characteristics. Our approach follows the approach of a thermodynamic theory developed earlier for chalcogenide memory and threshold switches and largely independent of their microscopic details. It explains, without adjustable parameters, such features as the domains of filament formation and switching, voltage-independent current in set and current-independent voltage in reset regimes, the relation between the set and reset voltages, filament resistance independent of its length, etc. Furthermore, it expresses the observed features through the material and circuitry parameters, thus paving the way to device improvements.

  2. Incoherent magnetization dynamics in strain mediated switching of magnetostrictive nanomagnets

    NASA Astrophysics Data System (ADS)

    Bhattacharya, Dhritiman; Mamun Al-Rashid, Md; D'Souza, Noel; Bandyopadhyay, Supriyo; Atulasimha, Jayasimha

    2017-01-01

    Micromagnetic studies of the magnetization change in magnetostrictive nanomagnets subjected to stress are performed for nanomagnets of different sizes. The interplay between demagnetization, exchange and stress anisotropy energies is used to explain the rich physics of size-dependent magnetization dynamics induced by modulating stress anisotropy in planar nanomagnets. These studies have important implications for strain mediated ultralow energy magnetization control in nanomagnets and its application in energy-efficient nanomagnetic computing devices.

  3. A Locust Phase Change Model with Multiple Switching States and Random Perturbation

    NASA Astrophysics Data System (ADS)

    Xiang, Changcheng; Tang, Sanyi; Cheke, Robert A.; Qin, Wenjie

    2016-12-01

    Insects such as locusts and some moths can transform from a solitarious phase when they remain in loose populations and a gregarious phase, when they may swarm. Therefore, the key to effective management of outbreaks of species such as the desert locust Schistocercagregaria is early detection of when they are in the threshold state between the two phases, followed by timely control of their hopper stages before they fledge because the control of flying adult swarms is costly and often ineffective. Definitions of gregarization thresholds should assist preventive control measures and avoid treatment of areas that might not lead to gregarization. In order to better understand the effects of the threshold density which represents the gregarization threshold on the outbreak of a locust population, we developed a model of a discrete switching system. The proposed model allows us to address: (1) How frequently switching occurs from solitarious to gregarious phases and vice versa; (2) When do stable switching transients occur, the existence of which indicate that solutions with larger amplitudes can switch to a stable attractor with a value less than the switching threshold density?; and (3) How does random perturbation influence the switching pattern? Our results show that both subsystems have refuge equilibrium points, outbreak equilibrium points and bistable equilibria. Further, the outbreak equilibrium points and bistable equilibria can coexist for a wide range of parameters and can switch from one to another. This type of switching is sensitive to the intrinsic growth rate and the initial values of the locust population, and may result in locust population outbreaks and phase switching once a small perturbation occurs. Moreover, the simulation results indicate that the switching transient patterns become identical after some generations, suggesting that the evolving process of the perturbation system is not related to the initial value after some fixed number of

  4. Redox regulation of resveratrol-mediated switching of death signal into survival signal.

    PubMed

    Das, Samarjit; Khan, Nadeem; Mukherjee, Subhendu; Bagchi, Debasis; Gurusamy, Narasimman; Swartz, Harold; Das, Dipak K

    2008-01-01

    In this study, we determined the changes in the intracellular redox environment of the heart during ischemia and reperfusion and the effects of resveratrol on such changes. Because redox regulation by thioredoxin (Trx) plays a crucial role in signal transduction and cytoprotection against ROS, the effects of resveratrol on the changes in the amounts of thioredoxin were monitored in an attempt to determine the role of intracellular thioredoxin in resveratrol-mediated changes in intracellular redox environment and its role in resveratrol-mediated cardioprotection. Rats were randomly divided into four groups: group I, control (rats were gavaged with vehicle only); group II, rats were gavaged with 2.5 mg/kg body wt resveratrol per day for 10 days; group III, rats were given resveratrol for 10 days, but on the 7th day, they were treated with shRNA against Trx-1; group IV, rats were given resveratrol for 10 days, but were injected (iv) with cisplatin (1 mg/kg body wt) on days 1, 3, 5, 7, and 9. In concert, two groups of mice (Dn-Trx-1) and a corresponding wild-type group were also gavaged with 2.5 mg/kg body wt resveratrol for 10 days. After 10 days, isolated rat and mouse hearts perfused via working mode were made globally ischemic for 30 min followed by 2 h of reperfusion. Ischemia/reperfusion developed an infarct size of about 40% and resulted in about 25% apoptotic cardiomyocytes, which were reduced by resveratrol. Cisplatin, but not shRNA-Trx-1, abolished the cardioprotective abilities of resveratrol. In the experiments with mouse hearts, similar to rat hearts, resveratrol significantly reduced the ischemia/reperfusion-mediated increase in infarct size and apoptosis in both groups. MDA formation, a presumptive marker for lipid peroxidation, was increased in the I/R group and reduced in the resveratrol group, and resveratrol-mediated reduction in MDA formation was abolished with cisplatin, but not with shRNA-Trx-1. I/R-induced reduction in GSH/GSSH ratio was

  5. Week 96 results of the randomized, multicentre Maraviroc Switch (MARCH) study.

    PubMed

    Pett, S L; Amin, J; Horban, A; Andrade-Villanueva, J; Losso, M; Porteiro, N; Madero, J S; Belloso, W; Tu, E; Silk, D; Kelleher, A; Harrigan, R; Clark, A; Sugiura, W; Wolff, M; Gill, J; Gatell, J; Clarke, A; Ruxrungtham, K; Prazuck, T; Kaiser, R; Woolley, I; Alberto Arnaiz, J; Cooper, D; Rockstroh, J K; Mallon, P; Emery, S

    2017-07-13

    The Maraviroc Switch (MARCH) study week 48 data demonstrated that maraviroc, a chemokine receptor-5 (CCR5) inhibitor, was a safe and effective switch for the ritonavir-boosted protease inhibitor (PI/r) component of a two nucleos(t)ide reverse transcriptase inhibitor [N(t)RTI] plus PI/r-based antiretroviral regimen in patients with R5-tropic virus. Here we report the durability of this finding. MARCH, an international, multicentre, randomized, 96-week open-label switch study, enrolled HIV-1-infected adults with R5-tropic virus who were stable (> 24 weeks) and virologically suppressed [plasma viral load (pVL) < 50 HIV-1 RNA copies/mL]. Participants were randomized to continue their current PI/r-based regimen (PI/r) or to switch to MVC plus two N(t)RTIs (MVC) (1:2 randomization). The primary endpoint was the difference in the proportion with pVL < 200 copies/mL at 96 weeks. The switch arm was defined as noninferior if the lower limit of the 95% confidence interval (CI) for the difference was < -12% in the intention-to-treat (ITT) population. Safety endpoints (the difference in the mean change from baseline or a comparison of proportions) were analysed as key secondary endpoints. Eighty-two (PI/r) and 156 (MVC) participants were randomized and included in the ITT analysis; 71 (87%) and 130 (83%) were in follow-up and on therapy at week 96. At week 96, 89.0% and 90.4% in the PI/r and MVC arms, respectively, had pVL < 50 copies/mL (95% CI -6.6, 10.2). Moreover, in those switching away from PI/r, there were significant reductions in mean total cholesterol (differences 0.31 mmol/L; P = 0.02) and triglycerides (difference 0.44 mmol/L; P < 0.001). Changes in CD4 T-cell count, renal function, and serious and nonserious adverse events were similar in the two arms. MVC as a switch for a PI/r is safe and effective at maintaining virological suppression while having significant lipid benefits over 96 weeks. © 2017 British HIV Association.

  6. Spin-transfer torque switched magnetic tunnel junctions in magnetic random access memory

    NASA Astrophysics Data System (ADS)

    Sun, Jonathan Z.

    2016-10-01

    Spin-transfer torque (or spin-torque, or STT) based magnetic tunnel junction (MTJ) is at the heart of a new generation of magnetism-based solid-state memory, the so-called spin-transfer-torque magnetic random access memory, or STT-MRAM. Over the past decades, STT-based switchable magnetic tunnel junction has seen progress on many fronts, including the discovery of (001) MgO as the most favored tunnel barrier, which together with (bcc) Fe or FeCo alloy are yielding best demonstrated tunnel magneto-resistance (TMR); the development of perpendicularly magnetized ultrathin CoFeB-type of thin films sufficient to support high density memories with junction sizes demonstrated down to 11nm in diameter; and record-low spin-torque switching threshold current, giving best reported switching efficiency over 5 kBT/μA. Here we review the basic device properties focusing on the perpendicularly magnetized MTJs, both in terms of switching efficiency as measured by sub-threshold, quasi-static methods, and of switching speed at super-threshold, forced switching. We focus on device behaviors important for memory applications that are rooted in fundamental device physics, which highlights the trade-off of device parameters for best suitable system integration.

  7. Competition-Mediated Pyrene-Switching Aptasensor: Probing Lysozyme in Human Serum with a Monomer-Excimer Fluorescence Switch

    PubMed Central

    Huang, Jin; Zhu, Zhi; Bamrungsap, Suwussa; Zhu, Guizhi; You, Mingxu; He, Xiaoxiao; Wang, Kemin; Tan, Weihong

    2010-01-01

    Lysozyme (Lys) plays crucial roles in the innate immune system, and the detection of Lys in urine and serum has considerable clinical importance. Traditionally, the presence of Lys has been detected by immunoassays; however, these assays are limited by the availability of commercial antibodies and tedious protein modification, and prior sample purification. To address these limitations, we report here the design, synthesis and application of a competition-mediated pyrene-switching aptasensor for selective detection of Lys in buffer and human serum. The detection strategy is based on the attachment of pyrene molecules to both ends of a hairpin DNA strand, which becomes the partially complementary competitor to an anti-Lys aptamer. In the presence of target Lys, the aptamer hybridizes with part of the competitor, which opens the hairpin such that both pyrene molecules are spatially separated. In the presence of target Lys, however, the competitor is displaced from the aptamer by the target, subsequently forming an initial hairpin structure. This brings the two pyrene moieties into close proximity to generate an excimer, which, in turn, results in a shift of fluorescence emission from ca. 400 nm (pyrene monomer) to 495 nm (pyrene excimer). The proposed method for Lys detection showed sensitivity as low as 200 pM and high selectivity in buffer. When measured by steady-state fluorescence spectrum, the detection of Lys in human serum showed a strong fluorescent background, which obscured detection of the excimer signal. However, time-resolved emission measurement (TREM) supported the potential of the method in complex environments with background fluorescence by demonstrating the temporal separation of probe fluorescence emission decay from the intense background signal. We have also demonstrated that the same strategy can be applied to the detection of small biomolecules such as adenosine triphosphate (ATP), sowing the generality of our approach. Therefore, the

  8. Differential Regulation of White-Opaque Switching by Individual Subunits of Candida albicans Mediator

    PubMed Central

    Zhang, Anda; Liu, Zhongle

    2013-01-01

    The multisubunit eukaryotic Mediator complex integrates diverse positive and negative gene regulatory signals and transmits them to the core transcription machinery. Mutations in individual subunits within the complex can lead to decreased or increased transcription of certain subsets of genes, which are highly specific to the mutated subunit. Recent studies suggest a role for Mediator in epigenetic silencing. Using white-opaque morphological switching in Candida albicans as a model, we have shown that Mediator is required for the stability of both the epigenetic silenced (white) and active (opaque) states of the bistable transcription circuit driven by the master regulator Wor1. Individual deletions of eight C. albicans Mediator subunits have shown that different Mediator subunits have dramatically diverse effects on the directionality, frequency, and environmental induction of epigenetic switching. Among the Mediator deletion mutants analyzed, only Med12 has a steady-state transcriptional effect on the components of the Wor1 circuit that clearly corresponds to its effect on switching. The MED16 and MED9 genes have been found to be among a small subset of genes that are required for the stability of both the white and opaque states. Deletion of the Med3 subunit completely destabilizes the opaque state, even though the Wor1 transcription circuit is intact and can be driven by ectopic expression of Wor1. The highly impaired ability of the med3 deletion mutant to mate, even when Wor1 expression is ectopically induced, reveals that the activation of the Wor1 circuit can be decoupled from the opaque state and one of its primary biological consequences. PMID:23873866

  9. Differential regulation of white-opaque switching by individual subunits of Candida albicans mediator.

    PubMed

    Zhang, Anda; Liu, Zhongle; Myers, Lawrence C

    2013-09-01

    The multisubunit eukaryotic Mediator complex integrates diverse positive and negative gene regulatory signals and transmits them to the core transcription machinery. Mutations in individual subunits within the complex can lead to decreased or increased transcription of certain subsets of genes, which are highly specific to the mutated subunit. Recent studies suggest a role for Mediator in epigenetic silencing. Using white-opaque morphological switching in Candida albicans as a model, we have shown that Mediator is required for the stability of both the epigenetic silenced (white) and active (opaque) states of the bistable transcription circuit driven by the master regulator Wor1. Individual deletions of eight C. albicans Mediator subunits have shown that different Mediator subunits have dramatically diverse effects on the directionality, frequency, and environmental induction of epigenetic switching. Among the Mediator deletion mutants analyzed, only Med12 has a steady-state transcriptional effect on the components of the Wor1 circuit that clearly corresponds to its effect on switching. The MED16 and MED9 genes have been found to be among a small subset of genes that are required for the stability of both the white and opaque states. Deletion of the Med3 subunit completely destabilizes the opaque state, even though the Wor1 transcription circuit is intact and can be driven by ectopic expression of Wor1. The highly impaired ability of the med3 deletion mutant to mate, even when Wor1 expression is ectopically induced, reveals that the activation of the Wor1 circuit can be decoupled from the opaque state and one of its primary biological consequences.

  10. Ultrafast switching in nanoscale phase-change random access memory with superlattice-like structures.

    PubMed

    Loke, Desmond; Shi, Luping; Wang, Weijie; Zhao, Rong; Yang, Hongxin; Ng, Lung-Tat; Lim, Kian-Guan; Chong, Tow-Chong; Yeo, Yee-Chia

    2011-06-24

    Phase-change random access memory cells with superlattice-like (SLL) GeTe/Sb(2)Te(3) were demonstrated to have excellent scaling performance in terms of switching speed and operating voltage. In this study, the correlations between the cell size, switching speed and operating voltage of the SLL cells were identified and investigated. We found that small SLL cells can achieve faster switching speed and lower operating voltage compared to the large SLL cells. Fast amorphization and crystallization of 300 ps and 1 ns were achieved in the 40 nm SLL cells, respectively, both significantly faster than those observed in the Ge(2)Sb(2)Te(5) (GST) cells of the same cell size. 40 nm SLL cells were found to switch with low amorphization voltage of 0.9 V when pulse-widths of 5 ns were employed, which is much lower than the 1.6 V required by the GST cells of the same cell size. These effects can be attributed to the fast heterogeneous crystallization, low thermal conductivity and high resistivity of the SLL structures. Nanoscale PCRAM with SLL structure promises applications in high speed and low power memory devices.

  11. Effects of Electrodes on the Switching Behavior of Strontium Titanate Nickelate Resistive Random Access Memory

    PubMed Central

    Lee, Ke-Jing; Wang, Li-Wen; Chiang, Te-Kung; Wang, Yeong-Her

    2015-01-01

    Strontium titanate nickelate (STN) thin films on indium tin oxide (ITO)/glass substrate were synthesized using the sol-gel method for resistive random access memory (RRAM) applications. Aluminum (Al), titanium (Ti), tungsten (W), gold (Au) and platinum (Pt) were used as top electrodes in the STN-based RRAM to probe the switching behavior. The bipolar resistive switching behavior of the set and reset voltages is in opposite bias in the Al/STN/ITO and Pt/STN/ITO RRAMs, which can be partly ascribed to the different work functions of top electrodes in the ITO. Analyses of the fitting results and temperature-dependent performances showed that the Al/STN/ITO switching was mainly attributed to the absorption/release of oxygen-based functional groups, whereas the Pt/STN/ITO switching can be associated with the diffusion of metal electrode ions. The Al/STN/ITO RRAM demonstrated a high resistance ratio of >106 between the high-resistance state (HRS) and the low-resistance state (LRS), as well as a retention ability of >105 s. Furthermore, the Pt/STN/ITO RRAM displayed a HRS/LRS resistance ratio of >103 and a retention ability of >105 s. PMID:28793630

  12. SCO2 Mediates Oxidative Stress-Induced Glycolysis to Oxidative Phosphorylation Switch in Hematopoietic Stem Cells.

    PubMed

    Du, Wei; Amarachintha, Surya; Wilson, Andrew F; Pang, Qishen

    2016-04-01

    Fanconi anemia (FA) is an inherited bone marrow (BM) failure syndrome, presumably resulting from defects in hematopoietic stem cells (HSCs). Normal HSCs depend more on glycolysis than on oxidative phosphorylation (OXPHOS) for energy production. Here, we show that FA HSCs are more sensitive to the respiration inhibitor NaN3 treatment than to glycolytic inhibitor 2-deoxy-d-glucose (2-DG), indicating more dependence on OXPHOS. FA HSCs undergo glycolysis-to-OXPHOS switch in response to oxidative stress through a p53-dependent mechanism. Metabolic stresses induce upregulation of p53 metabolic targets in FA HSCs. Inactivation of p53 in FA HSCs prevents glycolysis-to-OXPHOS switch. Furthermore, p53-deficient FA HSCs are more sensitive to 2-DG-mediated metabolic stress. Finally, oxidative stress-induced glycolysis-to-OXPHOS switch is mediated by synthesis of cytochrome c oxidase 2 (SCO2). These findings demonstrate p53-mediated OXPHOS function as a compensatory alteration in FA HSCs to ensure a functional but mildly impaired energy metabolism and suggest a cautious approach to manipulating p53 signaling in FA. © 2015 AlphaMed Press.

  13. S-nitrosylation-mediated redox transcriptional switch modulates neurogenesis and neuronal cell death.

    PubMed

    Okamoto, Shu-Ichi; Nakamura, Tomohiro; Cieplak, Piotr; Chan, Shing Fai; Kalashnikova, Evgenia; Liao, Lujian; Saleem, Sofiyan; Han, Xuemei; Clemente, Arjay; Nutter, Anthony; Sances, Sam; Brechtel, Christopher; Haus, Daniel; Haun, Florian; Sanz-Blasco, Sara; Huang, Xiayu; Li, Hao; Zaremba, Jeffrey D; Cui, Jiankun; Gu, Zezong; Nikzad, Rana; Harrop, Anne; McKercher, Scott R; Godzik, Adam; Yates, John R; Lipton, Stuart A

    2014-07-10

    Redox-mediated posttranslational modifications represent a molecular switch that controls major mechanisms of cell function. Nitric oxide (NO) can mediate redox reactions via S-nitrosylation, representing transfer of an NO group to a critical protein thiol. NO is known to modulate neurogenesis and neuronal survival in various brain regions in disparate neurodegenerative conditions. However, a unifying molecular mechanism linking these phenomena remains unknown. Here, we report that S-nitrosylation of myocyte enhancer factor 2 (MEF2) transcription factors acts as a redox switch to inhibit both neurogenesis and neuronal survival. Structure-based analysis reveals that MEF2 dimerization creates a pocket, facilitating S-nitrosylation at an evolutionally conserved cysteine residue in the DNA binding domain. S-Nitrosylation disrupts MEF2-DNA binding and transcriptional activity, leading to impaired neurogenesis and survival in vitro and in vivo. Our data define a molecular switch whereby redox-mediated posttranslational modification controls both neurogenesis and neurodegeneration via a single transcriptional signaling cascade. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  14. S-Nitrosylation—Mediated Redox Transcriptional Switch Modulates Neurogenesis and Neuronal Cell Death

    PubMed Central

    Okamoto, Shu-ichi; Nakamura, Tomohiro; Cieplak, Piotr; Chan, Shing Fai; Kalashnikova, Evgenia; Liao, Lujian; Saleem, Sofiyan; Han, Xuemei; Clemente, Arjay; Nutter, Anthony; Sances, Sam; Brechtel, Christopher; Haus, Daniel; Haun, Florian; Sanz-Blasco, Sara; Huang, Xiayu; Li, Hao; Zaremba, Jeffrey D.; Cui, Jiankun; Gu, Zezong; Nikzad, Rana; Harrop, Anne; McKercher, Scott R.; Godzik, Adam; Yates, John R.; Lipton, Stuart A.

    2014-01-01

    SUMMARY Redox-mediated posttranslational modifications represent a molecular switch that controls major mechanisms of cell function. Nitric oxide (NO) can mediate redox reactions via S-nitrosylation, representing transfer of an NO group to a critical protein thiol. NO is known to modulate neurogenesis and neuronal survival in various brain regions in disparate neurodegenerative conditions. However, a unifying molecular mechanism linking these phenomena remains unknown. Here we report that S-nitrosylation of myocyte enhancer factor 2 (MEF2) transcription factors acts as a redox switch to inhibit both neurogenesis and neuronal survival. Structure-based analysis reveals that MEF2 dimerization creates a pocket, facilitating S-nitrosylation at an evolutionally conserved cysteine residue in the DNA binding domain. S-Nitrosylation disrupts MEF2-DNA binding and transcriptional activity, leading to impaired neurogenesis and survival in vitro and in vivo. Our data define a novel molecular switch whereby redox-mediated posttranslational modification controls both neurogenesis and neurodegeneration via a single transcriptional signaling cascade. PMID:25001280

  15. Voltage induced magnetostrictive switching of nanomagnets: Strain assisted strain transfer torque random access memory

    SciTech Connect

    Khan, Asif Nikonov, Dmitri E.; Manipatruni, Sasikanth; Ghani, Tahir; Young, Ian A.

    2014-06-30

    A spintronic device, called the “strain assisted spin transfer torque (STT) random access memory (RAM),” is proposed by combining the magnetostriction effect and the spin transfer torque effect which can result in a dramatic improvement in the energy dissipation relative to a conventional STT-RAM. Magnetization switching in the device which is a piezoelectric-ferromagnetic heterostructure via the combined magnetostriction and STT effect is simulated by solving the Landau-Lifshitz-Gilbert equation incorporating the influence of thermal noise. The simulations show that, in such a device, each of these two mechanisms (magnetostriction and spin transfer torque) provides in a 90° rotation of the magnetization leading a deterministic 180° switching with a critical current significantly smaller than that required for spin torque alone. Such a scheme is an attractive option for writing magnetic RAM cells.

  16. A Schelling model with switching agents: decreasing segregation via random allocation and social mobility

    NASA Astrophysics Data System (ADS)

    Hazan, Aurélien; Randon-Furling, Julien

    2013-10-01

    We study the behaviour of a Schelling-class system in which a fraction f of spatially-fixed switching agents is introduced. This new model allows for multiple interpretations, including: (i) random, non-preferential allocation (e.g. by housing associations) of given, fixed sites in an open residential system, and (ii) superimposition of social and spatial mobility in a closed residential system. We find that the presence of switching agents in a segregative Schelling-type dynamics can lead to the emergence of intermediate patterns (e.g. mixture of patches, fuzzy interfaces) as the ones described in [E. Hatna, I. Benenson, J. Artif. Soc. Social. Simul. 15, 6 (2012)]. We also investigate different transitions between segregated and mixed phases both at f = 0 and along lines of increasing f, where the nature of the transition changes.

  17. Bipolar resistive switching characteristics in tantalum nitride-based resistive random access memory devices

    SciTech Connect

    Kim, Myung Ju; Jeon, Dong Su; Park, Ju Hyun; Kim, Tae Geun

    2015-05-18

    This paper reports the bipolar resistive switching characteristics of TaN{sub x}-based resistive random access memory (ReRAM). The conduction mechanism is explained by formation and rupture of conductive filaments caused by migration of nitrogen ions and vacancies; this mechanism is in good agreement with either Ohmic conduction or the Poole-Frenkel emission model. The devices exhibit that the reset voltage varies from −0.82 V to −0.62 V, whereas the set voltage ranges from 1.01 V to 1.30 V for 120 DC sweep cycles. In terms of reliability, the devices exhibit good retention (>10{sup 5 }s) and pulse-switching endurance (>10{sup 6} cycles) properties. These results indicate that TaN{sub x}-based ReRAM devices have a potential for future nonvolatile memory devices.

  18. A mediator effect size in randomized clinical trials.

    PubMed

    Kraemer, Helena Chmura

    2014-12-01

    To understand the process by which a treatment (T) achieves an effect on outcome (O) and thus to improve the effect of T on O, it is vital to detect mediators, to compare the impact of different mediators, and to develop hypotheses about the causal factors (all mediators) linking T and O. An index is needed to facilitate interpretation of the potential clinical importance of a mediator (M) of choice of T on treatment O in randomized clinical trials (RCTs). Ideally such a mediator effect size should (1) be invariant under any rescaling of M and O consistent with the model used, and (2) reflect the difference between the overall observed effect of T on O and what the maximal effect of T on O could be were the association between T and M broken. A mediator effect size is derived first for the traditional linear model, and then more generally for any categorical (ordered or non-ordered) potential mediator. Issues such as the problem of multiple treatments, outcomes and mediators, and of causal inferences, and the correspondence between this approach and earlier ones, are discussed. Illustrations are given of the application of the approach. Copyright © 2014 John Wiley & Sons, Ltd.

  19. A physical layer secure wireless communication method using random antenna switching

    NASA Astrophysics Data System (ADS)

    Mu, Pengcheng; Yin, Qinye

    2011-10-01

    A method of using random antenna switching (RAS) is proposed to guarantee the information security during the physical layer transmission. The method uses multiple antennas at the base station and a single antenna at the mobile terminal. The expected mobile terminal (target user) first transmits a training symbol which is used by the base station to estimate the channel. The base station then randomly selects several antennas to transmit each symbol. The weighting coefficients are obtained according to the estimated channel, which is similar to the distributed beamforming except that the magnitudes are random in this paper. Signals from all the selected antennas are finally superimposed in phase at the target user so that the maximum likelihood demodulation can be directly implemented. The RAS makes the channel for an eavesdropper change fast and randomly to prevent the eavesdropper from demodulating the signals. Simulation results show that the target user's bit error rate of RAS is lower with less transmission power than the traditional method of using random weighting coefficients, while the eavesdropper cannot correctly demodulate and hence the low probability of interception is achieved.

  20. A spin-based true random number generator exploiting the stochastic precessional switching of nanomagnets

    NASA Astrophysics Data System (ADS)

    Rangarajan, Nikhil; Parthasarathy, Arun; Rakheja, Shaloo

    2017-06-01

    In this paper, we propose a spin-based true random number generator (TRNG) that uses the inherent stochasticity in nanomagnets as the source of entropy. In contrast to previous works on spin-based TRNGs, we focus on the precessional switching strategy in nanomagnets to generate a truly random sequence. Using the NIST SP 800-22 test suite for randomness, we demonstrate that the output of the proposed TRNG circuit is statistically random with 99% confidence levels. The effects of process and temperature variability on the device are studied and shown to have no effect on the quality of randomness of the device. To benchmark the performance of the TRNG in terms of area, throughput, and power, we use SPICE (Simulation Program with Integrated Circuit Emphasis)-based models of the nanomagnet and combine them with CMOS device models at the 45 nm technology node. The throughput, power, and area footprints of the proposed TRNG are shown to be better than those of existing state-of-the-art TRNGs. We identify the optimal material and geometrical parameters of the nanomagnet to minimize the energy per bit at a given throughput of the TRNG circuit. Our results provide insights into the device-level modifications that can yield significant system-level improvements. Overall, the proposed spin-based TRNG circuit shows significant robustness, reliability, and fidelity and, therefore, has a potential for on-chip implementation.

  1. Narrow-linewidth Q-switched random distributed feedback fiber laser.

    PubMed

    Xu, Jiangming; Ye, Jun; Xiao, Hu; Leng, Jinyong; Wu, Jian; Zhang, Hanwei; Zhou, Pu

    2016-08-22

    A narrow-linewidth Q-switched random fiber laser (RFL) based on a half-opened cavity, which is realized by narrow-linewidth fiber Bragg grating (FBG) and a section of 3 km passive fiber, has been proposed and experimentally investigated. The narrow-linewidth lasing is generated by the spectral filtering of three FBGs with linewidth of 1.21 nm, 0.56 nm, and 0.12 nm, respectively. The Q switching of the distributed cavity is achieved by placing an acousto-optical modulator (AOM) between the FBG and the passive fiber. The maximal output powers of the narrow-linewidth RFLs with the three different FBGs are 0.54 W, 0.27 W, and 0.08 W, respectively. Furthermore, the repetition rates of the output pulses are 500 kHz, and the pulse durations are about 500 ns. The corresponding pulse energies are about 1.08 μJ, 0.54 μJ, and 0.16 μJ, accordingly. The linewidth of FBG can influence the output characteristics in full scale. The narrower the FBG, the higher the pump threshold; the lower the output power at the same pump level, the more serious the linewidth broadening; and thus the higher the proportion of the CW-ground exists in the output pulse trains. Thanks to the assistance of the band-pass filter (BPF), the proportion of the CW-ground of narrow-linewidth Q-switched RFL under the relative high-pump-low-output condition can be reduced effectively. The experimental results indicate that it is challenging to demonstrate a narrow-linewidth Q-switched RFL with high quality output. But further power scaling and linewidth narrowing is possible in the case of operating parameters, optimization efforts, and a more powerful pump source. To the best of our knowledge, this is the first demonstration of narrow-linewidth generation in a Q-switched RFL.

  2. Infusion of brain-derived neurotrophic factor into the ventral tegmental area switches the substrates mediating ethanol motivation.

    PubMed

    Ting-A-Kee, Ryan; Vargas-Perez, Hector; Bufalino, Mary-Rose; Bahi, Amine; Dreyer, Jean-Luc; Tyndale, Rachel F; van der Kooy, Derek

    2013-03-01

    Recent work has shown that infusion of brain-derived neurotrophic factor (BDNF) into the ventral tegmental area (VTA) promotes a switch in the mechanisms mediating morphine motivation, from a dopamine-independent to a dopamine-dependent pathway. Here we showed that a single infusion of intra-VTA BDNF also promoted a switch in the mechanisms mediating ethanol motivation, from a dopamine-dependent to a dopamine-independent pathway (exactly opposite to that seen with morphine). We suggest that intra-VTA BDNF, via its actions on TrkB receptors, precipitates a switch similar to that which occurs naturally when mice transit from a drug-naive, non-deprived state to a drug-deprived state. The opposite switching of the mechanisms underlying morphine and ethanol motivation by BDNF in previously non-deprived animals is consistent with their proposed actions on VTA GABAA receptors.

  3. Social defeat stress switches the neural system mediating benzodiazepine conditioned motivation.

    PubMed

    Riad-Allen, Lilian; van der Kooy, Derek

    2013-08-01

    Benzodiazepines have been demonstrated to have a high abuse liability in persons suffering from anxiety but have demonstrated mixed abuse liability findings in preclinical models. We hypothesized that by modeling anxiety in a male C57BL/6 mouse model it would be possible to reveal a preference for benzodiazepines within this subpopulation through negative reinforcement. Using the Tube Test of Social Dominance and the Resident/Intruder Paradigm we investigated whether animals identified as dominant or submissive/defeated would differentially display a preference for midazolam (a short acting benzodiazepine) in a conditioned place preference paradigm. Consistent with our hypotheses, benzodiazepine conditioned motivation was mediated by negative reinforcement as submissive but not dominant mice displayed a preference for midazolam. Furthermore, different neural systems mediated midazolam conditioned motivation depending on the stress status of the animal (single vs. repeated stress-as induced by the Resident/Intruder Paradigm). Singly stressed animals showed midazolam place preferences through a dopamine-independent pathway, whereas the place preferences of repeatedly stressed animals were mediated through a dopamine-dependent pathway. This demonstrates that stress is sufficient for switching the neural system mediating midazolam conditioned motivation. Finally, midazolam reinforcement in the conditioned place preference paradigm was shown to be predictive for dominance/submission status.

  4. Distributed Synchronization in Networks of Agent Systems With Nonlinearities and Random Switchings.

    PubMed

    Tang, Yang; Gao, Huijun; Zou, Wei; Kurths, Jürgen

    2013-02-01

    In this paper, the distributed synchronization problem of networks of agent systems with controllers and nonlinearities subject to Bernoulli switchings is investigated. Controllers and adaptive updating laws injected in each vertex of networks depend on the state information of its neighborhood. Three sets of Bernoulli stochastic variables are introduced to describe the occurrence probabilities of distributed adaptive controllers, updating laws and nonlinearities, respectively. By the Lyapunov functions method, we show that the distributed synchronization of networks composed of agent systems with multiple randomly occurring nonlinearities, multiple randomly occurring controllers, and multiple randomly occurring updating laws can be achieved in mean square under certain criteria. The conditions derived in this paper can be solved by semi-definite programming. Moreover, by mathematical analysis, we find that the coupling strength, the probabilities of the Bernoulli stochastic variables, and the form of nonlinearities have great impacts on the convergence speed and the terminal control strength. The synchronization criteria and the observed phenomena are demonstrated by several numerical simulation examples. In addition, the advantage of distributed adaptive controllers over conventional adaptive controllers is illustrated.

  5. Switching characteristics for ferroelectric random access memory based on RC model in poly(vinylidene fluoride-trifluoroethylene) ultrathin films

    SciTech Connect

    Liu, ChangLi; Wang, XueJun; Zhang, XiuLi; Du, XiaoLi; Xu, HaiSheng

    2016-05-15

    The switching characteristic of the poly(vinylidene fluoride-trifluoroethlene) (P(VDF-TrFE)) films have been studied at different ranges of applied electric field. It is suggest that the increase of the switching speed upon nucleation protocol and the deceleration of switching could be related to the presence of a non-ferroelectric layer. Remarkably, a capacitor and resistor (RC) links model plays significant roles in the polarization switching dynamics of the thin films. For P(VDF-TrFE) ultrathin films with electroactive interlayer, it is found that the switching dynamic characteristics are strongly affected by the contributions of resistor and non-ferroelectric (non-FE) interface factors. A corresponding experiment is designed using poly(3,4-ethylene dioxythiophene):poly(styrene sulfonic) (PEDOT-PSSH) as interlayer with different proton concentrations, and the testing results show that the robust switching is determined by the proton concentration in interlayer and lower leakage current in circuit to reliable applications of such polymer films. These findings provide a new feasible method to enhance the polarization switching for the ferroelectric random access memory.

  6. Observation of AlO x material in electrical resistive switching for nonvolatile random access memory application

    NASA Astrophysics Data System (ADS)

    Jung, Kyun-Ho; Song, Seung-Gon; Park, Kyoung-Wan; Sok, Jung-Hyun; Kim, Kyong-Min; Park, Yun-Sun

    2017-03-01

    We fabricated an Al / AlO x / Al device by using a RF magnetron sputter system. The device showed a unipolar resistive switching process. In this study, the switching mechanism of the device followed the conductive filament model. The conduction mechanisms for the conductive filament model were explained by using Ohmic conduction for the low resistance state (LRS) and Schottky emission for the high resistance state (HRS). The average value of the resistance ratio between the HRS and the LRS was about 3.48 × 107 when the reading voltage (0.1 V) was achieved. The electrical property of the endurance was achieved under 50 switching cycles. A low switching voltage could be obtained for a low power consuming device. These results proved that the AlO x material has various possibilities for use in nonvolatile random access memory applications.

  7. The role of commitment strength in enhancing safe water consumption: mediation analysis of a cluster-randomized trial.

    PubMed

    Inauen, Jennifer; Tobias, Robert; Mosler, Hans-Joachim

    2014-11-01

    The objectives of this study were to investigate the importance of commitment strength in the theory of planned behaviour (TPB) and to test whether behaviour change techniques (BCTs) aimed at increasing commitment strength indeed promote switching to arsenic-safe wells by changing commitment strength. A cluster-randomized controlled trial with four arms was conducted to compare an information-only intervention to information plus one, two, or three commitment-enhancing BCTs. Randomly selected households (N = 340) of Monoharganj, Bangladesh, in seven geographically separate areas, whose members were drinking arsenic-contaminated water at baseline and had access to arsenic-safe wells, participated in this trial. The areas were randomly allocated to the four intervention arms. Water consumption behaviour, variables of the TPB, commitment strength, and socio-demographic characteristics were assessed at baseline and at 3-month follow-up by structured face-to-face interviews. Mediation analysis was used to investigate the mechanisms of behaviour change. Changes in commitment strength significantly increased the explanatory power of the TPB to predict well-switching. Commitment-enhancing BCTs - public self-commitment, implementation intentions, and reminders - increased the behaviour change effects of information by up to 50%. Mediation analyses confirmed that the BCTs indeed increased well-switching by increasing commitment strength. Unexpectedly, however, mediation via changes in behavioural intentions was the strongest mechanism of the intervention effects. Commitment is an important construct to consider in water- and health-related behaviour change and may be for other health behaviours as well. BCTs that alter behavioural intentions and commitment strength proved highly effective at enhancing the behaviour change effects of information alone. Statement of contribution What is already known on this subject? Millions of people drink contaminated water even if they

  8. The CP12 protein family: a thioredoxin-mediated metabolic switch?

    PubMed Central

    López-Calcagno, Patricia E.; Howard, Thomas P.; Raines, Christine A.

    2014-01-01

    CP12 is a small, redox-sensitive protein, representatives of which are found in most photosynthetic organisms, including cyanobacteria, diatoms, red and green algae, and higher plants. The only clearly defined function for CP12 in any organism is in the thioredoxin-mediated regulation of the Calvin–Benson cycle. CP12 mediates the formation of a complex between glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and phosphoribulokinase (PRK) in response to changes in light intensity. Under low light, the formation of the GAPDH/PRK/CP12 complex results in a reduction in the activity of both PRK and GAPDH and, under high light conditions, thioredoxin mediates the disassociation of the complex resulting in an increase in both GAPDH and PRK activity. Although the role of CP12 in the redox-mediated formation of the GAPDH/PRK/CP12 multiprotein complex has been clearly demonstrated, a number of studies now provide evidence that the CP12 proteins may play a wider role. In Arabidopsis thaliana CP12 is expressed in a range of tissue including roots, flowers, and seeds and antisense suppression of tobacco CP12 disrupts metabolism and impacts on growth and development. Furthermore, in addition to the higher plant genomes which encode up to three forms of CP12, analysis of cyanobacterial genomes has revealed that, not only are there multiple forms of the CP12 protein, but that in these organisms CP12 is also found fused to cystathionine-β-synthase domain containing proteins. In this review we present the latest information on the CP12 protein family and explore the possibility that CP12 proteins form part of a redox-mediated metabolic switch, allowing organisms to respond to rapid changes in the external environment. PMID:24523724

  9. Standardized Effect Size Measures for Mediation Analysis in Cluster-Randomized Trials

    ERIC Educational Resources Information Center

    Stapleton, Laura M.; Pituch, Keenan A.; Dion, Eric

    2015-01-01

    This article presents 3 standardized effect size measures to use when sharing results of an analysis of mediation of treatment effects for cluster-randomized trials. The authors discuss 3 examples of mediation analysis (upper-level mediation, cross-level mediation, and cross-level mediation with a contextual effect) with demonstration of the…

  10. Standardized Effect Size Measures for Mediation Analysis in Cluster-Randomized Trials

    ERIC Educational Resources Information Center

    Stapleton, Laura M.; Pituch, Keenan A.; Dion, Eric

    2015-01-01

    This article presents 3 standardized effect size measures to use when sharing results of an analysis of mediation of treatment effects for cluster-randomized trials. The authors discuss 3 examples of mediation analysis (upper-level mediation, cross-level mediation, and cross-level mediation with a contextual effect) with demonstration of the…

  11. Stress-stiffening-mediated stem-cell commitment switch in soft responsive hydrogels

    NASA Astrophysics Data System (ADS)

    Das, Rajat K.; Gocheva, Veronika; Hammink, Roel; Zouani, Omar F.; Rowan, Alan E.

    2016-03-01

    Bulk matrix stiffness has emerged as a key mechanical cue in stem cell differentiation. Here, we show that the commitment and differentiation of human mesenchymal stem cells encapsulated in physiologically soft (~0.2-0.4 kPa), fully synthetic polyisocyanopeptide-based three-dimensional (3D) matrices that mimic the stiffness of adult stem cell niches and show biopolymer-like stress stiffening, can be readily switched from adipogenesis to osteogenesis by changing only the onset of stress stiffening. This mechanical behaviour can be tuned by simply altering the material’s polymer length whilst maintaining stiffness and ligand density. Our findings introduce stress stiffening as an important parameter that governs stem cell fate in a 3D microenvironment, and reveal a correlation between the onset of stiffening and the expression of the microtubule-associated protein DCAMKL1, thus implicating DCAMKL1 in a stress-stiffening-mediated, mechanotransduction pathway that involves microtubule dynamics in stem cell osteogenesis.

  12. Nanoscale switch for vortex polarization mediated by Bloch core formation in magnetic hybrid systems.

    PubMed

    Wohlhüter, Phillip; Bryan, Matthew Thomas; Warnicke, Peter; Gliga, Sebastian; Stevenson, Stephanie Elizabeth; Heldt, Georg; Saharan, Lalita; Suszka, Anna Kinga; Moutafis, Christoforos; Chopdekar, Rajesh Vilas; Raabe, Jörg; Thomson, Thomas; Hrkac, Gino; Heyderman, Laura Jane

    2015-08-04

    Vortices are fundamental magnetic topological structures characterized by a curling magnetization around a highly stable nanometric core. The control of the polarization of this core and its gyration is key to the utilization of vortices in technological applications. So far polarization control has been achieved in single-material structures using magnetic fields, spin-polarized currents or spin waves. Here we demonstrate local control of the vortex core orientation in hybrid structures where the vortex in an in-plane Permalloy film coexists with out-of-plane maze domains in a Co/Pd multilayer. The vortex core reverses its polarization on crossing a maze domain boundary. This reversal is mediated by a pair of magnetic singularities, known as Bloch points, and leads to the transient formation of a three-dimensional magnetization structure: a Bloch core. The interaction between vortex and domain wall thus acts as a nanoscale switch for the vortex core polarization.

  13. Nanoscale switch for vortex polarization mediated by Bloch core formation in magnetic hybrid systems

    NASA Astrophysics Data System (ADS)

    Wohlhüter, Phillip; Bryan, Matthew Thomas; Warnicke, Peter; Gliga, Sebastian; Stevenson, Stephanie Elizabeth; Heldt, Georg; Saharan, Lalita; Suszka, Anna Kinga; Moutafis, Christoforos; Chopdekar, Rajesh Vilas; Raabe, Jörg; Thomson, Thomas; Hrkac, Gino; Heyderman, Laura Jane

    2015-08-01

    Vortices are fundamental magnetic topological structures characterized by a curling magnetization around a highly stable nanometric core. The control of the polarization of this core and its gyration is key to the utilization of vortices in technological applications. So far polarization control has been achieved in single-material structures using magnetic fields, spin-polarized currents or spin waves. Here we demonstrate local control of the vortex core orientation in hybrid structures where the vortex in an in-plane Permalloy film coexists with out-of-plane maze domains in a Co/Pd multilayer. The vortex core reverses its polarization on crossing a maze domain boundary. This reversal is mediated by a pair of magnetic singularities, known as Bloch points, and leads to the transient formation of a three-dimensional magnetization structure: a Bloch core. The interaction between vortex and domain wall thus acts as a nanoscale switch for the vortex core polarization.

  14. Nanoscale switch for vortex polarization mediated by Bloch core formation in magnetic hybrid systems

    PubMed Central

    Wohlhüter, Phillip; Bryan, Matthew Thomas; Warnicke, Peter; Gliga, Sebastian; Stevenson, Stephanie Elizabeth; Heldt, Georg; Saharan, Lalita; Suszka, Anna Kinga; Moutafis, Christoforos; Chopdekar, Rajesh Vilas; Raabe, Jörg; Thomson, Thomas; Hrkac, Gino; Heyderman, Laura Jane

    2015-01-01

    Vortices are fundamental magnetic topological structures characterized by a curling magnetization around a highly stable nanometric core. The control of the polarization of this core and its gyration is key to the utilization of vortices in technological applications. So far polarization control has been achieved in single-material structures using magnetic fields, spin-polarized currents or spin waves. Here we demonstrate local control of the vortex core orientation in hybrid structures where the vortex in an in-plane Permalloy film coexists with out-of-plane maze domains in a Co/Pd multilayer. The vortex core reverses its polarization on crossing a maze domain boundary. This reversal is mediated by a pair of magnetic singularities, known as Bloch points, and leads to the transient formation of a three-dimensional magnetization structure: a Bloch core. The interaction between vortex and domain wall thus acts as a nanoscale switch for the vortex core polarization. PMID:26238042

  15. HIV-1 Drug Resistance and Second-line Treatment in Children Randomized to Switch at Low versus Higher RNA Thresholds

    PubMed Central

    Harrison, Linda; Melvin, Ann; Fiscus, Susan; Saidi, Yacine; Nastouli, Eleni; Harper, Lynda; Compagnucci, Alexandra; Babiker, Abdel; McKinney, Ross; Gibb, Diana; Tudor-Williams, Gareth

    2015-01-01

    Background The PENPACT-1 trial compared virologic thresholds to determine when to switch to second-line antiretroviral therapy (ART). Using PENPACT-1 data, we aimed to describe HIV-1 drug resistance accumulation on first-line ART by virologic threshold. Methods PENPACT-1 had a 2x2 factorial design, randomizing HIV-infected children to start protease inhibitor (PI) versus non-nucleoside reverse transcriptase inhibitor (NNRTI) based ART, and switch at a 1000c/ml versus 30000c/ml threshold. Switch-criteria were: not achieving the threshold by week 24, confirmed rebound above the threshold thereafter, or CDC-C event. Resistance tests were performed on samples ≥1000c/ml before switch, re-suppression and at 4-year/trial-end. Results Sixty-seven children started PI-based ART and were randomized to switch at 1000c/ml (PI-1000), 64 PIs and 30000c/ml (PI-30000), 67 NNRTIs and 1000c/ml (NNRTI-1000), and 65 NNRTI and 30000c/ml (NNRTI-30000). Ninety-four (36%) children reached the 1000c/ml switch-criteria during 5 years follow-up. In 30000c/ml threshold arms, median time from 1000c/ml to 30000c/ml switch-criteria was 58 (PI) versus 80 (NNRTI) weeks (P=0.81). In NNRTI-30000 more NRTI resistance mutations accumulated than other groups. NNRTI mutations were selected before switching at 1000c/ml (23% NNRTI-1000, 27% NNRTI-30000). Sixty-two children started abacavir+lamivudine, 166 lamivudine+zidovudine or stavudine, and 35 other NRTIs. The abacavir+lamivudine group acquired fewest NRTI mutations. Of 60 switched to second-line, 79% PI-1000, 63% PI-30000, 64% NNRTI-1000 and 100% NNRTI-30000 were <400c/ml 24 weeks later. Conclusion Children on first-line NNRTI-based ART who were randomized to switch at a higher virologic threshold developed the most resistance, yet re-suppressed on second-line. An abacavir+lamivudine NRTI combination seemed protective against development of NRTI resistance. PMID:26322666

  16. Screen-Time Weight-loss Intervention Targeting Children at Home (SWITCH): a randomized controlled trial.

    PubMed

    Maddison, Ralph; Marsh, Samantha; Foley, Louise; Epstein, Leonard H; Olds, Timothy; Dewes, Ofa; Heke, Ihirangi; Carter, Karen; Jiang, Yannan; Mhurchu, Cliona Ni

    2014-09-10

    Screen-based activities, such as watching television (TV), playing video games, and using computers, are common sedentary behaviors among young people and have been linked with increased energy intake and overweight. Previous home-based sedentary behaviour interventions have been limited by focusing primarily on the child, small sample sizes, and short follow-up periods. The SWITCH (Screen-Time Weight-loss Intervention Targeting Children at Home) study aimed to determine the effect of a home-based, family-delivered intervention to reduce screen-based sedentary behaviour on body composition, sedentary behaviour, physical activity, and diet over 24 weeks in overweight and obese children. A two-arm, parallel, randomized controlled trial was conducted. Children and their primary caregiver living in Auckland, New Zealand were recruited via schools, community centres, and word of mouth. The intervention, delivered over 20 weeks, consisted of a face-to-face meeting with the parent/caregiver and the child to deliver intervention content, which focused on training and educating them to use a wide range of strategies designed to reduce their child's screen time. Families were given Time Machine TV monitoring devices to assist with allocating screen time, activity packages to promote alternative activities, online support via a website, and monthly newsletters. Control participants were given the intervention material on completion of follow-up. The primary outcome was change in children's BMI z-score from baseline to 24 weeks. Children (n = 251) aged 9-12 years and their primary caregiver were randomized to receive the SWITCH intervention (n = 127) or no intervention (controls; n = 124). There was no significant difference in change of zBMI between the intervention and control groups, although a favorable trend was observed (-0.016; 95% CI: -0.084, 0.051; p = 0.64). There were also no significant differences on secondary outcomes, except for a trend towards

  17. FLIP switches Fas-mediated glucose signaling in human pancreatic cells from apoptosis to cell replication

    NASA Astrophysics Data System (ADS)

    Maedler, Kathrin; Fontana, Adriano; Ris, Frédéric; Sergeev, Pavel; Toso, Christian; Oberholzer, José; Lehmann, Roger; Bachmann, Felix; Tasinato, Andrea; Spinas, Giatgen A.; Halban, Philippe A.; Donath, Marc Y.

    2002-06-01

    Type 2 diabetes mellitus results from an inadequate adaptation of the functional pancreatic cell mass in the face of insulin resistance. Changes in the concentration of glucose play an essential role in the regulation of cell turnover. In human islets, elevated glucose concentrations impair cell proliferation and induce cell apoptosis via up-regulation of the Fas receptor. Recently, it has been shown that the caspase-8 inhibitor FLIP may divert Fas-mediated death signals into those for cell proliferation in lymphatic cells. We observed expression of FLIP in human pancreatic cells of nondiabetic individuals, which was decreased in tissue sections of type 2 diabetic patients. In vitro exposure of islets from nondiabetic organ donors to high glucose levels decreased FLIP expression and increased the percentage of apoptotic terminal deoxynucleotidyltransferase-mediated UTP end labeling (TUNEL)-positive cells; FLIP was no longer detectable in such TUNEL-positive cells. Up-regulation of FLIP, by incubation with transforming growth factor or by transfection with an expression vector coding for FLIP, protected cells from glucose-induced apoptosis, restored cell proliferation, and improved cell function. The beneficial effects of FLIP overexpression were blocked by an antagonistic anti-Fas antibody, indicating their dependence on Fas receptor activation. The present data provide evidence for expression of FLIP in the human cell and suggest a novel approach to prevent and treat diabetes by switching Fas signaling from apoptosis to proliferation.

  18. Population-level consequences of polymorphism, plasticity and randomized phenotype switching: a review of predictions.

    PubMed

    Wennersten, Lena; Forsman, Anders

    2012-08-01

    The consequences of among-individual phenotypic variation for the performance and ecological success of populations and species has attracted growing interest in recent years. Earlier reviews of this field typically address the consequences for population processes of one specific source of variation (plasticity or polymorphism), or consider one specific aspect of population performance, such as rate of speciation. Here we take a broader approach and study earlier reviews in order to summarize and compare predictions regarding several population-level consequences of phenotypic variation stemming from genetic polymorphism, developmental plasticity or randomized phenotype switching. Unravelling cause-dependent consequences of variation may increase our ability to understand the ecological dynamics of natural populations and communities, develop more informed management plans for protection of biodiversity, suggest possible routes to increased productivity and yield in natural and managed biological systems, and resolve inconsistencies in patterns and results seen in studies of different model systems. We find an overall agreement regarding the effects of higher levels of phenotypic variation generated by different sources, but also some differences between fine-grained and coarse-grained environments, modular and unitary organisms, mobile and sessile organisms, and between flexible and fixed traits. We propose ways to test the predictions and identify issues where current knowledge is limited and future lines of investigation promise to provide important novel insights. © 2012 The Authors. Biological Reviews © 2012 Cambridge Philosophical Society.

  19. Spectral shifts and spectral switches produced by scattering from a random hollow scatterer with adjustable shell thickness

    NASA Astrophysics Data System (ADS)

    Zhou, Jianyang; Zhao, Daomu

    2017-05-01

    Within the accuracy of the first-order Born approximation, the spectral shifts and spectral switches produced by the scattering of an electromagnetic light wave from a random hollow scatterer with adjustable shell thickness have been investigated. The effects of the properties of the scatterer and the incident light wave on the far-zone scattered spectrum have been discussed in detail by using numerical examples. It is shown that, as the scattering angle increases, the scattered spectrum will split into two peaks, and subsequently the two peaks will make a rapid transition as a spectral switch. The position at which the spectral switch occurs is affected by the shell thickness, the outer and inner correlation lengths of the scatterer as well as the polarization of the incident light. Besides, the polarization of the incident light also has an impact on the spectral width of the scattered field.

  20. Antibody-mediated pure red cell aplasia (PRCA) on switching from darbepoetin alfa to epoetin beta: what are the implications?

    PubMed Central

    Assunção, José; Vinhas, José

    2008-01-01

    We report the development of antibody-mediated pure red cell aplasia (PRCA) in a 63-year-old man with end-stage renal disease following a switch from darbepoetin alfa to epoetin beta. Haemoglobin levels began to decrease 6 months after the switch. Increasing the epoetin beta dose produced no response and regular blood transfusions were required; PRCA was confirmed and epoetin beta was discontinued. The patient responded positively to immunosuppression; after 2 months on prednisone and cyclophosphamide, haemoglobin levels stabilized and no further transfusions were required. This case highlights the difficulty in establishing a cause-effect relationship where more than one erythropoiesis-stimulating agent is involved. PMID:25983889

  1. Antibody-mediated pure red cell aplasia (PRCA) on switching from darbepoetin alfa to epoetin beta: what are the implications?

    PubMed

    Assunção, José; Vinhas, José

    2008-08-01

    We report the development of antibody-mediated pure red cell aplasia (PRCA) in a 63-year-old man with end-stage renal disease following a switch from darbepoetin alfa to epoetin beta. Haemoglobin levels began to decrease 6 months after the switch. Increasing the epoetin beta dose produced no response and regular blood transfusions were required; PRCA was confirmed and epoetin beta was discontinued. The patient responded positively to immunosuppression; after 2 months on prednisone and cyclophosphamide, haemoglobin levels stabilized and no further transfusions were required. This case highlights the difficulty in establishing a cause-effect relationship where more than one erythropoiesis-stimulating agent is involved.

  2. Using observational data to emulate a randomized trial of dynamic treatment-switching strategies: an application to antiretroviral therapy.

    PubMed

    Cain, Lauren E; Saag, Michael S; Petersen, Maya; May, Margaret T; Ingle, Suzanne M; Logan, Roger; Robins, James M; Abgrall, Sophie; Shepherd, Bryan E; Deeks, Steven G; John Gill, M; Touloumi, Giota; Vourli, Georgia; Dabis, François; Vandenhende, Marie-Anne; Reiss, Peter; van Sighem, Ard; Samji, Hasina; Hogg, Robert S; Rybniker, Jan; Sabin, Caroline A; Jose, Sophie; Del Amo, Julia; Moreno, Santiago; Rodríguez, Benigno; Cozzi-Lepri, Alessandro; Boswell, Stephen L; Stephan, Christoph; Pérez-Hoyos, Santiago; Jarrin, Inma; Guest, Jodie L; D'Arminio Monforte, Antonella; Antinori, Andrea; Moore, Richard; Campbell, Colin Nj; Casabona, Jordi; Meyer, Laurence; Seng, Rémonie; Phillips, Andrew N; Bucher, Heiner C; Egger, Matthias; Mugavero, Michael J; Haubrich, Richard; Geng, Elvin H; Olson, Ashley; Eron, Joseph J; Napravnik, Sonia; Kitahata, Mari M; Van Rompaey, Stephen E; Teira, Ramón; Justice, Amy C; Tate, Janet P; Costagliola, Dominique; Sterne, Jonathan Ac; Hernán, Miguel A

    2016-12-01

    When a clinical treatment fails or shows suboptimal results, the question of when to switch to another treatment arises. Treatment switching strategies are often dynamic because the time of switching depends on the evolution of an individual's time-varying covariates. Dynamic strategies can be directly compared in randomized trials. For example, HIV-infected individuals receiving antiretroviral therapy could be randomized to switching therapy within 90 days of HIV-1 RNA crossing above a threshold of either 400 copies/ml (tight-control strategy) or 1000 copies/ml (loose-control strategy). We review an approach to emulate a randomized trial of dynamic switching strategies using observational data from the Antiretroviral Therapy Cohort Collaboration, the Centers for AIDS Research Network of Integrated Clinical Systems and the HIV-CAUSAL Collaboration. We estimated the comparative effect of tight-control vs. loose-control strategies on death and AIDS or death via inverse-probability weighting. Of 43 803 individuals who initiated an eligible antiretroviral therapy regimen in 2002 or later, 2001 met the baseline inclusion criteria for the mortality analysis and 1641 for the AIDS or death analysis. There were 21 deaths and 33 AIDS or death events in the tight-control group, and 28 deaths and 41 AIDS or death events in the loose-control group. Compared with tight control, the adjusted hazard ratios (95% confidence interval) for loose control were 1.10 (0.73, 1.66) for death, and 1.04 (0.86, 1.27) for AIDS or death. Although our effective sample sizes were small and our estimates imprecise, the described methodological approach can serve as an example for future analyses.

  3. Platform switch versus platform match in the posterior mandible – 1-year results of a multicentre randomized clinical trial.

    PubMed

    Guerra, Fernando; Wagner, Wilfried; Wiltfang, Jörg; Rocha, Salomão; Moergel, Maximilian; Behrens, Eleonore; Nicolau, Pedro

    2014-05-01

    The purpose of this ongoing randomized study was to assess differences in bone level changes and success rates using implants supporting single crowns in the posterior mandible either with platform matched or platform switched abutments. Patients aged 18 and above, missing at least two teeth in the posterior mandible and with a natural tooth mesial to the most proximal implant site were enrolled. Randomization followed implant placement. Definitive restorations were placed after a minimum transgingival healing period of 8 weeks. Changes in crestal bone level from surgery and loading (baseline) to 12-month post-loading were radiographically measured. Implant survival and success were determined. Sixty-eight patients received 74 implants in the platform switching group and 72 in the other one. The difference of mean marginal bone level change from surgery to 12 months was significant between groups (p < 0.004). Radiographical mean bone gain or no bone loss from loading was noted for 67.1% of the platform switching and 49.2% of the platform matching implants. Implant success rates were 97.3% and 100%, respectively. Within the same implant system the platform switching concept showed a positive effect on marginal bone levels when compared with restorations with platform matching.

  4. Temperature-Independent Switching Rates for a Random Telegraph Signal in a Silicon Metal-Oxide-Semiconductor Field-Effect Transistor at Low Temperatures

    SciTech Connect

    Borland, Nick; Fleetwood, D.M.; Scofield, John H.

    1999-07-19

    We have observed discrete random telegraph signals (RTS'S) in the drain voltages of three, observed above 30 K were thermally activated. The switching rate for the only RTS observed below 30 K was thermally activated above 30 K but temperature-independent below 10 K. To our knowledge, this cross-over from thermal activation to tunneling behavior has not been previously observed for RTS's Metal-oxide-semiconductor field-effect transistors (MCEWETS) often exhibit relatively large levels of low-frequency (1/fl noise) [1,2]. Much evidence suggests that this noise is related to the capture all cases, switching rates have been thermally activated, often with different activation energies for capture and/or emission is accompanied by lattice relaxation. Though thermally activated behavior has sufficiently low temperatures [7,9]. While not observed in MOSFETS, cross-over from thermal activation to configurational tunneling has been observed for RTS's in junctions [13]. drain voltage was observed to randomly switch between two discrete levels, designated as Vup and Vdn, similar to RTS's reported by others [2,7'- 11 ]. We have characterized six RTS `S for temperatures above 30 K where thermally activated switching rates are observed. The properties of five of these have been the trap, i.e., the mean time a captured charge carrier spends in the trap before it is emitted. Similarly, we identify the mean time in the low resistance state ( trup in state Vup) as the capture time rc. F@ure 1 shows a typical time trace of the drain-voltage fluctuation &d(t)= Vd(t)+Vd>. This indicate that both the mean capture and emission times become independent of Tat low temperatures and where a= capture or emission, is temperature independent. The solid curve in Figure 3(a) (mean capture time) was obtained using a weighted nonlinear charge carriers are not in thermal equilibrium with the lattice, i.e., that while the lattice is being cooled Instead, we believe that the transition from thermally

  5. MxaY regulates the lanthanide-mediated methanol dehydrogenase switch in Methylomicrobium buryatense

    PubMed Central

    Chu, Frances; Beck, David A.C.

    2016-01-01

    Many methylotrophs, microorganisms that consume carbon compounds lacking carbon–carbon bonds, use two different systems to oxidize methanol for energy production and biomass accumulation. The MxaFI methanol dehydrogenase (MDH) contains calcium in its active site, while the XoxF enzyme contains a lanthanide in its active site. The genes encoding the MDH enzymes are differentially regulated by the presence of lanthanides. In this study, we found that the histidine kinase MxaY controls the lanthanide-mediated switch in Methylomicrobium buryatense 5GB1C. MxaY controls the transcription of genes encoding MxaFI and XoxF at least partially by controlling the transcript levels of the orphan response regulator MxaB. We identify a constitutively active version of MxaY, and identify the mutated residue that may be involved in lanthanide sensing. Lastly, we find evidence to suggest that tight control of active MDH production is required for wild-type growth rates. PMID:27651996

  6. Differential submitochondrial localization of PINK1 as a molecular switch for mediating distinct mitochondrial signaling pathways.

    PubMed

    Fallaize, Dana; Chin, Lih-Shen; Li, Lian

    2015-12-01

    Mutations in mitochondrial kinase PINK1 cause Parkinson disease (PD), but the submitochondrial site(s) of PINK1 action remains unclear. Here, we report that three-dimensional structured illumination microscopy (3D-SIM) enables super-resolution imaging of protein submitochondrial localization. Dual-color 3D-SIM imaging analysis revealed that PINK1 resides in the cristae membrane and intracristae space but not on the outer mitochondrial membrane (OMM) of healthy mitochondria. Under normal physiological conditions, PINK1 colocalizes with its substrate TRAP1 in the cristae membrane and intracristae space. In response to mitochondrial depolarization, PINK1, but not TRAP1, translocates to the OMM. The PINK1 translocation to the OMM of depolarized mitochondria is independent of new protein synthesis and requires combined action of PINK1 transmembrane domain and C-terminal region. We found that mitochondrial depolarization-induced PINK1 OMM translocation is required for recruitment of parkin to the OMM of damaged mitochondria. Our findings suggest that differential submitochondrial localization of PINK1 serves as a molecular switch for mediating two distinct mitochondrial signaling pathways in maintenance of mitochondrial homeostasis. Furthermore, our study provides evidence for the involvement of deregulated PINK1 submitochondrial localization in PD pathogenesis.

  7. MxaY regulates the lanthanide-mediated methanol dehydrogenase switch in Methylomicrobium buryatense

    DOE PAGES

    Chu, Frances; Beck, David A. C.; Lidstrom, Mary E.

    2016-09-07

    Many methylotrophs, microorganisms that consume carbon compounds lacking carbon–carbon bonds, use two different systems to oxidize methanol for energy production and biomass accumulation. The MxaFI methanol dehydrogenase (MDH) contains calcium in its active site, while the XoxF enzyme contains a lanthanide in its active site. The genes encoding the MDH enzymes are differentially regulated by the presence of lanthanides. In this study, we found that the histidine kinase MxaY controls the lanthanide-mediated switch in Methylomicrobium buryatense 5GB1C. MxaY controls the transcription of genes encoding MxaFI and XoxF at least partially by controlling the transcript levels of the orphan response regulatormore » MxaB. We identify a constitutively active version of MxaY, and identify the mutated residue that may be involved in lanthanide sensing. Finally, we find evidence to suggest that tight control of active MDH production is required for wild-type growth rates.« less

  8. Age-related increases in right frontal activation during task switching are mediated by reaction time and white matter microstructure.

    PubMed

    Zhu, Z; Hakun, J G; Johnson, N F; Gold, B T

    2014-10-10

    Age-related increases in right frontal cortex activation are a common finding in the neuroimaging literature. However, neurocognitive factors contributing to right frontal over-recruitment remain poorly understood. Here we investigated the influence of age-related reaction time (RT) slowing and white matter (WM) microstructure reductions as potential explanatory factors for age-related increases in right frontal activation during task switching. Groups of younger (N=32) and older (N=33) participants completed a task switching paradigm while functional magnetic resonance imaging (fMRI) was performed, and rested while diffusion tensor imaging (DTI) was performed. Two right frontal regions of interest (ROIs), the dorsolateral prefrontal cortex (DLPFC) and insula, were selected for further analyses from a common network of regions recruited by both age groups during task switching. Results demonstrated age-related activation increases in both ROIs. In addition, the older adult group showed longer RT and decreased fractional anisotropy in regions of the corpus callosum with direct connections to the fMRI ROIs. Subsequent mediation analyses indicated that age-related increases in right insula activation were mediated by RT slowing and age-related increases in right DLPFC activation were mediated by WM microstructure. Our results suggest that age-related RT slowing and WM microstructure declines contribute to age-related increases in right frontal activation during cognitive task performance.

  9. Switching characteristics in Cu:SiO2 by chemical soak methods for resistive random access memory (ReRAM)

    NASA Astrophysics Data System (ADS)

    Chin, Fun-Tat; Lin, Yu-Hsien; Yang, Wen-Luh; Liao, Chin-Hsuan; Lin, Li-Min; Hsiao, Yu-Ping; Chao, Tien-Sheng

    2015-01-01

    A limited copper (Cu)-source Cu:SiO2 switching layer composed of various Cu concentrations was fabricated using a chemical soaking (CS) technique. The switching layer was then studied for developing applications in resistive random access memory (ReRAM) devices. Observing the resistive switching mechanism exhibited by all the samples suggested that Cu conductive filaments formed and ruptured during the set/reset process. The experimental results indicated that the endurance property failure that occurred was related to the joule heating effect. Moreover, the endurance switching cycle increased as the Cu concentration decreased. In high-temperature tests, the samples demonstrated that the operating (set/reset) voltages decreased as the temperature increased, and an Arrhenius plot was used to calculate the activation energy of the set/reset process. In addition, the samples demonstrated stable data retention properties when baked at 85 °C, but the samples with low Cu concentrations exhibited short retention times in the low-resistance state (LRS) during 125 °C tests. Therefore, Cu concentration is a crucial factor in the trade-off between the endurance and retention properties; furthermore, the Cu concentration can be easily modulated using this CS technique.

  10. A Randomized Controlled ERP Study on the Effects of Multi-Domain Cognitive Training and Task Difficulty on Task Switching Performance in Older Adults.

    PubMed

    Küper, Kristina; Gajewski, Patrick D; Frieg, Claudia; Falkenstein, Michael

    2017-01-01

    Executive functions are subject to a marked age-related decline, but have been shown to benefit from cognitive training interventions. As of yet, it is, however, still relatively unclear which neural mechanism can mediate training-related performance gains. In the present electrophysiological study, we examined the effects of multi-domain cognitive training on performance in an untrained cue-based task switch paradigm featuring Stroop color words: participants either had to indicate the word meaning of Stroop stimuli (word task) or perform the more difficult task of color naming (color task). One-hundred and three older adults (>65 years old) were randomly assigned to a training group receiving a 4-month multi-domain cognitive training, a passive no-contact control group or an active (social) control group receiving a 4-month relaxation training. For all groups, we recorded performance and EEG measures before and after the intervention. For the cognitive training group, but not for the two control groups, we observed an increase in response accuracy at posttest, irrespective of task and trial type. No training-related effects on reaction times were found. Cognitive training was also associated with an overall increase in N2 amplitude and a decrease of P2 latency on single trials. Training-related performance gains were thus likely mediated by an enhancement of response selection and improved access to relevant stimulus-response mappings. Additionally, cognitive training was associated with an amplitude decrease in the time window of the target-locked P3 at fronto-central electrodes. An increase in the switch positivity during advance task preparation emerged after both cognitive and relaxation training. Training-related behavioral and event-related potential (ERP) effects were not modulated by task difficulty. The data suggest that cognitive training increased slow negative potentials during target processing which enhanced the N2 and reduced a subsequent P3-like

  11. Temperature induced complementary switching in titanium oxide resistive random access memory

    SciTech Connect

    Panda, D.; Simanjuntak, F. M.; Tseng, T.-Y.

    2016-07-15

    On the way towards high memory density and computer performance, a considerable development in energy efficiency represents the foremost aspiration in future information technology. Complementary resistive switch consists of two antiserial resistive switching memory (RRAM) elements and allows for the construction of large passive crossbar arrays by solving the sneak path problem in combination with a drastic reduction of the power consumption. Here we present a titanium oxide based complementary RRAM (CRRAM) device with Pt top and TiN bottom electrode. A subsequent post metal annealing at 400°C induces CRRAM. Forming voltage of 4.3 V is required for this device to initiate switching process. The same device also exhibiting bipolar switching at lower compliance current, Ic <50 μA. The CRRAM device have high reliabilities. Formation of intermediate titanium oxi-nitride layer is confirmed from the cross-sectional HRTEM analysis. The origin of complementary switching mechanism have been discussed with AES, HRTEM analysis and schematic diagram. This paper provides valuable data along with analysis on the origin of CRRAM for the application in nanoscale devices.

  12. Temperature induced complementary switching in titanium oxide resistive random access memory

    NASA Astrophysics Data System (ADS)

    Panda, D.; Simanjuntak, F. M.; Tseng, T.-Y.

    2016-07-01

    On the way towards high memory density and computer performance, a considerable development in energy efficiency represents the foremost aspiration in future information technology. Complementary resistive switch consists of two antiserial resistive switching memory (RRAM) elements and allows for the construction of large passive crossbar arrays by solving the sneak path problem in combination with a drastic reduction of the power consumption. Here we present a titanium oxide based complementary RRAM (CRRAM) device with Pt top and TiN bottom electrode. A subsequent post metal annealing at 400°C induces CRRAM. Forming voltage of 4.3 V is required for this device to initiate switching process. The same device also exhibiting bipolar switching at lower compliance current, Ic <50 μA. The CRRAM device have high reliabilities. Formation of intermediate titanium oxi-nitride layer is confirmed from the cross-sectional HRTEM analysis. The origin of complementary switching mechanism have been discussed with AES, HRTEM analysis and schematic diagram. This paper provides valuable data along with analysis on the origin of CRRAM for the application in nanoscale devices.

  13. Switching to Clozapine Using Immediate Versus Gradual Antipsychotic Discontinuation: A Pilot, Double-Blind, Randomized Controlled Trial.

    PubMed

    Takeuchi, Hiroyoshi; Lee, Jimmy; Fervaha, Gagan; Foussias, George; Agid, Ofer; Remington, Gary

    2017-02-01

    To examine effects of different antipsychotic discontinuation strategies on clinical outcomes in patients with schizophrenia undergoing a switch to clozapine. This pilot, 8-week, double-blind, randomized controlled trial was conducted from May 1999 to July 2004. Outpatients with a diagnosis of schizophrenia or schizoaffective disorder based on the Structured Clinical Interview for DSM-IV and eligible for a switch to clozapine were included. Participants were randomly assigned to the immediate discontinuation (prior antipsychotics were discontinued at baseline) or gradual discontinuation (prior antipsychotics were reduced by 25% each week) group. For each group, clozapine was gradually increased to 300 mg/d at day 12, with this dose maintained for 3 weeks and thereafter adjusted as needed. Clinical outcome measures included the Brief Psychiatric Rating Scale (BPRS), UKU Side Effect Rating Scale, and extrapyramidal symptoms scales. Thirty-three patients were enrolled; 15 and 18 patients were assigned to the immediate and gradual discontinuation groups, respectively. While significant improvements were observed in BPRS total scores after the switch to clozapine in both groups (P values < .001), no significant differences were found on any clinical outcome measures between the groups; however, additional analyses revealed a significant interaction between group and time for the UKU Psychic Side Effects subscale scores (P = .038). This preliminary study demonstrated no statistically significant differences in efficacy or tolerability between immediate and gradual antipsychotic discontinuation strategies when switching to clozapine in patients with schizophrenia; however, due to the small sample size, larger-scale trials are needed to confirm these results. ClinicalTrials.gov identifier: NCT02640300.

  14. Time dependent Bloch mode transmittance in self-assembled random photonic crystal for photonic time delay switching

    NASA Astrophysics Data System (ADS)

    Bingi, Jayachandra; Nair, Radhika V.; Vijayan, C.

    2017-02-01

    Light propagation and localization in a random structure with a periodic background is an upcoming paradigm for novel photonic applications. This paper demonstrates the phenomenon of time dependent transmittance of evanescent Bloch modes (EBM) in ZnS random photonic crystal (RPC) which forms the basis for photonic delay switching. The RPC is fabricated by colloidal self-assembly with ZnS nanospheres of size 215 nm. An anomalous reciprocity and time dependent transmission at EBM (mid band gap wavelength) are observed in coherent back scattering and transmission studies respectively. These are explained on the basis of restricted propagation of EBMs through random channels in the periodic background and enhanced field storage inside RPC. The channelized propagation of EBMs is evident from decreasing time delay of transmittance at reduced thicknesses. The proportionality between transmission time delay and incident power confirms photon (field) storage within the RPC. The results indicate that structures with systematically engineered EBM channels can work as wavelength selective delay switch and further provide a short time photon storage system under non-absorbing conditions.

  15. Resistive Switching of Plasma–Treated Zinc Oxide Nanowires for Resistive Random Access Memory

    PubMed Central

    Lai, Yunfeng; Qiu, Wenbiao; Zeng, Zecun; Cheng, Shuying; Yu, Jinling; Zheng, Qiao

    2016-01-01

    ZnO nanowires (NWs) were grown on Si(100) substrates at 975 °C by a vapor-liquid-solid method with ~2 nm and ~4 nm gold thin films as catalysts, followed by an argon plasma treatment for the as-grown ZnO NWs. A single ZnO NW–based memory cell with a Ti/ZnO/Ti structure was then fabricated to investigate the effects of plasma treatment on the resistive switching. The plasma treatment improves the homogeneity and reproducibility of the resistive switching of the ZnO NWs, and it also reduces the switching (set and reset) voltages with less fluctuations, which would be associated with the increased density of oxygen vacancies to facilitate the resistive switching as well as to average out the stochastic movement of individual oxygen vacancies. Additionally, a single ZnO NW–based memory cell with self-rectification could also be obtained, if the inhomogeneous plasma treatment is applied to the two Ti/ZnO contacts. The plasma-induced oxygen vacancy disabling the rectification capability at one of the Ti/ZnO contacts is believed to be responsible for the self-rectification in the memory cell.

  16. Code-Switching: L1-Coded Mediation in a Kindergarten Foreign Language Classroom

    ERIC Educational Resources Information Center

    Lin, Zheng

    2012-01-01

    This paper is based on a qualitative inquiry that investigated the role of teachers' mediation in three different modes of coding in a kindergarten foreign language classroom in China (i.e. L2-coded intralinguistic mediation, L1-coded cross-lingual mediation, and L2-and-L1-mixed mediation). Through an exploratory examination of the varying effects…

  17. Enhanced resistive switching performance for bilayer HfO2/TiO2 resistive random access memory

    NASA Astrophysics Data System (ADS)

    Ye, Cong; Deng, Tengfei; Zhang, Junchi; Shen, Liangping; He, Pin; Wei, Wei; Wang, Hao

    2016-10-01

    We prepared bilayer HfO2/TiO2 resistive random accessory memory (RRAM) using magnetron sputtering on an ITO/PEN flexible substrate. The switching voltages (V SET and V RESET) were smaller for the Pt/HfO2/TiO2/ITO device than for a Pt/HfO2/ITO memory device. The insertion of a TiO2 layer in the switching layer was inferred to act as an oxygen reservoir to reduce the switching voltages. In addition, greatly improved uniformity was achieved, which showed the coefficient of the variations of V SET and V RESET to be 9.90% and 6.35% for the bilayer structure RRAM. We deduced that occurrence of conductive filament connection/rupture at the interface of the HfO2 and TiO2, in combination with the HfO2 acting as a virtual cathode, led to the improved uniformity. A multilevel storage capability can be obtained by varying the stop voltage in the RESET process for bilayer HfO2/TiO2 RRAM. By analyzing the current conduction mechanism, we demonstrated that the multilevel high resistance state (HRS) was attributable to the increased barrier height when the stop voltage was increased.

  18. The role of the local chemical environment of Ag on the resistive switching mechanism of conductive bridging random access memories.

    PubMed

    Souchier, E; D'Acapito, F; Noé, P; Blaise, P; Bernard, M; Jousseaume, V

    2015-10-07

    Conductive bridging random access memories (CBRAMs) are one of the most promising emerging technologies for the next generation of non-volatile memory. However, the lack of understanding of the switching mechanism at the nanoscale level prevents successful transfer to industry. In this paper, Ag/GeSx/W CBRAM devices are analyzed using depth selective X-ray Absorption Spectroscopy before and after switching. The study of the local environment around Ag atoms in such devices reveals that Ag is in two very distinct environments with short Ag-S bonds due to Ag dissolved in the GeSx matrix, and longer Ag-Ag bonds related to an Ag metallic phase. These experiments allow the conclusion that the switching process involves the formation of metallic Ag nano-filaments initiated at the Ag electrode. All these experimental features are well supported by ab initio molecular dynamics simulations showing that Ag favorably bonds to S atoms, and permit the proposal of a model at the microscopic level that can explain the instability of the conductive state in these Ag-GeSx CBRAM devices. Finally, the principle of the nondestructive method described here can be extended to other types of resistive memory concepts.

  19. Mediator facilitates transcriptional activation and dynamic long-range contacts at the IgH locus during class switch recombination

    PubMed Central

    Thomas-Claudepierre, Anne-Sophie; Robert, Isabelle; Rocha, Pedro P.; Raviram, Ramya; Schiavo, Ebe; Heyer, Vincent; Bonneau, Richard; Luo, Vincent M.; Reddy, Janardan K.; Borggrefe, Tilman; Skok, Jane A.

    2016-01-01

    Immunoglobulin (Ig) class switch recombination (CSR) is initiated by the transcription-coupled recruitment of activation-induced cytidine deaminase (AID) to Ig switch regions (S regions). During CSR, the IgH locus undergoes dynamic three-dimensional structural changes in which promoters, enhancers, and S regions are brought to close proximity. Nevertheless, little is known about the underlying mechanisms. In this study, we show that Med1 and Med12, two subunits of the mediator complex implicated in transcription initiation and long-range enhancer/promoter loop formation, are dynamically recruited to the IgH locus enhancers and the acceptor regions during CSR and that their knockdown in CH12 cells results in impaired CSR. Furthermore, we show that conditional inactivation of Med1 in B cells results in defective CSR and reduced acceptor S region transcription. Finally, we show that in B cells undergoing CSR, the dynamic long-range contacts between the IgH enhancers and the acceptor regions correlate with Med1 and Med12 binding and that they happen at a reduced frequency in Med1-deficient B cells. Our results implicate the mediator complex in the mechanism of CSR and are consistent with a model in which mediator facilitates the long-range contacts between S regions and the IgH locus enhancers during CSR and their transcriptional activation. PMID:26903242

  20. Mediator facilitates transcriptional activation and dynamic long-range contacts at the IgH locus during class switch recombination.

    PubMed

    Thomas-Claudepierre, Anne-Sophie; Robert, Isabelle; Rocha, Pedro P; Raviram, Ramya; Schiavo, Ebe; Heyer, Vincent; Bonneau, Richard; Luo, Vincent M; Reddy, Janardan K; Borggrefe, Tilman; Skok, Jane A; Reina-San-Martin, Bernardo

    2016-03-07

    Immunoglobulin (Ig) class switch recombination (CSR) is initiated by the transcription-coupled recruitment of activation-induced cytidine deaminase (AID) to Ig switch regions (S regions). During CSR, the IgH locus undergoes dynamic three-dimensional structural changes in which promoters, enhancers, and S regions are brought to close proximity. Nevertheless, little is known about the underlying mechanisms. In this study, we show that Med1 and Med12, two subunits of the mediator complex implicated in transcription initiation and long-range enhancer/promoter loop formation, are dynamically recruited to the IgH locus enhancers and the acceptor regions during CSR and that their knockdown in CH12 cells results in impaired CSR. Furthermore, we show that conditional inactivation of Med1 in B cells results in defective CSR and reduced acceptor S region transcription. Finally, we show that in B cells undergoing CSR, the dynamic long-range contacts between the IgH enhancers and the acceptor regions correlate with Med1 and Med12 binding and that they happen at a reduced frequency in Med1-deficient B cells. Our results implicate the mediator complex in the mechanism of CSR and are consistent with a model in which mediator facilitates the long-range contacts between S regions and the IgH locus enhancers during CSR and their transcriptional activation.

  1. A random six-phase switch regulates pneumococcal virulence via global epigenetic changes

    PubMed Central

    Manso, Ana Sousa; Chai, Melissa H.; Atack, John M.; Furi, Leonardo; De Ste Croix, Megan; Haigh, Richard; Trappetti, Claudia; Ogunniyi, Abiodun D.; Shewell, Lucy K.; Boitano, Matthew; Clark, Tyson A.; Korlach, Jonas; Blades, Matthew; Mirkes, Evgeny; Gorban, Alexander N.; Paton, James C.; Jennings, Michael P.; Oggioni, Marco R.

    2014-01-01

    Streptococcus pneumoniae (the pneumococcus) is the world’s foremost bacterial pathogen in both morbidity and mortality. Switching between phenotypic forms (or ‘phases’) that favour asymptomatic carriage or invasive disease was first reported in 1933. Here, we show that the underlying mechanism for such phase variation consists of genetic rearrangements in a Type I restriction-modification system (SpnD39III). The rearrangements generate six alternative specificities with distinct methylation patterns, as defined by single-molecule, real-time (SMRT) methylomics. The SpnD39III variants have distinct gene expression profiles. We demonstrate distinct virulence in experimental infection and in vivo selection for switching between SpnD39III variants. SpnD39III is ubiquitous in pneumococci, indicating an essential role in its biology. Future studies must recognize the potential for switching between these heretofore undetectable, differentiated pneumococcal subpopulations in vitro and in vivo. Similar systems exist in other bacterial genera, indicating the potential for broad exploitation of epigenetic gene regulation. PMID:25268848

  2. Probing Cu doped Ge0.3Se0.7 based resistance switching memory devices with random telegraph noise

    NASA Astrophysics Data System (ADS)

    Soni, R.; Meuffels, P.; Petraru, A.; Weides, M.; Kügeler, C.; Waser, R.; Kohlstedt, H.

    2010-01-01

    The ultimate sensitivity of any solid state device is limited by fluctuations. Fluctuations are manifestations of the thermal motion of matter and the discreteness of its structure which are also inherent ingredients during the resistive switching process of resistance random access memory (RRAM) devices. In quest for the role of fluctuations in different memory states and to develop resistive switching based nonvolatile memory devices, here we present our study on random telegraph noise (RTN) resistance fluctuations in Cu doped Ge0.3Se0.7 based RRAM cells. The influence of temperature and electric field on the RTN fluctuations is studied on different resistance states of the memory cells to reveal the dynamics of the underlying fluctuators. Our analysis indicates that the observed fluctuations could arise from thermally activated transpositions of Cu ions inside ionic or redox "double-site traps" triggering fluctuations in the current transport through a filamentary conducting path. Giant RTN fluctuations characterized by relative resistance variations of up to 50% in almost macroscopic samples clearly point to the existence of weak links with small effective cross-sectional areas along the conducting paths. Such large resistance fluctuations can be an important issue for the industrial applications of RRAM devices because they might lead to huge bit-error rates during reading cycles.

  3. Mediation and Spillover Effects in Group-Randomized Trials with Application to the 4Rs Evaluation

    ERIC Educational Resources Information Center

    VanderWeele, Tyler J.; Hong, Guanglei; Jones, Stephanie M.; Brown, Joshua L.

    2011-01-01

    In this paper the authors extend recent work on mediation in a multilevel setting and on causal inference under interference among units to develop a template for the mediation analysis of group randomized educational interventions. The present work will contribute to the literature on interference, in particular on interference in the context of…

  4. Spectral shifts and switches in random fields upon interaction with negative-phase materials

    SciTech Connect

    Tong Zhisong; Korotkova, Olga

    2010-07-15

    Spectral shifts in stochastic beam-like fields on interaction with layers of positive- and negative-phase materials are examined on the basis of the ABCD-matrix approach and generalized Huygens-Fresnel principle. It is found that boundaries between such materials may cause spectral switches. Effect of absorption of negative-phase materials on the beam spectrum is discussed. Our results may find applications in connection with spectrum-selection optical interconnects, spectrally encoded information transfer, image formation in systems involving negative-phase materials, and geometrically tunable metamaterials.

  5. Switching time of electrical tuning of permeability in strain-mediated multiferroic heterostructures

    NASA Astrophysics Data System (ADS)

    Phuoc, Nguyen N.; Ong, C. K.

    2017-08-01

    The switching time of the electrically tunable permeability of the NiFeTa/[Pb(Mg1/3Nb2/3)O3]0.68-[PbTiO3]0.32 multiferroic material was characterized by using a Vector Network Analyzer and a pulse generator. The measured switching time for the permeability to be electrically tuned from the initial value to the final value upon the change of the applied electrical field is 0.15 s, which is independent of the magnitude of the electrical field and the measured frequency. The result is verified by the measurement of the time response permeability under a series of pulses with different pulse widths. It was found that for the cases of the pulse width smaller than the switching time, the rise time of the permeability response pulse is the same as the pulse width and the pulse height of the response permeability is linearly dependent on the pulse width. It is suggested that the temporal relaxation process of the interface arising from the strain transfer delay time between the film and the substrate plays a dominant role in the contribution of the total switching time of the material.

  6. RNase L Cleavage Products Promote Switch from Autophagy to Apoptosis by Caspase-Mediated Cleavage of Beclin-1

    PubMed Central

    Siddiqui, Mohammad Adnan; Mukherjee, Sushovita; Manivannan, Praveen; Malathi, Krishnamurthy

    2015-01-01

    Autophagy and apoptosis share regulatory molecules enabling crosstalk in pathways that affect cellular homeostasis including response to viral infections and survival of tumor cells. Ribonuclease L (RNase L) is an antiviral endonuclease that is activated in virus-infected cells and cleaves viral and cellular single-stranded RNAs to produce small double-stranded RNAs with roles in amplifying host responses. Activation of RNase L induces autophagy and apoptosis in many cell types. However, the mechanism by which RNase L mediates crosstalk between these two pathways remains unclear. Here we show that small dsRNAs produced by RNase L promote a switch from autophagy to apoptosis by caspase-mediated cleavage of Beclin-1, terminating autophagy. The caspase 3-cleaved C-terminal fragment of Beclin-1 enhances apoptosis by translocating to the mitochondria along with proapoptotic protein, Bax, and inducing release of cytochrome C to the cytosol. Cleavage of Beclin-1 determines switch to apoptosis since expression of caspase-resistant Beclin-1 inhibits apoptosis and sustains autophagy. Moreover, inhibiting RNase L-induced autophagy promotes cell death and inhibiting apoptosis prolongs autophagy in a cross-inhibitory mechanism. Our results demonstrate a novel role of RNase L generated small RNAs in cross-talk between autophagy and apoptosis that impacts the fate of cells during viral infections and cancer. PMID:26263979

  7. Antisense Oligonucleotides Modulating Activation of a Nonsense-Mediated RNA Decay Switch Exon in the ATM Gene

    PubMed Central

    Kralovicova, Jana; Moreno, Pedro M.D.; Cross, Nicholas C.P.; Pêgo, Ana Paula

    2016-01-01

    ATM (ataxia-telangiectasia, mutated) is an important cancer susceptibility gene that encodes a key apical kinase in the DNA damage response pathway. ATM mutations in the germ line result in ataxia-telangiectasia (A-T), a rare genetic syndrome associated with hypersensitivity to double-strand DNA breaks and predisposition to lymphoid malignancies. ATM expression is limited by a tightly regulated nonsense-mediated RNA decay (NMD) switch exon (termed NSE) located in intron 28. In this study, we identify antisense oligonucleotides that modulate NSE inclusion in mature transcripts by systematically targeting the entire 3.1-kb-long intron. Their identification was assisted by a segmental deletion analysis of transposed elements, revealing NSE repression upon removal of a distant antisense Alu and NSE activation upon elimination of a long terminal repeat transposon MER51A. Efficient NSE repression was achieved by delivering optimized splice-switching oligonucleotides to embryonic and lymphoblastoid cells using chitosan-based nanoparticles. Together, these results provide a basis for possible sequence-specific radiosensitization of cancer cells, highlight the power of intronic antisense oligonucleotides to modify gene expression, and demonstrate transposon-mediated regulation of NSEs. PMID:27658045

  8. Switch Rates During Acute Treatment for Bipolar II Depression With Lithium, Sertraline, or the Two Combined: A Randomized Double-Blind Comparison.

    PubMed

    Altshuler, Lori L; Sugar, Catherine A; McElroy, Susan L; Calimlim, Brian; Gitlin, Michael; Keck, Paul E; Aquino-Elias, Ana; Martens, Brian E; Fischer, E Grace; English, Teri L; Roach, Janine; Suppes, Trisha

    2017-03-01

    The authors compared medication-induced mood switch risk (primary outcome), as well as treatment response and side effects (secondary outcomes) with three acute-phase treatments for bipolar II depression. In a 16-week, double-blind, multisite comparison study, 142 participants with bipolar II depression were randomly assigned to receive lithium monotherapy (N=49), sertraline monotherapy (N=45), or combination treatment with lithium and sertraline (N=48). At each visit, mood was assessed using standardized rating scales. Rates of switch were compared, as were rates of treatment response and the presence and severity of treatment-emergent side effects. Twenty participants (14%) experienced a switch during the study period (hypomania, N=17; severe hypomania, N=3). Switch rates did not differ among the three treatment groups, even after accounting for dropout. No patient had a manic switch or was hospitalized for a switch. Most switches occurred within the first 5 weeks of treatment. The treatment response rate for the overall sample was 62.7% (N=89), without significant differences between groups after accounting for dropout. The lithium/sertraline combination group had a significantly higher overall dropout rate than the monotherapy groups but did not have an accelerated time to response. Lithium monotherapy, sertraline monotherapy, and lithium/sertraline combination therapy were associated with similar switch and treatment response rates in participants with bipolar II depression. The dropout rate was higher in the lithium/sertraline combination treatment group, without any treatment acceleration advantage.

  9. Causal Inference in Randomized Experiments with Mediational Processes

    ERIC Educational Resources Information Center

    Jo, Booil

    2008-01-01

    This article links the structural equation modeling (SEM) approach with the principal stratification (PS) approach, both of which have been widely used to study the role of intermediate posttreatment outcomes in randomized experiments. Despite the potential benefit of such integration, the 2 approaches have been developed in parallel with little…

  10. 14-3-3 proteins regulate a cell-intrinsic switch from sonic hedgehog-mediated commissural axon attraction to repulsion after midline crossing.

    PubMed

    Yam, Patricia T; Kent, Christopher B; Morin, Steves; Farmer, W Todd; Alchini, Ricardo; Lepelletier, Léa; Colman, David R; Tessier-Lavigne, Marc; Fournier, Alyson E; Charron, Frédéric

    2012-11-21

    Axons must switch responsiveness to guidance cues during development for correct pathfinding. Sonic Hedgehog (Shh) attracts spinal cord commissural axons ventrally toward the floorplate. We show that after crossing the floorplate, commissural axons switch their response to Shh from attraction to repulsion, so that they are repelled anteriorly by a posterior-high/anterior-low Shh gradient along the longitudinal axis. This switch is recapitulated in vitro with dissociated commissural neurons as they age, indicating that the switch is intrinsic and time dependent. 14-3-3 protein inhibition converted Shh-mediated repulsion of aged dissociated neurons to attraction and prevented the correct anterior turn of postcrossing commissural axons in vivo, an effect mediated through PKA. Conversely, overexpression of 14-3-3 proteins was sufficient to drive the switch from Shh-mediated attraction to repulsion both in vitro and in vivo. Therefore, we identify a 14-3-3 protein-dependent mechanism for a cell-intrinsic temporal switch in the polarity of axon turning responses. Copyright © 2012 Elsevier Inc. All rights reserved.

  11. Obligatory participation of macrophages in an angiopoietin 2-mediated cell death switch

    PubMed Central

    Rao, Sujata; Lobov, Ivan B.; Vallance, Jefferson E.; Tsujikawa, Kaoru; Shiojima, Ichiro; Akunuru, Shailaja; Walsh, Kenneth; Benjamin, Laura E.; Lang, Richard A.

    2013-01-01

    Macrophages have a critical function in the recognition and engulfment of dead cells. In some settings, macrophages also actively signal programmed cell death. Here we show that during developmentally scheduled vascular regression, resident macrophages are an obligatory participant in a signaling switch that favors death over survival. This switch occurs when the signaling ligand angiopoietin 2 has the dual effect of suppressing survival signaling in vascular endothelial cells (VECs) and stimulating Wnt ligand production by macrophages. In response to the Wnt ligand, VECs enter the cell cycle and in the absence of survival signals, die from G1 phase of the cell cycle. We propose that this mechanism represents an adaptation to ensure that the macrophage and its disposal capability are on hand when cell death occurs. PMID:18039971

  12. Realization of a reversible switching in TaO{sub 2} polymorphs via Peierls distortion for resistance random access memory

    SciTech Connect

    Zhu, Linggang; Sun, Zhimei; Zhou, Jian; Guo, Zhonglu

    2015-03-02

    Transition-metal-oxide based resistance random access memory (RRAM) is a promising candidate for next-generation universal non-volatile memories. Searching and designing appropriate materials used in the memories becomes an urgent task. Here, a structure with the TaO{sub 2} formula was predicted using evolutionary algorithms in combination with first-principles calculations. This triclinic structure (T-TaO{sub 2}) is both energetically and dynamically more favorable than the commonly believed rutile structure (R-TaO{sub 2}). The metal-insulator transition (MIT) between metallic R-TaO{sub 2} and T-TaO{sub 2} (band gap: 1.0 eV) is via a Peierls distortion, which makes TaO{sub 2} a potential candidate for RRAM. The energy barrier for the reversible phase transition is 0.19 eV/atom and 0.23 eV/atom, respectively, suggesting low power consumption for the resistance switch. The present findings about the MIT as the resistance-switch mechanism in Ta-O system will stimulate experimental work to fabricate tantalum oxides based RRAM.

  13. Molecular dynamics simulation reveals conformational switching of water-mediated uracil-cytosine base-pairs in an RNA duplex.

    PubMed

    Schneider, C; Brandl, M; Sühnel, J

    2001-01-26

    A 4 ns molecular dynamics simulation of an RNA duplex (r-GGACUUCGGUCC)(2 )in solution with Na+ and Cl- as counterions was performed. The X-ray structure of this duplex includes two water-mediated uracil-cytosine pairs. In contrast to the other base-pairs in the duplex the water-mediated pairs switch between different conformations. One conformation corresponds to the geometry of the water-mediated UC pairs in the duplex X-ray structure with water acting both as hydrogen-bond donor and acceptor. Another conformation is close to that of a water-mediated UC base-pair found in the X-ray structure of the 23 S rRNA sarcin/ricin domain. In this case the oxygen of the water molecule is linked to two-base donor sites. For a very short time also a direct UC base-pair and a further conformation that is similar to the one found in the RNA duplex structure but exhibits an increased H3(U)...N3(C) distance is observed. Water molecules with unusually long residence times are involved in the water-mediated conformations. These results indicate that the dynamic behaviour of the water-mediated UC base-pairs differs from that of the duplex Watson-Crick and non-canonical guanine-uracil pairs with two or three direct hydrogen bonds. The conformational variability and increased flexibility has to be taken into account when considering these base-pairs as RNA building blocks and as recognition motifs. Copyright 2001 Academic Press.

  14. An engineered small RNA-mediated genetic switch based on a ribozyme expression platform

    PubMed Central

    Klauser, Benedikt; Hartig, Jörg S.

    2013-01-01

    An important requirement for achieving many goals of synthetic biology is the availability of a large repertoire of reprogrammable genetic switches and appropriate transmitter molecules. In addition to engineering genetic switches, the interconnection of individual switches becomes increasingly important for the construction of more complex genetic networks. In particular, RNA-based switches of gene expression have become a powerful tool to post-transcriptionally program genetic circuits. RNAs used for regulatory purposes have the advantage to transmit, sense, process and execute information. We have recently used the hammerhead ribozyme to control translation initiation in a small molecule-dependent fashion. In addition, riboregulators have been constructed in which a small RNA acts as transmitter molecule to control translation of a target mRNA. In this study, we combine both concepts and redesign the hammerhead ribozyme to sense small trans-acting RNAs (taRNAs) as input molecules resulting in repression of translation initiation in Escherichia coli. Importantly, our ribozyme-based expression platform is compatible with previously reported artificial taRNAs, which were reported to act as inducers of gene expression. In addition, we provide several insights into key requirements of riboregulatory systems, including the influences of varying transcriptional induction of the taRNA and mRNA transcripts, 5′-processing of taRNAs, as well as altering the secondary structure of the taRNA. In conclusion, we introduce an RNA-responsive ribozyme-based expression system to the field of artificial riboregulators that can serve as reprogrammable platform for engineering higher-order genetic circuits. PMID:23585277

  15. Switch-mediated activation and retargeting of CAR-T cells for B-cell malignancies

    PubMed Central

    Rodgers, David T.; Mazagova, Magdalena; Hampton, Eric N.; Cao, Yu; Ramadoss, Nitya S.; Hardy, Ian R.; Schulman, Andrew; Du, Juanjuan; Wang, Feng; Singer, Oded; Ma, Jennifer; Nunez, Vanessa; Shen, Jiayin; Woods, Ashley K.; Wright, Timothy M.; Schultz, Peter G.; Kim, Chan Hyuk; Young, Travis S.

    2016-01-01

    Chimeric antigen receptor T (CAR-T) cell therapy has produced impressive results in clinical trials for B-cell malignancies. However, safety concerns related to the inability to control CAR-T cells once infused into the patient remain a significant challenge. Here we report the engineering of recombinant antibody-based bifunctional switches that consist of a tumor antigen-specific Fab molecule engrafted with a peptide neo-epitope, which is bound exclusively by a peptide-specific switchable CAR-T cell (sCAR-T). The switch redirects the activity of the bio-orthogonal sCAR-T cells through the selective formation of immunological synapses, in which the sCAR-T cell, switch, and target cell interact in a structurally defined and temporally controlled manner. Optimized switches specific for CD19 controlled the activity, tissue-homing, cytokine release, and phenotype of sCAR-T cells in a dose-titratable manner in a Nalm-6 xenograft rodent model of B-cell leukemia. The sCAR–T-cell dosing regimen could be tuned to provide efficacy comparable to the corresponding conventional CART-19, but with lower cytokine levels, thereby offering a method of mitigating cytokine release syndrome in clinical translation. Furthermore, we demonstrate that this methodology is readily adaptable to targeting CD20 on cancer cells using the same sCAR-T cell, suggesting that this approach may be broadly applicable to heterogeneous and resistant tumor populations, as well as other liquid and solid tumor antigens. PMID:26759369

  16. Switch-mediated activation and retargeting of CAR-T cells for B-cell malignancies.

    PubMed

    Rodgers, David T; Mazagova, Magdalena; Hampton, Eric N; Cao, Yu; Ramadoss, Nitya S; Hardy, Ian R; Schulman, Andrew; Du, Juanjuan; Wang, Feng; Singer, Oded; Ma, Jennifer; Nunez, Vanessa; Shen, Jiayin; Woods, Ashley K; Wright, Timothy M; Schultz, Peter G; Kim, Chan Hyuk; Young, Travis S

    2016-01-26

    Chimeric antigen receptor T (CAR-T) cell therapy has produced impressive results in clinical trials for B-cell malignancies. However, safety concerns related to the inability to control CAR-T cells once infused into the patient remain a significant challenge. Here we report the engineering of recombinant antibody-based bifunctional switches that consist of a tumor antigen-specific Fab molecule engrafted with a peptide neo-epitope, which is bound exclusively by a peptide-specific switchable CAR-T cell (sCAR-T). The switch redirects the activity of the bio-orthogonal sCAR-T cells through the selective formation of immunological synapses, in which the sCAR-T cell, switch, and target cell interact in a structurally defined and temporally controlled manner. Optimized switches specific for CD19 controlled the activity, tissue-homing, cytokine release, and phenotype of sCAR-T cells in a dose-titratable manner in a Nalm-6 xenograft rodent model of B-cell leukemia. The sCAR-T-cell dosing regimen could be tuned to provide efficacy comparable to the corresponding conventional CART-19, but with lower cytokine levels, thereby offering a method of mitigating cytokine release syndrome in clinical translation. Furthermore, we demonstrate that this methodology is readily adaptable to targeting CD20 on cancer cells using the same sCAR-T cell, suggesting that this approach may be broadly applicable to heterogeneous and resistant tumor populations, as well as other liquid and solid tumor antigens.

  17. Control of randomly scattered surface plasmon polaritons for multiple-input and multiple-output plasmonic switching devices

    PubMed Central

    Choi, Wonjun; Jo, Yonghyeon; Ahn, Joonmo; Seo, Eunsung; Park, Q-Han; Jhon, Young Min; Choi, Wonshik

    2017-01-01

    Merging multiple microprocessors with high-speed optical networks has been considered a promising strategy for the improvement of overall computation power. However, the loss of the optical communication bandwidth is inevitable when interfacing between optical and electronic components. Here we present an on-chip plasmonic switching device consisting of a two-dimensional (2D) disordered array of nanoholes on a thin metal film that can provide multiple-input and multiple-output channels for transferring information from a photonic to an electronic platform. In this device, the surface plasmon polaritons (SPPs) generated at individual nanoholes become uncorrelated on their way to the detection channel due to random multiple scattering. We exploit this decorrelation effect to use individual nanoholes as independent antennas, and demonstrated that more than 40 far-field incident channels can be delivered simultaneously to the SPP channels, an order of magnitude improvement over conventional 2D patterned devices. PMID:28262721

  18. Control of randomly scattered surface plasmon polaritons for multiple-input and multiple-output plasmonic switching devices.

    PubMed

    Choi, Wonjun; Jo, Yonghyeon; Ahn, Joonmo; Seo, Eunsung; Park, Q-Han; Jhon, Young Min; Choi, Wonshik

    2017-03-06

    Merging multiple microprocessors with high-speed optical networks has been considered a promising strategy for the improvement of overall computation power. However, the loss of the optical communication bandwidth is inevitable when interfacing between optical and electronic components. Here we present an on-chip plasmonic switching device consisting of a two-dimensional (2D) disordered array of nanoholes on a thin metal film that can provide multiple-input and multiple-output channels for transferring information from a photonic to an electronic platform. In this device, the surface plasmon polaritons (SPPs) generated at individual nanoholes become uncorrelated on their way to the detection channel due to random multiple scattering. We exploit this decorrelation effect to use individual nanoholes as independent antennas, and demonstrated that more than 40 far-field incident channels can be delivered simultaneously to the SPP channels, an order of magnitude improvement over conventional 2D patterned devices.

  19. Control of randomly scattered surface plasmon polaritons for multiple-input and multiple-output plasmonic switching devices

    NASA Astrophysics Data System (ADS)

    Choi, Wonjun; Jo, Yonghyeon; Ahn, Joonmo; Seo, Eunsung; Park, Q.-Han; Jhon, Young Min; Choi, Wonshik

    2017-03-01

    Merging multiple microprocessors with high-speed optical networks has been considered a promising strategy for the improvement of overall computation power. However, the loss of the optical communication bandwidth is inevitable when interfacing between optical and electronic components. Here we present an on-chip plasmonic switching device consisting of a two-dimensional (2D) disordered array of nanoholes on a thin metal film that can provide multiple-input and multiple-output channels for transferring information from a photonic to an electronic platform. In this device, the surface plasmon polaritons (SPPs) generated at individual nanoholes become uncorrelated on their way to the detection channel due to random multiple scattering. We exploit this decorrelation effect to use individual nanoholes as independent antennas, and demonstrated that more than 40 far-field incident channels can be delivered simultaneously to the SPP channels, an order of magnitude improvement over conventional 2D patterned devices.

  20. Switching mechanism in resistive random access memory by first-principles calculation using practical model based on experimental results

    NASA Astrophysics Data System (ADS)

    Moriyama, Takumi; Yamasaki, Takahiro; Hida, Sohta; Ohno, Takahisa; Kishida, Satoru; Kinoshita, Kentaro

    2017-04-01

    For the practical use of resistive random access memory (ReRAM), many formation/rupture models of conductive paths are proposed. In this paper, we report both the probability of conductive path formation on grain surfaces and the marked drastic change in conductivity caused by a small number of atoms migrating on grain surfaces, determined by using experimental and calculation results complementarily. Experimental results of resistive switching operating modes suggest that resistance changes at grain boundaries, to which our calculation results can give an explanation. The energy for the conductive change from a low-resistance state to a high-resistance state is estimated to be about 0.05 eV per surface atom, which is much smaller than the formation and migration energies of vacancies (1.44-4.42 eV) and is comparable to the estimated temperature of the conductive path in the reset process.

  1. Calculation of energy-barrier lowering by incoherent switching in spin-transfer torque magnetoresistive random-access memory

    NASA Astrophysics Data System (ADS)

    Munira, Kamaram; Visscher, P. B.

    2015-05-01

    To make a useful spin-transfer torque magnetoresistive random-access memory (STT-MRAM) device, it is necessary to be able to calculate switching rates, which determine the error rates of the device. In a single-macrospin model, one can use a Fokker-Planck equation to obtain a low-current thermally activated rate ∝exp(-Ee f f/kBT ) . Here, the effective energy barrier Eeff scales with the single-macrospin energy barrier KV, where K is the effective anisotropy energy density and V the volume. A long-standing paradox in this field is that the actual energy barrier appears to be much smaller than this. It has been suggested that incoherent motions may lower the barrier, but this has proved difficult to quantify. In the present paper, we show that the coherent precession has a magnetostatic instability, which allows quantitative estimation of the energy barrier and may resolve the paradox.

  2. Switching from clozapine to zotepine in patients with schizophrenia: a 12-week prospective, randomized, rater blind, and parallel study.

    PubMed

    Lin, Chao-Cheng; Chiu, Hsien-Jane; Chen, Jen-Yeu; Liou, Ying-Jay; Wang, Ying-Chieh; Chen, Tzu-Ting; Bai, Ya-Mei

    2013-04-01

    Clozapine is the most effective antipsychotic for patients with treatment-refractory schizophrenia, but many adverse effects are noted. Clinicians usually hesitate to switch from clozapine to other antipsychotics because of the risk of a re-emergence or worsening of the psychosis, although empirical studies are very limited. Zotepine, an atypical antipsychotic with a pharmacologic profile similar to clozapine, was found to be an effective treatment for patients with treatment-resistant schizophrenia in Japan. This 12-week study is the first prospective, randomized, and rater-blind study to investigate the efficacy and tolerability of switching from clozapine to zotepine. Fifty-nine patients with schizophrenia, who had taken clozapine for at least 6 months with a Clinical Global Impression-Severity score of at least 3, were randomly allocated to the zotepine and the clozapine groups. At the end of the study, 52 patients (88%) had completed the trial. The 7 withdrawal cases were all in the zotepine group. The final mean (SD) dose of zotepine and clozapine was 397.1 (75.7) versus 377.1 (62.5) mg/d, respectively. Patients in the zotepine group showed a significant increase in the Brief Psychiatric Rating Scale [mean (SD), 4.7 (8.7) vs -1.3 (6.3); P = 0.005], more general adverse effects as revealed by the Udvalg for Kliniske Undersogelser Rating Scale [mean (SD), 1.74 (3.9) vs -0.2 (2.8); P = 0.039], more extrapyramidal adverse effects as demonstrated by the Simpson and Angus Scale [mean (SD), 1.29 (3.5) vs 0.17 (2.1); P = 0.022], an increased use of propranolol (37.1% vs 0%, P < 0.0001) and anticholinergics (25.7% vs 0%, P = 0.008), and an increased level of prolactin (29.6 vs -3.8 ng/ mL, P < 0.0005), compared with the clozapine group. The results suggested that switching from clozapine to zotepine treatment should be done with caution.

  3. Five-year outcomes after laparoscopic gastric bypass and laparoscopic duodenal switch in patients with body mass index of 50 to 60: a randomized clinical trial.

    PubMed

    Risstad, Hilde; Søvik, Torgeir T; Engström, My; Aasheim, Erlend T; Fagerland, Morten W; Olsén, Monika Fagevik; Kristinsson, Jon A; le Roux, Carel W; Bøhmer, Thomas; Birkeland, Kåre I; Mala, Tom; Olbers, Torsten

    2015-04-01

    There is no consensus as to which bariatric procedure is preferred to reduce weight and improve health in patients with a body mass index higher than 50. To compare 5-year outcomes after Roux-en-Y gastric bypass (gastric bypass) and biliopancreatic diversion with duodenal switch (duodenal switch). Randomized clinical open-label trial at Oslo University Hospital, Oslo, Norway, and Sahlgrenska University Hospital, Gothenburg, Sweden. Participants were recruited between March 17, 2006, and August 20, 2007, and included 60 patients aged 20 to 50 years with a body mass index of 50 to 60. The current study provides the 5-year follow-up analyses by intent to treat, excluding one participant accepted for inclusion who declined being operated on prior to knowing to what group he was randomized. Laparoscopic gastric bypass and laparoscopic duodenal switch. Body mass index and secondary outcomes including anthropometric measures, cardiometabolic risk factors, pulmonary function, vitamin status, gastrointestinal symptoms, health-related quality of life, and adverse events. Sixty patients were randomly assigned and operated on with gastric bypass (n = 31) and duodenal switch (n = 29). Fifty-five patients (92%) completed the study. Five years after surgery, the mean reductions in body mass index were 13.6 (95% CI, 11.0-16.1) and 22.1 (95% CI, 19.5-24.7) after gastric bypass and duodenal switch, respectively. The mean between-group difference was 8.5 (95% CI, 4.9-12.2; P < .001). Remission rates of type 2 diabetes mellitus and metabolic syndrome and changes in blood pressure and lung function were similar between groups. Reductions in total cholesterol, low-density lipoprotein cholesterol, triglycerides, and fasting glucose were significantly greater after duodenal switch compared with gastric bypass. Serum concentrations of vitamin A and 25-hydroxyvitamin D were significantly reduced after duodenal switch compared with gastric bypass. Duodenal switch was associated

  4. HIF-mediated metabolic switching in bladder outlet obstruction mitigates the relaxing effect of mitochondrial inhibition.

    PubMed

    Ekman, Mari; Uvelius, Bengt; Albinsson, Sebastian; Swärd, Karl

    2014-05-01

    Prior work demonstrated increased levels of hypoxia-inducible factor-1α (HIF-1α) in the bladder following outlet obstruction, associated with bladder growth and fibrosis. Here we hypothesized that HIF induction in outlet obstruction also switches energetic support of contraction from mitochondrial respiration to glycolysis. To address this hypothesis, we created infravesical outlet obstruction in female Sprague-Dawley rats and examined HIF induction and transcriptional activation. HIF-1α increased after 6 weeks of outlet obstruction as assessed by western blotting and yet transcription factor-binding site analysis indicated HIF activation already at 10 days of obstruction. Accumulation HIF-2α and of Arnt2 proteins were found at 10 days, providing an explanation for the lack of correlation between HIF-1α protein and transcriptional activation. HIF signature targets, including Slc2a1, Tpi1, Eno1 and Ldha increased in obstructed compared with sham-operated bladders. The autophagy markers Bnip3 and LC3B-II were also increased at 6 week of obstruction, but electron microscopy did not support mitophagy. Mitochondria were, however, remodeled with increased expression of Cox4 compared with other markers. In keeping with a switch toward glycolytic support of contraction, we found that relaxation by the mitochondrial inhibitor cyanide was reduced in obstructed bladders. This was mimicked by organ culture with the HIF-inducer dimethyloxalylglycine, which also upregulated expression of Ldha. On the basis of these findings, we conclude that HIF activation in outlet obstruction involves mechanisms beyond the accumulation of HIF-1α protein and that it results in a switch of the energetic support of contraction to anaerobic glycolysis. This metabolic adaptation encompasses increased expression of glucose transporters and glycolytic enzymes combined with mitochondrial remodeling. Together, these changes uphold contractility when mitochondrial respiration is limited.

  5. A meta-analysis of randomized controlled trials of telmisartan for flow-mediated dilatation.

    PubMed

    Takagi, Hisato; Umemoto, Takuya

    2014-09-01

    There have been a number of small-sized underpowered randomized controlled trials to assess effects of telmisartan on flow-mediated dilatation (FMD). To determine whether telmisartan increases FMD, we performed a meta-analysis of these trials. MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were searched through December 2013. Eligible studies were prospective randomized controlled trials of telmisartan reporting FMD as an outcome. Search terms included: telmisartan; endothelial function/dysfunction; flow-mediated dilation/dilatation/vasodilation/vasodilatation; and randomized, randomly or randomization. Included studies were reviewed to determine the number of patients randomized, mean duration of treatment and percent changes of FMD. Of 25 potentially relevant articles screened initially, seven reports of randomized trials enrolling a total of 398 patients were identified and included. A pooled analysis of the seven trials demonstrated a statistically significant increase in FMD by 48.7%, with telmisartan relative to control in the random-effects model (mean difference, 48.72%; 95% confidence interval, 15.37-82.08%; P for effect=0.004; P for heterogeneity <0.00001). Exclusion of any single trial from the analysis did not substantively alter the overall result of our analysis. There was no evidence of significant publication bias. In conclusion, the present meta-analysis of seven randomized controlled trials enrolling a total of 398 patients confirmed the evidence of a significant increase in FMD with telmisartan, which suggests that telmisartan may improve endothelial dysfunction.

  6. Aging as a mitochondria-mediated atavistic program: can aging be switched off?

    PubMed

    Skulachev, Vladimir P; Longo, Valter D

    2005-12-01

    Programmed death phenomena have been demonstrated on subcellular (mitoptosis), cellular (apoptosis), and supracellular (collective apoptosis) levels. There are numerous examples of suicide mechanisms at the organismal level (phenoptosis). In yeast, it was recently shown that the death of aging cells is programmed. Many of the steps of programmed cell death are shown to be common for yeast and animals, including mammals. In particular, generation of the mitochondrial reactive oxygen species (ROS) is involved in the suicide programs. Aging of higher animals is accompanied by an increase in damage induced by mitochondrial ROS. Perhaps prevention of such damage by scavenging of mitochondrial ROS might slow down or even switch off the aging programs.

  7. EZH2 phosphorylation by JAK3 mediates a switch to noncanonical function in natural killer/T-cell lymphoma.

    PubMed

    Yan, Junli; Li, Boheng; Lin, Baohong; Lee, Pei Tsung; Chung, Tae-Hoon; Tan, Joy; Bi, Chonglei; Lee, Xue Ting; Selvarajan, Viknesvaran; Ng, Siok-Bian; Yang, Henry; Yu, Qiang; Chng, Wee-Joo

    2016-08-18

    The best-understood mechanism by which EZH2 exerts its oncogenic function is through polycomb repressive complex 2 (PRC2)-mediated gene repression, which requires its histone methyltransferase activity. However, small-molecule inhibitors of EZH2 that selectively target its enzymatic activity turn out to be potent only for lymphoma cells with EZH2-activating mutation. Intriguingly, recent discoveries, including ours, have placed EZH2 into the category of transcriptional coactivators and thus raised the possibility of noncanonical signaling pathways. However, it remains unclear how EZH2 switches to this catalytic independent function. In the current study, using natural killer/T-cell lymphoma (NKTL) as a disease model, we found that phosphorylation of EZH2 by JAK3 promotes the dissociation of the PRC2 complex leading to decreased global H3K27me3 levels, while it switches EZH2 to a transcriptional activator, conferring higher proliferative capacity of the affected cells. Gene expression data analysis also suggests that the noncanonical function of EZH2 as a transcriptional activator upregulates a set of genes involved in DNA replication, cell cycle, biosynthesis, stemness, and invasiveness. Consistently, JAK3 inhibitor was able to significantly reduce the growth of NKTL cells, in an EZH2 phosphorylation-dependent manner, whereas various compounds recently developed to inhibit EZH2 methyltransferase activity have no such effect. Thus, pharmacological inhibition of JAK3 activity may provide a promising treatment option for NKTL through the novel mechanism of suppressing noncanonical EZH2 activity.

  8. Chromatin remodelling and antisense-mediated up-regulation of the developmental switch gene eud-1 control predatory feeding plasticity

    PubMed Central

    Serobyan, Vahan; Xiao, Hua; Namdeo, Suryesh; Rödelsperger, Christian; Sieriebriennikov, Bogdan; Witte, Hanh; Röseler, Waltraud; Sommer, Ralf J.

    2016-01-01

    Phenotypic plasticity has been suggested to act through developmental switches, but little is known about associated molecular mechanisms. In the nematode Pristionchus pacificus, the sulfatase eud-1 was identified as part of a developmental switch controlling mouth-form plasticity governing a predatory versus bacteriovorous mouth-form decision. Here we show that mutations in the conserved histone-acetyltransferase Ppa-lsy-12 and the methyl-binding-protein Ppa-mbd-2 mimic the eud-1 phenotype, resulting in the absence of one mouth-form. Mutations in both genes cause histone modification defects and reduced eud-1 expression. Surprisingly, Ppa-lsy-12 mutants also result in the down-regulation of an antisense-eud-1 RNA. eud-1 and antisense-eud-1 are co-expressed and further experiments suggest that antisense-eud-1 acts through eud-1 itself. Indeed, overexpression of the antisense-eud-1 RNA increases the eud-1-sensitive mouth-form and extends eud-1 expression. In contrast, this effect is absent in eud-1 mutants indicating that antisense-eud-1 positively regulates eud-1. Thus, chromatin remodelling and antisense-mediated up-regulation of eud-1 control feeding plasticity in Pristionchus. PMID:27487725

  9. The ABA-mediated switch between submersed and emersed life-styles in aquatic macrophytes.

    PubMed

    Wanke, Dierk

    2011-07-01

    Hydrophytes comprise aquatic macrophytes from various taxa that are able to sustain and to complete their lifecycle in a flooded environment. Their ancestors, however, underwent adaptive processes to withstand drought on land and became partially or completely independent of water for sexual reproduction. Interestingly, the step backwards into the high-density aquatic medium happened independently several times in numerous plant taxa. For flowering plants, this submersed life-style is especially difficult as they need to erect their floral organs above the water surface to be pollinated. Moreover, fresh-water plants evolved the adaptive mechanism of heterophylly, which enabled them to switch between a submersed and an emersed leaf morphology. The plant hormone abscisic acid (ABA) is a key factor of heterophylly induction in aquatic plants and is a major switch between a submersed and emersed life. The mechanisms of ABA signal perception and transduction appear to be conserved throughout the evolution of basal plants to angiosperms and from terrestrial to aquatic plants. This review summarizes the interplay of environmental factors that act through ABA to orchestrate adaptation of plants to their aquatic environment.

  10. Inflammatory pain hypersensitivity mediated by phenotypic switch in myelinated primary sensory neurons

    NASA Astrophysics Data System (ADS)

    Neumann, Simona; Doubell, Tim P.; Leslie, Tabi; Woolf, Clifford J.

    1996-11-01

    PAIN is normally evoked only by stimuli that are sufficiently intense to activate high-threshold Aδ and C sensory fibres, which relay the signal to the spinal cord. Peripheral inflammation leads to profoundly increased pain sensitivity: noxious stimuli generate a greater response and stimuli that are normally innocuous elicit pain. Inflammation increases the sensitivity of the peripheral terminals of Aδ and C fibres at the site of inflammation1. It also increases the excitability of spinal cord neurons2,3, which now amplify all sensory inputs including the normally innocuous tactile stimuli that are conveyed by low-threshold Aβ fibres. This central sensitization has been attributed to the enhanced activity of C fibres4, which increase the excitability of their postsynaptic targets by releasing glutamate and the neuropeptide substance P5-7. Here we show that inflammation results in Aβ fibres also acquiring the capacity to increase the excitability of spinal cord neurons. This is due to a phenotypic switch in a subpopulation of these fibres so that they, like C-fibres, now express substance P. Aβ fibres thus appear to contribute to inflammatory hypersensitivity by switching their phenotype to one resembling pain fibres, thereby enhancing synaptic transmission in the spinal cord and exaggerating the central response to innocuous stimuli.

  11. Antisense COOLAIR mediates the coordinated switching of chromatin states at FLC during vernalization

    PubMed Central

    Csorba, Tibor; Questa, Julia I.; Sun, Qianwen; Dean, Caroline

    2014-01-01

    Long noncoding RNAs (lncRNAs) have been proposed to play important roles in gene regulation. However, their importance in epigenetic silencing and how specificity is determined remain controversial. We have investigated the cold-induced epigenetic switching mechanism involved in the silencing of Arabidopsis thaliana FLOWERING LOCUS C (FLC), which occurs during vernalization. Antisense transcripts, collectively named COOLAIR, are induced by prolonged cold before the major accumulation of histone 3 lysine 27 trimethylation (H3K27me3), characteristic of Polycomb silencing. We have found that COOLAIR is physically associated with the FLC locus and accelerates transcriptional shutdown of FLC during cold exposure. Removal of COOLAIR disrupted the synchronized replacement of H3K36 methylation with H3K27me3 at the intragenic FLC nucleation site during the cold. Consistently, genetic analysis showed COOLAIR and Polycomb complexes work independently in the cold-dependent silencing of FLC. Our data reveal a role for lncRNA in the coordinated switching of chromatin states that occurs during epigenetic regulation. PMID:25349421

  12. Hepatitis C virus RNA: molecular switches mediated by long-range RNA–RNA interactions?

    PubMed Central

    Shetty, Sumangala; Stefanovic, Snezana; Mihailescu, Mihaela Rita

    2013-01-01

    Multiple conserved structural cis-acting regulatory elements have been recognized both in the coding and untranslated regions (UTRs) of the hepatitis C virus (HCV) genome. For example, the cis-element 5BSL3.2 in the HCV-coding region has been predicted to use both its apical and internal loops to interact with the X RNA in the 3′-UTR, with the IIId domain in the 5′-UTR and with the Alt sequence in the coding region. Additionally, the X RNA region uses a palindromic sequence that overlaps the sequence required for the interaction with 5BSL3.2, to dimerize with another HCV genome. The ability of the 5BSL3.2 and X RNA regions to engage in multi-interactions suggests the existence of one or more molecular RNA switches which may regulate different steps of the HCV life cycle. In this study, we used biophysical methods to characterize the essential interactions of these HCV cis-elements at the molecular level. Our results indicate that X RNA interacts with 5BSL3.2 and another X RNA molecule by adopting two different conformations and that 5BSL3.2 engages simultaneously in kissing interactions using its apical and internal loops. Based on these results, we propose a mode of action for possible molecular switches involving the HCV RNA. PMID:23275555

  13. Viral RNA switch mediates the dynamic control of flavivirus replicase recruitment by genome cyclization

    PubMed Central

    Liu, Zhong-Yu; Li, Xiao-Feng; Jiang, Tao; Deng, Yong-Qiang; Ye, Qing; Zhao, Hui; Yu, Jiu-Yang; Qin, Cheng-Feng

    2016-01-01

    Viral replicase recruitment and long-range RNA interactions are essential for RNA virus replication, yet the mechanism of their interplay remains elusive. Flaviviruses include numerous important human pathogens, e.g., dengue virus (DENV) and Zika virus (ZIKV). Here, we revealed a highly conserved, conformation-tunable cis-acting element named 5′-UAR-flanking stem (UFS) in the flavivirus genomic 5′ terminus. We demonstrated that the UFS was critical for efficient NS5 recruitment and viral RNA synthesis in different flaviviruses. Interestingly, stabilization of the DENV UFS impaired both genome cyclization and vRNA replication. Moreover, the UFS unwound in response to genome cyclization, leading to the decreased affinity of NS5 for the viral 5′ end. Thus, we propose that the UFS is switched by genome cyclization to regulate dynamic RdRp binding for vRNA replication. This study demonstrates that the UFS enables communication between flavivirus genome cyclization and RdRp recruitment, highlighting the presence of switch-like mechanisms among RNA viruses. DOI: http://dx.doi.org/10.7554/eLife.17636.001 PMID:27692070

  14. Tunable switch mediated shikimate biosynthesis in an engineered non-auxotrophic Escherichia coli

    PubMed Central

    Gu, Pengfei; Su, Tianyuan; Wang, Qian; Liang, Quanfeng; Qi, Qingsheng

    2016-01-01

    Shikimate is a key intermediate in the synthesis of neuraminidase inhibitors. Compared with traditional methods, microbial production of shikimate has the advantages of environmental friendliness, low cost, feed stock renewability, and product selectivity and diversity. Despite these advantages, shikimate kinase I and II respectively encoded by aroK and aroL are inactivated in most shikimate microbial producers, thus requiring the addition of aromatic compounds during the fermentation process. To overcome this problem, we constructed a non-auxotrophic, shikimate-synthesising strain of Escherichia coli. By inactivation of repressor proteins, blocking of competitive pathways and overexpression of key enzymes, we increased the shikimate production of wild-type E. coli BW25113 to 1.73 g/L. We then designed a tunable switch that can conditionally decrease gene expression and substituted it for the original aroK promoters. Expression of aroK in the resulting P-9 strain was maintained at a high level during the growth phase and then reduced at a suitable time by addition of an optimal concentration of inducer. In 5-L fed-batch fermentation, strain P-9 produced 13.15 g/L shikimate without the addition of any aromatic compounds. The tunable switch developed in this study is an efficient tool for regulating indispensable genes involved in critical metabolic pathways. PMID:27406890

  15. Correcting treatment effect for treatment switching in randomized oncology trials with a modified iterative parametric estimation method.

    PubMed

    Zhang, Jin; Chen, Cong

    2016-09-20

    In randomized oncology trials, patients in the control arm are sometimes permitted to switch to receive experimental drug after disease progression. This is mainly due to ethical reasons or to reduce the patient dropout rate. While progression-free survival is not usually impacted by crossover, the treatment effect on overall survival can be highly confounded. The rank-preserving structural failure time (RPSFT) model and iterative parametric estimation (IPE) are the main randomization-based methods used to adjust for confounding in the analysis of overall survival. While the RPSFT has been extensively studied, the properties of the IPE have not been thoroughly examined and its application is not common. In this manuscript, we clarify the re-censoring algorithm needed for IPE estimation and incorporate it into a method we propose as modified IPE (MIPE). We compared the MIPE and RPSFT via extensive simulations and then walked through the analysis using the modified IPE in a real clinical trial. We provided practical guidance on bootstrap by examining the performance in estimating the variance and confidence interval for the MIPE. Our results indicate that the MIPE method with the proposed re-censoring rule is an attractive alternative to the RPSFT method. Copyright © 2016 John Wiley & Sons, Ltd.

  16. Total synthesis of marinomycin A using salicylate as a molecular switch to mediate dimerization.

    PubMed

    Evans, P Andrew; Huang, Mu-Hua; Lawler, Michael J; Maroto, Sergio

    2012-07-01

    Antibiotics play a significant role in human health because of their ability to treat life-threatening bacterial infections. The growing problems with antibiotic resistance have made the development of new antibiotics a World Health Organization priority. Marinomycin A is a member of a new class of bis-salicylate-containing polyene macrodiolides, which have potent antibiotic activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. Herein, we describe a triply convergent synthesis of this agent using the salicylate as a novel molecular switch for the chemoselective construction of the macrodiolide. This strategy raises new questions regarding the biosynthetic role of the salicylate and its potential impact on the mechanism of action of these types of agents. For instance, in contrast to penicillin, which enhances the electrophilicity of the cyclic amide through ring strain, salicylates reduce the electrophilicity of the aryl ester through an intramolecular resonance-assisted hydrogen bond to provide an amide surrogate.

  17. Total synthesis of marinomycin A using salicylate as a molecular switch to mediate dimerization

    NASA Astrophysics Data System (ADS)

    Evans, P. Andrew; Huang, Mu-Hua; Lawler, Michael J.; Maroto, Sergio

    2012-08-01

    Antibiotics play a significant role in human health because of their ability to treat life-threatening bacterial infections. The growing problems with antibiotic resistance have made the development of new antibiotics a World Health Organization priority. Marinomycin A is a member of a new class of bis-salicylate-containing polyene macrodiolides, which have potent antibiotic activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. Herein, we describe a triply convergent synthesis of this agent using the salicylate as a novel molecular switch for the chemoselective construction of the macrodiolide. This strategy raises new questions regarding the biosynthetic role of the salicylate and its potential impact on the mechanism of action of these types of agents. For instance, in contrast to penicillin, which enhances the electrophilicity of the cyclic amide through ring strain, salicylates reduce the electrophilicity of the aryl ester through an intramolecular resonance-assisted hydrogen bond to provide an amide surrogate.

  18. Effect of platform switching on crestal bone levels around implants in the posterior mandible: 3 years results from a multicentre randomized clinical trial.

    PubMed

    Rocha, Salomão; Wagner, Wilfried; Wiltfang, Jörg; Nicolau, Pedro; Moergel, Maximilian; Messias, Ana; Behrens, Eleonore; Guerra, Fernando

    2016-04-01

    Evaluation of differences in the clinical performance and crestal bone levels between implants restored with single crowns with platform-matched or platform-switched abutments after 3 years. The study enrolled adult patients missing two or more adjacent teeth in the posterior mandible with natural teeth mesial to the implant site. Randomization followed open-flap implant insertion and the corresponding matching or switching healing abutments placed at surgery. Conventional loading was made with cemented crowns. Clinical follow-up took place annually after loading up to 3 years. Bone level changes were measured in standardized radiographs as the variation in crestal bone from one evaluation to the next. Sixty-three patients with a total of 135 implants (66 platform matching, 69 platform switching) were analysed. From surgery to 36 months, mean bone loss was 0.28 ± 0.56 mm for the platform-switching group and 0.68 ± 0.64 mm for the platform-matching group. A statistically significant difference was found between groups (p = 0.002) with an estimate of 0.39 mm (0.15-0.64, 95% CI) in favour of platform switching. After 3 years, platform-switching restorations showed a significant effect in the preservation of marginal bone levels compared to platform-matching restorations. © 2016 The Authors. Journal of Clinical Periodontology Published by John Wiley & Sons Ltd.

  19. Comparison of Antipsychotics for Metabolic Problems (CAMP): A randomized trial examining the effectiveness of switching from olanzapine, quetiapine, or risperidone to aripiprazole to reduce metabolic risk

    PubMed Central

    Stroup, T. Scott; McEvoy, Joseph P.; Ring, Kimberly D.; Hamer, Robert H.; LaVange, Lisa M.; Swartz, Marvin S.; Rosenheck, Robert A.; Perkins, Diana O.; Nussbaum, Abraham M.; Lieberman, Jeffrey A.

    2013-01-01

    Objective We conducted a multi-site, randomized controlled trial examining the strategy of switching from olanzapine, quetiapine, or risperidone to aripiprazole to ameliorate metabolic risk factors for cardiovascular disease. Method Patients with schizophrenia or schizoaffective disorder with BMI ≥ 27 and non-HDL cholesterol (non-HDL-C) ≥ 130 mg/dl on a stable dosage of olanzapine, quetiapine, or risperidone were randomly assigned to stay on the current medication (n=106) or switch to aripiprazole (n=109) for 24 weeks. All participants were enrolled in a behaviorally oriented diet and exercise program. Raters were blinded to treatment assignment. The primary and key secondary outcomes were non-HDL-C change and efficacy failure, respectively. Results The pre-specified primary analysis included 89 switchers and 98 stayers who had at least one post-baseline non-HDL-C measurement. The least squares mean estimates of non-HDL-C decreased more for the switch than the stay groups (−20.2 vs. −10.8 mg/dl). Switching was associated with larger reductions in weight (2.9 kg) and a net reduction of serum triglycerides of 32.7 mg/dl. Twenty-two (20.6%) switchers and 18 (17.0%) stayers experienced protocol-defined efficacy failure. Forty-seven (43.9%) switchers and 26 (24.5%) stayers discontinued the assigned antipsychotic before 24 weeks. Conclusion Switching to aripiprazole led to improvement of non-HDL-C and other metabolic parameters. Rates of efficacy failure were similar between groups, but switching to aripiprazole was associated with a higher rate of treatment discontinuation. In the context of close clinical monitoring, switching from an antipsychotic with high metabolic risk to one with lower risk to improve metabolic parameters is an effective strategy. PMID:21768610

  20. FLIP switches Fas-mediated glucose signaling in human pancreatic β cells from apoptosis to cell replication

    PubMed Central

    Maedler, Kathrin; Fontana, Adriano; Ris, Frédéric; Sergeev, Pavel; Toso, Christian; Oberholzer, José; Lehmann, Roger; Bachmann, Felix; Tasinato, Andrea; Spinas, Giatgen A.; Halban, Philippe A.; Donath, Marc Y.

    2002-01-01

    Type 2 diabetes mellitus results from an inadequate adaptation of the functional pancreatic β cell mass in the face of insulin resistance. Changes in the concentration of glucose play an essential role in the regulation of β cell turnover. In human islets, elevated glucose concentrations impair β cell proliferation and induce β cell apoptosis via up-regulation of the Fas receptor. Recently, it has been shown that the caspase-8 inhibitor FLIP may divert Fas-mediated death signals into those for cell proliferation in lymphatic cells. We observed expression of FLIP in human pancreatic β cells of nondiabetic individuals, which was decreased in tissue sections of type 2 diabetic patients. In vitro exposure of islets from nondiabetic organ donors to high glucose levels decreased FLIP expression and increased the percentage of apoptotic terminal deoxynucleotidyltransferase-mediated UTP end labeling (TUNEL)-positive β cells; FLIP was no longer detectable in such TUNEL-positive β cells. Up-regulation of FLIP, by incubation with transforming growth factor β or by transfection with an expression vector coding for FLIP, protected β cells from glucose-induced apoptosis, restored β cell proliferation, and improved β cell function. The beneficial effects of FLIP overexpression were blocked by an antagonistic anti-Fas antibody, indicating their dependence on Fas receptor activation. The present data provide evidence for expression of FLIP in the human β cell and suggest a novel approach to prevent and treat diabetes by switching Fas signaling from apoptosis to proliferation. PMID:12060768

  1. Neuronal Stress Pathway Mediating a Histone Methyl/Phospho Switch is Required for Herpes Simplex Virus Reactivation

    PubMed Central

    Cliffe, Anna R.; Arbuckle, Jesse H.; L.Vogel, Jodi; Geden, Matthew J.; Rothbart, Scott B.; Cusack, Corey L.; Strahl, Brian D.; Kristie, Thomas M.; Deshmukh, Mohanish

    2015-01-01

    SUMMARY Herpes simplex virus (HSV) reactivation from latent neuronal infection requires stimulation of lytic gene expression from promoters associated with repressive heterochromatin. Various neuronal stresses trigger reactivation, but how these stimuli activate silenced promoters remains unknown. We show that a neuronal pathway involving activation of c-Jun N-terminal kinase (JNK), common to many stress responses, is essential for initial HSV gene expression during reactivation. This JNK activation in neurons is mediated by dual leucine zipper kinase (DLK) and JNK-interacting protein 3 (JIP3), which direct JNK towards stress responses instead of other cellular functions. Surprisingly, JNK-mediated viral gene induction occurs independently of histone demethylases that remove repressive lysine modifications. Rather, JNK signaling results in a histone methyl/phospho switch on HSV lytic promoters, a mechanism permitting gene expression in the presence of repressive lysine methylation. JNK is present on viral promoters during reactivation, thereby linking a neuronal-specific stress pathway and HSV reactivation from latency. PMID:26651941

  2. Randomized Controlled Caregiver Mediated Joint Engagement Intervention for Toddlers with Autism

    ERIC Educational Resources Information Center

    Kasari, Connie; Gulsrud, Amanda C.; Wong, Connie; Kwon, Susan; Locke, Jill

    2010-01-01

    This study aimed to determine if a joint attention intervention would result in greater joint engagement between caregivers and toddlers with autism. The intervention consisted of 24 caregiver-mediated sessions with follow-up 1 year later. Compared to caregivers and toddlers randomized to the waitlist control group the immediate treatment (IT)…

  3. Testing Mediators of Intervention Effects in Randomized Controlled Trials: An Evaluation of Three Depression Prevention Programs

    ERIC Educational Resources Information Center

    Stice, Eric; Rohde, Paul; Seeley, John R.; Gau, Jeff M.

    2010-01-01

    Objective: Evaluate a new 5-step method for testing mediators hypothesized to account for the effects of depression prevention programs. Method: In this indicated prevention trial, at-risk teens with elevated depressive symptoms were randomized to a group cognitive-behavioral (CB) intervention, group supportive expressive intervention, CB…

  4. A Randomized Switch From Nevirapine-Based Antiretroviral Therapy to Single Tablet Rilpivirine/Emtricitabine/Tenofovir Disoproxil Fumarate in Virologically Suppressed Human Immunodeficiency Virus-1-Infected Rwandans.

    PubMed

    Collins, Sean E; Grant, Philip M; Uwinkindi, Francois; Talbot, Annie; Seruyange, Eric; Slamowitz, Deborah; Mugeni, Adeline; Remera, Eric; Niyonsenga, Simon Pierre; Nyirimigabo, Josbert; Uwizihiwe, Jean Paul; Dongier, Pierre; Muhayimpundu, Ribakare; Mazarati, Jean-Baptiste; Zolopa, Andrew; Nsanzimana, Sabin

    2016-09-01

    Background.  Many human immunodeficiency virus (HIV)-infected patients remain on nevirapine-based antiretroviral therapy (ART) despite safety and efficacy concerns. Switching to a rilpivirine-based regimen is an alternative, but there is little experience with rilpivirine in sub-Saharan Africa where induction of rilpivirine metabolism by nevirapine, HIV subtype, and dietary differences could potentially impact efficacy. Methods.  We conducted an open-label noninferiority study of virologically suppressed (HIV-1 ribonucleic acid [RNA] < 50 copies/mL) HIV-1-infected Rwandan adults taking nevirapine plus 2 nucleos(t)ide reverse-transcriptase inhibitors. One hundred fifty participants were randomized 2:1 to switch to coformulated rilpivirine-emtricitabine-tenofovir disoproxil fumarate (referenced as the Switch Arm) or continue current therapy. The primary efficacy endpoint was HIV-1 RNA < 200 copies/mL at week 24 assessed by the US Food and Drug Administration Snapshot algorithm with a noninferiority margin of 12%. Results.  Between April and September 2014, 184 patients were screened, and 150 patients were enrolled; 99 patients switched to rilpivirine-emtricitabine-tenofovir, and 51 patients continued their nevirapine-based ART. The mean age was 42 years and 43% of participants were women. At week 24, virologic suppression (HIV-1 RNA level <200 copies/mL) was maintained in 93% and 92% in the Switch Arm versus the continuation arm, respectively. The Switch Arm was noninferior to continued nevirapine-based ART (efficacy difference 0.8%; 95% confidence interval, -7.5% to +12.0%). Both regimens were generally safe and well tolerated, although 2 deaths, neither attributed to study medications, occurred in participants in the Switch Arm. Conclusions.  A switch from nevirapine-based ART to rilpivirine-emtricitabine-tenofovir disoproxil fumarate had similar virologic efficacy to continued nevirapine-based ART after 24 weeks with few adverse events.

  5. A Randomized Switch From Nevirapine-Based Antiretroviral Therapy to Single Tablet Rilpivirine/Emtricitabine/Tenofovir Disoproxil Fumarate in Virologically Suppressed Human Immunodeficiency Virus-1-Infected Rwandans

    PubMed Central

    Collins, Sean E.; Grant, Philip M.; Uwinkindi, Francois; Talbot, Annie; Seruyange, Eric; Slamowitz, Deborah; Mugeni, Adeline; Remera, Eric; Niyonsenga, Simon Pierre; Nyirimigabo, Josbert; Uwizihiwe, Jean Paul; Dongier, Pierre; Muhayimpundu, Ribakare; Mazarati, Jean-Baptiste; Zolopa, Andrew; Nsanzimana, Sabin

    2016-01-01

    Background. Many human immunodeficiency virus (HIV)-infected patients remain on nevirapine-based antiretroviral therapy (ART) despite safety and efficacy concerns. Switching to a rilpivirine-based regimen is an alternative, but there is little experience with rilpivirine in sub-Saharan Africa where induction of rilpivirine metabolism by nevirapine, HIV subtype, and dietary differences could potentially impact efficacy. Methods. We conducted an open-label noninferiority study of virologically suppressed (HIV-1 ribonucleic acid [RNA] < 50 copies/mL) HIV-1-infected Rwandan adults taking nevirapine plus 2 nucleos(t)ide reverse-transcriptase inhibitors. One hundred fifty participants were randomized 2:1 to switch to coformulated rilpivirine-emtricitabine-tenofovir disoproxil fumarate (referenced as the Switch Arm) or continue current therapy. The primary efficacy endpoint was HIV-1 RNA < 200 copies/mL at week 24 assessed by the US Food and Drug Administration Snapshot algorithm with a noninferiority margin of 12%. Results. Between April and September 2014, 184 patients were screened, and 150 patients were enrolled; 99 patients switched to rilpivirine-emtricitabine-tenofovir, and 51 patients continued their nevirapine-based ART. The mean age was 42 years and 43% of participants were women. At week 24, virologic suppression (HIV-1 RNA level <200 copies/mL) was maintained in 93% and 92% in the Switch Arm versus the continuation arm, respectively. The Switch Arm was noninferior to continued nevirapine-based ART (efficacy difference 0.8%; 95% confidence interval, −7.5% to +12.0%). Both regimens were generally safe and well tolerated, although 2 deaths, neither attributed to study medications, occurred in participants in the Switch Arm. Conclusions. A switch from nevirapine-based ART to rilpivirine-emtricitabine-tenofovir disoproxil fumarate had similar virologic efficacy to continued nevirapine-based ART after 24 weeks with few adverse events. PMID:27704000

  6. Reducing operation voltages by introducing a low-k switching layer in indium-tin-oxide-based resistance random access memory

    NASA Astrophysics Data System (ADS)

    Jin, Fu-Yuan; Chang, Kuan-Chang; Chang, Ting-Chang; Tsai, Tsung-Ming; Pan, Chih-Hung; Lin, Chih-Yang; Chen, Po-Hsun; Chen, Min-Chen; Huang, Hui-Chun; Lo, Ikai; Zheng, Jin-Cheng; Sze, Simon M.

    2016-06-01

    In this letter, we inserted a low dielectric constant (low-k) or high dielectric constant (high-k) material as a switching layer in indium-tin-oxide-based resistive random-access memory. After measuring the two samples, we found that the low-k material device has very low operating voltages (-80 and 110 mV for SET and RESET operations, respectively). Current fitting results were then used with the COMSOL software package to simulate electric field distribution in the layers. After combining the electrical measurement results with simulations, a conduction model was proposed to explain resistance switching behaviors in the two structures.

  7. Ribosome biogenesis; the KsgA protein throws a methyl-mediated switch in ribosome assembly.

    PubMed

    Mangat, Chand S; Brown, Eric D

    2008-12-01

    Many trans-acting factors that aid in ribosome biogenesis have been identified in higher organisms but relatively few such factors are known in prokaryotes. In bacteria, the list of such factors includes ATP-energized helicases and chaperones as well as an emerging cadre of switch GTPases. The KsgA protein is a universally conserved methyltransferase that dimethylates both A1518 and A1519 of the 16S rRNA of the small ribosomal subunit. Methylation has long been thought to be solely for fine-tuning of protein translation. In this issue of Molecular Microbiology, Connolly et al. present data suggesting KsgA might function in the assembly of the small subunit of the ribosome. Indeed, the work indicates that KsgA might have a checkpoint role in ribosome biogenesis where methylation by this protein marks the completion of its assembly role. These findings open our thinking to new candidate assembly factors and provide a new direction for understanding ribosome assembly.

  8. Resistance switching behavior of ZnO resistive random access memory with a reduced graphene oxide capping layer

    NASA Astrophysics Data System (ADS)

    Lin, Cheng-Li; Chang, Wei-Yi; Huang, Yen-Lun; Juan, Pi-Chun; Wang, Tse-Wen; Hung, Ke-Yu; Hsieh, Cheng-Yu; Kang, Tsung-Kuei; Shi, Jen-Bin

    2015-04-01

    In this work, we investigate the characteristics of ZnO resistive random access memory (RRAM) with a reduced graphene oxide (rGO) capping layer and the polarity effect of the SET/RESET bias on the RRAM. The rGO film insertion enhances the stability of the current-voltage (I-V) switching curve and the superior resistance ratio (˜105) of high-resistance state (HRS) to low-resistance state (LRS). Using the appropriate polarity of the SET/RESET bias applied to the rGO-capped ZnO RRAM enables the oxygen ions to move mainly at the interface of the rGO and ZnO films, resulting in the best performance. Presumably, the rGO film acts as an oxygen reservoir and enhances the easy in and out motion of the oxygen ions from the rGO film. The rGO film also prevents the interaction of oxygen ions and the Al electrode, resulting in excellent performance. In a pulse endurance test, the rGO-capped ZnO RRAM reveals superior endurance of up to 108 cycles over that of the ZnO RRAM without rGO insertion (106 cycles).

  9. Cu impurity in insulators and in metal-insulator-metal structures: Implications for resistance-switching random access memories

    SciTech Connect

    Pandey, Sumeet C. Meade, Roy; Sandhu, Gurtej S.

    2015-02-07

    We present numerical results from atomistic simulations of Cu in SiO{sub 2} and Al{sub 2}O{sub 3}, with an emphasis on the thermodynamic, kinetic, and electronic properties. The calculated properties of Cu impurity at various concentrations (9.91 × 10{sup 20 }cm{sup −3} and 3.41 × 10{sup 22 }cm{sup −3}) in bulk oxides are presented. The metal-insulator interfaces result in up to a ∼4 eV reduction in the formation energies relative to the crystalline bulk. Additionally, the importance of Cu-Cu interaction in lowering the chemical potential is introduced. These concepts are then discussed in the context of formation and stability of localized conductive paths in resistance-switching Random Access Memories (RRAM-M). The electronic density of states and non-equilibrium transmission through these localized paths are studied, confirming conduction by showing three orders of magnitude increase in the electron transmission. The dynamic behavior of the conductive paths is investigated with atomistic drift-diffusion calculations. Finally, the paper concludes with a molecular dynamics simulation of a RRAM-M cell that attempts to combine the aforementioned phenomena in one self-consistent model.

  10. Cu impurity in insulators and in metal-insulator-metal structures: Implications for resistance-switching random access memories

    NASA Astrophysics Data System (ADS)

    Pandey, Sumeet C.; Meade, Roy; Sandhu, Gurtej S.

    2015-02-01

    We present numerical results from atomistic simulations of Cu in SiO2 and Al2O3, with an emphasis on the thermodynamic, kinetic, and electronic properties. The calculated properties of Cu impurity at various concentrations (9.91 × 1020 cm-3 and 3.41 × 1022 cm-3) in bulk oxides are presented. The metal-insulator interfaces result in up to a ˜4 eV reduction in the formation energies relative to the crystalline bulk. Additionally, the importance of Cu-Cu interaction in lowering the chemical potential is introduced. These concepts are then discussed in the context of formation and stability of localized conductive paths in resistance-switching Random Access Memories (RRAM-M). The electronic density of states and non-equilibrium transmission through these localized paths are studied, confirming conduction by showing three orders of magnitude increase in the electron transmission. The dynamic behavior of the conductive paths is investigated with atomistic drift-diffusion calculations. Finally, the paper concludes with a molecular dynamics simulation of a RRAM-M cell that attempts to combine the aforementioned phenomena in one self-consistent model.

  11. Calculation of energy-barrier lowering by incoherent switching in spin-transfer torque magnetoresistive random-access memory

    SciTech Connect

    Munira, Kamaram; Visscher, P. B.

    2015-05-07

    To make a useful spin-transfer torque magnetoresistive random-access memory (STT-MRAM) device, it is necessary to be able to calculate switching rates, which determine the error rates of the device. In a single-macrospin model, one can use a Fokker-Planck equation to obtain a low-current thermally activated rate ∝exp(−E{sub eff}/k{sub B}T). Here, the effective energy barrier E{sub eff} scales with the single-macrospin energy barrier KV, where K is the effective anisotropy energy density and V the volume. A long-standing paradox in this field is that the actual energy barrier appears to be much smaller than this. It has been suggested that incoherent motions may lower the barrier, but this has proved difficult to quantify. In the present paper, we show that the coherent precession has a magnetostatic instability, which allows quantitative estimation of the energy barrier and may resolve the paradox.

  12. Magnetoelectric assisted 180° magnetization switching for electric field addressable writing in magnetoresistive random-access memory.

    PubMed

    Wang, Zhiguang; Zhang, Yue; Wang, Yaojin; Li, Yanxi; Luo, Haosu; Li, Jiefang; Viehland, Dwight

    2014-08-26

    Magnetization-based memories, e.g., hard drive and magnetoresistive random-access memory (MRAM), use bistable magnetic domains in patterned nanomagnets for information recording. Electric field (E) tunable magnetic anisotropy can lower the energy barrier between two distinct magnetic states, promising reduced power consumption and increased recording density. However, integration of magnetoelectric heterostructure into MRAM is a highly challenging task owing to the particular architecture requirements of each component. Here, we show an epitaxial growth of self-assembled CoFe2O4 nanostripes with bistable in-plane magnetizations on Pb(Mg,Nb)O3-PbTiO3 (PMN-PT) substrates, where the magnetic switching can be triggered by E-induced elastic strain effect. An unprecedented magnetic coercive field change of up to 600 Oe was observed with increasing E. A near 180° magnetization rotation can be activated by E in the vicinity of the magnetic coercive field. These findings might help to solve the 1/2-selection problem in traditional MRAM by providing reduced magnetic coercive field in E field selected memory cells.

  13. Effect of embedded metal nanocrystals on the resistive switching characteristics in NiN-based resistive random access memory cells

    SciTech Connect

    Yun, Min Ju; Kim, Hee-Dong; Man Hong, Seok; Hyun Park, Ju; Su Jeon, Dong; Geun Kim, Tae

    2014-03-07

    The metal nanocrystals (NCs) embedded-NiN-based resistive random access memory cells are demonstrated using several metal NCs (i.e., Pt, Ni, and Ti) with different physical parameters in order to investigate the metal NC's dependence on resistive switching (RS) characteristics. First, depending on the electronegativity of metal, the size of metal NCs is determined and this affects the operating current of memory cells. If metal NCs with high electronegativity are incorporated, the size of the NCs is reduced; hence, the operating current is reduced owing to the reduced density of the electric field around the metal NCs. Second, the potential wells are formed by the difference of work function between the metal NCs and active layer, and the barrier height of the potential wells affects the level of operating voltage as well as the conduction mechanism of metal NCs embedded memory cells. Therefore, by understanding these correlations between the active layer and embedded metal NCs, we can optimize the RS properties of metal NCs embedded memory cells as well as predict their conduction mechanisms.

  14. A Two-Metal-Ion-Mediated Conformational Switching Pathway for HDV Ribozyme Activation

    PubMed Central

    Lee, Tai-Sung; Radak, Brian K.; Harris, Michael E.; York, Darrin M.

    2016-01-01

    RNA enzymes serve as a potentially powerful platform from which to design catalysts and engineer new biotechnology. A fundamental understanding of these systems provides insight to guide design. The hepatitis delta virus ribozyme (HDVr) is a small, self-cleaving RNA motif widely distributed in nature, that has served as a paradigm for understanding basic principles of RNA catalysis. Nevertheless, questions remain regarding the precise roles of divalent metal ions and key nucleotides in catalysis. In an effort to establish a reaction mechanism model consistent with available experimental data, we utilize molecular dynamics simulations to explore different conformations and metal ion binding modes along the HDVr reaction path. Building upon recent crystallographic data, our results provide a dynamic model of the HDVr reaction mechanism involving a conformational switch between multiple non-canonical G25:U20 base pair conformations in the active site. These local nucleobase dynamics play an important role in catalysis by modulating the metal binding environments of two Mg2+ ions that support catalysis at different steps of the reaction pathway. The first ion plays a structural role by inducing a base pair flip necessary to obtain the catalytic fold in which C75 moves towards to the scissile phosphate in the active site. Ejection of this ion then permits a second ion to bind elsewhere in the active site and facilitate nucleophile activation. The simulations collectively describe a mechanistic scenario that is consistent with currently available experimental data from crystallography, phosphorothioate substitutions, and chemical probing studies. Avenues for further experimental verification are suggested. PMID:27774349

  15. Timing of the developmental switch in GABA(A) mediated signaling from excitation to inhibition in CA3 rat hippocampus using gramicidin perforated patch and extracellular recordings.

    PubMed

    Tyzio, Roman; Holmes, Gregory L; Ben-Ari, Yehezkiel; Khazipov, Roustem

    2007-01-01

    The timing of the developmental switch in the GABA(A) mediated responses from excitatory to inhibitory was studied in Wistar rat CA3 hippocampal pyramidal cells using gramicidin perforated patch-clamp and extracellular recordings. Gramicidin perforated patch recordings revealed a gradual developmental shift in the reversal potential of synaptic and isoguvacine-induced GABA(A) mediated responses from -55 +/- 4 mV at postnatal days P0-2 to -74 +/- 3 mV at P13-15 with a midpoint of disappearance of the excitatory effects of GABA at around P8. Extracellular recordings in CA3 pyramidal cell layer revealed that the effect of isoguvacine on multiple unit activity (MUA) switched from an increase to a decrease at around P10. The effect of synaptic GABA(A) mediated responses on MUA switched from an increase to a decrease at around P8. It is concluded that the developmental switch in the action of GABA via GABA(A) receptors from excitatory to inhibitory occurs in Wistar rat CA3 pyramidal cells at around P8-10, an age that coincides with the transition from immature to mature hippocampal rhythms. We propose that excitatory GABA contributes to enhanced excitability and ictogenesis in the neonatal rat hippocampus.

  16. Nonsense-mediated RNA decay – a switch and dial for regulating gene expression

    PubMed Central

    Smith, Jenna E.; Baker, Kristian E.

    2015-01-01

    Nonsense-mediated RNA decay (NMD) represents an established quality control checkpoint for gene expression that protects cells from consequences of gene mutations and errors during RNA biogenesis that lead to premature termination during translation. Characterization of NMD-sensitive transcriptomes has revealed, however, that NMD targets not only aberrant transcripts but also a broad array of mRNA isoforms expressed from many endogenous genes. NMD is thus emerging as a master regulator that drives both fine and coarse adjustments in steady-state RNA levels in the cell. Importantly, while NMD activity is subject to autoregulation as a means to maintain homeostasis, modulation of the pathway by external cues providesa means to reprogram gene expression and drive important biological processes. Finally, the unanticipated observation that transcripts predicted to lack protein-coding capacity are also sensitive to this translation-dependent surveillance mechanism implicates NMD in regulating RNA function in new and diverse ways. PMID:25820233

  17. A mechanistic hypothesis for the aspirin-induced switch in lipid mediator production by cyclooxygenase-2.

    PubMed

    Tosco, Paolo

    2013-07-17

    Cyclooxygenase (COX) carries out stereospecific oxygen addition to arachidonic acid to generate prostaglandins, plus smaller amounts of 11- and 15-hydroxyeicosatetraenoic acids. For COX-2, the stereochemistry and relative abundance of generated products is influenced by Ser530 acetylation following aspirin treatment. The molecular bases of the high degree of stereospecificity which characterizes COX-2-catalyzed oxygenations are not yet completely understood, nor are the reasons behind the aspirin-induced shift in lipid mediator production. A mechanistic hypothesis is proposed which identifies steric shielding as the main determinant of oxygenation stereospecificity. This hypothesis is supported by a computational model which accurately reproduces experimental oxygenation patterns on both native and aspirin-inhibited COX-2.

  18. A coiled coil switch mediates cold sensing by the thermosensory protein DesK.

    PubMed

    Saita, Emilio; Abriata, Luciano A; Tsai, Yi Ting; Trajtenberg, Felipe; Lemmin, Thomas; Buschiazzo, Alejandro; Dal Peraro, Matteo; de Mendoza, Diego; Albanesi, Daniela

    2015-10-01

    The thermosensor histidine kinase DesK from Bacillus subtilis senses changes in membrane fluidity initiating an adaptive response. Structural changes in DesK have been implicated in transmembrane signaling, but direct evidence is still lacking. On the basis of structure-guided mutagenesis, we now propose a mechanism of DesK-mediated signal sensing and transduction. The data indicate that stabilization/destabilization of a 2-helix coiled coil, which connects the transmembrane sensory domain of DesK to its cytosolic catalytic region, is crucial to control its signaling state. Computational modeling and simulations reveal couplings between protein, water and membrane mechanics. We propose that membrane thickening is the main driving force for signal sensing and that it acts by inducing helix stretching and rotation prompting an asymmetric kinase-competent state. Overall, the known structural changes of the sensor kinase, as well as further dynamic rearrangements that we now predict, consistently link structure determinants to activity modulation.

  19. Effects of switching from olanzapine, quetiapine, and risperidone to aripiprazole on 10-year coronary heart disease risk and metabolic syndrome status: Results from a randomized controlled trial

    PubMed Central

    Stroup, T. Scott; Byerly, Matthew J.; Nasrallah, Henry A.; Ray, Neepa; Khan, Ahsan Y.; Lamberti, J. Steven; Glick, Ira D.; Steinbook, Richard M.; McEvoy, Joseph P.; Hamer, Robert M.

    2013-01-01

    Purpose This study examined the clinical significance of switching from olanzapine, quetiapine, or risperidone to aripiprazole by examining changes in predicted risk of cardiovascular disease (CVD) according to the Framingham Risk Score (FRS) and metabolic syndrome status. FRS estimates 10-year risk of “hard” coronary heart disease (CHD) outcomes (myocardial infarction and coronary death) while metabolic syndrome is associated with increased risk of CVD, stroke, and diabetes mellitus. Method Changes in FRS and metabolic syndrome status were compared between patients with BMI ≥ 27 and non-HDL-C ≥ 130 mg/dL randomly assigned to stay on stable current treatment (olanzapine, quetiapine, or risperidone) or switch to treatment with aripiprazole with 24 weeks of follow-up. All study participants were enrolled in a behavioral program that promoted healthy diet and exercise. Results The pre-specified analyses included 89 switchers and 98 stayers who had post-baseline measurements needed to assess changes. Least squares mean estimates of 10-year CHD risk decreased more for the switch (from 7.0% to 5.2%) than the stay group (from 7.4% to 6.4%) (p=0.0429). The odds ratio for having metabolic syndrome (stay vs. switch) at the last observation was 1.748 (95% CI 0.919, 3.324, p=0.0885). Conclusion Switching from olanzapine, quetiapine, or risperidone to aripiprazole was associated with larger reductions in predicted 10-year risk of CHD than the behavioral program alone. The advantage of switching on metabolic syndrome was not statistically significant. The benefits of switching must be balanced against its risks, which in this study included more discontinuations of the study treatment but no significant increase in symptoms or hospitalizations. PMID:23434503

  20. A simple device unit consisting of all NiO storage and switch elements for multilevel terabit nonvolatile random access memory.

    PubMed

    Lee, Myoung-Jae; Ahn, Seung-Eon; Lee, Chang Bum; Kim, Chang-Jung; Jeon, Sanghun; Chung, U-In; Yoo, In-Kyeong; Park, Gyeong-Su; Han, Seungwu; Hwang, In Rok; Park, Bae-Ho

    2011-11-01

    Present charge-based silicon memories are unlikely to reach terabit densities because of scaling limits. As the feature size of memory shrinks to just tens of nanometers, there is insufficient volume available to store charge. Also, process temperatures higher than 800 °C make silicon incompatible with three-dimensional (3D) stacking structures. Here we present a device unit consisting of all NiO storage and switch elements for multilevel terabit nonvolatile random access memory using resistance switching. It is demonstrated that NiO films are scalable to around 30 nm and compatible with multilevel cell technology. The device unit can be a building block for 3D stacking structure because of its simple structure and constituent, high performance, and process temperature lower than 300 °C. Memory resistance switching of NiO storage element is accompanied by an increase in density of grain boundary while threshold resistance switching of NiO switch element is controlled by current flowing through NiO film.

  1. Sustained Resistive Switching in a Single Cu:7,7,8,8-tetracyanoquinodimethane Nanowire: A Promising Material for Resistive Random Access Memory

    PubMed Central

    Basori, Rabaya; Kumar, Manoranjan; Raychaudhuri, Arup K.

    2016-01-01

    We report a new type of sustained and reversible unipolar resistive switching in a nanowire device made from a single strand of Cu:7,7,8,8-tetracyanoquinodimethane (Cu:TCNQ) nanowire (diameter <100 nm) that shows high ON/OFF ratio (~103), low threshold voltage of switching (~3.5 V) and large cycling endurance (>103). This indicates a promising material for high density resistive random access memory (ReRAM) device integration. Switching is observed in Cu:TCNQ single nanowire devices with two different electrode configuration: symmetric (C-Pt/Cu:TCNQ/C-Pt) and asymmetric (Cu/Cu:TCNQ/C-Pt), where contacts connecting the nanowire play an important role. This report also developed a method of separating out the electrode and material contributions in switching using metal-semiconductor-metal (MSM) device model along with a direct 4-probe resistivity measurement of the nanowire in the OFF as well as ON state. The device model was followed by a phenomenological model of current transport through the nanowire device which shows that lowering of potential barrier at the contacts likely occur due to formation of Cu filaments in the interface between nanowire and contact electrodes. We obtain quantitative agreement of numerically analyzed results with the experimental switching data. PMID:27245099

  2. A Single Regulator Mediates Strategic Switching between Attachment/Spread and Growth/Virulence in the Plant Pathogen Ralstonia solanacearum

    PubMed Central

    Khokhani, Devanshi; Lowe-Power, Tiffany M.; Tran, Tuan Minh

    2017-01-01

    ABSTRACT The PhcA virulence regulator in the vascular wilt pathogen Ralstonia solanacearum responds to cell density via quorum sensing. To understand the timing of traits that enable R. solanacearum to establish itself inside host plants, we created a ΔphcA mutant that is genetically locked in a low-cell-density condition. Comparing levels of gene expression of wild-type R. solanacearum and the ΔphcA mutant during tomato colonization revealed that the PhcA transcriptome includes an impressive 620 genes (>2-fold differentially expressed; false-discovery rate [FDR], ≤0.005). Many core metabolic pathways and nutrient transporters were upregulated in the ΔphcA mutant, which grew faster than the wild-type strain in tomato xylem sap and on dozens of specific metabolites, including 36 found in xylem. This suggests that PhcA helps R. solanacearum to survive in nutrient-poor environmental habitats and to grow rapidly during early pathogenesis. However, after R. solanacearum reaches high cell densities in planta, PhcA mediates a trade-off from maximizing growth to producing costly virulence factors. R. solanacearum infects through roots, and low-cell-density-mode-mimicking ΔphcA cells attached to tomato roots better than the wild-type cells, consistent with their increased expression of several adhesins. Inside xylem vessels, ΔphcA cells formed aberrantly dense mats. Possibly as a result, the mutant could not spread up or down tomato stems as well as the wild type. This suggests that aggregating improves R. solanacearum survival in soil and facilitates infection and that it reduces pathogenic fitness later in disease. Thus, PhcA mediates a second strategic switch between initial pathogen attachment and subsequent dispersal inside the host. PhcA helps R. solanacearum optimally invest resources and correctly sequence multiple steps in the bacterial wilt disease cycle. PMID:28951474

  3. Cu(2+)-mediated fluorescence switching of gold nanoclusters for the selective detection of clioquinol.

    PubMed

    Wang, Jian; Chang, Yong; Zhang, Pu; Lie, Shao Qing; Gao, Peng Fei; Huang, Cheng Zhi

    2015-12-21

    It is of great significance to sense clioquinol (CQ) in a simple and fast way because of its potential application in the treatment of neurodegenerative diseases. In this contribution, we proposed a Cu(2+)-mediated fluorescence switchable strategy to detect CQ by taking bovine serum albumin (BSA) protected gold nanoclusters (AuNCs) as probes. It was found that the strong red fluorescence of BSA-protected AuNCs at 610 nm could be effectively quenched by Cu(2+) (off state) and reversibly recovered by CQ (on state) owing to the specific coordination of CQ and Cu(2+). Under the optimal conditions, there was a good linear relationship between the off-on efficiency (Eoff-on) and the amount of CQ in the range of 1-12 μM (R(2) = 0.9902), with a detection limit of 0.63 μM (3σ). The "turn off-on" mode and the fast and unique complexation of CQ and Cu(2+) endow AuNCs with high specificity for CQ sensing. The proposed strategy is label-free, fast and selective, which is applicable to the analysis of CQ in cream with satisfactory results.

  4. MxaY regulates the lanthanide-mediated methanol dehydrogenase switch in Methylomicrobium buryatense

    SciTech Connect

    Chu, Frances; Beck, David A. C.; Lidstrom, Mary E.

    2016-09-07

    Many methylotrophs, microorganisms that consume carbon compounds lacking carbon–carbon bonds, use two different systems to oxidize methanol for energy production and biomass accumulation. The MxaFI methanol dehydrogenase (MDH) contains calcium in its active site, while the XoxF enzyme contains a lanthanide in its active site. The genes encoding the MDH enzymes are differentially regulated by the presence of lanthanides. In this study, we found that the histidine kinase MxaY controls the lanthanide-mediated switch in Methylomicrobium buryatense 5GB1C. MxaY controls the transcription of genes encoding MxaFI and XoxF at least partially by controlling the transcript levels of the orphan response regulator MxaB. We identify a constitutively active version of MxaY, and identify the mutated residue that may be involved in lanthanide sensing. Finally, we find evidence to suggest that tight control of active MDH production is required for wild-type growth rates.

  5. Molecular characterization of a new scorpion venom lipolysis activating peptide: Evidence for disulfide bridge-mediated functional switch of peptides.

    PubMed

    Zhu, S; Gao, B

    2006-12-22

    Venoms from scorpions contain extremely rich bioactive peptides that often carry diverse functions and are presumably needed to achieve synergistic effects for rapidly immobilizing prey and defending themselves. BotLVP1 is a unique heterodimer protein recently found in the scorpion Buthus occitanus tunetanus venom that is structurally related to scorpion toxins affecting sodium channels (NaScTxs) but exhibits adipocyte lipolysis activity. We have isolated and identified two cDNA clones encoding subunits alpha and beta of a BotLVP1-like peptide (named BmLVP1) from the Chinese scorpion Buthus martensii venom gland and determined the first complete gene structure of this subfamily. These results highlight a genetic link between these lipolysis activating peptides and NaScTxs. Comparison of cDNA and genomic sequences combined with protein structural and functional analysis provides evidence supporting the existence of RNA editing mechanism in scorpion venom glands, which could mediate functional switch of BmLVP1 gene, from adipocyte lipolysis to neurotoxicity, by altering the wrapper disulfide bridge (WDB) pattern of the peptides.

  6. Cyclic di-GMP mediates a histidine kinase/phosphatase switch by noncovalent domain cross-linking

    PubMed Central

    Dubey, Badri N.; Lori, Christian; Ozaki, Shogo; Fucile, Geoffrey; Plaza-Menacho, Ivan; Jenal, Urs; Schirmer, Tilman

    2016-01-01

    Histidine kinases are key components of regulatory networks in bacteria. Although many of these enzymes are bifunctional, mediating both phosphorylation and dephosphorylation of downstream targets, the molecular details of this central regulatory switch are unclear. We showed recently that the universal second messenger cyclic di–guanosine monophosphate (c-di-GMP) drives Caulobacter crescentus cell cycle progression by forcing the cell cycle kinase CckA from its default kinase into phosphatase mode. We use a combination of structure determination, modeling, and functional analysis to demonstrate that c-di-GMP reciprocally regulates the two antagonistic CckA activities through noncovalent cross-linking of the catalytic domain with the dimerization histidine phosphotransfer (DHp) domain. We demonstrate that both c-di-GMP and ADP (adenosine diphosphate) promote phosphatase activity and propose that c-di-GMP stabilizes the ADP-bound quaternary structure, which allows the receiver domain to access the dimeric DHp stem for dephosphorylation. In silico analyses predict that c-di-GMP control is widespread among bacterial histidine kinases, arguing that it can replace or modulate canonical transmembrane signaling. PMID:27652341

  7. Cdk1 and Plk1 mediate a CLASP2 phospho-switch that stabilizes kinetochore–microtubule attachments

    PubMed Central

    Garcia, Zaira; Kabeche, Lilian; Barisic, Marin; Maffini, Stefano; Macedo-Ribeiro, Sandra; Cheeseman, Iain M.; Compton, Duane A.; Kaverina, Irina

    2012-01-01

    Accurate chromosome segregation during mitosis relies on a dynamic kinetochore (KT)–microtubule (MT) interface that switches from a labile to a stable condition in response to correct MT attachments. This transition is essential to satisfy the spindle-assembly checkpoint (SAC) and couple MT-generated force with chromosome movements, but the underlying regulatory mechanism remains unclear. In this study, we show that during mitosis the MT- and KT-associated protein CLASP2 is progressively and distinctively phosphorylated by Cdk1 and Plk1 kinases, concomitant with the establishment of KT–MT attachments. CLASP2 S1234 was phosphorylated by Cdk1, which primed CLASP2 for association with Plk1. Plk1 recruitment to KTs was enhanced by CLASP2 phosphorylation on S1234. This was specifically required to stabilize KT–MT attachments important for chromosome alignment and to coordinate KT and non-KT MT dynamics necessary to maintain spindle bipolarity. CLASP2 C-terminal phosphorylation by Plk1 was also required for chromosome alignment and timely satisfaction of the SAC. We propose that Cdk1 and Plk1 mediate a fine CLASP2 “phospho-switch” that temporally regulates KT–MT attachment stability. PMID:23045552

  8. Randomized Controlled Caregiver Mediated Joint Engagement Intervention for Toddlers with Autism

    PubMed Central

    Gulsrud, Amanda C.; Wong, Connie; Kwon, Susan; Locke, Jill

    2010-01-01

    This study aimed to determine if a joint attention intervention would result in greater joint engagement between caregivers and toddlers with autism. The intervention consisted of 24 caregiver-mediated sessions with follow-up 1 year later. Compared to caregivers and toddlers randomized to the waitlist control group the immediate treatment (IT) group made significant improvements in targeted areas of joint engagement. The IT group demonstrated significant improvements with medium to large effect sizes in their responsiveness to joint attention and their diversity of functional play acts after the intervention with maintenance of these skills 1 year post-intervention. These are among the first randomized controlled data to suggest that short-term parent-mediated interventions can have important effects on core impairments in toddlers with autism. Clinical Trials #: NCT00065910. PMID:20145986

  9. Macrophages Mediate a Switch between Canonical and Non-Canonical Wnt Pathways in Canine Mammary Tumors

    PubMed Central

    Król, Magdalena; Mucha, Joanna; Majchrzak, Kinga; Homa, Agata; Bulkowska, Małgorzata; Majewska, Alicja; Gajewska, Małgorzata; Pietrzak, Marta; Perszko, Mikołaj; Romanowska, Karolina; Pawłowski, Karol; Manuali, Elisabetta; Hellmen, Eva; Motyl, Tomasz

    2014-01-01

    Objective According to the current hypothesis, tumor-associated macrophages (TAMs) are “corrupted” by cancer cells and subsequently facilitate, rather than inhibit, tumor metastasis. Because the molecular mechanisms of cancer cell–TAM interactions are complicated and controversial we aimed to better define this phenomenon. Methods and Results Using microRNA microarrays, Real-time qPCR and Western blot we showed that co-culture of canine mammary tumor cells with TAMs or treatment with macrophage-conditioned medium inhibited the canonical Wnt pathway and activated the non-canonical Wnt pathway in tumor cells. We also showed that co-culture of TAMs with tumor cells increased expression of canonical Wnt inhibitors in TAMs. Subsequently, we demonstrated macrophage-induced invasive growth patterns and epithelial–mesenchymal transition of tumor cells. Validation of these results in canine mammary carcinoma tissues (n = 50) and xenograft tumors indicated the activation of non-canonical and canonical Wnt pathways in metastatic tumors and non-metastatic malignancies, respectively. Activation of non-canonical Wnt pathway correlated with number of TAMs. Conclusions We demonstrated that TAMs mediate a “switch” between canonical and non-canonical Wnt signaling pathways in canine mammary tumors, leading to increased tumor invasion and metastasis. Interestingly, similar changes in neoplastic cells were observed in the presence of macrophage-conditioned medium or live macrophages. These observations indicate that rather than being “corrupted” by cancer cells, TAMs constitutively secrete canonical Wnt inhibitors that decrease tumor proliferation and development, but as a side effect, they induce the non-canonical Wnt pathway, which leads to tumor metastasis. These data challenge the conventional understanding of TAM–cancer cell interactions. PMID:24404146

  10. Interactions between HIV-1 Gag molecules in solution: an inositol phosphate-mediated switch.

    PubMed

    Datta, Siddhartha A K; Zhao, Zhuojun; Clark, Patrick K; Tarasov, Sergey; Alexandratos, Jerry N; Campbell, Stephen J; Kvaratskhelia, Mamuka; Lebowitz, Jacob; Rein, Alan

    2007-01-19

    Retrovirus particle assembly is mediated by the Gag protein. Gag is a multi-domain protein containing discrete domains connected by flexible linkers. When recombinant HIV-1 Gag protein (lacking myristate at its N terminus and the p6 domain at its C terminus) is mixed with nucleic acid, it assembles into virus-like particles (VLPs) in a fully defined system in vitro. However, this assembly is defective in that the radius of curvature of the VLPs is far smaller than that of authentic immature virions. This defect can be corrected to varying degrees by addition of inositol phosphates to the assembly reaction. We have now explored the binding of inositol hexakisphosphate (IP6) to Gag and its effects upon the interactions between Gag protein molecules in solution. Our data indicate that basic regions at both ends of the protein contribute to IP6 binding. Gag is in monomer-dimer equilibrium in solution, and mutation of the previously described dimer interface within its capsid domain drastically reduces Gag dimerization. In contrast, when IP6 is added, Gag is in monomer-trimer rather than monomer-dimer equilibrium. The Gag protein with a mutation at the dimer interface also remains almost exclusively monomeric in IP6; thus the "dimer interface" is essential for the trimeric interaction in IP6. We discuss possible explanations for these results, including a change in conformation within the capsid domain induced by the binding of IP6 to other domains within the protein. The participation of both ends of Gag in IP6 interaction suggests that Gag is folded over in solution, with its ends near each other in three-dimensional space; direct support for this conclusion is provided in a companion manuscript. As Gag is an extended rod in immature virions, this apparent proximity of the ends in solution implies that it undergoes a major conformational change during particle assembly.

  11. Effects of switching from olanzapine to aripiprazole on the metabolic profiles of patients with schizophrenia and metabolic syndrome: a double-blind, randomized, open-label study

    PubMed Central

    Wani, Rayees Ahmad; Dar, Mansoor Ahmad; Chandel, Rajesh Kumar; Rather, Yasir Hassan; Haq, Inaamul; Hussain, Arshad; Malla, Altaf Ahmad

    2015-01-01

    Background Patients with schizophrenia suffer high rates of metabolic derangements on some antipsychotic medications that predispose them to cardiovascular diseases. Keeping this fact in mind, we planned this open-label study to see the effect on various metabolic parameters after switching stable schizophrenia subjects, who had developed metabolic syndrome on olanzapine, to aripiprazole. Methods Sixty-two patients with schizophrenia who were stable on olanzapine and were fulfilling modified National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP-III) criteria for the presence of metabolic syndrome were enrolled on the study. Patients were randomly assigned either to switch to aripiprazole or to stay on olanzapine, on a 1:1 basis. Cross-tapering over a period of 1 month was done while switching patients to aripiprazole. Laboratory assessment for metabolic parameters was done at baseline, 8 weeks, and 24 weeks after enrollment; efficacy assessment was done using the Positive and Negative Syndrome Scale (PANSS) at baseline and 24 weeks, the Clinical Global Impressions severity subscale (CGI-S) at baseline, and the Clinical Global Impressions improvement subscale (CGI-I) at 24 weeks. Results All parameters of metabolic syndrome (waist circumference, blood pressure, triglyceride level, fasting blood glucose, and high-density lipoprotein cholesterol) kept deteriorating in the stay group, compared with a continuous improvement in the switch group over time. At the end of the study, 26 patients (100%) from the stay group and 15 patients (42.8%) from switch group met the modified NCEP ATP-III criteria for presence of metabolic syndrome (P<0.001). There were no statistically significant differences between groups in psychopathology changes as measured by the PANSS total score and CGI-I scores. Conclusion Clinically stable patients with schizophrenia who are taking olanzapine and who have evidence of metabolic syndrome can be successfully switched to

  12. Agrobacterium-mediated transformation (AMT) of Trichoderma reesei as an efficient tool for random insertional mutagenesis.

    PubMed

    Zhong, Yao Hua; Wang, Xiao Li; Wang, Tian Hong; Jiang, Qiao

    2007-01-01

    Filamentous fungus Trichoderma reesei QM9414 was successfully transformed with Agrobacterium tumefaciens AGL-1 for random integration of transforming DNA (T-DNA). Co-cultivation of T. reesei conidia or protoplasts with A. tumefaciens in the presence of acetosyringone resulted in the formation of hygromycin B-resistant fungal colonies with high transformation frequency. Nine randomly selected resistant clones were proved to be stable through mitotic cell division. The integration of the hph gene into T. reesei genome was determined by PCR and dot blot analysis. Transgenic T. reesei strains were analyzed using TAIL-PCR for their T-DNA contents. The results showed that T-DNA inserts occurred evidently by fusing DNA at T-DNA borders via random recombination, which suggests that Agrobacterium-mediated transformation is a potentially powerful tool towards tagged mutagenesis and gene transfer technology for T. reesei.

  13. Testing Mediators of Intervention Effects in Randomized Controlled Trials: An Evaluation of Two Eating Disorder Prevention Programs

    PubMed Central

    Stice, Eric; Presnell, Katherine; Gau, Jeff; Shaw, Heather

    2009-01-01

    We investigated mediators hypothesized to account for the effects of two eating disorder prevention programs using data from 355 adolescent females who were randomized to a dissonance or healthy weight intervention or an active control condition. The dissonance intervention produced significant reductions in outcomes (body dissatisfaction, dieting, negative affect, bulimic symptoms) and the mediator (thin-ideal internalization), change in the mediator correlated with change in outcomes and usually occurred before change in outcomes, and intervention effects became significantly weaker when change in the mediator was partialed, providing support for the hypothesized mediators and this new approach to testing mediation in randomized trials. Findings provided somewhat less support for the hypothesis that change in healthy eating and exercise mediated the healthy weight intervention effects. PMID:17295560

  14. Using mobile technology to support lower-salt food choices for people with cardiovascular disease: protocol for the SaltSwitch randomized controlled trial.

    PubMed

    Eyles, Helen; McLean, Rebecca; Neal, Bruce; Doughty, Robert N; Jiang, Yannan; Ni Mhurchu, Cliona

    2014-09-12

    Cardiovascular disease (CVD) is the leading cause of early death worldwide, responsible for an estimated 29% of all global deaths. Reducing salt intake lowers blood pressure and risk of secondary cardiac events. However, identifying low salt foods can be challenging. SaltSwitch is a simple smartphone application (app) that enables shoppers to scan the barcode of packaged foods and receive an immediate, interpretive, traffic light nutrition label on the screen, along with suggestions for healthier lower-salt alternatives. A growing body of evidence suggests mobile technologies can support healthy behaviour change. However, robust evidence for the impact of smartphone interventions is lacking. This manuscript outlines the rationale and methods for a randomized controlled trial designed to determine the effectiveness of SaltSwitch in supporting people with CVD to make lower-salt food choices. A 6-week, two-arm, parallel, randomized controlled trial is being undertaken in New Zealand (2 weeks baseline and 4 weeks intervention). Three hundred adults aged 40 years and older with CVD and their main household shoppers are recruited from research lists, cardiac rehabilitation clinics, and communities in Auckland. Participants are randomized to receive either the SaltSwitch smartphone app or no intervention (control). Randomisation is stratified by ethnicity and age. The primary outcome is the salt content of household food purchases. Secondary outcomes are the saturated fat and energy content of household food purchases, household food expenditure, use and acceptability of the SaltSwitch app by shoppers, and urinary sodium and blood pressure of participants with CVD. Ambulatory blood pressure and potential longer-term impact (12 weeks) of SaltSwitch will be assessed in sub-studies (n ~ 40 and n ~ 20, respectively). Household purchases of salt and other nutrients will be assessed using till receipt data electronically linked with branded food composition data

  15. Switching operation and degradation of resistive random access memory composed of tungsten oxide and copper investigated using in-situ TEM

    PubMed Central

    Arita, Masashi; Takahashi, Akihito; Ohno, Yuuki; Nakane, Akitoshi; Tsurumaki-Fukuchi, Atsushi; Takahashi, Yasuo

    2015-01-01

    In-situ transmission electron microscopy (in-situ TEM) was performed to investigate the switching operation of a resistive random access memory (ReRAM) made of copper, tungsten oxide and titanium nitride (Cu/WOx/TiN). In the first Set (Forming) operation to initialize the device, precipitation appeared inside the WOx layer. It was presumed that a Cu conducting filament was formed, lowering the resistance (on-state). The Reset operation induced a higher resistance (the off-state). No change in the microstructure was identified in the TEM images. Only when an additional Reset current was applied after switching to the off-state could erasure of the filament be seen (over-Reset). Therefore, it was concluded that structural change relating to the resistance switch was localized in a very small area around the filament. With repeated switching operations and increasing operational current, the WOx/electrode interfaces became indistinct. At the same time, the resistance of the off-state gradually decreased. This is thought to be caused by Cu condensation at the interfaces because of leakage current through the area other than through the filament. This will lead to device degradation through mechanisms such as endurance failure. This is the first accelerated aging test of ReRAM achieved using in-situ TEM. PMID:26611856

  16. Switching to aripiprazole in outpatients with schizophrenia experiencing insufficient efficacy and/or safety/tolerability issues with risperidone: a randomized, multicentre, open-label study.

    PubMed

    Ryckmans, V; Kahn, J P; Modell, S; Werner, C; McQuade, R D; Kerselaers, W; Lissens, J; Sanchez, R

    2009-05-01

    This study evaluated the safety/tolerability and effectiveness of aripiprazole titrated-dose versus fixed-dose switching strategies from risperidone in patients with schizophrenia experiencing insufficient efficacy and/or safety/tolerability issues. Patients were randomized to an aripiprazole titrated-dose (starting dose 5 mg/day) or fixed-dose (dose 15 mg/day) switching strategy with risperidone down-tapering. Primary endpoint was rate of discontinuation due to adverse events (AEs) during the 12-week study. Secondary endpoints included positive and negative syndrome scale (PANSS), clinical global impressions - improvement of illness scale (CGI-I), preference of medication (POM), subjective well-being under neuroleptics (SWN-K) and GEOPTE (Grupo Español para la Optimización del Tratamiento de la Esquizofrenia) scales. Rates of discontinuations due to AEs were similar between titrated-dose and fixed-dose strategies (3.5% vs. 5.0%; p=0.448). Improvements in mean PANSS total scores were similar between aripiprazole titrated-dose and fixed-dose strategies (-14.8 vs. -17.2; LOCF), as were mean CGI-I scores (2.9 vs. 2.8; p=0.425; LOCF) and SWN-K scores (+8.6 vs.+10.3; OC,+7.8 vs.+9.8; LOCF). Switching can be effectively and safely achieved through a titrated-dose or fixed-dose switching strategy for aripiprazole, with down-titration of risperidone.

  17. Switching operation and degradation of resistive random access memory composed of tungsten oxide and copper investigated using in-situ TEM

    NASA Astrophysics Data System (ADS)

    Arita, Masashi; Takahashi, Akihito; Ohno, Yuuki; Nakane, Akitoshi; Tsurumaki-Fukuchi, Atsushi; Takahashi, Yasuo

    2015-11-01

    In-situ transmission electron microscopy (in-situ TEM) was performed to investigate the switching operation of a resistive random access memory (ReRAM) made of copper, tungsten oxide and titanium nitride (Cu/WOx/TiN). In the first Set (Forming) operation to initialize the device, precipitation appeared inside the WOx layer. It was presumed that a Cu conducting filament was formed, lowering the resistance (on-state). The Reset operation induced a higher resistance (the off-state). No change in the microstructure was identified in the TEM images. Only when an additional Reset current was applied after switching to the off-state could erasure of the filament be seen (over-Reset). Therefore, it was concluded that structural change relating to the resistance switch was localized in a very small area around the filament. With repeated switching operations and increasing operational current, the WOx/electrode interfaces became indistinct. At the same time, the resistance of the off-state gradually decreased. This is thought to be caused by Cu condensation at the interfaces because of leakage current through the area other than through the filament. This will lead to device degradation through mechanisms such as endurance failure. This is the first accelerated aging test of ReRAM achieved using in-situ TEM.

  18. Structural basis of the mercury(II)-mediated conformational switching of the dual-function transcriptional regulator MerR

    PubMed Central

    Chang, Chih-Chiang; Lin, Li-Ying; Zou, Xiao-Wei; Huang, Chieh-Chen; Chan, Nei-Li

    2015-01-01

    The mer operon confers bacterial resistance to inorganic mercury (Hg2+) and organomercurials by encoding proteins involved in sensing, transport and detoxification of these cytotoxic agents. Expression of the mer operon is under tight control by the dual-function transcriptional regulator MerR. The metal-free, apo MerR binds to the mer operator/promoter region as a repressor to block transcription initiation, but is converted into an activator upon Hg2+-binding. To understand how MerR interacts with Hg2+ and how Hg2+-binding modulates MerR function, we report here the crystal structures of apo and Hg2+-bound MerR from Bacillus megaterium, corresponding respectively to the repressor and activator conformation of MerR. To our knowledge, the apo-MerR structure represents the first visualization of a MerR family member in its intact and inducer-free form. And the Hg2+-MerR structure offers the first view of a triligated Hg2+-thiolate center in a metalloprotein, confirming that MerR binds Hg2+ via trigonal planar coordination geometry. Structural comparison revealed the conformational transition of MerR is coupled to the assembly/disassembly of a buried Hg2+ binding site, thereby providing a structural basis for the Hg2+-mediated functional switching of MerR. The pronounced Hg2+-induced repositioning of the MerR DNA-binding domains suggests a plausible mechanism for the transcriptional regulation of the mer operon. PMID:26150423

  19. Cell signaling switches HOX-PBX complexes from repressors to activators of transcription mediated by histone deacetylases and histone acetyltransferases.

    PubMed

    Saleh, M; Rambaldi, I; Yang, X J; Featherstone, M S

    2000-11-01

    The Hoxb1 autoregulatory element comprises three HOX-PBX binding sites. Despite the presence of HOXB1 and PBX1, this enhancer fails to activate reporter gene expression in retinoic acid-treated P19 cell monolayers. Activation requires cell aggregation in addition to RA. This suggests that HOX-PBX complexes may repress transcription under some conditions. Consistent with this, multimerized HOX-PBX binding sites repress reporter gene expression in HEK293 cells. We provide a mechanistic basis for repressor function by demonstrating that a corepressor complex, including histone deacetylases (HDACs) 1 and 3, mSIN3B, and N-CoR/SMRT, interacts with PBX1A. We map a site of interaction with HDAC1 to the PBX1 N terminus and show that the PBX partner is required for repression by the HOX-PBX complex. Treatment with the deacetylase inhibitor trichostatin A not only relieves repression but also converts the HOX-PBX complex to a net activator of transcription. We show that this activation function is mediated by the recruitment of the coactivator CREB-binding protein by the HOX partner. Interestingly, HOX-PBX complexes are switched from transcriptional repressors to activators in response to protein kinase A signaling or cell aggregation. Together, our results suggest a model whereby the HOX-PBX complex can act as a repressor or activator of transcription via association with corepressors and coactivators. The model implies that cell signaling is a direct determinant of HOX-PBX function in the patterning of the animal embryo.

  20. Cell Signaling Switches HOX-PBX Complexes from Repressors to Activators of Transcription Mediated by Histone Deacetylases and Histone Acetyltransferases

    PubMed Central

    Saleh, Maya; Rambaldi, Isabel; Yang, Xiang-Jiao; Featherstone, Mark S.

    2000-01-01

    The Hoxb1 autoregulatory element comprises three HOX-PBX binding sites. Despite the presence of HOXB1 and PBX1, this enhancer fails to activate reporter gene expression in retinoic acid-treated P19 cell monolayers. Activation requires cell aggregation in addition to RA. This suggests that HOX-PBX complexes may repress transcription under some conditions. Consistent with this, multimerized HOX-PBX binding sites repress reporter gene expression in HEK293 cells. We provide a mechanistic basis for repressor function by demonstrating that a corepressor complex, including histone deacetylases (HDACs) 1 and 3, mSIN3B, and N-CoR/SMRT, interacts with PBX1A. We map a site of interaction with HDAC1 to the PBX1 N terminus and show that the PBX partner is required for repression by the HOX-PBX complex. Treatment with the deacetylase inhibitor trichostatin A not only relieves repression but also converts the HOX-PBX complex to a net activator of transcription. We show that this activation function is mediated by the recruitment of the coactivator CREB-binding protein by the HOX partner. Interestingly, HOX-PBX complexes are switched from transcriptional repressors to activators in response to protein kinase A signaling or cell aggregation. Together, our results suggest a model whereby the HOX-PBX complex can act as a repressor or activator of transcription via association with corepressors and coactivators. The model implies that cell signaling is a direct determinant of HOX-PBX function in the patterning of the animal embryo. PMID:11046157

  1. Oral-nasopharyngeal dendritic cells mediate T cell-independent IgA class switching on B-1 B cells.

    PubMed

    Kataoka, Kosuke; Fujihashi, Keiko; Terao, Yutaka; Gilbert, Rebekah S; Sekine, Shinichi; Kobayashi, Ryoki; Fukuyama, Yoshiko; Kawabata, Shigetada; Fujihashi, Kohtaro

    2011-01-01

    Native cholera toxin (nCT) as a nasal adjuvant was shown to elicit increased levels of T-independent S-IgA antibody (Ab) responses through IL-5- IL-5 receptor interactions between CD4+ T cells and IgA+ B-1 B cells in murine submandibular glands (SMGs) and nasal passages (NPs). Here, we further investigate whether oral-nasopharyngeal dendritic cells (DCs) play a central role in the induction of B-1 B cell IgA class switch recombination (CSR) for the enhancement of T cell-independent (TI) mucosal S-IgA Ab responses. High expression levels of activation-induced cytidine deaminase, Iα-Cμ circulation transcripts and Iμ-Cα transcripts were seen on B-1 B cells purified from SMGs and NPs of both TCRβ⁻/⁻ mice and wild-type mice given nasal trinitrophenyl (TNP)-LPS plus nCT, than in the same tissues of mice given nCT or TNP-LPS alone. Further, DCs from SMGs, NPs and NALT of mice given nasal TNP-LPS plus nCT expressed significantly higher levels of a proliferation-inducing ligand (APRIL) than those in mice given TNP-LPS or nCT alone, whereas the B-1 B cells in SMGs and NPs showed elevated levels of transmembrane activator and calcium modulator cyclophilin ligand interactor (TACI) expression. Interestingly, high frequencies of IgA+ B-1 B cells were induced when peritoneal IgA⁻ IgM+ B cells were stimulated with mucosal DCs from mice given nasal TNP-LPS plus nCT. Taken together, these findings show that nasal nCT plays a key role in the enhancement of mucosal DC-mediated TI IgA CSR by B-1 B cells through their interactions with APRIL and TACI.

  2. Contribution of Central μ-Receptors to Switching Pulmonary C-Fibers-Mediated Rapid Shallow Breathing into An Apnea by Fentanyl in Anesthetized Rats

    PubMed Central

    Zhang, Zhenxiong; Zhang, Cancan; Zhuang, Jianguo; Xu, Fadi

    2012-01-01

    Our previous study has shown that activating peripheral μ-receptors is necessary for switching the bronchopulmonary C-fibers (PCFs)-mediated rapid shallow breathing (RSB) into an apnea by systemic administration of fentanyl. The brainstem nuclei, such as the medial nucleus tractus solitarius (mNTS) and the Pre-Botzinger Complex (PBC), are required for completing the PCF-mediated respiratory reflexes. Moreover, these areas contain abundant μ-receptors and their activation prolongs expiratory duration (TE). Thus, we asked if central μ-receptors, especially those in the mNTS and PBC, are involved in fully expressing this RSB-apnea switch by fentanyl. In anesthetized rats, the cardiorespiratory responses to right atrial injection of phenylbiguanide (PBG, 3–6 μg/kg) were repeated after: 1) fentanyl (iv), a μ-receptor agonist, alone (8 μg/kg, iv); 2) fentanyl following microinjection of naloxone methiodide (NXM, an opioid receptor antagonist) into the cisterna magna (10 μg/4 μl); 3) the bilateral mNTS (10 mM, 20 nl); or 4) PBC (10 mM, 20 nl). Our results showed that PBG shortened TE by 37 ± 6 % (RSB, from 0.41 ± 0.05 to 0.26 ± 0.03 s, P < 0.01), but it markedly prolonged TE by 5.8-fold (an apnea, from 0.50 ± 0.04 s to 2.9 ± 0.57 s, P < 0.01) after fentanyl (iv). Pretreatment with NXM injected into the cisterna magna or the PBC, but not the mNTS, prevented the fentanyl-induced switch. This study, along with our previous results mentioned above, suggests that although peripheral μ-receptors are essential for triggering the fentanyl-induced switch, central μ-receptors, especially those in the PBC, are required to fully exhibit such switch. PMID:22759907

  3. Q-switched YAG laser vs. punch biopsy excision for iatrogenic radiation tattoo markers--a randomized controlled trial.

    PubMed

    Bregnhøj, A; Haedersdal, M

    2010-10-01

    Ink markers are tattooed as landmarks before radiotherapy of breast cancer with the purpose of obtaining a precise radiation field. The black tattoo spots may cause potential psychological distress for the affected women. The objective of this study was to evaluate the efficacy and adverse effects in a side-by-side comparison of Q-switched (Q-sw) YAG laser vs. punch biopsy excision of iatrogenic radiation tattoo markers. Ten female volunteers with black tattoo markers after previous radiotherapy for breast cancer were included. Subjects received one punch biopsy excision and a series of three treatments at 6-week intervals with Q-sw YAG laser (Q-YAG 5 system, 1064 nm, Palomar Inc., Burlington, VT, USA); the interventions was randomly assigned to two closely located tattoos (n = 20). Treatment measures were evaluated 12 weeks after final treatment and included clinical efficacy, patient satisfaction, preferred treatment and adverse effects. A blinded observer evaluated the efficacy and adverse effects from photographs. Ten patients completed the study. Blinded photographic evaluations showed an overall excellent clearance (75-100% reduction in tattoo appearance) from both excision and laser treatments (P = 0.317). Patients were equally satisfied with Q-sw YAG laser treatment [median 9 (5.75-10, 25-75 percentiles)] and excision therapy [median 10 (5.75-10)] (P = 0.672). However, the majority of the patients preferred YAG laser (n = 8) to excision (n = 2) (P = 0.022) because adverse effects in terms of hypopigmentation (0/10 vs. 8/10 patients) and scarring (1/10 vs. 8/10 patients) occurred more frequently and appeared more pronounced in excision biopsy (hypopigmentation P = 0.014, scarring P = 0.021). Q-sw YAG laser and punch biopsy excision are effective to clear iatrogenic radiation tattoo markers, but patients preferred the laser treatment because of less pronounced adverse effects. © 2010 The Authors. Journal of the European Academy of Dermatology and Venereology

  4. Temperature-independent switching rates for a random telegraph signal in a silicon metal-oxide-semiconductor field-effect transistor at low temperatures

    SciTech Connect

    Scofield, John H.; Borland, Nick; Fleetwood, D. M.

    2000-05-29

    We have observed discrete random telegraph signals (RTSs) in the drain voltages of three, nominally 1.25 {mu}mx1.25 {mu}m, enhancement-mode p-channel metal-oxide-semiconductor transistors operated in strong inversion in their linear regimes with constant drain-current and gate-voltage bias, for temperatures ranging from 4.2 to 300 K. The switching rates for all RTSs observed above 30 K were thermally activated. The switching rate for the only RTS observed below 30 K was thermally activated above 30 K but temperature independent below 10 K. This response is consistent with a crossover from thermal activation to tunneling at low temperatures. Implications are discussed for models of change exchange between the Si and the near-interfacial SiO{sub 2}. (c) 2000 American Institute of Physics.

  5. Evaluation of Biomarkers of Exposure in Smokers Switching to a Carbon-Heated Tobacco Product: A Controlled, Randomized, Open-Label 5-Day Exposure Study

    PubMed Central

    Haziza, Christelle; Weitkunat, Rolf; Magnette, John

    2016-01-01

    Introduction: Tobacco harm reduction aims to provide reduced risk alternatives to adult smokers who would otherwise continue smoking combustible cigarettes (CCs). This randomized, open-label, three-arm, parallel-group, single-center, short-term confinement study aimed to investigate the effects of exposure to selected harmful and potentially harmful constituents (HPHCs) of cigarette smoke in adult smokers who switched to a carbon-heated tobacco product (CHTP) compared with adult smokers who continued to smoke CCs and those who abstained from smoking for 5 days. Methods: Biomarkers of exposure to HPHCs, including nicotine and urinary excretion of mutagenic material, were measured in 24-hour urine and blood samples in 112 male and female Caucasian smokers switching from CCs to the CHTP ad libitum use. Puffing topography was assessed during product use. Results: Switching to the CHTP or smoking abstinence (SA) resulted in marked decreases from baseline to Day 5 in all biomarkers of exposure measured, including carboxyhemoglobin (43% and 55% decrease in the CHTP and SA groups, respectively). The urinary excretion of mutagenic material was also markedly decreased on Day 5 compared with baseline (89% and 87% decrease in the CHTP and SA groups, respectively). No changes in biomarkers of exposure to HPHCs or urinary mutagenic material were observed between baseline and Day 5 in the CC group. Conclusions: Our results provide clear evidence supporting a reduction in the level of exposure to HPHCs of tobacco smoke in smokers who switch to CHTP under controlled conditions, similar to that observed in SA. Implications: The reductions observed in biomarkers of exposure to HPHCs of tobacco smoke in this short-term study could potentially also reduce the incidence of cancer, cardiovascular and respiratory diseases in those smokers who switch to a heated tobacco product. PMID:26817490

  6. Randomized Clinical Trial: Moderators and Mediators of a Psycho-education Group Intervention on IBS Symptoms

    PubMed Central

    Labus, Jennifer; Gupta, Arpana; Gill, Harkiran K.; Posserud, Iris; Mayer, Minou; Raeen, Heidi; Bolus, Roger; Simren, Magnus; Naliboff, Bruce D.; Mayer, Emeran A.

    2013-01-01

    Summary Background & aims Evidence supports the effectiveness of cognitive behavioral approaches in improving IBS symptoms. Duration, cost, and resistance of many patients towards a psychological therapy have limited their acceptance. We evaluated the effectiveness of a psycho-educational intervention on IBS symptoms. Methods 69 IBS patients (72% female) were randomized to an intervention or a wait-list control group. The IBS class consisted of education on a biological mind body disease model emphasizing self-efficacy and practical relaxation techniques. Results Patients in the intervention showed significant improvement on GI symptom severity, visceral sensitivity, depression, and QoL post intervention and most of these gains were maintained at 3 month follow up (Hedge’s g =−.46 to .77). Moderated mediation analyses indicated change in anxiety, visceral sensitivity, QoL and catastrophizing due to the intervention had moderate mediation effects (Hedge’s g= −.38 to −.60) on improvements in GI symptom severity for patients entering the trial with low to average QoL. Also, change in GI symptom severity due to the intervention had moderate mediation effects on improvements in QoL especially patients with low to average levels of QoL at baseline. Moderated mediation analyses indicated mediation was less effective for patients entering the intervention with high QoL. Conclusions A brief psycho-educational group intervention is efficacious in changing cognitions and fears about IBS symptoms, and these changes are associated with clinically meaningful improvement in IBS symptoms and QoL. The intervention seems particularly tailored to patients with low to moderate QoL baseline levels. PMID:23205588

  7. Nonblocking photonic switching for P2P self-organized optical concurrent communications network using pseudo-random numbers

    NASA Astrophysics Data System (ADS)

    Oshima, Naoki; Nozaki, Yusuke; Sasaki, Wakao

    2007-02-01

    Peer-to-peer (P2P) optical communication network is presently attracting much attention in the application of smallscale network. We proposed a network element called as a node fabricated by optoelectronics hardware based on the optical bistable devices. These nodes can compose a self-organizing optical network being interconnected with each other. We also proposed an adaptive node with gate function which detects the differences of signal types as to the amplitude modulation (AM) signal in the network and switches their routings. Thus, the adaptive node allows optical P2P concurrent communications between multiple pairs of communicators in the network simultaneously. Moreover, we have proposed in the present work an optical nonblocking operation using the pseudorandom numbers fabricated into the above mentioned adaptive nodes. We have newly considered a switching scheme which identifies such pseudorandom numbers and forms automatically a signal propagation path so that the nodes with the same input pseudorandom numbers are to be linked. Since such a pseudorandom-number based switching may also prevent any irregular interception of established links among nodes, our scheme is proved to be a nonblocking operation. Therefore, this scheme allows multiple signals from input nodes to travel in the network simultaneously via only a single propagation path being established by the self-organized adaptive nodes. We have also demonstrated this switching operation experimentally by fabricating it into our optoelectronics hardware based on the optical bistable devices. As a consequence, nonblocking photonic switching scheme for P2P self-organized optical concurrent communications network has been achieved by our pseudorandom-number based adaptive nodes proposed by the present work.

  8. Messages for Clinicians: Moderators and Mediators of Treatment Outcome in Randomized Clinical Trials.

    PubMed

    Kraemer, Helena Chmura

    2016-07-01

    Many problems in randomized clinical trial design, execution, analysis, presentation and interpretation stem in part from an inadequate understanding of the roles of moderators and mediators of treatment outcome. As a result, 1) the results of clinical research are slow to have an impact on clinical decision making and thus to benefit patients; 2) it is difficult for clinicians or patients to apply randomized clinical trial results comparing two treatments (treatment versus control); 3) when such trials are conducted at various sites, the results often do not replicate; 4) when the results influence clinical decision making, the results clinicians obtain do not match what researchers report; and 5) the treatment effects comparing treatment and control conditions, particularly for psychiatric treatments, often seem trivial. In this review article, the author reviews and integrates the methodological literature concerning dealing with covariates in trials to emphasize their impact on clinical decision making. The goal of trials should ultimately be to establish who should get the treatment condition rather than the control condition (moderators) and to determine how to obtain the best outcomes with whatever is the preferred treatment (mediators). The author makes recommendations to clinicians as to which trials might best be ignored and which carefully considered, and urges clinical researchers to focus on studies best designed to reduce the burden of mental illness on patients.

  9. Amino-Mediated Anchoring Perovskite Quantum Dots for Stable and Low-Threshold Random Lasing.

    PubMed

    Li, Xiaoming; Wang, Yue; Sun, Handong; Zeng, Haibo

    2017-09-01

    Halide perovskite quantum dots (Pe-QDs) have been considered as outstanding candidates for photodetector, light-emitting diode, and lasing applications, but these perspectives are being impeded by the severe stability, including both chemical and optical degradations. This study reports on amino-mediated anchoring Pe-QDs onto the surfaces of monodisperse silica to effectively depress the optical degradation of their photoluminescence (PL) and random lasing stabilities, hence achieving highly stable and low-threshold lasing. An amination-mediated nucleation and growth process is designed for the general and one-pot synthesis of Pe-QDs on the surfaces of silica spheres. The facile synthetic process, which can be finished within several minutes, insures scalable production. Surprisingly, almost no PL degradation is observed after 40 d storage under ambient conditions, even 80% PL intensity can be maintained after persistently illuminated by UV lamps for 108 h. Subsequently, extremely stable random lasing is achieved after storage for 2 months or over continuously optical pumping for 8 h. Such high PL and lasing stabilities originate from the isolation effects due to the effective anchoring, which separate the Pe-QDs from each other and inhibit the photoinduced regrowth and deterioration. This work will also open the window of perovskite-based multifunctional systems. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. A Single Regulator Mediates Strategic Switching between Attachment/Spread and Growth/Virulence in the Plant Pathogen Ralstonia solanacearum.

    PubMed

    Khokhani, Devanshi; Lowe-Power, Tiffany M; Tran, Tuan Minh; Allen, Caitilyn

    2017-09-26

    The PhcA virulence regulator in the vascular wilt pathogen Ralstonia solanacearum responds to cell density via quorum sensing. To understand the timing of traits that enable R. solanacearum to establish itself inside host plants, we created a ΔphcA mutant that is genetically locked in a low-cell-density condition. Comparing levels of gene expression of wild-type R. solanacearum and the ΔphcA mutant during tomato colonization revealed that the PhcA transcriptome includes an impressive 620 genes (>2-fold differentially expressed; false-discovery rate [FDR], ≤0.005). Many core metabolic pathways and nutrient transporters were upregulated in the ΔphcA mutant, which grew faster than the wild-type strain in tomato xylem sap and on dozens of specific metabolites, including 36 found in xylem. This suggests that PhcA helps R. solanacearum to survive in nutrient-poor environmental habitats and to grow rapidly during early pathogenesis. However, after R. solanacearum reaches high cell densities in planta, PhcA mediates a trade-off from maximizing growth to producing costly virulence factors. R. solanacearum infects through roots, and low-cell-density-mode-mimicking ΔphcA cells attached to tomato roots better than the wild-type cells, consistent with their increased expression of several adhesins. Inside xylem vessels, ΔphcA cells formed aberrantly dense mats. Possibly as a result, the mutant could not spread up or down tomato stems as well as the wild type. This suggests that aggregating improves R. solanacearum survival in soil and facilitates infection and that it reduces pathogenic fitness later in disease. Thus, PhcA mediates a second strategic switch between initial pathogen attachment and subsequent dispersal inside the host. PhcA helps R. solanacearum optimally invest resources and correctly sequence multiple steps in the bacterial wilt disease cycle.IMPORTANCERalstonia solanacearum is a destructive soilborne crop pathogen that wilts plants by colonizing their

  11. Brief Report: Switch to Ritonavir-Boosted Atazanavir Plus Raltegravir in Virologically Suppressed Patients With HIV-1 Infection: A Randomized Pilot Study

    PubMed Central

    van Lunzen, Jan; Pozniak, Anton; Gatell, Jose M.; Antinori, Andrea; Serrano, Oscar; Baakili, Adyb; Osiyemi, Olayemi; Sevinsky, Heather; Girard, Pierre-Marie

    2016-01-01

    Abstract: This open-label, multinational, pilot study randomized (1:2 ratio) adults with HIV-1 RNA <40 copies per milliliter and nucleos(t)ide-related safety/tolerability issues to switch to ritonavir-boosted atazanavir (ATV/r) plus tenofovir disoproxil fumarate/emtricitabine (n = 37) or the nucleos(t)ide reverse transcriptase inhibitor-sparing regimen of ATV/r plus raltegravir (RAL) (n = 72). At 24 weeks, 35/37 (94.6%) and 58/72 (80.6%) of patients, respectively, maintained virological suppression, the primary endpoint, and 1 (2.7%) and 7 (9.7%), respectively, experienced virological rebound. Corresponding 48-week proportions were 86.5%, 69.4%, 2.7%, and 12.5%, respectively. Adherence was lower and treatment discontinuation was higher with ATV/r+RAL. In conclusion, switching to ATV/r+RAL resulted in a higher virological rebound rate than switching to ATV/r plus tenofovir disoproxil fumarate/emtricitabine. PMID:26605505

  12. Spin Hall effect mediated current-induced deterministic switching in all-metallic perpendicularly magnetized Pt/Co/Pt trilayers

    NASA Astrophysics Data System (ADS)

    P, Vineeth Mohanan; Ganesh, K. R.; Kumar, P. S. Anil

    2017-09-01

    A magnetic field free current-induced deterministic switching is demonstrated in a perpendicularly magnetized all-metallic Pt/Co/Pt thin film system with a small tilt in anisotropy axis. We realized this in devices where the ultrathin Co layer was grown using an oblique angle sputter deposition technique that had resulted in a small tilt of magnetic anisotropy from the film normal. By performing out-of-plane magnetization hysteresis measurements under bias magnetic field applied along various in-plane directions the tilt angle was estimated to be around 3 .3∘ (±0 .3∘ ). A deterministic current-induced magnetization switching could be achieved when the in-plane current was applied perpendicular to the anisotropy tilt axis, but the switching was stochastic when the current was applied in the direction of the tilt (in the tilt plane). By preparing Pt/Co/Pt stacks with unequal top and bottom Pt thickness, sufficient spin-orbit torque (SOT) could be applied to switch the magnetization of the Co layer at current densities as low as 1.5 ×107 A/cm2. The switching phase diagram (SPD) constructed by plotting the critical current density versus applied in-plane magnetic field (HxIB) confirms spin Hall effect based SOT mechanism to be responsible for the magnetization switching. The asymmetry observed in the SPD (about HxIB=0 ) is in agreement with the macrospin simulations and it suggests that the tilt in the magnetic anisotropy from the film normal makes the switching deterministic even without an in-plane magnetic field bias.

  13. Resistance Switching Characteristics Induced by O2 Plasma Treatment of an Indium Tin Oxide Film for Use as an Insulator in Resistive Random Access Memory.

    PubMed

    Chen, Po-Hsun; Chang, Ting-Chang; Chang, Kuan-Chang; Tsai, Tsung-Ming; Pan, Chih-Hung; Chen, Min-Chen; Su, Yu-Ting; Lin, Chih-Yang; Tseng, Yi-Ting; Huang, Hui-Chun; Wu, Huaqiang; Deng, Ning; Qian, He; Sze, Simon M

    2017-01-25

    In this study, an O2 inductively coupled plasma (ICP) treatment was developed in order to modify the characteristics of indium tin oxide (ITO) film for use as an insulator in resistive random access memory (RRAM). After the O2 plasma treatment, the previously conductive ITO film is oxidized and becomes less conductive. In addition, after capping the same ITO material for use as a top electrode, we found that the ITO/ITO(O2 plasma)/TiN device exhibits very stable and robust resistive switching characteristics. On the contrary, the nontreated ITO film for use as an insulator in the ITO/ITO/TiN device cannot perform resistance switching behaviors. The material analysis initially investigated the ITO film characteristics with and without O2 plasma treatment. The surface was less rough after O2 plasma treatment. However, the molar concentration of each element and measured sheet resistance results for the O2-plasma-treated ITO film were dramatically modified. Next, electrical measurements were carried out to examine the resistance switching stability under continuous DC and AC operation in this ITO/ITO(O2 plasma)/TiN device. Reliability tests, including endurance and retention, also proved its capability for use in data storage applications. In addition to these electrical measurements, current fitting method experiments at different temperatures were performed to examine and confirm the resistance switching mechanisms. This easily fabricated device, using a simple material combination, achieves excellent performance by using ITO with an O2 plasma treatment and can further the abilities of RRAM for use in remarkable potential applications.

  14. The role of internal structure in the anomalous switching dynamics of metal-oxide/polymer resistive random access memories

    NASA Astrophysics Data System (ADS)

    Rocha, Paulo R. F.; Kiazadeh, Asal; De Leeuw, Dago M.; Meskers, Stefan C. J.; Verbakel, Frank; Taylor, David M.; Gomes, Henrique L.

    2013-04-01

    The dynamic response of a non-volatile, bistable resistive memory fabricated in the form of Al2O3/polymer diodes has been probed in both the off- and on-state using triangular and step voltage profiles. The results provide insight into the wide spread in switching times reported in the literature and explain an apparently anomalous behaviour of the on-state, namely the disappearance of the negative differential resistance region at high voltage scan rates which is commonly attributed to a "dead time" phenomenon. The off-state response follows closely the predictions based on a classical, two-layer capacitor description of the device. As voltage scan rates increase, the model predicts that the fraction of the applied voltage, Vox, appearing across the oxide decreases. Device responses to step voltages in both the off- and on-state show that switching events are characterized by a delay time. Coupling such delays to the lower values of Vox attained during fast scan rates, the anomalous observation in the on-state that, device currents decrease with increasing voltage scan rate, is readily explained. Assuming that a critical current is required to turn off a conducting channel in the oxide, a tentative model is suggested to explain the shift in the onset of negative differential resistance to lower voltages as the voltage scan rate increases. The findings also suggest that the fundamental limitations on the speed of operation of a bilayer resistive memory are the time- and voltage-dependences of the switch-on mechanism and not the switch-off process.

  15. Load-Dependent Interference of Deep Brain Stimulation of the Subthalamic Nucleus with Switching from Automatic to Controlled Processing During Random Number Generation in Parkinson's Disease.

    PubMed

    Williams, Isobel Anne; Wilkinson, Leonora; Limousin, Patricia; Jahanshahi, Marjan

    2015-01-01

    Deep brain stimulation of the subthalamic nucleus (STN DBS) ameliorates the motor symptoms of Parkinson's disease (PD). However, some aspects of executive control are impaired with STN DBS. We tested the prediction that (i) STN DBS interferes with switching from automatic to controlled processing during fast-paced random number generation (RNG) (ii) STN DBS-induced cognitive control changes are load-dependent. Fifteen PD patients with bilateral STN DBS performed paced-RNG, under three levels of cognitive load synchronised with a pacing stimulus presented at 1, 0.5 and 0.33 Hz (faster rates require greater cognitive control), with DBS on or off. Measures of output randomness were calculated. Countscore 1 (CS1) indicates habitual counting in steps of one (CS1). Countscore 2 (CS2) indicates a more controlled strategy of counting in twos. The fastest rate was associated with an increased CS1 score with STN DBS on compared to off. At the slowest rate, patients had higher CS2 scores with DBS off than on, such that the differences between CS1 and CS2 scores disappeared. We provide evidence for a load-dependent effect of STN DBS on paced RNG in PD. Patients could switch to more controlled RNG strategies during conditions of low cognitive load at slower rates only when the STN stimulators were off, but when STN stimulation was on, they engaged in more automatic habitual counting under increased cognitive load. These findings are consistent with the proposal that the STN implements a switch signal from the medial frontal cortex which enables a shift from automatic to controlled processing.

  16. Load-Dependent Interference of Deep Brain Stimulation of the Subthalamic Nucleus with Switching from Automatic to Controlled Processing During Random Number Generation in Parkinson’s Disease

    PubMed Central

    Williams, Isobel Anne; Wilkinson, Leonora; Limousin, Patricia; Jahanshahi, Marjan

    2015-01-01

    Background: Deep brain stimulation of the subthalamic nucleus (STN DBS) ameliorates the motor symptoms of Parkinson’s disease (PD). However, some aspects of executive control are impaired with STN DBS. Objective: We tested the prediction that (i) STN DBS interferes with switching from automatic to controlled processing during fast-paced random number generation (RNG) (ii) STN DBS-induced cognitive control changes are load-dependent. Methods: Fifteen PD patients with bilateral STN DBS performed paced-RNG, under three levels of cognitive load synchronised with a pacing stimulus presented at 1, 0.5 and 0.33 Hz (faster rates require greater cognitive control), with DBS on or off. Measures of output randomness were calculated. Countscore 1 (CS1) indicates habitual counting in steps of one (CS1). Countscore 2 (CS2) indicates a more controlled strategy of counting in twos. Results: The fastest rate was associated with an increased CS1 score with STN DBS on compared to off. At the slowest rate, patients had higher CS2 scores with DBS off than on, such that the differences between CS1 and CS2 scores disappeared. Conclusions: We provide evidence for a load-dependent effect of STN DBS on paced RNG in PD. Patients could switch to more controlled RNG strategies during conditions of low cognitive load at slower rates only when the STN stimulators were off, but when STN stimulation was on, they engaged in more automatic habitual counting under increased cognitive load. These findings are consistent with the proposal that the STN implements a switch signal from the medial frontal cortex which enables a shift from automatic to controlled processing. PMID:25720447

  17. Quantum cryptography without switching.

    PubMed

    Weedbrook, Christian; Lance, Andrew M; Bowen, Warwick P; Symul, Thomas; Ralph, Timothy C; Lam, Ping Koy

    2004-10-22

    We propose a new coherent state quantum key distribution protocol that eliminates the need to randomly switch between measurement bases. This protocol provides significantly higher secret key rates with increased bandwidths than previous schemes that only make single quadrature measurements. It also offers the further advantage of simplicity compared to all previous protocols which, to date, have relied on switching.

  18. Effect of Antidepressant Switching vs Augmentation on Remission Among Patients With Major Depressive Disorder Unresponsive to Antidepressant Treatment: The VAST-D Randomized Clinical Trial.

    PubMed

    Mohamed, Somaia; Johnson, Gary R; Chen, Peijun; Hicks, Paul B; Davis, Lori L; Yoon, Jean; Gleason, Theresa C; Vertrees, Julia E; Weingart, Kimberly; Tal, Ilanit; Scrymgeour, Alexandra; Lawrence, David D; Planeta, Beata; Thase, Michael E; Huang, Grant D; Zisook, Sidney; Rao, Sanjai D; Pilkinton, Patricia D; Wilcox, James A; Iranmanesh, Ali; Sapra, Mamta; Jurjus, George; Michalets, James P; Aslam, Muhammed; Beresford, Thomas; Anderson, Keith D; Fernando, Ronald; Ramaswamy, Sriram; Kasckow, John; Westermeyer, Joseph; Yoon, Gihyun; D'Souza, D Cyril; Larson, Gunnar; Anderson, William G; Klatt, Mary; Fareed, Ayman; Thompson, Shabnam I; Carrera, Carlos J; Williams, Solomon S; Juergens, Timothy M; Albers, Lawrence J; Nasdahl, Clifford S; Villarreal, Gerardo; Winston, Julia L; Nogues, Cristobal A; Connolly, K Ryan; Tapp, Andre; Jones, Kari A; Khatkhate, Gauri; Marri, Sheetal; Suppes, Trisha; LaMotte, Joseph; Hurley, Robin; Mayeda, Aimee R; Niculescu, Alexander B; Fischer, Bernard A; Loreck, David J; Rosenlicht, Nicholas; Lieske, Steven; Finkel, Mitchell S; Little, John T

    2017-07-11

    Less than one-third of patients with major depressive disorder (MDD) achieve remission with their first antidepressant. To determine the relative effectiveness and safety of 3 common alternate treatments for MDD. From December 2012 to May 2015, 1522 patients at 35 US Veterans Health Administration medical centers who were diagnosed with nonpsychotic MDD, unresponsive to at least 1 antidepressant course meeting minimal standards for treatment dose and duration, participated in the study. Patients were randomly assigned (1:1:1) to 1 of 3 treatments and evaluated for up to 36 weeks. Switch to a different antidepressant, bupropion (switch group, n = 511); augment current treatment with bupropion (augment-bupropion group, n = 506); or augment with an atypical antipsychotic, aripiprazole (augment-aripiprazole group, n = 505) for 12 weeks (acute treatment phase) and up to 36 weeks for longer-term follow-up (continuation phase). The primary outcome was remission during the acute treatment phase (16-item Quick Inventory of Depressive Symptomatology-Clinician Rated [QIDS-C16] score ≤5 at 2 consecutive visits). Secondary outcomes included response (≥50% reduction in QIDS-C16 score or improvement on the Clinical Global Impression Improvement scale), relapse, and adverse effects. Among 1522 randomized patients (mean age, 54.4 years; men, 1296 [85.2%]), 1137 (74.7%) completed the acute treatment phase. Remission rates at 12 weeks were 22.3% (n = 114) for the switch group, 26.9% (n = 136)for the augment-bupropion group, and 28.9% (n = 146) for the augment-aripiprazole group. The augment-aripiprazole group exceeded the switch group in remission (relative risk [RR], 1.30 [95% CI, 1.05-1.60]; P = .02), but other remission comparisons were not significant. Response was greater for the augment-aripiprazole group (74.3%) than for either the switch group (62.4%; RR, 1.19 [95% CI, 1.09-1.29]) or the augment-bupropion group (65.6%; RR, 1.13 [95% CI, 1

  19. High switching efficiency in FePt exchange coupled composite media mediated by MgO exchange control layers

    NASA Astrophysics Data System (ADS)

    Dutta, Tanmay; Piramanayagam, S. N.; Saifullah, M. S. M.; Bhatia, C. S.

    2017-07-01

    Satisfying the mutually conflicting requirements of easy switchability and high thermal stability still remains a hindrance to achieving ultra-high areal densities in hard disk drives. Exchange coupled composite media used with proper exchange control layers (ECLs) presents a potential solution to circumvent this hindrance. In this work, we have studied the role of MgO and Ta ECLs of different thicknesses in reducing the switching field of FePt media. MgO ECL was found to be more effective than a Ta ECL. For a 2 nm MgO ECL, the switching field could be reduced by 41% and at the cost of only a limited loss in thermal stability. Furthermore, a very high switching efficiency of 1.9 was obtained using 2 nm MgO ECL. So, with a proper choice of ECL material and thickness, the switching field of FePt media can be substantially reduced while ensuring high thermal stability and a better signal-to-noise ratio, thus potentially paving the way for very high areal density media.

  20. Coping Mediates Outcome Following a Randomized Group Intervention for HIV-Positive Bereaved Individuals

    PubMed Central

    Smith, Nathan Grant; Tarakeshwar, Nalini; Hansen, Nathan B.; Kochman, Arlene; Sikkema, Kathleen J.

    2013-01-01

    The purpose of this study was to examine the mechanisms responsible for the beneficial psychological effects of a coping-focused group intervention for HIV-positive individuals who had lost loved ones to AIDS. Data from 235 HIV-positive men and women enrolled in a randomized controlled clinical trial testing a coping-focused group intervention were analyzed using a multiple-indicator-multiple-cause (MIMIC) structural equation model. Results revealed that the effects of the intervention on decreases in depression and grief were mediated by decreases in avoidant coping. Specifically, participants in the intervention condition decreased their use of avoidant coping. Decreases in avoidant coping, in turn, were related to decreased depression and grief. The results of this study help to validate the use of coping-focused interventions for HIV-positive bereaved individuals. PMID:19152338

  1. High light-induced switch from C(3)-photosynthesis to Crassulacean acid metabolism is mediated by UV-A/blue light.

    PubMed

    Grams, Thorsten E E; Thiel, Stephan

    2002-06-01

    The high light-induced switch in Clusia minor from C(3)-photosynthesis to Crassulacean acid metabolism (CAM) is fast (within a few days) and reversible. Although this C(3)/CAM transition has been studied intensively, the nature of the photoreceptor at the beginning of the CAM-induction signal chain is still unknown. Using optical filters that only transmit selected wavelengths, the CAM light induction of single leaves was tested. As controls the opposite leaf of the same leaf pair was studied in which CAM was induced by high unfiltered radiation (c. 2100 micromol m(-2) s(-1)). To evaluate the C(3)-photosynthesis/CAM transition, nocturnal CO(2) uptake, daytime stomatal closure and organic acid levels were monitored. Light at wavelengths longer than 530 nm was not effective for the induction of the C(3)/CAM switch in C. minor. In this case CAM was present in the control leaf while the opposite leaf continued performing C(3)-photosynthesis, indicating that CAM induction triggered by high light conditions is wavelength-dependent and a leaf internal process. Leaves subjected to wavelengths in the range of 345-530 nm performed nocturnal CO(2) uptake, (partial) stomatal closure during the day (CAM-phase III), and decarboxylation of citric acid within the first 2 d after the switch to high light conditions. Based on these experiments and evidence from the literature, it is suggested that a UV-A/blue light receptor mediates the light-induced C(3)-photosynthesis/CAM switch in C. minor.

  2. Randomized trial of switching from prescribed non-selective non-steroidal anti-inflammatory drugs to prescribed celecoxib: the Standard care vs. Celecoxib Outcome Trial (SCOT).

    PubMed

    MacDonald, Thomas M; Hawkey, Chris J; Ford, Ian; McMurray, John J V; Scheiman, James M; Hallas, Jesper; Findlay, Evelyn; Grobbee, Diederick E; Hobbs, F D Richard; Ralston, Stuart H; Reid, David M; Walters, Matthew R; Webster, John; Ruschitzka, Frank; Ritchie, Lewis D; Perez-Gutthann, Susana; Connolly, Eugene; Greenlaw, Nicola; Wilson, Adam; Wei, Li; Mackenzie, Isla S

    2017-06-14

    Selective cyclooxygenase-2 inhibitors and conventional non-selective non-steroidal anti-inflammatory drugs (nsNSAIDs) have been associated with adverse cardiovascular (CV) effects. We compared the CV safety of switching to celecoxib vs. continuing nsNSAID therapy in a European setting. Patients aged 60 years and over with osteoarthritis or rheumatoid arthritis, free from established CV disease and taking chronic prescribed nsNSAIDs, were randomized to switch to celecoxib or to continue their previous nsNSAID. The primary endpoint was hospitalization for non-fatal myocardial infarction or other biomarker positive acute coronary syndrome, non-fatal stroke or CV death analysed using a Cox model with a pre-specified non-inferiority limit of 1.4 for the hazard ratio (HR). In total, 7297 participants were randomized. During a median 3-year follow-up, fewer subjects than expected developed an on-treatment (OT) primary CV event and the rate was similar for celecoxib, 0.95 per 100 patient-years, and nsNSAIDs, 0.86 per 100 patient-years (HR = 1.12, 95% confidence interval, 0.81-1.55; P = 0.50). Comparable intention-to-treat (ITT) rates were 1.14 per 100 patient-years with celecoxib and 1.10 per 100 patient-years with nsNSAIDs (HR = 1.04; 95% confidence interval, 0.81-1.33; P = 0.75). Pre-specified non-inferiority was achieved in the ITT analysis. The upper bound of the 95% confidence limit for the absolute increase in OT risk associated with celecoxib treatment was two primary events per 1000 patient-years exposure. There were only 15 adjudicated secondary upper gastrointestinal complication endpoints (0.078/100 patient-years on celecoxib vs. 0.053 on nsNSAIDs OT, 0.078 vs. 0.053 ITT). More gastrointestinal serious adverse reactions and haematological adverse reactions were reported on nsNSAIDs than celecoxib, but more patients withdrew from celecoxib than nsNSAIDs (50.9% patients vs. 30.2%; P < 0.0001). In subjects 60 years and over, free from CV disease and

  3. Continuation of quetiapine versus switching to placebo or lithium for maintenance treatment of bipolar I disorder (Trial 144: a randomized controlled study).

    PubMed

    Weisler, Richard H; Nolen, Willem A; Neijber, Anders; Hellqvist, Asa; Paulsson, Björn

    2011-11-01

    Quetiapine, combined with lithium or divalproex, demonstrates efficacy in the maintenance treatment of bipolar I disorder. This study investigated the efficacy and safety of quetiapine monotherapy as maintenance treatment in bipolar I disorder compared with switching to placebo or lithium. Patients aged ≥ 18 years with DSM-IV-diagnosed bipolar I disorder and a current or recent manic, depressive, or mixed episode received open-label quetiapine (300-800 mg/d) for 4-24 weeks. Patients achieving stabilization were randomized to continue quetiapine or to switch to placebo or lithium (0.6-1.2 mEq/L) for up to 104 weeks in a double-blind trial. Outcome measures included times to recurrence of any mood event (primary outcome measure), manic event, or depressive event. Safety assessments included adverse events and laboratory values. The study was terminated early after planned interim analysis provided positive results. The study was conducted between March 2005 and July 2007. Of 2,438 patients starting open-label quetiapine, 1,226 (50.3%) were randomized to double-blind treatment, including 1,172 (95.6%) in the intent-to-treat population. Time to recurrence of any mood event was significantly longer for quetiapine versus placebo (hazard ratio [HR] = 0.29; 95% CI, 0.23-0.38; P < .0001) and for lithium versus placebo (HR = 0.46; 95% CI, 0.36-0.59; P < .0001). Quetiapine and lithium significantly increased time to recurrence of both manic events (quetiapine: HR = 0.29; 95% CI, 0.21-0.40; P < .0001; lithium: HR = 0.37; 95% CI, 0.27-0.53; P < .0001) and depressive events (quetiapine: HR = 0.30; 95% CI, 0.20-0.44; P < .0001; lithium: HR = 0.59; 95% CI, 0.42-0.84; P < .004) compared with placebo. Overall rates of adverse events were generally similar between treatment groups, and safety findings for quetiapine were consistent with its known profile. In patients stabilized during acute quetiapine treatment, continuation of quetiapine significantly increased time to recurrence

  4. Randomized comparative efficacy study of parent-mediated interventions for toddlers with autism.

    PubMed

    Kasari, Connie; Gulsrud, Amanda; Paparella, Tanya; Hellemann, Gerhard; Berry, Kathleen

    2015-06-01

    This study compared effects of two parent-mediated interventions on joint engagement outcomes as augmentations of an early intervention program for toddlers with autism spectrum disorder (ASD). Participants included 86 toddlers (range 22-36 months) with ASD and their primary caregiver. Caregiver-child dyads were randomized to receive 10 weeks of hands-on parent training in a naturalistic, developmental behavioral intervention (joint attention, symbolic play, engagement and regulation-JASPER) or a parent-only psychoeducational intervention (PEI). Dose was controlled in terms of researcher-parent contact and early intervention services received by the child. Results yielded significant effects of the JASPER intervention on the primary outcome of joint engagement. The treatment effect was large (Cohen's f² = .69) and maintained over the 6-month follow-up. JASPER effects were also found on secondary outcomes of play diversity, highest play level achieved, and generalization to the child's classroom for child-initiated joint engagement. The PEI intervention was found to be effective in reducing parenting stress associated with child characteristics. All secondary effects were generally small to moderate. These data highlight the benefit of a brief, targeted, parent-mediated intervention on child outcomes. Future studies may consider the combination of JASPER and PEI treatments for optimal parent and child outcomes. Trial registry no. NCT00999778. (c) 2015 APA, all rights reserved).

  5. Self-Monitoring as a Mediator of Weight Loss in the SMART Randomized Clinical Trial

    PubMed Central

    Turk, Melanie Warziski; Elci, Okan U.; Wang, Jing; Sereika, Susan M.; Ewing, Linda J.; Acharya, Sushama D.; Glanz, Karen; Burke, Lora E.

    2012-01-01

    Background Integral components of behavioral weight-loss treatment include self-monitoring of diet and physical activity along with feedback to participants regarding their behaviors. While providing feedback has been associated with weight loss, no studies have examined the impact of feedback frequency on weight loss, or the mediating role of self-monitoring adherence in this relationship. Purpose This study examined the effect of participant feedback frequency on weight loss and determined if this effect was mediated by adherence to self-monitoring in a behavioral weight-loss trial conducted in the United States. Method Participants (N=210) were randomly assigned to one of three self-monitoring methods with either no daily feedback messages or daily feedback messages: 1) paper diary (PD)- no daily feedback, 2) personal digital assistant (PDA)- no daily feedback, and 3) PDA- daily, tailored feedback messages (PDA+FB). The Sobel test via bootstrapping examined the direct effect of feedback frequency on weight loss and the indirect effect through self-monitoring adherence. Results Receiving daily feedback messages significantly increased participants’ self-monitoring adherence. A significant effect of feedback frequency on weight loss was noted; however, after adjusting for self-monitoring adherence, the effect of feedback frequency on weight loss was no longer significant. Feedback frequency had a significant indirect effect on weight loss through self-monitoring adherence. Conclusion Self-monitoring adherence mediated the effect of feedback frequency on weight loss. Increasing the frequency with which participants receive feedback could enhance self-monitoring adherence, a critical component of behavioral weight-loss treatment. PMID:22936524

  6. Agrobacterium tumefaciens-mediated transformation of Valsa mali: an efficient tool for random insertion mutagenesis.

    PubMed

    Wang, Caixia; Guan, Xiangnan; Wang, Hanyan; Li, Guifang; Dong, Xiangli; Wang, Guoping; Li, Baohua

    2013-01-01

    Valsa mali is a causal agent of apple and pear trees canker disease, which is a destructive disease that causes serious economic losses in eastern Asia, especially in China. The lack of an efficient transformation system for Valsa mali retards its investigation, which poses difficulties to control the disease. In this research, a transformation system for this pathogen was established for the first time using A. tumefaciens-mediated transformation (ATMT), with the optimal transformation conditions as follows: 10(6)/mL conidia suspension, cocultivation temperature 22°C, cocultivation time 72 hours, and 200  μ M acetosyringone (AS) in the inductive medium. The average transformation efficiency was 1015.00 ± 37.35 transformants per 10(6) recipient conidia. Thirty transformants were randomly selected for further confirmation and the results showed the presence of T-DNA in all hygromycin B resistant transformants and also revealed random and single gene integration with genetic stability. Compared with wild-type strain, those transformants exhibited various differences in morphology, conidia production, and conidia germination ability. In addition, pathogenicity assays revealed that 14 transformants had mitigated pathogenicity, while one had enhanced infection ability. The results suggest that ATMT of V. mali is a useful tool to gain novel insight into this economically important pathogen at molecular levels.

  7. A conformational switch in PRP8 mediates metal ion coordination that promotes pre-mRNA exon ligation.

    PubMed

    Schellenberg, Matthew J; Wu, Tao; Ritchie, Dustin B; Fica, Sebastian; Staley, Jonathan P; Atta, Karim A; LaPointe, Paul; MacMillan, Andrew M

    2013-06-01

    Splicing of pre-mRNAs in eukaryotes is catalyzed by the spliceosome, a large RNA-protein metalloenzyme. The catalytic center of the spliceosome involves a structure comprising the U2 and U6 snRNAs and includes a metal bound by U6 snRNA. The precise architecture of the splicesome active site, however, and the question of whether it includes protein components, remains unresolved. A wealth of evidence places the protein PRP8 at the heart of the spliceosome through assembly and catalysis. Here we provide evidence that the RNase H domain of PRP8 undergoes a conformational switch between the two steps of splicing, rationalizing yeast prp8 alleles that promote either the first or second step. We also show that this switch unmasks a metal-binding site involved in the second step. Together, these data establish that PRP8 is a metalloprotein that promotes exon ligation within the spliceosome.

  8. Early switch therapy from intravenous sulbactam/ampicillin to oral garenoxacin in patients with community-acquired pneumonia: a multicenter, randomized study in Japan.

    PubMed

    Kohno, Shigeru; Yanagihara, Katsunori; Yamamoto, Yoshihiro; Tokimatsu, Issei; Hiramatsu, Kazufumi; Higa, Futoshi; Tateyama, Masao; Fujita, Jiro; Kadota, Jun-Ichi

    2013-12-01

    The switch from intravenous to oral antibiotic therapy is recommended for treating hospitalized patients with community-acquired pneumonia (CAP). We performed a multicenter, randomized study to assess the benefit of switching from intravenous sulbactam/ampicillin (SBT/ABPC) to oral garenoxacin (GRNX) in patients with CAP. Among adult CAP patients who must be hospitalized for intravenous antibiotic treatment, those with Pneumonia Patient Outcomes Research Team (PORT) scores of II-IV (mild to moderate) were initially treated with intravenous SBT/ABPC (6 g/day) for 3 days. A total of 108 patients who fulfilled the inclusion criteria (improved respiratory symptoms, CRP < 15 mg/dl, adequately improved oral intake, fever ≤ 38 °C for ≥ 12 h), were divided into two groups based on the antibiotic administered, the GRNX (switch to GRNX 400 mg/day) and SBT/ABPC groups (continuous administration of SBT/ABPC), for 4 days. Improvement in clinical symptoms, chest radiographic findings, and clinical effectiveness were evaluated by a central review board. Improvement in clinical symptoms was 96.3 and 90.2% in the GRNX and SBT/ABPC groups, respectively. Improvement in chest radiographic findings was 94.4 and 90.2% and clinical effectiveness was 94.4 and 90.2% in the GRNX and SBT/ABPC groups, respectively. Microbiological efficacy was 90.9 and 69.2% in the GRNX and SBT/ABPC groups, respectively. There were no significant differences between the groups. Converting to GRNX was as effective as continuous SBT/ABPC treatment in mild to moderate CAP patients in whom initial intravenous antibiotic treatment was successful.

  9. Decrease in hnRNP A/B expression during erythropoiesis mediates a pre-mRNA splicing switch

    SciTech Connect

    Hou, Victor C.; Lersch, Robert; Gee, Sherry L.; Ponthier, Julie L.; Lo, Annie J.; Wu, Michael; Turck, Chris W.; Koury, Mark; Krainer, Adrian R.; Mayeda, Akila; Conboy, John G.

    2002-10-17

    A physiologically important alternative pre-mRNA splicing switch, involving activation of protein 4.1R exon 16 (E16) splicing, is required for establishing proper mechanical integrity of the erythrocyte membrane during erythropoiesis. Here we identify a conserved exonic splicing silencer element (CE16) in E16 that interacts with hnRNP A/B proteins and plays a role in repression of E16 splicing during early erythropoiesis. Experiments with model pre-mRNAs showed that CE16 can repress splicing of upstream introns, and that mutagenesis or replacement of CE16 can relieve this inhibition. An affinity selection assay with biotinylated CE16 RNA demonstrated specific binding of hnRNP A/B proteins. Depletion of hnRNP A/B proteins from nuclear extract significantly increased E16 inclusion, while repletion with recombinant hnRNP A/B restored E16 silencing. Most importantly, differentiating mouse erythroblasts exhibited a stage-specific activation of the E16 splicing switch in concert with a drama tic and specific down-regulation of hnRNP A/B protein expression. These findings demonstrate that natural developmental changes in hnRNP A/B proteins can effect physiologically important switches in pre-mRNA splicing.

  10. Decrease in hnRNP A/B expression during erythropoiesis mediates a pre-mRNA splicing switch.

    PubMed

    Hou, Victor C; Lersch, Robert; Gee, Sherry L; Ponthier, Julie L; Lo, Annie J; Wu, Michael; Turck, Chris W; Koury, Mark; Krainer, Adrian R; Mayeda, Akila; Conboy, John G

    2002-11-15

    A physiologically important alternative pre-mRNA splicing switch, involving activation of protein 4.1R exon 16 (E16) splicing, is required for the establishment of proper mechanical integrity of the erythrocyte membrane during erythropoiesis. Here we identify a conserved exonic splicing silencer element (CE(16)) in E16 that interacts with hnRNP A/B proteins and plays a role in repression of E16 splicing during early erythropoiesis. Experiments with model pre-mRNAs showed that CE(16) can repress splicing of upstream introns, and that mutagenesis or replacement of CE(16) can relieve this inhibition. An affinity selection assay with biotinylated CE(16) RNA demonstrated specific binding of hnRNP A/B proteins. Depletion of hnRNP A/B proteins from nuclear extract significantly increased E16 inclusion, while repletion with recombinant hnRNP A/B restored E16 silencing. Most importantly, differentiating mouse erythroblasts exhibited a stage-specific activation of the E16 splicing switch in concert with a dramatic and specific down-regulation of hnRNP A/B protein expression. These findings demonstrate that natural developmental changes in hnRNP A/B proteins can effect physiologically important switches in pre-mRNA splicing.

  11. Influence of Thermal Annealing Treatment on Bipolar Switching Properties of Vanadium Oxide Thin-Film Resistance Random-Access Memory Devices

    NASA Astrophysics Data System (ADS)

    Chen, Kai-Huang; Cheng, Chien-Min; Kao, Ming-Cheng; Chang, Kuan-Chang; Chang, Ting-Chang; Tsai, Tsung-Ming; Wu, Sean; Su, Feng-Yi

    2017-04-01

    The bipolar switching properties and electrical conduction mechanism of vanadium oxide thin-film resistive random-access memory (RRAM) devices obtained using a rapid thermal annealing (RTA) process have been investigated in high-resistive status/low-resistive status (HRS/LRS) and are discussed herein. In addition, the resistance switching properties and quality improvement of the vanadium oxide thin-film RRAM devices were measured by x-ray diffraction (XRD) analysis, x-ray photoelectron spectrometry (XPS), scanning electron microscopy (SEM), atomic force microscopy (AFM), and current-voltage ( I- V) measurements. The activation energy of the hopping conduction mechanism in the devices was investigated based on Arrhenius plots in HRS and LRS. The hopping conduction distance and activation energy barrier were obtained as 12 nm and 45 meV, respectively. The thermal annealing process is recognized as a candidate method for fabrication of thin-film RRAM devices, being compatible with integrated circuit technology for nonvolatile memory devices.

  12. Immediately loaded platform-switched implants in the anterior mandible with fixed prostheses: a randomized, split-mouth, masked prospective trial.

    PubMed

    Romanos, Georgios E; Malmstrom, Hans; Feng, Changyong; Ercoli, Carlo; Caton, Jack

    2014-12-01

    Platform-switched implants have been demonstrated to maintain marginal bone-level stability after immediate loading. The present study evaluated crestal bone loss and soft tissue stability around ANKYLOS plus® implants (A-implants) and Certain® PREVAIL(TM) (B-implants). Patients were identified to receive three A- or three B-implants on each side of their mandibles, with randomization. All implants were loaded immediately after their insertion and splinted with a cemented provisional prosthesis. Final prostheses were delivered 3 months after implantation. Peri-implant crestal bone loss, gingival recession, and other soft tissue changes were evaluated throughout a 2-year follow-up. A total of one hundred seven implants were placed in 18 patients. Two of the group A-implants and one group B-implant failed. At the final 24-month assessment, bone loss of at least 2 mm (mesially or distally) was recorded at 5 of the 44 surviving A-implants (11%) and 33 of the 47 B-implants (70%), a success rate of 88.63% for the A- and 29.78% for the B-implants. Significant changes in the level of the crestal bone loss around immediately loaded platform-switched dental implants seem to be related to the platform shape and size, as well as the implant-abutment connection, when abutments are not removed. © 2013 Wiley Periodicals, Inc.

  13. Influence of Thermal Annealing Treatment on Bipolar Switching Properties of Vanadium Oxide Thin-Film Resistance Random-Access Memory Devices

    NASA Astrophysics Data System (ADS)

    Chen, Kai-Huang; Cheng, Chien-Min; Kao, Ming-Cheng; Chang, Kuan-Chang; Chang, Ting-Chang; Tsai, Tsung-Ming; Wu, Sean; Su, Feng-Yi

    2016-12-01

    The bipolar switching properties and electrical conduction mechanism of vanadium oxide thin-film resistive random-access memory (RRAM) devices obtained using a rapid thermal annealing (RTA) process have been investigated in high-resistive status/low-resistive status (HRS/LRS) and are discussed herein. In addition, the resistance switching properties and quality improvement of the vanadium oxide thin-film RRAM devices were measured by x-ray diffraction (XRD) analysis, x-ray photoelectron spectrometry (XPS), scanning electron microscopy (SEM), atomic force microscopy (AFM), and current-voltage (I-V) measurements. The activation energy of the hopping conduction mechanism in the devices was investigated based on Arrhenius plots in HRS and LRS. The hopping conduction distance and activation energy barrier were obtained as 12 nm and 45 meV, respectively. The thermal annealing process is recognized as a candidate method for fabrication of thin-film RRAM devices, being compatible with integrated circuit technology for nonvolatile memory devices.

  14. A randomized, open-label study of the safety and efficacy of switching stavudine or zidovudine to tenofovir disoproxil fumarate in HIV-1-infected children with virologic suppression.

    PubMed

    Saez-Llorens, Xavier; Castaño, Elizabeth; Rathore, Mobeen; Church, Joseph; Deville, Jaime; Gaur, Aditya; Estripeaut, Dora; White, Kirsten; Arterburn, Sarah; Enejosa, Jeffrey V; Cheng, Andrew K; Chuck, Steven L; Rhee, Martin S

    2015-04-01

    The safety and efficacy of tenofovir disoproxil fumarate (TDF) in HIV-1-infected children have not been evaluated in a randomized controlled trial. Subjects (2 to <16 years) on a stavudine (d4T) or zidovudine (ZDV) containing regimen with HIV-1 RNA <400 copies/mL were randomized to either switch d4T or ZDV to TDF or continue d4T or ZDV. The primary endpoint was the proportion of subjects with HIV-1 RNA < 400 copies/mL at Week 48 with a prespecified noninferiority margin of 15%. After the 48-week randomized phase, eligible subjects were rolled over to an extension phase. Ninety-seven children (48 TDF vs. 49 d4T or ZDV) were randomized and treated. The percent of subjects who maintained virologic suppression in the TDF versus d4T or ZDV group at Week 24 were 93.8% versus 89.8% (difference 4.0%; 95% confidence interval:: -6.9% to 14.9%) and at Week 48 were 83.3% versus 91.8% (difference: -8.5%; 95% confidence interval: -21.5% to 4.5%; missing = failure, intent-to-treat analysis). No subjects discontinued study drug because of an adverse event in the 48 weeks of randomized phase. Four subjects discontinued TDF because of proximal renal tubulopathy in the extension phase. Our study did not demonstrate noninferiority of TDF versus d4T or ZDV at Week 48. Overall safety and tolerability of TDF in children were consistent with adults. TDF may be considered as an alternative to d4T or ZDV in HIV-infected children.

  15. Total ionizing dose effect of γ-ray radiation on the switching characteristics and filament stability of HfOx resistive random access memory

    SciTech Connect

    Fang, Runchen; Yu, Shimeng; Gonzalez Velo, Yago; Chen, Wenhao; Holbert, Keith E.; Kozicki, Michael N.; Barnaby, Hugh

    2014-05-05

    The total ionizing dose (TID) effect of gamma-ray (γ-ray) irradiation on HfOx based resistive random access memory was investigated by electrical and material characterizations. The memory states can sustain TID level ∼5.2 Mrad (HfO{sub 2}) without significant change in the functionality or the switching characteristics under pulse cycling. However, the stability of the filament is weakened after irradiation as memory states are more vulnerable to flipping under the electrical stress. X-ray photoelectron spectroscopy was performed to ascertain the physical mechanism of the stability degradation, which is attributed to the Hf-O bond breaking by the high-energy γ-ray exposure.

  16. Retrospective Analysis of Serotype Switching of Vibrio cholerae O1 in a Cholera Endemic Region Shows It Is a Non-random Process

    PubMed Central

    Karlsson, Stefan L.; Thomson, Nicholas; Mutreja, Ankur; Connor, Thomas; Sur, Dipika; Ali, Mohammad; Clemens, John; Dougan, Gordon; Holmgren, Jan; Lebens, Michael

    2016-01-01

    Genomic data generated from clinical Vibrio cholerae O1 isolates collected over a five year period in an area of Kolkata, India with seasonal cholera outbreaks allowed a detailed genetic analysis of serotype switching that occurred from Ogawa to Inaba and back to Ogawa. The change from Ogawa to Inaba resulted from mutational disruption of the methyltransferase encoded by the wbeT gene. Re-emergence of the Ogawa serotype was found to result either from expansion of an already existing Ogawa clade or reversion of the mutation in an Inaba clade. Our data suggests that such transitions are not random events but rather driven by as yet unidentified selection mechanisms based on differences in the structure of the O1 antigen or in the serotype-determining wbeT gene. PMID:27706170

  17. Retrospective Analysis of Serotype Switching of Vibrio cholerae O1 in a Cholera Endemic Region Shows It Is a Non-random Process.

    PubMed

    Karlsson, Stefan L; Thomson, Nicholas; Mutreja, Ankur; Connor, Thomas; Sur, Dipika; Ali, Mohammad; Clemens, John; Dougan, Gordon; Holmgren, Jan; Lebens, Michael

    2016-10-01

    Genomic data generated from clinical Vibrio cholerae O1 isolates collected over a five year period in an area of Kolkata, India with seasonal cholera outbreaks allowed a detailed genetic analysis of serotype switching that occurred from Ogawa to Inaba and back to Ogawa. The change from Ogawa to Inaba resulted from mutational disruption of the methyltransferase encoded by the wbeT gene. Re-emergence of the Ogawa serotype was found to result either from expansion of an already existing Ogawa clade or reversion of the mutation in an Inaba clade. Our data suggests that such transitions are not random events but rather driven by as yet unidentified selection mechanisms based on differences in the structure of the O1 antigen or in the serotype-determining wbeT gene.

  18. Multi-step resistive switching behavior of Li-doped ZnO resistance random access memory device controlled by compliance current

    SciTech Connect

    Lin, Chun-Cheng; Tang, Jian-Fu; Su, Hsiu-Hsien; Hong, Cheng-Shong; Huang, Chih-Yu; Chu, Sheng-Yuan

    2016-06-28

    The multi-step resistive switching (RS) behavior of a unipolar Pt/Li{sub 0.06}Zn{sub 0.94}O/Pt resistive random access memory (RRAM) device is investigated. It is found that the RRAM device exhibits normal, 2-, 3-, and 4-step RESET behaviors under different compliance currents. The transport mechanism within the device is investigated by means of current-voltage curves, in-situ transmission electron microscopy, and electrochemical impedance spectroscopy. It is shown that the ion transport mechanism is dominated by Ohmic behavior under low electric fields and the Poole-Frenkel emission effect (normal RS behavior) or Li{sup +} ion diffusion (2-, 3-, and 4-step RESET behaviors) under high electric fields.

  19. Effects of Joint Attention Mediated Learning for Toddlers with Autism Spectrum Disorders: An Initial Randomized Controlled Study

    ERIC Educational Resources Information Center

    Schertz, Hannah H.; Odom, Samuel L.; Baggett, Kathleen M.; Sideris, John H.

    2013-01-01

    The purpose of this study was to determine effects of the Joint Attention Mediated Learning (JAML) intervention on acquisition of joint attention and other early social communication competencies for toddlers with autism spectrum disorders (ASD). Twenty-three parents and their toddlers were randomly assigned to JAML or a control condition.…

  20. Effects of Joint Attention Mediated Learning for Toddlers with Autism Spectrum Disorders: An Initial Randomized Controlled Study

    ERIC Educational Resources Information Center

    Schertz, Hannah H.; Odom, Samuel L.; Baggett, Kathleen M.; Sideris, John H.

    2013-01-01

    The purpose of this study was to determine effects of the Joint Attention Mediated Learning (JAML) intervention on acquisition of joint attention and other early social communication competencies for toddlers with autism spectrum disorders (ASD). Twenty-three parents and their toddlers were randomly assigned to JAML or a control condition.…

  1. Testing Mediators of Intervention Effects in Randomized Controlled Trials: An Evaluation of Two Eating Disorder Prevention Programs

    ERIC Educational Resources Information Center

    Stice, Eric; Presnell, Katherine; Gau, Jeff; Shaw, Heather

    2007-01-01

    The authors investigated mediators hypothesized to account for the effects of 2 eating disorder prevention programs using data from 355 adolescent girls who were randomized to a dissonance or a healthy weight intervention or an active control condition. The dissonance intervention produced significant reductions in outcomes (body…

  2. Methodological Issues in Internet-Mediated Research: A Randomized Comparison of Internet Versus Mailed Questionnaires

    PubMed Central

    2011-01-01

    Background The majority of Internet-mediated studies use measures developed as paper-and-pencil measures or face-to-face-delivered material. Previous research suggests that the equivalence between online and offline measures must be demonstrated rather than assumed. Objective The objective of this study was to explore the equivalence 4 measures completed in an online or offline setting. Methods A sample of students (n = 1969) was randomly assigned to complete 4 popular scales (the SF-12v2, the Hospital Anxiety and Depression Scale (HADS), the Fatigue Symptom Inventory, and a single-item fatigue measure) either online or by mail survey (pencil and paper). The response rate was 52.51% (n = 1034) and comparable between the online and offline groups. Results Significant differences were noted in fatigue levels between the online and offline group (P = .01) as measured by the Fatigue Symptom Inventory, with the online sample demonstrating higher levels of fatigue. Equivalency was noted for the SF-12v2, the Hospital Anxiety and Depression Scale, and the single-item fatigue measure. Internal consistency was high except for the SF-12v2. The SF-12v2 may not be an ideal measure to use for remote administration. Conclusions Equivalency of the Hospital Anxiety and Depression Scale (HADS) and the Physical Component Score and Mental Component Score of the SF-12v2 for online and offline data were demonstrated. Equivalency was not demonstrated for the Fatigue Symptom Inventory. Explanations for the difference in fatigue score between the online and offline samples are unclear. Research that seeks to match samples and control for extraneous online and offline variables is called for, along with exploration of factors that may mediate the completion of questionnaires or alter the respondents’ relationship with the same, to enhance progress in this area. PMID:22155721

  3. Mediators in the randomized trial of Child- and Family-Focused Cognitive-Behavioral Therapy for pediatric bipolar disorder.

    PubMed

    MacPherson, Heather A; Weinstein, Sally M; Henry, David B; West, Amy E

    2016-10-01

    Mediation analyses can identify mechanisms of change in Cognitive-Behavioral Therapy (CBT). However, few studies have analyzed mediators of CBT for youth internalizing disorders; only one trial evaluated treatment mechanisms for youth with mixed mood diagnoses. This study evaluated mediators in the randomized trial of Child- and Family-Focused CBT (CFF-CBT) versus Treatment As Usual (TAU) for pediatric bipolar disorder (PBD), adjunctive to pharmacotherapy. Sixty-nine children ages 7-13 with PBD were randomly assigned to CFF-CBT or TAU. Primary outcomes (child mood, functioning) and candidate mediators (family functioning, parent/child coping) were assessed at baseline and 4-, 8-, 12- (post-treatment), and 39-weeks (follow-up). Compared with TAU, children receiving CFF-CBT exhibited greater improvement in mania, depression, and global functioning. Several parent and family factors significantly improved in response to CFF-CBT versus TAU, and were associated with the CFF-CBT treatment effect. Specifically, parenting skills and coping, family flexibility, and family positive reframing showed promise as mediators of child mood symptoms and global functioning. Main or mediating effects for youth coping were not significant. CFF-CBT may impact children's mood and functioning by improving parenting skills and coping, family flexibility, and family positive reframing. Findings highlight the importance of parent coping and family functioning in the treatment of PBD. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. A randomized, split-face clinical trial of Q-switched alexandrite laser versus Q-switched Nd:YAG laser in the treatment of bilateral nevus of Ota.

    PubMed

    Wen, Xiang; Li, Yong; Jiang, Xian

    2016-01-01

    Different types of Q-switched (QS) lasers have been used successfully to treat nevus of Ota. The purpose of this study was to compare the clinical efficacy and complication of QS alexandrite (QS Alex) laser versus QS neodymium:yttrium aluminum garnet (Nd:YAG) (QS Nd:YAG) laser for bilateral nevus of Ota. Seventeen patients with bilateral nevus of Ota were treated randomly with QS Alex in one half of face and QS Nd:YAG in the other half with an interval of at least 3 months between each. Subjective assessment was made by both patients and dermatologists. Patients were also examined for evidence of complications. All patients experienced improvement (p < 0.05). There was no statistically significant difference between the two sides (p > 0.05). The pain after a short period of laser therapy was more severe for QS Alex than for QS Nd:YAG laser. Vesicles developed in 1 patient after QS Alex therapy. Both QS Alex laser and QS Nd:YAG laser were equally effective at improving bilateral nevus of Ota. Patients tolerate QS Nd:YAG laser better than QS Alex laser.

  5. Inducible CTCF insulator delays the IgH 3' regulatory region-mediated activation of germline promoters and alters class switching.

    PubMed

    Braikia, Fatima-Zohra; Oudinet, Chloé; Haddad, Dania; Oruc, Zeliha; Orlando, Domenico; Dauba, Audrey; Le Bert, Marc; Khamlichi, Ahmed Amine

    2017-06-06

    Class switch recombination (CSR) plays an important role in adaptive immune response by enabling mature B cells to switch from IgM expression to the expression of downstream isotypes. CSR is preceded by inducible germline (GL) transcription of the constant genes and is controlled by the 3' regulatory region (3'RR) in a stimulus-dependent manner. Why the 3'RR-mediated up-regulation of GL transcription is delayed to the mature B-cell stage is presently unknown. Here we show that mice devoid of an inducible CTCF binding element, located in the α constant gene, display a marked isotype-specific increase of GL transcription in developing and resting splenic B cells and altered CSR in activated B cells. Moreover, insertion of a GL promoter downstream of the CTCF insulator led to premature activation of the ectopic promoter. This study provides functional evidence that the 3'RR has a developmentally controlled potential to constitutively activate GL promoters but that this activity is delayed, at least in part, by the CTCF insulator, which borders a transcriptionally active domain established by the 3'RR in developing B cells.

  6. UV irradiation/cold shock-mediated apoptosis is switched to bubbling cell death at low temperatures

    PubMed Central

    Lin, Hsin-Ping; Huang, Shenq-Shyang; Sheu, Hamm-Ming; Hsu, Li-Jin; Chang, Nan-Shan

    2015-01-01

    When COS7 fibroblasts and other cells were exposed to UVC irradiation and cold shock at 4°C for 5 min, rapid upregulation and nuclear accumulation of NOS2, p53, WWOX, and TRAF2 occurred in 10–30 min. By time-lapse microscopy, an enlarging gas bubble containing nitric oxide (NO) was formed in the nucleus in each cell that finally popped out to cause “bubbling death”. Bubbling occurred effectively at 4 and 22°C, whereas DNA fragmentation was markedly blocked at 4°C. When temperature was increased to 37°C, bubbling was retarded and DNA fragmentation occurred in 1 hr, suggesting that bubbling death is switched to apoptosis with increasing temperatures. Bubbling occurred prior to nuclear uptake of propidium iodide and DAPI stains. Arginine analog Nω-LAME inhibited NO synthase NOS2 and significantly suppressed the bubbling death. Unlike apoptosis, there were no caspase activation and flip-over of membrane phosphatidylserine (PS) during bubbling death. Bubbling death was significantly retarded in Wwox knockout MEF cells, as well as in cells overexpressing TRAF2 and dominant-negative p53. Together, UV/cold shock induces bubbling death at 4°C and the event is switched to apoptosis at 37°C. Presumably, proapoptotic WWOX and p53 block the protective TRAF2 to execute the bubbling death. PMID:25779665

  7. A stochastic model for adhesion-mediated cell random motility and haptotaxis.

    PubMed

    Dickinson, R B; Tranquillo, R T

    1993-01-01

    The active migration of blood and tissue cells is important in a number of physiological processes including inflammation, wound healing, embryogenesis, and tumor cell metastasis. These cells move by transmitting cytoplasmic force through membrane receptors which are bound specifically to adhesion ligands in the surrounding substratum. Recently, much research has focused on the influence of the composition of extracellular matrix and the distribution of its components on the speed and direction of cell migration. It is commonly believed that the magnitude of the adhesion influences cell speed and/or random turning behavior, whereas a gradient of adhesion may bias the net direction of the cell movement, a phenomenon known as haptotaxis. The mechanisms underlying these responses are presently not understood. A stochastic model is presented to provide a mechanistic understanding of how the magnitude and distribution of adhesion ligands in the substratum influence cell movement. The receptor-mediated cell migration is modeled as an interrelation of random processes on distinct time scales. Adhesion receptors undergo rapid binding and transport, resulting in a stochastic spatial distribution of bound receptors fluctuating about some mean distribution. This results in a fluctuating spatio-temporal pattern of forces on the cell, which in turn affects the speed and turning behavior on a longer time scale. The model equations are a system of nonlinear stochastic differential equations (SDE's) which govern the time evolution of the spatial distribution of bound and free receptors, and the orientation and position of the cell. These SDE's are integrated numerically to simulate the behavior of the model cell on both a uniform substratum, and on a gradient of adhesion ligand concentration. Furthermore, analysis of the governing SDE system and corresponding Fokker-Planck equation (FPE) yields analytical expressions for indices which characterize cell movement on multiple time

  8. Compact biocompatible quantum dots via RAFT-mediated synthesis of imidazole-based random copolymer ligand

    PubMed Central

    Liu, Wenhao; Greytak, Andrew B.; Lee, Jungmin; Wong, Cliff R.; Park, Jongnam; Marshall, Lisa F.; Jiang, Wen; Curtin, Peter N.; Ting, Alice Y.; Nocera, Daniel G.; Fukumura, Dai; Jain, Rakesh K.; Bawendi, Moungi G.

    2010-01-01

    We present a new class of polymeric ligands for quantum dot (QD) water solubilization to yield biocompatible and derivatizable QDs with compact size (~10-12 nm diameter), high quantum yields (>50%), excellent stability across a large pH range (pH 5-10.5), and low nonspecific binding. To address the fundamental problem of thiol instability in traditional ligand exchange systems, the polymers here employ a stable multidentate imidazole binding motif to the QD surface. The polymers are synthesized via reversible addition-fragmentation chain transfer (RAFT)-mediated polymerization to produce molecular weight controlled monodisperse random copolymers from three types of monomers that feature imidazole groups for QD binding, polyethylene glycol (PEG) groups for water solubilization, and either primary amines or biotin groups for derivatization. The polymer architecture can be tuned by the monomer ratios to yield aqueous QDs with targeted surface functionalities. By incorporating amino-PEG monomers, we demonstrate covalent conjugation of a dye to form a highly efficient QD-dye energy transfer pair as well as covalent conjugation to streptavidin for high-affinity single molecule imaging of biotinylated receptors on live cells with minimal non-specific binding. The small size and low serum binding of these polymer-coated QDs also allow us to demonstrate their utility for in-vivo imaging of the tumor microenvironment in live mice. PMID:20025223

  9. Phenobarbital Mediates an Epigenetic Switch at the Constitutive Androstane Receptor (CAR) Target Gene Cyp2b10 in the Liver of B6C3F1 Mice

    PubMed Central

    Brasa, Sarah; Teo, Soon-Siong; Roloff, Tim-Christoph; Morawiec, Laurent; Zamurovic, Natasa; Vicart, Axel; Funhoff, Enrico; Couttet, Philippe; Schübeler, Dirk; Grenet, Olivier; Marlowe, Jennifer; Moggs, Jonathan; Terranova, Rémi

    2011-01-01

    Evidence suggests that epigenetic perturbations are involved in the adverse effects associated with some drugs and toxicants, including certain classes of non-genotoxic carcinogens. Such epigenetic changes (altered DNA methylation and covalent histone modifications) may take place at the earliest stages of carcinogenesis and their identification holds great promise for biomedical research. Here, we evaluate the sensitivity and specificity of genome-wide epigenomic and transcriptomic profiling in phenobarbital (PB)-treated B6C3F1 mice, a well-characterized rodent model of non-genotoxic liver carcinogenesis. Methylated DNA Immunoprecipitation (MeDIP)-coupled microarray profiling of 17,967 promoter regions and 4,566 intergenic CpG islands was combined with genome-wide mRNA expression profiling to identify liver tissue-specific PB-mediated DNA methylation and transcriptional alterations. Only a limited number of significant anti-correlations were observed between PB-induced transcriptional and promoter-based DNA methylation perturbations. However, the constitutive androstane receptor (CAR) target gene Cyp2b10 was found to be concomitantly hypomethylated and transcriptionally activated in a liver tissue-specific manner following PB treatment. Furthermore, analysis of active and repressive histone modifications using chromatin immunoprecipitation revealed a strong PB-mediated epigenetic switch at the Cyp2b10 promoter. Our data reveal that PB-induced transcriptional perturbations are not generally associated with broad changes in the DNA methylation status at proximal promoters and suggest that the drug-inducible CAR pathway regulates an epigenetic switch from repressive to active chromatin at the target gene Cyp2b10. This study demonstrates the utility of integrated epigenomic and transcriptomic profiling for elucidating early mechanisms and biomarkers of non-genotoxic carcinogenesis. PMID:21455306

  10. Improvement of switching endurance of conducting-bridge random access memory by addition of metal-ion-containing ionic liquid

    NASA Astrophysics Data System (ADS)

    Kinoshita, Kentaro; Sakaguchi, Atsushi; Harada, Akinori; Yamaoka, Hiroki; Kishida, Satoru; Fukaya, Yukinobu; Nokami, Toshiki; Itoh, Toshiyuki

    2017-04-01

    A remarkable improvement of cycling endurance was achieved by the addition of a trace amount of an ionic liquid ([bmim][Tf2N]) containing Cu(Tf2N)2 to the HfO2 layer of a conducting-bridge random access memory (CBRAM) with a Cu/HfO2/Pt structure. The improvement was brought about by the significant improvement of the dispersion of a set voltage and the suppression of the generation and migration of oxygen vacancies owing to the smooth diffusion of Cu ions in ionic liquids.

  11. C-type lectin-like receptor LOX-1 promotes dendritic cell-mediated class-switched B cell responses.

    PubMed

    Joo, HyeMee; Li, Dapeng; Dullaers, Melissa; Kim, Tae-Whan; Duluc, Dorothee; Upchurch, Katherine; Xue, Yaming; Zurawski, Sandy; Le Grand, Roger; Liu, Yong-Jun; Kuroda, Marcelo; Zurawski, Gerard; Oh, SangKon

    2014-10-16

    Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a pattern-recognition receptor for a variety of endogenous and exogenous ligands. However, LOX-1 function in the host immune response is not fully understood. Here, we report that LOX-1 expressed on dendritic cells (DCs) and B cells promotes humoral responses. On B cells LOX-1 signaling upregulated CCR7, promoting cellular migration toward lymphoid tissues. LOX-1 signaling on DCs licensed the cells to promote B cell differentiation into class-switched plasmablasts and led to downregulation of chemokine receptor CXCR5 and upregulation of chemokine receptor CCR10 on plasmablasts, enabling their exit from germinal centers and migration toward local mucosa and skin. Finally, we found that targeting influenza hemagglutinin 1 (HA1) subunit to LOX-1 elicited HA1-specific protective antibody responses in rhesus macaques. Thus, LOX-1 expressed on B cells and DC cells has complementary functions to promote humoral immune responses.

  12. Safety and Efficacy Outcomes 3 Years After Switching to Belatacept From a Calcineurin Inhibitor in Kidney Transplant Recipients: Results From a Phase 2 Randomized Trial.

    PubMed

    Grinyó, Josep M; Del Carmen Rial, Maria; Alberu, Josefina; Steinberg, Steven M; Manfro, Roberto C; Nainan, Georgy; Vincenti, Flavio; Jones-Burton, Charlotte; Kamar, Nassim

    2017-05-01

    In a phase 2 study, kidney transplant recipients of low immunologic risk who switched from a calcineurin inhibitor (CNI) to belatacept had improved kidney function at 12 months postconversion versus those continuing CNI therapy, with a low rate of acute rejection and no transplant loss. 36-month follow-up of the intention-to-treat population. CNI-treated adult kidney transplant recipients with stable transplant function (estimated glomerular filtration rate [eGFR], 35-75mL/min/1.73m(2)). At 6 to 36 months posttransplantation, patients were randomly assigned to switch to belatacept-based immunosuppression (n=84) or continue CNI-based therapy (n=89). Safety was the primary outcome. eGFR, acute rejection, transplant loss, and death were also assessed. Treatment exposure-adjusted incidence rates for safety, repeated-measures modeling for eGFR, Kaplan-Meier analyses for efficacy. Serious adverse events occurred in 33 (39%) belatacept-treated patients and 36 (40%) patients in the CNI group. Treatment exposure-adjusted incidence rates for serious infections (belatacept vs CNI, 10.21 vs 9.31 per 100 person-years) and malignancies (3.01 vs 3.41 per 100 person-years) were similar. More patients in the belatacept versus CNI group had any-grade viral infections (14.60 vs 11.00 per 100 person-years). No posttransplantation lymphoproliferative disorder was reported. Belatacept-treated patients had a significantly greater estimated gain in mean eGFR (1.90 vs 0.07mL/min/1.73m(2) per year; P for time-by-treatment interaction effect = 0.01). The probability of acute rejection was not significantly different for belatacept (8.38% vs 3.60%; HR, 2.50 [95% CI, 0.65-9.65; P=0.2). HR for the comparison of belatacept to the CNI group for time to death or transplant loss was 1.00 (95% CI, 0.14-7.07; P=0.9). Exploratory post hoc analysis with a small sample size. Switching patients from a CNI to belatacept may represent a safe approach to immunosuppression and is being further explored in

  13. Barriers encountered during enrollment in an internet-mediated randomized controlled trial

    PubMed Central

    Buis, Lorraine R; Janney, Adrienne W; Hess, Michael L; Culver, Silas A; Richardson, Caroline R

    2009-01-01

    Background Online technology is a promising resource for conducting clinical research. While the internet may improve a study's reach, as well as the efficiency of data collection, it may also introduce a number of challenges for participants and investigators. The objective of this research was to determine the challenges that potential participants faced during the enrollment phase of a randomized controlled intervention trial of Stepping Up to Health, an internet-mediated walking program that utilized a multi-step online enrollment process. Methods We conducted a quantitative content analysis of 623 help tickets logged in a participant management database during the enrollment phase of a clinical trial investigating the effect of an automated internet-mediated walking intervention. Qualitative coding was performed by two trained coders, and 10% of the sample was coded by both coders to determine inter-coder reliability. Quantitative analyses included standard descriptive statistics on ticket characteristics and theme frequency, and a Poisson regression analysis identified characteristics of potential participants who reported more frequent problems during enrollment. Results In total, 880 potential participants visited the study website and 80% completed the enrollment screening. Of the potential participants who visited the study website, 38% had help tickets logged in the participant management database. The total number of help tickets associated with individual potential participants ranged from 0 to 7 (M = .71). Overall, 46% of help tickets were initiated by email and 54% were initiated by phone. The most common help ticket theme was issues related to the study process (48%). The next most prominent theme was discussion related to obtaining medical clearance (34%), followed by issues related to pedometers and uploading (31%). Older individuals, women, and those with lower self-rated internet ability were more likely to report problems during the enrollment

  14. Screen-time Weight-loss Intervention Targeting Children at Home (SWITCH): A randomized controlled trial study protocol

    PubMed Central

    2011-01-01

    Background Approximately one third of New Zealand children and young people are overweight or obese. A similar proportion (33%) do not meet recommendations for physical activity, and 70% do not meet recommendations for screen time. Increased time being sedentary is positively associated with being overweight. There are few family-based interventions aimed at reducing sedentary behavior in children. The aim of this trial is to determine the effects of a 24 week home-based, family oriented intervention to reduce sedentary screen time on children's body composition, sedentary behavior, physical activity, and diet. Methods/Design The study design is a pragmatic two-arm parallel randomized controlled trial. Two hundred and seventy overweight children aged 9-12 years and primary caregivers are being recruited. Participants are randomized to intervention (family-based screen time intervention) or control (no change). At the end of the study, the control group is offered the intervention content. Data collection is undertaken at baseline and 24 weeks. The primary trial outcome is child body mass index (BMI) and standardized body mass index (zBMI). Secondary outcomes are change from baseline to 24 weeks in child percentage body fat; waist circumference; self-reported average daily time spent in physical and sedentary activities; dietary intake; and enjoyment of physical activity and sedentary behavior. Secondary outcomes for the primary caregiver include change in BMI and self-reported physical activity. Discussion This study provides an excellent example of a theory-based, pragmatic, community-based trial targeting sedentary behavior in overweight children. The study has been specifically designed to allow for estimation of the consistency of effects on body composition for Māori (indigenous), Pacific and non-Māori/non-Pacific ethnic groups. If effective, this intervention is imminently scalable and could be integrated within existing weight management programs. Trial

  15. Inflammation and psychosocial factors mediate exercise effects on sleep quality in breast cancer survivors: Pilot randomized controlled trial

    PubMed Central

    Rogers, Laura Q.; Fogleman, Amanda; Trammell, Rita; Hopkins-Price, Patricia; Spenner, Allison; Vicari, Sandra; Rao, Krishna; Courneya, Kerry S.; Hoelzer, Karen; Robbs, Randall; Verhulst, Steven

    2014-01-01

    Objective To improve mechanistic understanding, this pilot randomized controlled trial examined mediators of an exercise intervention effects on sleep in breast cancer survivors (BCS). Methods Forty-six postmenopausal BCS (≤ Stage II, off primary treatment) were randomized to a 3-month exercise intervention or control group. Intervention included 160 minutes/week of moderate intensity aerobic walking, twice weekly resistance training (resistance bands), and six discussion groups (to improve adherence). Blinded assessments at baseline and post-intervention included sleep disturbance (PSQI and PROMIS®), objective sleep quality (accelerometer), serum cytokines, accelerometer physical activity, cardiorespiratory fitness, body composition, fatigue, and psychosocial factors. Mediation was tested using Freedman-Schatzkin difference-in-coefficients tests. Results When compared with control, the intervention group demonstrated a significant increase in PSQI sleep duration (i.e., fewer hours of sleep/night) (d=0.73, p=.03). Medium to large but non-significant standardized effect sizes were noted for PSQI daytime somnolence (d=-0.63, p=.05) and accelerometer latency (d=-0.49, p=.14). No statistically significant mediators were detected for PSQI sleep duration score or accelerometer latency. Daytime somnolence was mediated by tumor necrosis factor (TNF)-alpha (mediated 23% of intervention effect, p<.05), interleukin (IL)-6: IL-10 (16%, p<.01), IL-8:IL-10 (26%, p<.01), and fatigue (38%, p<.05). Mediating or enhancing relationships for several of the sleep outcomes were noted for accelerometer physical activity, PROMIS® fatigue, exercise social support, and/or physical activity enjoyment. Conclusions Inflammation and psychosocial factors may mediate or enhance sleep response to our exercise intervention. Further study is warranted to confirm our results and translate our findings into more effective interventions aimed at improving sleep quality in BCS. PMID:24916951

  16. Inflammation and psychosocial factors mediate exercise effects on sleep quality in breast cancer survivors: pilot randomized controlled trial.

    PubMed

    Rogers, Laura Q; Fogleman, Amanda; Trammell, Rita; Hopkins-Price, Patricia; Spenner, Allison; Vicari, Sandra; Rao, Krishna; Courneya, Kerry S; Hoelzer, Karen; Robbs, Randall; Verhulst, Steven

    2015-03-01

    To improve mechanistic understanding, this pilot randomized controlled trial examined mediators of an exercise intervention effects on sleep in breast cancer survivors (BCS). Forty-six postmenopausal BCS (≤Stage II, off primary treatment) were randomized to a 3-month exercise intervention or control group. Intervention included 160 min/week of moderate intensity aerobic walking, twice weekly resistance training (resistance bands), and six discussion groups (to improve adherence). Blinded assessments at baseline and post-intervention included sleep disturbance (PSQI and PROMIS®), objective sleep quality (accelerometer), serum cytokines, accelerometer physical activity, cardiorespiratory fitness, body composition, fatigue, and psychosocial factors. Mediation was tested using Freedman-Schatzkin difference-in-coefficients tests. When compared with control, the intervention group demonstrated a significant increase in PSQI sleep duration (i.e., fewer hours of sleep/night) (d = 0.73, p = .03). Medium to large but non-significant standardized effect sizes were noted for PSQI daytime somnolence (d = -0.63, p = .05) and accelerometer latency (d = -0.49, p = .14). No statistically significant mediators were detected for PSQI sleep duration score or accelerometer latency. Daytime somnolence was mediated by tumor necrosis factor-alpha (mediated 23% of intervention effect, p < .05), interleukin (IL)-6:IL-10 (16%, p < .01), IL-8:IL-10 (26%, p < .01), and fatigue (38%, p < .05). Mediating or enhancing relationships for several of the sleep outcomes were noted for accelerometer physical activity, PROMIS® fatigue, exercise social support, and/or physical activity enjoyment. Inflammation and psychosocial factors may mediate or enhance sleep response to our exercise intervention. Further study is warranted to confirm our results and translate our findings into more effective interventions aimed at improving sleep quality in BCS. Copyright

  17. Steric Switching from Photochemical to Thermal Reaction Pathways for Enhanced Efficiency in Metal-Mediated Nitrogen Fixation.

    PubMed

    Duman, Leila M; Farrell, Wesley S; Zavalij, Peter Y; Sita, Lawrence R

    2016-11-16

    Programmed manipulation of the subtle interplay of nonbonded steric interactions within a supporting ligand environment has been used for the conversion of a photochemically driven chemical cycle for group 6 metal-mediated nitrogen fixation into a thermally promoted process with increased energy efficiency and atom economy for key transformations involving N≡N bond cleavage and N-atom functionalization of coordinated N2.

  18. Cell speed is independent of force in a mathematical model of amoeboidal cell motion with random switching terms.

    PubMed

    Dallon, J C; Evans, E J; Grant, Christopher P; Smith, W V

    2013-11-01

    In this paper the motion of a single cell is modeled as a nucleus and multiple integrin based adhesion sites. Numerical simulations and analysis of the model indicate that when the stochastic nature of the adhesion sites is a memoryless and force independent random process, the cell speed is independent of the force these adhesion sites exert on the cell. Furthermore, understanding the dynamics of the attachment and detachment of the adhesion sites is key to predicting cell speed. We introduce a differential equation describing the cell motion and then introduce a conjecture about the expected drift of the cell, the expected average velocity relation conjecture. Using Markov chain theory, we analyze our conjecture in the context of a related (but simpler) model of cell motion, and then numerically compare the results for the simpler model and the full differential equation model. We also heuristically describe the relationship between the simplified and full models as well as provide a discussion of the biological significance of these results. Copyright © 2013 Elsevier Inc. All rights reserved.

  19. Self-Assembly of Gold Nanoparticles Shows Microenvironment-Mediated Dynamic Switching and Enhanced Brain Tumor Targeting.

    PubMed

    Feng, Qishuai; Shen, Yajing; Fu, Yingjie; Muroski, Megan E; Zhang, Peng; Wang, Qiaoyue; Xu, Chang; Lesniak, Maciej S; Li, Gang; Cheng, Yu

    2017-01-01

    Inorganic nanoparticles with unique physical properties have been explored as nanomedicines for brain tumor treatment. However, the clinical applications of the inorganic formulations are often hindered by the biological barriers and failure to be bioeliminated. The size of the nanoparticle is an essential design parameter which plays a significant role to affect the tumor targeting and biodistribution. Here, we report a feasible approach for the assembly of gold nanoparticles into ~80 nm nanospheres as a drug delivery platform for enhanced retention in brain tumors with the ability to be dynamically switched into the single formulation for excretion. These nanoassemblies can target epidermal growth factor receptors on cancer cells and are responsive to tumor microenvironmental characteristics, including high vascular permeability and acidic and redox conditions. Anticancer drug release was controlled by a pH-responsive mechanism. Intracellular L-glutathione (GSH) triggered the complete breakdown of nanoassemblies to single gold nanoparticles. Furthermore, in vivo studies have shown that nanospheres display enhanced tumor-targeting efficiency and therapeutic effects relative to single-nanoparticle formulations. Hence, gold nanoassemblies present an effective targeting strategy for brain tumor treatment.

  20. Reactive oxygen species-mediated switching expression of MMP-3 in stromal fibroblasts and cancer cells during prostate cancer progression.

    PubMed

    Hsieh, Chia-Ling; Liu, Che-Ming; Chen, Hsin-An; Yang, Shun-Tai; Shigemura, Katsumi; Kitagawa, Koichi; Yamamichi, Fukashi; Fujisawa, Masato; Liu, Yun-Ru; Lee, Wei-Hua; Chen, Kuan-Chou; Shen, Chia-Ning; Lin, Cheng-Chieh; Chung, Leland W K; Sung, Shian-Ying

    2017-08-22

    Studies on the aberrant control of extracellular matrices (ECMs) have mainly focused on the role of malignant cells but less on that of stromal fibroblasts during cancer development. Herein, by using paired normal and prostate cancer-associated stromal fibroblasts (CAFs) derived from a coculture cell model and clinical patient samples, we demonstrated that although CAFs promoted prostate cancer growth, matrix metalloproteinase-3 (MMP-3) was lower in CAFs but elevated in prostate cancer cells relative to their normal counterparts. Furthermore, hydrogen peroxide was characterized as the central modulator for altered MMP-3 expression in prostate cancer cells and CAFs, but through different regulatory mechanisms. Treatment of CAFs but not prostate cancer cells with hydrogen peroxide directly inhibited mmp-3 promoter activity with concomitant nuclear translocation of nuclear factor-κB (NF-κB), indicating that NF-κB is the downstream pathway for the transcriptional repression of MMP-3 in CAFs. Hydrogen peroxide reduced thrombospondin 2 (an MMP-3 suppressor) expression in prostate cancer cells by upregulating microRNA-128. To the best of our knowledge, this is the first study to demonstrate the crucial role of reactive oxygen species in the switching expression of MMP-3 in stromal fibroblasts and prostate cancer cells during tumor progression, clarifying how the tumor microenvironment modulates ECM homeostasis control.

  1. Biomechanical insult switches PEA-15 activity to uncouple its anti-apoptotic function and promote erk mediated tissue remodeling.

    PubMed

    Exler, Rachel E; Guo, Xiaoxin; Chan, Darren; Livne-Bar, Izhar; Vicic, Nevena; Flanagan, John G; Sivak, Jeremy M

    2016-01-15

    Biomechanical insult contributes to many chronic pathological processes, yet the resulting influences on signal transduction mechanisms are poorly understood. The retina presents an excellent mechanotransduction model, as mechanical strain on sensitive astrocytes of the optic nerve head (ONH) is intimately linked to chronic tissue remodeling and excavation by matrix metalloproteinases (MMPs), and apoptotic cell death. However, the mechanism by which these effects are induced by biomechanical strain is unclear. We previously identified the small adapter protein, PEA-15 (phosphoprotein enriched in astrocytes), through proteomic analyses of human ONH astrocytes subjected to pathologically relevant biomechanical insult. Under resting conditions PEA-15 is regulated through phosphorylation of two key serine residues to inhibit extrinsic apoptosis and ERK1/2 signaling. However, we surprisingly observed that biomechanical insult dramatically switches PEA-15 phosphorylation and function to uncouple its anti-apoptotic activity, and promote ERK1/2-dependent MMP-2 and MMP-9 secretion. These results reveal a novel cell autonomous mechanism by which biomechanical strain rapidly modifies this signaling pathway to generate altered tissue injury responses.

  2. Liver X receptor α mediates hepatic triglyceride accumulation through upregulation of G0/G1 Switch Gene 2 expression

    PubMed Central

    Heckmann, Bradlee L.; Zhang, Xiaodong; Saarinen, Alicia M.; Schoiswohl, Gabriele; Kershaw, Erin E.; Zechner, Rudolf

    2017-01-01

    Liver X receptors (LXRs) are transcription factors essential for cholesterol homeostasis and lipogenesis. LXRα has been implicated in regulating hepatic triglyceride (TG) accumulation upon both influx of adipose-derived fatty acids (FAs) during fasting and stimulation of de novo FA synthesis by chemical agonism of LXR. However, whether or not a convergent mechanism is employed to drive deposition of FAs from these 2 different sources in TGs is undetermined. Here, we report that the G0/G1 Switch Gene 2 (G0S2), a selective inhibitor of intracellular TG hydrolysis/lipolysis, is a direct target gene of LXRα. Transcriptional activation is conferred by LXRα binding to a direct repeat 4 (DR4) motif in the G0S2 promoter. While LXRα–/– mice exhibited decreased hepatic G0S2 expression, adenoviral expression of G0S2 was sufficient to restore fasting-induced TG storage and glycogen depletion in the liver of these mice. In response to LXR agonist T0901317, G0S2 ablation prevented hepatic steatosis and hypertriglyceridemia without affecting the beneficial effects on HDL. Thus, the LXRα-G0S2 axis plays a distinct role in regulating hepatic TG during both fasting and pharmacological activation of LXR. PMID:28239648

  3. Androgens Regulate Prostate Cancer Cell Growth via an AMPK-PGC-1α-Mediated Metabolic Switch

    PubMed Central

    Tennakoon, Jayantha B.; Shi, Yan; Han, Jenny J.; Tsouko, Efrosini; White, Mark A.; Burns, Alan R.; Zhang, Aijun; Xia, Xuefeng; Ilkayeva, Olga R.; Xin, Li; Ittmann, Michael M.; Rick, Ferenc G.; Schally, Andrew V.; Frigo, Daniel E.

    2014-01-01

    Prostate cancer is the most commonly diagnosed malignancy among men in industrialized countries, accounting for the second leading cause of cancer-related deaths. While we now know that the androgen receptor (AR) is important for progression to the deadly advanced stages of the disease, it is poorly understood what AR-regulated processes drive this pathology. Here, we demonstrate that AR regulates prostate cancer cell growth via the metabolic sensor 5′-AMP-activated protein kinase (AMPK), a kinase that classically regulates cellular energy homeostasis. In patients, activation of AMPK correlated with prostate cancer progression. Using a combination of radiolabeled assays and emerging metabolomic approaches, we also show that prostate cancer cells respond to androgen treatment by increasing not only rates of glycolysis, as is commonly seen in many cancers, but also glucose and fatty acid oxidation. Importantly, this effect was dependent on androgen-mediated AMPK activity. Our results further indicate that the AMPK-mediated metabolic changes increased intracellular ATP levels and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)-mediated mitochondrial biogenesis, affording distinct growth advantages to the prostate cancer cells. Correspondingly, we used outlier analysis to determine that PGC-1α is overexpressed in a subpopulation of clinical cancer samples. This was in contrast to what was observed in immortalized benign human prostate cells and a testosterone-induced rat model of benign prostatic hyperplasia. Taken together, our findings converge to demonstrate that androgens can co-opt the AMPK-PGC-1α signaling cascade, a known homeostatic mechanism, to increase prostate cancer cell growth. The current study points to the potential utility of developing metabolic-targeted therapies directed towards the AMPK-PGC-1α signaling axis for the treatment of prostate cancer. PMID:24186207

  4. A Developmental Switch of Gene Expression in the Barley Seed Mediated by HvVP1 (Viviparous-1) and HvGAMYB Interactions.

    PubMed

    Abraham, Zamira; Iglesias-Fernández, Raquel; Martínez, Manuel; Rubio-Somoza, Ignacio; Díaz, Isabel; Carbonero, Pilar; Vicente-Carbajosa, Jesús

    2016-04-01

    The accumulation of storage compounds in the starchy endosperm of developing cereal seeds is highly regulated at the transcriptional level. These compounds, mainly starch and proteins, are hydrolyzed upon germination to allow seedling growth. The transcription factor HvGAMYB is a master activator both in the maturation phase of seed development and upon germination, acting in combination with other transcription factors. However, the precise mechanism controlling the switch from maturation to germination programs remains unclear. We report here the identification and molecular characterization of Hordeum vulgare VIVIPAROUS1 (HvVP1), orthologous to ABA-INSENSITIVE3 from Arabidopsis thaliana HvVP1 transcripts accumulate in the endosperm and the embryo of developing seeds at early stages and in the embryo and aleurone of germinating seeds up to 24 h of imbibition. In transient expression assays, HvVP1 controls the activation of Hor2 and Amy6.4 promoters exerted by HvGAMYB. HvVP1 interacts with HvGAMYB in Saccharomyces cerevisiae and in the plant nuclei, hindering its interaction with other transcription factors involved in seed gene expression programs, like BPBF. Similarly, this interaction leads to a decrease in the DNA binding of HvGAMYB and the Barley Prolamine-Box binding Factor (BPBF) to their target sequences. Our results indicate that the HvVP1 expression pattern controls the full Hor2 expression activated by GAMYB and BPBF in the developing endosperm and the Amy6.4 activation in postgerminative reserve mobilization mediated by GAMYB. All these data demonstrate the participation of HvVP1 in antagonistic gene expression programs and support its central role as a gene expression switch during seed maturation and germination. © 2016 American Society of Plant Biologists. All Rights Reserved.

  5. A Developmental Switch of Gene Expression in the Barley Seed Mediated by HvVP1 (Viviparous-1) and HvGAMYB Interactions1

    PubMed Central

    Abraham, Zamira; Iglesias-Fernández, Raquel; Carbonero, Pilar

    2016-01-01

    The accumulation of storage compounds in the starchy endosperm of developing cereal seeds is highly regulated at the transcriptional level. These compounds, mainly starch and proteins, are hydrolyzed upon germination to allow seedling growth. The transcription factor HvGAMYB is a master activator both in the maturation phase of seed development and upon germination, acting in combination with other transcription factors. However, the precise mechanism controlling the switch from maturation to germination programs remains unclear. We report here the identification and molecular characterization of Hordeum vulgare VIVIPAROUS1 (HvVP1), orthologous to ABA-INSENSITIVE3 from Arabidopsis thaliana. HvVP1 transcripts accumulate in the endosperm and the embryo of developing seeds at early stages and in the embryo and aleurone of germinating seeds up to 24 h of imbibition. In transient expression assays, HvVP1 controls the activation of Hor2 and Amy6.4 promoters exerted by HvGAMYB. HvVP1 interacts with HvGAMYB in Saccharomyces cerevisiae and in the plant nuclei, hindering its interaction with other transcription factors involved in seed gene expression programs, like BPBF. Similarly, this interaction leads to a decrease in the DNA binding of HvGAMYB and the Barley Prolamine-Box binding Factor (BPBF) to their target sequences. Our results indicate that the HvVP1 expression pattern controls the full Hor2 expression activated by GAMYB and BPBF in the developing endosperm and the Amy6.4 activation in postgerminative reserve mobilization mediated by GAMYB. All these data demonstrate the participation of HvVP1 in antagonistic gene expression programs and support its central role as a gene expression switch during seed maturation and germination. PMID:26858366

  6. Combination of Q-Switched Nd:YAG and Fractional Erbium:YAG Lasers in Treatment of Melasma: A Randomized Controlled Clinical Trial

    PubMed Central

    Alavi, Shiva; Abolhasani, Ehsan; Asadi, Sharin; Nilforoushzadeh, Mohammadali

    2017-01-01

    Introduction: Ablative and nonablative lasers have been used to treat melasma. We aimed to assess and compare the combining Q-switched Nd:YAG laser (QSNYL) and fractional erbium:YAG laser (FEYL) with QSNYL alone in treatment of melasma. Methods: This randomized controlled clinical trial was performed in our Research Center during 2013-2014. Women with melasma and without a history of keloid formation, hypersensitivity to hydroquinone, or pigmentary changes due to laser therapy were randomly allocated to receive four sessions of either QSNYL-FEYL combination or QSNYL alone. All patients received topical treatment with Kligman’s formula. Before laser therapy and 4 weeks after the last treatment session, patients’ skin was assessed for changes in skin color, melanin content, and erythema intensity of melasma lesions quantitatively. Results: Finally, 21 patients in QSNYL-FEYL and 20 in QSNYL group (mean age, 38.57 [5.60] and 42.60 [8.44] years, respectively) completed study. The skin color had become lighter in both groups (mean [SD] percentage change of 56.95 [40.29] and 29.25 [13.20] in QSNYL-FEYL and QSNYL groups, respectively) with significantly better results in QSNYL-FEYL group (P = 0.006). Percentage of decrease of melanin content was significantly higher in QSNYL-FEYL group (22.01 [10.67] vs. 7.69 [4.75]; P < 0.001). After adjustment for baseline values, the post treatment intensity of erythema was significantly lower in QSNYL-FEYL group (P < 0.001). The patients reported no adverse events. Conclusion: QSNYL-FEYL was significantly more effective in decreasing melanin content of lesions than QSNYL and led to a lighter skin. PMID:28912936

  7. A σE-Mediated Temperature Gauge Controls a Switch from LuxR-Mediated Virulence Gene Expression to Thermal Stress Adaptation in Vibrio alginolyticus

    PubMed Central

    Gu, Dan; Guo, Min; Yang, Minjun; Zhang, Yuanxing; Zhou, Xiaohui; Wang, Qiyao

    2016-01-01

    In vibrios, the expression of virulence factors is often controlled by LuxR, the master quorum-sensing regulator. Here, we investigate the interplay between LuxR and σE, an alternative sigma factor, during the control of virulence-related gene expression and adaptations to temperature elevations in the zoonotic pathogen Vibrio alginolyticus. An rpoE null V. alginolyticus mutant was unable to adapt to various stresses and was survival-deficient in fish. In wild type V. alginolyticus, the expression of LuxR-regulated virulence factors increased as the temperature was increased from 22°C to 37°C, but mutants lacking σE did not respond to temperature, indicating that σE is critical for the temperature-dependent upregulation of virulence genes. Further analyses revealed that σE binds directly to -10 and -35 elements in the luxR promoter that drive its transcription. ChIP assays showed that σE binds to the promoter regions of luxR, rpoH and rpoE at high temperatures (e.g., 30°C and 37°C). However, at higher temperatures (42°C) that induce thermal stress, σE binding to the luxR promoter decreased, while its binding to the rpoH and rpoE promoters was unchanged. Thus, the temperature-dependent binding of σE to distinct promoters appears to underlie a σE-controlled switch between the expression of virulence genes and adaptation to thermal stress. This study illustrates how a conserved temperature response mechanism integrates into quorum-sensing circuits to regulate both virulence and stress adaptation. PMID:27253371

  8. Integrating mitosis, toxicity, and transgene expression in a telecommunications packet-switched network model of lipoplex-mediated gene delivery.

    PubMed

    Martin, Timothy M; Wysocki, Beata J; Beyersdorf, Jared P; Wysocki, Tadeusz A; Pannier, Angela K

    2014-08-01

    Gene delivery systems transport exogenous genetic information to cells or biological systems with the potential to directly alter endogenous gene expression and behavior with applications in functional genomics, tissue engineering, medical devices, and gene therapy. Nonviral systems offer advantages over viral systems because of their low immunogenicity, inexpensive synthesis, and easy modification but suffer from lower transfection levels. The representation of gene transfer using models offers perspective and interpretation of complex cellular mechanisms,including nonviral gene delivery where exact mechanisms are unknown. Here, we introduce a novel telecommunications model of the nonviral gene delivery process in which the delivery of the gene to a cell is synonymous with delivery of a packet of information to a destination computer within a packet-switched computer network. Such a model uses nodes and layers to simplify the complexity of modeling the transfection process and to overcome several challenges of existing models. These challenges include a limited scope and limited time frame, which often does not incorporate biological effects known to affect transfection. The telecommunication model was constructed in MATLAB to model lipoplex delivery of the gene encoding the green fluorescent protein to HeLa cells. Mitosis and toxicity events were included in the model resulting in simulation outputs of nuclear internalization and transfection efficiency that correlated with experimental data. A priori predictions based on model sensitivity analysis suggest that increasing endosomal escape and decreasing lysosomal degradation, protein degradation, and GFP-induced toxicity can improve transfection efficiency by three-fold. Application of the telecommunications model to nonviral gene delivery offers insight into the development of new gene delivery systems with therapeutically relevant transfection levels.

  9. Forming-free, bipolar resistivity switching characteristics of fully transparent resistive random access memory with IZO/α-IGZO/ITO structure

    NASA Astrophysics Data System (ADS)

    Lo, Chun-Chieh; Hsieh, Tsung-Eong

    2016-09-01

    Fully transparent resistive random access memory (TRRAM) containing amorphous indium gallium zinc oxide as the resistance switching (RS) layer and transparent conducting oxides (indium zinc oxide and indium tin oxide) as the electrodes was prepared. Optical measurement indicated the transmittance of device exceeds 80% in visible-light wavelength range. TRRAM samples exhibited the forming-free feature and the best electrical performance (V SET  =  0.61 V V RESET  =  -0.76 V R HRS/R LRS (i.e. the R-ratio)  >103) was observed in the device subject to a post-annealing at 300 °C for 1 hr in atmospheric ambient. Such a sample also exhibited satisfactory endurance and retention properties at 85 °C as revealed by the reliability tests. Electrical measurement performed in vacuum ambient indicated that the RS mechanism correlates with the charge trapping/de-trapping process associated with oxygen defects in the RS layer.

  10. Cognitive Training Sustainably Improves Executive Functioning in Middle-Aged Industry Workers Assessed by Task Switching: A Randomized Controlled ERP Study

    PubMed Central

    Gajewski, Patrick D.; Freude, Gabriele; Falkenstein, Michael

    2017-01-01

    Recently, we reported results of a cross-sectional study investigating executive functions in dependence of aging and type of work. That study showed deficits in performance and electrophysiological activity in middle-aged workers with long-term repetitive and unchallenging work. Based on these findings, we conducted a longitudinal study that aimed at ameliorating these cognitive deficits by means of a trainer-guided cognitive training (CT) in 57 further middle-aged workers with repetitive type of work from the same factory. This study was designed as a randomized controlled trail with pre- (t1), post- (t2), and a 3-month follow-up (t3) measure. The waiting control group was trained between t2 and t3. The training lasted 3 months (20 sessions) and was evaluated with the same task switching paradigm used in the previous cross-sectional study. The CT improved performance in accuracy at the behavioral level and affected the electrophysiological correlates of retrieval of stimulus-response sets (P2), response selection (N2), and error detection (Ne), thus unveiling the neuronal background of the behavioral effects. The same training effects were observed in the waiting control group after CT at t3. Moreover, at t3, most of the behavioral and electrophysiological training-induced changes were found stable. Hence, CT appears to be an important intervention for compensating cognitive deficits in executive functions in middle-aged employees with cognitively unchallenging work. PMID:28275347

  11. Cognitive Training Sustainably Improves Executive Functioning in Middle-Aged Industry Workers Assessed by Task Switching: A Randomized Controlled ERP Study.

    PubMed

    Gajewski, Patrick D; Freude, Gabriele; Falkenstein, Michael

    2017-01-01

    Recently, we reported results of a cross-sectional study investigating executive functions in dependence of aging and type of work. That study showed deficits in performance and electrophysiological activity in middle-aged workers with long-term repetitive and unchallenging work. Based on these findings, we conducted a longitudinal study that aimed at ameliorating these cognitive deficits by means of a trainer-guided cognitive training (CT) in 57 further middle-aged workers with repetitive type of work from the same factory. This study was designed as a randomized controlled trail with pre- (t1), post- (t2), and a 3-month follow-up (t3) measure. The waiting control group was trained between t2 and t3. The training lasted 3 months (20 sessions) and was evaluated with the same task switching paradigm used in the previous cross-sectional study. The CT improved performance in accuracy at the behavioral level and affected the electrophysiological correlates of retrieval of stimulus-response sets (P2), response selection (N2), and error detection (Ne), thus unveiling the neuronal background of the behavioral effects. The same training effects were observed in the waiting control group after CT at t3. Moreover, at t3, most of the behavioral and electrophysiological training-induced changes were found stable. Hence, CT appears to be an important intervention for compensating cognitive deficits in executive functions in middle-aged employees with cognitively unchallenging work.

  12. Src, a Molecular Switch Governing Gain Control of Synaptic Transmission Mediated by N-methyl-D-Aspartate Receptors

    NASA Astrophysics Data System (ADS)

    Yu, Xian-Min; Salter, Michael W.

    1999-07-01

    The N-methyl-D-aspartate (NMDA) receptor is a principal subtype of glutamate receptor mediating fast excitatory transmission at synapses in the dorsal horn of the spinal cord and other regions of the central nervous system. NMDA receptors are crucial for the lasting enhancement of synaptic transmission that occurs both physiologically and in pathological conditions such as chronic pain. Over the past several years, evidence has accumulated indicating that the activity of NMDA receptors is regulated by the protein tyrosine kinase, Src. Recently it has been discovered that, by means of up-regulating NMDA receptor function, activation of Src mediates the induction of the lasting enhancement of excitatory transmission known as long-term potentiation in the CA1 region of the hippocampus. Also, Src has been found to amplify the up-regulation of NMDA receptor function that is produced by raising the intracellular concentration of sodium. Sodium concentration increases in neuronal dendrites during high levels of firing activity, which is precisely when Src becomes activated. Therefore, we propose that the boost in NMDA receptor function produced by the coincidence of activating Src and raising intracellular sodium may be important in physiological and pathophysiological enhancement of excitatory transmission in the dorsal horn of the spinal cord and elsewhere in the central nervous system.

  13. Statistical grand rounds: understanding the mechanism: mediation analysis in randomized and nonrandomized studies.

    PubMed

    Mascha, Edward J; Dalton, Jarrod E; Kurz, Andrea; Saager, Leif

    2013-10-01

    In comparative clinical studies, a common goal is to assess whether an exposure, or intervention, affects the outcome of interest. However, just as important is to understand the mechanism(s) for how the intervention affects outcome. For example, if preoperative anemia was shown to increase the risk of postoperative complications by 15%, it would be important to quantify how much of that effect was due to patients receiving intraoperative transfusions. Mediation analysis attempts to quantify how much, if any, of the effect of an intervention on outcome goes though prespecified mediator, or "mechanism" variable(s), that is, variables sitting on the causal pathway between exposure and outcome. Effects of an exposure on outcome can thus be divided into direct and indirect, or mediated, effects. Mediation is claimed when 2 conditions are true: the exposure affects the mediator and the mediator (adjusting for the exposure) affects the outcome. Understanding how an intervention affects outcome can validate or invalidate one's original hypothesis and also facilitate further research to modify the responsible factors, and thus improve patient outcome. We discuss the proper design and analysis of studies investigating mediation, including the importance of distinguishing mediator variables from confounding variables, the challenge of identifying potential mediators when the exposure is chronic versus acute, and the requirements for claiming mediation. Simple designs are considered, as well as those containing multiple mediators, multiple outcomes, and mixed data types. Methods are illustrated with data collected by the National Surgical Quality Improvement Project (NSQIP) and utilized in a companion paper which assessed the effects of preoperative anemic status on postoperative outcomes.

  14. B cell Rab7 mediates induction of activation-induced cytidine deaminase expression and class-switching in T-dependent and T-independent antibody responses.

    PubMed

    Pone, Egest J; Lam, Tonika; Lou, Zheng; Wang, Rui; Chen, Yuhui; Liu, Dongfang; Edinger, Aimee L; Xu, Zhenming; Casali, Paolo

    2015-04-01

    Class switch DNA recombination (CSR) is central to the maturation of the Ab response because it diversifies Ab effector functions. Like somatic hypermutation, CSR requires activation-induced cytidine deaminase (AID), whose expression is restricted to B cells, as induced by CD40 engagement or dual TLR-BCR engagement (primary CSR-inducing stimuli). By constructing conditional knockout Igh(+/C)γ(1-cre)Rab7(fl/fl) mice, we identified a B cell-intrinsic role for Rab7, a small GTPase involved in intracellular membrane functions, in mediating AID induction and CSR. Igh(+/C)γ(1-cre)Rab7(fl/fl) mice displayed normal B and T cell development and were deficient in Rab7 only in B cells undergoing Igh(C)γ(1-cre) Iγ1-Sγ1-Cγ1-cre transcription, as induced--like Igh germline Iγ1-Sγ1-Cγ1 and Iε-Sε-Cε transcription--by IL-4 in conjunction with a primary CSR-inducing stimulus. These mice could not mount T-independent or T-dependent class-switched IgG1 or IgE responses while maintaining normal IgM levels. Igh(+/C)γ(1-cre)Rab7(fl/fl) B cells showed, in vivo and in vitro, normal proliferation and survival, normal Blimp-1 expression and plasma cell differentiation, as well as intact activation of the noncanonical NF-κB, p38 kinase, and ERK1/2 kinase pathways. They, however, were defective in AID expression and CSR in vivo and in vitro, as induced by CD40 engagement or dual TLR1/2-, TLR4-, TLR7-, or TLR9-BCR engagement. In Igh(+/C)γ(1-cre)Rab7(fl/fl) B cells, CSR was rescued by enforced AID expression. These findings, together with our demonstration that Rab7-mediated canonical NF-κB activation, as critical to AID induction, outline a novel role of Rab7 in signaling pathways that lead to AID expression and CSR, likely by promoting assembly of signaling complexes along intracellular membranes.

  15. Mediation and spillover effects in group-randomized trials: a case study of the 4Rs educational intervention.

    PubMed

    Vanderweele, Tyler J; Hong, Guanglei; Jones, Stephanie M; Brown, Joshua L

    2013-06-01

    Peer influence and social interactions can give rise to spillover effects in which the exposure of one individual may affect outcomes of other individuals. Even if the intervention under study occurs at the group or cluster level as in group-randomized trials, spillover effects can occur when the mediator of interest is measured at a lower level than the treatment. Evaluators who choose groups rather than individuals as experimental units in a randomized trial often anticipate that the desirable changes in targeted social behaviors will be reinforced through interference among individuals in a group exposed to the same treatment. In an empirical evaluation of the effect of a school-wide intervention on reducing individual students' depressive symptoms, schools in matched pairs were randomly assigned to the 4Rs intervention or the control condition. Class quality was hypothesized as an important mediator assessed at the classroom level. We reason that the quality of one classroom may affect outcomes of children in another classroom because children interact not simply with their classmates but also with those from other classes in the hallways or on the playground. In investigating the role of class quality as a mediator, failure to account for such spillover effects of one classroom on the outcomes of children in other classrooms can potentially result in bias and problems with interpretation. Using a counterfactual conceptualization of direct, indirect and spillover effects, we provide a framework that can accommodate issues of mediation and spillover effects in group randomized trials. We show that the total effect can be decomposed into a natural direct effect, a within-classroom mediated effect and a spillover mediated effect. We give identification conditions for each of the causal effects of interest and provide results on the consequences of ignoring "interference" or "spillover effects" when they are in fact present. Our modeling approach disentangles these

  16. Mediation and spillover effects in group-randomized trials: a case study of the 4Rs educational intervention

    PubMed Central

    VanderWeele, Tyler J.; Hong, Guanglei; Jones, Stephanie M.; Brown, Joshua L.

    2013-01-01

    Peer influence and social interactions can give rise to spillover effects in which the exposure of one individual may affect outcomes of other individuals. Even if the intervention under study occurs at the group or cluster level as in group-randomized trials, spillover effects can occur when the mediator of interest is measured at a lower level than the treatment. Evaluators who choose groups rather than individuals as experimental units in a randomized trial often anticipate that the desirable changes in targeted social behaviors will be reinforced through interference among individuals in a group exposed to the same treatment. In an empirical evaluation of the effect of a school-wide intervention on reducing individual students’ depressive symptoms, schools in matched pairs were randomly assigned to the 4Rs intervention or the control condition. Class quality was hypothesized as an important mediator assessed at the classroom level. We reason that the quality of one classroom may affect outcomes of children in another classroom because children interact not simply with their classmates but also with those from other classes in the hallways or on the playground. In investigating the role of class quality as a mediator, failure to account for such spillover effects of one classroom on the outcomes of children in other classrooms can potentially result in bias and problems with interpretation. Using a counterfactual conceptualization of direct, indirect and spillover effects, we provide a framework that can accommodate issues of mediation and spillover effects in group randomized trials. We show that the total effect can be decomposed into a natural direct effect, a within-classroom mediated effect and a spillover mediated effect. We give identification conditions for each of the causal effects of interest and provide results on the consequences of ignoring “interference” or “spillover effects” when they are in fact present. Our modeling approach

  17. Outcomes of switching directly to oral fingolimod from injectable therapies: Results of the randomized, open-label, multicenter, Evaluate Patient OutComes (EPOC) study in relapsing multiple sclerosis.

    PubMed

    Fox, Edward; Edwards, Keith; Burch, Gordon; Wynn, Daniel R; LaGanke, Chris; Crayton, Heidi; Hunter, Samuel F; Huffman, Cynthia; Kim, Edward; Pestreich, Linda; McCague, Kevin; Barbato, Luigi

    2014-09-01

    The Evaluate Patient OutComes (ClinicalTrials.gov Identifier: NCT01216072) study was conducted in North America to assess patient- and physician-reported treatment satisfaction in patients with relapsing multiple sclerosis (MS) who received oral fingolimod for 6 months after switching from an injectable disease-modifying therapy (iDMT), without an intervening washout. In this open-label, multicenter study, patients were randomized 3:1 to once-daily fingolimod 0.5mg or iDMT. The primary study objective was to evaluate differences in satisfaction measured using the Treatment Satisfaction Questionnaire for Medication v1.4. Of 1053 patients randomized, 790 patients received fingolimod and 263 patients received iDMT. Treatment satisfaction improved significantly in patients who switched to fingolimod compared with those who continued iDMT. Patients also reported significant improvements in health-related quality of life, reduced depression, and reduced fatigue severity after a switch to fingolimod. No difference between the treatment groups was detected on the Patient Reported Indices for MS Activities scale. The safety profile of fingolimod was consistent with that reported in the pivotal phase 3 studies. The most commonly reported adverse events were more prevalent in patients who switched to fingolimod than in those who continued iDMT (headache: 12% vs 3%; fatigue: 12% vs 6%). No significant relationship between lymphocyte counts and infection rates was observed and there was no evidence of additive immune-system effects, which might be expected when switching to a different class of immunomodulatory therapy with no intervening washout. Patients who switched from iDMT to fingolimod had significant improvements in most self-reported outcomes compared with those who continued iDMT. Copyright © 2014 Elsevier B.V. All rights reserved.

  18. Exciter switch

    NASA Technical Reports Server (NTRS)

    Mcpeak, W. L.

    1975-01-01

    A new exciter switch assembly has been installed at the three DSN 64-m deep space stations. This assembly provides for switching Block III and Block IV exciters to either the high-power or 20-kW transmitters in either dual-carrier or single-carrier mode. In the dual-carrier mode, it provides for balancing the two drive signals from a single control panel located in the transmitter local control and remote control consoles. In addition to the improved switching capabilities, extensive monitoring of both the exciter switch assembly and Transmitter Subsystem is provided by the exciter switch monitor and display assemblies.

  19. Switch wear leveling

    DOEpatents

    Wu, Hunter; Sealy, Kylee; Gilchrist, Aaron

    2015-09-01

    An apparatus for switch wear leveling includes a switching module that controls switching for two or more pairs of switches in a switching power converter. The switching module controls switches based on a duty cycle control technique and closes and opens each switch in a switching sequence. The pairs of switches connect to a positive and negative terminal of a DC voltage source. For a first switching sequence a first switch of a pair of switches has a higher switching power loss than a second switch of the pair of switches. The apparatus includes a switch rotation module that changes the switching sequence of the two or more pairs of switches from the first switching sequence to a second switching sequence. The second switch of a pair of switches has a higher switching power loss than the first switch of the pair of switches during the second switching sequence.

  20. Sequential Effects in Deduction: Cost of Inference Switch

    ERIC Educational Resources Information Center

    Milan, Emilio G.; Moreno-Rios, Sergio; Espino, Orlando; Santamaria, Carlos; Gonzalez-Hernandez, Antonio

    2010-01-01

    The task-switch paradigm has helped psychologists gain insight into the processes involved in changing from one activity to another. The literature has yielded consistent results about switch cost reconfiguration (abrupt offset in regular task-switch vs. gradual reduction in random task-switch; endogenous and exogenous components of switch cost;…

  1. A Mortalin/HSPA9-Mediated Switch in Tumor-Suppressive Signaling of Raf/MEK/Extracellular Signal-Regulated Kinase

    PubMed Central

    Wu, Pui-Kei; Hong, Seung-Keun; Veeranki, Sudhakar; Karkhanis, Mansi; Starenki, Dmytro; Plaza, Jose A.

    2013-01-01

    Dysregulated Raf/MEK/extracellular signal-regulated kinase (ERK) signaling, a common hallmark of tumorigenesis, can trigger innate tumor-suppressive mechanisms, which must be inactivated for carcinogenesis to occur. This innate tumor-suppressive signaling may provide a potential therapeutic target. Here we report that mortalin (HSPA9/GRP75/PBP74) is a novel negative regulator of Raf/MEK/ERK and may provide a target for the reactivation of tumor-suppressive signaling of the pathway in cancer. We found that mortalin is present in the MEK1/MEK2 proteome and is upregulated in human melanoma biopsy specimens. In different MEK/ERK-activated cancer cell lines, mortalin depletion induced cell death and growth arrest, which was accompanied by increased p21CIP1 transcription and MEK/ERK activity. Remarkably, MEK/ERK activity was necessary for mortalin depletion to induce p21CIP1 expression in B-RafV600E-transformed cancer cells regardless of their p53 status. In contrast, in cell types exhibiting normal MEK/ERK status, mortalin overexpression suppressed B-RafV600E- or ΔRaf-1:ER-induced MEK/ERK activation, p21CIP1 expression, and cell cycle arrest. Other HSP70 family chaperones could not effectively replace mortalin for p21CIP1 regulation, suggesting a unique role for mortalin. These findings reveal a novel mechanism underlying p21CIP1 regulation in MEK/ERK-activated cancer and identify mortalin as a molecular switch that mediates the tumor-suppressive versus oncogenic result of dysregulated Raf/MEK/ERK signaling. Our study also demonstrates that p21CIP1 has dual effects under mortalin-depleted conditions, i.e., mediating cell cycle arrest while limiting cell death. PMID:23959801

  2. Autophagy induced by deficiency of sphingosine-1-phosphate phosphohydrolase 1 is switched to apoptosis by calpain-mediated autophagy-related gene 5 (Atg5) cleavage.

    PubMed

    Lépine, Sandrine; Allegood, Jeremy C; Edmonds, Yvette; Milstien, Sheldon; Spiegel, Sarah

    2011-12-30

    Sphingosine 1-phosphate (S1P) and ceramide have been implicated in both autophagy and apoptosis. However, the roles of these sphingolipid metabolites in the links between these two processes are not completely understood. Depletion of S1P phosphohydrolase-1 (SPP1), which degrades intracellular S1P, induces the unfolded protein response and endoplasmic reticulum stress-induced autophagy (Lépine, S., Allegood, J. C., Park, M., Dent, P., Milstien, S., and Spiegel, S. (2011) Cell Death Differ. 18, 350-361). Surprisingly, however, treatment with doxorubicin, which by itself also induced autophagy, markedly reduced the extent of autophagy mediated by depletion of SPP1. Concomitantly, doxorubicin-induced apoptosis was greatly enhanced by down-regulation of SPP1. Autophagy and apoptosis seemed to be sequentially linked because inhibiting autophagy with 3-methyladenine also markedly attenuated apoptosis. Moreover, silencing Atg5 or the three sensors of the unfolded protein response, IRE1α, ATF6, and PKR-like eIF2α kinase (PERK), significantly decreased both autophagy and apoptosis. Doxorubicin stimulated calpain activity and Atg5 cleavage, which were significantly enhanced in SPP1-depleted cells. Inhibition or depletion of calpain not only suppressed Atg5 cleavage, it also markedly decreased the robust apoptosis induced by doxorubicin in SPP1-deficient cells. Importantly, doxorubicin also increased de novo synthesis of the pro-apoptotic sphingolipid metabolite ceramide. Elevation of ceramide in turn stimulated calpain; conversely, inhibiting ceramide formation suppressed Atg5 cleavage and apoptosis. Hence, doxorubicin switches protective autophagy in SPP1-depleted cells to apoptosis by calpain-mediated Atg5 cleavage.

  3. Regulation of Wheat Seed Dormancy by After-Ripening Is Mediated by Specific Transcriptional Switches That Induce Changes in Seed Hormone Metabolism and Signaling

    PubMed Central

    Kanno, Yuri; Jordan, Mark C.; Kamiya, Yuji; Seo, Mitsunori; Ayele, Belay T.

    2013-01-01

    Treatments that promote dormancy release are often correlated with changes in seed hormone content and/or sensitivity. To understand the molecular mechanisms underlying the role of after-ripening (seed dry storage) in triggering hormone related changes and dormancy decay in wheat (Triticum aestivum), temporal expression patterns of genes related to abscisic acid (ABA), gibberellin (GA), jasmonate and indole acetic acid (IAA) metabolism and signaling, and levels of the respective hormones were examined in dormant and after-ripened seeds in both dry and imbibed states. After-ripening mediated developmental switch from dormancy to germination appears to be associated with declines in seed sensitivity to ABA and IAA, which are mediated by transcriptional repressions of PROTEIN PHOSPHATASE 2C, SNF1-RELATED PROTEIN KINASE2, ABA INSENSITIVE5 and LIPID PHOSPHATE PHOSPHTASE2, and AUXIN RESPONSE FACTOR and RELATED TO UBIQUITIN1 genes. Transcriptomic analysis of wheat seed responsiveness to ABA suggests that ABA inhibits the germination of wheat seeds partly by repressing the transcription of genes related to chromatin assembly and cell wall modification, and activating that of GA catabolic genes. After-ripening induced seed dormancy decay in wheat is also associated with the modulation of seed IAA and jasmonate contents. Transcriptional control of members of the ALLENE OXIDE SYNTHASE, 3-KETOACYL COENZYME A THIOLASE, LIPOXYGENASE and 12-OXOPHYTODIENOATE REDUCTASE gene families appears to regulate seed jasmonate levels. Changes in the expression of GA biosynthesis genes, GA 20-OXIDASE and GA 3-OXIDASE, in response to after-ripening implicate this hormone in enhancing dormancy release and germination. These findings have important implications in the dissection of molecular mechanisms underlying regulation of seed dormancy in cereals. PMID:23437172

  4. A Comparison of Single Sample and Bootstrap Methods to Assess Mediation in Cluster Randomized Trials

    ERIC Educational Resources Information Center

    Pituch, Keenan A.; Stapleton, Laura M.; Kang, Joo Youn

    2006-01-01

    A Monte Carlo study examined the statistical performance of single sample and bootstrap methods that can be used to test and form confidence interval estimates of indirect effects in two cluster randomized experimental designs. The designs were similar in that they featured random assignment of clusters to one of two treatment conditions and…

  5. A senescence secretory switch mediated by PI3K/AKT/mTOR activation controls chemoprotective endothelial secretory responses

    PubMed Central

    Bent, Eric H.; Gilbert, Luke A.; Hemann, Michael T.

    2016-01-01

    Cancer therapy targets malignant cells that are surrounded by a diverse complement of nonmalignant stromal cells. Therapy-induced damage of normal cells can alter the tumor microenvironment, causing cellular senescence and activating cancer-promoting inflammation. However, how these damage responses are regulated (both induced and resolved) to preserve tissue homeostasis and prevent chronic inflammation is poorly understood. Here, we detail an acute chemotherapy-induced secretory response that is self-limiting in vitro and in vivo despite the induction of cellular senescence. We used tissue-specific knockout mice to demonstrate that endothelial production of the proinflammatory cytokine IL-6 promotes chemoresistance and show that the chemotherapeutic doxorubicin induces acute IL-6 release through reactive oxygen species-mediated p38 activation in vitro. Doxorubicin causes endothelial senescence but, surprisingly, without a typical senescence secretory response. We found that endothelial cells repress senescence-associated inflammation through the down-regulation of PI3K/AKT/mTOR signaling and that reactivation of this pathway restores senescence-associated inflammation. Thus, we describe a mechanism by which damage-associated paracrine secretory responses are restrained to preserve tissue homeostasis and prevent chronic inflammation. PMID:27566778

  6. Tyrosine kinase nerve growth factor receptor switches from prosurvival to proapoptotic activity via Abeta-mediated phosphorylation

    PubMed Central

    Matrone, C.; Marolda, R.; Ciafrè, S.; Ciotti, M. T.; Mercanti, D.; Calissano, P.

    2009-01-01

    The present study shows that increased Abeta production in hippocampal neurons, due to a failure of NGF signal, induces an unexpected phosphorylation of tyrosine kinase receptor A (TrkA), followed by activation of the phospholipase C γ (PLCγ) pathway and neuronal death. Such phosphorylation seems causally connected with 2 kinases known be involved in amyloidogenesis, Src and CDK5, and associated with α and γ secretase–mediated p75 processing. Pharmacologic inhibition of TrkA phosphorylation and partial silencing of TrkA and/or p75 receptors prevent PLCγ activation and protect neurons from death. Concomitantly with these events, TrkA, p75, Abeta peptides, and PS1 protein coimmunoprecipitate, suggesting their direct interplay in the subsequent onset of apoptotic death. Together, these findings depict a cellular mechanism whereby the same cellular transducing system may invert its intracellular message from trophic and antiapoptotic to a death signaling, which could also have relevance in the onset of Alzheimer's disease. PMID:19549834

  7. Tyrosine kinase nerve growth factor receptor switches from prosurvival to proapoptotic activity via Abeta-mediated phosphorylation.

    PubMed

    Matrone, C; Marolda, R; Ciafrè, S; Ciotti, M T; Mercanti, D; Calissano, P

    2009-07-07

    The present study shows that increased Abeta production in hippocampal neurons, due to a failure of NGF signal, induces an unexpected phosphorylation of tyrosine kinase receptor A (TrkA), followed by activation of the phospholipase C gamma (PLCgamma) pathway and neuronal death. Such phosphorylation seems causally connected with 2 kinases known be involved in amyloidogenesis, Src and CDK5, and associated with alpha and gamma secretase-mediated p75 processing. Pharmacologic inhibition of TrkA phosphorylation and partial silencing of TrkA and/or p75 receptors prevent PLCgamma activation and protect neurons from death. Concomitantly with these events, TrkA, p75, Abeta peptides, and PS1 protein coimmunoprecipitate, suggesting their direct interplay in the subsequent onset of apoptotic death. Together, these findings depict a cellular mechanism whereby the same cellular transducing system may invert its intracellular message from trophic and antiapoptotic to a death signaling, which could also have relevance in the onset of Alzheimer's disease.

  8. Robust intestinal homeostasis relies on cellular plasticity in enteroblasts mediated by miR-8–Escargot switch

    PubMed Central

    Antonello, Zeus A; Reiff, Tobias; Ballesta-Illan, Esther; Dominguez, Maria

    2015-01-01

    The intestinal epithelium is remarkably robust despite perturbations and demand uncertainty. Here, we investigate the basis of such robustness using novel tracing methods that allow simultaneously capturing the dynamics of stem and committed progenitor cells (called enteroblasts) and intestinal cell turnover with spatiotemporal resolution. We found that intestinal stem cells (ISCs) divide “ahead” of demand during Drosophila midgut homeostasis. Their newborn enteroblasts, on the other hand, take on a highly polarized shape, acquire invasive properties and motility. They extend long membrane protrusions that make cell–cell contact with mature cells, while exercising a capacity to delay their final differentiation until a local demand materializes. This cellular plasticity is mechanistically linked to the epithelial–mesenchymal transition (EMT) programme mediated by escargot, a snail family gene. Activation of the conserved microRNA miR-8/miR-200 in “pausing” enteroblasts in response to a local cell loss promotes timely terminal differentiation via a reverse MET by antagonizing escargot. Our findings unveil that robust intestinal renewal relies on hitherto unrecognized plasticity in enteroblasts and reveal their active role in sensing and/or responding to local demand. PMID:26077448

  9. LARP1 functions as a molecular switch for mTORC1-mediated translation of an essential class of mRNAs

    PubMed Central

    Hong, Sungki; Freeberg, Mallory A; Han, Ting; Kamath, Avani; Yao, Yao; Fukuda, Tomoko; Suzuki, Tsukasa; Kim, John K; Inoki, Ken

    2017-01-01

    The RNA binding protein, LARP1, has been proposed to function downstream of mTORC1 to regulate the translation of 5’TOP mRNAs such as those encoding ribosome proteins (RP). However, the roles of LARP1 in the translation of 5’TOP mRNAs are controversial and its regulatory roles in mTORC1-mediated translation remain unclear. Here we show that LARP1 is a direct substrate of mTORC1 and Akt/S6K1. Deep sequencing of LARP1-bound mRNAs reveal that non-phosphorylated LARP1 interacts with both 5’ and 3’UTRs of RP mRNAs and inhibits their translation. Importantly, phosphorylation of LARP1 by mTORC1 and Akt/S6K1 dissociates it from 5’UTRs and relieves its inhibitory activity on RP mRNA translation. Concomitantly, phosphorylated LARP1 scaffolds mTORC1 on the 3’UTRs of translationally-competent RP mRNAs to facilitate mTORC1-dependent induction of translation initiation. Thus, in response to cellular mTOR activity, LARP1 serves as a phosphorylation-sensitive molecular switch for turning off or on RP mRNA translation and subsequent ribosome biogenesis. DOI: http://dx.doi.org/10.7554/eLife.25237.001 PMID:28650797

  10. Cambrian origin of the CYP27C1-mediated vitamin A1-to-A2 switch, a key mechanism of vertebrate sensory plasticity

    USGS Publications Warehouse

    Morshedian, Ala; Toomery, Matthew B.; Pollock, Gabriel E.; Frederiksen, Rikard; Enright, Jennifer; McCormick, Stephen; Cornwall, M. Carter; Fain, Gordon L.; Corbo, Joseph C.

    2017-01-01

    The spectral composition of ambient light varies across both space and time. Many species of jawed vertebrates adapt to this variation by tuning the sensitivity of their photoreceptors via the expression of CYP27C1, an enzyme that converts vitamin A1 into vitamin A2, thereby shifting the ratio of vitamin A1-based rhodopsin to red-shifted vitamin A2-based porphyropsin in the eye. Here, we show that the sea lamprey (Petromyzon marinus), a jawless vertebrate that diverged from jawed vertebrates during the Cambrian period (approx. 500 Ma), dynamically shifts its photoreceptor spectral sensitivity via vitamin A1-to-A2 chromophore exchange as it transitions between photically divergent aquatic habitats. We further show that this shift correlates with high-level expression of the lamprey orthologue of CYP27C1, specifically in the retinal pigment epithelium as in jawed vertebrates. Our results suggest that the CYP27C1-mediated vitamin A1-to-A2 switch is an evolutionarily ancient mechanism of sensory plasticity that appeared not long after the origin of vertebrates.

  11. Cambrian origin of the CYP27C1-mediated vitamin A1-to-A2 switch, a key mechanism of vertebrate sensory plasticity.

    PubMed

    Morshedian, Ala; Toomey, Matthew B; Pollock, Gabriel E; Frederiksen, Rikard; Enright, Jennifer M; McCormick, Stephen D; Cornwall, M Carter; Fain, Gordon L; Corbo, Joseph C

    2017-07-01

    The spectral composition of ambient light varies across both space and time. Many species of jawed vertebrates adapt to this variation by tuning the sensitivity of their photoreceptors via the expression of CYP27C1, an enzyme that converts vitamin A1 into vitamin A2, thereby shifting the ratio of vitamin A1-based rhodopsin to red-shifted vitamin A2-based porphyropsin in the eye. Here, we show that the sea lamprey (Petromyzon marinus), a jawless vertebrate that diverged from jawed vertebrates during the Cambrian period (approx. 500 Ma), dynamically shifts its photoreceptor spectral sensitivity via vitamin A1-to-A2 chromophore exchange as it transitions between photically divergent aquatic habitats. We further show that this shift correlates with high-level expression of the lamprey orthologue of CYP27C1, specifically in the retinal pigment epithelium as in jawed vertebrates. Our results suggest that the CYP27C1-mediated vitamin A1-to-A2 switch is an evolutionarily ancient mechanism of sensory plasticity that appeared not long after the origin of vertebrates.

  12. Proteasome Activation is Mediated via a Functional Switch of the Rpt6 C-terminal Tail Following Chaperone-dependent Assembly

    PubMed Central

    Sokolova, Vladyslava; Li, Frances; Polovin, George; Park, Soyeon

    2015-01-01

    In the proteasome, the proteolytic 20S core particle (CP) associates with the 19S regulatory particle (RP) to degrade polyubiquitinated proteins. Six ATPases (Rpt1-Rpt6) of the RP form a hexameric Rpt ring and interact with the heptameric α ring (α1–α7) of the CP via the Rpt C-terminal tails individually binding to the α subunits. Importantly, the Rpt6 tail has been suggested to be crucial for RP assembly. Here, we show that the interaction of the CP and Rpt6 tail promotes a CP-Rpt3 tail interaction, and that they jointly mediate proteasome activation via opening the CP gate for substrate entry. The Rpt6 tail forms a novel relationship with the Nas6 chaperone, which binds to Rpt3 and regulates the CP-Rpt3 tail interaction, critically influencing cell growth and turnover of polyubiquitinated proteins. CP-Rpt6 tail binding promotes the release of Nas6 from the proteasome. Based on disulfide crosslinking that detects cognate α3-Rpt6 tail and α2-Rpt3 tail interactions in the proteasome, decreased α3-Rpt6 tail interaction facilitates robust α2-Rpt3 tail interaction that is also strongly ATP-dependent. Together, our data support the reported role of Rpt6 during proteasome assembly, and suggest that its function switches from anchoring for RP assembly into promoting Rpt3-dependent activation of the mature proteasome. PMID:26449534

  13. Proteasome Activation is Mediated via a Functional Switch of the Rpt6 C-terminal Tail Following Chaperone-dependent Assembly.

    PubMed

    Sokolova, Vladyslava; Li, Frances; Polovin, George; Park, Soyeon

    2015-10-09

    In the proteasome, the proteolytic 20S core particle (CP) associates with the 19S regulatory particle (RP) to degrade polyubiquitinated proteins. Six ATPases (Rpt1-Rpt6) of the RP form a hexameric Rpt ring and interact with the heptameric α ring (α1-α7) of the CP via the Rpt C-terminal tails individually binding to the α subunits. Importantly, the Rpt6 tail has been suggested to be crucial for RP assembly. Here, we show that the interaction of the CP and Rpt6 tail promotes a CP-Rpt3 tail interaction, and that they jointly mediate proteasome activation via opening the CP gate for substrate entry. The Rpt6 tail forms a novel relationship with the Nas6 chaperone, which binds to Rpt3 and regulates the CP-Rpt3 tail interaction, critically influencing cell growth and turnover of polyubiquitinated proteins. CP-Rpt6 tail binding promotes the release of Nas6 from the proteasome. Based on disulfide crosslinking that detects cognate α3-Rpt6 tail and α2-Rpt3 tail interactions in the proteasome, decreased α3-Rpt6 tail interaction facilitates robust α2-Rpt3 tail interaction that is also strongly ATP-dependent. Together, our data support the reported role of Rpt6 during proteasome assembly, and suggest that its function switches from anchoring for RP assembly into promoting Rpt3-dependent activation of the mature proteasome.

  14. Policing Behaviors, Safe Injection Self-Efficacy, and Intervening on Injection Risks: Moderated Mediation Results from a Randomized Trial

    PubMed Central

    Pitpitan, Eileen V.; Patterson, Thomas L.; Abramovitz, Daniela; Vera, Alicia; Martinez, Gustavo; Staines, Hugo; Strathdee, Steffanie A.

    2015-01-01

    Objective We aim to use conditional, or moderated mediation to simultaneously test how and for whom an injection risk intervention was efficacious at reducing receptive needle sharing among female sex workers who inject drugs (FSWs-IDUs) in Mexico. Methods Secondary analysis of data from a randomized trial. A total of 300 FSW-IDUs participated in Mujer Mas Segura in Ciudad Juarez, Mexico and were randomized to an interactive injection risk intervention or a didactic injection risk intervention. We measured safe injection self-efficacy as the hypothesized mediator, and policing behaviors (being arrested and syringe confiscation) as hypothesized moderators. 213 women provided complete data for the current analyses. Results Conditional (moderated) mediation showed that the intervention affected receptive needle sharing through safe injection self-efficacy among women who experienced syringe confiscation. On average, police syringe confiscation was associated with lower safe injection self-efficacy (p = 0.04). Among those who experienced syringe confiscation, those who received the interactive (vs. didactic) intervention reported higher self-efficacy, which in turn predicted lower receptive needle sharing (p = 0.04). Conclusions Whereas syringe confiscation by the police negatively impacted safe injection self-efficacy and ultimately injection risk behavior, our interactive intervention helped to “buffer” this negative impact of police behavior on risky injection practices. The theory-based, active skills building elements included in the interactive condition, which were absent from the didactic condition, helped participants’ self-efficacy for safer injection in the face of syringe confiscation. PMID:26120851

  15. Longitudinal mediators of a randomized prevention program effect on cortisol for youth from parentally-bereaved families

    PubMed Central

    Luecken, Linda J.; Hagan, Melissa J.; Sandler, Irwin N.; Tein, Jenn-Yun; Ayers, Tim S.; Wolchik, Sharlene A.

    2013-01-01

    Objective We recently reported that a randomized controlled trial of a family-focused intervention for parentally-bereaved youth predicted higher cortisol output 6 years later relative to a control group of bereaved youth (Luecken et al., 2010). The current study evaluated longitudinal mediators of the preventive intervention effect on cortisol 6 years later. Method Parentally bereaved children (N=139; mean age 11.4, SD = 2.4; age range = 8-16 years; 54% male; 61% Caucasian, 17% Hispanic, 7% African American, 15% other ethnicities) were randomly assigned to the 12-week preventive intervention (n=78) or a self-study control (n=61) condition. Six years later (mean age 17.5, SD 2.4), cortisol was sampled as youth participated in a parent-child conflict interaction task. Using 4 waves of data across the 6 years, longitudinal mediators of the program impact on cortisol were evaluated. Results Program-induced increases in positive parenting, decreases in child exposure to negative life events, and lower externalizing symptoms significantly mediated the intervention effect on cortisol 6 years later. Conclusions An intervention targeting improved parenting and reduced child exposure to additional life stressors following the death of a parent may have long-term neuroendocrine effects. PMID:23529870

  16. Policing behaviors, safe injection self-efficacy, and intervening on injection risks: Moderated mediation results from a randomized trial.

    PubMed

    Pitpitan, Eileen V; Patterson, Thomas L; Abramovitz, Daniela; Vera, Alicia; Martinez, Gustavo; Staines, Hugo; Strathdee, Steffanie A

    2016-01-01

    We aim to use conditional or moderated mediation to simultaneously test how and for whom an injection risk intervention was efficacious at reducing receptive needle sharing among female sex workers who inject drugs (FSWs-IDUs) in Mexico. Secondary analysis of data from a randomized trial. A total of 300 FSW-IDUs participated in Mujer Mas Segura in Ciudad Juarez, Mexico, and were randomized to an interactive injection risk intervention or a didactic injection risk intervention. We measured safe injection self-efficacy as the hypothesized mediator and policing behaviors (being arrested and syringe confiscation) as hypothesized moderators. In total, 213 women provided complete data for the current analyses. Conditional (moderated) mediation showed that the intervention affected receptive needle sharing through safe injection self-efficacy among women who experienced syringe confiscation. On average, police syringe confiscation was associated with lower safe injection self-efficacy (p = .04). Among those who experienced syringe confiscation, those who received the interactive (vs. didactic) intervention reported higher self-efficacy, which in turn predicted lower receptive needle sharing (p = .04). Whereas syringe confiscation by the police negatively affected safe injection self-efficacy and ultimately injection risk behavior, our interactive intervention helped to "buffer" this negative impact of police behavior on risky injection practices. The theory-based, active skills building elements included in the interactive condition, which were absent from the didactic condition, helped participants' self-efficacy for safer injection in the face of syringe confiscation. (c) 2015 APA, all rights reserved).

  17. Switching from latanoprost to fixed-combination latanoprost-timolol: a 21-day, randomized, double-masked, active-control study in patients with glaucoma and ocular hypertension.

    PubMed

    Olander, Kenneth; Zimmerman, Thom J; Downes, Nina; Schoenfelder, John

    2004-10-01

    Approximately 40% of patients with glaucoma are concomitantly prescribed >or=2 different intraocular pressure (IOP)-lowering medications. An effective and well-tolerated fixed combination of agents requiring once-daily instillation may improve patient compliance. The purpose of this study was to compare the efficacy and safety profile of the fixed combination latanoprost 0.005% + timolol maleate 0.5% QD with those of latanoprost 0.005% monotherapy QD in patients whose elevated IOP (>or=21 mm Hg) was inadequately controlled by latanoprost. This 21-day, randomized, double-masked, active-control study was conducted at 49 study sites in Argentina, Brazil, Colombia, Mexico, Peru, the United States, and Venezuela. Adults with glaucoma or ocular hypertension who had failed to reach an IOP of <21 mm Hg while receiving latanoprost for at least 28 days were enrolled. After an additional 28 days of latanoprost run-in, patients were randomly assigned to continue latanoprost monotherapy or to switch to the fixed combination for 21 days. The intent-to-treat (ITT) population included all patients who received at least 1 dose of double-masked study medication; the per-protocol (PP) analysis included patients who completed the study without a major protocol violation and who had IOP measurements both at baseline and at day 21. The primary end point was the proportion of patients whose IOP was decreased >or=2 mm Hg from the baseline level on day 21. Proportions of patients demonstrating IOP decreases >or=3, >or=4, or >or=5 mm Hg from the baseline level and of patients reaching an 10P

  18. A Randomized, Open-Label Trial to Evaluate Switching to Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Plus Darunavir in Treatment-Experienced HIV-1-Infected Adults

    PubMed Central

    Tebas, Pablo; Gallant, Joel; Wilkin, Timothy; Cheng, Andrew; Yan, Mingjin; Zhong, Lijie; Callebaut, Christian; Custodio, Joseph M.; Fordyce, Marshall W.; Das, Moupali; McCallister, Scott

    2017-01-01

    Background: HIV-infected, treatment-experienced adults with a history of prior resistance and regimen failure can be virologically suppressed but may require multitablet regimens associated with lower adherence and potential resistance development. Methods: We enrolled HIV-infected, virologically suppressed adults with 2-class to 3-class drug resistance and at least 2 prior regimen failures into this phase 3, open-label, randomized study. The primary endpoint was the percentage of participants with HIV-1 RNA <50 copies per milliliter at week 24 [Food and Drug Administration (FDA) snapshot algorithm]. Results: For 135 participants [elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) plus darunavir (DRV), n = 89; baseline regimen, n = 46], most of whom were taking a median of 5 tablets/d, simplification to E/C/F/TAF plus DRV was noninferior to continuation of baseline regimens at week 24 (plasma HIV-1 RNA <50 copies per milliliter: 96.6% vs. 91.3%, difference 5.3%, 95.001% CI: −3.4% to 17.4%). E/C/F/TAF plus DRV met prespecified criteria for noninferiority and superiority at week 48 for the same outcome. E/C/F/TAF plus DRV was well tolerated and had an improved renal safety profile compared with baseline regimens, with statistically significant differences between groups in quantitative total proteinuria and markers of proximal tubular proteinuria. Compared with baseline regimens, participants who switched to E/C/F/TAF plus DRV reported higher mean treatment satisfaction scale total scores and fewer days with missed doses. Conclusions: This study demonstrated that regimen simplification from a 5-tablet regimen to the 2-tablet, once-daily combination of E/C/F/TAF plus DRV has durable maintenance of virologic suppression and improvements in specific markers of renal safety. Such a strategy may lead to greater adherence and improved quality of life. PMID:27753684

  19. Coaxial Switch

    DTIC Science & Technology

    2014-04-23

    08-2015 Publication Coaxial Switch David J. Bamford et al Naval Undersea Warfare Center Division, Newport 1176 Howell Street, Bldg 102T, Code 00L...Distribution A A coaxial switch having a housing and a shaft extending through and rotatably mounted to the housing. The shaft extends from opposite...conductor members are electrically connected together. When the coaxial switch is engaged, the conductor members are inserted into the connector body

  20. Fibrate therapy and flow-mediated dilation: A systematic review and meta-analysis of randomized placebo-controlled trials.

    PubMed

    Sahebkar, Amirhossein; Giua, Renato; Pedone, Claudio; Ray, Kausik K; Vallejo-Vaz, Antonio J; Costanzo, Luisa

    2016-09-01

    Flow-mediated dilation (FMD) of the brachial artery reflects endothelium-dependent vasodilator function; since it correlates with coronary endothelial function, its reduction could predict cardiovascular events. Several studies have investigated the potential impact of fibrates therapy on endothelial function, but clinical findings have not been fully consistent. We aimed to conduct a meta-analysis of randomized placebo-controlled trials in order to clarify whether fibrate therapy could improve endothelial function. A systematic search in PubMed-Medline, SCOPUS, Web of Science and Google Scholar databases was performed to identify randomized placebo-controlled trials investigating the effect of fibrates on endothelial function as estimated by FMD. A random-effects model and generic inverse variance method were used for meta-analysis. Sensitivity analysis, risk of bias evaluation, and publication bias assessment were carried out using standard methods. Random-effects meta-regression was used to evaluate the impact of treatment duration on the estimated effect size. Fifteen trials with a total of 556 subjects met the eligibility criteria. Fibrate therapy significantly improves FMD (weighted mean difference [WMD]: 1.64%, 95% CI: 1.15, 2.13, p<0.001) and the result was confirmed in both subgroups with treatment durations ≤8 weeks (WMD: 1.35%, 95% CI: 0.85, 1.86, p<0.001) and >8 weeks (WMD: 2.55%, 95% CI: 1.21, 3.89, p<0.001). When the analysis was stratified according to the fibrate type, a significant effect was observed with fenofibrate but not with gemfibrozil, though difference between the two subgroups was not significant. Meta-analysis of data from trials where nitrate mediated dilation (NMD) was available did not suggest a significant change in NMD following treatment with fibrates. The results of this meta-analysis suggest that fibrates may exert beneficial effects on endothelial function, even over a short-term treatment course.

  1. Do Savings Mediate Changes in Adolescents' Future Orientation and Health-Related Outcomes? Findings From Randomized Experiment in Uganda.

    PubMed

    Karimli, Leyla; Ssewamala, Fred M

    2015-10-01

    This present study tests the proposition that an economic strengthening intervention for families caring for AIDS-orphaned adolescents would positively affect adolescent future orientation and psychosocial outcomes through increased asset accumulation (in this case, by increasing family savings). Using longitudinal data from the cluster-randomized experiment, we ran generalized estimating equation models with robust standard errors clustering on individual observations. To examine whether family savings mediate the effect of the intervention on adolescents' future orientation and psychosocial outcomes, analyses were conducted in three steps: (1) testing the effect of intervention on mediator; (2) testing the effect of mediator on outcomes, controlling for the intervention; and (3) testing the significance of mediating effect using Sobel-Goodman method. Asymmetric confidence intervals for mediated effect were obtained through bootstrapping-to address the assumption of normal distribution. Results indicate that participation in a matched Child Savings Account (CSA) program improved adolescents' future orientation and psychosocial outcomes by reducing hopelessness, enhancing self-concept, and improving adolescents' confidence about their educational plans. However, the positive intervention effect on adolescent future orientation and psychosocial outcomes was not transmitted through saving. In other words, participation in the matched CSA program improved adolescent future orientation and psychosocial outcomes regardless of its impact on reported savings. Further research is necessary to understand exactly how participation in economic strengthening interventions, for example, those that employ matched CSAs, shape adolescent future orientation and psychosocial outcomes: what, if not savings, transmits the treatment effect and how? Copyright © 2015 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.

  2. Do savings mediate changes in adolescents’ future orientation and health-related outcomes? Findings from randomized experiment in Uganda

    PubMed Central

    Karimli, Leyla; Ssewamala, Fred M.

    2015-01-01

    Purpose This present study tests the proposition that an economic strengthening intervention for families caring for AIDS-orphaned adolescents would positively affect adolescent future orientation and psychosocial outcomes through increased asset-accumulation (in this case, by increasing family savings). Methods Using longitudinal data from the cluster-randomized experiment we ran generalized estimating equation (GEE) models with robust standard errors clustering on individual observations. To examine whether family savings mediate the effect of the intervention on adolescents’ future orientation and psychosocial outcomes, analyses were conducted in three steps: (1) testing the effect of intervention on mediator; (2) testing the effect of mediator on outcomes, controlling for the intervention; and (3) testing the significance of mediating effect using Sobel-Goodman method. Asymmetric confidence intervals for mediated effect were obtained through bootstrapping—to address the assumption of normal distribution. Results Results indicate that participation in a matched Child Savings Account program improved adolescents’ future orientation and psychosocial outcomes by reducing hopelessness, enhancing self-concept, and improving adolescents’ confidence about their educational plans. However, the positive intervention effect on adolescent future orientation and psychosocial outcomes was not transmitted through saving. In other words, participation in the matched Child Savings Account program improved adolescent future orientation and psychosocial outcomes regardless of its impact on reported savings. Conclusions Further research is necessary to understand exactly how participation in economic strengthening interventions, for example, those that employ matched Child Savings Accounts, shape adolescent future orientation and psychosocial outcomes: what, if not savings, transmits the treatment effect and how? PMID:26271162

  3. Molecular DNA switches and DNA chips

    NASA Astrophysics Data System (ADS)

    Sabanayagam, Chandran R.; Berkey, Cristin; Lavi, Uri; Cantor, Charles R.; Smith, Cassandra L.

    1999-06-01

    We present an assay to detect single-nucleotide polymorphisms on a chip using molecular DNA switches and isothermal rolling- circle amplification. The basic principle behind the switch is an allele-specific oligonucleotide circularization, mediated by DNA ligase. A DNA switch is closed when perfect hybridization between the probe oligonucleotide and target DNA allows ligase to covalently circularize the probe. Mismatches around the ligation site prevent probe circularization, resulting in an open switch. DNA polymerase is then used to preferentially amplify the closed switches, via rolling-circle amplification. The stringency of the molecular switches yields 102 - 103 fold discrimination between matched and mismatched sequences.

  4. Two-step polarization switching mediated by a nonpolar intermediate phase in Hf0.4Zr0.6O2 thin films

    NASA Astrophysics Data System (ADS)

    Park, Min Hyuk; Kim, Han Joon; Lee, Young Hwan; Kim, Yu Jin; Moon, Taehwan; Kim, Keum Do; Hyun, Seung Dam; Hwang, Cheol Seong

    2016-07-01

    The broken ferroelectric hysteresis loop achieved from a Hf0.4Zr0.6O2 film was interpreted based on the first order phase transition theory. The two-step polarization switching, which was expected from the theory, could be observed by dynamic pulse switching measurement. The variations in the interfacial capacitance values along with switching time and number of switching cycles could also be estimated from the pulse switching test. Being different from the one-step polarization switching in other ferroelectric films, two-step polarization switching produced two slanted plateau regions where the estimated interfacial capacitance values were different from each other. This could be understood based on the quantitative model of the two-step polarization switching with the involvement of an intermediate nonpolar phase. The Hf0.4Zr0.6O2 film was changed from antiferroelectric-like to ferroelectric-like with the increasing number of electric field cycles, which could be induced by the field driven phase change.

  5. Two-step polarization switching mediated by a nonpolar intermediate phase in Hf0.4Zr0.6O2 thin films.

    PubMed

    Park, Min Hyuk; Kim, Han Joon; Lee, Young Hwan; Kim, Yu Jin; Moon, Taehwan; Kim, Keum Do; Hyun, Seung Dam; Hwang, Cheol Seong

    2016-07-21

    The broken ferroelectric hysteresis loop achieved from a Hf0.4Zr0.6O2 film was interpreted based on the first order phase transition theory. The two-step polarization switching, which was expected from the theory, could be observed by dynamic pulse switching measurement. The variations in the interfacial capacitance values along with switching time and number of switching cycles could also be estimated from the pulse switching test. Being different from the one-step polarization switching in other ferroelectric films, two-step polarization switching produced two slanted plateau regions where the estimated interfacial capacitance values were different from each other. This could be understood based on the quantitative model of the two-step polarization switching with the involvement of an intermediate nonpolar phase. The Hf0.4Zr0.6O2 film was changed from antiferroelectric-like to ferroelectric-like with the increasing number of electric field cycles, which could be induced by the field driven phase change.

  6. Terminal protection-mediated autocatalytic cascade amplification coupled with graphene oxide fluorescence switch for sensitive and rapid detection of folate receptor.

    PubMed

    Wang, Rui; Xu, Xiaowen; Li, Pei; Wang, Yan; Jiang, Wei

    2017-11-01

    Folate receptor (FR) is over-expressed in most human tumors and has been regarded as biomarker and therapeutic target. Specific and sensitive detection of FR is essential for tumor treatment and drug development. Here, a specific, sensitive and rapid FR detection strategy was proposed based on terminal protection-mediated autocatalytic cascade amplification coupled with graphene oxide fluorescence switch. Firstly, the specific binding of FR to the folate terminally-labeled on a primary trigger DNA (PT-DNA) could protect the PT-DNA from exonuclease I degradation, converting FR detection to PT-DNA detection. Subsequently, the PT-DNA hybridized with the overhang of 3'-FAM labeled hairpin probe to initiate exonuclease III-assisted hydrolysis, accompanied with the PT-DNA recycling and autonomous generation of secondary trigger DNA and fluorophore. The secondary trigger DNA could as a PT-DNA analogue for the successive hybridization and hydrolysis process, liberating numerous fluorophores within 40min. Finally, The fluorophores kept away from the surface of graphene oxide, achieving significantly amplified fluorescence signal. The specific interaction between FR and folate guaranteed the FR could be distinguished from other proteins with high selectivity. The high fluorescence quenching efficiency of graphene oxide guaranteed a low background. Due to the highly autocatalytic cascade amplification efficiency and low background, sensitive detection of FR had been achieved with the detection limit of 0.44pM. The recoveries from 92% to 107% were achieved by detecting FR in spiked human serum. These results indicate this strategy holds a great potential for reliable quantification of FR in clinical diagnosis and disease treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Src subfamily kinases regulate nuclear export and degradation of transcription factor Nrf2 to switch off Nrf2-mediated antioxidant activation of cytoprotective gene expression.

    PubMed

    Niture, Suryakant K; Jain, Abhinav K; Shelton, Phillip M; Jaiswal, Anil K

    2011-08-19

    Nrf2 (NF-E2-related factor 2) is a nuclear transcription factor that in response to chemical and radiation stress regulates coordinated induction of a battery of cytoprotective gene expressions leading to cellular protection. In this study, we investigated the role of Src kinases in the regulation of Nrf2 and downstream signaling. siRNA-mediated inhibition of Fyn, Src, Yes, and Fgr, but not Lyn, in mouse hepatoma Hepa-1 cells, led to nuclear accumulation of Nrf2 and up-regulation of Nrf2 downstream gene expression. Mouse embryonic fibroblasts with combined deficiency of Fyn/Src/Yes/Fgr supported results from siRNA. In addition, steady-state overexpression of Fyn, Src, and Yes phosphorylated Nrf2Tyr568 that triggered nuclear export and degradation of Nrf2 and down-regulation of Nrf2 downstream gene expression. Exposure of cells to antioxidant, oxidant, or UV radiation increased nuclear import of Fyn, Src, and Yes kinases, which phosphorylated Nrf2Tyr568 resulting in nuclear export and degradation of Nrf2. Further analysis revealed that stress-activated GSK3β acted upstream to the Src kinases and phosphorylated the Src kinases, leading to their nuclear localization and Nrf2 phosphorylation. The overexpression of Src kinases in Hepa-1 cells led to decreased Nrf2, increased apoptosis, and decreased cell survival. Mouse embryonic fibroblasts deficient in Src kinases showed nuclear accumulation of Nrf2, induction of Nrf2 and downstream gene expression, reduced apoptosis, and increased cell survival. The studies together demonstrate that Src kinases play a critical role in nuclear export and degradation of Nrf2, thereby providing a negative feedback mechanism to switch off Nrf2 activation and restore normal cellular homeostasis.

  8. Which neural mechanisms mediate the effects of a parenting intervention program on parenting behavior: design of a randomized controlled trial.

    PubMed

    Kolijn, Laura; Euser, Saskia; van den Bulk, Bianca G; Huffmeijer, Renske; van IJzendoorn, Marinus H; Bakermans-Kranenburg, Marian J

    2017-03-21

    The Video-feedback Intervention to promote Positive Parenting and Sensitive Discipline (VIPP-SD) has proven effective in increasing parental sensitivity. However, the mechanisms involved are largely unknown. In a randomized controlled trial we examine parental neurocognitive factors that may mediate the intervention effects on parenting behavior. Our aims are to (1) examine whether the intervention influences parents' neural processing of children's emotional expressions and the neural precursors of response inhibition and to (2) test whether neural changes mediate intervention effects on parenting behavior. We will test 100 mothers of 4-6 year old same-sex twins. A random half of the mothers will receive the VIPP-SD Twins (i.e. VIPP-SD adapted for twin families), consisting of 5 home visits in a 3-months period; the other half will receive a dummy intervention. Neurocognitive measures are acquired approximately 2 weeks before and 2 weeks after the intervention. Mothers' electroencephalographic (EEG) activity is measured while performing a stop signal task and in response to children's facial expressions. To obtain a complementary behavioral measure, mothers also perform an emotion recognition task. Parenting behavior will be assessed during parent-child interactions at pre and post intervention lab visits. Our results will shed light on the neurocognitive factors underlying changes in parenting behavior after a parenting support program, which may benefit the development of such programs. Dutch Trial Register: NTR5312 ; Date registered: January 3, 2017.

  9. High-Dimensional Explanatory Random Item Effects Models for Rater-Mediated Assessments

    ERIC Educational Resources Information Center

    Kelcey, Ben; Wang, Shanshan; Cox, Kyle

    2016-01-01

    Valid and reliable measurement of unobserved latent variables is essential to understanding and improving education. A common and persistent approach to assessing latent constructs in education is the use of rater inferential judgment. The purpose of this study is to develop high-dimensional explanatory random item effects models designed for…

  10. Conceptualizing and Testing Random Indirect Effects and Moderated Mediation in Multilevel Models: New Procedures and Recommendations

    ERIC Educational Resources Information Center

    Bauer, Daniel J.; Preacher, Kristopher J.; Gil, Karen M.

    2006-01-01

    The authors propose new procedures for evaluating direct, indirect, and total effects in multilevel models when all relevant variables are measured at Level 1 and all effects are random. Formulas are provided for the mean and variance of the indirect and total effects and for the sampling variances of the average indirect and total effects.…

  11. Optical switches and switching methods

    DOEpatents

    Doty, Michael

    2008-03-04

    A device and method for collecting subject responses, particularly during magnetic imaging experiments and testing using a method such as functional MRI. The device comprises a non-metallic input device which is coupled via fiber optic cables to a computer or other data collection device. One or more optical switches transmit the subject's responses. The input device keeps the subject's fingers comfortably aligned with the switches by partially immobilizing the forearm, wrist, and/or hand of the subject. Also a robust nonmetallic switch, particularly for use with the input device and methods for optical switching.

  12. Resistance Exercise and Inflammation in Breast Cancer Patients Undergoing Adjuvant Radiation Therapy: Mediation Analysis From a Randomized, Controlled Intervention Trial.

    PubMed

    Schmidt, Martina E; Meynköhn, Anna; Habermann, Nina; Wiskemann, Joachim; Oelmann, Jan; Hof, Holger; Wessels, Sabine; Klassen, Oliver; Debus, Jürgen; Potthoff, Karin; Steindorf, Karen; Ulrich, Cornelia M

    2016-02-01

    To explore the mediating role of inflammatory parameters in the development of fatigue, pain, and potentially related depressive symptoms during radiation therapy for breast cancer and its mitigation by resistance exercise. Breast cancer patients scheduled for adjuvant radiation therapy were randomized to 12-week progressive resistance exercise training (EX) or a relaxation control group. Interleukin-6 (IL-6) and interleukin-1 receptor antagonist (IL-1ra) were measured in serum samples collected before, at the end, and 6 weeks after radiation therapy from 103 chemotherapy-naïve participants. Fatigue was assessed with the multidimensional Fatigue Assessment Questionnaire, pain with the European Organization for Research and Treatment of Cancer QLQ-C30, and depressive symptoms with the Center for Epidemiologic Studies Depression Scale. Analysis of covariance models, partial correlations, Freedman-Schatzkin tests, and R(2) effect-size measures for mediation were calculated. The analysis of covariance models revealed a significant intervention effect on IL-6 (P=.010) and the IL-6/IL-1ra ratio (P=.018), characterized by a marked increase during radiation therapy among controls, but no significant change in EX. Interleukin-1 receptor antagonist did not change significantly in either group (P=.88). Increased IL-6 and IL-6/IL-1ra levels at the end of radiation therapy were significantly associated with increased physical fatigue and pain 6 weeks after radiation. We observed significant partial mediation by IL-6 and IL-6/IL-1ra of the effect of resistance exercise on physical fatigue (Freedman-Schatzkin P=.023 and P<.001) and pain (both P<.001). Hereby IL-6 and IL-6/IL-1ra mediated between 15% and 24% of the variance of physical fatigue and pain explained by the intervention. This randomized, controlled trial showed a significantly increased proinflammatory cytokine level after adjuvant radiation therapy in breast cancer patients. This effect was counteracted by

  13. Influence of carbon content on the copper-telluride phase formation and on the resistive switching behavior of carbon alloyed Cu-Te conductive bridge random access memory cells

    SciTech Connect

    Devulder, Wouter De Schutter, Bob; Detavernier, Christophe; Opsomer, Karl; Franquet, Alexis; Meersschaut, Johan; Muller, Robert; Van Elshocht, Sven; Jurczak, Malgorzata; Goux, Ludovic; Belmonte, Attilio

    2014-02-07

    In this paper, we investigate the influence of the carbon content on the Cu-Te phase formation and on the resistive switching behavior in carbon alloyed Cu{sub 0.6}Te{sub 0.4} based conductive bridge random access memory (CBRAM) cells. Carbon alloying of copper-tellurium inhibits the crystallization, while attractive switching behavior is preserved when using the material as Cu-supply layer in CBRAM cells. The phase formation is first investigated in a combinatorial way. With increasing carbon content, an enlargement of the temperature window in which the material stays amorphous was observed. Moreover, if crystalline phases are formed, subsequent phase transformations are inhibited. The electrical switching behavior of memory cells with different carbon contents is then investigated by implementing them in 580 μm diameter dot TiN/Cu{sub 0.6}Te{sub 0.4}-C/Al{sub 2}O{sub 3}/Si memory cells. Reliable switching behavior is observed for carbon contents up to 40 at. %, with a resistive window of more than 2 orders of magnitude, whereas for 50 at. % carbon, a higher current in the off state and only a small resistive window are present after repeated cycling. This degradation can be ascribed to the higher thermal and lower drift contribution to the reset operation due to a lower Cu affinity towards the supply layer, leading cycle-after-cycle to an increasing amount of Cu in the switching layer, which contributes to the current. The thermal diffusion of Cu into Al{sub 2}O{sub 3} under annealing also gives an indication of the Cu affinity of the source layer. Time of flight secondary ion mass spectroscopy was used to investigate this migration depth in Al{sub 2}O{sub 3} before and after annealing, showing a higher Cu, Te, and C migration for high carbon contents.

  14. Polycrystalline nanowires of gadolinium-doped ceria via random alignment mediated by supercritical carbon dioxide

    NASA Astrophysics Data System (ADS)

    Kim, Sang Woo; Ahn, Jae-Pyoung

    2013-04-01

    This study proposes a seed/template-free method that affords high-purity semiconducting nanowires from nanoclusters, which act as basic building blocks for nanomaterials, under supercritical CO2 fluid. Polycrystalline nanowires of Gd-doped ceria (Gd-CeO2) were formed by CO2-mediated non-oriented attachment of the nanoclusters resulting from the dissociation of single-crystalline aggregates. The unique formation mechanism underlying this morphological transition may be exploited for the facile growth of high-purity polycrystalline nanowires.

  15. Polycrystalline nanowires of gadolinium-doped ceria via random alignment mediated by supercritical carbon dioxide.

    PubMed

    Kim, Sang Woo; Ahn, Jae-Pyoung

    2013-01-01

    This study proposes a seed/template-free method that affords high-purity semiconducting nanowires from nanoclusters, which act as basic building blocks for nanomaterials, under supercritical CO2 fluid. Polycrystalline nanowires of Gd-doped ceria (Gd-CeO2) were formed by CO2-mediated non-oriented attachment of the nanoclusters resulting from the dissociation of single-crystalline aggregates. The unique formation mechanism underlying this morphological transition may be exploited for the facile growth of high-purity polycrystalline nanowires.

  16. Polycrystalline nanowires of gadolinium-doped ceria via random alignment mediated by supercritical carbon dioxide

    PubMed Central

    Kim, Sang Woo; Ahn, Jae-Pyoung

    2013-01-01

    This study proposes a seed/template-free method that affords high-purity semiconducting nanowires from nanoclusters, which act as basic building blocks for nanomaterials, under supercritical CO2 fluid. Polycrystalline nanowires of Gd-doped ceria (Gd-CeO2) were formed by CO2-mediated non-oriented attachment of the nanoclusters resulting from the dissociation of single-crystalline aggregates. The unique formation mechanism underlying this morphological transition may be exploited for the facile growth of high-purity polycrystalline nanowires. PMID:23572061

  17. A randomized, double-blind, phase II, exploratory trial evaluating the palliative benefit of either continuing pamidronate or switching to zoledronic acid in patients with high-risk bone metastases from breast cancer.

    PubMed

    Jacobs, C; Kuchuk, I; Bouganim, N; Smith, S; Mazzarello, S; Vandermeer, L; Dranitsaris, G; Dent, S; Gertler, S; Verma, S; Song, X; Simos, S; Cella, D; Clemons, M

    2016-01-01

    Previous studies suggest switching from pamidronate to a more potent bone-targeted agent is associated with biomarker and palliative response in breast cancer patients with bone metastases. Until now, this has not been addressed in a double-blind, randomized trial. Breast cancer patients with high-risk bone metastases, despite >3 months of pamidronate, were randomized to either continue pamidronate or switch to zoledronic acid every 4 weeks for 12 weeks. Primary outcome was the proportion of patients achieving a fall in serum C-telopeptide (sCTx) at 12 weeks. Secondary outcomes included difference in mean sCTx, pain scores, quality of life, toxicity, and skeletal-related events (SREs). Seventy-three patients entered the study; median age 61 years (range 37-87). Proportion of patients achieving a fall in sCTx over the 12-week evaluation period was 26/32 (81 %) with zoledronic acid and 18/29 (62 %) with pamidronate (p = 0.095). Mean decrease in sCTx (mean difference between groups = 50 ng/L, 95 % CI 18-84; p = 0.003) was significantly greater in patients who received zoledronic acid. Quality of life, pain scores, toxicity, and frequency of new SREs were comparable between the two arms. While a switch from pamidronate to zoledronic acid resulted in reduction in mean sCTx, there were no significant differences between the arms for proportion of patients achieving a reduction in sCTx, quality of life, pain scores, toxicity or SREs. Given the lack of palliative improvement, the current data do not support a switching strategy.

  18. ION SWITCH

    DOEpatents

    Cook, B.

    1959-02-10

    An ion switch capable of transferring large magnitudes of power is described. An ion switch constructed in accordance with the invention includes a pair of spaced control electrodes disposed in a highly evacuated region for connection in a conventional circuit to control the passing of power therethrough. A controllable ionic conduction path is provided directiy between the control electrodes by a source unit to close the ion switch. Conventional power supply means are provided to trigger the source unit and control the magnitude, durations and pulse repetition rate of the aforementioned ionic conduction path.

  19. A split-face, evaluator-blind randomized study on the early effects of Q-switched Nd:YAG laser versus Er:YAG micropeel in light solar lentigines in Asians.

    PubMed

    Jun, Hee Jin; Kim, So Min; Choi, Won Joon; Cho, Sang Hyun; Lee, Jeong Deuk; Kim, Hei Sung

    2014-04-01

    Asians are prone to develop epidermal pigmentary lesions as a result of photoaging. Solar lentigines, especially those which are light in color, show somewhat limited response to pigment lasers and intense pulsed light sources. We sought to compare the early effects as well as side effects of Q-switched Nd:YAG and Er:YAG micropeel in treating light solar lentigines in Asians. This was a split-face, evaluator-blind, randomized controlled study. A single session of treatment was performed on Asian patients with light facial lentigines. Q-switched Nd:YAG laser was allocated to one half of the face, and Er:YAG micropeel to the other half. The response to therapy was evaluated by two independent dermatologists with standardized photographs taken 2 weeks and 1 month after the laser treatment. Patients' satisfaction and preference in treatment were also assessed. Fifteen patients completed the study and were analyzed. A reduction in pigment was observed with both lasers during the study period. The degree of pigment reduction in the Q-switched Nd:YAG treated side of the face was significantly higher than that of the Er:YAG micropeel treated side at 2-week follow-up (p < 0.001). The degree of pigment reduction between the Q-switched Nd:YAG-treated side and the Er:YAG micropeel-treated side was similar at 1-month follow-up (p = 0.110). While there is no perfect therapy for light solar lentigines, a single session of Q-switched Nd:YAG laser and Er:YAG micropeel was shown to reduce pigmentation. The immediate effects (2-week follow-up) were better with the Q-switched Nd:YAG laser but there was no great difference between the two laser types at 1-month follow-up due to the greater degree of post-inflammatory hyperpigmentation following Q-switched Nd:YAG. Both laser types could be applied either singly in turns, or in combination for maximal efficacy in future.

  20. Randomized Controlled Theory-Based, E-Mail-Mediated Walking Intervention.

    PubMed

    Richards, Elizabeth A; Ogata, Niwako; Cheng, Ching-Wei

    2017-02-01

    The purpose of this study was to evaluate the ability of two concurrent randomized controlled interventions based on social cognitive theory to increase walking. A second purpose was to compare the efficacy of the intervention between two distinct groups: dog owners and non-dog owners. Adult dog owners ( n = 40) and non-dog owners ( n = 65) were randomized into control or intervention groups. Intervention groups received bi-weekly emails for first 4 weeks and then weekly email for the next 8 weeks targeting self-efficacy, social support, goal setting, and benefits/barriers to walking. Dog owner messages focused on dog walking while non-dog owners received general walking messages. Control groups received a 1-time email reviewing current physical activity guidelines. At 6 months, both intervention groups reported greater increases in walking and maintained these increases at 12 months. The greatest increases were seen in the dog owner intervention group. In conclusion, dog owners accumulated more walking, which may be attributed to the dog-owner relationship.

  1. Agaricus blazei Murrill and inflammatory mediators in elderly women: a randomized clinical trial.

    PubMed

    Lima, C U J O; Souza, V C; Morita, M C; Chiarello, M D; Karnikowski, M G de Oliveira

    2012-03-01

    There is scientific evidence to suggest that the medicinal mushroom Agaricus blazei Murrill (AbM) has immunomodulatory effects on cytokine synthesis, both in vitro and in vivo. This study was the first randomized, double-blind, placebo-controlled trial designed to investigate these purported actions in elderly women. The objective of this study was to ascertain the effects of AbM intake on serum levels of interleukin-6 (IL-6), interferon-gamma (IFN-γ) and tumour necrosis factor-alpha (TNF-α) in community-living seniors. The sample consisted of 57 elderly females who were carriers or homozygous for the majority allele of functional polymorphisms for the chosen cytokines. Subjects were randomly allocated to receive placebo (n = 29) or AbM dry extract (n = 28), 900 mg/day for 60 days. Body mass index, abdominal girth, body composition, blood pressure and cytokine (IL-6, IFN-γ, and TNF-α) levels were measured, and food intake was assessed as a possible confounder. Analysis of these parameters showed the sample was characterized by overweight and excess adiposity. After the study period, no changes from baseline were detectable for any parameter in either group. In this study, AbM extract had no modulating effect on IL-6, IFN-γ or TNF-α levels in elderly females.

  2. Arterial switch.

    PubMed

    Planche, C; Lacour-Gayet, F; Serraf, A

    1998-01-01

    A relatively large spectra of anatomic variations are found within the unifying features of discordant ventriculoarterial connections. Variants that lend themselves to anatomic repair by the arterial switch operation are discussed, these include transposition of the great arteries with intact ventricular septum (TGA IVS), TGA associated with a ventricular septal defect (TGA VSD), double-outlet right ventricle with subpulmonary VSD (DORV VSD), and TGA or DORV with VSD associated with coarctation. Double discordance with VSD, which is currently treated by double switch or Rastelli and atrial switch and which probably represents, in our department, the only remaining indication for atrial switch, is not discussed. Also, we exclude TGA associated with pulmonary stenosis, which is treated by Rastelli or REV operation.

  3. Magnetic switching

    NASA Astrophysics Data System (ADS)

    Kirbie, H. C.

    1989-04-01

    Magnetic switching is a pulse compression technique that uses a saturable inductor (reactor) to pass pulses of energy between two capacitors. A high degree of pulse compression can be achieved in a network when several of these simple, magnetically switched circuits are connected in series. Individual inductors are designed to saturate in cascade as a pulse moves along the network. The technique is particularly useful when a single-pulse network must be very reliable or when a multi-pulse network must operate at a high pulse repetition frequency (PRF). Today, magnetic switches trigger spark gaps, sharpen the risetimes of high energy pulses, power large lasers, and drive high PRF linear induction accelerators. This paper will describe the technique of magnetic pulse compression using simple networks and design equations. A brief review of modern magnetic materials and of their role in magnetic switch design will be presented.

  4. Acceleration switch

    DOEpatents

    Abbin, J.P. Jr.; Devaney, H.F.; Hake, L.W.

    1979-08-29

    The disclosure relates to an improved integrating acceleration switch of the type having a mass suspended within a fluid filled chamber, with the motion of the mass initially opposed by a spring and subsequently not so opposed.

  5. Acceleration switch

    DOEpatents

    Abbin, Jr., Joseph P.; Devaney, Howard F.; Hake, Lewis W.

    1982-08-17

    The disclosure relates to an improved integrating acceleration switch of the type having a mass suspended within a fluid filled chamber, with the motion of the mass initially opposed by a spring and subsequently not so opposed.

  6. Autocrine CSF1R signaling mediates switching between invasion and proliferation downstream of TGFβ in claudin-low breast tumor cells.

    PubMed

    Patsialou, A; Wang, Y; Pignatelli, J; Chen, X; Entenberg, D; Oktay, M; Condeelis, J S

    2015-05-21

    Patient data suggest that colony-stimulating factor-1 (CSF1) and its receptor (CSF1R) have critical roles during breast cancer progression. We have previously shown that in human breast tumors expressing both CSF1 and CSF1R, invasion in vivo is dependent both on a paracrine interaction with tumor-associated macrophages and an autocrine regulation of CSF1R in the tumor cells themselves. Although the role of the paracrine interaction between tumor cells and macrophages has been extensively studied, very little is known about the mechanism by which the autocrine CSF1R signaling contributes to tumor progression. We show here that breast cancer patients of the claudin-low subtype have significantly increased expression of CSF1R. Using a panel of breast cancer cell lines, we confirm that CSF1R expression is elevated and regulated by TGFβ specifically in claudin-low cell lines. Abrogation of autocrine CSF1R signaling in MDA-MB-231 xenografts (a claudin-low cell line) leads to increased tumor size by enhanced proliferation, but significantly reduced invasion, dissemination and metastasis. Indeed, we show that proliferation and invasion are oppositely regulated by CSF1R downstream of TGFβ only in claudin-low cell lines. Intravital multiphoton imaging revealed that inhibition of CSF1R in the tumor cells leads to decreased in vivo motility and a more cohesive morphology. We show that, both in vitro and in vivo, CSF1R inhibition results in a reversal of claudin-low marker expression by significant upregulation of luminal keratins and tight-junction proteins such as claudins. Finally, we show that artificial overexpression of claudins in MDA-MB-231 cells is sufficient to tip the cells from an invasive state to a proliferative state. Our results suggest that autocrine CSF1R signaling is essential in maintaining low claudin expression and that it mediates a switch between the proliferative and the invasive state in claudin-low tumor cells downstream of TGFβ.

  7. Autocrine CSF1R signaling mediates switching between invasion and proliferation downstream of TGFβ in claudin-low breast tumor cells

    PubMed Central

    Patsialou, Antonia; Wang, Yarong; Pignatelli, Jeanine; Chen, Xiaoming; Entenberg, David; Oktay, Maja; Condeelis, John S.

    2014-01-01

    Patient data suggest that colony stimulating factor-1 (CSF1) and its receptor (CSF1R) play critical roles during breast cancer progression. We have previously shown that in human breast tumors expressing both CSF1 and CSF1R, invasion in vivo is dependent both on a paracrine interaction with tumor-associated macrophages and an autocrine regulation of CSF1R in the tumor cells themselves. Although the role of the paracrine interaction between tumor cells and macrophages has been extensively studied, very little is known about the mechanism by which the autocrine CSF1R signaling contributes to tumor progression. We show here that breast cancer patients of the claudin-low subtype have significantly increased expression of CSF1R. Using a panel of breast cancer cells lines, we confirm that CSF1R expression is elevated and regulated by TGFβ specifically in claudin-low cell lines. Abrogation of autocrine CSF1R signaling in MDA-MB-231 xenografts (a claudin-low cell line) leads to increased tumor size by enhanced proliferation, but significantly reduced invasion, dissemination and metastasis. Indeed, we show that proliferation and invasion are oppositely regulated by CSF1R downstream of TGFβ only in claudin-low cells lines. Intravital multiphoton imaging revealed that inhibition of CSF1R in the tumor cells leads to decreased in vivo motility and a more cohesive morphology. We show that, both in vitro and in vivo, CSF1R inhibition results in a reversal of claudin-low marker expression by significant upregulation of luminal keratins and tight junction proteins such as claudins. Finally, we show that artificial overexpression of claudins in MDA-MB-231 cells is sufficient to tip the cells from an invasive state to a proliferative state. Our results suggest that autocrine CSF1R signaling is essential in maintaining low claudin expression and that it mediates a switch between the proliferative and the invasive state in claudin-low tumor cells downstream of TGFβ. PMID:25088194

  8. Nucleosome Switches

    NASA Astrophysics Data System (ADS)

    Schwab, David J.; Bruinsma, Robijn F.; Rudnick, Joseph; Widom, Jonathan

    2008-06-01

    We present a statistical-mechanical model for the positioning of nucleosomes along genomic DNA molecules as a function of the strength of the binding potential and the chemical potential of the nucleosomes. We show that a significant section of the DNA is composed of two-level nucleosome switching regions where the nucleosome distribution undergoes a localized, first-order transition. The location of the nucleosome switches shows a strong correlation with the location of gene-regulation regions.

  9. Nucleosome switches.

    PubMed

    Schwab, David J; Bruinsma, Robijn F; Rudnick, Joseph; Widom, Jonathan

    2008-06-06

    We present a statistical-mechanical model for the positioning of nucleosomes along genomic DNA molecules as a function of the strength of the binding potential and the chemical potential of the nucleosomes. We show that a significant section of the DNA is composed of two-level nucleosome switching regions where the nucleosome distribution undergoes a localized, first-order transition. The location of the nucleosome switches shows a strong correlation with the location of gene-regulation regions.

  10. Health-related quality of life in two randomized controlled trials of phentermine/topiramate for obesity: What mediates improvement?

    PubMed

    Kolotkin, Ronette L; Gadde, Kishore M; Peterson, Craig A; Crosby, Ross D

    2016-05-01

    Phentermine/topiramate combination therapy resulted in significant weight loss and improvements in cardiometabolic risk factors in patients with obesity/overweight in two published 56-week randomized, placebo-controlled trials (EQUIP and CONQUER). The purpose of the current study was to examine whether phentermine/topiramate is also associated with greater improvements in health-related quality of life (HRQOL) and whether HRQOL improvements are solely attributable to weight reduction. Patients in EQUIP (n = 751) had a body mass index (BMI) ≥ 35 with no obesity-related comorbidity. Patients in CONQUER (n = 1623) had a BMI ≥ 27 and ≤ 45 and at least two obesity-related comorbid conditions. HRQOL was assessed with Impact of Weight on Quality of Life-Lite (IWQOL-Lite) and Medical Outcomes Study Short Form (SF-36) (CONQUER only). Significant improvements in both obesity-specific and physical HRQOL were observed at 56 weeks in both trials (p < .0001). In EQUIP, BMI reduction fully mediated improvements in IWQOL-Lite total score (p < .0001). In CONQUER, both BMI reduction (all p values < .0001) and change in depressive symptoms (all p values < .025) were significant mediators of improved IWQOL-Lite total score and SF-36 Physical Component Summary score. Gender, psychiatric history, and baseline triglycerides moderated these relationships. Both trials demonstrated that treatment with phentermine/topiramate improved HRQOL compared with placebo. Although reduction in BMI accounted for the majority of improvements in obesity-specific and physical HRQOL, decrease in depressive symptoms was also a significant mediator. Results highlight the predominance of weight reduction as a key factor in improving HRQOL in obesity.

  11. Sleep-Related Safety Behaviors and Dysfunctional Beliefs Mediate the Efficacy of Online CBT for Insomnia: A Randomized Controlled Trial.

    PubMed

    Lancee, Jaap; Eisma, Maarten C; van Straten, Annemieke; Kamphuis, Jan H

    2015-01-01

    Several trials have demonstrated the efficacy of online cognitive behavioral therapy (CBT) for insomnia. However, few studies have examined putative mechanisms of change based on the cognitive model of insomnia. Identification of modifiable mechanisms by which the treatment works may guide efforts to further improve the efficacy of insomnia treatment. The current study therefore has two aims: (1) to replicate the finding that online CBT is effective for insomnia and (2) to test putative mechanism of change (i.e., safety behaviors and dysfunctional beliefs). Accordingly, we conducted a randomized controlled trial in which individuals with insomnia were randomized to either online CBT for insomnia (n = 36) or a waiting-list control group (n = 27). Baseline and posttest assessments included questionnaires assessing insomnia severity, safety behaviors, dysfunctional beliefs, anxiety and depression, and a sleep diary. Three- and six-month assessments were administered to the CBT group only. Results show moderate to large statistically significant effects of the online treatment compared to the waiting list on insomnia severity, sleep measures, sleep safety behaviors, and dysfunctional beliefs. Furthermore, dysfunctional beliefs and safety behaviors mediated the effects of treatment on insomnia severity and sleep efficiency. Together, these findings corroborate the efficacy of online CBT for insomnia, and suggest that these effects were produced by changing maladaptive beliefs, as well as safety behaviors. Treatment protocols for insomnia may specifically be enhanced by more focused attention on the comprehensive fading of sleep safety behaviors, for instance through behavioral experiments.

  12. Randomized Trial Comparing a Web-Mediated Follow-up With Routine Surveillance in Lung Cancer Patients.

    PubMed

    Denis, Fabrice; Lethrosne, Claire; Pourel, Nicolas; Molinier, Olivier; Pointreau, Yoann; Domont, Julien; Bourgeois, Hugues; Senellart, Hélène; Trémolières, Pierre; Lizée, Thibaut; Bennouna, Jaafar; Urban, Thierry; El Khouri, Claude; Charron, Alexandre; Septans, Anne-Lise; Balavoine, Magali; Landry, Sébastien; Solal-Céligny, Philippe; Letellier, Christophe

    2017-09-01

    The use of web-based monitoring for lung cancer patients is growing in interest because of promising recent results suggesting improvement in cancer and resource utilization outcomes. It remains an open question whether the overall survival (OS) in these patients could be improved by using a web-mediated follow-up rather than classical scheduled follow-up and imaging. Advanced-stage lung cancer patients without evidence of disease progression after or during initial treatment were randomly assigned in a multicenter phase III trial to compare a web-mediated follow-up algorithm (experimental arm), based on weekly self-scored patient symptoms, with routine follow-up with CT scans scheduled every three to six months according to the disease stage (control arm). In the experimental arm, an alert email was automatically sent to the oncologist when self-scored symptoms matched predefined criteria. The primary outcome was OS. From June 2014 to January 2016, 133 patients were enrolled and 121 were retained in the intent-to-treat analysis; 12 deemed ineligible after random assignment were not subsequently followed. Most of the patients (95.1%) had stage III or IV disease. The median follow-up was nine months. The median OS was 19.0 months (95% confidence interval [CI] = 12.5 to noncalculable) in the experimental and 12.0 months (95% CI = 8.6 to 16.4) in the control arm (one-sided P = .001) (hazard ratio = 0.32, 95% CI = 0.15 to 0.67, one-sided P = .002). The performance status at first detected relapse was 0 to 1 for 75.9% of the patients in the experimental arm and for 32.5% of those in the control arm (two-sided P < .001). Optimal treatment was initiated in 72.4% of the patients in the experimental arm and in 32.5% of those in the control arm (two-sided P < .001). A web-mediated follow-up algorithm based on self-reported symptoms improved OS due to early relapse detection and better performance status at relapse.

  13. Treatment of chronic antibody mediated rejection with intravenous immunoglobulins and rituximab: a multicenter, prospective, randomized, double blind clinical trial.

    PubMed

    Moreso, Francesc; Crespo, Marta; Ruiz, Juan C; Torres, Armando; Gutierrez-Dalmau, Alex; Osuna, Antonio; Perelló, Manel; Pascual, Julio; Torres, Irina B; Redondo-Pachón, Dolores; Rodrigo, Emilio; Lopez-Hoyos, Marcos; Seron, Daniel

    2017-09-26

    There are no approved treatments for chronic antibody mediated rejection (ABMR). We conducted a multicenter, prospective, randomized, placebo-controlled, double blind clinical trial to evaluate efficacy and safety of intravenous immunoglobulins (IVIG) combined with rituximab (RTX) (EudraCT 2010-023746-67). Patients with transplant glomerulopathy and anti-HLA donor-specific antibodies (DSA) were eligible. Patients with estimated glomerular filtration rate (eGFR) < 20 mL/min/1.73m(2) and/or severe interstitial fibrosis/tubular atrophy were excluded. Patients were randomized to receive IVIG (4 doses of 0.5 g/kg) and RTX (375 mg/m(2) ) or a wrapped isovolumetric saline infusion. Primary efficacy variable was the decline of eGFR at one year. Secondary efficacy variables included evolution of proteinuria, renal lesions and DSA at one year. The planned sample size was 25 patients per group. During 2012-2015, twenty-five patients were randomized (13 to the treatment and 12 to the placebo group). The planned patient enrollment was not achieved because of budgetary constraints and slow patient recruitment. There were no differences between the treatment and placebo groups in eGFR decline (-4.2±14.4 vs. -6.6±12.0 mL/min/1.73 m(2,) p-value=0.475), increase of proteinuria (+0.9±2.1 vs. +0.9±2.1 g/day, p-value=0.378), Banff scores at one year and MFI of the immunodominant DSA. Safety was similar between groups. These data suggest that the combination of IVIG and RTX is not useful in patients displaying transplant glomerulopathy and DSA. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  14. A large-scale in vivo RNAi screen to identify genes involved in Notch-mediated follicle cell differentiation and cell cycle switches

    PubMed Central

    Jia, Dongyu; Soylemez, Muhammed; Calvin, Gabriel; Bornmann, Randy; Bryant, Jamal; Hanna, Cameron; Huang, Yi-Chun; Deng, Wu-Min

    2015-01-01

    During Drosophila oogenesis, follicle cells sequentially undergo three distinct cell-cycle programs: the mitotic cycle, endocycle, and gene amplification. Notch signaling plays a central role in regulating follicle-cell differentiation and cell-cycle switches; its activation is essential for the mitotic cycle/endocycle (M/E) switch. Cut, a linker between Notch signaling and cell-cycle regulators, is specifically downregulated by Notch during the endocycle stage. To determine how signaling pathways coordinate during the M/E switch and to identify novel genes involved in follicle cell differentiation, we performed an in vivo RNAi screen through induced knockdown of gene expression and examination of Cut expression in follicle cells. We screened 2205 RNAi lines and found 33 genes regulating Cut expression during the M/E switch. These genes were confirmed with the staining of two other Notch signaling downstream factors, Hindsight and Broad, and validated with multiple independent RNAi lines. We applied gene ontology software to find enriched biological meaning and compared our results with other publications to find conserved genes across tissues. Specifically, we found earlier endocycle entry in anterior follicle cells than those in the posterior, identified that the insulin-PI3K pathway participates in the precise M/E switch, and suggested Nejire as a cofactor of Notch signaling during oogenesis. PMID:26205122

  15. A large-scale in vivo RNAi screen to identify genes involved in Notch-mediated follicle cell differentiation and cell cycle switches.

    PubMed

    Jia, Dongyu; Soylemez, Muhammed; Calvin, Gabriel; Bornmann, Randy; Bryant, Jamal; Hanna, Cameron; Huang, Yi-Chun; Deng, Wu-Min

    2015-07-24

    During Drosophila oogenesis, follicle cells sequentially undergo three distinct cell-cycle programs: the mitotic cycle, endocycle, and gene amplification. Notch signaling plays a central role in regulating follicle-cell differentiation and cell-cycle switches; its activation is essential for the mitotic cycle/endocycle (M/E) switch. Cut, a linker between Notch signaling and cell-cycle regulators, is specifically downregulated by Notch during the endocycle stage. To determine how signaling pathways coordinate during the M/E switch and to identify novel genes involved in follicle cell differentiation, we performed an in vivo RNAi screen through induced knockdown of gene expression and examination of Cut expression in follicle cells. We screened 2205 RNAi lines and found 33 genes regulating Cut expression during the M/E switch. These genes were confirmed with the staining of two other Notch signaling downstream factors, Hindsight and Broad, and validated with multiple independent RNAi lines. We applied gene ontology software to find enriched biological meaning and compared our results with other publications to find conserved genes across tissues. Specifically, we found earlier endocycle entry in anterior follicle cells than those in the posterior, identified that the insulin-PI3K pathway participates in the precise M/E switch, and suggested Nejire as a cofactor of Notch signaling during oogenesis.

  16. How Does Cognitive Behavior Therapy for IBS Work?: A Mediational Analysis of a Randomized Clinical Trial

    PubMed Central

    Lackner, Jeffrey M.; Jaccard, James; Krasner, Susan S.; Katz, Leonard A.; Gudleski, Gregory D.; Blanchard, Edward B.

    2009-01-01

    Background & Aims: While multiple clinical trials support the efficacy of psychological treatments for reducing IBS symptoms, the mechanisms responsible for symptomatic improvement are unknown. One hypothesis is that psychological treatments work by alleviating comorbid psychological distress implicated in the worsening of bowel symptoms and quality of life. An alternative hypothesis assumes that changes in distress are not strictly a cause but a consequence of IBS that will decrease with symptomatic improvement. Methods: We evaluated these two hypothesis by applying structural equation modeling (SEM) to the data set of a large number (N = 147) of Rome II diagnosed participants randomized to cognitive behavior therapy (CBT), psychoeducation, or wait list. Per Rome guidelines, the primary endpoint was global improvement of GI symptoms measured two weeks after a 10-week regimen. Secondary endpoints were distress and quality of life (QOL). Results: SEM analyses lend support to a model in which CBT is associated with improvements in IBS symptoms, but that therapeutic gains are not dependent on changes in patients' overall level of psychological distress. Symptom severity, but not clinical status (pain catastrophizing, predominant bowel habits, symptom duration, abuse, diagnosable psychiatric disorder) or relevant sociodemographic variables (e.g., gender, age) moderated treatment outcome. Conclusion: CBT has a direct effect on global IBS symptom improvement independent of its effects on distress. Improvement in IBS symptoms is associated with improvements in the QOL, which may lower distress. Symptom improvements are not moderated by variables reflecting the mental well being of IBS patients. PMID:17681164

  17. An online community improves adherence in an internet-mediated walking program. Part 1: results of a randomized controlled trial.

    PubMed

    Richardson, Caroline R; Buis, Lorraine R; Janney, Adrienne W; Goodrich, David E; Sen, Ananda; Hess, Michael L; Mehari, Kathleen S; Fortlage, Laurie A; Resnick, Paul J; Zikmund-Fisher, Brian J; Strecher, Victor J; Piette, John D

    2010-12-17

    Approximately half of American adults do not meet recommended physical activity guidelines. Face-to-face lifestyle interventions improve health outcomes but are unlikely to yield population-level improvements because they can be difficult to disseminate, expensive to maintain, and inconvenient for the recipient. In contrast, Internet-based behavior change interventions can be disseminated widely at a lower cost. However, the impact of some Internet-mediated programs is limited by high attrition rates. Online communities that allow participants to communicate with each other by posting and reading messages may decrease participant attrition. Our objective was to measure the impact of adding online community features to an Internet-mediated walking program on participant attrition and average daily step counts. This randomized controlled trial included sedentary, ambulatory adults who used email regularly and had at least 1 of the following: overweight (body mass index [BMI] ≥ 25), type 2 diabetes, or coronary artery disease. All participants (n = 324) wore enhanced pedometers throughout the 16-week intervention and uploaded step-count data to the study server. Participants could log in to the study website to view graphs of their walking progress, individually-tailored motivational messages, and weekly calculated goals. Participants were randomized to 1 of 2 versions of a Web-based walking program. Those randomized to the "online community" arm could post and read messages with other participants while those randomized to the "no online community" arm could not read or post messages. The main outcome measures were participant attrition and average daily step counts over 16 weeks. Multiple regression analyses assessed the effect of the online community access controlling for age, sex, disease status, BMI, and baseline step counts. Both arms significantly increased their average daily steps between baseline and the end of the intervention period, but there were no

  18. An Online Community Improves Adherence in an Internet-Mediated Walking Program. Part 1: Results of a Randomized Controlled Trial

    PubMed Central

    2010-01-01

    Background Approximately half of American adults do not meet recommended physical activity guidelines. Face-to-face lifestyle interventions improve health outcomes but are unlikely to yield population-level improvements because they can be difficult to disseminate, expensive to maintain, and inconvenient for the recipient. In contrast, Internet-based behavior change interventions can be disseminated widely at a lower cost. However, the impact of some Internet-mediated programs is limited by high attrition rates. Online communities that allow participants to communicate with each other by posting and reading messages may decrease participant attrition. Objective Our objective was to measure the impact of adding online community features to an Internet-mediated walking program on participant attrition and average daily step counts. Methods This randomized controlled trial included sedentary, ambulatory adults who used email regularly and had at least 1 of the following: overweight (body mass index [BMI] ≥ 25), type 2 diabetes, or coronary artery disease. All participants (n = 324) wore enhanced pedometers throughout the 16-week intervention and uploaded step-count data to the study server. Participants could log in to the study website to view graphs of their walking progress, individually-tailored motivational messages, and weekly calculated goals. Participants were randomized to 1 of 2 versions of a Web-based walking program. Those randomized to the “online community” arm could post and read messages with other participants while those randomized to the “no online community" arm could not read or post messages. The main outcome measures were participant attrition and average daily step counts over 16 weeks. Multiple regression analyses assessed the effect of the online community access controlling for age, sex, disease status, BMI, and baseline step counts. Results Both arms significantly increased their average daily steps between baseline and the end of

  19. Switching from suppressive protease inhibitor-based regimens to nevirapine-based regimens: a meta-analysis of randomized controlled trials.

    PubMed

    Ena, J; Leach, A; Nguyen, P

    2008-10-01

    We performed a meta-analysis to assess the efficacy and safety of switching from protease inhibitor (PI)- to nevirapine (NVP)-based regimens in HIV-infected patients in whom virological suppression had been achieved. Six trials (550 patients) were analysed. The demographics showed that 11-48% of participants were female and 40-53% had hepatitis C or B virus infection, and the mean CD4 lymphocyte count was >500 cells/microL at study entry. NVP-based regimens showed noninferiority compared with continuation of PI therapy to maintain virological suppression in 'intention to treat' (80 vs. 78%; P=0.35) and 'on treatment' analyses (91 vs. 89%; P=0.10). Overall rates of discontinuation because of adverse events were similar in the two groups (11 vs. 10%; P=0.79). However, NVP-based therapies caused more discontinuations because of liver toxicity than PI-based therapies (7 vs. 0%; P=0.0009). At the end of follow-up there was no statistical difference in CD4, cholesterol, triglyceride and body shape measurements between the two groups. Two studies reported greater improvement in quality of life in patients who were switched to the NVP group. Switching from suppressive PI- to NVP-based regimens is virologically and immunologically safe; however, the risk of liver toxicity requires monitoring of clinical symptoms and liver chemistry during NVP therapy.

  20. Efficacy and safety of switching from basal insulin to once-daily insulin IDegAsp in Japanese patients with inadequately controlled type 2 diabetes: A 4-week, randomized, open-label, treat-to-target study.

    PubMed

    Nagai, Yoshio; Nishine, Ami; Hashimoto, Eriko; Nakayama, Taiga; Sasaki, Yosuke; Murakami, Mariko; Ishii, Satoshi; Kato, Hiroyuki; Tanaka, Yasushi

    2017-09-16

    A prospective, 4-week, single-center, randomized, open-label, parallel-group, treat-to-target study was performed to develop an algorithm for safe and effective switching from basal insulin to once-daily insulin degludec/insulin aspart (IDegAsp) in patients with inadequately controlled type 2 diabetes. Patients were randomly assigned to continue their current basal insulin therapy (n=10) or to switch to IDegAsp on a 1: 1 unit basis (n=10). The insulin dose could be titrated once weekly, targeting a self-measured blood glucose of 80 to 100 mg/dL before breakfast. A mixed meal test was performed at baseline and after 4 weeks. After 4 weeks, the mean daily dose of insulin was similarly increased by 60% in both groups, and there was a significant decrease of mean plasma glucose and glucose AUC0-2h in the meal test. The mean estimated treatment difference (IDegAsp group - basal insulin group) of the mean plasma glucose level was -28 mg/dL (95% CI -47, -8, p=0.008) after 4 weeks and that of the glucose AUC0-2h was -2,800 mg·min/dL (95% CI -5,300, -350, p=0.028), confirming the superiority of IDegAsp to basal insulin. In the IDegAsp group, the 2-hour postprandial plasma glucose level was significantly decreased to the fasting plasma glucose range. There were no confirmed hypoglycemic episodes in either group during the 4-week study period. After switching from basal insulin, the IDegAsp dose can be up-titrated by 60% based on fasting plasma glucose data. However, monitoring of postprandial glucose should be considered before further up-titration of IDegAsp. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  1. Optical switch

    DOEpatents

    Reedy, Robert P.

    1987-01-01

    An optical switching device (10) is provided whereby light from a first glass fiber (16) or a second glass fiber (14) may be selectively transmitted into a third glass fiber (18). Each glass fiber is provided with a focusing and collimating lens system (26, 28, 30). In one mode of operation, light from the first glass fiber (16) is reflected by a planar mirror (36) into the third glass fiber (18). In another mode of operation, light from the second glass fiber (14) passes directly into the third glass fiber (18). The planar mirror (36) is attached to a rotatable table (32) which is rotated to provide the optical switching.

  2. Optical switch

    DOEpatents

    Reedy, R.P.

    1987-11-10

    An optical switching device is provided whereby light from a first glass fiber or a second glass fiber may be selectively transmitted into a third glass fiber. Each glass fiber is provided with a focusing and collimating lens system. In one mode of operation, light from the first glass fiber is reflected by a planar mirror into the third glass fiber. In another mode of operation, light from the second glass fiber passes directly into the third glass fiber. The planar mirror is attached to a rotatable table which is rotated to provide the optical switching. 3 figs.

  3. Optical switch

    DOEpatents

    Reedy, R.P.

    1985-01-18

    An optical switching device is provided whereby light from a first glass fiber or a second glass fiber may be selectively transmitted into a third glass fiber. Each glass fiber is provided with a focusing and collimating lens system. In one mode of operation, light from the first glass fiber is reflected by a planar mirror into the third glass fiber. In another mode of operation, light from the second glass fiber passes directly into the third glass fiber. The planar mirror is attached to a rotatable table which is rotated to provide the optical switching.

  4. A Parent-Mediated Intervention that Targets Responsive Parental Behaviors Increases Attachment Behaviors in Children with ASD: Results from a Randomized Clinical Trial

    ERIC Educational Resources Information Center

    Siller, Michael; Swanson, Meghan; Gerber, Alan; Hutman, Ted; Sigman, Marian

    2014-01-01

    The current study is a randomized clinical trial evaluating the efficacy of Focused Playtime Intervention (FPI) in a sample of 70 children with Autism Spectrum Disorder. This parent-mediated intervention has previously been shown to significantly increase responsive parental communication (Siller et al. in "J Autism Dev Disord"…

  5. A Parent-Mediated Intervention that Targets Responsive Parental Behaviors Increases Attachment Behaviors in Children with ASD: Results from a Randomized Clinical Trial

    ERIC Educational Resources Information Center

    Siller, Michael; Swanson, Meghan; Gerber, Alan; Hutman, Ted; Sigman, Marian

    2014-01-01

    The current study is a randomized clinical trial evaluating the efficacy of Focused Playtime Intervention (FPI) in a sample of 70 children with Autism Spectrum Disorder. This parent-mediated intervention has previously been shown to significantly increase responsive parental communication (Siller et al. in "J Autism Dev Disord"…

  6. Testing a Path-Analytic Mediation Model of How Self-Regulated Writing Strategies Improve Fourth Graders' Composition Skills: A Randomized Controlled Trial

    ERIC Educational Resources Information Center

    Brunstein, Joachim C.; Glaser, Cornelia

    2011-01-01

    This study was designed to identify, through mediation analysis, potential causal mechanisms by which procedures of self-regulated learning increase the efficaciousness of teaching young students strategies for writing stories. In a randomized controlled trial with 3 measurement points (pretest, posttest, maintenance), 117 fourth graders either…

  7. Inflammatory Mediators in Tracheal Aspirates of Preterm Infants Participating in a Randomized Trial of Inhaled Nitric Oxide

    PubMed Central

    Amann, Elena; Uhlig, Ulrike; Yang, Yang; Fuchs, Hans W.; Zemlin, Michael; Mercier, Jean-Christophe; Maier, Rolf F.; Hummler, Helmut D.; Uhlig, Stefan; Thome, Ulrich H.

    2017-01-01

    Background Ventilated preterm infants frequently develop bronchopulmonary dysplasia (BPD) which is associated with elevated inflammatory mediators in their tracheal aspirates (TA). In animal models of BPD, inhaled nitric oxide (iNO) has been shown to reduce lung inflammation, but data for human preterm infants is missing. Methods Within a European multicenter trial of NO inhalation for preterm infants to prevent BPD (EUNO), TA was collected to determine the effects of iNO on pulmonary inflammation. TA was collected from 43 premature infants randomly assigned to receive either iNO or placebo gas (birth weight 530–1230 g, median 800 g, gestational age 24 to 28 2/7 weeks, median 26 weeks). Interleukin (IL)-1β, IL-6, IL-8, transforming growth factor (TGF)-β1, interferon γ-induced protein 10 (IP-10), macrophage inflammatory protein (MIP)-1α, acid sphingomyelinase (ASM), neuropeptide Y and leukotriene B4 were measured in serial TA samples from postnatal day 2 to 14. Furthermore, TA levels of nitrotyrosine and nitrite were determined under iNO therapy. Results The TA levels of IP-10, IL-6, IL-8, MIP-1α, IL-1β, ASM and albumin increased with advancing postnatal age in critically ill preterm infants, whereas nitrotyrosine TA levels declined in both, iNO-treated and placebo-treated infants. The iNO treatment generally increased nitrite TA levels, whereas nitrotyrosine TA levels were not affected by iNO treatment. Furthermore, iNO treatment transiently reduced early inflammatory and fibrotic markers associated with BPD development including TGF-β1, IP-10 and IL-8, but induced a delayed increase of ASM TA levels. Conclusion Treatment with iNO may have played a role in reducing several inflammatory and fibrotic mediators in TA of preterm infants compared to placebo-treated infants. However, survival without BPD was not affected in the main EUNO trial. Trial registration NCT00551642 PMID:28046032

  8. Switching Transistor

    NASA Technical Reports Server (NTRS)

    1981-01-01

    Westinghouse Electric Corporation's D60T transistors are used primarily as switching devices for controlling high power in electrical circuits. It enables reduction in the number and size of circuit components and promotes more efficient use of energy. Wide range of application from a popcorn popper to a radio frequency generator for solar cell production.

  9. Switched power workshop. [Switched power electron guns

    SciTech Connect

    Palmer, R.B.

    1988-01-01

    This paper discusses the design of a switched power electron gun. Particular topics discussed are: vacuum photodiode switch; laser switched solid state diodes; gun performance; charging supply; and laser requirements. (LSP)

  10. Resistive switching characteristic and uniformity of low-power HfO x -based resistive random access memory with the BN insertion layer

    NASA Astrophysics Data System (ADS)

    Su, Shuai; Jian, Xiao-Chuan; Wang, Fang; Han, Ye-Mei; Tian, Yu-Xian; Wang, Xiao-Yang; Zhang, Hong-Zhi; Zhang, Kai-Liang

    2016-10-01

    In this letter, the Ta/HfO x /BN/TiN resistive switching devices are fabricated and they exhibit low power consumption and high uniformity each. The reset current is reduced for the HfO x /BN bilayer device compared with that for the Ta/HfO x /TiN structure. Furthermore, the reset current decreases with increasing BN thickness. The HfO x layer is a dominating switching layer, while the low-permittivity and high-resistivity BN layer acts as a barrier of electrons injection into TiN electrode. The current conduction mechanism of low resistance state in the HfO x /BN bilayer device is space-charge-limited current (SCLC), while it is Ohmic conduction in the HfO x device. Project supported by the National Natural Science Foundation of China (Grant Nos. 61274113, 11204212, 61404091, 51502203, and 51502204), the Tianjin Natural Science Foundation, China (Grant Nos. 14JCZDJC31500 and 14JCQNJC00800), and the Tianjin Science and Technology Developmental Funds of Universities and Colleges, China (Grant No. 20130701).

  11. A role for WDR5 in TRA-1/Gli mediated transcriptional control of the sperm/oocyte switch in C. elegans.

    PubMed

    Li, Tengguo; Kelly, William G

    2014-05-01

    The hermaphrodite germline of Caenorhabditis elegans initially engages in spermatogenesis and then switches to oogenesis during late stages of larval development. TRA-1, a member of the Ci/Gli family of transcriptional repressors, plays an essential role in this switch by repressing genes that promote spermatogenesis. WDR5 proteins are conserved components of histone methyltransferase complexes normally associated with gene activation. However, two C. elegans WDR5 homologs, wdr-5.1 and wdr-5.2 are redundantly required for normal TRA-1 dependent repression, and this function is independent of their roles in histone methylation. Animals lacking wdr-5.1/wdr-5.2 function fail to switch to oogenesis at 25°C, resulting in a masculinization of germline (Mog) phenotype. The Mog phenotype is caused by ectopic expression of fog-3, a direct target of TRA-1 repression. WDR-5.1 associates with the fog-3 promoter and is required for TRA-1 to bind to fog-3 promoter. Other direct targets of TRA-1 are similarly derepressed in the double mutant. These results show that WDR5 plays a novel and important role in stabilizing transcriptional repression during C. elegans sex determination, and provide evidence that this important protein may operate independently of its established role in histone methyltransferase complexes. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

  12. A role for WDR5 in TRA-1/Gli mediated transcriptional control of the sperm/oocyte switch in C. elegans

    PubMed Central

    Li, Tengguo; Kelly, William G.

    2014-01-01

    The hermaphrodite germline of Caenorhabditis elegans initially engages in spermatogenesis and then switches to oogenesis during late stages of larval development. TRA-1, a member of the Ci/Gli family of transcriptional repressors, plays an essential role in this switch by repressing genes that promote spermatogenesis. WDR5 proteins are conserved components of histone methyltransferase complexes normally associated with gene activation. However, two C. elegans WDR5 homologs, wdr-5.1 and wdr-5.2 are redundantly required for normal TRA-1 dependent repression, and this function is independent of their roles in histone methylation. Animals lacking wdr-5.1/wdr-5.2 function fail to switch to oogenesis at 25°C, resulting in a masculinization of germline (Mog) phenotype. The Mog phenotype is caused by ectopic expression of fog-3, a direct target of TRA-1 repression. WDR-5.1 associates with the fog-3 promoter and is required for TRA-1 to bind to fog-3 promoter. Other direct targets of TRA-1 are similarly derepressed in the double mutant. These results show that WDR5 plays a novel and important role in stabilizing transcriptional repression during C. elegans sex determination, and provide evidence that this important protein may operate independently of its established role in histone methyltransferase complexes. PMID:24682813

  13. Switch for serial or parallel communication networks

    DOEpatents

    Crosette, Dario B.

    1994-01-01

    A communication switch apparatus and a method for use in a geographically extensive serial, parallel or hybrid communication network linking a multi-processor or parallel processing system has a very low software processing overhead in order to accommodate random burst of high density data. Associated with each processor is a communication switch. A data source and a data destination, a sensor suite or robot for example, may also be associated with a switch. The configuration of the switches in the network are coordinated through a master processor node and depends on the operational phase of the multi-processor network: data acquisition, data processing, and data exchange. The master processor node passes information on the state to be assumed by each switch to the processor node associated with the switch. The processor node then operates a series of multi-state switches internal to each communication switch. The communication switch does not parse and interpret communication protocol and message routing information. During a data acquisition phase, the communication switch couples sensors producing data to the processor node associated with the switch, to a downlink destination on the communications network, or to both. It also may couple an uplink data source to its processor node. During the data exchange phase, the switch couples its processor node or an uplink data source to a downlink destination (which may include a processor node or a robot), or couples an uplink source to its processor node and its processor node to a downlink destination.

  14. Switch for serial or parallel communication networks

    DOEpatents

    Crosette, D.B.

    1994-07-19

    A communication switch apparatus and a method for use in a geographically extensive serial, parallel or hybrid communication network linking a multi-processor or parallel processing system has a very low software processing overhead in order to accommodate random burst of high density data. Associated with each processor is a communication switch. A data source and a data destination, a sensor suite or robot for example, may also be associated with a switch. The configuration of the switches in the network are coordinated through a master processor node and depends on the operational phase of the multi-processor network: data acquisition, data processing, and data exchange. The master processor node passes information on the state to be assumed by each switch to the processor node associated with the switch. The processor node then operates a series of multi-state switches internal to each communication switch. The communication switch does not parse and interpret communication protocol and message routing information. During a data acquisition phase, the communication switch couples sensors producing data to the processor node associated with the switch, to a downlink destination on the communications network, or to both. It also may couple an uplink data source to its processor node. During the data exchange phase, the switch couples its processor node or an uplink data source to a downlink destination (which may include a processor node or a robot), or couples an uplink source to its processor node and its processor node to a downlink destination. 9 figs.

  15. Up-down hand position switch may delay the fatigue of non-dominant hand position rescuers and improve chest compression quality during cardiopulmonary resuscitation: a randomized crossover manikin study.

    PubMed

    Zhou, Xian-Long; Li, Lei; Jiang, Cheng; Xu, Bing; Wang, Huang-Lei; Xiong, Dan; Sheng, Li-Pin; Yang, Qi-Sheng; Jiang, Shan; Xu, Peng; Chen, Zhi-Qiao; Zhao, Yan

    2015-01-01

    Previous studies have shown improved external chest compression (ECC) quality and delayed rescuer fatigue when the dominant hand (DH) was in contact with the sternum. However, many rescuers prefer placing the non-dominant hand (NH) in contact with the sternum during ECC. We aimed to investigate the effects of up-down hand position switch on the quality of ECC and the fatigue of rescuers during cardiopulmonary resuscitation (CPR). After completion of a review of the standard adult basic life support (BLS) course, every candidate performed 10 cycles of single adult CPR twice on an adult manikin with either a constant hand position (CH) or a switched hand position (SH) in random order at 7-day intervals. The rescuers' general characteristics, hand positions, physiological signs, fatigue appearance and ECC qualities were recorded. Our results showed no significant differences in chest compression quality for the DH position rescuers between the CH and SH sessions (p>0.05, resp.). And also no significant differences were found for Borg score (p = 0.437) or cycle number (p = 0.127) of fatigue appearance after chest compressions between the two sessions. However, for NH position rescuers, the appearance of fatigue was delayed (p = 0.046), with a lower Borg score in the SH session (12.67 ± 2.03) compared to the CH session (13.33 ± 1.95) (p = 0.011). Moreover, the compression depth was significantly greater in the SH session (39.3 ± 7.2 mm) compared to the CH session (36.3 ± 8.1 mm) (p = 0.015). Our data suggest that the up-down hand position switch during CPR may delay the fatigue of non-dominant hand position rescuers and improve the quality of chest compressions.

  16. Impact of platform switching on inter-proximal bone levels around 8.5 mm implants in the posterior region; 5-year results from a randomized clinical trial.

    PubMed

    Telleman, Gerdien; Raghoebar, Gerry M; Vissink, Arjan; Meijer, Henny J A

    2017-03-01

    To assess the medium-term results of 8.5 mm implants supplied with a conventional platform-matched implant-abutment connection or a platform-switched design. Eighty patients with one or more missing teeth in the maxillary or mandibular posterior zone were randomly assigned for treatment with implants with a conventional (control group) or platform-switched (test group) implant-abutment connection. Follow-up visits were conducted 1 month, 1 year and 5 years after functional loading. Inter-proximal bone loss, assessed with standardized peri-apical radiographs, clinical parameters, survival of implants and satisfaction of patients were the outcome parameters studied. After 5 years of loading, five of the 80 patients were lost to follow-up. The inter-proximal bone loss in the test group (0.38 ± 0.61 mm) was comparable to the bone loss in the control group (0.41 ± 0.47 mm; p = 0.201). Remarkably, bone loss has not progressed compared to the 1-year results. Implant survival, clinical parameters and satisfaction of the patients were favourable and comparable for the test and control group. The 5-years results showed that inter-proximal bone resorption was minor and comparable around platform-matched and platform-switched implants, and implant survival, peri-implant health and patients' satisfaction were favourable. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  17. Up-Down Hand Position Switch May Delay the Fatigue of Non-Dominant Hand Position Rescuers and Improve Chest Compression Quality during Cardiopulmonary Resuscitation: A Randomized Crossover Manikin Study

    PubMed Central

    Xu, Bing; Wang, Huang-Lei; Xiong, Dan; Sheng, Li-Pin; Yang, Qi-Sheng; Jiang, Shan; Xu, Peng; Chen, Zhi-Qiao; Zhao, Yan

    2015-01-01

    Previous studies have shown improved external chest compression (ECC) quality and delayed rescuer fatigue when the dominant hand (DH) was in contact with the sternum. However, many rescuers prefer placing the non-dominant hand (NH) in contact with the sternum during ECC. We aimed to investigate the effects of up-down hand position switch on the quality of ECC and the fatigue of rescuers during cardiopulmonary resuscitation (CPR). After completion of a review of the standard adult basic life support (BLS) course, every candidate performed 10 cycles of single adult CPR twice on an adult manikin with either a constant hand position (CH) or a switched hand position (SH) in random order at 7-day intervals. The rescuers’ general characteristics, hand positions, physiological signs, fatigue appearance and ECC qualities were recorded. Our results showed no significant differences in chest compression quality for the DH position rescuers between the CH and SH sessions (p>0.05, resp.). And also no significant differences were found for Borg score (p = 0.437) or cycle number (p = 0.127) of fatigue appearance after chest compressions between the two sessions. However, for NH position rescuers, the appearance of fatigue was delayed (p = 0.046), with a lower Borg score in the SH session (12.67 ± 2.03) compared to the CH session (13.33 ± 1.95) (p = 0.011). Moreover, the compression depth was significantly greater in the SH session (39.3 ± 7.2 mm) compared to the CH session (36.3 ± 8.1 mm) (p = 0.015). Our data suggest that the up-down hand position switch during CPR may delay the fatigue of non-dominant hand position rescuers and improve the quality of chest compressions. PMID:26267353

  18. Direct observation of type 1 fimbrial switching.

    PubMed

    Adiciptaningrum, Aileen M; Blomfield, Ian C; Tans, Sander J

    2009-05-01

    The defining feature of bacterial phase variation is a stochastic 'all-or-nothing' switching in gene expression. However, direct observations of these rare switching events have so far been lacking, obscuring possible correlations between switching events themselves, and between switching and other cellular events, such as division and DNA replication. We monitored the phase variation of type 1 fimbriae in individual Escherichia coli in real time and simultaneously tracked the chromosome replication process. We observed distinctive patterns of fim (fimbriae) expression in multiple genealogically related lineages. These patterns could be explained by a model that combines a single switching event with chromosomal fim replication, as well as the epigenetic inheritance of expressed fim protein and RNA, and their dilution by growth. Analysis of the moment of switching at sub-cell-cycle resolution revealed a correlation between fim switching and cell age, which challenges the traditional idea of phase variation as a random Poissonian phenomenon.

  19. Paternal Lifestyle-Related Parenting Practices Mediate Changes in Children's Dietary and Physical Activity Behaviors: Findings From the Healthy Dads, Healthy Kids Community Randomized Controlled Trial.

    PubMed

    Lloyd, Adam B; Lubans, David R; Plotnikoff, Ronald C; Morgan, Philip J

    2015-09-01

    This study examined potential parenting-related mediators of children's physical activity and dietary behavior change in the Healthy Dads, Healthy Kids (HDHK) community program. A randomized controlled trial was conducted with 45 overweight/obese (mean [SD] age = 39.8 [5.4] years; BMI = 32.4 [3.8]) fathers and their children (n = 77; 58% boys; mean [SD] age = 7.7 [2.5] years). Families were randomized to either the HDHK program or wait-list control group. The program involved 7 sessions. Fathers and their children were assessed at baseline and at 14 weeks for physical activity (pedometery) and core food intake (Questionnaire). Fathers' lifestyle-related parenting practices included; self-efficacy, beliefs, modeling, logistic support, rules, cophysical activity, shared mealtime frequency and intentions. Significant intervention effects were found for cophysical activity and modeling physical activity. Cophysical activity mediated children's physical activity in the intervention ('mediated effect,' AB = 653, 95% CI = 4-2050) and was responsible for 59.5% of the intervention effect. Fathers' beliefs mediated children's percent energy from core foods (AB = 1.51, 95% CI = 0.05-5.55) and accounted for 72.9% of the intervention effect. Participation in the HDHK program positively impacted on fathers' cophysical activity with their child and beliefs about healthy eating which mediated changes in children's diet and physical activity behaviors.

  20. Engineering interface-type resistance switching based on forming current compliance in ITO/Ga2O3:ITO/TiN resistance random access memory: Conduction mechanisms, temperature effects, and electrode influence

    NASA Astrophysics Data System (ADS)

    Pan, Chih-Hung; Chang, Ting-Chang; Tsai, Tsung-Ming; Chang, Kuan-Chang; Chen, Po-Hsun; Chang-Chien, Shi-Wang; Chen, Min-Chen; Huang, Hui-Chun; Wu, Huaqiang; Deng, Ning; Qian, He; Sze, Simon M.

    2016-10-01

    In this paper, an ITO/Ga2O3:ITO/TiN structured resistance random access memory is introduced. Either interface or filament conduction mechanism can be induced depending on the forming compliance current, which has not been investigated before. Material analyses and electrical I-V measurements on this ITO/Ga2O3:ITO/TiN have also been carried out. The interface conduction mechanism was confirmed by a size-effect experiment, where resistance varied inversely to via size. In addition, the current fitting results show that Schottky emission dominates the on- and off-state currents. All physical mechanisms of device resistive switching behaviors are explained by our models and also confirmed by I-V characteristics.

  1. Ames Lab 101: Ultrafast Magnetic Switching

    ScienceCinema

    Jigang Wang

    2016-07-12

    Ames Laboratory physicists have found a new way to switch magnetism that is at least 1000 times faster than currently used in magnetic memory technologies. Magnetic switching is used to encode information in hard drives, magnetic random access memory and other computing devices. The discovery potentially opens the door to terahertz and faster memory speeds.

  2. Ames Lab 101: Ultrafast Magnetic Switching

    SciTech Connect

    Jigang Wang

    2013-04-08

    Ames Laboratory physicists have found a new way to switch magnetism that is at least 1000 times faster than currently used in magnetic memory technologies. Magnetic switching is used to encode information in hard drives, magnetic random access memory and other computing devices. The discovery potentially opens the door to terahertz and faster memory speeds.

  3. Caregiver-mediated intervention can improve physical functional recovery of patients with chronic stroke: a randomized controlled trial.

    PubMed

    Wang, Tzu-Chi; Tsai, Alan C; Wang, Jiun-Yi; Lin, Yu-Te; Lin, Ko-Long; Chen, Jiun Jiang; Lin, Bei Yi; Lin, Tai Ching

    2015-01-01

    Background and Purpose. Patients with chronic stroke may benefit from continuing rehabilitation training after hospital discharge. This study examined whether caregiver-mediated, home-based intervention (CHI) could improve physical functioning and social participation in these patients. Methods. A single-blind, randomized, controlled 12-week trial conducted with 51 patients from 3 hospitals in Taiwan who had chronic stroke (>6 months; Brunnstrom recovery stages III-V). Patients and their caregivers in the intervention arm (n = 25) were given weekly personalized CHI trainings designed by a physical therapist. Patients in the control arm (n = 26) received visits from the therapist without intervention. All were evaluated for physical recovery through the Stroke Impact Scale, Berg Balance Scale, 10-Meter Walk Test, 6-Minute Walk Test, and Barthel Index at baseline and endpoint. Caregivers were evaluated with the Caregiver Burden Scale. Results were analyzed through Mann-Whitney U test. Results. CHI significantly improved scores of the Stroke Impact Scale: strength (control vs intervention, respectively: 1.4 vs 15.5; P = .002), mobility (-0.5 vs 13.7; P < .001), composite physical (-0.7 vs 11.2; P < .001), and general recovery domain (0.2 vs 17.4; P < .001). CHI also significantly improved free-walking velocity (-1.4 vs 7.5 cm/s; P = .006), 6-minute walk distance (-10.5 vs 15.8 m; P = .003), Berg Balance Scale score (-0.8 vs 4.5; P = .006), and Barthel Index score (0.6 vs 7.2; P = .008). CHI did not significantly increase caregiver burden at endpoint. Conclusion. CHI can improve physical functional recovery and, possibly, social participation in patients with chronic stroke.

  4. Behavioral Determinants of Switching to Arsenic-Safe Water Wells: An Analysis of a Randomized Controlled Trial of Health Education Interventions Coupled With Water Arsenic Testing

    ERIC Educational Resources Information Center

    George, Christine Marie; Inauen, Jennifer; Perin, Jamie; Tighe, Jennifer; Hasan, Khaled; Zheng, Yan

    2017-01-01

    More than 100 million people globally are estimated to be exposed to arsenic in drinking water that exceeds the World Health Organization guideline of 10 µg/L. In an effort to develop and test a low-cost sustainable approach for water arsenic testing in Bangladesh, we conducted a randomized controlled trial which found arsenic educational…

  5. Behavioral Determinants of Switching to Arsenic-Safe Water Wells: An Analysis of a Randomized Controlled Trial of Health Education Interventions Coupled With Water Arsenic Testing

    ERIC Educational Resources Information Center

    George, Christine Marie; Inauen, Jennifer; Perin, Jamie; Tighe, Jennifer; Hasan, Khaled; Zheng, Yan

    2017-01-01

    More than 100 million people globally are estimated to be exposed to arsenic in drinking water that exceeds the World Health Organization guideline of 10 µg/L. In an effort to develop and test a low-cost sustainable approach for water arsenic testing in Bangladesh, we conducted a randomized controlled trial which found arsenic educational…

  6. A randomized, split-face clinical trial of low-fluence Q-switched neodymium-doped yttrium aluminum garnet (1,064 nm) laser versus low-fluence Q-switched alexandrite laser (755 nm) for the treatment of facial melasma.

    PubMed

    Fabi, Sabrina G; Friedmann, Daniel P; Niwa Massaki, Ane B; Goldman, Mitchel P

    2014-09-01

    Melasma is distressing for patients and challenging for physicians to treat. Clinical data from controlled comparative studies is lacking to support the efficacy, longevity, and safety of laser treatments for melasma. Compare the efficacy and safety of low fluence Q-switched neodymium-doped yttrium aluminum garnet (1,064 nm) laser (Nd:YAG) versus low-fluence Q-switched alexandrite laser (755 nm) (QSAL) for the treatment of facial melasma. Twenty male and female subjects with moderate to severe mixed-type melasma on both sides of the face were randomized to six, weekly treatments with the low-fluence Q-switched Nd:YAG laser on one side and the low-fluence QSAL to the other side. Two independent investigators conducted Modified Melasma Area and Severity Index (MMASI) evaluations and subjects completed self-assessment questionnaires at baseline, after three treatments and each follow-up visit 2, 12, and 24 weeks after the last treatment. Standardized digital photographs were taken at baseline and at each subsequent follow-up visit. One male and fifteen females, mean age of 43.4 (range 32-64) years, completed the 29-week study. Both laser treated sides showed a significant improvement in MMASI evaluations after two treatments (22% improvement on the QS-Nd:YAG, 17% QSAL) and each follow-up visit 2 (36% QS-Nd:YAG; 44% QSAL), 12 (27% QS-Nd:YAG; and 24% QSAL), and 24 weeks (27% QS-Nd:YAG; and 19% QSAL) after the last treatment, but no significant difference was seen between study groups at any visit. There was also no significant difference in subject evaluation of improvement between both treatment sides at any visit. Both laser treated sides were tolerated well, and no serious adverse events were noted. Only one subject was taken out of the study due to development of post-inflammatory hyperpigmentation bilaterally. Both low-fluence Q-switched Nd:YAG and low-fluence QSAL were equally effective at improving moderate to severe mixed-type facial melasma. This was a

  7. Analysis of Individual Social-ecological Mediators and Moderators and Their Ability to Explain Effect of a Randomized Neighborhood Walking Intervention

    PubMed Central

    Michael, Yvonne L; Carlson, Nichole E

    2009-01-01

    Background Using data from the SHAPE trial, a randomized 6-month neighborhood-based intervention designed to increase walking activity among older adults, this study identified and analyzed social-ecological factors mediating and moderating changes in walking activity. Methods Three potential mediators (social cohesion, walking efficacy, and perception of neighborhood problems) and minutes of brisk walking were assessed at baseline, 3-months, and 6-months. One moderator, neighborhood walkability, was assessed using an administrative GIS database. The mediating effect of change in process variables on change in brisk walking was tested using a product-of-coefficients test, and we evaluated the moderating effect of neighborhood walkability on change in brisk walking by testing the significance of the interaction between walkability and intervention status. Results Only one of the hypothesized mediators, walking efficacy, explained the intervention effect (product of the coefficients (95% CI) = 8.72 (2.53, 15.56). Contrary to hypotheses, perceived neighborhood problems appeared to suppress the intervention effects (product of the coefficients (95% CI = -2.48, -5.6, -0.22). Neighborhood walkability did not moderate the intervention effect. Conclusion Walking efficacy may be an important mediator of lay-lead walking interventions for sedentary older adults. Social-ecologic theory-based analyses can support clinical interventions to elucidate the mediators and moderators responsible for producing intervention effects. PMID:19643024

  8. Analysis of Individual Social-ecological Mediators and Moderators and Their Ability to Explain Effect of a Randomized Neighborhood Walking Intervention.

    PubMed

    Michael, Yvonne L; Carlson, Nichole E

    2009-07-30

    Using data from the SHAPE trial, a randomized 6-month neighborhood-based intervention designed to increase walking activity among older adults, this study identified and analyzed social-ecological factors mediating and moderating changes in walking activity. Three potential mediators (social cohesion, walking efficacy, and perception of neighborhood problems) and minutes of brisk walking were assessed at baseline, 3-months, and 6-months. One moderator, neighborhood walkability, was assessed using an administrative GIS database. The mediating effect of change in process variables on change in brisk walking was tested using a product-of-coefficients test, and we evaluated the moderating effect of neighborhood walkability on change in brisk walking by testing the significance of the interaction between walkability and intervention status. Only one of the hypothesized mediators, walking efficacy, explained the intervention effect (product of the coefficients (95% CI) = 8.72 (2.53, 15.56). Contrary to hypotheses, perceived neighborhood problems appeared to suppress the intervention effects (product of the coefficients (95% CI = -2.48, -5.6, -0.22). Neighborhood walkability did not moderate the intervention effect. Walking efficacy may be an important mediator of lay-lead walking interventions for sedentary older adults. Social-ecologic theory-based analyses can support clinical interventions to elucidate the mediators and moderators responsible for producing intervention effects.

  9. EDITORIAL: Molecular switches at surfaces Molecular switches at surfaces

    NASA Astrophysics Data System (ADS)

    Weinelt, Martin; von Oppen, Felix

    2012-10-01

    -assembled monolayers of azobenzene photoswitches with trifluoromethyl and cyano end groupsDaniel Brete, Daniel Przyrembel, Christian Eickhoff, Robert Carley, Wolfgang Freyer, Karsten Reuter, Cornelius Gahl and Martin Weinelt Reversible electron-induced cis-trans isomerization mediated by intermolecular interactionsCh Lotze, Y Luo, M Corso, K J Franke, R Haag and J I Pascual Transport properties of graphene functionalized with molecular switchesNiels Bode, Eros Mariani and Felix von Oppen

  10. Effect of naturally random allocation to lower low-density lipoprotein cholesterol on the risk of coronary heart disease mediated by polymorphisms in NPC1L1, HMGCR, or both: a 2 × 2 factorial Mendelian randomization study.

    PubMed

    Ference, Brian A; Majeed, Faisal; Penumetcha, Raju; Flack, John M; Brook, Robert D

    2015-04-21

    Considerable uncertainty exists as to whether lowering low-density lipoprotein cholesterol (LDL-C) by inhibiting the Niemann-Pick C1-Like 1 (NPC1L1) receptor with ezetimibe, either alone or in combination with a 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibitor (statin), will reduce the risk of coronary heart disease (CHD). This study evaluated the effect of naturally random allocation to lower LDL-C mediated by polymorphisms in the NPC1L1 gene (target of ezetimibe), the HMGCR gene (target of statins), or both (target of combination therapy) on the risk of CHD. We constructed NPC1L1 and HMGCR genetic LDL-C scores to naturally randomize participants into 4 groups: reference, lower LDL-C mediated by NPC1L1 polymorphisms, lower LDL-C mediated by HMGCR polymorphisms, or lower LDL-C mediated by polymorphisms in both NPC1L1 and HMGCR. We compared the risk of CHD (fatal or nonfatal myocardial infarction) among each group using a 2 × 2 factorial mendelian randomization study design. A total of 108,376 persons (10,464 CHD events) from 14 studies were included. There were no significant differences in baseline characteristics among the 4 groups, thus confirming that allocation was random. Compared to the reference group, the NPC1L1 group had 2.4 mg/dl lower LDL-C and 4.8% lower risk of CHD (odds ratio [OR]: 0.952, 95% confidence interval [CI]: 0.920 to 0.985); whereas the HMGCR group had 2.9 mg/dl lower LDL-C and a similar 5.3% lower risk of CHD (OR: 0.947, 95% CI: 0.909 to 0.986). The group with lower LDL-C mediated by both NPC1L1 and HMGCR polymorphisms had 5.8 mg/dl additively lower LDL-C and a 10.8% log-linearly additive lower risk of CHD (OR: 0.892, 95% CI: 0.854 to 0.932). The effect of lower LDL-C on the risk of CHD mediated by polymorphisms in NPC1L1, HMGCR, or both is approximately the same per unit lower LDL-C and log-linearly proportional to the absolute exposure to lower LDL-C. Copyright © 2015 American College of Cardiology Foundation

  11. Enhanced stability of complementary resistance switching in the TiN/HfOx/TiN resistive random access memory device via interface engineering

    NASA Astrophysics Data System (ADS)

    Zhang, H. Z.; Ang, D. S.; Yew, K. S.; Wang, X. P.

    2016-02-01

    This study shows that a majority (70%) of TiN/HfOx/TiN devices exhibit failed complementary resistance switching (CRS) after forming. In conjunction with the consistent observation of a large non-polar reset loop in the first post-forming voltage-sweep measurement, it is proposed that breakdown of the TiN/HfOx interfacial oxide layers (crucial in enabling CRS) and the accompanied formation of Ti filaments (due to Ti migration from the TiN cathode into the breakdown path) resulted in CRS failure and the observed non-polar reset behavior. This hypothesis is supported by the significant reduction or complete elimination of the large non-polar reset and CRS failure in devices with a thin Al2O3 layer incorporated at the TiN-cathode/HfOx or both TiN/HfOx interfaces. The higher breakdown field of the thin Al2O3 enables it to sustain the forming voltage until the forming process is interrupted, thus enabling CRS via oxygen exchange with the adjacent vacancy-type filament formed in the HfOx.

  12. Cardiovascular Parameters to 2 years After Kidney Transplantation Following Early Switch to Everolimus Without Calcineurin Inhibitor Therapy: An Analysis of the Randomized ELEVATE Study.

    PubMed

    Holdaas, Hallvard; de Fijter, Johan W; Cruzado, Josep M; Massari, Pablo; Nashan, Björn; Kanellis, John; Witzke, Oliver; Gutierrez-Dalmau, Alex; Turkmen, Aydin; Wang, Zailong; Lopez, Patricia; Bernhardt, Peter; Kochuparampil, Jossy; van der Giet, Markus; Murbraech, Klaus

    2017-03-22

    Mammalian target of rapamycin (mTOR) inhibitors may confer cardioprotective advantages but clinical data are limited. In the open-label ELEVATE trial, kidney transplant patients were randomized at 10-14 weeks posttransplant to convert from calcineurin inhibitor (CNI) to everolimus or remain on standard CNI therapy. Prespecified endpoints included left ventricular mass index (LVMi) and, in a subpopulation of patients, arterial stiffness as measured by pulse wave velocity (PWV). The mean change in LVMi from randomization was similar with everolimus versus CNI (month 24: -4.37 g/m versus -5.26 g/m; mean difference 0.89 [p=0.392]). At month 24, LVH was present in 41.7% versus 37.7% of everolimus and CNI patients, respectively. Mean PWV remained stable with both everolimus (mean change from randomization to month 12: -0.24 m/s; month 24: -0.03 m/s) or CNI (month 12: 0.11 m/s; month 24: 0.16 m/s). The change in mean ambulatory night time blood pressure from randomization showed a benefit for diastolic pressure at month 12 (p=0.039) but not month 24. Major adverse cardiac events occurred in 1.1% and 4.2% of everolimus-treated and CNI-treated patients, respectively by month 12 (p=0.018) and 2.3% (8/353) and 4.5% by month 24 (p=0.145). Overall, these data do not suggest a clinically relevant effect on cardiac endpoints following early conversion from CNI to a CNI-free everolimus-based regimen.

  13. A prospective, randomized, double dummy, placebo-controlled trial of oral cefditoren pivoxil 400mg once daily as switch therapy after intravenous ceftriaxone in the treatment of acute pyelonephritis.

    PubMed

    Monmaturapoj, Teerapong; Montakantikul, Preecha; Mootsikapun, Piroon; Tragulpiankit, Pramote

    2012-12-01

    To compare the clinical and bacteriological effectiveness of intravenous (IV) ceftriaxone followed by oral cefditoren pivoxil or IV ceftriaxone for acute pyelonephritis. A prospective randomized controlled trial of patients with a presumptive diagnosis of acute pyelonephritis was performed. Daily 2g IV ceftriaxone was initially given to all patients. After day 3, patients who satisfied the criteria for switch therapy were randomized to either group A (IV ceftriaxone) or group B (oral cefditoren pivoxil 400mg once daily). Eighty-two patients were enrolled; 41 (50%) patients in group A and 41 (50%) patients in group B were evaluated. There was no statistically significant difference in baseline characteristics between the two groups. Clinical cure was observed in 39 of 41 (95.1%) patients in group A and 41 of 41 (100%) patients in group B (p=0.15, 95% confidence interval (CI) -0.12 to 0.02). Urine bacteriological eradication was found in 63.4% in group A and 60% in group B (p=0.75, 95% CI -0.18 to 0.25). There was no statistically significant difference in adverse effects between the two treatment groups. These data suggest that IV ceftriaxone followed by oral cefditoren pivoxil is highly effective and well-tolerated for the treatment of acute pyelonephritis, even for uropathogens with a high proportion of quinolone-resistant strains. Copyright © 2012 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

  14. The Role of Response Repetition in Task Switching

    ERIC Educational Resources Information Center

    Cooper, Stephen; Mari-Beffa, Paloma

    2008-01-01

    When switching between tasks, participants are sometimes required to use different response sets for each task. Thus, task switch and response set switch are confounded. In 5 experiments, the authors examined transitions of response within a linear 4-finger arrangement. A random baseline condition was compared with the cuing of specific response…

  15. Nuclear magnetic relaxation induced by exchange-mediated orientational randomization: Longitudinal relaxation dispersion for spin I = 1

    NASA Astrophysics Data System (ADS)

    Nilsson, Tomas; Halle, Bertil

    2012-08-01

    The frequency dependence of the longitudinal relaxation rate, known as the magnetic relaxation dispersion (MRD), can provide a frequency-resolved characterization of molecular motions in complex biological and colloidal systems on time scales ranging from 1 ns to 100 μs. The conformational dynamics of immobilized proteins and other biopolymers can thus be probed in vitro or in vivo by exploiting internal water molecules or labile hydrogens that exchange with a dominant bulk water pool. Numerous water 1H and 2H MRD studies of such systems have been reported, but the widely different theoretical models currently used to analyze the MRD data have resulted in divergent views of the underlying molecular motions. We have argued that the essential mechanism responsible for the main dispersion is the exchange-mediated orientational randomization (EMOR) of anisotropic nuclear (electric quadrupole or magnetic dipole) couplings when internal water molecules or labile hydrogens escape from orientationally confining macromolecular sites. In the EMOR model, the exchange process is thus not just a means of mixing spin populations but it is also the direct cause of spin relaxation. Although the EMOR theory has been used in several studies to analyze water 2H MRD data from immobilized biopolymers, the fully developed theory has not been described. Here, we present a comprehensive account of a generalized version of the EMOR theory for spin I = 1 nuclides like 2H. As compared to a previously described version of the EMOR theory, the present version incorporates three generalizations that are all essential in applications to experimental data: (i) a biaxial (residual) electric field gradient tensor, (ii) direct and indirect effects of internal motions, and (iii) multiple sites with different exchange rates. In addition, we describe and assess different approximations to the exact EMOR theory that are useful in various regimes. In particular, we consider the experimentally important

  16. Effect of Folic Acid and Betaine Supplementation on Flow-Mediated Dilation: A Randomized, Controlled Study in Healthy Volunteers

    PubMed Central

    Olthof, Margreet R; Bots, Michiel L; Katan, Martijn B; Verhoef, Petra

    2006-01-01

    Objectives: We investigated whether lowering of fasting homocysteine concentrations, either with folic acid or with betaine supplementation, differentially affects vascular function, a surrogate marker for risk of cardiovascular disease, in healthy volunteers. As yet, it remains uncertain whether a high concentration of homocysteine itself or whether a low folate status—its main determinant—is involved in the pathogenesis of cardiovascular disease. To shed light on this issue, we performed this study. Design: This was a randomized, placebo-controlled, double-blind, crossover study. Setting: The study was performed at Wageningen University in Wageningen, the Netherlands. Participants: Participants were 39 apparently healthy men and women, aged 50–70 y. Interventions: Participants ingested 0.8 mg/d of folic acid, 6 g/d of betaine, and placebo for 6 wk each, with 6-wk washout in between. Outcome Measures: At the end of each supplementation period, plasma homocysteine concentrations and flow-mediated dilation (FMD) of the brachial artery were measured in duplicate. Results: Folic acid supplementation lowered fasting homocysteine by 20% (−2.0 μmol/l, 95% confidence interval [CI]: −2.3; −1.6), and betaine supplementation lowered fasting plasma homocysteine by 12% (−1.2 μmol/l; −1.6; −0.8) relative to placebo. Mean (± SD) FMD after placebo supplementation was 2.8 (± 1.8) FMD%. Supplementation with betaine or folic acid did not affect FMD relative to placebo; differences relative to placebo were −0.4 FMD% (95%CI, −1.2; 0.4) and −0.1 FMD% (−0.9; 0.7), respectively. Conclusions: Folic acid and betaine supplementation both did not improve vascular function in healthy volunteers, despite evident homocysteine lowering. This is in agreement with other studies in healthy participants, the majority of which also fail to find improved vascular function upon folic acid treatment. However, homocysteine or folate might of course affect cardiovascular

  17. Sex hormone associations with breast cancer risk and the mediation of randomized trial postmenopausal hormone therapy effects.

    PubMed

    Zhao, Shanshan; Chlebowski, Rowan T; Anderson, Garnet L; Kuller, Lewis H; Manson, JoAnn E; Gass, Margery; Patterson, Ruth; Rohan, Thomas E; Lane, Dorothy S; Beresford, Shirley Aa; Lavasani, Sayeh; Rossouw, Jacques E; Prentice, Ross L

    2014-03-26

    Paradoxically, a breast cancer risk reduction with conjugated equine estrogens (CEE) and a risk elevation with CEE plus medroxyprogesterone acetate (CEE + MPA) were observed in the Women's Health Initiative (WHI) randomized controlled trials. The effects of hormone therapy on serum sex hormone levels, and on the association between baseline sex hormones and disease risk, may help explain these divergent breast cancer findings. Serum sex hormone concentrations were measured for 348 breast cancer cases in the CEE + MPA trial and for 235 cases in the CEE trial along with corresponding pair-matched controls, nested within the WHI trials of healthy postmenopausal women. Association and mediation analyses, to examine the extent to which sex hormone levels and changes can explain the breast cancer findings, were conducted using logistic regression. Following CEE treatment, breast cancer risk was associated with higher concentrations of baseline serum estrogens, and with lower concentrations of sex hormone binding globulin. However, following CEE + MPA, there was no association of breast cancer risk with baseline sex hormone levels. The sex hormone changes from baseline to year 1 provided an explanation for much of the reduced breast cancer risk with CEE. Specifically, the treatment odds ratio (95% confidence interval) increased from 0.71 (0.43, 1.15) to 0.92 (0.41, 2.09) when the year 1 measures were included in the logistic regression analysis. In comparison, the CEE + MPA odds ratio was essentially unchanged when these year 1 measures were included. Breast cancer risk remains low following CEE use among women having favorable baseline sex hormone profiles, but CEE + MPA evidently produces a breast cancer risk for all women similar to that for women having an unfavorable baseline sex hormone profile. These patterns could reflect breast ductal epithelial cell stimulation by CEE + MPA that is substantially avoided with CEE, in conjunction with

  18. Nuclear magnetic relaxation induced by exchange-mediated orientational randomization: longitudinal relaxation dispersion for spin I = 1.

    PubMed

    Nilsson, Tomas; Halle, Bertil

    2012-08-07

    The frequency dependence of the longitudinal relaxation rate, known as the magnetic relaxation dispersion (MRD), can provide a frequency-resolved characterization of molecular motions in complex biological and colloidal systems on time scales ranging from 1 ns to 100 μs. The conformational dynamics of immobilized proteins and other biopolymers can thus be probed in vitro or in vivo by exploiting internal water molecules or labile hydrogens that exchange with a dominant bulk water pool. Numerous water (1)H and (2)H MRD studies of such systems have been reported, but the widely different theoretical models currently used to analyze the MRD data have resulted in divergent views of the underlying molecular motions. We have argued that the essential mechanism responsible for the main dispersion is the exchange-mediated orientational randomization (EMOR) of anisotropic nuclear (electric quadrupole or magnetic dipole) couplings when internal water molecules or labile hydrogens escape from orientationally confining macromolecular sites. In the EMOR model, the exchange process is thus not just a means of mixing spin populations but it is also the direct cause of spin relaxation. Although the EMOR theory has been used in several studies to analyze water (2)H MRD data from immobilized biopolymers, the fully developed theory has not been described. Here, we present a comprehensive account of a generalized version of the EMOR theory for spin I = 1 nuclides like (2)H. As compared to a previously described version of the EMOR theory, the present version incorporates three generalizations that are all essential in applications to experimental data: (i) a biaxial (residual) electric field gradient tensor, (ii) direct and indirect effects of internal motions, and (iii) multiple sites with different exchange rates. In addition, we describe and assess different approximations to the exact EMOR theory that are useful in various regimes. In particular, we consider the experimentally

  19. Pedometer-based internet-mediated intervention for adults with chronic low back pain: randomized controlled trial.

    PubMed

    Krein, Sarah L; Kadri, Reema; Hughes, Maria; Kerr, Eve A; Piette, John D; Holleman, Rob; Kim, Hyungjin Myra; Richardson, Caroline R

    2013-08-19

    Chronic pain, especially back pain, is a prevalent condition that is associated with disability, poor health status, anxiety and depression, decreased quality of life, and increased health services use and costs. Current evidence suggests that exercise is an effective strategy for managing chronic pain. However, there are few clinical programs that use generally available tools and a relatively low-cost approach to help patients with chronic back pain initiate and maintain an exercise program. The objective of the study was to determine whether a pedometer-based, Internet-mediated intervention can reduce chronic back pain-related disability. A parallel group randomized controlled trial was conducted with 1:1 allocation to the intervention or usual care group. 229 veterans with nonspecific chronic back pain were recruited from one Department of Veterans Affairs (VA) health care system. Participants randomized to the intervention received an uploading pedometer and had access to a website that provided automated walking goals, feedback, motivational messages, and social support through an e-community (n=111). Usual care participants (n=118) also received the uploading pedometer but did not receive the automated feedback or have access to the website. The primary outcome was measured using the Roland Morris Disability Questionnaire (RDQ) at 6 months (secondary) and 12 months (primary) with a difference in mean scores of at least 2 considered clinically meaningful. Both a complete case and all case analysis, using linear mixed effects models, were conducted to assess differences between study groups at both time points. Baseline mean RDQ scores were greater than 9 in both groups. Primary outcome data were provided by approximately 90% of intervention and usual care participants at both 6 and 12 months. At 6 months, average RDQ scores were 7.2 for intervention participants compared to 9.2 for usual care, an adjusted difference of 1.6 (95% CI 0.3-2.8, P=.02) for the

  20. Pedometer-Based Internet-Mediated Intervention For Adults With Chronic Low Back Pain: Randomized Controlled Trial

    PubMed Central

    Kadri, Reema; Hughes, Maria; Kerr, Eve A; Piette, John D; Holleman, Rob; Kim, Hyungjin Myra; Richardson, Caroline R

    2013-01-01

    Background Chronic pain, especially back pain, is a prevalent condition that is associated with disability, poor health status, anxiety and depression, decreased quality of life, and increased health services use and costs. Current evidence suggests that exercise is an effective strategy for managing chronic pain. However, there are few clinical programs that use generally available tools and a relatively low-cost approach to help patients with chronic back pain initiate and maintain an exercise program. Objective The objective of the study was to determine whether a pedometer-based, Internet-mediated intervention can reduce chronic back pain-related disability. Methods A parallel group randomized controlled trial was conducted with 1:1 allocation to the intervention or usual care group. 229 veterans with nonspecific chronic back pain were recruited from one Department of Veterans Affairs (VA) health care system. Participants randomized to the intervention received an uploading pedometer and had access to a website that provided automated walking goals, feedback, motivational messages, and social support through an e-community (n=111). Usual care participants (n=118) also received the uploading pedometer but did not receive the automated feedback or have access to the website. The primary outcome was measured using the Roland Morris Disability Questionnaire (RDQ) at 6 months (secondary) and 12 months (primary) with a difference in mean scores of at least 2 considered clinically meaningful. Both a complete case and all case analysis, using linear mixed effects models, were conducted to assess differences between study groups at both time points. Results Baseline mean RDQ scores were greater than 9 in both groups. Primary outcome data were provided by approximately 90% of intervention and usual care participants at both 6 and 12 months. At 6 months, average RDQ scores were 7.2 for intervention participants compared to 9.2 for usual care, an adjusted difference of 1

  1. Involuntary switching of attention mediates differences in event-related responses to complex tones between early and late Spanish-English bilinguals.

    PubMed

    Ortiz-Mantilla, Silvia; Choudhury, Naseem; Alvarez, Barbara; Benasich, April A

    2010-11-29

    Most research with bilinguals has used speech stimuli to demonstrate differences in auditory processing abilities. Two main factors have been identified as modulators of such differences: proficiency and age of acquisition of the second language (L2). However, whether the bilingual brain differs from the monolingual in the efficient processing of non-verbal auditory events (known to be critical to the acoustic analysis of the speech stream) remains unclear. In this EEG/ERP study, using the mismatch negativity (MMN), P3a, and late negativity (LN), we examined differences in discrimination, involuntary switching of attention and reorienting of attention between monolinguals and bilinguals as they processed complex tones. Further, we examined the role that age of acquisition plays in modulating such responses. A group of English monolinguals and a group of proficient Spanish-English bilinguals were presented with a multiple-deviant oddball paradigm with four deviant conditions (duration, frequency, silent gap, and frequency modulation). Late bilinguals, who learned English after age 10, exhibited larger MMN and P3a responses than early bilinguals, across all deviant conditions. Significant associations were found between amplitude of the responses and both age of L2 acquisition and years of L2 experience. Individuals who acquired English at later ages and had fewer years of L2 experience had larger MMN, P3a, and LN responses than those who learned it earlier. These findings demonstrate that age of L2 acquisition is an important modulator of auditory responses in bilinguals even when processing non-speech signals. Involuntary attention switching is suggested as the main factor driving these differences.

  2. Temperature-controlled flow switching in nanocapillary array membranes mediated by poly(N-isopropylacrylamide) polymer brushes grafted by atom transfer radical polymerization.

    PubMed

    Lokuge, Ishika; Wang, Xuejun; Bohn, Paul W

    2007-01-02

    We report actively controlled transport that is thermally switchable and size-selective in a nanocapillary array membrane (NCAM) prepared by grafting poly(N-isopropylacrylamide) (PNIPAAm) brushes onto the exterior surface of a Au-coated polycarbonate track-etched membrane. A smooth Au layer on the membrane surface, which is key to obtaining a uniform polymer film, was prepared by thermal evaporation of approximately 50 nm Au on both exterior surfaces. After evaporation, the inner diameter of the pore is reduced slightly, but the NCAM retains a narrow pore size distribution. PNIPPAm brushes with 10-30 nm (dry film) thickness were grafted onto the Au surface through surface-initiated atom transfer radical polymerization (ATRP) using a disulfide initiator, (BrC(CH3)2COO(CH2)11S)2. Molecular transport through the PNIPAAm polymer brush-modified NCAMs was investigated by real-time fluorescence measurements using fluorescein isothiocyanate (FITC)-labeled dextrans ranging from 4.4 to 282 kDa in membranes with variable initial pore diameters (80, 100, and 200 nm) and different PNIPAAm thicknesses. Manipulating the temperature of the NCAM through the PNIPAAm lower critical solution temperature (LCST) causes large, size-dependent changes in the transport rates. Over specific ranges of probe size, transport is completely blocked below the LCST but strongly allowed above the LCST. The combination of the highly uniform PNIPAAm brush and the monodisperse pore size distribution is critical in producing highly reproducible switching behavior. Furthermore, the reversible nature of the switching raises the possibility of using them as actively controlled filtration devices.

  3. PAWR-mediated suppression of BCL2 promotes switching of 3-azido withaferin A (3-AWA)-induced autophagy to apoptosis in prostate cancer cells

    PubMed Central

    Rah, Bilal; Rasool, Reyaz ur; Nayak, Debasis; Yousuf, Syed Khalid; Mukherjee, Debaraj; Kumar, Lekha Dinesh; Goswami, Anindya

    2015-01-01

    An active medicinal component of plant origin with an ability to overcome autophagy by inducing apoptosis should be considered a therapeutically active lead pharmacophore to control malignancies. In this report, we studied the effect of concentration-dependent 3-AWA (3-azido withaferin A) sensitization to androgen-independent prostate cancer (CaP) cells which resulted in a distinct switching of 2 interrelated conserved biological processes, i.e. autophagy and apoptosis. We have observed 3 distinct parameters which are hallmarks of autophagy in our studies. First, a subtoxic concentration of 3-AWA resulted in an autophagic phenotype with an elevation of autophagy markers in prostate cancer cells. This led to a massive accumulation of MAP1LC3B and EGFP-LC3B puncta coupled with gradual degradation of SQSTM1. Second, higher toxic concentrations of 3-AWA stimulated ER stress in CaP cells to turn on apoptosis within 12 h by elevating the expression of the proapoptotic protein PAWR, which in turn suppressed the autophagy-related proteins BCL2 and BECN1. This inhibition of BECN1 in CaP cells, leading to the disruption of the BCL2-BECN1 interaction by overexpressed PAWR has not been reported so far. Third, we provide evidence that pawr-KO MEFs exhibited abundant autophagy signs even at toxic concentrations of 3-AWA underscoring the relevance of PAWR in switching of autophagy to apoptosis. Last but not least, overexpression of EGFP-LC3B and DS-Red-BECN1 revealed a delayed apoptosis turnover at a higher concentration of 3-AWA in CaP cells. In summary, this study provides evidence that 3-AWA is a strong anticancer candidate to abrogate protective autophagy. It also enhanced chemosensitivity by sensitizing prostate cancer cells to apoptosis through induction of PAWR endorsing its therapeutic potential. PMID:25803782

  4. Magnetic switching

    SciTech Connect

    Birx, D.; Cook, E.; Hawkins, S.; Poor, S.; Reginato, L.; Schmidt, J.; Smith, M.

    1983-06-01

    The paper discusses the development program in magnetic switching which was aimed at solving the rep-rate and reliability limitations of the ATA spark gaps. The end result has been a prototype physically very similar to the present Advanced Test Accelerator (ATA) pulse power unit but vastly superior in performance. This prototype, which is easily adaptable to the existing systems, has achieved a burst rep-rate of 20 kHz and an output voltage of 500 kV. A one-on-one substitution of the existing pulse power module would result in a 100 MeV accelerator. Furthermore, the high efficiency of the magnetic pulse compression stages has allowed CW operation of the prototype at one kilohertz opening up other applications for the pulse power. Performance and design details will be described.

  5. Stochastic resonance in bistable atomic switches.

    PubMed

    Yoshida, Kenji; Hirakawa, Kazuhiko

    2017-03-24

    We have investigated the conductance of bistable gold atomic switches as a function of periodic input voltages mixed with a random noise. With increasing noise amplitude, the atomic switches biased below the threshold voltage for conductance switching start exhibiting switching in conductance between two stable states. Clear synchronization between the input and output signals is observed when an optimized noise amplitude is mixed with the periodic input voltage, even when the atomic switches are driven by an input voltage as low as approximately 10% of the threshold voltage. The observed behavior can be explained in terms of the stochastic resonance. The results presented here indicate that utilization of noise can dramatically reduce the operation voltage of metal atomic switches.

  6. Stochastic resonance in bistable atomic switches

    NASA Astrophysics Data System (ADS)

    Yoshida, Kenji; Hirakawa, Kazuhiko

    2017-03-01

    We have investigated the conductance of bistable gold atomic switches as a function of periodic input voltages mixed with a random noise. With increasing noise amplitude, the atomic switches biased below the threshold voltage for conductance switching start exhibiting switching in conductance between two stable states. Clear synchronization between the input and output signals is observed when an optimized noise amplitude is mixed with the periodic input voltage, even when the atomic switches are driven by an input voltage as low as approximately 10% of the threshold voltage. The observed behavior can be explained in terms of the stochastic resonance. The results presented here indicate that utilization of noise can dramatically reduce the operation voltage of metal atomic switches.

  7. Prospective randomized controlled clinical and histopathological study of acne vulgaris treated with dual mode of quasi-long pulse and Q-switched 1064-nm Nd:YAG laser assisted with a topically applied carbon suspension.

    PubMed

    Jung, Jae Yoon; Hong, Jong Soo; Ahn, Chang Ho; Yoon, Ji Young; Kwon, Hyuck Hoon; Suh, Dae Hun

    2012-04-01

    Acne treatments using laser and light devices have been reported to have varying degrees of efficacy. However, there has been no study of treatment of acne using a dual mode (quasi-long pulse and Q-switched mode) 1064-nm Nd:YAG laser assisted with a topically applied carbon suspension. To evaluate the clinical efficacy, safety, and histological changes of new laser treatment method for acne vulgaris. Twenty-two patients received 3 sessions of quasi-long pulse and Q-switched Nd:YAG laser treatment assisted with a topically applied carbon suspension at 2-week intervals in a randomized split face manner. At the final visit, the inflammatory acne lesions were reduced on the laser-treated side by 58.6% (P < .001), but increased on the untreated side by 5%. The noninflammatory acne lesions were reduced on the laser-treated side by 52.4% (P < .001). Sebum output reduction, inflammatory cell and cytokine reductions, a decrease of the thickness of a perifollicular stratum corneum and a full epithelium, and skin rejuvenation effect were found. The histopathologic examination of the acne lesions showed decreased inflammation and immunostaining intensity for interleukin 8, matrix metalloproteinase-9, toll-like receptor-2, and nuclear factor kappa B, and tumor necrosis factor alpha was reduced significantly. No severe adverse reactions were reported. All patients reported mild transient erythema that disappeared in a few hours. The number of subjects studied was small. This laser treatment was rapid and effective for treating not only the inflammatory but also the noninflammatory acne lesions when compared with the control side. The histopathologic findings correlated well with the clinical acne grade and treatment response. This novel laser treatment appears to be safe and effective for acne treatment. Copyright © 2012 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

  8. Recovery of fat following a switch to nucleoside reverse transcriptase inhibitor-sparing therapy in patients with lipoatrophy: results from the 96-week randomized ANRS 108 NoNuke Trial.

    PubMed

    Valantin, M A; Lanoy, E; Bentata, M; Kalmykova, O; Boutekadjirt, A; Allavena, C; Rozenbaum, W; Peytavin, G; Amellal, B; Calvez, V; Costagliola, D; Katlama, C

    2008-10-01

    To evaluate the impact on peripheral fat tissue of a nucleoside reverse transcriptase inhibitor (NRTI)-sparing regimen in lipoatrophic HIV-1 infected patients. This 96-week prospective, randomized study compared lipoatrophic patients switched to an NRTI-sparing regimen with patients remaining on an NRTI-containing regimen. The primary endpoint was the change in thigh subcutaneous fat tissue volume between baseline and week 48, as assessed by computerized tomography. One hundred patients were included, 50 in each arm. At baseline, patients had been on highly active antiretroviral therapy (HAART) for a median time of 6.6 years (4.9-9.7); 71% of the patients had received thymidine analogues [stavudine (37%), zidovudine (34%)]. The mean change in fat volume between baseline and week 48 significantly favoured the NRTI-sparing arm over the NRTI-maintaining arm in the intent-to-treat analysis, with a last-observation-carried-forward approach [+34 cm(3); 95% confidence interval (CI) 5-63 cm(3); P=0.002]. This was confirmed in the intent-to-treat analysis of available data, with a mean difference of +109 cm(3) (95% CI 34-185 cm(3)) at week 96 (n=53; P=0.001). This corresponded to increases of 12 and 30% in fat volume at weeks 48 and 96, respectively, in the NRTI-sparing arm. Switching from an effective NRTI-containing regimen to an NRTI-sparing regimen preserves immunovirological status and increases subcutaneous fat volume at weeks 48 and 96.

  9. Cdk5-mediated inhibition of APC/C-Cdh1 switches on the cyclin D1-Cdk4-pRb pathway causing aberrant S-phase entry of postmitotic neurons.

    PubMed

    Veas-Pérez de Tudela, Miguel; Maestre, Carolina; Delgado-Esteban, María; Bolaños, Juan P; Almeida, Angeles

    2015-12-10

    The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase that regulates cell cycle progression in proliferating cells. To enter the S-phase, APC/C must be inactivated by phosphorylation of its cofactor, Cdh1. In post-mitotic cells such as neurons APC/C-Cdh1 complex is highly active and responsible for the continuous degradation of mitotic cyclins. However, the specific molecular pathway that determines neuronal cell cycle blockade in post-mitotic neurons is unknown. Here, we show that activation of glutamatergic receptors in rat cortical primary neurons endogenously triggers cyclin-dependent kinase-5 (Cdk5)-mediated phosphorylation of Cdh1 leading to its cytoplasmic accumulation and disassembly from the APC3 core protein, causing APC/C inactivation. Conversely, pharmacological or genetic inhibition of Cdk5 promotes Cdh1 ubiquitination and proteasomal degradation. Furthermore, we show that Cdk5-mediated phosphorylation and inactivation of Cdh1 leads to p27 depletion, which switches on the cyclin D1-cyclin-dependent kinase-4 (Cdk4)-retinoblastoma protein (pRb) pathway to allow the S-phase entry of neurons. However, neurons do not proceed through the cell cycle and die by apoptosis. These results indicate that APC/C-Cdh1 actively suppresses an aberrant cell cycle entry and death of neurons, highlighting its critical function in neuroprotection.

  10. Plasma Switch Development.

    DTIC Science & Technology

    1984-06-08

    switch :9 (1) the low-pressure gas switch 17 (2) the surface flashover switch ,18 (3) the thyrtron,’ŕ (4) the high pressure...spark gap, (5) the magnetic switch .’ 9 20 and (6) the ECS. The ongoing research for both the low pressure gas and surface flashover closing- switches has... investigations into optimizing gas mixtures for opening switch applications 1 ’"’"’’’a𔃻 ; and a preliminary study of the discharge stabili-

  11. The efficacy and safety of continued hydroxycarbamide therapy versus switching to ruxolitinib in patients with polycythaemia vera: a randomized, double-blind, double-dummy, symptom study (RELIEF).

    PubMed

    Mesa, Ruben; Vannucchi, Alessandro M; Yacoub, Abdulraheem; Zachee, Pierre; Garg, Mamta; Lyons, Roger; Koschmieder, Steffen; Rinaldi, Ciro; Byrne, Jennifer; Hasan, Yasmin; Passamonti, Francesco; Verstovsek, Srdan; Hunter, Deborah; Jones, Mark M; Zhen, Huiling; Habr, Dany; Martino, Bruno

    2017-01-01

    The randomized, double-blind, double-dummy, phase 3b RELIEF trial evaluated polycythaemia vera (PV)-related symptoms in patients who were well controlled with a stable dose of hydroxycarbamide (also termed hydroxyurea) but reported PV-related symptoms. Patients were randomized 1:1 to ruxolitinib 10 mg BID (n = 54) or hydroxycarbamide (prerandomization dose/schedule; n = 56); crossover to ruxolitinib was permitted after Week 16. The primary endpoint, ≥50% improvement from baseline in myeloproliferative neoplasm -symptom assessment form total symptom score cytokine symptom cluster (TSS-C; sum of tiredness, itching, muscle aches, night sweats, and sweats while awake) at Week 16, was achieved by 43·4% vs. 29·6% of ruxolitinib- and hydroxycarbamide-treated patients, respectively (odds ratio, 1·82; 95% confidence interval, 0·82-4·04; P = 0·139). The primary endpoint was achieved by 34% of a subgroup who maintained their hydroxycarbamide dose from baseline to Weeks 13-16. In a post hoc analysis, the primary endpoint was achieved by more patients with stable screening-to-baseline TSS-C scores (ratio ≤ 2) receiving ruxolitinib than hydroxycarbamide (47·4% vs. 25·0%; P = 0·0346). Ruxolitinib treatment after unblinding was associated with continued symptom score improvements. Adverse events were primarily grades 1/2 with no unexpected safety signals. Ruxolitinib was associated with a nonsignificant trend towards improved PV-related symptoms versus hydroxycarbamide, although an unexpectedly large proportion of patients who maintained their hydroxycarbamide dose reported symptom improvement. © 2016 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.

  12. Social cognitive theory mediators of physical activity in a lifestyle program for cancer survivors and carers: findings from the ENRICH randomized controlled trial.

    PubMed

    Stacey, F G; James, E L; Chapman, K; Lubans, D R

    2016-04-14

    Despite increasing numbers of cancer survivors and evidence that diet and physical activity improves the health of cancer survivors, most do not meet guidelines. Some social cognitive theory (SCT)-based interventions have increased physical activity behavior, however few have used objective physical activity measures. The Exercise and Nutrition Routine Improving Cancer Health (ENRICH) randomized controlled trial reported a significant intervention effect for the primary outcome of pedometer-assessed step counts at post-test (8-weeks) and follow-up (20-weeks). The aim of this study was to test whether the SCT constructs operationalized in the ENRICH intervention were mediators of physical activity behavior change. Randomized controlled trial with 174 cancer survivors and carers assessed at baseline, post-test (8-weeks), and follow-up (20-weeks). Participants were randomized to the ENRICH six session face-to-face healthy lifestyle program, or to a wait-list control. Hypothesized SCT mediators of physical activity behavior change (self-efficacy, behavioral goal, outcome expectations, impediments, and social expectations) were assessed using valid and reliable scales. Mediation was assessed using the Preacher and Hayes SPSS INDIRECT macro. At eight weeks, there was a significant intervention effect on behavioral goal (A = 9.12, p = 0.031) and outcome expectations (A = 0.25, p = 0.042). At 20 weeks, the intervention had a significant effect on self-efficacy (A = 0.31, p = 0.049) and behavioral goal (A = 13.15, p = 0.011). Only changes in social support were significantly associated with changes in step counts at eight weeks (B = 633.81, p = 0.023). Behavioral goal was the only SCT construct that had a significant mediating effect on step counts, and explained 22 % of the intervention effect at 20 weeks (AB = 397.9, 95 % CI 81.5-1025.5). SCT constructs had limited impact on objectively-assessed step counts in a multiple health

  13. End-to-end crosstalk within the hepatitis C virus genome mediates the conformational switch of the 3′X-tail region

    PubMed Central

    Romero-López, Cristina; Barroso-delJesus, Alicia; García-Sacristán, Ana; Briones, Carlos; Berzal-Herranz, Alfredo

    2014-01-01

    The hepatitis C virus (HCV) RNA genome contains multiple structurally conserved domains that make long-distance RNA–RNA contacts important in the establishment of viral infection. Microarray antisense oligonucelotide assays, improved dimethyl sulfate probing methods and 2′ acylation chemistry (selective 2’-hydroxyl acylation and primer extension, SHAPE) showed the folding of the genomic RNA 3′ end to be regulated by the internal ribosome entry site (IRES) element via direct RNA–RNA interactions. The essential cis-acting replicating element (CRE) and the 3′X-tail region adopted different 3D conformations in the presence and absence of the genomic RNA 5′ terminus. Further, the structural transition in the 3′X-tail from the replication-competent conformer (consisting of three stem-loops) to the dimerizable form (with two stem-loops), was found to depend on the presence of both the IRES and the CRE elements. Complex interplay between the IRES, the CRE and the 3′X-tail region would therefore appear to occur. The preservation of this RNA–RNA interacting network, and the maintenance of the proper balance between different contacts, may play a crucial role in the switch between different steps of the HCV cycle. PMID:24049069

  14. Dynamic recruitment of Ets1 to both nucleosome-occupied and -depleted enhancer regions mediates a transcriptional program switch during early T-cell differentiation

    PubMed Central

    Cauchy, Pierre; Maqbool, Muhammad A.; Zacarias-Cabeza, Joaquin; Vanhille, Laurent; Koch, Frederic; Fenouil, Romain; Gut, Marta; Gut, Ivo; Santana, Maria A.; Griffon, Aurélien; Imbert, Jean; Moraes-Cabé, Carolina; Bories, Jean-Christophe; Ferrier, Pierre; Spicuglia, Salvatore; Andrau, Jean-Christophe

    2016-01-01

    Ets1 is a sequence-specific transcription factor that plays an important role during hematopoiesis, and is essential for the transition of CD4−/CD8− double negative (DN) to CD4+/CD8+ double positive (DP) thymocytes. Using genome-wide and functional approaches, we investigated the binding properties, transcriptional role and chromatin environment of Ets1 during this transition. We found that while Ets1 binding at distal sites was associated with active genes at both DN and DP stages, its enhancer activity was attained at the DP stage, as reflected by levels of the core transcriptional hallmarks H3K4me1/3, RNA Polymerase II and eRNA. This dual, stage-specific ability reflected a switch from non-T hematopoietic toward T-cell specific gene expression programs during the DN-to-DP transition, as indicated by transcriptome analyses of Ets1−/− thymic cells. Coincidentally, Ets1 associates more specifically with Runx1 in DN and with TCF1 in DP cells. We also provide evidence that Ets1 predominantly binds distal nucleosome-occupied regions in DN and nucleosome-depleted regions in DP. Finally and importantly, we demonstrate that Ets1 induces chromatin remodeling by displacing H3K4me1-marked nucleosomes. Our results thus provide an original model whereby the ability of a transcription factor to bind nucleosomal DNA changes during differentiation with consequences on its cognate enhancer activity. PMID:26673693

  15. The Ets-1 transcription factor is required for Stat1-mediated T-bet expression and IgG2a class switching in mouse B cells.

    PubMed

    Nguyen, Hai Vu; Mouly, Enguerran; Chemin, Karine; Luinaud, Romain; Despres, Raymonde; Fermand, Jean-Paul; Arnulf, Bertrand; Bories, Jean-Christophe

    2012-05-03

    In response to antigens and cytokines, mouse B cells undergo class-switch recombination (CSR) and differentiate into Ig-secreting cells. T-bet, a T-box transcription factor that is up-regulated in lymphocytes by IFN-γ or IL-27, was shown to regulate CSR to IgG2a after T cell-independent B-cell stimulations. However, the molecular mechanisms controlling this process remain unclear. In the present study, we show that inactivation of the Ets-1 transcription factor results in a severe decrease in IgG2a secretion in vivo and in vitro. No T-bet expression was observed in Ets-1-deficient (Ets-1(-/-)) B cells stimulated with IFN-γ and lipopolysaccharide, and forced expression of T-bet in these cells rescued IgG2a secretion. Furthermore, we identified a transcriptional enhancer in the T-bet locus with an activity in B cells that relies on ETS-binding sites. After IFN-γ stimulation of Ets-1(-/-) B cells, activated Stat1, which forms a complex with Ets-1 in wild-type cells, no longer binds to the T-bet enhancer or promotes histone modifications at this site. These results demonstrate that Ets-1 is critical for IgG2a CSR and acts as an essential cofactor for Stat1 in the regulation of T-bet expression in B cells.

  16. TDP-43 loss-of-function causes neuronal loss due to defective steroid receptor-mediated gene program switching in Drosophila.

    PubMed

    Vanden Broeck, Lies; Naval-Sánchez, Marina; Adachi, Yoshitsugu; Diaper, Danielle; Dourlen, Pierre; Chapuis, Julien; Kleinberger, Gernot; Gistelinck, Marc; Van Broeckhoven, Christine; Lambert, Jean-Charles; Hirth, Frank; Aerts, Stein; Callaerts, Patrick; Dermaut, Bart

    2013-01-31

    TDP-43 proteinopathy is strongly implicated in the pathogenesis of amyotrophic lateral sclerosis and related neurodegenerative disorders. Whether TDP-43 neurotoxicity is caused by a novel toxic gain-of-function mechanism of the aggregates or by a loss of its normal function is unknown. We increased and decreased expression of TDP-43 (dTDP-43) in Drosophila. Although upregulation of dTDP-43 induced neuronal ubiquitin and dTDP-43-positive inclusions, both up- and downregulated dTDP-43 resulted in selective apoptosis of bursicon neurons and highly similar transcriptome alterations at the pupal-adult transition. Gene network analysis and genetic validation showed that both up- and downregulated dTDP-43 directly and dramatically increased the expression of the neuronal microtubule-associated protein Map205, resulting in cytoplasmic accumulations of the ecdysteroid receptor (EcR) and a failure to switch EcR-dependent gene programs from a pupal to adult pattern. We propose that dTDP-43 neurotoxicity is caused by a loss of its normal function.

  17. Regulatory switch enforced by basic helix-loop-helix and ACT-domain mediated dimerizations of the maize transcription factor R.

    PubMed

    Kong, Que; Pattanaik, Sitakanta; Feller, Antje; Werkman, Joshua R; Chai, Chenglin; Wang, Yongqin; Grotewold, Erich; Yuan, Ling

    2012-07-24

    The maize R2R3-MYB regulator C1 cooperates with the basic helix-loop-helix (bHLH) factor R to activate the expression of anthocyanin biosynthetic genes coordinately. As is the case for other bHLH factors, R harbors several protein-protein interaction domains. Here we show that not the classical but rather a briefly extended R bHLH region forms homodimers that bind canonical G-box DNA motifs. This bHLH DNA-binding activity is abolished if the C-terminal ACT (aspartokinase, chorismate, and TyrA) domain is licensed to homodimerize. Then the bHLH remains in the monomeric form, allowing it to interact with R-interacting factor 1 (RIF1). In this configuration, the R-RIF1 complex is recruited to the promoters of a subset of anthocyanin biosynthetic genes, such as A1, through the interaction with its MYB partner C1. If, however, the ACT domain remains monomeric, the bHLH region dimerizes and binds to G-boxes present in several anthocyanin genes, such as Bz1. Our results provide a mechanism by which a dimerization domain in a bHLH factor behaves as a switch that permits distinct configurations of a regulatory complex to be tethered to different promoters. Such a combinatorial gene regulatory framework provides one mechanism by which genes lacking obviously conserved cis-regulatory elements are regulated coordinately.

  18. Heat shock protein 90-mediated inactivation of nuclear factor-κB switches autophagy to apoptosis through becn1 transcriptional inhibition in selenite-induced NB4 cells.

    PubMed

    Jiang, Qian; Wang, Yuhan; Li, Tianjiao; Shi, Kejian; Li, Zhushi; Ma, Yushi; Li, Feng; Luo, Hui; Yang, Yang; Xu, Caimin

    2011-04-15

    Autophagy can protect cells while also contributing to cell damage, but the precise interplay between apoptosis and autophagy and the contribution of autophagy to cell death are still not clear. Previous studies have shown that supranutritional doses of sodium selenite promote apoptosis in human leukemia NB4 cells. Here, we report that selenite treatment triggers opposite patterns of autophagy in the NB4, HL60, and Jurkat leukemia cell lines during apoptosis and provide evidence that the suppressive effect of selenite on autophagy in NB4 cells is due to the decreased expression of the chaperone protein Hsp90 (heat shock protein 90), suggesting a novel regulatory function of Hsp90 in apoptosis and autophagy. Excessive or insufficient expression indicates that Hsp90 protects NB4 cells from selenite-induced apoptosis, and selenite-induced decreases in the expression of Hsp90, especially in NB4 cells, inhibit the activities of the IκB kinase/nuclear factor-κB (IKK/NF-κB) signaling pathway, leading to less nuclear translocation and inactivation of NF-κB and the subsequent weak binding of the becn1 promoter, which facilitates the transition from autophagy to apoptosis. Taken together, our observations provide novel insights into the mechanisms underlying the balance between apoptosis and autophagy, and we also identified Hsp90-NF-κB-Beclin1 as a potential biological pathway for signaling the switch from autophagy to apoptosis in selenite-treated NB4 cells.

  19. The preparation effect in task switching: carryover of SOA.

    PubMed

    Altmann, Erik M

    2004-01-01

    A common finding in task-switching studies is switch preparation (commonly known as the preparation effect), in which a longer interval between task cue and trial stimulus (i.e., a longer stimulus onset asynchrony, or SOA) reduces the cost of switching to a different task. Three experiments link switch preparation to within-subjects manipulations of SOA. In Experiment 1, SOA was randomized within subjects, producing switch preparation that was more pronounced when the SOA switched from the previous trial than when the SOA repeated. In Experiment 2, SOA was blocked within subjects, producing switch preparation but not on the first block of trials. In Experiment 3, SOA was manipulated between subjects with sufficient statistical power to detect switch preparation, but the effect was absent. The results favor an encoding view of cognitive control, but show that any putative switching mechanism reacts lazily when exposed to only one SOA.

  20. The Brassinosteroid-Activated BRI1 Receptor Kinase Is Switched off by Dephosphorylation Mediated by Cytoplasm-Localized PP2A B' Subunits.

    PubMed

    Wang, Ruiju; Liu, Mengmeng; Yuan, Min; Oses-Prieto, Juan A; Cai, Xingbo; Sun, Ying; Burlingame, Alma L; Wang, Zhi-Yong; Tang, Wenqiang

    2016-01-04

    Brassinosteroid (BR) binding activates the receptor kinase BRI1 by inducing heterodimerization with its co-receptor kinase BAK1; however, the mechanisms that reversibly inactivate BRI1 remain unclear. Here we show that cytoplasm-localized protein phosphatase 2A (PP2A) B' regulatory subunits interact with BRI1 to mediate its dephosphorylation and inactivation. Loss-of-function and overexpression experiments showed that a group of PP2A B' regulatory subunits, represented by B'η, negatively regulate BR signaling by decreasing BRI1 phosphorylation. BR increases the expression levels of these B' subunits, and B'η interacts preferentially with phosphorylated BRI1, suggesting that the dynamics of BR signaling are modulated by the PP2A-mediated feedback inactivation of BRI1. Compared with PP2A B'α and B'β, which promote BR responses by dephosphorylating the downstream transcription factor BZR1, the BRI1-inactivating B' subunits showed similar binding to BRI1 and BZR1 but distinct subcellular localization. Alteration of the nuclear/cytoplasmic localization of the B' subunits revealed that cytoplasmic PP2A dephosphorylates BRI1 and inhibits the BR response, whereas nuclear PP2A dephosphorylates BZR1 and activates the BR response. Our findings not only identify the PP2A regulatory B subunits that mediate the binding and dephosphorylation of BRI1, but also demonstrate that the subcellular localization of PP2A specifies its substrate selection and distinct effects on BR signaling.

  1. Coupling switch of P2Y-IP3 receptors mediates differential Ca(2+) signaling in human embryonic stem cells and derived cardiovascular progenitor cells.

    PubMed

    Huang, Jijun; Zhang, Min; Zhang, Peng; Liang, He; Ouyang, Kunfu; Yang, Huang-Tian

    2016-09-01

    Purinergic signaling mediated by P2 receptors (P2Rs) plays important roles in embryonic and stem cell development. However, how it mediates Ca(2+) signals in human embryonic stem cells (hESCs) and derived cardiovascular progenitor cells (CVPCs) remains unclear. Here, we aimed to determine the role of P2Rs in mediating Ca(2+) mobilizations of these cells. hESCs were induced to differentiate into CVPCs by our recently established methods. Gene expression of P2Rs and inositol 1,4,5-trisphosphate receptors (IP3Rs) was analyzed by quantitative/RT-PCR. IP3R3 knockdown (KD) or IP3R2 knockout (KO) hESCs were established by shRNA- or TALEN-mediated gene manipulations, respectively. Confocal imaging revealed that Ca(2+) responses in CVPCs to ATP and UTP were more sensitive and stronger than those in hESCs. Consistently, the gene expression levels of most P2YRs except P2Y1 were increased in CVPCs. Suramin or PPADS blocked ATP-induced Ca(2+) transients in hESCs but only partially inhibited those in CVPCs. Moreover, the P2Y1 receptor-specific antagonist MRS2279 abolished most ATP-induced Ca(2+) signals in hESCs but not in CVPCs. P2Y1 receptor-specific agonist MRS2365 induced Ca(2+) transients only in hESCs but not in CVPCs. Furthermore, IP3R2KO but not IP3R3KD decreased the proportion of hESCs responding to MRS2365. In contrast, both IP3R2 and IP3R3 contributed to UTP-induced Ca(2+) responses while ATP-induced Ca(2+) responses were more dependent on IP3R2 in the CVPCs. In conclusion, a predominant role of P2Y1 receptors in hESCs and a transition of P2Y-IP3R coupling in derived CVPCs are responsible for the differential Ca(2+) mobilization between these cells.

  2. Bilingual Language Switching and the Frontal Lobes: Modulatory Control in Language Selection.

    ERIC Educational Resources Information Center

    Meuter, Renata; Humphreys, Glyn; Rumiati, Raffaella

    2002-01-01

    Discusses the brain mechanisms mediating the switching of languages in bilingual subjects. To ascertain the brain mechanisms mediating the control of language switching, switching was examined in a bilingual patient with frontal lobe damage and impaired control processes. (Author/VWL)

  3. Bilingual Language Switching and the Frontal Lobes: Modulatory Control in Language Selection.

    ERIC Educational Resources Information Center

    Meuter, Renata; Humphreys, Glyn; Rumiati, Raffaella

    2002-01-01

    Discusses the brain mechanisms mediating the switching of languages in bilingual subjects. To ascertain the brain mechanisms mediating the control of language switching, switching was examined in a bilingual patient with frontal lobe damage and impaired control processes. (Author/VWL)

  4. Switch Transcripts in Immunoglobulin Class Switching

    NASA Astrophysics Data System (ADS)

    Lorenz, Matthias; Jung, Steffen; Radbruch, Andreas

    1995-03-01

    B cells can exchange gene segments for the constant region of the immunoglobulin heavy chain, altering the class and effector function of the antibodies that they produce. Class switching is directed to distinct classes by cytokines, which induce transcription of the targeted DNA sequences. These transcripts are processed, resulting in spliced "switch" transcripts. Switch recombination can be directed to immunoglobulin G1 (IgG1) by the heterologous human metallothionein II_A promoter in mutant mice. Induction of the structurally conserved, spliced switch transcripts is sufficient to target switch recombination to IgG1, whereas transcription alone is not.

  5. Examination of mid-intervention mediating effects on objectively assessed sedentary time among children in the Transform-Us! cluster-randomized controlled trial

    PubMed Central

    2013-01-01

    Background The optimal targets and strategies for effectively reducing sedentary behavior among young people are unknown. Intervention research that explores changes in mediated effects as well as in outcome behaviors is needed to help inform more effective interventions. Therefore, the purpose of this study was to examine the mid-intervention mediating effects on children’s objectively assessed classroom and total weekday sedentary time in the Transform-Us! intervention. Methods The results are based on 293 children, aged 7- to 9-years-old at baseline, from 20 schools in Melbourne, Australia. Each school was randomly allocated to one of four groups, which targeted reducing sedentary time in the school and family settings (SB; n = 74), increasing or maintaining moderate- to vigorous-intensity physical activity in the school and family settings (PA; n = 75), combined SB and PA (SB + PA; n = 80), or the current practice control (C; n = 64). Baseline and mid-intervention data (5–9 months) were collected in 2010 and analyzed in 2012. Classroom and total weekday sedentary time was objectively assessed using ActiGraph accelerometers. The hypothesized mediators including, child enjoyment, parent and teacher outcome expectancies, and child perceived access to standing opportunities in the classroom environment, were assessed by questionnaire. Results The SB + PA group spent 13.3 min/day less in weekday sedentary time at mid-intervention compared to the control group. At mid-intervention, children in the SB group had higher enjoyment of standing in class (0.9 units; 5-unit scale) and all intervention groups had more positive perceptions of access to standing opportunities in the classroom environment (0.3-0.4 units; 3-unit scale), compared to the control group. However, none of the hypothesized mediator variables had an effect on sedentary time; thus, no mediating effects were observed. Conclusions While beneficial intervention effects were

  6. N-Glycosylation of integrin α5 acts as a switch for EGFR-mediated complex formation of integrin α5β1 to α6β4

    PubMed Central

    Hang, Qinglei; Isaji, Tomoya; Hou, Sicong; Zhou, Ying; Fukuda, Tomohiko; Gu, Jianguo

    2016-01-01

    N-Glycosylation of integrin α5β1 is involved in multiple cell behaviors. We previously reported that the N-glycosylations of the calf domain on integrin α5 (S3–5,10–14) are essential for its inhibitory effect on EGFR signaling in regulating cell proliferation. However, the importance of the individual N-glycosylation and the underlying mechanisms of inhibition remain unclear. Here, we characterize the S3–5,10–14 mutants in detail and found that the N-glycosylation of site-11 (Asn712) is key for cell growth. The restoration of site-11, unlike the other individual sites, significantly suppressed cell growth and EGFR signaling in a manner that was similar to that of wild-type (WT). Mechanistically, this N-glycosylation inhibited the response abilities upon EGF stimulation and EGFR dimerization. Interestingly, we found this N-glycosylation controlled the EGFR complex formation with integrin α5β1 or α6β4; i.e., the loss of site-11 switched EGFR-α5β1 to EGFR-α6β4, which is well known to promote cellular signaling for cell growth. Moreover, the site-11 N-glycan exhibited a more branching structure compared with other sites, which may be required for EGFR-α5β1 formation. Taken together, these data clearly demonstrate that the site-11 N-glycosylation on α5 is most important for its inhibitory effect on EGFR signaling, which may provide a novel regulatory mechanism for crosstalks between integrins and EGFR. PMID:27641064

  7. Integrative genomic analysis of CREB defines a critical role for transcription factor networks in mediating the fed/fasted switch in liver

    PubMed Central

    2013-01-01

    Background Metabolic homeostasis in mammals critically depends on the regulation of fasting-induced genes by CREB in the liver. Previous genome-wide analysis has shown that only a small percentage of CREB target genes are induced in response to fasting-associated signaling pathways. The precise molecular mechanisms by which CREB specifically targets these genes in response to alternating hormonal cues remain to be elucidated. Results We performed chromatin immunoprecipitation coupled to high-throughput sequencing of CREB in livers from both fasted and re-fed mice. In order to quantitatively compare the extent of CREB-DNA interactions genome-wide between these two physiological conditions we developed a novel, robust analysis method, termed the ‘single sample independence’ (SSI) test that greatly reduced the number of false-positive peaks. We found that CREB remains constitutively bound to its target genes in the liver regardless of the metabolic state. Integration of the CREB cistrome with expression microarrays of fasted and re-fed mouse livers and ChIP-seq data for additional transcription factors revealed that the gene expression switches between the two metabolic states are associated with co-localization of additional transcription factors at CREB sites. Conclusions Our results support a model in which CREB is constitutively bound to thousands of target genes, and combinatorial interactions between DNA-binding factors are necessary to achieve the specific transcriptional response of the liver to fasting. Furthermore, our genome-wide analysis identifies thousands of novel CREB target genes in liver, and suggests a previously unknown role for CREB in regulating ER stress genes in response to nutrient influx. PMID:23682854

  8. Induction of apoptosis after switch-on of the hepatitis B virus X gene mediated by the Cre/loxP recombination system.

    PubMed

    Shintani, Y; Yotsuyanagi, H; Moriya, K; Fujie, H; Tsutsumi, T; Kanegae, Y; Kimura, S; Saito, I; Koike, K

    1999-12-01

    The HBx protein of hepatitis B virus is a multifunctional protein that is implicated in the pathogenesis of hepatocellular carcinoma by regulating gene transcription, causing cell proliferation and, as shown recently, inducing cell death. However, analysis of the effects of HBx in stable cultured cell clones has been hampered because only cell lines that adapted to the effects of HBx were selected during the establishment of cell clones. Here, we describe a system in which transcription of the X gene of hepatitis B virus is switched on by the use of the site-specific Cre recombinase. Two human liver cell lines, HLF and HepG2, were used, the former with a mutant p53 allele and the latter with wild-type p53. The stable cell clones isolated, which carried the X gene in a transcriptionally silent state, were infected with recombinant adenovirus carrying Cre recombinase. Ninety-six hours after adenovirus infection, cell clones that expressed HBx had undergone TUNEL-positive cell death with characteristics of apoptosis. Apoptosis was induced despite concomitant inactivation of the p53 protein as a result of its cytoplasmic translocation by HBx. In contrast, neither the X gene-carrying cells infected with wild-type adenovirus nor various control cells infected with Cre-expressing adenovirus exhibited apoptosis. These results indicate that the expression of HBx protein leads to liver cell apoptosis independently of the p53 pathway. The significance of HBx-induced apoptosis in natural infection is unclear, but it may contribute to the development of hepatitis and serve to spread progeny virus to neighbouring cells while evading the host immune responses.

  9. Gold nanoclusters as switch-off fluorescent probe for detection of uric acid based on the inner filter effect of hydrogen peroxide-mediated enlargement of gold nanoparticles.

    PubMed

    Liu, Yanyan; Li, Hongchang; Guo, Bin; Wei, Lijuan; Chen, Bo; Zhang, Youyu

    2017-05-15

    Herein we report a novel switch-off fluorescent probe for highly selective determination of uric acid (UA) based on the inner filter effect (IFE), by using poly-(vinylpyrrolidone)-protected gold nanoparticles (PVP-AuNPs) and chondroitin sulfate-stabilized gold nanoclusters (CS-AuNCs) as the IFE absorber/fluorophore pair. In this IFE-based fluorometric assay, the newly designed CS-AuNCs were explored as an original fluorophore and the hydrogen peroxide (H2O2) -driven formed PVP-AuNPs can be a powerful absorber to influence the excitation of the fluorophore, due to the complementary overlap between the absorption band of PVP-AuNPs and the emission band of CS-AuNCs. Under the optimized conditions, the extent of the signal quenching depends linearly on the H2O2 concentration in the range of 1-100μM (R(2) =0.995) with a detection limit down to 0.3μM. Based on the H2O2-dependent fluorescence IFE principle, we further developed a new assay strategy to enable selective sensing of UA by using a specific uricase-catalyzed UA oxidation as the in situ H2O2 generator. The proposed uricase-linked IFE-based assay exhibited excellent analytical performance for measuring UA over the concentration ranging from 5 to 100μM (R(2)=0.991), and can be successfully applied to detection of UA as low as 1.7μM (3σ) in diluted human serum samples.

  10. The PPAR α / γ Agonist, Tesaglitazar, Improves Insulin Mediated Switching of Tissue Glucose and Free Fatty Acid Utilization In Vivo in the Obese Zucker Rat.

    PubMed

    Wallenius, Kristina; Kjellstedt, Ann; Thalén, Pia; Löfgren, Lars; Oakes, Nicholas D

    2013-01-01

    lean controls, obese controls, and obese rats treated with the dual peroxisome proliferator activated receptor (PPAR) α/γ agonist, tesaglitazar, 3  μ mol/kg/day for 3 weeks. Whole body glucose disposal rate (R d ) and hepatic glucose output (HGO) were assessed under basal fasting and hyperinsulinemic isoglycemic clamp conditions using [3,(3)H]glucose. Indices of tissue specific glucose utilization (R g ') were measured at basal, physiological, and supraphysiological levels of insulinemia using 2-deoxy-D-[2,6-(3)H]glucose. Finally, whole body and tissue specific FFA and glucose utilization and metabolic fate were evaluated under basal and hyperinsulinemic conditions using a combination of [U-(13)C]glucose, 2-deoxy-D-[U-(14)C]glucose, [U-(14)C]palmitate, and [9,10-(3)H]-(R)-bromopalmitate. Tesaglitazar improved whole body insulin action by greater suppression of HGO and stimulation of R d compared to obese controls. This involved increased insulin stimulation of R g ' in fat and skeletal muscle as well as increased glycogen synthesis. Tesaglitazar dramatically improved insulin mediated suppression of plasma FFA level, whole body turnover (R fa ), and muscle, liver, and fat utilization. At basal insulin levels, tesaglitazar failed to lower HGO or R fa compared to obese controls. In conclusion, the results demonstrate that tesaglitazar has a remarkable ability to improve insulin mediated control of glucose and FFA fluxes in obese Zucker rats.

  11. The PPARα/γ Agonist, Tesaglitazar, Improves Insulin Mediated Switching of Tissue Glucose and Free Fatty Acid Utilization In Vivo in the Obese Zucker Rat

    PubMed Central

    Wallenius, Kristina; Kjellstedt, Ann; Thalén, Pia; Löfgren, Lars; Oakes, Nicholas D.

    2013-01-01

    Metabolic flexibility was assessed in male Zucker rats: lean controls, obese controls, and obese rats treated with the dual peroxisome proliferator activated receptor (PPAR) α/γ agonist, tesaglitazar, 3 μmol/kg/day for 3 weeks. Whole body glucose disposal rate (R d) and hepatic glucose output (HGO) were assessed under basal fasting and hyperinsulinemic isoglycemic clamp conditions using [3,3H]glucose. Indices of tissue specific glucose utilization (R g′) were measured at basal, physiological, and supraphysiological levels of insulinemia using 2-deoxy-D-[2,6-3H]glucose. Finally, whole body and tissue specific FFA and glucose utilization and metabolic fate were evaluated under basal and hyperinsulinemic conditions using a combination of [U-13C]glucose, 2-deoxy-D-[U-14C]glucose, [U-14C]palmitate, and [9,10-3H]-(R)-bromopalmitate. Tesaglitazar improved whole body insulin action by greater suppression of HGO and stimulation of R d compared to obese controls. This involved increased insulin stimulation of R g′ in fat and skeletal muscle as well as increased glycogen synthesis. Tesaglitazar dramatically improved insulin mediated suppression of plasma FFA level, whole body turnover (R fa), and muscle, liver, and fat utilization. At basal insulin levels, tesaglitazar failed to lower HGO or R fa compared to obese controls. In conclusion, the results demonstrate that tesaglitazar has a remarkable ability to improve insulin mediated control of glucose and FFA fluxes in obese Zucker rats. PMID:24285952

  12. A BTLA-mediated bait-and-switch strategy permits Listeria expansion in CD8α+ DCs to promote long term T cell responses

    PubMed Central

    Yang, Xuanming; Zhang, Xunmin; Sun, Yonglian; Tu, Tony; Fu, May Lynne; Miller, Mendy; Fu, Yang-Xin

    2014-01-01

    SUMMARY Listeria monocytogenes infected CD8α+ DCs in the spleen are essential for CD8+ T cell generation. CD8α+ DCs are also necessary for Listeria expansion and dissemination within the host. The mechanisms that regulate CD8α+ DCs to allow Listeria expansion are unclear. We find that activating the B and T lymphocyte attenuator (BTLA), a co-inhibitory receptor on CD8α+ DCs, suppresses, while blocking BTLA enhances both the primary and memory CD8 T cell responses against Listeria. Btla−/− mice have lower effector and memory CD8+ T cells while paradoxically also being more resistant to Listeria. Although bacterial entry into Btla−/− CD8α+ DCs is unaffected, Listeria fails to expand within these cells. BTLA signaling limits Fas/FasL-mediated suppression of Listeria expansion within CD8α+ DCs to more effectively alert adaptive immune cells. This study uncovers a BTLA-mediated strategy used by the host that permits Listeria proliferation to enable increasing T cell responses for long-term protection. PMID:25011109

  13. Pacemaker therapy in patients with neurally mediated syncope and documented asystole: Third International Study on Syncope of Uncertain Etiology (ISSUE-3): a randomized trial.

    PubMed

    Brignole, Michele; Menozzi, Carlo; Moya, Angel; Andresen, Dietrich; Blanc, Jean Jacques; Krahn, Andrew D; Wieling, Wouter; Beiras, Xulio; Deharo, Jean Claude; Russo, Vitantonio; Tomaino, Marco; Sutton, Richard

    2012-05-29

    The efficacy of cardiac pacing for prevention of syncopal recurrences in patients with neurally mediated syncope is controversial. We wanted to determine whether pacing therapy reduces syncopal recurrences in patients with severe asystolic neurally mediated syncope. Double-blind, randomized placebo-controlled study conducted in 29 centers in the Third International Study on Syncope of Uncertain Etiology (ISSUE-3) trial. Patients were ≥40 years, had experienced ≥3 syncopal episodes in the previous 2 years. Initially, 511 patients, received an implantable loop recorder; 89 of these had documentation of syncope with ≥3 s asystole or ≥6 s asystole without syncope within 12 ± 10 months and met criteria for pacemaker implantation; 77 of 89 patients were randomly assigned to dual-chamber pacing with rate drop response or to sensing only. The data were analyzed on intention-to-treat principle. There was syncope recurrence during follow-up in 27 patients, 19 of whom had been assigned to pacemaker OFF and 8 to pacemaker ON. The 2-year estimated syncope recurrence rate was 57% (95% CI, 40-74) with pacemaker OFF and 25% (95% CI, 13-45) with pacemaker ON (log rank: P=0.039 at the threshold of statistical significance of 0.04). The risk of recurrence was reduced by 57% (95% CI, 4-81). Five patients had procedural complications: lead dislodgment in 4 requiring correction and subclavian vein thrombosis in 1 patient. Dual-chamber permanent pacing is effective in reducing recurrence of syncope in patients ≥40 years with severe asystolic neurally mediated syncope. The observed 32% absolute and 57% relative reduction in syncope recurrence support this invasive treatment for the relatively benign neurally mediated syncope. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00359203.

  14. Defect-mediated relaxation in the random tiling phase of a binary mixture: Birth, death and mobility of an atomic zipper

    NASA Astrophysics Data System (ADS)

    Tondl, Elisabeth; Ramsay, Malcolm; Harrowell, Peter; Widmer-Cooper, Asaph

    2014-03-01

    This paper describes the mechanism of defect-mediated relaxation in a dodecagonal square-triangle random tiling phase exhibited by a simulated binary mixture of soft discs in 2D. We examine the internal transitions within the elementary mobile defect (christened the "zipper") that allow it to move, as well as the mechanisms by which the zipper is created and annihilated. The structural relaxation of the random tiling phase is quantified and we show that this relaxation is well described by a model based on the distribution of waiting times for each atom to be visited by the diffusing zipper. This system, representing one of the few instances where a well defined mobile defect is capable of structural relaxation, can provide a valuable test case for general theories of relaxation in complex and disordered materials.

  15. Defect-mediated relaxation in the random tiling phase of a binary mixture: Birth, death and mobility of an atomic zipper

    SciTech Connect

    Tondl, Elisabeth; Ramsay, Malcolm; Harrowell, Peter; Widmer-Cooper, Asaph

    2014-03-14

    This paper describes the mechanism of defect-mediated relaxation in a dodecagonal square-triangle random tiling phase exhibited by a simulated binary mixture of soft discs in 2D. We examine the internal transitions within the elementary mobile defect (christened the “zipper”) that allow it to move, as well as the mechanisms by which the zipper is created and annihilated. The structural relaxation of the random tiling phase is quantified and we show that this relaxation is well described by a model based on the distribution of waiting times for each atom to be visited by the diffusing zipper. This system, representing one of the few instances where a well defined mobile defect is capable of structural relaxation, can provide a valuable test case for general theories of relaxation in complex and disordered materials.

  16. A Parent-Mediated Intervention That Targets Responsive Parental Behaviors Increases Attachment Behaviors in Children with ASD: Results from a Randomized Clinical Trial

    PubMed Central

    Swanson, Meghan; Gerber, Alan; Hutman, Ted; Sigman, Marian

    2015-01-01

    The current study is a randomized clinical trial evaluating the efficacy of Focused Playtime Intervention (FPI) in a sample of 70 children with Autism Spectrum Disorder. This parent-mediated intervention has previously been shown to significantly increase responsive parental communication (Siller et al. in J Autism Dev Disord 43:540–555, 2013a). The current analyses focus on children’s attachment related outcomes. Results revealed that children who were randomly assigned to FPI showed bigger increases in attachment-related behaviors, compared to children assigned to the control condition. Significant treatment effects of FPI were found for both an observational measure of attachment-related behaviors elicited during a brief separation-reunion episode and a questionnaire measure evaluating parental perceptions of child attachment. The theoretical and clinical implications of these findings are discussed. PMID:24488157

  17. Latching relay switch assembly

    DOEpatents

    Duimstra, Frederick A.

    1991-01-01

    A latching relay switch assembly which includes a coil section and a switch or contact section. The coil section includes at least one permanent magnet and at least one electromagnet. The respective sections are, generally, arranged in separate locations or cavities in the assembly. The switch is latched by a permanent magnet assembly and selectively switched by an overriding electromagnetic assembly.

  18. Hypoxia induces a phenotypic switch of fibroblasts to myofibroblasts through a MMP-2/TIMP mediated pathway: Implications for venous neointimal hyperplasia in hemodialysis access

    PubMed Central

    Misra, Sanjay; Fu, Alex A.; Misra, Khamal D.; Shergill, Uday M.; Leof, Edward B; Mukhopadhyay, Debabrata

    2010-01-01

    Purpose Hemodialysis grafts fail because of venous neointimal hyperplasia formation caused by adventitial fibroblasts which have become myofibroblasts (α-smooth muscle actin positive cells) and migrate to the neointima. There is increased expression of hypoxia inducible factor-1 alpha (HIF-1α in venous neointimal hyperplasia formation in experimental animal model and clinical samples. We hypothesized that under hypoxic stimulus (HIF-1α fibroblasts will convert to myofibroblasts through a matrix metalloproteinase-2 (MMP-2) mediated pathway. Materials and methods Murine AKR-2B fibroblasts were made hypoxic or normoxic for 24, 48, and 72 hours. Protein expression for HIF-1α, α-smooth muscle actin, MMP-2, MMP-9, TIMP-1, and TIMP-2 was performed to determine the kinetic changes of these proteins. Immunostaining for α-smooth muscle actin, collagen, and fibronectin was performed. Results At all time points, there was significantly increased expression of HIF-1α in the hypoxic fibroblasts when compared to normoxic fibroblasts (P<0.05). There was significantly increased expression α-smooth muscle actin at all time points which peaked by 48 hours in hypoxic fibroblasts when compared to normoxic fibroblasts (P<0.05). There was a significant increase in the expression of active MMP-2 by 48-72 hours and a significant increase in tissue inhibitor of metalloproteinase-1 (TIMP-1) by 48-72 hours by hypoxic fibroblasts (P<0.05). By 72 hours, there was significant increase in TIMP-2 expression (P<0.05). Immunohistochemical analysis demonstrated increased expression for α-smooth muscle actin, collagen, and fibronectin as the length of hypoxia increased. Conclusions Under hypoxia, fibroblasts will convert to myofibroblasts through a MMP-2 mediated pathway which may provide insight into the mechanism of venous neointimal hyperplasia. PMID:20434368

  19. The Minimum Requirements of Language Control: Evidence from Sequential Predictability Effects in Language Switching

    ERIC Educational Resources Information Center

    Declerck, Mathieu; Koch, Iring; Philipp, Andrea M.

    2015-01-01

    The current study systematically examined the influence of sequential predictability of languages and concepts on language switching. To this end, 2 language switching paradigms were combined. To measure language switching with a random sequence of languages and/or concepts, we used a language switching paradigm that implements visual cues and…

  20. The Minimum Requirements of Language Control: Evidence from Sequential Predictability Effects in Language Switching

    ERIC Educational Resources Information Center

    Declerck, Mathieu; Koch, Iring; Philipp, Andrea M.

    2015-01-01

    The current study systematically examined the influence of sequential predictability of languages and concepts on language switching. To this end, 2 language switching paradigms were combined. To measure language switching with a random sequence of languages and/or concepts, we used a language switching paradigm that implements visual cues and…

  1. Self-Induced Switchings between Multiple Space-Time Patterns on Complex Networks of Excitable Units

    NASA Astrophysics Data System (ADS)

    Ansmann, Gerrit; Lehnertz, Klaus; Feudel, Ulrike

    2016-01-01

    We report on self-induced switchings between multiple distinct space-time patterns in the dynamics of a spatially extended excitable system. These switchings between low-amplitude oscillations, nonlinear waves, and extreme events strongly resemble a random process, although the system is deterministic. We show that a chaotic saddle—which contains all the patterns as well as channel-like structures that mediate the transitions between them—is the backbone of such a pattern-switching dynamics. Our analyses indicate that essential ingredients for the observed phenomena are that the system behaves like an inhomogeneous oscillatory medium that is capable of self-generating spatially localized excitations and that is dominated by short-range connections but also features long-range connections. With our findings, we present an alternative to the well-known ways to obtain self-induced pattern switching, namely, noise-induced attractor hopping, heteroclinic orbits, and adaptation to an external signal. This alternative way can be expected to improve our understanding of pattern switchings in spatially extended natural dynamical systems like the brain and the heart.

  2. Radiation hard vacuum switch

    DOEpatents

    Boettcher, Gordon E.

    1990-03-06

    A vacuum switch with an isolated trigger probe which is not directly connected to the switching electrodes. The vacuum switch within the plasmatron is triggered by plasma expansion initiated by the trigger probe which travels through an opening to reach the vacuum switch elements. The plasma arc created is directed by the opening to the space between the anode and cathode of the vacuum switch to cause conduction.

  3. Radiation hard vacuum switch

    DOEpatents

    Boettcher, Gordon E.

    1990-01-01

    A vacuum switch with an isolated trigger probe which is not directly connected to the switching electrodes. The vacuum switch within the plasmatron is triggered by plasma expansion initiated by the trigger probe which travels through an opening to reach the vacuum switch elements. The plasma arc created is directed by the opening to the space between the anode and cathode of the vacuum switch to cause conduction.

  4. Impaired 53BP1/RIF1 DSB mediated end-protection stimulates CtIP-dependent end resection and switches the repair to PARP1-dependent end joining in G1

    PubMed Central

    Bakr, Ali; Köcher, Sabrina; Volquardsen, Jennifer; Petersen, Cordula; Borgmann, Kerstin; Dikomey, Ekkehard; Rothkamm, Kai; Mansour, Wael Y.

    2016-01-01

    End processing at DNA double strand breaks (DSB) is a decisive step in repair pathway selection. Here, we investigated the role of 53BP1/RIF1 in limiting BRCA1/CtIP-mediated end resection to control DSB repair pathway choice. ATM orchestrates this process through 53BP1 phosphorylation to promote RIF1 recruitment. As cells enter S/G2-phase, end resection is activated, which displaces pATM from DSB sites and diminishes 53BP1 phosphorylation and RIF1 recruitment. Consistently, the kinetics of ATM and 53BP1 phosphorylation in S/G2-phase concur. We show that defective 53BP1/RIF1-mediated DSB end-protection in G1-phase stimulates CtIP/MRE11-dependent end-resection, which requires Polo-like kinase 3. This end resection activity in G1 was shown to produce only short tracks of ssDNA overhangs, as evidenced by the findings that in 53BP1 depleted cells, (i) RPA focus intensity was significantly lower in G1 compared to that in S/G2 phase, and (ii) EXO1 knockdown did not alter either number or intensity of RPA foci in G1 but significantly decreased the RPA focus intensity in S/G2 phase. Importantly, we report that the observed DSB end resection in G1 phase inhibits DNA-PK-dependent nonhomologous end joining but is not sufficient to stimulate HR. Instead, it switches the repair to the alternative PARP1-dependent end joining pathway. PMID:27494840

  5. Impaired 53BP1/RIF1 DSB mediated end-protection stimulates CtIP-dependent end resection and switches the repair to PARP1-dependent end joining in G1.

    PubMed

    Bakr, Ali; Köcher, Sabrina; Volquardsen, Jennifer; Petersen, Cordula; Borgmann, Kerstin; Dikomey, Ekkehard; Rothkamm, Kai; Mansour, Wael Y

    2016-09-06

    End processing at DNA double strand breaks (DSB) is a decisive step in repair pathway selection. Here, we investigated the role of 53BP1/RIF1 in limiting BRCA1/CtIP-mediated end resection to control DSB repair pathway choice. ATM orchestrates this process through 53BP1 phosphorylation to promote RIF1 recruitment. As cells enter S/G2-phase, end resection is activated, which displaces pATM from DSB sites and diminishes 53BP1 phosphorylation and RIF1 recruitment. Consistently, the kinetics of ATM and 53BP1 phosphorylation in S/G2-phase concur. We show that defective 53BP1/RIF1-mediated DSB end-protection in G1-phase stimulates CtIP/MRE11-dependent end-resection, which requires Polo-like kinase 3. This end resection activity in G1 was shown to produce only short tracks of ssDNA overhangs, as evidenced by the findings that in 53BP1 depleted cells, (i) RPA focus intensity was significantly lower in G1 compared to that in S/G2 phase, and (ii) EXO1 knockdown did not alter either number or intensity of RPA foci in G1 but significantly decreased the RPA focus intensity in S/G2 phase. Importantly, we report that the observed DSB end resection in G1 phase inhibits DNA-PK-dependent nonhomologous end joining but is not sufficient to stimulate HR. Instead, it switches the repair to the alternative PARP1-dependent end joining pathway.

  6. Intrinsic noise in systems with switching environments

    NASA Astrophysics Data System (ADS)

    Hufton, Peter G.; Lin, Yen Ting; Galla, Tobias; McKane, Alan J.

    2016-05-01

    We study individual-based dynamics in finite populations, subject to randomly switching environmental conditions. These are inspired by models in which genes transition between on and off states, regulating underlying protein dynamics. Similarly, switches between environmental states are relevant in bacterial populations and in models of epidemic spread. Existing piecewise-deterministic Markov process approaches focus on the deterministic limit of the population dynamics while retaining the randomness of the switching. Here we go beyond this approximation and explicitly include effects of intrinsic stochasticity at the level of the linear-noise approximation. Specifically, we derive the stationary distributions of a number of model systems, in good agreement with simulations. This improves existing approaches which are limited to the regimes of fast and slow switching.

  7. Switch from inhibition to activation of the mitochondrial permeability transition during hematoporphyrin-mediated photooxidative stress. Unmasking pore-regulating external thiols.

    PubMed

    Petronilli, Valeria; Sileikyte, Justina; Zulian, Alessandra; Dabbeni-Sala, Federica; Jori, Giulio; Gobbo, Silvano; Tognon, Giuseppe; Nikolov, Peter; Bernardi, Paolo; Ricchelli, Fernanda

    2009-07-01

    We have studied the mitochondrial permeability transition pore (PTP) under oxidizing conditions with mitochondria-bound hematoporphyrin, which generates reactive oxygen species (mainly singlet oxygen, (1)O(2)) upon UV/visible light-irradiation and promotes the photooxidative modification of vicinal targets. We have characterized the PTP-modulating properties of two major critical sites endowed with different degrees of photosensitivity: (i) the most photovulnerable site comprises critical histidines, whose photomodification by vicinal hematoporphyrin causes a drop in reactivity of matrix-exposed (internal), PTP-regulating cysteines thus stabilizing the pore in a closed conformation; (ii) the most photoresistant site coincides with the binding domains of (external) cysteines sensitive to membrane-impermeant reagents, which are easily unmasked when oxidation of internal cysteines is prevented. Photooxidation of external cysteines promoted by vicinal hematoporphyrin reactivates the PTP after the block caused by histidine photodegradation. Thus, hematoporphyrin-mediated photooxidative stress can either inhibit or activate the mitochondrial permeability transition depending on the site of hematoporphyrin localization and on the nature of the substrate; and selective photomodification of different hematoporphyrin-containing pore domains can be achieved by fine regulation of the sensitizer/light doses. These findings shed new light on PTP modulation by oxidative stress.

  8. Hh-induced Smoothened conformational switch is mediated by differential phosphorylation at its C-terminal tail in a dose- and position-dependent manner.

    PubMed

    Fan, Junkai; Liu, Yajuan; Jia, Jianhang

    2012-06-15

    The activation of Smoothened (Smo) requires phosphorylation at three clusters of Serine residues in Drosophila Hedgehog (Hh) signaling. However, the mechanism by which phosphorylation promotes Smo conformational change and subsequently activates Smo in response to Hh gradient remains unclear. Here, we show that the conformational states of Smo are determined by not only the amount but also the position of the negative charges provided by phosphorylation. By using a Smo phospho-specific antibody, we demonstrate that Smo is differentially phosphorylated at three clusters of serine residues in response to levels of Hh activity. Mutating the first cluster, compared to mutating the other clusters, impairs Smo activity more severely, whereas mutating the last cluster prohibits C-terminus dimerization. In addition, phosphorylation of the membrane proximal cluster promotes phosphorylation of the distal cluster. We propose a zipper-lock model in which the gradual phosphorylation at these clusters induces a gradual conformational change in the Smo cytoplasmic tail, which promotes the interaction between Smo and Costal2 (Cos2). Moreover, we show that Hh regulates both PKA and CK1 phosphorylation of Smo. Thus, the differential phosphorylation of Smo mediates the thresholds of Hh activity.

  9. Quality control of ER synthesized proteins: an exposed thiol group as a three-way switch mediating assembly, retention and degradation.

    PubMed Central

    Fra, A M; Fagioli, C; Finazzi, D; Sitia, R; Alberini, C M

    1993-01-01

    Plasma cells secrete IgM only in the polymeric form: the C-terminal cysteine of the mu heavy chain (Cys575) is responsible for both intracellular retention and assembly of IgM subunits. Polymerization is not quantitative, and part of IgM is degraded intracellularly. Neither chloroquine nor brefeldin A (BFA) inhibits degradation, suggesting that this process occurs in a pre-Golgi compartment. Degradation of IgM assembly intermediates requires Cys575: the monomeric IgMala575 mutant is stable also when endoplasmic reticulum (ER) to Golgi transport is blocked by BFA. Addition of the 20 C-terminal residues of mu to the lysosomal protease cathepsin D is sufficient to induce pre-Golgi retention and degradation of the chimeric protein: the small amounts of molecules which exit from the ER are mostly covalent dimers. By contrast, when retained by the KDEL sequence, cathepsin D is stable in the ER, indicating that retention is not sufficient to cause degradation. Replacing the C-terminal cysteine with serine restores transport through the Golgi. As all chimeric cathepsin D constructs display comparable protease activity in vitro, their different fates are not determined by gross alterations in folding. Thus, also out of its normal context, the mu chain Cys575 plays a crucial role in quality control, mediating assembly, retention and degradation. Images PMID:8223484

  10. The challenges of incorporating random animal-mediated nitrogen transfers in process-based modelling of grazed agricultural systems

    USDA-ARS?s Scientific Manuscript database

    Animals are well known to be important in lateral transfers of nitrogen within the farm boundary. Those transfers can be categorised into those that are: (a) primarily random and small-scale dung and urine patches within a grazed paddock, (b) larger and systematic transfers resulting from preferred...

  11. Randomized Trial of Group Interventions to Reduce HIV/STD Risk and Change Theoretical Mediators among Detained Adolescents

    ERIC Educational Resources Information Center

    Schmiege, Sarah J.; Broaddus, Michelle R.; Levin, Michael; Bryan, Angela D.

    2009-01-01

    Criminally involved adolescents engage in high levels of risky sexual behavior and alcohol use, and alcohol use may contribute to lack of condom use. Detained adolescents (n = 484) were randomized to (1) a theory-based sexual risk reduction intervention (GPI), (2) the GPI condition with a group-based alcohol risk reduction motivational enhancement…

  12. Randomized Trial of Group Interventions to Reduce HIV/STD Risk and Change Theoretical Mediators among Detained Adolescents

    ERIC Educational Resources Information Center

    Schmiege, Sarah J.; Broaddus, Michelle R.; Levin, Michael; Bryan, Angela D.

    2009-01-01

    Criminally involved adolescents engage in high levels of risky sexual behavior and alcohol use, and alcohol use may contribute to lack of condom use. Detained adolescents (n = 484) were randomized to (1) a theory-based sexual risk reduction intervention (GPI), (2) the GPI condition with a group-based alcohol risk reduction motivational enhancement…

  13. Temporal switching jitter in photoconductive switches

    SciTech Connect

    GAUDET,JOHN A.; SKIPPER,MICHAEL C.; ABDALLA,MICHAEL D.; AHERN,SEAN M.; MAR,ALAN; LOUBRIEL,GUILLERMO M.; ZUTAVERN,FRED J.; O'MALLEY,MARTIN W.; HELGESON,WESLEY D.; ROMERO,SAMUEL P.

    2000-04-13

    This paper reports on a recent comparison made between the Air Force Research Laboratory (AFRL) gallium arsenide, optically-triggered switch test configuration and the Sandia National Laboratories (SNL) gallium arsenide, optically-triggered switch test configuration. The purpose of these measurements was to compare the temporal switch jitter times. It is found that the optical trigger laser characteristics are dominant in determining the PCSS jitter.

  14. Exploring Mediators of Physical Activity in Young Adult Cancer Survivors: Evidence from a Randomized Trial of a Facebook-Based Physical Activity Intervention.

    PubMed

    Valle, Carmina G; Tate, Deborah F; Mayer, Deborah K; Allicock, Marlyn; Cai, Jianwen

    2015-03-01

    This study examined the effects of a physical activity (PA) intervention for young adult cancer survivors on changes in self-efficacy, social support, and self-monitoring and determined whether changes in these social cognitive theory constructs mediated the relationship between the intervention and changes in PA. A 12-week randomized trial compared a Facebook-based intervention (FITNET) aimed at increasing moderate-to-vigorous intensity PA to a Facebook-based self-help comparison group. Young adult cancer survivors (N=86, aged 21-39) were randomly assigned to one of the two groups. Self-report measures of PA and psychosocial variables were collected at baseline and after 12 weeks. The FITNET group reported lower self-efficacy for sticking to exercise (mean change=-0.38; 95% CI: -0.62 to -0.12; p=0.025) and social support from friends on social networking websites (mean change=-0.47; 95% CI: -1.45 to 0.65; p=0.039) relative to the self-help comparison group over time. Changes in social support from friends on social networking websites partially mediated the intervention effects on moderate-to-vigorous PA (mean indirect effect=-22.4; 95% CI: -62.0 to -2.8) in the unexpected direction. Across both groups, social support from friends and self-monitoring were positively associated with changes in moderate-to-vigorous PA. The proposed mediators did not explain the positive effects of the FITNET intervention on mild PA. The lack of significant improvements in psychosocial constructs among FITNET participants may partly explain why the intervention did not increase moderate-to-vigorous PA relative to the self-help comparison group. Future PA interventions with young adult cancer survivors should examine targeting social support from friends and self-monitoring.

  15. Neural correlates for task switching in the macaque superior colliculus.

    PubMed

    Chan, Jason L; Koval, Michael J; Johnston, Kevin; Everling, Stefan

    2017-10-01

    Successful task switching requires a network of brain areas to select, maintain, implement, and execute the appropriate task. Although frontoparietal brain areas are thought to play a critical role in task switching by selecting and encoding task rules and exerting top-down control, how brain areas closer to the execution of tasks participate in task switching is unclear. The superior colliculus (SC) integrates information from various brain areas to generate saccades and is likely influenced by task switching. Here, we investigated switch costs in nonhuman primates and their neural correlates in the activity of SC saccade-related neurons in monkeys performing cued, randomly interleaved pro- and anti-saccade trials. We predicted that behavioral switch costs would be associated with differential modulations of SC activity in trials on which the task was switched vs. repeated, with activity on the current trial resembling that associated with the task set of the previous trial when a switch occurred. We observed both error rate and reaction time switch costs and changes in the discharge rate and timing of activity in SC neurons between switch and repeat trials. These changes were present later in the task only after fixation on the cue stimuli but before saccade onset. These results further establish switch costs in macaque monkeys and suggest that SC activity is modulated by task-switching processes in a manner inconsistent with the concept of task set inertia.NEW & NOTEWORTHY Task-switching behavior and superior colliculus (SC) activity were investigated in nonhuman primates performing randomly interleaved pro- and anti-saccade tasks. Here, we report error rate and reaction time switch costs in macaque monkeys and associated differences in stimulus-related activity of saccade-related neurons in the SC. These results provide a neural correlate for task switching and suggest that the SC is modulated by task-switching processes and may reflect the completion of task

  16. Latching micro optical switch

    DOEpatents

    Garcia, Ernest J; Polosky, Marc A

    2013-05-21

    An optical switch reliably maintains its on or off state even when subjected to environments where the switch is bumped or otherwise moved. In addition, the optical switch maintains its on or off state indefinitely without requiring external power. External power is used only to transition the switch from one state to the other. The optical switch is configured with a fixed optical fiber and a movable optical fiber. The movable optical fiber is guided by various actuators in conjunction with a latching mechanism that configure the switch in one position that corresponds to the on state and in another position that corresponds to the off state.

  17. Evidence for a fragile X mental retardation protein-mediated translational switch in metabotropic glutamate receptor-triggered Arc translation and long-term depression.

    PubMed

    Niere, Farr; Wilkerson, Julia R; Huber, Kimberly M

    2012-04-25

    Group 1 metabotropic glutamate receptor (mGluR)-stimulated protein synthesis and long-term synaptic depression (mGluR-LTD) are altered in the mouse model of fragile X syndrome, Fmr1 knock-out (KO) mice. Fmr1 encodes fragile X mental retardation protein (FMRP), a dendritic RNA binding protein that functions, in part, as a translational suppressor. It is unknown whether and how FMRP acutely regulates LTD and/or the rapid synthesis of new proteins required for LTD, such as the activity-regulated cytoskeletal-associated protein (Arc). The protein phosphatase PP2A dephosphorylates FMRP, which contributes to translational activation of some target mRNAs. Here, we report that PP2A and dephosphorylation of FMRP at S500 are required for an mGluR-induced, rapid (5 min) increase in dendritic Arc protein and LTD in rat and mouse hippocampal neurons. In Fmr1 KO neurons, basal, dendritic Arc protein levels and mGluR-LTD are enhanced, but mGluR-triggered Arc synthesis is absent. Lentiviral-mediated expression of wild-type FMRP in Fmr1 KO neurons suppresses basal dendritic Arc levels and mGluR-LTD, and restores rapid mGluR-triggered Arc synthesis. A phosphomimic of FMRP (S500D) suppresses steady-state dendritic Arc levels but does not rescue mGluR-induced Arc synthesis. A dephosphomimic of FMRP (S500A) neither suppresses dendritic Arc nor supports mGluR-induced Arc synthesis. Accordingly, S500D-FMRP expression in Fmr1 KO neurons suppresses mGluR-LTD, whereas S500A-FMRP has no effect. These data support a model in which phosphorylated FMRP functions to suppress steady-state translation of Arc and LTD. Upon mGluR activation of PP2A, FMRP is rapidly dephosphorylated, which contributes to rapid new synthesis of Arc and mGluR-LTD.

  18. Heparin in pregnant women with previous placenta-mediated pregnancy complications: a prospective, randomized, multicenter, controlled clinical trial.

    PubMed

    Martinelli, Ida; Ruggenenti, Piero; Cetin, Irene; Pardi, Giorgio; Perna, Annalisa; Vergani, Patrizia; Acaia, Barbara; Facchinetti, Fabio; La Sala, Giovanni Battista; Bozzo, Maddalena; Rampello, Stefania; Marozio, Luca; Diadei, Olimpia; Gherardi, Giulia; Carminati, Sergio; Remuzzi, Giuseppe; Mannucci, Pier Mannuccio

    2012-04-05

    To assess whether antithrombotic prophylaxis with low-molecular-weight heparin effectively prevents recurrence of late pregnancy complications, 135 women with previous history of preeclampsia, hemolytic anemia, elevated liver enzymes and low platelet count syndrome, intrauterine fetal death, fetal growth restriction, or placental abruption who had been referred within the 12th gestational week were randomized to medical surveillance alone (n = 68) or combined to open-label nadroparin (3800 IU daily subcutaneous injections) treatment (n = 67) in the setting of a randomized, parallel-group, superiority trial, run in Italy from April 2007 to April 2010. Primary outcome was a composite end point of late-pregnancy complications. Analysis was by intention to treat. The study was stopped for futility at the time of the first planned interim analysis. Among the 128 women eventually available for final analyses, 13 of the 63 (21%) randomized to nadroparin compared with 12 of the 65 (18%) on medical surveillance alone progressed to the primary end point. The absolute event risk difference between treatment arms (2.2; -1.6 to 16.0) was not statistically significant (P = .76). Thus, nadroparin did not prevent late-pregnancy complications in women at risk of recurrence. This finding challenges the role of antithrombotic prophylaxis with low-molecular-weight heparin in the prevention of recurrent late pregnancy complications The trial was registered at http://ricerca-clinica.agenziafarmaco.it as EudraCT 2006-004205-26.

  19. A randomized controlled trial of liraglutide versus insulin detemir plus sitagliptin: Effective switch from intensive insulin therapy to the once-daily injection in patients with well-controlled type 2 diabetes.

    PubMed

    Inoue, Yuichiro; Nakamura, Akinobu; Kondo, Yoshinobu; Hamano, Kumiko; Satoh, Shinobu; Terauchi, Yasuo

    2015-07-01

    This study aimed to compare the efficacy and safety of liraglutide versus insulin detemir plus sitagliptin in Japanese patients with type 2 diabetes treated with a basal-bolus insulin regimen. In this multicenter, open-label trial, 90 patients whose diabetes had been controlled well or moderately (glycated hemoglobin [HbA1c ] ≤ 7.3%) with basal-bolus insulin regimen were randomly assigned to a liraglutide group or a detemir group and were followed up for 24 weeks. The primary end point was HbA1c change from baseline to 24 weeks. Of the 90 enrolled patients, 82 completed this trial. At 24 weeks, the mean changes in HbA1c from baseline were 0.1% ± 0.9% versus 0.3% ± 0.8% in the liraglutide versus detemir groups, respectively (P = .46). The "overall" satisfaction score for the Diabetes Treatment Satisfaction Questionnaire changed from 25.2 ± 7.4 to 29.9 ± 5.3 (P < .001) and from 26.4 ± 6.1 to 28.3 ± 6.4 (P = .12) in the liraglutide and detemir groups, respectively. Although the mean change difference in HbA1c between both groups was not significant, switching from a basal-bolus insulin regimen to liraglutide once daily improved patient satisfaction levels without loss of glycemic control.

  20. First-dose effects of fingolimod after switching from injectable therapies in the randomized, open-label, multicenter, Evaluate Patient OutComes (EPOC) study in relapsing multiple sclerosis.

    PubMed

    Hughes, Bruce; Cascione, Mark; Freedman, Mark S; Agius, Mark; Kantor, Daniel; Gudesblatt, Mark; Goldstick, Lawrence P; Agashivala, Neetu; Schofield, Lesley; McCague, Kevin; Hashmonay, Ron; Barbato, Luigi

    2014-09-01

    In pivotal phase 3 studies, fingolimod treatment initiation was associated with a transient reduction in heart rate (HR). Atrioventricular (AV) conduction delays, which were typically asymptomatic, were detected in a small minority of patients. We report the first-dose effects of fingolimod in patients who switched from injectable therapies during the Evaluate Patient OutComes (EPOC) study (ClinicalTrials.gov Identifier: NCT01216072). This was a phase 4, 6-month, randomized, active-comparator, open-label, multicenter study. It included over 900 fingolimod-treated patients with relapsing multiple sclerosis, with subgroups of individuals who were receiving common concomitant HR-lowering medications or had pre-existing cardiac conditions (PCCs). Vital signs were recorded hourly for 6h post-dose. A 12-lead electrocardiogram was obtained at baseline and at 6h post-dose. A transient decrease in mean HR and blood pressure occurred within 6h of the first fingolimod dose. The incidence of symptomatic bradycardia was low (1%); eight patients reported dizziness and there was one case each of fatigue, palpitations, dyspnea, cardiac discomfort, and gait disturbance. These symptomatic events were typically mild or moderate in severity and all resolved spontaneously, without intervention or fingolimod discontinuation. First-dose effects in patients with PCCs and in those receiving concomitant HR-lowering medications were consistent with effects observed in the overall study population and with results from previous clinical trials. The EPOC study provides additional data demonstrating the transient and generally benign nature of fingolimod first-dose effects on HR and AV conduction in a large population that is more representative of patients encountered in routine clinical practice than in the pivotal trials. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. The immediate effect of facial candling on inflammatory mediators, substance P, symptoms severity, and quality of life in allergic rhinitis patients: Study protocol for a randomized controlled trial.

    PubMed

    Ismail, Nor Faizatul Fatikah; Neoh, Chin Fen; Lim, Siong Meng; Abdullah, Amir Heberd; Mastuki, Mohd Fahmi; Ramasamy, Kalavathy; Zainuddin, Nazli; Saim, Lokman; Ming, Long Chiau

    2017-07-01

    Asian countries have a variety of ethnic groups and culture that provide their own traditional treatment in health care. Facial candling appears to be one of the popular traditional treatments in Southeast Asian. The complementary medicine practitioners promote that the facial candling treatment would help in reducing the symptoms of allergic rhinitis and other problems related to sinus. Due to the lack of evidence available, the effectiveness of this treatment method and its mechanism, however, remains unknown. The objective of this research is therefore to study impact of facial candling on inflammatory mediators, substance P (SP), symptoms severity, and quality of life (QoL) in allergic rhinitis patients. A randomized, nonblinded, controlled trial will be carried out by recruiting a total of 66 eligible allergic rhinitis patients who fulfill the inclusion criteria from a university health center. The subjects will be randomly assigned into 2 groups: intervention group receiving facial candling treatment and control group (no treatment given). Samples of blood and nasal mucus will be collected right before and after intervention. Samples collected will be analyzed. The primary outcomes are the changes in the level of SP in both blood and mucus samples between both groups. The secondary outcomes include the levels of inflammatory mediators (ie, tumor necrosis factor alpha, interleukin (IL)-3, IL-5, IL-6, IL-10, and IL-13) and the severity of allergic rhinitis symptoms as measured by a visual analogous scale and QoL using the Rhinitis Quality of Life Questionnaire (RQLQ). The study protocols are approved from the Ethical and Research Committee of the Universiti Teknologi MARA (REC/113/15). The trial is registered under the Australia New Zealand Clinical Trial Registry (ACTRN12616000299404). The trial was registered on 03/07/2016 and the first patient was enrolled on 10/12/2016. Facial candling is one of the unique treatments using candles to reduce the severity of

  2. Heat Switches for ADRs

    NASA Technical Reports Server (NTRS)

    DiPirro, M. J.; Shirron, P. J.

    2014-01-01

    Heat switches are key elements in the cyclic operation of Adiabatic Demagnetization Refrigerators (ADRs). Several of the types of heat switches that have been used for ADRs are described in this paper. Key elements in selection and design of these switches include not only ON/OFF switching ratio, but also method of actuation, size, weight, and structural soundness. Some of the trade-off are detailed in this paper.

  3. Heat switches for ADRs

    NASA Astrophysics Data System (ADS)

    DiPirro, M. J.; Shirron, P. J.

    2014-07-01

    Heat switches are key elements in the cyclic operation of Adiabatic Demagnetization Refrigerators (ADRs). Several of the types of heat switches that have been used for ADRs are described in this paper. Key elements in selection and design of these switches include not only ON/OFF switching ratio, but also method of actuation, size, weight, and structural soundness. Some of the trade-off are detailed in this paper.

  4. Remote switch actuator

    DOEpatents

    Haas, Edwin Gerard; Beauman, Ronald; Palo, Jr., Stefan

    2013-01-29

    The invention provides a device and method for actuating electrical switches remotely. The device is removably attached to the switch and is actuated through the transfer of a user's force. The user is able to remain physically removed from the switch site obviating need for protective equipment. The device and method allow rapid, safe actuation of high-voltage or high-current carrying electrical switches or circuit breakers.

  5. Apollo Ring Optical Switch

    SciTech Connect

    Maestas, J.H.

    1987-03-01

    An optical switch was designed, built, and installed at Sandia National Laboratories in Albuquerque, New Mexico, to facilitate the integration of two Apollo computer networks into a single network. This report presents an overview of the optical switch as well as its layout, switch testing procedure and test data, and installation.

  6. Triggered plasma opening switch

    DOEpatents

    Mendel, Clifford W.

    1988-01-01

    A triggerable opening switch for a very high voltage and current pulse includes a transmission line extending from a source to a load and having an intermediate switch section including a plasma for conducting electrons between transmission line conductors and a magnetic field for breaking the plasma conduction path and magnetically insulating the electrons when it is desired to open the switch.

  7. Designing pH induced fold switch in proteins

    NASA Astrophysics Data System (ADS)

    Baruah, Anupaul; Biswas, Parbati

    2015-05-01

    This work investigates the computational design of a pH induced protein fold switch based on a self-consistent mean-field approach by identifying the ensemble averaged characteristics of sequences that encode a fold switch. The primary challenge to balance the alternative sets of interactions present in both target structures is overcome by simultaneously optimizing two foldability criteria corresponding to two target structures. The change in pH is modeled by altering the residual charge on the amino acids. The energy landscape of the fold switch protein is found to be double funneled. The fold switch sequences stabilize the interactions of the sites with similar relative surface accessibility in both target structures. Fold switch sequences have low sequence complexity and hence lower sequence entropy. The pH induced fold switch is mediated by attractive electrostatic interactions rather than hydrophobic-hydrophobic contacts. This study may provide valuable insights to the design of fold switch proteins.

  8. Designing pH induced fold switch in proteins.

    PubMed

    Baruah, Anupaul; Biswas, Parbati

    2015-05-14

    This work investigates the computational design of a pH induced protein fold switch based on a self-consistent mean-field approach by identifying the ensemble averaged characteristics of sequences that encode a fold switch. The primary challenge to balance the alternative sets of interactions present in both target structures is overcome by simultaneously optimizing two foldability criteria corresponding to two target structures. The change in pH is modeled by altering the residual charge on the amino acids. The energy landscape of the fold switch protein is found to be double funneled. The fold switch sequences stabilize the interactions of the sites with similar relative surface accessibility in both target structures. Fold switch sequences have low sequence complexity and hence lower sequence entropy. The pH induced fold switch is mediated by attractive electrostatic interactions rather than hydrophobic-hydrophobic contacts. This study may provide valuable insights to the design of fold switch proteins.

  9. Randomized controlled trial of primary care pediatric parenting programs: effect on reduced media exposure in infants, mediated through enhanced parent-child interaction.

    PubMed

    Mendelsohn, Alan L; Dreyer, Benard P; Brockmeyer, Carolyn A; Berkule-Silberman, Samantha B; Huberman, Harris S; Tomopoulos, Suzy

    2011-01-01

    To determine whether pediatric primary care-based programs to enhance parenting and early child development reduce media exposure and whether enhanced parenting mediates the effects. Randomized controlled trial. Urban public hospital pediatric primary care clinic. A total of 410 mother-newborn dyads enrolled after childbirth. Patients were randomly assigned to 1 of 2 interventions, the Video Interaction Project (VIP) and Building Blocks (BB) interventions, or to a control group. The VIP intervention comprised 1-on-1 sessions with a child development specialist who facilitated interactions in play and shared reading through review of videotapes made of the parent and child on primary care visit days; learning materials and parenting pamphlets were also provided. The BB intervention mailed parenting materials, including age-specific newsletters suggesting activities to facilitate interactions, learning materials, and parent-completed developmental questionnaires (Ages and Stages questionnaires). Electronic media exposure in the home using a 24-hour recall diary. The mean (SD) exposure at 6 months was 146.5 (125.0) min/d. Exposure to VIP was associated with reduced total duration of media exposure compared with the BB and control groups (mean [SD] min/d for VIP, 131.6 [118.7]; BB, 151.2 [116.7]; control, 155.4 [138.7]; P = .009). Enhanced parent-child interactions were found to partially mediate relations between VIP and media exposure for families with a ninth grade or higher literacy level (Sobel statistic = 2.49; P = .01). Pediatric primary care may represent an important venue for addressing the public health problem of media exposure in young children at a population level. clinicaltrials.gov Identifier: NCT00212576.

  10. bicoid mRNA localises to the Drosophila oocyte anterior by random Dynein-mediated transport and anchoring

    PubMed Central

    Trovisco, Vítor; Belaya, Katsiaryna; Nashchekin, Dmitry; Irion, Uwe; Sirinakis, George; Butler, Richard; Lee, Jack J; Gavis, Elizabeth R; St Johnston, Daniel

    2016-01-01

    bicoid mRNA localises to the Drosophila oocyte anterior from stage 9 of oogenesis onwards to provide a local source for Bicoid protein for embryonic patterning. Live imaging at stage 9 reveals that bicoid mRNA particles undergo rapid Dynein-dependent movements near the oocyte anterior, but with no directional bias. Furthermore, bicoid mRNA localises normally in shot2A2, which abolishes the polarised microtubule organisation. FRAP and photo-conversion experiments demonstrate that the RNA is stably anchored at the anterior, independently of microtubules. Thus, bicoid mRNA is localised by random active transport and anterior anchoring. Super-resolution imaging reveals that bicoid mRNA forms 110–120 nm particles with variable RNA content, but constant size. These particles appear to be well-defined structures that package the RNA for transport and anchoring. DOI: http://dx.doi.org/10.7554/eLife.17537.001 PMID:27791980

  11. Efficacy and Mediation of a Theory-Based Physical Activity Intervention for African American Men Who Have Sex with Men: A Randomized Controlled Trial.

    PubMed

    Zhang, Jingwen; Jemmott, John B; O'Leary, Ann; Stevens, Robin; Jemmott, Loretta Sweet; Icard, Larry D; Hsu, Janet; Rutledge, Scott E

    2017-02-01

    Few trials have tested physical-activity interventions among sexual minorities, including African American men who have sex with men (MSM). We examined the efficacy and mediation of the Being Responsible for Ourselves (BRO) physical-activity intervention among African American MSM. African American MSM were randomized to the physical-activity intervention consisting of three 90-min one-on-one sessions or an attention-matched control intervention and completed pre-intervention, immediately post-intervention, and 6- and 12-month post-intervention audio computer-based surveys. Of the 595 participants, 503 completed the 12-month follow-up. Generalized estimating equation models revealed that the intervention increased self-reported physical activity compared with the control intervention, adjusted for pre-intervention physical activity. Mediation analyses suggested that the intervention increased reasoned action approach variables, subjective norm and self-efficacy, increasing intention immediately post-intervention, which increased physical activity during the follow-up period. Interventions targeting reasoned action approach variables may contribute to efforts to increase African American MSM's physical activity. The trial was registered with the ClinicalTrials.gov Identifier NCT02561286 .

  12. Long-term moderate calorie restriction inhibits inflammation without impairing cell-mediated immunity: a randomized controlled trial in non-obese humans

    PubMed Central

    Meydani, Simin N.; Das, Sai K.; Pieper, Carl F.; Lewis, Michael R.; Klein, Sam; Dixit, Vishwa D.; Gupta, Alok K.; Villareal, Dennis T.; Bhapkar, Manjushri; Huang, Megan; Fuss, Paul J.; Roberts, Susan B.; Holloszy, John O.; Fontana, Luigi

    2016-01-01

    Calorie restriction (CR) inhibits inflammation and slows aging in many animal species, but in rodents housed in pathogen-free facilities, CR impairs immunity against certain pathogens. However, little is known about the effects of long-term moderate CR on immune function in humans. In this multi-center, randomized clinical trial to determine CR's effect on inflammation and cell-mediated immunity, 218 healthy non-obese adults (20-50 y), were assigned 25% CR (n=143) or an ad-libitum (AL) diet (n=75), and outcomes tested at baseline, 12, and 24 months of CR. CR induced a 10.4% weight loss over the 2-y period. Relative to AL group, CR reduced circulating inflammatory markers, including total WBC and lymphocyte counts, ICAM-1 and leptin. Serum CRP and TNF-α concentrations were about 40% and 50% lower in CR group, respectively. CR had no effect on the delayed-type hypersensitivity skin response or antibody response to vaccines, nor did it cause difference in clinically significant infections. In conclusion, long-term moderate CR without malnutrition induces a significant and persistent inhibition of inflammation without impairing key in vivo indicators of cell-mediated immunity. Given the established role of these pro-inflammatory molecules in the pathogenesis of multiple chronic diseases, these CR-induced adaptations suggest a shift toward a healthy phenotype. PMID:27410480

  13. Drinking water to reduce alcohol craving? A randomized controlled study on the impact of ghrelin in mediating the effects of forced water intake in alcohol addiction.

    PubMed

    Koopmann, Anne; Lippmann, Katharina; Schuster, Rilana; Reinhard, Iris; Bach, Patrick; Weil, Georg; Rietschel, Marcella; Witt, Stephanie H; Wiedemann, Klaus; Kiefer, Falk

    2017-08-05

    Recent data suggest that ghrelin is involved in the pathophysiology of alcohol use disorders, affecting alcohol self-administration and craving. Gastric ghrelin secretion is reduced by stomach distension. We now tested the hypothesis whether the clinically well-known effects of high-volume water intake on craving reduction in alcoholism is mediated by acute changes in ghrelin secretion. In this randomized human laboratory study, we included 23 alcohol-dependent male inpatient subjects who underwent alcohol cue exposure. Participants of the intervention group drank 1000ml of mineral water within 10min directly thereafter, compared to the participants of the control group who did not. Craving and plasma concentrations of acetylated ghrelin were measured ten times during the 120min following the alcohol cue exposure session. In the intervention group, a significant decrease in acetylated ghrelin in plasma compared to the control group was observed. This decrease was correlated to a reduction in patients' subjective level of craving. In the control group, no decrease of acetylated ghrelin in plasma and no association between alcohol craving and changes in plasma concentrations of acetylated ghrelin were observed. Our results present new evidence that the modulation in the ghrelin system by oral water intake mediates the effects of volume intake with craving reduction in alcohol use disorders. Hence, in addition to pharmacological interventions with ghrelin antagonists, the reduction of physiological ghrelin secretion might be a target for future interventions in the treatment of alcohol craving. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. Efficacy of a randomized controlled self-regulation based physical activity intervention for chronic fatigue: Mediation effects of physical activity progress and self-regulation skills.

    PubMed

    Marques, M M; de Gucht, V; Leal, I; Maes, S

    2017-03-01

    Examine the medium-term effects of a brief physical activity (PA) self-regulation (SR) based intervention (4-STEPS program) for chronic fatigue, and explore the mediating effects of PA related variables and SR skills. A two-arm randomized controlled trial (Usual Care vs 4-STEPS) was carried out. The 4-STEPS program consisted of Motivational Interviewing and SR-skills training. Fatigue severity (primary outcome) and impact, PA, health-related quality of life (HrQoL), and somatic and psychological distress were assessed at baseline, post-treatment (12weeks) and 12months follow-up. Ninety-one patients (45 intervention and 46 controls) were included. At follow-up, there were significant treatment effects on fatigue severity (g=0.72) and fatigue impact, leisure-time PA, and physical and psychological HrQoL. No significant effects were found for number of daily steps and somatic and psychological distress. Fatigue severity at follow-up was partially mediated by post-treatment progress on a personal PA goal (effect ratio=18%). Results suggest that a brief intervention, focusing on the formulation and pursuit of personal PA goals and the use of SR skills, produces sustained benefits for fatigue severity. Despite these promising results, dropout was high and the intervention was not beneficial for all secondary outcomes. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. REMOTE CONTROLLED SWITCHING DEVICE

    DOEpatents

    Hobbs, J.C.

    1959-02-01

    An electrical switching device which can be remotely controlled and in which one or more switches may be accurately operated at predetermined times or with predetermined intervening time intervals is described. The switching device consists essentially of a deck, a post projecting from the deck at right angles thereto, cam means mounted for rotation around said posts and a switch connected to said deck and actuated by said cam means. Means is provided for rotating the cam means at a constant speed and the switching apparatus is enclosed in a sealed container with external adjusting means and electrical connection elements.

  16. Photodynamic Therapy for Actinic Keratoses: A Randomized Prospective Non-sponsored Cost-effectiveness Study of Daylight-mediated Treatment Compared with Light-emitting Diode Treatment.

    PubMed

    Neittaanmäki-Perttu, Noora; Grönroos, Mari; Karppinen, Toni; Snellman, Erna; Rissanen, Pekka

    2016-02-01

    Daylight-mediated photodynamic therapy (DL-PDT) is considered as effective as conventional PDT using artificial light (light-emitting diode (LED)-PDT) for treatment of actinic keratoses (AK). This randomized prospective non-sponsored study assessed the cost-effectiveness of DL-PDT compared with LED-PDT. Seventy patients with 210 AKs were randomized to DL-PDT or LED-PDT groups. Effectiveness was assessed at 6 months. The costs included societal costs and private costs, including the time patients spent in treatment. Results are presented as incremental cost-effectiveness ratio (ICER). The total costs per patient were significantly lower for DL-PDT (€132) compared with LED-PDT (€170), giving a cost saving of €38 (p = 0.022). The estimated probabilities for patients' complete response were 0.429 for DL-PDT and 0.686 for LED-PDT; a difference in probability of being healed of 0.257. ICER showed a monetary gain of €147 per unit of effectiveness lost. DL-PDT is less costly and less effective than LED-PDT. In terms of cost-effectiveness analysis, DL-PDT provides lower value for money compared with LED-PDT.

  17. On the Switching Control

    NASA Astrophysics Data System (ADS)

    Balas, Valentina E.; Balas, Marius M.

    2009-04-01

    The paper is discussing the measures able to reject the instability that may unexpectedly appear in particular conditions, in switching controllers applications. The switching controllers' effect is explained by the combined effects of the unsuitable choice of the switching moments (in the first or third quadrants of the phase trajectory of the switching error) and of the temporal aliasing that can distort the digital control systems when the sampling rate is close to the frequency of the oscillations that are produced by the commutation. The correct switching moments are located into the second and fourth quadrants of the phase trajectory of the switching error, but an active preparation of the commutation may be simply achieved by using a tracking controller, that is driving the output of open loop controller to follow the output of the close loop controller, permanently minimizing the switching error. Simulations issued from a dc driver speed controller and from an aircraft are provided.

  18. Resistance switching memory in perovskite oxides

    SciTech Connect

    Yan, Z.B. Liu, J.-M.

    2015-07-15

    The resistance switching behavior has recently attracted great attentions for its application as resistive random access memories (RRAMs) due to a variety of advantages such as simple structure, high-density, high-speed and low-power. As a leading storage media, the transition metal perovskite oxide owns the strong correlation of electrons and the stable crystal structure, which brings out multifunctionality such as ferroelectric, multiferroic, superconductor, and colossal magnetoresistance/electroresistance effect, etc. The existence of rich electronic phases, metal–insulator transition and the nonstoichiometric oxygen in perovskite oxide provides good platforms to insight into the resistive switching mechanisms. In this review, we first introduce the general characteristics of the resistance switching effects, the operation methods and the storage media. Then, the experimental evidences of conductive filaments, the transport and switching mechanisms, and the memory performances and enhancing methods of perovskite oxide based filamentary RRAM cells have been summarized and discussed. Subsequently, the switching mechanisms and the performances of the uniform RRAM cells associating with the carrier trapping/detrapping and the ferroelectric polarization switching have been discussed. Finally, the advices and outlook for further investigating the resistance switching and enhancing the memory performances are given.

  19. Testing the Mediating Effects of Obsessive Beliefs in Internet-Based Cognitive Behaviour Therapy for Obsessive-Compulsive Disorder: Results from a Randomized Controlled Trial.

    PubMed

    Andersson, Erik; Ljótsson, Brjánn; Hedman, Erik; Hesser, Hugo; Enander, Jesper; Kaldo, Viktor; Andersson, Gerhard; Lindefors, Nils; Rück, Christian

    2015-01-01

    Although cognitive interventions for obsessive-compulsive disorder (OCD) have been tested in randomized trials, there are few trials that have tested the specific mechanisms of cognitive interventions, i.e. how they achieve their effects. In this study, we aimed to investigate the mediating effects of a short cognitive intervention in the treatment of OCD and used data from a recently conducted randomized controlled trial where 101 participants were allocated to either Internet-based CBT (ICBT) or to a control condition. Obsessive beliefs were measured at pre-treatment, at the time they had received the cognitive intervention, and also at post-treatment. Weekly OCD symptoms were measured throughout the 10 weeks of treatment. We hypothesized that (1) the ICBT group would have greater reductions in obsessive beliefs (controlling for change in OCD symptoms) after completing the cognitive intervention, and that (2) this reduction would, in turn, predict greater OCD symptom reduction throughout the rest of the treatment period. Contrary to our expectations, the longitudinal mediation analysis indicated that (1) being randomized to ICBT actually increased the degree of obsessive beliefs after receiving the cognitive intervention at weeks 1-3, and (2) increase in obsessive beliefs predicted better outcome later in treatment. However, when repeating the analysis using cross-sectional data at post-treatment, the results were in line with the initial hypotheses. Results were replicated when the control condition received ICBT. We conclude that, although obsessive beliefs were significantly reduced at post-treatment for the ICBT group, early increase rather than decrease in obsessive beliefs predicted favourable outcome. This study investigated the impact of cognitive interventions on obsessive beliefs for patients with obsessive-compulsive disorder. Results showed that a sudden increase in obsessive beliefs is not an indicator of worse treatment response. On the contrary

  20. Multistate resistive switching in silver nanoparticle films

    PubMed Central

    Sandouk, Eric J; Gimzewski, James K; Stieg, Adam Z

    2015-01-01

    Resistive switching devices have garnered significant consideration for their potential use in nanoelectronics and non-volatile memory applications. Here we investigate the nonlinear current–voltage behavior and resistive switching properties of composite nanoparticle films comprising a large collective of metal–insulator–metal junctions. Silver nanoparticles prepared via the polyol process and coated with an insulating polymer layer of tetraethylene glycol were deposited onto silicon oxide substrates. Activation required a forming step achieved through application of a bias voltage. Once activated, the nanoparticle films exhibited controllable resistive switching between multiple discrete low resistance states that depended on operational parameters including the applied bias voltage, temperature and sweep frequency. The films’ resistance switching behavior is shown here to be the result of nanofilament formation due to formative electromigration effects. Because of their tunable and distinct resistance states, scalability and ease of fabrication, nanoparticle films have a potential place in memory technology as resistive random access memory cells. PMID:27877824

  1. Gastric electrical stimulation treatment of type 2 diabetes: effects of implantation versus meal-mediated stimulation. A randomized blinded cross-over trial

    PubMed Central

    Lebovitz, Harold E; Ludvik, Bernhard; Kozakowski, Jaroslaw; Tarnowski, Wieslaw; Zelewski, Mateusz; Yaniv, Irit; Schwartz, Tse’ela

    2015-01-01

    Gastric electrical stimulation with the implanted DIAMOND device has been shown to improve glycemic control and decrease weight and systolic blood pressure in patients with type 2 diabetes inadequately controlled with oral antidiabetic agents. The objective of this study was to determine if device implantation alone (placebo effect) contributes to the long-term metabolic benefits of DIAMOND® meal-mediated gastric electrical stimulation in patients with type 2 diabetes. The study was a 48 week randomized, blinded, cross-over trial in university centers comparing glycemic improvement of DIAMOND® implanted patients with type 2 diabetic with no activation of the electrical stimulation (placebo) versus meal-mediated activation of the electrical signal. The endpoint was improvement in glycemic control (HbA1c) from baseline to 24 and 48 weeks. In period 1 (0–24 weeks), equal improvement in HbA1c occurred independent of whether the meal-mediated electrical stimulation was turned on or left off (HbA1c −0.80% and −0.85% [−8.8 and −9.0 mmol/mol]). The device placebo improvement proved to be transient as it was lost in period 2 (25–48 weeks). With electrical stimulation turned off, HbA1c returned toward baseline values (8.06 compared to 8.32%; 64.2 to 67.4 mmol/mol, P = 0.465). In contrast, turning the electrical stimulation on in period 2 sustained the decrease in HbA1c from baseline (−0.93%, −10.1mmol/mol, P = 0.001) observed in period 1. The results indicate that implantation of the DIAMOND device causes a transient improvement in HbA1c which is not sustained beyond 24 weeks. Meal-mediated electrical stimulation accounts for the significant improvement in HbA1c beyond 24 weeks. PMID:26177957

  2. Optoelectronic techniques for broadband switching

    NASA Astrophysics Data System (ADS)

    Su, S. F.; Jou, L.; Lenart, J.

    1988-01-01

    Optoelectronic switching employs a hybrid optical/electronic principle to perform the switching function and is applicable for either analog broadband or high-bit rate digital switching. The major advantages of optoelectronic switching include high isolation, low crosstalk, small physical size, light weight, and low power consumption. These advantages make optoelectronic switching an excellent candidate for on-board satellite switching. This paper describes a number of optoelectronic switching architectures. System components required for implementing these switching architectures are discussed. Performance of these architectures are evaluated by calculating their crosstalk, isolation, insertion loss, matrix size, drive power, throughput, and switching speed. Technologies needed for monolithic optoelectronic switching are also identified.

  3. Antibody Isotype Switching in Vertebrates.

    PubMed

    Senger, Kate; Hackney, Jason; Payandeh, Jian; Zarrin, Ali A

    2015-01-01

    The humoral or antibody-mediated immune response in vertebrates has evolved to respond to diverse antigenic challenges in various anatomical locations. Diversification of the immunoglobulin heavy chain (IgH) constant region via isotype switching allows for remarkable plasticity in the immune response, including versatile tissue distribution, Fc receptor binding, and complement fixation. This enables antibody molecules to exert various biological functions while maintaining antigen-binding specificity. Different immunoglobulin (Ig) classes include IgM, IgD, IgG, IgE, and IgA, which exist as surface-bound and secreted forms. High-affinity autoantibodies are associated with various autoimmune diseases such as lupus and arthritis, while defects in components of isotype switching are associated with infections. A major route of infection used by a large number of pathogens is invasion of mucosal surfaces within the respiratory, digestive, or urinary tract. Most infections of this nature are initially limited by effector mechanisms such as secretory IgA antibodies. Mucosal surfaces have been proposed as a major site for the genesis of adaptive immune responses, not just in fighting infections but also in tolerating commensals and constant dietary antigens. We will discuss the evolution of isotype switching in various species and provide an overview of the function of various isotypes with a focus on IgA, which is universally important in gut homeostasis as well as pathogen clearance. Finally, we will discuss the utility of antibodies as therapeutic modalities.

  4. Maraviroc, as a Switch Option, in HIV-1-infected Individuals With Stable, Well-controlled HIV Replication and R5-tropic Virus on Their First Nucleoside/Nucleotide Reverse Transcriptase Inhibitor Plus Ritonavir-boosted Protease Inhibitor Regimen: Week 48 Results of the Randomized, Multicenter MARCH Study.

    PubMed

    Pett, Sarah Lilian; Amin, Janaki; Horban, Andrejz; Andrade-Villanueva, Jaime; Losso, Marcelo; Porteiro, Norma; Sierra Madero, Juan; Belloso, Waldo; Tu, Elise; Silk, David; Kelleher, Anthony; Harrigan, Richard; Clark, Andrew; Sugiura, Wataru; Wolff, Marcelo; Gill, John; Gatell, Jose; Fisher, Martin; Clarke, Amanda; Ruxrungtham, Kiat; Prazuck, Thierry; Kaiser, Rolf; Woolley, Ian; Arnaiz, Juan Alberto; Cooper, David; Rockstroh, Jürgen K; Mallon, Patrick; Emery, Sean

    2016-07-01

    Alternative combination antiretroviral therapies in virologically suppressed human immunodeficiency virus (HIV)-infected patients experiencing side effects and/or at ongoing risk of important comorbidities from current therapy are needed. Maraviroc (MVC), a chemokine receptor 5 antagonist, is a potential alternative component of therapy in those with R5-tropic virus. The Maraviroc Switch Study is a randomized, multicenter, 96-week, open-label switch study in HIV type 1-infected adults with R5-tropic virus, virologically suppressed on a ritonavir-boosted protease inhibitor (PI/r) plus double nucleoside/nucleotide reverse transcriptase inhibitor (2 N(t)RTI) backbone. Participants were randomized 1:2:2 to current combination antiretroviral therapy (control), or replacing the protease inhibitor (MVC + 2 N(t)RTI arm) or the nucleoside reverse transcriptase inhibitor backbone (MVC + PI/r arm) with twice-daily MVC. The primary endpoint was the difference (switch minus control) in proportion with plasma viral load (VL) <200 copies/mL at 48 weeks. The switch arms were judged noninferior if the lower limit of the 95% confidence interval (CI) for the difference in the primary endpoint was < -12% in the intention-to-treat (ITT) population. The ITT population comprised 395 participants (control, n = 82; MVC + 2 N(t)RTI, n = 156; MVC + PI/r, n = 157). Baseline characteristics were well matched. At week 48, noninferior rates of virological suppression were observed in those switching away from a PI/r (93.6% [95% CI, -9.0% to 2.2%] and 91.7% [95% CI, -9.6% to 3.8%] with VL <200 and <50 copies/mL, respectively) compared to the control arm (97.6% and 95.1% with VL <200 and <50 copies/mL, respectively). In contrast, MVC + PI/r did not meet noninferiority bounds and was significantly inferior (84.1% [95% CI, -19.8% to -5.8%] and 77.7% [95% CI, -24.9% to -8.4%] with VL <200 and <50 copies/mL, respectively) to the control arm in the ITT analysis. These data support MVC as a switch

  5. Monolithic Microwave Switching Matrix

    NASA Technical Reports Server (NTRS)

    Fujikawa, Gene; Ch'en, Daniel R.; Petersen, Wendell C.

    1989-01-01

    Gallium arsenide integrated-circuit chip switches any of three microwave input signals to any of three output ports. Measuring 4.9 mm on side, chip contains nine field-effect transistor (FET) crosspoint switches. Housed in custom-designed package with standard connectors for easy integration into system. FET's on chip operated as passive switches and consume no static power and insignificant amounts of switching power. Chip module cascades with similar modules into large arrays handling as many as 100 inputs and 100 outputs. Applications include switching and routing vast amounts of data between computers at extremely high speed. On communications satellite, chip switches microwave signals to and from Earth stations and other satellites.

  6. Effective switching frequency multiplier inverter

    DOEpatents

    Su, Gui-Jia; Peng, Fang Z.

    2007-08-07

    A switching frequency multiplier inverter for low inductance machines that uses parallel connection of switches and each switch is independently controlled according to a pulse width modulation scheme. The effective switching frequency is multiplied by the number of switches connected in parallel while each individual switch operates within its limit of switching frequency. This technique can also be used for other power converters such as DC/DC, AC/DC converters.

  7. Double-Bounce Switching

    DTIC Science & Technology

    1983-06-01

    module. Adjustments provided to investigate double- bounce switching are noted. limitation is at a higher level and occurs in the conventionally...To be presented at the 4th IEEE PUlsed Power Conference, June 6-8, 1983, Albuquerque, NM. DOUBLE- BOUNCE SWITCHING* George B. Frazier and Steven R...Ashby Physics International Company 2700 Merced Street San Leandro, California 94577 Abstract Double- bounce switching is a technique for

  8. Avalanche Photoconductive Switching

    DTIC Science & Technology

    1989-06-01

    held off across the switch. In our case this corresponds to 70 kV/cm and is limited by surface flashover . The pulse length is determined by the...off across the gap of the switch, which in turn appears to be limited by surface flashover . There appears to be a threshold electric field of 20-60...and understand this mode of operation. Introduction Laser activated photoconductive switching in semiconductors is a promising technology for high

  9. Thermally actuated thermionic switch

    DOEpatents

    Barrus, Donald M.; Shires, Charles D.

    1988-01-01

    A thermally actuated thermionic switch which responds to an increase of temperature by changing from a high impedance to a low impedance at a predictable temperature set point. The switch has a bistable operation mode switching only on temperature increases. The thermionic material may be a metal which is liquid at the desired operation temperature and held in matrix in a graphite block reservoir, and which changes state (ionizes, for example) so as to be electrically conductive at a desired temperature.

  10. Thermally actuated thermionic switch

    DOEpatents

    Barrus, D.M.; Shires, C.D.

    1982-09-30

    A thermally actuated thermionic switch which responds to an increase of temperature by changing from a high impedance to a low impedance at a predictable temperature set point. The switch has a bistable operation mode switching only on temperature increases. The thermionic material may be a metal which is liquid at the desired operation temperature and held in matrix in a graphite block reservoir, and which changes state (ionizes, for example) so as to be electrically conductive at a desired temperature.

  11. Solid state switch

    DOEpatents

    Merritt, Bernard T.; Dreifuerst, Gary R.

    1994-01-01

    A solid state switch, with reverse conducting thyristors, is designed to operate at 20 kV hold-off voltage, 1500 A peak, 1.0 .mu.s pulsewidth, and 4500 pps, to replace thyratrons. The solid state switch is more reliable, more economical, and more easily repaired. The switch includes a stack of circuit card assemblies, a magnetic assist and a trigger chassis. Each circuit card assembly contains a reverse conducting thyristor, a resistor capacitor network, and triggering circuitry.

  12. AC magnetohydrodynamic microfluidic switch

    SciTech Connect

    Lemoff, A V; Lee, A P

    2000-03-02

    A microfluidic switch has been demonstrated using an AC Magnetohydrodynamic (MHD) pumping mechanism in which the Lorentz force is used to pump an electrolytic solution. By integrating two AC MHD pumps into different arms of a Y-shaped fluidic circuit, flow can be switched between the two arms. This type of switch can be used to produce complex fluidic routing, which may have multiple applications in {micro}TAS.

  13. Effects of Quercetin on Adiponectin-Mediated Insulin Sensitivity in Polycystic Ovary Syndrome: A Randomized Placebo-Controlled Double-Blind Clinical Trial.

    PubMed

    Rezvan, N; Moini, A; Janani, L; Mohammad, K; Saedisomeolia, A; Nourbakhsh, M; Gorgani-Firuzjaee, S; Mazaherioun, M; Hosseinzadeh-Attar, M J

    2017-02-01

    Polycystic ovary syndrome (PCOS) is a heterogeneous, multi-causal, and genetically complex disorder, which is related to the failure in endocrine glands. Adiponectin has been reported to be low in PCOS, even in the absence of adiposity. Quercetin reduces serum glucose, insulin, triglycerides, and cholesterol levels and increases the expression and secretion of adiponectin. The aim of this study was to determine the effect of quercetin on the adiponectin-mediated insulin sensitivity in PCOS patients. Eighty-four women with PCOS were selected and randomly assigned to 2 groups of treatment and control. The treatment group received 1 g quercetin (two 500 mg capsules) daily for 12 weeks, and the control group received placebo. In addition to anthropometric assessments, fasting serum levels of total adiponectin, high-molecular-weight (HMW) adiponectin, glucose, insulin, testosterone, LH, and SHBG were also measured at the baseline and at the end of the trial. Quercetin could slightly increase the level of adiponectin by 5.56% as compared to placebo (adjusted p-value=0.001) and HMW adiponectin by 3.9% as compared to placebo (adjusted p-value=0.017), while it reduced the level of testosterone (0.71 ng/dl in quercetin vs. 0.77 ng/dl in placebo; p<0.001) and LH (8.42 IU/l in quercetin vs. 8.68 IU/l in placebo; p=0.009). HOMA-IR levels were also significantly (p<0.001) lower in quercetin (1.84) group compared to placebo group (2.21). Oral quercetin supplementation was effective in improving the adiponectin-mediated insulin resistance and hormonal profile of women with PCOS. © Georg Thieme Verlag KG Stuttgart · New York.

  14. Effect of low-level laser therapy on inflammatory mediator release during chemotherapy-induced oral mucositis: a randomized preliminary study.

    PubMed

    Silva, Geisa Badauy Lauria; Sacono, Nancy Tomoko; Othon-Leite, Angélica Ferreira; Mendonça, Elismauro Francisco; Arantes, Adriano Moraes; Bariani, César; Duarte, Luciana Garcia Lobo; Abreu, Mauro Henrique Nogueira; Queiroz-Júnior, Celso Martins; Silva, Tarcília Aparecida; Batista, Aline Carvalho

    2015-01-01

    Patients undergoing hematopoietic stem cell transplantation (HSCT) are submitted to a conditioning regimen of high-dose chemotherapy, with or without radiation therapy, which usually results in oral ulcerations and mucosal barrier breakdown. Oral mucositis (OM) is a common and debilitating toxicity side effect of autologous and allogeneic HSCT. The aim of this study was to evaluate the effect of low-level laser therapy (LLLT) on the severity of OM and inflammatory mediator (TNF-α, IL-6, IL-1β, IL-10, TGF-β, metalloproteinases, and growth factors) levels in saliva and blood of HSCT patients. Thirty patients were randomly assigned to two groups: control (n = 15) and laser (n = 15). LLLT was applied from the first day of the conditioning regimen until day 7 post-HSCT (D + 7). Saliva and blood were collected from patients on admission (AD), D-1, D + 3, D + 7, and on marrow engraftment day (ME). Clinical results showed less severe OM in the laser group (p < 0.05). The LLLT group showed increased matrix metalloproteinase 2 (MMP-2) levels in saliva on D + 7 (p = 0.04). Significant differences were also observed for IL-10 on D + 7 and on ME in blood plasma, when compared to the control group (p < 0.05). No significant differences were seen in saliva or blood for the other inflammatory mediators investigated. LLLT was clinically effective in reducing the severity of chemotherapy-induced OM in HSCT patients, and its mechanism of action does not seem to be completely linked to the modulation of pro- or anti-inflammatory cytokines, growth factors or matrix metalloproteinases.

  15. Alarm toe switch

    DOEpatents

    Ganyard, Floyd P.

    1982-01-01

    An alarm toe switch inserted within a shoe for energizing an alarm circuit n a covert manner includes an insole mounting pad into which a miniature reed switch is fixedly molded. An elongated slot perpendicular to the reed switch is formed in the bottom surface of the mounting pad. A permanent cylindrical magnet positioned in the forward portion of the slot with a diameter greater than the pad thickness causes a bump above the pad. A foam rubber block is also positioned in the slot rearwardly of the magnet and holds the magnet in normal inoperative relation. A non-magnetic support plate covers the slot and holds the magnet and foam rubber in the slot. The plate minimizes bending and frictional forces to improve movement of the magnet for reliable switch activation. The bump occupies the knuckle space beneath the big toe. When the big toe is scrunched rearwardly the magnet is moved within the slot relative to the reed switch, thus magnetically activating the switch. When toe pressure is released the foam rubber block forces the magnet back into normal inoperative position to deactivate the reed switch. The reed switch is hermetically sealed with the magnet acting through the wall so the switch assembly S is capable of reliable operation even in wet and corrosive environments.

  16. Reusable fast opening switch

    DOEpatents

    Van Devender, J.P.; Emin, D.

    1983-12-21

    A reusable fast opening switch for transferring energy, in the form of a high power pulse, from an electromagnetic storage device such as an inductor into a load. The switch is efficient, compact, fast and reusable. The switch comprises a ferromagnetic semiconductor which undergoes a fast transition between conductive and metallic states at a critical temperature and which undergoes the transition without a phase change in its crystal structure. A semiconductor such as europium rich europhous oxide, which undergoes a conductor to insulator transition when it is joule heated from its conductor state, can be used to form the switch.

  17. Reusable fast opening switch

    DOEpatents

    Van Devender, John P.; Emin, David

    1986-01-01

    A reusable fast opening switch for transferring energy, in the form of a high power pulse, from an electromagnetic storage device such as an inductor into a load. The switch is efficient, compact, fast and reusable. The switch comprises a ferromagnetic semiconductor which undergoes a fast transition between conductive and insulating states at a critical temperature and which undergoes the transition without a phase change in its crystal structure. A semiconductor such as europium rich europhous oxide, which undergoes a conductor to insulator transition when it is joule heated from its conductor state, can be used to form the switch.

  18. Platform switching and bone platform switching.

    PubMed

    Carinci, Francesco; Brunelli, Giorgio; Danza, Matteo

    2009-01-01

    Bone platform switching involves an inward bone ring in the coronal part of the implant that is in continuity with the alveolar bone crest. Bone platform switching is obtained by using a dental fixture with a reverse conical neck. A retrospective study was performed to evaluate the effectiveness of conventional vs reverse conical neck implants. In the period between May 2004 and November 2007, 86 patients (55 females and 31 males; median age, 53 years) were operated and 234 implants were inserted: 40 and 194 were conventional vs reverse conical neck implants, respectively. Kaplan-Meier algorithm and Cox regression were used to detect those variables associated with the clinical outcome. No differences in survival and success rates were detected between conventional vs reverse conical neck implants alone or in combination with any of the studied variables. Although bone platform switching leads to several advantages, no statistical difference in alveolar crest resorption is detected in comparison with reverse conical neck implants. We suppose that the proximity of the implant abutment junction to the alveolar crestal bone gives no protection against the microflora contained in the micrograph. Additional studies on larger series and a combination of platform switching and bone platform switching could lead to improved clinical outcomes.

  19. Proteomic risk markers for coronary heart disease and stroke: validation and mediation of randomized trial hormone therapy effects on these diseases

    PubMed Central

    2013-01-01

    Background We previously reported mass spectrometry-based proteomic discovery research to identify novel plasma proteins related to the risk of coronary heart disease (CHD) and stroke, and to identify proteins with concentrations affected by the use of postmenopausal hormone therapy. Here we report CHD and stroke risk validation studies for highly ranked proteins, and consider the extent to which protein concentration changes relate to disease risk or provide an explanation for hormone therapy effects on these outcomes. Methods Five proteins potentially associated with CHD (beta-2 microglobulin (B2M), alpha-1-acid glycoprotein 1 (ORM1), thrombospondin-1(THBS1), complement factor D pre-protein (CFD), and insulin-like growth factor binding protein 1 (IGFBP1)) and five potentially associated with stroke (B2M, IGFBP2, IGFBP4, IGFBP6, and hemopexin (HPX)) had high discovery phase significance level ranking and an available ELISA assay, and were included in case-control validation studies within the Women’s Health Initiative (WHI) hormone therapy trials. Protein concentrations, at baseline and 1 year following randomization, were assessed for 358 CHD cases and 362 stroke cases, along with corresponding disease-free controls. Disease association, and mediation of estrogen-alone and estrogen plus progestin effects on CHD and stroke risk, were assessed using logistic regression. Results B2M, THBS1, and CFD were confirmed (P <0.05) as novel CHD risk markers, and B2M, IGFBP2, and IGFBP4 were confirmed as novel stroke disease risk markers, while the assay for HPX proved to be unreliable. The change from baseline to 1 year in B2M was associated (P <0.05) with subsequent stroke risk, and trended similarly with subsequent CHD risk. Change from baseline to 1 year in IGFBP1 was also associated with CHD risk, and this change provided evidence of hormone therapy effect mediation. Conclusions Plasma B2M is confirmed to be an informative risk marker for both CHD and stroke. The B2M

  20. Effectiveness, Mediators, and Effect Predictors of Internet Interventions for Chronic Cancer-Related Fatigue: The Design and an Analysis Plan of a 3-Armed Randomized Controlled Trial.

    PubMed

    Wolvers, Marije Dj; Bruggeman-Everts, Fieke Z; Van der Lee, Marije L; Van de Schoot, Rens; Vollenbroek-Hutten, Miriam Mr

    2015-06-23

    Internet interventions offer advantages that especially cancer survivors who suffer from fatigue could benefit from. Given the growing number of such patients, Internet interventions could supplement and strengthen currently available health care. This paper describes the design and analysis plan that will be used to study 2 Internet interventions aimed at reducing severe fatigue in cancer survivors: a mobile ambulant activity feedback therapy supported through a weekly email by a physiotherapist and a weekly Web- and mindfulness-based cognitive therapy supported online by a psychologist. The data resulting from this trial will be used to (1) investigate the effectiveness, (2) investigate potential mediators of these interventions, and (3) explore participant characteristics that can predict the effect of these interventions. A 3-armed randomized controlled trial is proposed that compares both Internet interventions with an active control condition that solely consists of receiving psycho-educational emails. The intervention period is 9 weeks for all 3 conditions. Six months after baseline, participants in the control condition can choose to follow 1 of the 2 experimental Internet interventions. Outcomes are measured in terms of fatigue severity, mental health, and self-perceived work ability. All are Web-assessed at baseline, 2 weeks after the intervention period, and at 6 and 12 months after baseline. Fatigue severity, mindfulness, physical activity, expectations and credibility of the intervention, therapeutic working alliance, sleep quality, and sense of control over fatigue are assessed 3 times during the intervention period for identifying mediators of the interventions. Recruitment is performed nationally throughout the Netherlands through patient organizations and their websites, newspapers, and by informing various types of health professionals. All participants register at an open-access website. We aim at including 330 cancer survivors who have finished

  1. Effectiveness, Mediators, and Effect Predictors of Internet Interventions for Chronic Cancer-Related Fatigue: The Design and an Analysis Plan of a 3-Armed Randomized Controlled Trial

    PubMed Central

    Bruggeman-Everts, Fieke Z; Van der Lee, Marije L; Van de Schoot, Rens; Vollenbroek-Hutten, Miriam MR

    2015-01-01

    Background Internet interventions offer advantages that especially cancer survivors who suffer from fatigue could benefit from. Given the growing number of such patients, Internet interventions could supplement and strengthen currently available health care. Objective This paper describes the design and analysis plan that will be used to study 2 Internet interventions aimed at reducing severe fatigue in cancer survivors: a mobile ambulant activity feedback therapy supported through a weekly email by a physiotherapist and a weekly Web- and mindfulness-based cognitive therapy supported online by a psychologist. The data resulting from this trial will be used to (1) investigate the effectiveness, (2) investigate potential mediators of these interventions, and (3) explore participant characteristics that can predict the effect of these interventions. Methods A 3-armed randomized controlled trial is proposed that compares both Internet interventions with an active control condition that solely consists of receiving psycho-educational emails. The intervention period is 9 weeks for all 3 conditions. Six months after baseline, participants in the control condition can choose to follow 1 of the 2 experimental Internet interventions. Outcomes are measured in terms of fatigue severity, mental health, and self-perceived work ability. All are Web-assessed at baseline, 2 weeks after the intervention period, and at 6 and 12 months after baseline. Fatigue severity, mindfulness, physical activity, expectations and credibility of the intervention, therapeutic working alliance, sleep quality, and sense of control over fatigue are assessed 3 times during the intervention period for identifying mediators of the interventions. Recruitment is performed nationally throughout the Netherlands through patient organizations and their websites, newspapers, and by informing various types of health professionals. All participants register at an open-access website. We aim at including 330 cancer

  2. Asymmetrical Switch Costs in Children

    ERIC Educational Resources Information Center

    Ellefson, Michelle R.; Shapiron, Laura R.; Chater, Nick

    2006-01-01

    Switching between tasks produces decreases in performance as compared to repeating the same task. Asymmetrical switch costs occur when switching between two tasks of unequal difficulty. This asymmetry occurs because the cost is greater when switching to the less difficult task than when switching to the more difficult task. Various theories about…

  3. Black Tea Increases Circulating Endothelial Progenitor Cells and Improves Flow Mediated Dilatation Counteracting Deleterious Effects from a Fat Load in Hypertensive Patients: A Randomized Controlled Study

    PubMed Central

    Grassi, Davide; Draijer, Richard; Schalkwijk, Casper; Desideri, Giovambattista; D’Angeli, Anatolia; Francavilla, Sandro; Mulder, Theo; Ferri, Claudio

    2016-01-01

    (1) Background: Endothelial dysfunction predicts cardiovascular events. Circulating angiogenic cells (CACs) maintain and repair the endothelium regulating its function. Tea flavonoids reduce cardiovascular risk. We investigated the effects of black tea on the number of CACs and on flow-mediated dilation (FMD) before and after an oral fat in hypertensives; (2) Methods: In a randomized, double-blind, controlled, cross-over study, 19 patients were assigned to black tea (150 mg polyphenols) or a placebo twice a day for eight days. Measurements were obtained in a fasted state and after consuming whipping cream, and FMD was measured at baseline and after consumption of the products; (3) Results: Compared with the placebo, black tea ingestion increased functionally active CACs (36 ± 22 vs. 56 ± 21 cells per high-power field; p = 0.006) and FMD (5.0% ± 0.3% vs. 6.6% ± 0.3%, p < 0.0001). Tea further increased FMD 1, 2, 3, and 4 h after consumption, with maximal response 2 h after intake (p < 0.0001). Fat challenge decreased FMD, while tea consumption counteracted FMD impairment (p < 0.0001); (4) Conclusions: We demonstrated the vascular protective properties of black tea by increasing the number of CACs and preventing endothelial dysfunction induced by acute oral fat load in hypertensive patients. Considering that tea is the most consumed beverage after water, our findings are of clinical relevance and interest. PMID:27854314

  4. Effects of Supplementation with the Fat-Soluble Vitamins E and D on Fasting Flow-Mediated Vasodilation in Adults: A Meta-Analysis of Randomized Controlled Trials

    PubMed Central

    Joris, Peter J.; Mensink, Ronald P.

    2015-01-01

    The effects of fat-soluble vitamin supplementation on cardiovascular disease (CVD) risk are not clear. Therefore, we performed a meta-analysis to quantify effects of fat-soluble vitamin supplements on fasting flow-mediated vasodilation (FMD) of the brachial artery, a validated marker to assess CVD risk. Randomized placebo-controlled trials (RCTs) were identified by a systematic search till July 2014. Seven RCTs studying the effects of vitamin E supplements (range: 300 to 1800 IU per day) and nine RCTs examining the effects of vitamin D supplements, that involved, respectively, 303 and 658 adults, were included. No studies with carotenoid or vitamin K supplements were found. Vitamin E supplementation increased FMD vs. control by 2.42% (95% CI: 0.46% to 4.37%; p = 0.015). No effects of vitamin D supplementation were found (0.15%; 95% CI: −0.21% to 0.51%; p = 0.41). These effects did not depend on subject characteristics, treatment characteristics or technical aspects of the FMD measurement. However, no dose-response relationship was evident for vitamin E, statistical significance depended on one study, while the levels of supplement were far above recommended intakes. The current meta-analysis, therefore, does not provide unambiguous evidence to support the use of fat-soluble vitamin supplements to improve fasting FMD in adults. PMID:25763531

  5. Black Tea Increases Circulating Endothelial Progenitor Cells and Improves Flow Mediated Dilatation Counteracting Deleterious Effects from a Fat Load in Hypertensive Patients: A Randomized Controlled Study.

    PubMed

    Grassi, Davide; Draijer, Richard; Schalkwijk, Casper; Desideri, Giovambattista; D'Angeli, Anatolia; Francavilla, Sandro; Mulder, Theo; Ferri, Claudio

    2016-11-16

    (1) Background: Endothelial dysfunction predicts cardiovascular events. Circulating angiogenic cells (CACs) maintain and repair the endothelium regulating its function. Tea flavonoids reduce cardiovascular risk. We investigated the effects of black tea on the number of CACs and on flow-mediated dilation (FMD) before and after an oral fat in hypertensives; (2) Methods: In a randomized, double-blind, controlled, cross-over study, 19 patients were assigned to black tea (150 mg polyphenols) or a placebo twice a day for eight days. Measurements were obtained in a fasted state and after consuming whipping cream, and FMD was measured at baseline and after consumption of the products; (3) Results: Compared with the placebo, black tea ingestion increased functionally active CACs (36 ± 22 vs. 56 ± 21 cells per high-power field; p = 0.006) and FMD (5.0% ± 0.3% vs. 6.6% ± 0.3%, p < 0.0001). Tea further increased FMD 1, 2, 3, and 4 h after consumption, with maximal response 2 h after intake (p < 0.0001). Fat challenge decreased FMD, while tea consumption counteracted FMD impairment (p < 0.0001); (4) Conclusions: We demonstrated the vascular protective properties of black tea by increasing the number of CACs and preventing endothelial dysfunction induced by acute oral fat load in hypertensive patients. Considering that tea is the most consumed beverage after water, our findings are of clinical relevance and interest.

  6. A randomized trial examining the effects of Conjoint Behavioral Consultation in rural schools: Student outcomes and the mediating role of the teacher-parent relationship.

    PubMed

    Sheridan, Susan M; Witte, Amanda L; Holmes, Shannon R; Coutts, Michael J; Dent, Amy L; Kunz, Gina M; Wu, ChaoRong

    2017-04-01

    The results of a large-scale randomized controlled trial of Conjoint Behavioral Consultation (CBC) on student outcomes and teacher-parent relationships in rural schools are presented. CBC is an indirect service delivery model that addresses concerns shared by teachers and parents about students. In the present study, the intervention was aimed at promoting positive school-related social-behavioral skills and strengthening teacher-parent relationships in rural schools. Participants were 267 students in grades K-3, their parents, and 152 teachers in 45 Midwest rural schools. Results revealed that, on average, improvement among students whose parents and teachers experienced CBC significantly outpaced that of control students in their teacher-reported school problems and observational measures of their inappropriate (off-task and motor activity) and appropriate (on-task and social interactions) classroom behavior. In addition, teacher responses indicated significantly different rates of improvement in their relationship with parents in favor of the CBC group. Finally, the teacher-parent relationship was found to partially mediate effects of CBC on several student outcomes. Unique contributions of this study, implications of findings for rural students, study limitations and suggestions for future research are discussed. Copyright © 2016 Society for the Study of School Psychology. Published by Elsevier Ltd. All rights reserved.

  7. HTLV-I Tax-Mediated Inactivation of Cell Cycle Checkpoints and DNA Repair Pathways Contribute to Cellular Transformation: “A Random Mutagenesis Model”

    PubMed Central

    Nicot, Christophe

    2015-01-01

    To achieve cellular transformation, most oncogenic retroviruses use transduction by proto-oncogene capture or insertional mutagenesis, whereby provirus integration disrupts expression of tumor suppressors or proto-oncogenes. In contrast, the Human T-cell leukemia virus type 1 (HTLV-I) has been classified in a separate class referred to as “transactivating retroviruses”. Current views suggest that the viral encoded Tax protein transactivates expression of cellular genes leading to deregulated growth and transformation. However, if Tax-mediated transactivation was indeed sufficient for cellular transformation, a fairly high frequency of infected cells would eventually become transformed. In contrast, the frequency of transformation by HTLV-I is very low, likely less than 5%. This review will discuss the current understanding and recent discoveries highlighting critical functions of Tax in cellular transformation. HTLV-I Tax carries out essential functions in order to override cell cycle checkpoints and deregulate cellular division. In addition, Tax expression is associated with increased DNA damage and genome instability. Since Tax can inhibit multiple DNA repair pathways and stimulate unfaithful DNA repair or bypass checkpoints, these processes allow accumulation of genetic mutations in the host genome. Given this, a “Random Mutagenesis” transformation model seems more suitable to characterize the oncogenic activities of HTLV-I. PMID:26835512

  8. Effects of supplementation with the fat-soluble vitamins E and D on fasting flow-mediated vasodilation in adults: a meta-analysis of randomized controlled trials.

    PubMed

    Joris, Peter J; Mensink, Ronald P

    2015-03-10

    The effects of fat-soluble vitamin supplementation on cardiovascular disease (CVD) risk are not clear. Therefore, we performed a meta-analysis to quantify effects of fat-soluble vitamin supplements on fasting flow-mediated vasodilation (FMD) of the brachial artery, a validated marker to assess CVD risk. Randomized placebo-controlled trials (RCTs) were identified by a systematic search till July 2014. Seven RCTs studying the effects of vitamin E supplements (range: 300 to 1800 IU per day) and nine RCTs examining the effects of vitamin D supplements, that involved, respectively, 303 and 658 adults, were included. No studies with carotenoid or vitamin K supplements were found. Vitamin E supplementation increased FMD vs. control by 2.42% (95% CI: 0.46% to 4.37%; p = 0.015). No effects of vitamin D supplementation were found (0.15%; 95% CI: -0.21% to 0.51%; p = 0.41). These effects did not depend on subject characteristics, treatment characteristics or technical aspects of the FMD measurement. However, no dose-response relationship was evident for vitamin E, statistical significance depended on one study, while the levels of supplement were far above recommended intakes. The current meta-analysis, therefore, does not provide unambiguous evidence to support the use of fat-soluble vitamin supplements to improve fasting FMD in adults.

  9. Plasma-Derived C1 Esterase Inhibitor for Acute Antibody-Mediated Rejection Following Kidney Transplantation: Results of a Randomized Double-Blind Placebo-Controlled Pilot Study.

    PubMed

    Montgomery, R A; Orandi, B J; Racusen, L; Jackson, A M; Garonzik-Wang, J M; Shah, T; Woodle, E S; Sommerer, C; Fitts, D; Rockich, K; Zhang, P; Uknis, M E

    2016-05-16

    Antibody-mediated rejection (AMR) is typically treated with plasmapheresis (PP) and intravenous immunoglobulin (standard of care; SOC); however, there is an unmet need for more effective therapy. We report a phase 2b, multicenter double-blind randomized placebo-controlled pilot study to evaluate the use of human plasma-derived C1 esterase inhibitor (C1 INH) as add-on therapy to SOC for AMR. Eighteen patients received 20 000 units of C1 INH or placebo (C1 INH n = 9, placebo n = 9) in divided doses every other day for 2 weeks. No discontinuations, graft losses, deaths, or study drug-related serious adverse events occurred. While the study's primary end point, a difference between groups in day 20 pathology or graft survival, was not achieved, the C1 INH group demonstrated a trend toward sustained improvement in renal function. Six-month biopsies performed in 14 subjects (C1 INH = 7, placebo = 7) showed no transplant glomerulopathy (TG) (PTC+cg≥1b) in the C1 INH group, whereas 3 of 7 placebo subjects had TG. Endogenous C1 INH measured before and after PP demonstrated decreased functional C1 INH serum concentration by 43.3% (p < 0.05) for both cohorts (C1 INH and placebo) associated with PP, although exogenous C1 INH-treated patients achieved supraphysiological levels throughout. This new finding suggests that C1 INH replacement may be useful in the treatment of AMR.

  10. Power-Switching Circuit

    NASA Technical Reports Server (NTRS)

    Praver, Gerald A.; Theisinger, Peter C.; Genofsky, John

    1987-01-01

    Functions of circuit breakers, meters, and switches combined. Circuit that includes power field-effect transistors (PFET's) provides on/off switching, soft starting, current monitoring, current tripping, and protection against overcurrent for 30-Vdc power supply at normal load currents up to 2 A. Has no moving parts.

  11. Reflective HTS switch

    DOEpatents

    Martens, J.S.; Hietala, V.M.; Hohenwarter, G.K.G.

    1994-09-27

    A HTS (High Temperature Superconductor) switch includes a HTS conductor for providing a superconducting path for an electrical signal and an serpentine wire actuator for controllably heating a portion of the conductor sufficiently to cause that portion to have normal, and not superconducting, resistivity. Mass of the portion is reduced to decrease switching time. 6 figs.

  12. Reflective HTS switch

    SciTech Connect

    Martens, Jon S.; Hietala, Vincent M.; Hohenwarter, Gert K. G.

    1994-01-01

    A HTS switch includes a HTS conductor for providing a superconducting path for an electrical signal and an serpentine wire actuator for controllably heating a portion of the conductor sufficiently to cause that portion to have normal, and not superconducting, resistivity. Mass of the portion is reduced to decrease switching time.

  13. Manually operated coded switch

    DOEpatents

    Barnette, Jon H.

    1978-01-01

    The disclosure relates to a manually operated recodable coded switch in which a code may be inserted, tried and used to actuate a lever controlling an external device. After attempting a code, the switch's code wheels must be returned to their zero positions before another try is made.

  14. A Novel Molecular Switch

    PubMed Central

    Daber, Robert; Lewis, Mitchell

    2009-01-01

    Transcriptional regulation is a fundamental process for regulating the flux of all metabolic pathways. For the last several decades, the lac operon has served as a valuable model for studying transcription. More recently, the switch that controls the operon has also been successfully adapted to function in mammalian cells. Here we describe how, using directed evolution, we have created a novel switch that recognizes an asymmetric operator sequence. The new switch has a repressor with altered headpiece domains for operator recognition, and a redesigned dimer interface to create a heterodimeric repressor. Quite unexpectedly, the heterodimeric switch functions better than the natural system. It can repress more tightly than the naturally occurring switch of the lac operon; it is less leaky and can be induced more efficiently. Ultimately these novel repressors could be evolved to recognize eukaryotic promoters and used to regulate gene expression in mammalian systems. PMID:19540845

  15. Erected mirror optical switch

    DOEpatents

    Allen, James J.

    2005-06-07

    A microelectromechanical (MEM) optical switching apparatus is disclosed that is based on an erectable mirror which is formed on a rotatable stage using surface micromachining. An electrostatic actuator is also formed on the substrate to rotate the stage and mirror with a high angular precision. The mirror can be erected manually after fabrication of the device and used to redirect an incident light beam at an arbitrary angel and to maintain this state in the absence of any applied electrical power. A 1.times.N optical switch can be formed using a single rotatable mirror. In some embodiments of the present invention, a plurality of rotatable mirrors can be configured so that the stages and mirrors rotate in unison when driven by a single micromotor thereby forming a 2.times.2 optical switch which can be used to switch a pair of incident light beams, or as a building block to form a higher-order optical switch.

  16. UDel switch: an approach to very large fast-packet switches

    NASA Astrophysics Data System (ADS)

    Shin, Jeong-Gyun; Boncelet, Charles G., Jr.

    1996-11-01

    We propose a new design for a self-routing, space-division fast packet switch for ATM B-ISDN. This is an expansion switch based on binary expansion, concentration, and combination of neighboring blocks of packets. Internal buffers are needed for local synchronization and packet buffering for eventualities of path collision and/or next stage buffer full. An expansion network such as the UDEL switch provides multiple paths for any input/output pair. These multiple paths help to alleviate many common problems including head-of-line (HOL), internal path conflicts, and output collisions. Our proposal provides 10-10 packet drop rate between two stages under random uniform traffic with a unique 3-dimensional arrangement of printed- circuit boards. Batcher-banyans or similar small switches may be used as the last stage.

  17. Mindfulness facets as differential mediators of short and long-term effects of Mindfulness-Based Cognitive Therapy in diabetes outpatients: Findings from the DiaMind randomized trial.

    PubMed

    Haenen, Sharon; Nyklíček, Ivan; van Son, Jenny; Pop, Victor; Pouwer, François

    2016-06-01

    There is increasing evidence that mindfulness-based interventions reduce psychological distress in various medical populations. However, it has hardly been studied if these effects are mediated by an increase in mindfulness. The aim of this study was to examine mediating effects of various mindfulness facets on effects of a Mindfulness Based Cognitive Therapy (MBCT) on perceived stress and mood. Outpatients with diabetes types 1 and 2 and low levels of emotional wellbeing were randomized into a group receiving MBCT (n=70) or a waiting-list control group (n=69). Primary outcomes were mood and perceived stress. Before, after and at follow-up (6months post intervention) relevant questionnaires were completed. Mediation analysis using bootstrap resampling indicated that increases in total mindfulness and the facets observing and nonreactivity mediated the effects of the intervention on depressed and angry mood, anxiety (only observing), and perceived stress (only nonreactivity) from pre- to post-intervention. In contrast, from post-intervention to follow-up, besides total mindfulness the facets of acting with awareness and nonjudging mediated the effects on depressed, anxious, and angry mood, while only nonjudging mediated the eff