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

Descending pathways controlling visually guided updating of reaching in cats.

PubMed

Pettersson, L-G; Perfiliev, S

2002-10-01

This study uses a previously described paradigm (Pettersson et al., 1997) to investigate the ability of cats to change the direction of ongoing reaching when the target is shifted sideways; the effect on the switching latency of spinal cord lesions was investigated. Large ventral lesions transecting the ventral funicle and the ventral half of the lateral funicle gave a 20-30 ms latency prolongation of switching in the medial (right) direction, but less prolongation of switching directed laterally (left), and in one cat the latencies of switching directed laterally were unchanged. It may be inferred that the command for switching in the lateral direction can be mediated by the dorsally located cortico- and rubrospinal tracts whereas the command for short-latency switching in the medial direction is mediated by ventral pathways. A restricted ventral lesion transecting the tectospinal pathway did not change the switching latency. Comparison of different ventral lesions revealed prolongation of the latency if the lesion included a region extending dorsally along the ventral horn and from there ventrally as a vertical strip, so it may be postulated that the command for fast switching, directed medially, is mediated by a reticulospinal pathway within this location. A hypothesis is forwarded suggesting that the visual control is exerted via ponto-cerebellar pathways.

A Model for the Epigenetic Switch Linking Inflammation to Cell Transformation: Deterministic and Stochastic Approaches

PubMed Central

Gérard, Claude; Gonze, Didier; Lemaigre, Frédéric; Novák, Béla

2014-01-01

Recently, a molecular pathway linking inflammation to cell transformation has been discovered. This molecular pathway rests on a positive inflammatory feedback loop between NF-κB, Lin28, Let-7 microRNA and IL6, which leads to an epigenetic switch allowing cell transformation. A transient activation of an inflammatory signal, mediated by the oncoprotein Src, activates NF-κB, which elicits the expression of Lin28. Lin28 decreases the expression of Let-7 microRNA, which results in higher level of IL6 than achieved directly by NF-κB. In turn, IL6 can promote NF-κB activation. Finally, IL6 also elicits the synthesis of STAT3, which is a crucial activator for cell transformation. Here, we propose a computational model to account for the dynamical behavior of this positive inflammatory feedback loop. By means of a deterministic model, we show that an irreversible bistable switch between a transformed and a non-transformed state of the cell is at the core of the dynamical behavior of the positive feedback loop linking inflammation to cell transformation. The model indicates that inhibitors (tumor suppressors) or activators (oncogenes) of this positive feedback loop regulate the occurrence of the epigenetic switch by modulating the threshold of inflammatory signal (Src) needed to promote cell transformation. Both stochastic simulations and deterministic simulations of a heterogeneous cell population suggest that random fluctuations (due to molecular noise or cell-to-cell variability) are able to trigger cell transformation. Moreover, the model predicts that oncogenes/tumor suppressors respectively decrease/increase the robustness of the non-transformed state of the cell towards random fluctuations. Finally, the model accounts for the potential effect of competing endogenous RNAs, ceRNAs, on the dynamics of the epigenetic switch. Depending on their microRNA targets, the model predicts that ceRNAs could act as oncogenes or tumor suppressors by regulating the occurrence of cell transformation. PMID:24499937

A class of generalized Ginzburg-Landau equations with random switching

NASA Astrophysics Data System (ADS)

Wu, Zheng; Yin, George; Lei, Dongxia

2018-09-01

This paper focuses on a class of generalized Ginzburg-Landau equations with random switching. In our formulation, the nonlinear term is allowed to have higher polynomial growth rate than the usual cubic polynomials. The random switching is modeled by a continuous-time Markov chain with a finite state space. First, an explicit solution is obtained. Then properties such as stochastic-ultimate boundedness and permanence of the solution processes are investigated. Finally, two-time-scale models are examined leading to a reduction of complexity.

Overlapping activation-induced cytidine deaminase hotspot motifs in Ig class-switch recombination

PubMed Central

Han, Li; Masani, Shahnaz; Yu, Kefei

2011-01-01

Ig class-switch recombination (CSR) is directed by the long and repetitive switch regions and requires activation-induced cytidine deaminase (AID). One of the conserved switch-region sequence motifs (AGCT) is a preferred site for AID-mediated DNA-cytosine deamination. By using somatic gene targeting and recombinase-mediated cassette exchange, we established a cell line-based CSR assay that allows manipulation of switch sequences at the endogenous locus. We show that AGCT is only one of a family of four WGCW motifs in the switch region that can facilitate CSR. We go on to show that it is the overlap of AID hotspots at WGCW sites on the top and bottom strands that is critical. This finding leads to a much clearer model for the difference between CSR and somatic hypermutation. PMID:21709240

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;…

N-state random switching based on quantum tunnelling

NASA Astrophysics Data System (ADS)

Bernardo Gavito, Ramón; Jiménez Urbanos, Fernando; Roberts, Jonathan; Sexton, James; Astbury, Benjamin; Shokeir, Hamzah; McGrath, Thomas; Noori, Yasir J.; Woodhead, Christopher S.; Missous, Mohamed; Roedig, Utz; Young, Robert J.

2017-08-01

In this work, we show how the hysteretic behaviour of resonant tunnelling diodes (RTDs) can be exploited for new functionalities. In particular, the RTDs exhibit a stochastic 2-state switching mechanism that could be useful for random number generation and cryptographic applications. This behaviour can be scaled to N-bit switching, by connecting various RTDs in series. The InGaAs/AlAs RTDs used in our experiments display very sharp negative differential resistance (NDR) peaks at room temperature which show hysteresis cycles that, rather than having a fixed switching threshold, show a probability distribution about a central value. We propose to use this intrinsic uncertainty emerging from the quantum nature of the RTDs as a source of randomness. We show that a combination of two RTDs in series results in devices with three-state outputs and discuss the possibility of scaling to N-state devices by subsequent series connections of RTDs, which we demonstrate for the up to the 4-state case. In this work, we suggest using that the intrinsic uncertainty in the conduction paths of resonant tunnelling diodes can behave as a source of randomness that can be integrated into current electronics to produce on-chip true random number generators. The N-shaped I-V characteristic of RTDs results in a two-level random voltage output when driven with current pulse trains. Electrical characterisation and randomness testing of the devices was conducted in order to determine the validity of the true randomness assumption. Based on the results obtained for the single RTD case, we suggest the possibility of using multi-well devices to generate N-state random switching devices for their use in random number generation or multi-valued logic devices.

Switching Phenomena

NASA Astrophysics Data System (ADS)

Stanley, H. E.; Buldyrev, S. V.; Franzese, G.; Havlin, S.; Mallamace, F.; Mazza, M. G.; Kumar, P.; Plerou, V.; Preis, T.; Stokely, K.; Xu, L.

One challenge of biology, medicine, and economics is that the systems treated by these serious scientific disciplines can suddenly "switch" from one behavior to another, even though they possess no perfect metronome in time. As if by magic, out of nothing but randomness one finds remarkably fine-tuned processes in time. 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 temporal patterns in physics, economics, and medicine and even begin to characterize the switching phenomena that enable a system to pass from one state to another. We discuss some applications of correlated randomness to understanding 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).

Low power consumption resistance random access memory with Pt/InOx/TiN structure

NASA Astrophysics Data System (ADS)

Yang, Jyun-Bao; Chang, Ting-Chang; Huang, Jheng-Jie; Chen, Yu-Ting; Tseng, Hsueh-Chih; Chu, Ann-Kuo; Sze, Simon M.; Tsai, Ming-Jinn

2013-09-01

In this study, the resistance switching characteristics of a resistive random access memory device with Pt/InOx/TiN structure is investigated. Unstable bipolar switching behavior is observed during the initial switching cycle, which then stabilizes after several switching cycles. Analyses indicate that the current conduction mechanism in the resistance state is dominated by Ohmic conduction. The decrease in electrical conductance can be attributed to the reduction of the cross-sectional area of the conduction path. Furthermore, the device exhibits low operation voltage and power consumption.

Interpreting instructional cues in task switching procedures: the role of mediator retrieval.

PubMed

Logan, Gordon D; Schneider, Darryl W

2006-03-01

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 (e.g., ODD-3) than to incongruent cue-target combinations (e.g., ODD-4). Experiment 1 revealed significant congruency effects with transparent word cues (ODD, EVEN, HIGH, and LOW) and with relatively transparent letter cues (O, E, H, and L) but not with nontransparent letter cues (D, V, G, and W). Experiment 2 revealed significant congruency effects after subjects who were trained with nontransparent letter cues were informed of the relations between cues and word mediators halfway through the experiment. Experiment 3 showed that congruency effects with relatively transparent letter cues diminished over 10 sessions of practice, suggesting that subjects used mediators less as practice progressed. The results are discussed in terms of the role of mediators in interpreting instructional cues.

Exploring the repetition bias in voluntary task switching.

PubMed

Mittelstädt, Victor; Dignath, David; Schmidt-Ott, Magdalena; Kiesel, Andrea

2018-01-01

In the voluntary task-switching paradigm, participants are required to randomly select tasks. We reasoned that the consistent finding of a repetition bias (i.e., participants repeat tasks more often than expected by chance) reflects reasonable adaptive task selection behavior to balance the goal of random task selection with the goals to minimize the time and effort for task performance. We conducted two experiments in which participants were provided with variable amount of preview for the non-chosen task stimuli (i.e., potential switch stimuli). We assumed that switch stimuli would initiate some pre-processing resulting in improved performance in switch trials. Results showed that reduced switch costs due to extra-preview in advance of each trial were accompanied by more task switches. This finding is in line with the characteristics of rational adaptive behavior. However, participants were not biased to switch tasks more often than chance despite large switch benefits. We suggest that participants might avoid effortful additional control processes that modulate the effects of preview on task performance and task choice.

Persistent random walk of cells involving anomalous effects and random death

NASA Astrophysics Data System (ADS)

Fedotov, Sergei; Tan, Abby; Zubarev, Andrey

2015-04-01

The purpose of this paper is to implement a random death process into a persistent random walk model which produces sub-ballistic superdiffusion (Lévy walk). We develop a stochastic two-velocity jump model of cell motility for which the switching rate depends upon the time which the cell has spent moving in one direction. It is assumed that the switching rate is a decreasing function of residence (running) time. This assumption leads to the power law for the velocity switching time distribution. This describes the anomalous persistence of cell motility: the longer the cell moves in one direction, the smaller the switching probability to another direction becomes. We derive master equations for the cell densities with the generalized switching terms involving the tempered fractional material derivatives. We show that the random death of cells has an important implication for the transport process through tempering of the superdiffusive process. In the long-time limit we write stationary master equations in terms of exponentially truncated fractional derivatives in which the rate of death plays the role of tempering of a Lévy jump distribution. We find the upper and lower bounds for the stationary profiles corresponding to the ballistic transport and diffusion with the death-rate-dependent diffusion coefficient. Monte Carlo simulations confirm these bounds.

Systematic identification of phosphorylation-mediated protein interaction switches

PubMed Central

Wichmann, Oliver; Utz, Mathias; Andre, Timon; Minguez, Pablo; Parca, Luca; Roth, Frederick P.; Gavin, Anne-Claude; Bork, Peer; Russell, Robert B.

2017-01-01

Proteomics techniques can identify thousands of phosphorylation sites in a single experiment, the majority of which are new and lack precise information about function or molecular mechanism. Here we present a fast method to predict potential phosphorylation switches by mapping phosphorylation sites to protein-protein interactions of known structure and analysing the properties of the protein interface. We predict 1024 sites that could potentially enable or disable particular interactions. We tested a selection of these switches and showed that phosphomimetic mutations indeed affect interactions. We estimate that there are likely thousands of phosphorylation mediated switches yet to be uncovered, even among existing phosphorylation datasets. The results suggest that phosphorylation sites on globular, as distinct from disordered, parts of the proteome frequently function as switches, which might be one of the ancient roles for kinase phosphorylation. PMID:28346509

Toward a Probabilistic Automata Model of Some Aspects of Code-Switching.

ERIC Educational Resources Information Center

Dearholt, D. W.; Valdes-Fallis, G.

1978-01-01

The purpose of the model is to select either Spanish or English as the language to be used; its goals at this stage of development include modeling code-switching for lexical need, apparently random code-switching, dependency of code-switching upon sociolinguistic context, and code-switching within syntactic constraints. (EJS)

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.

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. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Microwave-mediated magneto-optical trap for polar molecules

NASA Astrophysics Data System (ADS)

Dizhou, Xie; Wenhao, Bu; Bo, Yan

2016-05-01

Realizing a molecular magneto-optical trap has been a dream for cold molecular physicists for a long time. However, due to the complex energy levels and the small effective Lande g-factor of the excited states, the traditional magneto-optical trap (MOT) scheme does not work very well for polar molecules. One way to overcome this problem is the switching MOT, which requires very fast switching of both the magnetic field and the laser polarizations. Switching laser polarizations is relatively easy, but fast switching of the magnetic field is experimentally challenging. Here we propose an alternative approach, the microwave-mediated MOT, which requires a slight change of the current experimental setup to solve the problem. We calculate the MOT force and compare it with the traditional MOT and the switching MOT scheme. The results show that we can operate a good MOT with this simple setup. Project supported by the Fundamental Research Funds for the Central Universities of China.

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…

Parallel Algorithms for Switching Edges in Heterogeneous Graphs.

PubMed

Bhuiyan, Hasanuzzaman; Khan, Maleq; Chen, Jiangzhuo; Marathe, Madhav

2017-06-01

An edge switch is an operation on a graph (or network) where two edges are selected randomly and one of their end vertices are swapped with each other. Edge switch operations have important applications in graph theory and network analysis, such as in generating random networks with a given degree sequence, modeling and analyzing dynamic networks, and in studying various dynamic phenomena over a network. The recent growth of real-world networks motivates the need for efficient parallel algorithms. The dependencies among successive edge switch operations and the requirement to keep the graph simple (i.e., no self-loops or parallel edges) as the edges are switched lead to significant challenges in designing a parallel algorithm. Addressing these challenges requires complex synchronization and communication among the processors leading to difficulties in achieving a good speedup by parallelization. In this paper, we present distributed memory parallel algorithms for switching edges in massive networks. These algorithms provide good speedup and scale well to a large number of processors. A harmonic mean speedup of 73.25 is achieved on eight different networks with 1024 processors. One of the steps in our edge switch algorithms requires the computation of multinomial random variables in parallel. This paper presents the first non-trivial parallel algorithm for the problem, achieving a speedup of 925 using 1024 processors.

Parallel Algorithms for Switching Edges in Heterogeneous Graphs☆

PubMed Central

Khan, Maleq; Chen, Jiangzhuo; Marathe, Madhav

2017-01-01

An edge switch is an operation on a graph (or network) where two edges are selected randomly and one of their end vertices are swapped with each other. Edge switch operations have important applications in graph theory and network analysis, such as in generating random networks with a given degree sequence, modeling and analyzing dynamic networks, and in studying various dynamic phenomena over a network. The recent growth of real-world networks motivates the need for efficient parallel algorithms. The dependencies among successive edge switch operations and the requirement to keep the graph simple (i.e., no self-loops or parallel edges) as the edges are switched lead to significant challenges in designing a parallel algorithm. Addressing these challenges requires complex synchronization and communication among the processors leading to difficulties in achieving a good speedup by parallelization. In this paper, we present distributed memory parallel algorithms for switching edges in massive networks. These algorithms provide good speedup and scale well to a large number of processors. A harmonic mean speedup of 73.25 is achieved on eight different networks with 1024 processors. One of the steps in our edge switch algorithms requires the computation of multinomial random variables in parallel. This paper presents the first non-trivial parallel algorithm for the problem, achieving a speedup of 925 using 1024 processors. PMID:28757680

HIV-1 Drug Resistance and Second-Line Treatment in Children Randomized to Switch at Low Versus Higher RNA Thresholds.

PubMed

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

2015-09-01

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. PENPACT-1 had a 2 × 2 factorial design, randomizing HIV-infected children to start protease inhibitor (PI) versus nonnucleoside reverse transcriptase inhibitor (NNRTI)-based ART, and switch at a 1000 copies/mL versus 30,000 copies/mL threshold. Switch criteria were not achieving the threshold by week 24, confirmed rebound above the threshold thereafter, or Center for Disease Control and Prevention stage C event. Resistance tests were performed on samples ≥1000 copies/mL before switch, resuppression, and at 4-years/trial end. Sixty-seven children started PI-based ART and were randomized to switch at 1000 copies/mL (PI-1000), 64 PIs and 30,000 copies/mL (PI-30,000), 67 NNRTIs and 1000 copies/mL (NNRTI-1000), and 65 NNRTI and 30,000 copies/mL (NNRTI-30,000). Ninety-four (36%) children reached the 1000 copies/mL switch criteria during 5-year follow-up. In 30,000 copies/mL threshold arms, median time from 1000 to 30,000 copies/mL switch criteria was 58 (PI) versus 80 (NNRTI) weeks (P = 0.81). In NNRTI-30,000, more nucleoside reverse transcriptase inhibitor (NRTI) resistance mutations accumulated than other groups. NNRTI mutations were selected before switching at 1000 copies/mL (23% NNRTI-1000, 27% NNRTI-30,000). 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-30,000, 64% NNRTI-1000, and 100% NNRTI-30,000 were <400 copies/mL 24 weeks later. Children on first-line NNRTI-based ART who were randomized to switch at a higher virologic threshold developed the most resistance, yet resuppressed on second-line. An abacavir + lamivudine NRTI combination seemed protective against development of NRTI resistance.

Phenotypic switching of populations of cells in a stochastic environment

NASA Astrophysics Data System (ADS)

Hufton, Peter G.; Lin, Yen Ting; Galla, Tobias

2018-02-01

In biology phenotypic switching is a common bet-hedging strategy in the face of uncertain environmental conditions. Existing mathematical models often focus on periodically changing environments to determine the optimal phenotypic response. We focus on the case in which the environment switches randomly between discrete states. Starting from an individual-based model we derive stochastic differential equations to describe the dynamics, and obtain analytical expressions for the mean instantaneous growth rates based on the theory of piecewise-deterministic Markov processes. We show that optimal phenotypic responses are non-trivial for slow and intermediate environmental processes, and systematically compare the cases of periodic and random environments. The best response to random switching is more likely to be heterogeneity than in the case of deterministic periodic environments, net growth rates tend to be higher under stochastic environmental dynamics. The combined system of environment and population of cells can be interpreted as host-pathogen interaction, in which the host tries to choose environmental switching so as to minimise growth of the pathogen, and in which the pathogen employs a phenotypic switching optimised to increase its growth rate. We discuss the existence of Nash-like mutual best-response scenarios for such host-pathogen games.

The effects of psychotomimetics and psychomotor stimulants on two schedules promoting response switching in the rat.

PubMed

Evenden, John

2002-10-01

Psychosis and psychotomimetic drugs result in a disorganisation of the structure of thought and behaviour. Normalising these is one of the objects of antipsychotic therapy, and methods for predicting such a therapeutic effect would be of value. The effects of a number of psychotomimetic agents were examined on the way in which rats distributed responding over two response levers using two different procedures, to assay their effects on behavioural organisation. Previously, amphetamine has been found to increase response switching using these schedules. In the first, the random reinforcement procedure, one of the two levers was selected at random as "correct", and responses on this lever were reinforced with food under a random ratio schedule. No signal was given to distinguish the levers. Responding could also result in the food tray being illuminated, but no food pellet was delivered ("no-food" event). Responses on the second lever ("incorrect") had no programmed consequences. After each food delivery or "no-food" event the levers designated as "correct" and "incorrect" were reassigned at random, and the rat had to open the food tray to restart the schedule. In the second procedure, the rats were required to make 21 responses before a switch between the two levers resulted in food delivery [Fixed Ratio (FR) 21-switch]. The responses making up the FR could be distributed freely between the two levers. Phencyclidine (PCP), scopolamine, caffeine and ethanol increased switching under the random reinforcement procedure, but (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) and atropine did not. PCP, caffeine, lysergic acid diethylamide (LSD) and atropine increased switching under the FR21-switch procedure, but ethanol did not. The increases in switching produced by PCP, LSD and the anticholinergics were accompanied by marked reductions in response rate, whereas those produced by amphetamine and caffeine were not. The effects of amphetamine, and PCP were strongly dependent on the baseline probability of switching, those of atropine and caffeine moderately so, and those of LSD and ethanol only weakly so. Of the agents tested, psychomotor stimulants appear to produce the most selective increases in switching. The procedures described here may be useful for assaying the disorganisation of behaviour produced by other psychotomimetics and may have value in the detection of novel antipsychotic drugs.

Task-set switching under cue-based versus memory-based switching conditions in younger and older adults.

PubMed

Kray, Jutta

2006-08-11

Adult age differences in task switching and advance preparation were examined by comparing cue-based and memory-based switching conditions. Task switching was assessed by determining two types of costs that occur at the general (mixing costs) and specific (switching costs) level of switching. Advance preparation was investigated by varying the time interval until the next task (short, middle, very long). Results indicated that the implementation of task sets was different for cue-based switching with random task sequences and memory-based switching with predictable task sequences. Switching costs were strongly reduced under cue-based switching conditions, indicating that task-set cues facilitate the retrieval of the next task. Age differences were found for mixing costs and for switching costs only under cue-based conditions in which older adults showed smaller switching costs than younger adults. It is suggested that older adults adopt a less extreme bias between two tasks than younger adults in situations associated with uncertainty. For cue-based switching with random task sequences, older adults are less engaged in a complete reconfiguration of task sets because of the probability of a further task change. Furthermore, the reduction of switching costs was more pronounced for cue- than memory-based switching for short preparation intervals, whereas the reduction of switch costs was more pronounced for memory- than cue-based switching for longer preparation intervals at least for older adults. Together these findings suggest that the implementation of task sets is functionally different for the two types of task-switching conditions.

Dual operation characteristics of resistance random access memory in indium-gallium-zinc-oxide thin film transistors

NASA Astrophysics Data System (ADS)

Yang, Jyun-Bao; Chang, Ting-Chang; Huang, Jheng-Jie; Chen, Yu-Chun; Chen, Yu-Ting; Tseng, Hsueh-Chih; Chu, Ann-Kuo; Sze, Simon M.

2014-04-01

In this study, indium-gallium-zinc-oxide thin film transistors can be operated either as transistors or resistance random access memory devices. Before the forming process, current-voltage curve transfer characteristics are observed, and resistance switching characteristics are measured after a forming process. These resistance switching characteristics exhibit two behaviors, and are dominated by different mechanisms. The mode 1 resistance switching behavior is due to oxygen vacancies, while mode 2 is dominated by the formation of an oxygen-rich layer. Furthermore, an easy approach is proposed to reduce power consumption when using these resistance random access memory devices with the amorphous indium-gallium-zinc-oxide thin film transistor.

Categorization difficulty modulates the mediated route for response selection in task switching.

PubMed

Schneider, Darryl W

2017-12-22

Conflict during response selection in task switching is indicated by the response congruency effect: worse performance for incongruent targets (requiring different responses across tasks) than for congruent targets (requiring the same response). The effect can be explained by dual-task processing in a mediated route for response selection, whereby targets are categorized with respect to both tasks. In the present study, the author tested predictions for the modulation of response congruency effects by categorization difficulty derived from a relative-speed-of-processing hypothesis. Categorization difficulty was manipulated for the relevant and irrelevant task dimensions in a novel spatial task-switching paradigm that involved judging the locations of target dots in a grid, without repetition of dot configurations. Response congruency effects were observed and they varied systematically with categorization difficulty (e.g., being larger when irrelevant categorization was easy than when it was hard). These results are consistent with the relative-speed-of-processing hypothesis and suggest that task-switching models that implement variations of the mediated route for response selection need to address the time course of categorization.

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…

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, ChangLi; Complex and Intelligent System Research Center, East China University of Science and Technology, Shanghai 200237; Wang, XueJun

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 designedmore » 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.« less

Mindset switching increases the use of 'want-based' over 'should-based' behaviors

PubMed Central

Zhang, Nan-Nan; Xu, Dai-Xuan

2018-01-01

This study examines the consequences of mindset switching on behavioral choices in want/should conflicts. Building on the insights of the ego depletion literature, we propose that mindset switching depletes individuals’ self-control resources and therefore prompts the choice of want behavior, which provides immediate pleasure, over should behavior, which provides long-term utility. Four laboratory experiments with university students that stimulated individuals to switch mindsets were conducted to test our hypotheses. Experiment 1 demonstrated that switching between individualist and collectivist mindsets increased the subjects’ tendency to prefer popular magazines over scientific journals. Experiment 2 replicated the results by testing the relationship between an abstract/concrete mindset-switching task and want/should online behavioral choices. The mediating effect of ego depletion was also supported. Experiment 3 retested the main effect of language-switching on reading choices, and the mediating effect of ego-depletion. Experiment 3 also tested the moderating effect of the Need for Cognition, and eliminated the alternative explanation of cognitive fatigue. In Experiment 4, actual food choices were used as the direct measure of want/should behaviors to test the robustness of our findings. The results consistently supported our hypotheses that mindset switching has significant effects on behavioral choices in terms of overindulgence, such as increasing want behavior and thus foregoing should behavior. PMID:29709003

Influence of platform switching on bone-level alterations: a three-year randomized clinical trial.

PubMed

Enkling, N; Jöhren, P; Katsoulis, J; Bayer, S; Jervøe-Storm, P-M; Mericske-Stern, R; Jepsen, S

2013-12-01

The concept of platform switching has been introduced to implant dentistry based on clinical observations of reduced peri-implant crestal bone loss. However, published data are controversial, and most studies are limited to 12 months. The aim of the present randomized clinical trial was to test the hypothesis that platform switching has a positive impact on crestal bone-level changes after 3 years. Two implants with a diameter of 4 mm were inserted crestally in the posterior mandible of 25 patients. The intraindividual allocation of platform switching (3.3-mm platform) and the standard implant (4-mm platform) was randomized. After 3 months of submerged healing, single-tooth crowns were cemented. Patients were followed up at short intervals for monitoring of healing and oral hygiene. Statistical analysis for the influence of time and platform type on bone levels employed the Brunner-Langer model. At 3 years, the mean radiographic peri-implant bone loss was 0.69 ± 0.43 mm (platform switching) and 0.74 ± 0.57 mm (standard platform). The mean intraindividual difference was 0.05 ± 0.58 mm (95% confidence interval: -0.19, 0.29). Crestal bone-level alteration depended on time (p < .001) but not on platform type (p = .363). The present randomized clinical trial could not confirm the hypothesis of a reduced peri-implant crestal bone loss, when implants had been restored according to the concept of platform switching.

Survival behavior in the cyclic Lotka-Volterra model with a randomly switching reaction rate

NASA Astrophysics Data System (ADS)

West, Robert; Mobilia, Mauro; Rucklidge, Alastair M.

2018-02-01

We study the influence of a randomly switching reproduction-predation rate on the survival behavior of the nonspatial cyclic Lotka-Volterra model, also known as the zero-sum rock-paper-scissors game, used to metaphorically describe the cyclic competition between three species. In large and finite populations, demographic fluctuations (internal noise) drive two species to extinction in a finite time, while the species with the smallest reproduction-predation rate is the most likely to be the surviving one (law of the weakest). Here we model environmental (external) noise by assuming that the reproduction-predation rate of the strongest species (the fastest to reproduce and predate) in a given static environment randomly switches between two values corresponding to more and less favorable external conditions. We study the joint effect of environmental and demographic noise on the species survival probabilities and on the mean extinction time. In particular, we investigate whether the survival probabilities follow the law of the weakest and analyze their dependence on the external noise intensity and switching rate. Remarkably, when, on average, there is a finite number of switches prior to extinction, the survival probability of the predator of the species whose reaction rate switches typically varies nonmonotonically with the external noise intensity (with optimal survival about a critical noise strength). We also outline the relationship with the case where all reaction rates switch on markedly different time scales.

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

2018-01-01

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.

Studying the Polarization Switching in Polycrystalline BiFeO3 Films by 2D Piezoresponse Force Microscopy

NASA Astrophysics Data System (ADS)

Jin, Yaming; Lu, Xiaomei; Zhang, Junting; Kan, Yi; Bo, Huifeng; Huang, Fengzhen; Xu, Tingting; Du, Yingchao; Xiao, Shuyu; Zhu, Jinsong

2015-07-01

For rhombohedral multiferroelectrics, non-180° ferroelectric domain switching may induce ferroelastic and/or (anti-)ferromagnetic effect. So the determination and control of ferroelectric domain switching angles is crucial for nonvolatile information storage and exchange-coupled magnetoelectric devices. We try to study the intrinsic characters of polarization switching in BiFeO3 by introducing a special data processing method to determine the switching angle from 2D PFM (Piezoresponse Force Microscopy) images of randomly oriented samples. The response surface of BiFeO3 is first plotted using the piezoelectric tensor got from first principles calculations. Then from the normalized 2D PFM signals before and after switching, the switching angles of randomly oriented BiFeO3 grains can be determined through numerical calculations. In the polycrystalline BiFeO3 films, up to 34% of all switched area is that with original out-of-plane (OP) polarization parallel to the poling field. 71° polarization switching is more favorable, with the area percentages of 71°, 109° and 180° domain switching being about 42%, 29% and 29%, respectively. Our analysis further reveals that IP stress and charge migration have comparable effect on switching, and they are sensitive to the geometric arrangements. This work helps exploring a route to control polarization switching in BiFeO3, so as to realize desirable magnetoelectric coupling.

Chromosome rearrangements via template switching between diverged repeated sequences

PubMed Central

Anand, Ranjith P.; Tsaponina, Olga; Greenwell, Patricia W.; Lee, Cheng-Sheng; Du, Wei; Petes, Thomas D.

2014-01-01

Recent high-resolution genome analyses of cancer and other diseases have revealed the occurrence of microhomology-mediated chromosome rearrangements and copy number changes. Although some of these rearrangements appear to involve nonhomologous end-joining, many must have involved mechanisms requiring new DNA synthesis. Models such as microhomology-mediated break-induced replication (MM-BIR) have been invoked to explain these rearrangements. We examined BIR and template switching between highly diverged sequences in Saccharomyces cerevisiae, induced during repair of a site-specific double-strand break (DSB). Our data show that such template switches are robust mechanisms that give rise to complex rearrangements. Template switches between highly divergent sequences appear to be mechanistically distinct from the initial strand invasions that establish BIR. In particular, such jumps are less constrained by sequence divergence and exhibit a different pattern of microhomology junctions. BIR traversing repeated DNA sequences frequently results in complex translocations analogous to those seen in mammalian cells. These results suggest that template switching among repeated genes is a potent driver of genome instability and evolution. PMID:25367035

Non-coding RNA generated following lariat-debranching mediates targeting of AID to DNA

PubMed Central

Zheng, Simin; Vuong, Bao Q.; Vaidyanathan, Bharat; Lin, Jia-Yu; Huang, Feng-Ting; Chaudhuri, Jayanta

2015-01-01

SUMMARY Transcription through immunoglobulin switch (S) regions is essential for class switch recombination (CSR) but no molecular function of the transcripts has been described. Likewise, recruitment of activation-induced cytidine deaminase (AID) to S regions is critical for CSR; however, the underlying mechanism has not been fully elucidated. Here, we demonstrate that intronic switch RNA acts in trans to target AID to S region DNA. AID binds directly to switch RNA through G-quadruplexes formed by the RNA molecules. Disruption of this interaction by mutation of a key residue in the putative RNA-binding domain of AID impairs recruitment of AID to S region DNA, thereby abolishing CSR. Additionally, inhibition of RNA lariat processing leads to loss of AID localization to S regions and compromises CSR; both defects can be rescued by exogenous expression of switch transcripts in a sequence-specific manner. These studies uncover an RNA-mediated mechanism of targeting AID to DNA. PMID:25957684

Randomized equivalence study evaluating the possibility of switching hemodialysis patients receiving subcutaneous human erythropoietin directly to intravenous darbepoetin alfa.

PubMed

Chazot, Charles; Terrat, Jean Claude; Dumoulin, Alexandre; Ang, Kim-Seng; Gassia, Jean Paul; Chedid, Khalil; Maurice, Francois; Canaud, Bernard

2009-02-01

Darbepoetin alfa is an erythropoiesis-stimulating agent (ESA) used either intravenously or subcutaneously with no dose penalty; however, the direct switch from subcutaneous recombinant human erythropoietin (rHuEPO) to intravenous darbepoetin has barely been studied. To establish the equivalence of a direct switch from subcutaneous rHuEPO to intravenous darbepoetin versus an indirect switch from subcutaneous rHuEPO to intravenous darbepoetin after 2 months of subcutaneous darbepoetin in patients undergoing hemodialysis. In this open, randomized, 6-month, prospective study, patients with end-stage kidney disease who were on hemodialysis were randomized into 2 groups: direct switch from subcutaneous rHuEPO to intravenous darbepoetin (group 1) and indirect switch from subcutaneous rHuEPO to intravenous darbepoetin after 2 months of subcutaneous darbepoetin (group 2). A third, nonrandomized group (control), consisting of patients treated with intravenous rHuEPO who were switched to intravenous darbepoetin, was also studied to reflect possible variations of hemoglobin (Hb) levels due to change from one type of ESA to the other. The primary outcome was the proportion of patients with stable Hb levels at month 6. Secondary endpoints included Hb stability at month 3, dosage requirements for darbepoetin, and safety of the administration route. Among 154 randomized patients, the percentages with stable Hb levels were equivalent in groups 1 and 2, respectively, at month 3 (86.0% vs 91.3%) and month 6 (82.1% vs 81.6%; difference -0.5 [90% CI -12.8 to 11.8]). Mean Hb levels between baseline and month 6 remained stable in both groups, with no variation in mean darbepoetin dose. Mean ferritin levels remained above 100 microg/L in the 3 groups during the whole study, and darbepoetin was well tolerated. This study has shown equivalent efficacy on Hb stability without the need for dosage increase in patients switched directly from subcutaneous rHuEPO to intravenous darbepoetin.

Magneto-optic garnet and liquid crystal optical switches

NASA Technical Reports Server (NTRS)

Krawczak, J. A.; Torok, E. J.; Harvey, W. A.; Hewitt, F. G.; Nelson, G. L.

1984-01-01

Magnetic stripe domain and liquid crystal devices are being developed and evaluated as fiber optic switches that can be utilized for nonblocking type nxm optical matrix switches in networking and optical processing. Liquid crystal switches are characterized by very low insertion loss and crosstalk, while stripe domain switches commutate in less than one microsecond. Both switches operate on multimode, randomly polarized fiber light with potentially large values for (n,m). The applications of these magnetic stripe domain and liquid crystal devices are discussed.

Markov-switching multifractal models as another class of random-energy-like models in one-dimensional space

NASA Astrophysics Data System (ADS)

Saakian, David B.

2012-03-01

We map the Markov-switching multifractal model (MSM) onto the random energy model (REM). The MSM is, like the REM, an exactly solvable model in one-dimensional space with nontrivial correlation functions. According to our results, four different statistical physics phases are possible in random walks with multifractal behavior. We also introduce the continuous branching version of the model, calculate the moments, and prove multiscaling behavior. Different phases have different multiscaling properties.

Suppression of lethal autoimmunity by regulatory T cells with a single TCR specificity

PubMed Central

Hemmers, Saskia; Schizas, Michail; Faire, Mehlika B.; Konopacki, Catherine; Schmidt-Supprian, Marc; Germain, Ronald N.

2017-01-01

The regulatory T cell (T reg cell) T cell receptor (TCR) repertoire is highly diverse and skewed toward recognition of self-antigens. TCR expression by T reg cells is continuously required for maintenance of immune tolerance and for a major part of their characteristic gene expression signature; however, it remains unknown to what degree diverse TCR-mediated interactions with cognate self-antigens are required for these processes. In this study, by experimentally switching the T reg cell TCR repertoire to a single T reg cell TCR, we demonstrate that T reg cell function and gene expression can be partially uncoupled from TCR diversity. An induced switch of the T reg cell TCR repertoire to a random repertoire also preserved, albeit to a limited degree, the ability to suppress lymphadenopathy and T helper cell type 2 activation. At the same time, these perturbations of the T reg cell TCR repertoire led to marked immune cell activation, tissue inflammation, and an ultimately severe autoimmunity, indicating the importance of diversity and specificity for optimal T reg cell function. PMID:28130403

Age-related decline in task switching is linked to both global and tract-specific changes in white matter microstructure.

PubMed

Jolly, Todd A D; Cooper, Patrick S; Rennie, Jaime L; Levi, Christopher R; Lenroot, Rhoshel; Parsons, Mark W; Michie, Patricia T; Karayanidis, Frini

2017-03-01

Task-switching performance relies on a broadly distributed frontoparietal network and declines in older adults. In this study, they investigated whether this age-related decline in task switching performance was mediated by variability in global or regional white matter microstructural health. Seventy cognitively intact adults (43-87 years) completed a cued-trials task switching paradigm. Microstructural white matter measures were derived using diffusion tensor imaging (DTI) analyses on the diffusion-weighted imaging (DWI) sequence. Task switching performance decreased with increasing age and radial diffusivity (RaD), a measure of white matter microstructure that is sensitive to myelin structure. RaD mediated the relationship between age and task switching performance. However, the relationship between RaD and task switching performance remained significant when controlling for age and was stronger in the presence of cardiovascular risk factors. Variability in error and RT mixing cost were associated with RaD in global white matter and in frontoparietal white matter tracts, respectively. These findings suggest that age-related increase in mixing cost may result from both global and tract-specific disruption of cerebral white matter linked to the increased incidence of cardiovascular risks in older adults. Hum Brain Mapp 38:1588-1603, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Outcome switching in randomized controlled oncology trials reporting on surrogate endpoints: a cross-sectional analysis.

PubMed

Falk Delgado, Alberto; Falk Delgado, Anna

2017-08-23

Inconsistent reporting of clinical trials is well-known in the literature. Despite this, factors associated with poor practice such as outcome switching in clinical trials are poorly understood. We performed a cross-sectional analysis to evaluate the prevalence of, and the factors associated with outcome switching. PubMed and Embase were searched for pharmaceutical randomized controlled trials (RCTs) in oncology reporting on a surrogate primary outcome published in 2015. Outcome switching was present in 18% (39/216). First-author male sex was significantly more likely associated with outcome switching compared to female sex with an OR of 3.05 (95% CI 1.07-8.64, p = 0.04) after multivariable adjustment. For-profit funded RCTs were less likely associated with outcome switching compared to non-profit funded research with an OR of 0.22 (95% CI 0.07-0.74, p = 0.01). First author male sex was more likely associated with outcome switching compared to female sex in drug oncology RCTs reporting on a primary surrogate endpoint. For-profit funded research was less likely associated with outcome switching compared to research funded by non-profit organizations. Furthermore, 18 percent of drug oncology trials reporting on a surrogate endpoint could have a higher risk of false positive results due to primary outcome switching.

Robust reliable sampled-data control for switched systems with application to flight control

NASA Astrophysics Data System (ADS)

Sakthivel, R.; Joby, Maya; Shi, P.; Mathiyalagan, K.

2016-11-01

This paper addresses the robust reliable stabilisation problem for a class of uncertain switched systems with random delays and norm bounded uncertainties. The main aim of this paper is to obtain the reliable robust sampled-data control design which involves random time delay with an appropriate gain control matrix for achieving the robust exponential stabilisation for uncertain switched system against actuator failures. In particular, the involved delays are assumed to be randomly time-varying which obeys certain mutually uncorrelated Bernoulli distributed white noise sequences. By constructing an appropriate Lyapunov-Krasovskii functional (LKF) and employing an average-dwell time approach, a new set of criteria is derived for ensuring the robust exponential stability of the closed-loop switched system. More precisely, the Schur complement and Jensen's integral inequality are used in derivation of stabilisation criteria. By considering the relationship among the random time-varying delay and its lower and upper bounds, a new set of sufficient condition is established for the existence of reliable robust sampled-data control in terms of solution to linear matrix inequalities (LMIs). Finally, an illustrative example based on the F-18 aircraft model is provided to show the effectiveness of the proposed design procedures.

Selective randomized load balancing and mesh networks with changing demands

NASA Astrophysics Data System (ADS)

Shepherd, F. B.; Winzer, P. J.

2006-05-01

We consider the problem of building cost-effective networks that are robust to dynamic changes in demand patterns. We compare several architectures using demand-oblivious routing strategies. Traditional approaches include single-hop architectures based on a (static or dynamic) circuit-switched core infrastructure and multihop (packet-switched) architectures based on point-to-point circuits in the core. To address demand uncertainty, we seek minimum cost networks that can carry the class of hose demand matrices. Apart from shortest-path routing, Valiant's randomized load balancing (RLB), and virtual private network (VPN) tree routing, we propose a third, highly attractive approach: selective randomized load balancing (SRLB). This is a blend of dual-hop hub routing and randomized load balancing that combines the advantages of both architectures in terms of network cost, delay, and delay jitter. In particular, we give empirical analyses for the cost (in terms of transport and switching equipment) for the discussed architectures, based on three representative carrier networks. Of these three networks, SRLB maintains the resilience properties of RLB while achieving significant cost reduction over all other architectures, including RLB and multihop Internet protocol/multiprotocol label switching (IP/MPLS) networks using VPN-tree routing.

Deferred Pre-Emptive Switch from Calcineurin Inhibitor to Sirolimus Leads to Improvement in GFR and Expansion of T Regulatory Cell Population: A Randomized, Controlled Trial

PubMed Central

Bansal, Dinesh; Yadav, Ashok K.; Kumar, Vinod; Minz, Mukut; Sakhuja, Vinay; Jha, Vivekanand

2013-01-01

Background Measures to prevent chronic calcineurin inhibitor (CNI) toxicity have included limiting exposure by switching to sirolimus (SIR). SIR may favorably influence T regulator cell (Treg) population. This randomized controlled trial compares the effect of switching from CNI to SIR on glomerular filtration rate (GFR) and Treg frequency. Methods In this prospective open label randomized trial, primary living donor kidney transplant recipients on CNI-based immunosuppression were randomized to continue CNI or switched to sirolimus 2 months after surgery; 29 were randomized to receive CNI and 31 to SIR. All patients received mycophenolate mofetil and steroids. The main outcome parameter was estimated GFR (eGFR) at 180 days. Treg population was estimated by flowcytometry. Results Baseline characteristics in the two groups were similar. Forty-eight patients completed the trial. At six months, patients in the SIR group had significantly higher eGFR as compared to those in the CNI group (88.94±11.78 vs 80.59±16.51 mL/min, p = 0.038). Patients on SIR had a 12 mL/min gain of eGFR of at the end of six months. Patients in the SIR group showed significant increase in Treg population at 30 days, which persisted till day 180. There was no difference in the adverse events in terms of number of acute rejection episodes, death, infections, proteinuria, lipid profile, blood pressure control and hematological parameters between the two groups. Four patients taking SIR developed enthesitis. No patient left the study or switched treatment because of adverse event. Conclusions A deferred pre-emptive switch over from CNI to SIR safely improves renal function and Treg population at 6 months in living donor kidney transplant recipients. Registered in Clinical Trials Registry of India (CTRI/2011/091/000034) PMID:24146762

EGF-dependent re-routing of vesicular recycling switches spontaneous phosphorylation suppression to EGFR signaling

PubMed Central

Baumdick, Martin; Brüggemann, Yannick; Schmick, Malte; Xouri, Georgia; Sabet, Ola; Davis, Lloyd; Chin, Jason W; Bastiaens, Philippe IH

2015-01-01

Autocatalytic activation of epidermal growth factor receptor (EGFR) coupled to dephosphorylating activity of protein tyrosine phosphatases (PTPs) ensures robust yet diverse responses to extracellular stimuli. The inevitable tradeoff of this plasticity is spontaneous receptor activation and spurious signaling. We show that a ligand-mediated switch in EGFR trafficking enables suppression of spontaneous activation while maintaining EGFR’s capacity to transduce extracellular signals. Autocatalytic phosphorylation of tyrosine 845 on unliganded EGFR monomers is suppressed by vesicular recycling through perinuclear areas with high PTP1B activity. Ligand-binding results in phosphorylation of the c-Cbl docking tyrosine and ubiquitination of the receptor. This secondary signal relies on EGF-induced EGFR self-association and switches suppressive recycling to directional trafficking. The re-routing regulates EGFR signaling response by the transit-time to late endosomes where it is switched-off by high PTP1B activity. This ubiquitin-mediated switch in EGFR trafficking is a uniquely suited solution to suppress spontaneous activation while maintaining responsiveness to EGF. DOI: http://dx.doi.org/10.7554/eLife.12223.001 PMID:26609808

Resistance Switching Memory Characteristics of Si/CaF2/CdF2 Quantum-Well Structures Grown on Metal (CoSi2) Layer

NASA Astrophysics Data System (ADS)

Denda, Junya; Uryu, Kazuya; Watanabe, Masahiro

2013-04-01

A novel scheme of resistance switching random access memory (ReRAM) devices fabricated using Si/CaF2/CdF2/CaF2/Si quantum-well structures grown on metal CoSi2 layer formed on a Si substrate has been proposed, and embryonic write/erase memory operation has been demonstrated at room temperature. It has been found that the oxide-mediated epitaxy (OME) technique for forming the CoSi2 layer on Si dramatically improves the stability and reproducibility of the current-voltage (I-V) curve. This technology involves 10-nm-thick Co layer deposition on a protective oxide prepared by boiling in a peroxide-based solution followed by annealing at 550 °C for 30 min for silicidation in ultrahigh vacuum. A switching voltage of lower than 1 V, a peak current density of 32 kA/cm2, and an ON/OFF ratio of 10 have been observed for the sample with the thickness sequence of 0.9/0.9/2.5/0.9/5.0 nm for the respective layers in the Si/CaF2/CdF2/CaF2/Si structure. Results of surface morphology analysis suggest that the grain size of crystal islands with flat surfaces strongly affects the quality of device characteristics.

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

Immediate vs. Deferred Switching from a Boosted Protease Inhibitor (PI/r) Based Regimen to a Dolutegravir (DTG) Based Regimen in Virologically Suppressed Patients with High Cardiovascular Risk or Age ≥50 years: Final 96 Weeks Results of NEAT 022 study.

PubMed

Gatell, José M; Assoumou, Lambert; Moyle, Graeme; Waters, Laura; Johnson, Margaret; Domingo, Pere; Fox, Julie; Martinez, Esteban; Stellbrink, Hans-Jürgen; Guaraldi, Giovanni; Masia, Mar; Gompels, Mark; De Wit, Stephane; Florence, Eric; Esser, Stefan; Raffi, François; Stephan, Christoph; Rockstroh, Juergen; Giacomelli, Andrea; Vera, Jaime; Bernardino, José Ignacio; Winston, Alan; Saumoy, Maria; Gras, Julien; Katlama, Christine; Pozniak, Anton L

2018-06-14

Both immediate or deferred switching from a PI/r to DTG may improve lipid profile. NEAT022 is a European, open label, randomized, trial. HIV-infected adults ≥ 50 years or with a Framingham score ≥10% were eligible if HIV RNA < 50 copies/mL. Patients were randomized to switch the PI/r to DTG immediately (DTG-I) or to deferred switch at week 48 (DTG-D) . Week 96 end-points were: proportion of patients with HIV RNA < 50 copies/ml, percentage change of lipid fractions and adverse events. 415 patients were randomized: 205 to DTG-I and 210 to continue PI/r plus a deferred switch (DTG-D) at week 48 . The primary objective of non-inferiority at week 48 was met. At week 96, treatment success rate was 92.2 % in DTG-I arm and 87% in DTG-D arm (difference 5.2%, 95% CI -0.6 to 11). There were 5 virological failures in the DTG-I arm and 5 (1 while on PI/r and 4 after switching to DTG) in the DTG-D arm without selection of resistance mutations. There was no significant difference in terms of grade 3 or 4 AE´s or treatment modifying AE´s. Total cholesterol and other lipid fractions (except HDL) significantly (p<0.001) improved both after immediate and deferred switching to DTG overall and regardless of baseline PI/r strata. Both immediate and deferred switching from a PI/r to a DTG regimen in virologically suppressed HIV patients ≥ 50 years old or with a Framingham score ≥10% was highly efficacious, well tolerated and improved lipid profile.

The risks and benefits of switching patients with schizophrenia or schizoaffective disorder from two to one antipsychotic medication: a randomized controlled trial.

PubMed

Constantine, Robert J; Andel, Ross; McPherson, Marie; Tandon, Rajiv

2015-08-01

Despite little evidence to support its use and practice guidelines discouraging the practice, antipsychotic polypharmacy is widely prevalent in schizophrenia. This randomized controlled trial studied the effects of switching patients stable on two antipsychotic medications to one antipsychotic medication. 104 adult outpatients with schizophrenia from 7 community mental health centers clinically stable on concurrent treatment with 2 antipsychotics were randomly assigned to stay on polypharmacy or to switch to antipsychotic monotherapy. Participants were followed for 1-year with assessments of symptoms and side effects occurring every 60days (7 total assessments). We examined differences in time trajectories in symptoms (PANSS, CGI) and side effects (EPS, metabolic, other) as a function of group assignment (switch vs. stay) and time, using intention-to-treat analysis. Participants who switched to antipsychotic monotherapy experienced greater increases in symptoms than stay patients. These differences emerged in the second 6months of the trial. All-cause discontinuation rates over the 1-year trial were higher in the switch-to-monotherapy group than in the stay-on-polypharmacy group (42% vs. 13%; p<0.01). There were no differences in change over time in any of the side effect measures, except that stay patients experienced a greater decrease in Simpson Angus total scores than switch patients. Clinicians should be cautious in switching patients with chronic schizophrenia who are stable on 2 antipsychotics to one antipsychotic. Given the challenges in discontinuing antipsychotic polypharmacy, adequate trials of evidence-based treatments such as clozapine and long-acting injectable antipsychotics should be undertaken in inadequately responsive schizophrenia patients before moving to antipsychotic polypharmacy. Copyright © 2015 Elsevier B.V. All rights reserved.

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…

Sequenced treatment alternatives to relieve depression (STAR*D): rationale and design.

PubMed

Rush, A John; Fava, Maurizio; Wisniewski, Stephen R; Lavori, Philip W; Trivedi, Madhukar H; Sackeim, Harold A; Thase, Michael E; Nierenberg, Andrew A; Quitkin, Frederic M; Kashner, T Michael; Kupfer, David J; Rosenbaum, Jerrold F; Alpert, Jonathan; Stewart, Jonathan W; McGrath, Patrick J; Biggs, Melanie M; Shores-Wilson, Kathy; Lebowitz, Barry D; Ritz, Louise; Niederehe, George

2004-02-01

STAR*D is a multisite, prospective, randomized, multistep clinical trial of outpatients with nonpsychotic major depressive disorder. The study compares various treatment options for those who do not attain a satisfactory response with citalopram, a selective serotonin reuptake inhibitor antidepressant. The study enrolls 4000 adults (ages 18-75) from both primary and specialty care practices who have not had either a prior inadequate response or clear-cut intolerance to a robust trial of protocol treatments during the current major depressive episode. After receiving citalopram (level 1), participants without sufficient symptomatic benefit are eligible for randomization to level 2 treatments, which entail four switch options (sertraline, bupropion, venlafaxine, cognitive therapy) and three citalopram augment options (bupropion, buspirone, cognitive therapy). Those who receive cognitive therapy (switch or augment options) at level 2 without sufficient improvement are eligible for randomization to one of two level 2A switch options (venlafaxine or bupropion). Level 2 and 2A participants are eligible for random assignment to two switch options (mirtazapine or nortriptyline) and to two augment options (lithium or thyroid hormone) added to the primary antidepressant (citalopram, bupropion, sertraline, or venlafaxine) (level 3). Those without sufficient improvement at level 3 are eligible for level 4 random assignment to one of two switch options (tranylcypromine or the combination of mirtazapine and venlafaxine). The primary outcome is the clinician-rated, 17-item Hamilton Rating Scale for Depression, administered at entry and exit from each treatment level through telephone interviews by assessors masked to treatment assignments. Secondary outcomes include self-reported depressive symptoms, physical and mental function, side-effect burden, client satisfaction, and health care utilization and cost. Participants with an adequate symptomatic response may enter the 12-month naturalistic follow-up phase with brief monthly and more complete quarterly assessments.

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.

Nutritional and behavioral effects of gorge and fast feeding in captive lions.

PubMed

Altman, Joanne D; Gross, Kathy L; Lowry, Stephen R

2005-01-01

Nonhuman animals in captivity manifest behaviors and physiological conditions that are not common in the wild. Lions in captivity face problems of obesity, inactivity, and stereotypy. To mediate common problems of captive lions, this study implemented a gorge and fast feeding schedule that better models naturalistic patterns: African lions (Panthera leo) gradually adapted from a conventional feeding program to a random gorge and fast feeding schedule. Digestibility increased significantly and food intake and metabolizable energy intake correspondingly decreased. Lions also showed an increase in appetitive active behaviors, no increase in agonistic behavior, and paced half as frequently on fast days as on feeding days. Thus, switching captive lions to a gorge and fast feeding schedule resulted in improved nutritional status and increased activity.

Photoinduced charge carriers' accumulation and its impact on random lasing in Nd3+ doped (Pb,La)(Zr,Ti)O3 ceramics

NASA Astrophysics Data System (ADS)

Xu, Caixia; Zhang, Jingwen; Xu, Long; Ma, Xinyan; Zhao, Hua

2017-06-01

To pinpoint the driving forces behind the random lasing in Nd3+ doped lanthanum lead zirconate titanate (Nd:PLZT) ceramic plates, a combinatorial cavity with two gain media (Nd:YVO4 and Nd:PLZT) was used to study the switching feature between conventional lasing and random lasing oscillations. The complex laser output dynamics observed hinted that the photo-induced charge accumulation on the plate surface and the grain boundaries of Nd:PLZT is responsible for the lasing action switching, which was confirmed by a series of experiments, including strong electro-induced scattering, remarkable photoinduced currents, and light transmission reduction, along with measured single-pass-gain over the theoretical limit. It was found that the charge accumulation results in optical energy storage and nonuniform refractive index and hence strong scattering, which give rise to the random walks and weak localization of photons and long lasting lasing action and mode switching.

Anisotropy Induced Switching Field Distribution in High-Density Patterned Media

NASA Astrophysics Data System (ADS)

Talapatra, A.; Mohanty, J.

We present here micromagnetic study of variation of switching field distribution (SFD) in a high-density patterned media as a function of magnetic anisotropy of the system. We consider the manifold effect of magnetic anisotropy in terms of its magnitude, tilt in anisotropy axis and random arrangements of magnetic islands with random anisotropy values. Our calculation shows that reduction in anisotropy causes linear decrease in coercivity because the anisotropy energy tries to align the spins along a preferred crystallographic direction. Tilt in anisotropy axis results in decrease in squareness of the hysteresis loop and hence facilitates switching. Finally, the experimental challenges like lithographic distribution of magnetic islands, their orientation, creation of defects, etc. demanded the distribution of anisotropy to be random along with random repetitions. We have explained that the range of anisotropy values and the number of bits with different anisotropy play a key role over SFD, whereas the position of the bits and their repetitions do not show a considerable contribution.

Ames Lab 101: Ultrafast Magnetic Switching

ScienceCinema

Wang; Jigang

2018-01-01

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.

Static magnetism and thermal switching in randomly oriented L10 FePt thin films

NASA Astrophysics Data System (ADS)

Lisfi, A.; Pokharel, S.; Alqarni, A.; Akioya, O.; Morgan, W.; Wuttig, M.

2018-05-01

Static magnetism and thermally activated magnetic relaxation were investigated in granular FePt films (20 nm-200 nm thick) with random magnetic anisotropy through hysteresis loop, torque curve and magnetization time dependence measurements. While the magnetism of thicker film (200 nm thick) is dominated by a single switching of the ordered L10 phase, thinner film (20 nm) displays a double switching, which is indicative of the presence of the disordered cubic phase. The pronounced behavior of double switching in thinner film suggests that the film grain boundary is composed of soft cubic magnetic phase. The magnetic relaxation study reveals that magnetic viscosity S of the films is strongly dependent on the external applied field and exhibits a maximum value (12 kAm) around the switching field and a vanishing behavior at low (1 kOe) and large (12 kOe) fields. The activation volume of the thermal switching was found to be much smaller than the physical volume of the granular structure due to the incoherent rotation mode of the magnetization reversal mechanism, which is established to be domain wall nucleation.

Improving Unipolar Resistive Switching Uniformity with Cone-Shaped Conducting Filaments and Its Logic-In-Memory Application.

PubMed

Gao, Shuang; Liu, Gang; Chen, Qilai; Xue, Wuhong; Yang, Huali; Shang, Jie; Chen, Bin; Zeng, Fei; Song, Cheng; Pan, Feng; Li, Run-Wei

2018-02-21

Resistive random access memory (RRAM) with inherent logic-in-memory capability exhibits great potential to construct beyond von-Neumann computers. Particularly, unipolar RRAM is more promising because its single polarity operation enables large-scale crossbar logic-in-memory circuits with the highest integration density and simpler peripheral control circuits. However, unipolar RRAM usually exhibits poor switching uniformity because of random activation of conducting filaments and consequently cannot meet the strict uniformity requirement for logic-in-memory application. In this contribution, a new methodology that constructs cone-shaped conducting filaments by using chemically a active metal cathode is proposed to improve unipolar switching uniformity. Such a peculiar metal cathode will react spontaneously with the oxide switching layer to form an interfacial layer, which together with the metal cathode itself can act as a load resistor to prevent the overgrowth of conducting filaments and thus make them more cone-like. In this way, the rupture of conducting filaments can be strictly limited to the tip region, making their residual parts favorable locations for subsequent filament growth and thus suppressing their random regeneration. As such, a novel "one switch + one unipolar RRAM cell" hybrid structure is capable to realize all 16 Boolean logic functions for large-scale logic-in-memory circuits.

Workload Transition: Implications for Individual and Team Performance

DTIC Science & Technology

1993-01-01

a hrlf second) if they are motivated to do so, and they will choose one strategy or the other on the basis of the probability that it will best serve...Arousal, 106 Conclusion, 107 Mediating Effects, 107 Coping with Stress, 108 DesiZ.n Solutions. 108 Strategies , 109 Training, 109 Team Models: Implications...214 Cognitive Switching, 214 Strategy Switching, 215 Task Switching. 216 Implications for Workload Transition, 219 CONTENTS XV

Caudate Nucleus Volume Mediates the Link between Cardiorespiratory Fitness and Cognitive Flexibility in Older Adults

PubMed Central

Verstynen, Timothy D.; Lynch, Brighid; Miller, Destiny L.; Voss, Michelle W.; Prakash, Ruchika Shaurya; Chaddock, Laura; Basak, Chandramallika; Szabo, Amanda; Olson, Erin A.; Wojcicki, Thomas R.; Fanning, Jason; Gothe, Neha P.; McAuley, Edward; Kramer, Arthur F.; Erickson, Kirk I.

2012-01-01

The basal ganglia play a central role in regulating the response selection abilities that are critical for mental flexibility. In neocortical areas, higher cardiorespiratory fitness levels are associated with increased gray matter volume, and these volumetric differences mediate enhanced cognitive performance in a variety of tasks. Here we examine whether cardiorespiratory fitness correlates with the volume of the subcortical nuclei that make up the basal ganglia and whether this relationship predicts cognitive flexibility in older adults. Structural MRI was used to determine the volume of the basal ganglia nuclei in a group of older, neurologically healthy individuals (mean age 66 years, N = 179). Measures of cardiorespiratory fitness (VO2max), cognitive flexibility (task switching), and attentional control (flanker task) were also collected. Higher fitness levels were correlated with higher accuracy rates in the Task Switching paradigm. In addition, the volume of the caudate nucleus, putamen, and globus pallidus positively correlated with Task Switching accuracy. Nested regression modeling revealed that caudate nucleus volume was a significant mediator of the relationship between cardiorespiratory fitness, and task switching performance. These findings indicate that higher cardiorespiratory fitness predicts better cognitive flexibility in older adults through greater grey matter volume in the dorsal striatum. PMID:22900181

BRN2, a POUerful driver of melanoma phenotype switching and metastasis.

PubMed

Fane, Mitchell E; Chhabra, Yash; Smith, Aaron G; Sturm, Richard A

2018-05-21

The POU domain family of transcription factors play a central role in embryogenesis and are highly expressed in neural crest cells and the developing brain. BRN2 is a class III POU domain protein that is a key mediator of neuroendocrine and melanocytic development and differentiation. While BRN2 is a central regulator in numerous developmental programs, it has also emerged as a major player in the biology of tumourigenesis. In melanoma, BRN2 has been implicated as one of the master regulators of the acquisition of invasive behavior within the phenotype-switching model of progression. As a mediator of melanoma cell phenotype-switching it co-ordinates the transition to a de-differentiated, slow cycling and highly motile cell type. Its inverse expression relationship with MITF is believed to mediate tumour progression and metastasis within this model. Recent evidence has now outlined a potential epigenetic switching mechanism in melanoma cells driven by BRN2 expression that induces melanoma cell invasion. We summarise the role of BRN2 in tumour cell dissemination and metastasis in melanoma, while also examining it as a potential metastatic regulator in other tumour models. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

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 with more gastrointestinal adverse effects. Health-related quality of life was similar between groups. Patients with duodenal switch underwent more surgical procedures related to the initial procedure (13 [44.8%] vs 3 [9.7%] patients; P = .002) and had significantly more hospital admissions compared with patients with gastric bypass. In patients with a body mass index of 50 to 60, duodenal switch resulted in greater weight loss and greater improvements in low-density lipoprotein cholesterol, triglyceride, and glucose levels 5 years after surgery compared with gastric bypass while improvements in health-related quality of life were similar. However, duodenal switch was associated with more surgical, nutritional, and gastrointestinal adverse effects. clinicaltrials.gov Identifier: NCT00327912.

Dynamic-load-enabled ultra-low power multiple-state RRAM devices.

PubMed

Yang, Xiang; Chen, I-Wei

2012-01-01

Bipolar resistance-switching materials allowing intermediate states of wide-varying resistance values hold the potential of drastically reduced power for non-volatile memory. To exploit this potential, we have introduced into a nanometallic resistance-random-access-memory (RRAM) device an asymmetric dynamic load, which can reliably lower switching power by orders of magnitude. The dynamic load is highly resistive during on-switching allowing access to the highly resistive intermediate states; during off-switching the load vanishes to enable switching at low voltage. This approach is entirely scalable and applicable to other bipolar RRAM with intermediate states. The projected power is 12 nW for a 100 × 100 nm(2) device and 500 pW for a 10 × 10 nm(2) device. The dynamic range of the load can be increased to allow power to be further decreased by taking advantage of the exponential decay of wave-function in a newly discovered nanometallic random material, reaching possibly 1 pW for a 10×10 nm(2) nanometallic RRAM device.

Role of Al2O3 thin layer on improving the resistive switching properties of Ta5Si3-based conductive bridge random accesses memory device

NASA Astrophysics Data System (ADS)

Kumar, Dayanand; Aluguri, Rakesh; Chand, Umesh; Tseng, Tseung-Yuen

2018-04-01

Ta5Si3-based conductive bridge random access memory (CBRAM) devices have been investigated to improve their resistive switching characteristics for their application in future nonvolatile memory technology. Changes in the switching characteristics by the addition of a thin Al2O3 layer of different thicknesses at the bottom electrode interface of a Ta5Si3-based CBRAM devices have been studied. The double-layer device with a 1 nm Al2O3 layer has shown improved resistive switching characteristics over the single layer one with a high on/off resistance ratio of 102, high endurance of more than 104 cycles, and good retention for more than 105 s at the temperature of 130 °C. The higher thermal conductivity of Al2O3 over Ta5Si3 has been attributed to the enhanced switching properties of the double-layer devices.

SiGe epitaxial memory for neuromorphic computing with reproducible high performance based on engineered dislocations

NASA Astrophysics Data System (ADS)

Choi, Shinhyun; Tan, Scott H.; Li, Zefan; Kim, Yunjo; Choi, Chanyeol; Chen, Pai-Yu; Yeon, Hanwool; Yu, Shimeng; Kim, Jeehwan

2018-01-01

Although several types of architecture combining memory cells and transistors have been used to demonstrate artificial synaptic arrays, they usually present limited scalability and high power consumption. Transistor-free analog switching devices may overcome these limitations, yet the typical switching process they rely on—formation of filaments in an amorphous medium—is not easily controlled and hence hampers the spatial and temporal reproducibility of the performance. Here, we demonstrate analog resistive switching devices that possess desired characteristics for neuromorphic computing networks with minimal performance variations using a single-crystalline SiGe layer epitaxially grown on Si as a switching medium. Such epitaxial random access memories utilize threading dislocations in SiGe to confine metal filaments in a defined, one-dimensional channel. This confinement results in drastically enhanced switching uniformity and long retention/high endurance with a high analog on/off ratio. Simulations using the MNIST handwritten recognition data set prove that epitaxial random access memories can operate with an online learning accuracy of 95.1%.

Space-charge-mediated anomalous ferroelectric switching in P(VDF-TrEE) polymer films.

PubMed

Hu, Weijin; Wang, Zhihong; Du, Yuanmin; Zhang, Xi-Xiang; Wu, Tom

2014-11-12

We report on the switching dynamics of P(VDF-TrEE) copolymer devices and the realization of additional substable ferroelectric states via modulation of the coupling between polarizations and space charges. The space-charge-limited current is revealed to be the dominant leakage mechanism in such organic ferroelectric devices, and electrostatic interactions due to space charges lead to the emergence of anomalous ferroelectric loops. The reliable control of ferroelectric switching in P(VDF-TrEE) copolymers opens doors toward engineering advanced organic memories with tailored switching characteristics.

Improvement of Bipolar Switching Properties of Gd:SiOx RRAM Devices on Indium Tin Oxide Electrode by Low-Temperature Supercritical CO2 Treatment.

PubMed

Chen, Kai-Huang; Chang, Kuan-Chang; Chang, Ting-Chang; Tsai, Tsung-Ming; Liang, Shu-Ping; Young, Tai-Fa; Syu, Yong-En; Sze, Simon M

2016-12-01

Bipolar switching resistance behaviors of the Gd:SiO2 resistive random access memory (RRAM) devices on indium tin oxide electrode by the low-temperature supercritical CO2-treated technology were investigated. For physical and electrical measurement results obtained, the improvement on oxygen qualities, properties of indium tin oxide electrode, and operation current of the Gd:SiO2 RRAM devices were also observed. In addition, the initial metallic filament-forming model analyses and conduction transferred mechanism in switching resistance properties of the RRAM devices were verified and explained. Finally, the electrical reliability and retention properties of the Gd:SiO2 RRAM devices for low-resistance state (LRS)/high-resistance state (HRS) in different switching cycles were also measured for applications in nonvolatile random memory devices.

P-Tether-Mediated, Iterative SN2'-Cuprate Alkylation Strategy to Skipped Polyol Stereotetrads: Utility of an Oxidative "Function Switch" with Phosphite-Borane Tethers.

PubMed

Markley, Jana L; Hanson, Paul R

2017-05-19

The development of a P-tether-mediated, iterative S N 2'-cuprate alkylation protocol for the formation of 1,3-skipped polyol stereotetrads is reported. This two-directional synthetic strategy builds molecular complexity from simple, readily prepared C 2 -symmetric dienediols and unites the chemistry of both temporary phosphite-borane tethers and temporary phosphate tethers-through an oxidative "function switch" of the P-tether itself-to generate intermediates that were previously inaccessible via either method alone.

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.

Ultra-fast quantum randomness generation by accelerated phase diffusion in a pulsed laser diode.

PubMed

Abellán, C; Amaya, W; Jofre, M; Curty, M; Acín, A; Capmany, J; Pruneri, V; Mitchell, M W

2014-01-27

We demonstrate a high bit-rate quantum random number generator by interferometric detection of phase diffusion in a gain-switched DFB laser diode. Gain switching at few-GHz frequencies produces a train of bright pulses with nearly equal amplitudes and random phases. An unbalanced Mach-Zehnder interferometer is used to interfere subsequent pulses and thereby generate strong random-amplitude pulses, which are detected and digitized to produce a high-rate random bit string. Using established models of semiconductor laser field dynamics, we predict a regime of high visibility interference and nearly complete vacuum-fluctuation-induced phase diffusion between pulses. These are confirmed by measurement of pulse power statistics at the output of the interferometer. Using a 5.825 GHz excitation rate and 14-bit digitization, we observe 43 Gbps quantum randomness generation.

Evolution of a Fluctuating Population in a Randomly Switching Environment.

PubMed

Wienand, Karl; Frey, Erwin; Mobilia, Mauro

2017-10-13

Environment plays a fundamental role in the competition for resources, and hence in the evolution of populations. Here, we study a well-mixed, finite population consisting of two strains competing for the limited resources provided by an environment that randomly switches between states of abundance and scarcity. Assuming that one strain grows slightly faster than the other, we consider two scenarios-one of pure resource competition, and one in which one strain provides a public good-and investigate how environmental randomness (external noise) coupled to demographic (internal) noise determines the population's fixation properties and size distribution. By analytical means and simulations, we show that these coupled sources of noise can significantly enhance the fixation probability of the slower-growing species. We also show that the population size distribution can be unimodal, bimodal, or multimodal and undergoes noise-induced transitions between these regimes when the rate of switching matches the population's growth rate.

Evolution of a Fluctuating Population in a Randomly Switching Environment

NASA Astrophysics Data System (ADS)

Wienand, Karl; Frey, Erwin; Mobilia, Mauro

2017-10-01

Environment plays a fundamental role in the competition for resources, and hence in the evolution of populations. Here, we study a well-mixed, finite population consisting of two strains competing for the limited resources provided by an environment that randomly switches between states of abundance and scarcity. Assuming that one strain grows slightly faster than the other, we consider two scenarios—one of pure resource competition, and one in which one strain provides a public good—and investigate how environmental randomness (external noise) coupled to demographic (internal) noise determines the population's fixation properties and size distribution. By analytical means and simulations, we show that these coupled sources of noise can significantly enhance the fixation probability of the slower-growing species. We also show that the population size distribution can be unimodal, bimodal, or multimodal and undergoes noise-induced transitions between these regimes when the rate of switching matches the population's growth rate.

Long period pseudo random number sequence generator

NASA Technical Reports Server (NTRS)

Wang, Charles C. (Inventor)

1989-01-01

A circuit for generating a sequence of pseudo random numbers, (A sub K). There is an exponentiator in GF(2 sup m) for the normal basis representation of elements in a finite field GF(2 sup m) each represented by m binary digits and having two inputs and an output from which the sequence (A sub K). Of pseudo random numbers is taken. One of the two inputs is connected to receive the outputs (E sub K) of maximal length shift register of n stages. There is a switch having a pair of inputs and an output. The switch outputs is connected to the other of the two inputs of the exponentiator. One of the switch inputs is connected for initially receiving a primitive element (A sub O) in GF(2 sup m). Finally, there is a delay circuit having an input and an output. The delay circuit output is connected to the other of the switch inputs and the delay circuit input is connected to the output of the exponentiator. Whereby after the exponentiator initially receives the primitive element (A sub O) in GF(2 sup m) through the switch, the switch can be switched to cause the exponentiator to receive as its input a delayed output A(K-1) from the exponentiator thereby generating (A sub K) continuously at the output of the exponentiator. The exponentiator in GF(2 sup m) is novel and comprises a cyclic-shift circuit; a Massey-Omura multiplier; and, a control logic circuit all operably connected together to perform the function U(sub i) = 92(sup i) (for n(sub i) = 1 or 1 (for n(subi) = 0).

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.

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.

Realization of the Switching Mechanism in Resistance Random Access Memory™ Devices: Structural and Electronic Properties Affecting Electron Conductivity in a Hafnium Oxide-Electrode System Through First-Principles Calculations

NASA Astrophysics Data System (ADS)

Aspera, Susan Meñez; Kasai, Hideaki; Kishi, Hirofumi; Awaya, Nobuyoshi; Ohnishi, Shigeo; Tamai, Yukio

2013-01-01

The resistance random access memory (RRAM™) device, with its electrically induced nanoscale resistive switching capacity, has attracted considerable attention as a future nonvolatile memory device. Here, we propose a mechanism of switching based on an oxygen vacancy migration-driven change in the electronic properties of the transition-metal oxide film stimulated by set pulse voltages. We used density functional theory-based calculations to account for the effect of oxygen vacancies and their migration on the electronic properties of HfO2 and Ta/HfO2 systems, thereby providing a complete explanation of the RRAM™ switching mechanism. Furthermore, computational results on the activation energy barrier for oxygen vacancy migration were found to be consistent with the set and reset pulse voltage obtained from experiments. Understanding this mechanism will be beneficial to effectively realizing the materials design in these devices.

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.

Temperature control of molecular circuit switch responsible for virulent phenotype expression in uropathogenic Escherichia coli

NASA Astrophysics Data System (ADS)

Samoilov, Michael

2010-03-01

The behavior and fate of biological organisms are to a large extent dictated by their environment, which can be often viewed as a collection of features and constraints governed by physics laws. Since biological systems comprise networks of molecular interactions, one such key physical property is temperature, whose variations directly affect the rates of biochemical reactions involved. For instance, temperature is known to control many gene regulatory circuits responsible for pathogenicity in bacteria. One such example is type 1 fimbriae (T1F) -- the foremost virulence factor in uropathogenic E. coli (UPEC), which accounts for 80-90% of all community-acquired urinary tract infections (UTIs). The expression of T1F is randomly `phase variable', i.e. individual cells switch between virulent/fimbriate and avirulent/afimbriate phenotypes, with rates regulated by temperature. Our computational investigation of this process, which is based on FimB/FimE recombinase-mediated inversion of fimS DNA element, offers new insights into its discrete-stochastic kinetics. In particular, it elucidates the logic of T1F control optimization to the host temperature and contributes further understanding toward the development of novel therapeutic approaches to UPEC-caused UTIs.

Controllable Organic Resistive Switching Achieved by One-Step Integration of Cone-Shaped Contact.

PubMed

Ling, Haifeng; Yi, Mingdong; Nagai, Masaru; Xie, Linghai; Wang, Laiyuan; Hu, Bo; Huang, Wei

2017-09-01

Conductive filaments (CFs)-based resistive random access memory possesses the ability of scaling down to sub-nanoscale with high-density integration architecture, making it the most promising nanoelectronic technology for reclaiming Moore's law. Compared with the extensive study in inorganic switching medium, the scientific challenge now is to understand the growth kinetics of nanoscale CFs in organic polymers, aiming to achieve controllable switching characteristics toward flexible and reliable nonvolatile organic memory. Here, this paper systematically investigates the resistive switching (RS) behaviors based on a widely adopted vertical architecture of Al/organic/indium-tin-oxide (ITO), with poly(9-vinylcarbazole) as the case study. A nanoscale Al filament with a dynamic-gap zone (DGZ) is directly observed using in situ scanning transmission electron microscopy (STEM) , which demonstrates that the RS behaviors are related to the random formation of spliced filaments consisting of Al and oxygen vacancy dual conductive channels growing through carbazole groups. The randomicity of the filament formation can be depressed by introducing a cone-shaped contact via a one-step integration method. The conical electrode can effectively shorten the DGZ and enhance the localized electric field, thus reducing the switching voltage and improving the RS uniformity. This study provides a deeper insight of the multiple filamentary mechanisms for organic RS effect. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Simplification to single-tablet regimen of elvitegravir, cobicistat, emtricitabine, tenofovir DF from multi-tablet ritonavir-boosted protease inhibitor plus coformulated emtricitabine and tenofovir DF regimens: week 96 results of STRATEGY-PI.

PubMed

Arribas, Jose R; DeJesus, Edwin; van Lunzen, Jan; Zurawski, Christine; Doroana, Manuela; Towner, William; Lazzarin, Adriano; Nelson, Mark; McColl, Damian; Andreatta, Kristen; Swamy, Raji; Szwarcberg, Javier; Nguyen, Thai

2017-05-01

Antiretroviral therapy (ART) simplification to a single-tablet regimen can benefit HIV-1-infected, virologically suppressed, individuals on ART composed of multiple pills. We assessed long-term efficacy and safety of switching to co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (E/C/F/TDF) from multi-tablet ritonavir-boosted protease inhibitor (PI + RTV) plus F/TDF (TVD) regimens. STRATEGY-PI was a 96-week, phase 3b, randomized (2:1), open-label, non-inferiority study examining the efficacy, safety, and tolerability of switching to E/C/F/TDF from PI + RTV + TVD regimens in virologically suppressed individuals (HIV-1 RNA <50 copies/mL). Participants were randomized to switch to E/C/F/TDF (switch group) or to continue their PI + RTV + TVD regimens (no-switch group). Eligibility criteria included no resistance to F/TDF or history of virologic failure, and estimated creatinine clearance ≥70 mL/min. At week 96, 87% (252/290) of switch and 70% (97/139) of no-switch participants maintained HIV-1 RNA <50 copies/mL (difference: 17%, 95% CI 8.7-26.0%, p < 0.001). Superiority of the switch to E/C/F/TDF vs. no-switch was due to a smaller proportion of both virologic failures (switch, 1% [3/290]; no-switch, 6% [8/139]) and discontinuations for non-virologic reasons (switch, 11% [31/290]; no-switch, 24% [33/139]). No treatment-emergent resistance was observed in switch subjects with virologic failure. Discontinuation rates from adverse events were 3% in both groups (9/293, switch; 4/140, no-switch). Switching from PI + RTV + TVD to E/C/F/TDF was associated with significant improvements in patient-reported outcomes related to gastrointestinal symptoms (nausea and bloating). E/C/F/TDF is a safe, effective long-term alternative to multi-tablet PI + RTV + TVD-based regimens in virologically suppressed, HIV-1-infected adults, and improves patient-reported gastrointestinal symptoms.

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.

Changes in Biomarkers of Exposure on Switching From a Conventional Cigarette to Tobacco Heating Products: A Randomized, Controlled Study in Healthy Japanese Subjects.

PubMed

Gale, Nathan; McEwan, Mike; Eldridge, Alison C; Fearon, Ian M; Sherwood, Neil; Bowen, Edward; McDermott, Simon; Holmes, Emma; Hedge, Andrew; Hossack, Stuart; Wakenshaw, Louise; Glew, James; Camacho, Oscar M; Errington, Graham; McAughey, John; Murphy, James; Liu, Chuan; Proctor, Christopher J

2018-06-15

Smoking is a leading cause of numerous human disorders including pulmonary disease, cardiovascular disease, and cancer. Disease development is primarily caused by exposure to cigarette smoke constituents, many of which are known toxicants. Switching smokers to modified risk tobacco products (MRTPs) has been suggested as a potential means to reduce the risks of tobacco use, by reducing such exposure. This randomized, controlled study investigated whether biomarkers of toxicant exposure (BoE) were reduced when smokers switched from smoking combustible cigarettes to using a novel (glo™/THP1.0) or in-market comparator (iQOS/THS) tobacco heating product (THP). One hundred eighty Japanese smokers smoked combustible cigarettes during a 2-day baseline period, followed by randomization to either continue smoking cigarettes, switch to using mentholated or non-mentholated variants of glo™, switch to using a non-mentholated variant of iQOS, or quit nicotine and tobacco product use completely for 5 days. Baseline and post-randomization 24-h urine samples were collected for BoE analysis. Carbon monoxide was measured daily in exhaled breath (eCO). On day 5 after switching, urinary BoE (excluding for nicotine) and eCO levels were significantly (p < .05) reduced by medians between 20.9% and 92.1% compared with baseline in all groups either using glo™ or iQOS or quitting tobacco use. Between-group comparisons revealed that the reductions in the glo™ groups were similar (p > .05) to quitting in many cases. glo™ or iQOS use for 5 days reduced exposure to smoke toxicants in a manner comparable to quitting tobacco use. THPs are reduced exposure tobacco products with the potential to be MRTPs. This clinical study demonstrates that when smokers switched from smoking combustible cigarettes to using tobacco heating products their exposure to smoke toxicants was significantly decreased. In many cases, this was to the same extent as that seen when they quit smoking completely. This may indicate that these products have the potential to be reduced exposure and/or reduced risk tobacco products when used by smokers whose cigarette consumption is displaced completely. ISRCTN14301360 and UMIN000024988.

Designing clinical trials to test disease-modifying agents: application to the treatment trials of Alzheimer's disease.

PubMed

Xiong, Chengjie; van Belle, Gerald; Miller, J Philip; Morris, John C

2011-02-01

Therapeutic trials of disease-modifying agents on Alzheimer's disease (AD) require novel designs and analyses involving switch of treatments for at least a portion of subjects enrolled. Randomized start and randomized withdrawal designs are two examples of such designs. Crucial design parameters such as sample size and the time of treatment switch are important to understand in designing such clinical trials. The purpose of this article is to provide methods to determine sample sizes and time of treatment switch as well as optimum statistical tests of treatment efficacy for clinical trials of disease-modifying agents on AD. A general linear mixed effects model is proposed to test the disease-modifying efficacy of novel therapeutic agents on AD. This model links the longitudinal growth from both the placebo arm and the treatment arm at the time of treatment switch for these in the delayed treatment arm or early withdrawal arm and incorporates the potential correlation on the rate of cognitive change before and after the treatment switch. Sample sizes and the optimum time for treatment switch of such trials as well as optimum test statistic for the treatment efficacy are determined according to the model. Assuming an evenly spaced longitudinal design over a fixed duration, the optimum treatment switching time in a randomized start or a randomized withdrawal trial is half way through the trial. With the optimum test statistic for the treatment efficacy and over a wide spectrum of model parameters, the optimum sample size allocations are fairly close to the simplest design with a sample size ratio of 1:1:1 among the treatment arm, the delayed treatment or early withdrawal arm, and the placebo arm. The application of the proposed methodology to AD provides evidence that much larger sample sizes are required to adequately power disease-modifying trials when compared with those for symptomatic agents, even when the treatment switch time and efficacy test are optimally chosen. The proposed method assumes that the only and immediate effect of treatment switch is on the rate of cognitive change. Crucial design parameters for the clinical trials of disease-modifying agents on AD can be optimally chosen. Government and industry officials as well as academia researchers should consider the optimum use of the clinical trials design for disease-modifying agents on AD in their effort to search for the treatments with the potential to modify the underlying pathophysiology of AD.

Tight coupling between nucleus and cell migration through the perinuclear actin cap

PubMed Central

Kim, Dong-Hwee; Cho, Sangkyun; Wirtz, Denis

2014-01-01

ABSTRACT Although eukaryotic cells are known to alternate between ‘advancing’ episodes of fast and persistent movement and ‘hesitation’ episodes of low speed and low persistence, the molecular mechanism that controls the dynamic changes in morphology, speed and persistence of eukaryotic migratory cells remains unclear. Here, we show that the movement of the interphase nucleus during random cell migration switches intermittently between two distinct modes – rotation and translocation – that follow with high fidelity the sequential rounded and elongated morphologies of the nucleus and cell body, respectively. Nuclear rotation and translocation mediate the stop-and-go motion of the cell through the dynamic formation and dissolution, respectively, of the contractile perinuclear actin cap, which is dynamically coupled to the nuclear lamina and the nuclear envelope through LINC complexes. A persistent cell movement and nuclear translocation driven by the actin cap are halted following the disruption of the actin cap, which in turn allows the cell to repolarize for its next persistent move owing to nuclear rotation mediated by cytoplasmic dynein light intermediate chain 2. PMID:24639463

Ikaros controls isotype selection during immunoglobulin class switch recombination.

PubMed

Sellars, MacLean; Reina-San-Martin, Bernardo; Kastner, Philippe; Chan, Susan

2009-05-11

Class switch recombination (CSR) allows the humoral immune response to exploit different effector pathways through specific secondary antibody isotypes. However, the molecular mechanisms and factors that control immunoglobulin (Ig) isotype choice for CSR are unclear. We report that deficiency for the Ikaros transcription factor results in increased and ectopic CSR to IgG(2b) and IgG(2a), and reduced CSR to all other isotypes, regardless of stimulation. Ikaros suppresses active chromatin marks, transcription, and activation-induced cytidine deaminase (AID) accessibility at the gamma2b and gamma2a genes to inhibit class switching to these isotypes. Further, Ikaros directly regulates isotype gene transcription as it directly binds the Igh 3' enhancer and interacts with isotype gene promoters. Finally, Ikaros-mediated repression of gamma2b and gamma2a transcription promotes switching to other isotype genes by allowing them to compete for AID-mediated recombination at the single-cell level. Thus, our results reveal transcriptional competition between constant region genes in individual cells to be a critical and general mechanism for isotype specification during CSR. We show that Ikaros is a master regulator of this competition.

TREATMENT SWITCHING: STATISTICAL AND DECISION-MAKING CHALLENGES AND APPROACHES.

PubMed

Latimer, Nicholas R; Henshall, Chris; Siebert, Uwe; Bell, Helen

2016-01-01

Treatment switching refers to the situation in a randomized controlled trial where patients switch from their randomly assigned treatment onto an alternative. Often, switching is from the control group onto the experimental treatment. In this instance, a standard intention-to-treat analysis does not identify the true comparative effectiveness of the treatments under investigation. We aim to describe statistical methods for adjusting for treatment switching in a comprehensible way for nonstatisticians, and to summarize views on these methods expressed by stakeholders at the 2014 Adelaide International Workshop on Treatment Switching in Clinical Trials. We describe three statistical methods used to adjust for treatment switching: marginal structural models, two-stage adjustment, and rank preserving structural failure time models. We draw upon discussion heard at the Adelaide International Workshop to explore the views of stakeholders on the acceptability of these methods. Stakeholders noted that adjustment methods are based on assumptions, the validity of which may often be questionable. There was disagreement on the acceptability of adjustment methods, but consensus that when these are used, they should be justified rigorously. The utility of adjustment methods depends upon the decision being made and the processes used by the decision-maker. Treatment switching makes estimating the true comparative effect of a new treatment challenging. However, many decision-makers have reservations with adjustment methods. These, and how they affect the utility of adjustment methods, require further exploration. Further technical work is required to develop adjustment methods to meet real world needs, to enhance their acceptability to decision-makers.

Spin-transfer-torque efficiency enhanced by edge-damage of perpendicular magnetic random access memories

DOE Office of Scientific and Technical Information (OSTI.GOV)

Song, Kyungmi; Lee, Kyung-Jin, E-mail: kj-lee@korea.ac.kr; Department of Materials Science and Engineering, Korea University, Seoul 136-713

2015-08-07

We numerically investigate the effect of magnetic and electrical damages at the edge of a perpendicular magnetic random access memory (MRAM) cell on the spin-transfer-torque (STT) efficiency that is defined by the ratio of thermal stability factor to switching current. We find that the switching mode of an edge-damaged cell is different from that of an undamaged cell, which results in a sizable reduction in the switching current. Together with a marginal reduction of the thermal stability factor of an edge-damaged cell, this feature makes the STT efficiency large. Our results suggest that a precise edge control is viable formore » the optimization of STT-MRAM.« less

Power- and Low-Resistance-State-Dependent, Bipolar Reset-Switching Transitions in SiN-Based Resistive Random-Access Memory

NASA Astrophysics Data System (ADS)

Kim, Sungjun; Park, Byung-Gook

2016-08-01

A study on the bipolar-resistive switching of an Ni/SiN/Si-based resistive random-access memory (RRAM) device shows that the influences of the reset power and the resistance value of the low-resistance state (LRS) on the reset-switching transitions are strong. For a low LRS with a large conducting path, the sharp reset switching, which requires a high reset power (>7 mW), was observed, whereas for a high LRS with small multiple-conducting paths, the step-by-step reset switching with a low reset power (<7 mW) was observed. The attainment of higher nonlinear current-voltage ( I-V) characteristics in terms of the step-by-step reset switching is due to the steep current-increased region of the trap-controlled space charge-limited current (SCLC) model. A multilevel cell (MLC) operation, for which the reset stop voltage ( V STOP) is used in the DC sweep mode and an incremental amplitude is used in the pulse mode for the step-by-step reset switching, is demonstrated here. The results of the present study suggest that well-controlled conducting paths in a SiN-based RRAM device, which are not too strong and not too weak, offer considerable potential for the realization of low-power and high-density crossbar-array applications.

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

Flexible ordering of antibody class switch and V(D)J joining during B-cell ontogeny

PubMed Central

Kumar, Satyendra; Wuerffel, Robert; Achour, Ikbel; Lajoie, Bryan; Sen, Ranjan; Dekker, Job; Feeney, Ann J.; Kenter, Amy L.

2013-01-01

V(D)J joining is mediated by RAG recombinase during early B-lymphocyte development in the bone marrow (BM). Activation-induced deaminase initiates isotype switching in mature B cells of secondary lymphoid structures. Previous studies questioned the strict ontological partitioning of these processes. We show that pro-B cells undergo robust switching to a subset of immunoglobulin H (IgH) isotypes. Chromatin studies reveal that in pro-B cells, the spatial organization of the Igh locus may restrict switching to this subset of isotypes. We demonstrate that in the BM, V(D)J joining and switching are interchangeably inducible, providing an explanation for the hyper-IgE phenotype of Omenn syndrome. PMID:24240234

On-Chip Fluorescence Switching System for Constructing a Rewritable Random Access Data Storage Device.

PubMed

Nguyen, Hoang Hiep; Park, Jeho; Hwang, Seungwoo; Kwon, Oh Seok; Lee, Chang-Soo; Shin, Yong-Beom; Ha, Tai Hwan; Kim, Moonil

2018-01-10

We report the development of on-chip fluorescence switching system based on DNA strand displacement and DNA hybridization for the construction of a rewritable and randomly accessible data storage device. In this study, the feasibility and potential effectiveness of our proposed system was evaluated with a series of wet experiments involving 40 bits (5 bytes) of data encoding a 5-charactered text (KRIBB). Also, a flexible data rewriting function was achieved by converting fluorescence signals between "ON" and "OFF" through DNA strand displacement and hybridization events. In addition, the proposed system was successfully validated on a microfluidic chip which could further facilitate the encoding and decoding process of data. To the best of our knowledge, this is the first report on the use of DNA hybridization and DNA strand displacement in the field of data storage devices. Taken together, our results demonstrated that DNA-based fluorescence switching could be applicable to construct a rewritable and randomly accessible data storage device through controllable DNA manipulations.

Switching in Feedforward Control of Grip Force During Tool-Mediated Interaction With Elastic Force Fields

PubMed Central

White, Olivier; Karniel, Amir; Papaxanthis, Charalambos; Barbiero, Marie; Nisky, Ilana

2018-01-01

Switched systems are common in artificial control systems. Here, we suggest that the brain adopts a switched feedforward control of grip forces during manipulation of objects. We measured how participants modulated grip force when interacting with soft and rigid virtual objects when stiffness varied continuously between trials. We identified a sudden phase transition between two forms of feedforward control that differed in the timing of the synchronization between the anticipated load force and the applied grip force. The switch occurred several trials after a threshold stiffness level in the range 100–200 N/m. These results suggest that in the control of grip force, the brain acts as a switching control system. This opens new research questions as to the nature of the discrete state variables that drive the switching. PMID:29930504

Voltage Control of Antiferromagnetic Phases at Near-Terahertz Frequencies

NASA Astrophysics Data System (ADS)

Barra, Anthony; Domann, John; Kim, Ki Wook; Carman, Greg

2018-03-01

A method to control antiferromagnetism using voltage-induced strain is proposed and theoretically examined. Voltage-induced magnetoelastic anisotropy is shown to provide sufficient torque to switch an antiferromagnetic domain 90° either from out of plane to in plane or between in-plane axes. Numerical results indicate that strain-mediated antiferromagnetic switching can occur in an 80-nm nanopatterned disk at frequencies approaching 1 THz but that the switching speed heavily depends on the system's mechanical design. Furthermore, the energy cost to induce magnetic switching is only 450 aJ, indicating that magnetoelastic control of antiferromagnetism is substantially more energy efficient than other approaches.

Analysis of reliable sub-ns spin-torque switching under transverse bias magnetic fields

DOE Office of Scientific and Technical Information (OSTI.GOV)

D'Aquino, M., E-mail: daquino@uniparthenope.it; Perna, S.; Serpico, C.

2015-05-07

The switching process of a magnetic spin-valve nanosystem subject to spin-polarized current pulses is considered. The dependence of the switching probability on the current pulse duration is investigated. The further application of a transverse field along the intermediate anisotropy axis of the particle is used to control the quasi-random relaxation of magnetization to the reversed magnetization state. The critical current amplitudes to realize the switching are determined by studying the phase portrait of the Landau-Lifshtz-Slonczewski dynamics. Macrospin numerical simulations are in good agreement with the theoretical prediction and demonstrate reliable switching even for very short (below 100 ps) current pulses.

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

Highly uniform and reliable resistive switching characteristics of a Ni/WOx/p+-Si memory device

NASA Astrophysics Data System (ADS)

Kim, Tae-Hyeon; Kim, Sungjun; Kim, Hyungjin; Kim, Min-Hwi; Bang, Suhyun; Cho, Seongjae; Park, Byung-Gook

2018-02-01

In this paper, we investigate the resistive switching behavior of a bipolar resistive random-access memory (RRAM) in a Ni/WOx/p+-Si RRAM with CMOS compatibility. Highly unifrom and reliable bipolar resistive switching characteristics are observed by a DC voltage sweeping and its switching mechanism can be explained by SCLC model. As a result, the possibility of metal-insulator-silicon (MIS) structural WOx-based RRAM's application to Si-based 1D (diode)-1R (RRAM) or 1T (transistor)-1R (RRAM) structure is demonstrated.

Efficacy and safety of raltegravir in treatment-experienced HIV-1-infected patients switching from enfuvirtide-based regimens: 48 week results of the randomized EASIER ANRS 138 trial.

PubMed

Gallien, Sébastien; Braun, Joséphine; Delaugerre, Constance; Charreau, Isabelle; Reynes, Jacques; Jeanblanc, François; Verdon, Renaud; de Truchis, Pierre; May, Thierry; Madelaine-Chambrin, Isabelle; Aboulker, Jean-Pierre; Molina, Jean-Michel

2011-09-01

To assess the sustainable efficacy and safety of a switch from enfuvirtide to raltegravir in patients with multidrug-resistant HIV infection. One hundred and seventy patients with multidrug-resistant HIV infection and suppressed plasma HIV RNA levels < 400 copies/mL under an enfuvirtide-based regimen were randomized to maintain their regimen or to switch to a raltegravir-based regimen (immediate group) in a 48 week prospective, randomized, open-label trial. At week 24, patients in the maintenance arm also switched to raltegravir (deferred group). Baseline genotypic susceptibility scores (GSSs) were calculated using available historical resistance tests. Efficacy was assessed by the cumulative proportion of patients with virological failure, defined as a confirmed plasma HIV RNA ≥ 400 copies/mL up to week 48. The EASIER ANRS 138 trial is registered at ClinicalTrials.gov (NCT00454337). At baseline, 86% of patients had plasma HIV RNA levels <50 copies/mL and 86% had a GSS ≥ 1. Through to week 48, in the on-treatment analysis, only one patient in the immediate group, with a GSS of 0, developed virological failure. At week 48, 90% of patients in both the immediate and deferred groups had plasma HIV-1 RNA levels <50 copies/mL. Median CD4 cell counts remained stable during follow-up. Of note, 12 of 66 (18.2%) patients receiving a regimen combining raltegravir and ritonavir-boosted tipranavir experienced alanine aminotransferase elevations, which led to a switch from tipranavir to darunavir in 8 cases, without discontinuation of raltegravir. In well-suppressed patients with multidrug-resistant HIV infection, a switch from enfuvirtide to raltegravir is generally well tolerated and has sustained antiviral efficacy when combined with a potent background regimen.

Vortex-Core Reversal Dynamics: Towards Vortex Random Access Memory

NASA Astrophysics Data System (ADS)

Kim, Sang-Koog

2011-03-01

An energy-efficient, ultrahigh-density, ultrafast, and nonvolatile solid-state universal memory is a long-held dream in the field of information-storage technology. The magnetic random access memory (MRAM) along with a spin-transfer-torque switching mechanism is a strong candidate-means of realizing that dream, given its nonvolatility, infinite endurance, and fast random access. Magnetic vortices in patterned soft magnetic dots promise ground-breaking applications in information-storage devices, owing to the very stable twofold ground states of either their upward or downward core magnetization orientation and plausible core switching by in-plane alternating magnetic fields or spin-polarized currents. However, two technologically most important but very challenging issues --- low-power recording and reliable selection of each memory cell with already existing cross-point architectures --- have not yet been resolved for the basic operations in information storage, that is, writing (recording) and readout. Here, we experimentally demonstrate a magnetic vortex random access memory (VRAM) in the basic cross-point architecture. This unique VRAM offers reliable cell selection and low-power-consumption control of switching of out-of-plane core magnetizations using specially designed rotating magnetic fields generated by two orthogonal and unipolar Gaussian-pulse currents along with optimized pulse width and time delay. Our achievement of a new device based on a new material, that is, a medium composed of patterned vortex-state disks, together with the new physics on ultrafast vortex-core switching dynamics, can stimulate further fruitful research on MRAMs that are based on vortex-state dot arrays.

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. © 2016 Thomas-Claudepierre et al.

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

PubMed

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

2016-12-01

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.

Rad52 competes with Ku70/Ku86 for binding to S-region DSB ends to modulate antibody class-switch DNA recombination

PubMed Central

Zan, Hong; Tat, Connie; Qiu, Zhifang; Taylor, Julia R.; Guerrero, Justin A.; Shen, Tian; Casali, Paolo

2017-01-01

Antibody class-switch DNA recombination (CSR) is initiated by AID-introduced DSBs in the switch (S) regions targeted for recombination, as effected by Ku70/Ku86-mediated NHEJ. Ku-deficient B cells, however, undergo (reduced) CSR through an alternative(A)-NHEJ pathway, which introduces microhomologies in S–S junctions. As microhomology-mediated end-joining requires annealing of single-strand DNA ends, we addressed the contribution of single-strand annealing factors HR Rad52 and translesion DNA polymerase θ to CSR. Compared with their Rad52+/+ counterparts, which display normal CSR, Rad52−/− B cells show increased CSR, fewer intra-Sμ region recombinations, no/minimal microhomologies in S–S junctions, decreased c-Myc/IgH translocations and increased Ku70/Ku86 recruitment to S-region DSB ends. Rad52 competes with Ku70/Ku86 for binding to S-region DSB ends. It also facilitates a Ku-independent DSB repair, which favours intra-S region recombination and mediates, particularly in Ku absence, inter-S–S recombination, as emphasized by the significantly greater CSR reduction in Rad52−/− versus Rad52+/+ B cells on Ku86 knockdown. PMID:28176781

Rad52 competes with Ku70/Ku86 for binding to S-region DSB ends to modulate antibody class-switch DNA recombination.

PubMed

Zan, Hong; Tat, Connie; Qiu, Zhifang; Taylor, Julia R; Guerrero, Justin A; Shen, Tian; Casali, Paolo

2017-02-08

Antibody class-switch DNA recombination (CSR) is initiated by AID-introduced DSBs in the switch (S) regions targeted for recombination, as effected by Ku70/Ku86-mediated NHEJ. Ku-deficient B cells, however, undergo (reduced) CSR through an alternative(A)-NHEJ pathway, which introduces microhomologies in S-S junctions. As microhomology-mediated end-joining requires annealing of single-strand DNA ends, we addressed the contribution of single-strand annealing factors HR Rad52 and translesion DNA polymerase θ to CSR. Compared with their Rad52 +/+ counterparts, which display normal CSR, Rad52 -/- B cells show increased CSR, fewer intra-Sμ region recombinations, no/minimal microhomologies in S-S junctions, decreased c-Myc/IgH translocations and increased Ku70/Ku86 recruitment to S-region DSB ends. Rad52 competes with Ku70/Ku86 for binding to S-region DSB ends. It also facilitates a Ku-independent DSB repair, which favours intra-S region recombination and mediates, particularly in Ku absence, inter-S-S recombination, as emphasized by the significantly greater CSR reduction in Rad52 -/- versus Rad52 +/+ B cells on Ku86 knockdown.

Investigating the origins of high multilevel resistive switching in forming free Ti/TiO2-x-based memory devices through experiments and simulations

NASA Astrophysics Data System (ADS)

Bousoulas, P.; Giannopoulos, I.; Asenov, P.; Karageorgiou, I.; Tsoukalas, D.

2017-03-01

Although multilevel capability is probably the most important property of resistive random access memory (RRAM) technology, it is vulnerable to reliability issues due to the stochastic nature of conducting filament (CF) creation. As a result, the various resistance states cannot be clearly distinguished, which leads to memory capacity failure. In this work, due to the gradual resistance switching pattern of TiO2-x-based RRAM devices, we demonstrate at least six resistance states with distinct memory margin and promising temporal variability. It is shown that the formation of small CFs with high density of oxygen vacancies enhances the uniformity of the switching characteristics in spite of the random nature of the switching effect. Insight into the origin of the gradual resistance modulation mechanisms is gained by the application of a trap-assisted-tunneling model together with numerical simulations of the filament formation physical processes.

Signal and noise extraction from analog memory elements for neuromorphic computing.

PubMed

Gong, N; Idé, T; Kim, S; Boybat, I; Sebastian, A; Narayanan, V; Ando, T

2018-05-29

Dense crossbar arrays of non-volatile memory (NVM) can potentially enable massively parallel and highly energy-efficient neuromorphic computing systems. The key requirements for the NVM elements are continuous (analog-like) conductance tuning capability and switching symmetry with acceptable noise levels. However, most NVM devices show non-linear and asymmetric switching behaviors. Such non-linear behaviors render separation of signal and noise extremely difficult with conventional characterization techniques. In this study, we establish a practical methodology based on Gaussian process regression to address this issue. The methodology is agnostic to switching mechanisms and applicable to various NVM devices. We show tradeoff between switching symmetry and signal-to-noise ratio for HfO 2 -based resistive random access memory. Then, we characterize 1000 phase-change memory devices based on Ge 2 Sb 2 Te 5 and separate total variability into device-to-device variability and inherent randomness from individual devices. These results highlight the usefulness of our methodology to realize ideal NVM devices for neuromorphic computing.

Set statistics in conductive bridge random access memory device with Cu/HfO{sub 2}/Pt structure

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Meiyun; Long, Shibing, E-mail: longshibing@ime.ac.cn; Wang, Guoming

2014-11-10

The switching parameter variation of resistive switching memory is one of the most important challenges in its application. In this letter, we have studied the set statistics of conductive bridge random access memory with a Cu/HfO{sub 2}/Pt structure. The experimental distributions of the set parameters in several off resistance ranges are shown to nicely fit a Weibull model. The Weibull slopes of the set voltage and current increase and decrease logarithmically with off resistance, respectively. This experimental behavior is perfectly captured by a Monte Carlo simulator based on the cell-based set voltage statistics model and the Quantum Point Contact electronmore » transport model. Our work provides indications for the improvement of the switching uniformity.« less

Degradation-mediated cellular traction directs stem cell fate in covalently crosslinked three-dimensional hydrogels

NASA Astrophysics Data System (ADS)

Khetan, Sudhir; Guvendiren, Murat; Legant, Wesley R.; Cohen, Daniel M.; Chen, Christopher S.; Burdick, Jason A.

2013-05-01

Although cell-matrix adhesive interactions are known to regulate stem cell differentiation, the underlying mechanisms, in particular for direct three-dimensional encapsulation within hydrogels, are poorly understood. Here, we demonstrate that in covalently crosslinked hyaluronic acid (HA) hydrogels, the differentiation of human mesenchymal stem cells (hMSCs) is directed by the generation of degradation-mediated cellular traction, independently of cell morphology or matrix mechanics. hMSCs within HA hydrogels of equivalent elastic moduli that permit (restrict) cell-mediated degradation exhibited high (low) degrees of cell spreading and high (low) tractions, and favoured osteogenesis (adipogenesis). Moreover, switching the permissive hydrogel to a restrictive state through delayed secondary crosslinking reduced further hydrogel degradation, suppressed traction, and caused a switch from osteogenesis to adipogenesis in the absence of changes to the extended cellular morphology. Furthermore, inhibiting tension-mediated signalling in the permissive environment mirrored the effects of delayed secondary crosslinking, whereas upregulating tension induced osteogenesis even in the restrictive environment.

Evaluation of modified nasal to oral endotracheal tube switch-For modified alar base cinching after maxillary orthognathic surgery.

PubMed

Shaik, Taj Nizam Shakeel; Meka, Sridhar; Ch, Pavan Kumar; Kolli, Naga Neelima Devi; Chakravarthi, P Srinivas; Kattimani, Vivekanand S; L, Krishna Prasad

2017-01-01

Soft tissue changes secondary to Maxillary orthognathic surgery are many fold. The alar flare is one among them, which affects the appearance of the patient. Cinch suture has been used to prevent alar flare; but the presence of anaesthetic tube hinders cinching. So, the study was aimed to assess an efficacy of modified nasal to oral tube switch technique for modified alar cinching to prevent alar flare after orthognathic and nasal corrective surgeries. Patients were randomly allocated in each group, who underwent modified alar base cinching with and without nasal to oral tube switch. Changes in alar base width, upper lip length was measured with Digital Vernier Caliper and nasolabial angle (Cotg-Sn-Ls) on lateral cephalogram at 1st, 3rd, 6th, and 12th months after surgery. The time taken and ease of tube switch were noted. The data obtained were tabulated and interpreted using a test of significance. Study results showed no statistical significant difference in perinasal soft changes among both groups. But tube switch appears to be beneficial to prevent alar flare. Modified alar base cinching was performed effectively in patients with a modified tube switch technique. It increased positive results in comparison with non-shift. The technique of tube switch used is effective in prevention of alar flare. Because of small sample size and limited period of follow up, our study suggests multi centre, randomized studies to know the technical difficulties of tube switch for cinching and aesthetic results with varying anaesthetist and the surgeon's experience.

Analysis of the Bipolar Resistive Switching Behavior of a Biocompatible Glucose Film for Resistive Random Access Memory.

PubMed

Park, Sung Pyo; Tak, Young Jun; Kim, Hee Jun; Lee, Jin Hyeok; Yoo, Hyukjoon; Kim, Hyun Jae

2018-06-01

Resistive random access memory (RRAM) devices are fabricated through a simple solution process using glucose, which is a natural biomaterial for the switching layer of RRAM. The fabricated glucose-based RRAM device shows nonvolatile bipolar resistive switching behavior, with a switching window of 10 3 . In addition, the endurance and data retention capability of glucose-based RRAM exhibit stable characteristics up to 100 consecutive cycles and 10 4 s under constant voltage stress at 0.3 V. The interface between the top electrode and the glucose film is carefully investigated to demonstrate the bipolar switching mechanism of the glucose-based RRAM device. The glucose based-RRAM is also evaluated on a polyimide film to verify the possibility of a flexible platform. Additionally, a cross-bar array structure with a magnesium electrode is prepared on various substrates to assess the degradability and biocompatibility for the implantable bioelectronic devices, which are harmless and nontoxic to the human body. It is expected that this research can provide meaningful insights for developing the future bioelectronic devices. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Electroforming free controlled bipolar resistive switching in Al/CoFe2O4/FTO device with self-compliance effect

NASA Astrophysics Data System (ADS)

Munjal, Sandeep; Khare, Neeraj

2018-02-01

Controlled bipolar resistive switching (BRS) has been observed in nanostructured CoFe2O4 (CFO) films using an Al (aluminum)/CoFe2O4/FTO (fluorine-doped tin oxide) device. The fabricated device shows electroforming-free uniform BRS with two clearly distinguished and stable resistance states without any application of compliance current, with a resistance ratio of the high resistance state (HRS) and the low resistance state (LRS) of >102. Small switching voltage (<1 volt) and lower current in both the resistance states confirm the fabrication of a low power consumption device. In the LRS, the conduction mechanism was found to be Ohmic in nature, while the high-resistance state (HRS/OFF state) was governed by the space charge-limited conduction mechanism, which indicates the presence of an interfacial layer with an imperfect microstructure near the top Al/CFO interface. The device shows nonvolatile behavior with good endurance properties, an acceptable resistance ratio, uniform resistive switching due to stable, less random filament formation/rupture, and a control over the resistive switching properties by choosing different stop voltages, which makes the device suitable for its application in future nonvolatile resistive random access memory.

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.

Thin TiOx layer as a voltage divider layer located at the quasi-Ohmic junction in the Pt/Ta2O5/Ta resistance switching memory.

PubMed

Li, Xiang Yuan; Shao, Xing Long; Wang, Yi Chuan; Jiang, Hao; Hwang, Cheol Seong; Zhao, Jin Shi

2017-02-09

Ta 2 O 5 has been an appealing contender for the resistance switching random access memory (ReRAM). The resistance switching (RS) in this material is induced by the repeated formation and rupture of the conducting filaments (CFs) in the oxide layer, which are accompanied by the almost inevitable randomness of the switching parameters. In this work, a 1 to 2 nm-thick Ti layer was deposited on the 10 nm-thick Ta 2 O 5 RS layer, which greatly improved the RS performances, including the much-improved switching uniformity. The Ti metal layer was naturally oxidized to TiO x (x < 2) and played the role of a series resistor, whose resistance value was comparable to the on-state resistance of the Ta 2 O 5 RS layer. The series resistor TiO x efficiently suppressed the adverse effects of the voltage (or current) overshooting at the moment of switching by the appropriate voltage partake effect, which increased the controllability of the CF formation and rupture. The switching cycle endurance was increased by two orders of magnitude even during the severe current-voltage sweep tests compared with the samples without the thin TiO x layer. The Ti deposition did not induce any significant overhead to the fabrication process, making the process highly promising for the mass production of a reliable ReRAM.

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. Copyright © 2015 Elsevier Ltd. All rights reserved.

Mapping the "Depression Switch" During Intraoperative Testing of Subcallosal Cingulate Deep Brain Stimulation.

PubMed

Choi, Ki Sueng; Riva-Posse, Patricio; Gross, Robert E; Mayberg, Helen S

2015-11-01

The clinical utility of monitoring behavioral changes during intraoperative testing of subcallosal cingulate deep brain stimulation is unknown. To characterize the structural connectivity correlates of deep brain stimulation-evoked behavioral effects using probabilistic tractography in depression. Categorization of acute behavioral effects was conducted in 9 adults undergoing deep brain stimulation implantation surgery for chronic treatment-resistant depression in a randomized and blinded testing session at Emory University. Patients were studied from September 1, 2011, through June 30, 2013. Post hoc analyses of the structural tractography patterns mediating distinct categories of evoked behavioral effects were defined, including the best response overall. Data analyses were performed from May 1 through July 1, 2015. Categorization of stimulation-induced transient behavioral effects and delineation of the shared white matter tracts mediating response subtypes. Among the 9 patients, 72 active and 36 sham trials were recorded. The following stereotypical behavior patterns were identified: changes in interoceptive (noted changes in body state in 30 of 72 active and 4 of 36 sham trials) and in exteroceptive (shift in attention from patient to others in 9 of 72 active and 0 sham trials) awareness. The best response was a combination of exteroceptive and interoceptive changes at a single left contact for all 9 patients. Structural connectivity showed that the best response contacts had a pattern of connections to the bilateral ventromedial frontal cortex (via forceps minor and left uncinate fasciculus) and to the cingulate cortex (via left cingulum bundle), whereas behaviorally salient but nonbest contacts had only cingulate involvement. The involvement of the 3 white matter bundles during stimulation of the best contacts suggests a mechanism for the observed transient "depression switch." This analysis of transient behavior changes during intraoperative deep brain stimulation of the subcallosal cingulate and the subsequent identification of unique connectivity patterns may provide a biomarker of a rapid-onset depression switch to guide surgical implantation and to refine and optimize algorithms for the selection of contacts in long-term stimulation for treatment-resistant depression.

The Impact of Different CD4 Cell-Count Monitoring and Switching Strategies on Mortality in HIV-Infected African Adults on Antiretroviral Therapy: An Application of Dynamic Marginal Structural Models

PubMed Central

Ford, Deborah; Robins, James M.; Petersen, Maya L.; Gibb, Diana M.; Gilks, Charles F.; Mugyenyi, Peter; Grosskurth, Heiner; Hakim, James; Katabira, Elly; Babiker, Abdel G.; Walker, A. Sarah

2015-01-01

In Africa, antiretroviral therapy (ART) is delivered with limited laboratory monitoring, often none. In 2003–2004, investigators in the Development of Antiretroviral Therapy in Africa (DART) Trial randomized persons initiating ART in Uganda and Zimbabwe to either laboratory and clinical monitoring (LCM) or clinically driven monitoring (CDM). CD4 cell counts were measured every 12 weeks in both groups but were only returned to treating clinicians for management in the LCM group. Follow-up continued through 2008. In observational analyses, dynamic marginal structural models on pooled randomized groups were used to estimate survival under different monitoring-frequency and clinical/immunological switching strategies. Assumptions included no direct effect of randomized group on mortality or confounders and no unmeasured confounders which influenced treatment switch and mortality or treatment switch and time-dependent covariates. After 48 weeks of first-line ART, 2,946 individuals contributed 11,351 person-years of follow-up, 625 switches, and 179 deaths. The estimated survival probability after a further 240 weeks for post-48-week switch at the first CD4 cell count less than 100 cells/mm3 or non-Candida World Health Organization stage 4 event (with CD4 count <250) was 0.96 (95% confidence interval (CI): 0.94, 0.97) with 12-weekly CD4 testing, 0.96 (95% CI: 0.95, 0.97) with 24-weekly CD4 testing, 0.95 (95% CI: 0.93, 0.96) with a single CD4 test at 48 weeks (baseline), and 0.92 (95% CI: 0.91, 0.94) with no CD4 testing. Comparing randomized groups by 48-week CD4 count, the mortality risk associated with CDM versus LCM was greater in persons with CD4 counts of <100 (hazard ratio = 2.4, 95% CI: 1.3, 4.3) than in those with CD4 counts of ≥100 (hazard ratio = 1.1, 95% CI: 0.8, 1.7; interaction P = 0.04). These findings support a benefit from identifying patients immunologically failing first-line ART at 48 weeks. PMID:26316598

Self-Compliant Bipolar Resistive Switching in SiN-Based Resistive Switching Memory

PubMed Central

Kim, Sungjun; Chang, Yao-Feng; Kim, Min-Hwi; Kim, Tae-Hyeon; Kim, Yoon; Park, Byung-Gook

2017-01-01

Here, we present evidence of self-compliant and self-rectifying bipolar resistive switching behavior in Ni/SiNx/n+ Si and Ni/SiNx/n++ Si resistive-switching random access memory devices. The Ni/SiNx/n++ Si device’s Si bottom electrode had a higher dopant concentration (As ion > 1019 cm−3) than the Ni/SiNx/n+ Si device; both unipolar and bipolar resistive switching behaviors were observed for the higher dopant concentration device owing to a large current overshoot. Conversely, for the device with the lower dopant concentration (As ion < 1018 cm−3), self-rectification and self-compliance were achieved owing to the series resistance of the Si bottom electrode. PMID:28772819

The formation of the light-sensing compartment of cone photoreceptors coincides with a transcriptional switch

PubMed Central

Daum, Janine M; Keles, Özkan; Holwerda, Sjoerd JB; Kohler, Hubertus; Rijli, Filippo M

2017-01-01

High-resolution daylight vision is mediated by cone photoreceptors. The molecular program responsible for the formation of their light sensor, the outer segment, is not well understood. We correlated daily changes in ultrastructure and gene expression in postmitotic mouse cones, between birth and eye opening, using serial block-face electron microscopy (EM) and RNA sequencing. Outer segments appeared rapidly at postnatal day six and their appearance coincided with a switch in gene expression. The switch affected over 14% of all expressed genes. Genes that switched off were rich in transcription factors and neurogenic genes. Those that switched on contained genes relevant for cone function. Chromatin rearrangements in enhancer regions occurred before the switch was completed, but not after. We provide a resource comprised of correlated EM, RNAseq, and ATACseq data, showing that the growth of a key compartment of a postmitotic cell involves an extensive switch in gene expression and chromatin accessibility. PMID:29106373

Rev1 Recruits Ung to Switch Regions and Enhances dU Glycosylation for Immunoglobulin Class Switch DNA Recombination

PubMed Central

Zan, Hong; White, Clayton A.; Thomas, Lisa M.; Mai, Thach; Li, Guideng; Xu, Zhenming; Zhang, Jinsong; Casali, Paolo

2012-01-01

SUMMARY By diversifying the biological effector functions of antibodies, class switch DNA recombination (CSR) plays a critical role in the maturation of the immune response. It is initiated by AID-mediated dC deamination, yielding dUs, and dU glycosylation by Ung in antibody switch (S) region DNA. Here we showed that the translesion DNA synthesis polymerase Rev1 directly interacted with Ung and targeted in an AID-dependent and Ung-independent fashion the S regions undergoing CSR. Rev1–/– Ung+/+ B cells reduced Ung recruitment to S regions, DNA-dU glycosylation and CSR. This together with an S region spectrum of mutations similar to that of Rev1+/+ Ung–/– B cells suggested that Rev1 operated in the same pathway as Ung, as emphasized by further decreased CSR in Rev1–/– Msh2–/– B cells. Rescue of CSR in Rev1–/– B cells by a catalytically inactive Rev1 mutant showed that the important role of Rev1 in CSR is mediated by Rev1 scaffold, not enzymatic function. PMID:23140944

What Controls the "Off/On Switch" in the Toehold-Mediated Strand Displacement Reaction on DNA Conjugated Gold Nanoparticles?

PubMed

Yao, Dongbao; Wang, Bei; Xiao, Shiyan; Song, Tingjie; Huang, Fujian; Liang, Haojun

2015-06-30

In DNA dynamic nanotechnology, a toehold-mediated DNA strand-displacement reaction has demonstrated its capability in building complex autonomous system. In most cases, the reaction is performed in pure DNA solution that is essentially a one-phase system. In the present work, we systematically investigated the reaction in a heterogeneous media, in which the strand that implements a displacing action is conjugated on gold nanoparticles. By monitoring the kinetics of spherical nucleic acid (SNA) assembly driven by toehold-mediated strand displacement reaction, we observed significant differences, i.e., the abrupt jump in behavior of an "off/on switch", in the reaction rate when the invading toehold was extended to eight bases from seven bases. These phenomena are attributed to the effect of steric hindrance arising from the high density of invading strand conjugated to AuNPs. Based on these studies, an INHIBIT logic gate presenting good selectivity was developed.

Fast and efficient STT switching in MTJ using additional transient pulse current

NASA Astrophysics Data System (ADS)

Pathak, Sachin; Cha, Jongin; Jo, Kangwook; Yoon, Hongil; Hong, Jongill

2017-06-01

We propose a profile of write pulse current-density to switch magnetization in a perpendicular magnetic tunnel junction to reduce switching time and write energy as well. Our simulated results show that an overshoot transient pulse current-density (current spike) imposed to conventional rectangular-shaped pulse current-density (main pulse) significantly improves switching speed that yields the reduction in write energy accordingly. For example, we could dramatically reduce the switching time by 80% and thereby reduce the write energy over 9% in comparison to the switching without current spike. The current spike affects the spin dynamics of the free layer and reduces the switching time mainly due to spin torque induced. On the other hand, the large Oersted field induced causes changes in spin texture. We believe our proposed write scheme can make a breakthrough in magnetic random access memory technology seeking both high speed operation and low energy consumption.

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 generations for the same stochastic processes. However, the switching frequency and outbreak patterns can be significantly affected by the intensity of noise and the intrinsic growth rate of the locust population.

Reprogramming of G protein-coupled receptor recycling and signaling by a kinase switch

PubMed Central

Vistein, Rachel; Puthenveedu, Manojkumar A.

2013-01-01

The postendocytic recycling of signaling receptors is subject to multiple requirements. Why this is so, considering that many other proteins can recycle without apparent requirements, is a fundamental question. Here we show that cells can leverage these requirements to switch the recycling of the beta-2 adrenergic receptor (B2AR), a prototypic signaling receptor, between sequence-dependent and bulk recycling pathways, based on extracellular signals. This switch is determined by protein kinase A-mediated phosphorylation of B2AR on the cytoplasmic tail. The phosphorylation state of B2AR dictates its partitioning into spatially and functionally distinct endosomal microdomains mediating bulk and sequence-dependent recycling, and also regulates the rate of B2AR recycling and resensitization. Our results demonstrate that G protein-coupled receptor recycling is not always restricted to the sequence-dependent pathway, but may be reprogrammed as needed by physiological signals. Such flexible reprogramming might provide a versatile method for rapidly modulating cellular responses to extracellular signaling. PMID:24003153

Effect of TNF{alpha} on activities of different promoters of human apolipoprotein A-I gene

DOE Office of Scientific and Technical Information (OSTI.GOV)

Orlov, Sergey V., E-mail: serge@iem.sp.ru; Department of Embryology, St. Petersburg State University, 199034 St. Petersburg; Mogilenko, Denis A.

2010-07-23

Research highlights: {yields} TNF{alpha} stimulates the distal alternative promoter of human apoA-I gene. {yields} TNF{alpha} acts by weakening of promoter competition within apoA-I gene (promoter switching). {yields} MEK1/2 and nuclear receptors PPAR{alpha} and LXRs take part in apoA-I promoter switching. -- Abstract: Human apolipoprotein A-I (ApoA-I) is a major structural and functional protein component of high-density lipoproteins. The expression of the apolipoprotein A-I gene (apoA-I) in hepatocytes is repressed by pro-inflammatory cytokines such as IL-1{beta} and TNF{alpha}. Recently, two novel additional (alternative) promoters for human apoA-I gene have been identified. Nothing is known about the role of alternative promoters inmore » TNF{alpha}-mediated downregulation of apoA-I gene. In this article we report for the first time about the different effects of TNF{alpha} on two alternative promoters of human apoA-I gene. Stimulation of HepG2 cells by TNF{alpha} leads to activation of the distal alternative apoA-I promoter and downregulation of the proximal alternative and the canonical apoA-I promoters. This effect is mediated by weakening of the promoter competition within human apoA-I 5'-regulatory region (apoA-I promoter switching) in the cells treated by TNF{alpha}. The MEK1/2-ERK1/2 cascade and nuclear receptors PPAR{alpha} and LXRs are important for TNF{alpha}-mediated apoA-I promoter switching.« less

Responsive hairpin DNA aptamer switch to program the strand displacement reaction for the enhanced electrochemical assay of ATP.

PubMed

Wang, Li; Fang, Li; Liu, Shufeng

2015-09-07

A responsive hairpin DNA aptamer switch was ingeniously designed for enzyme-free, sensitive and selective electrochemical detection of ATP. It takes full advantage of the target-triggered liberation effect of the toehold region and the concomitant proximity effect with the branch-migration region to execute the toehold-mediated strand displacement reaction on the electrode surface.

Non-switching to switching transferring mechanism investigation for Ag/SiO x /p-Si structure with SiO x deposited by HWCVD

NASA Astrophysics Data System (ADS)

Liu, Yanhong; Wang, Ruoying; Li, Zhongyue; Wang, Song; Huang, Yang; Peng, Wei

2018-04-01

We proposed and fabricated an Ag/SiO x /p-Si sandwich structure, in which amorphous SiO x films were deposited through hot wire chemical vapor deposition (HWCVD) using tetraethylorthosilicate (TEOS) as Si and O precursor. Experimental results indicate that the I–V properties of this structure transfer from non-switching to switching operation as the SiO x deposition temperature increased. The device with SiO x deposited at high deposition temperature exhibits typical bipolar switching properties, which can be potentially used in resistive switching random accessible memory (RRAM). The transferring mechanism from non-switching to switching can be ascribed to the change of structural and electronic properties of SiO x active layer deposited at different temperatures, as evidenced by analyzing FTIR spectrum and fitting its I–V characteristics curves. This work demonstrates a safe and practicable low-temperature device-grade SiO x film deposition technology by conducting HWCVD from TEOS.

Multistage switching hardware and software implementations for student experiment purpose

NASA Astrophysics Data System (ADS)

Sani, A.; Suherman

2018-02-01

Current communication and internet networks are underpinned by the switching technologies that interconnect one network to the others. Students’ understanding on networks rely on how they conver the theories. However, understanding theories without touching the reality may exert spots in the overall knowledge. This paper reports the progress of the multistage switching design and implementation for student laboratory activities. The hardware and software designs are based on three stages clos switching architecture with modular 2x2 switches, controlled by an arduino microcontroller. The designed modules can also be extended for batcher and bayan switch, and working on circuit and packet switching systems. The circuit analysis and simulation show that the blocking probability for each switch combinations can be obtained by generating random or patterned traffics. The mathematic model and simulation analysis shows 16.4% blocking probability differences as the traffic generation is uniform. The circuits design components and interfacing solution have been identified to allow next step implementation.

Switching behavior of resistive change memory using oxide nanowires

NASA Astrophysics Data System (ADS)

Aono, Takashige; Sugawa, Kosuke; Shimizu, Tomohiro; Shingubara, Shoso; Takase, Kouichi

2018-06-01

Resistive change random access memory (ReRAM), which is expected to be the next-generation nonvolatile memory, often has wide switching voltage distributions due to many kinds of conductive filaments. In this study, we have tried to suppress the distribution through the structural restriction of the filament-forming area using NiO nanowires. The capacitor with Ni metal nanowires whose surface is oxidized showed good switching behaviors with narrow distributions. The knowledge gained from our study will be very helpful in producing practical ReRAM devices.

Origin of the OFF state variability in ReRAM cells

NASA Astrophysics Data System (ADS)

Salaoru, Iulia; Khiat, Ali; Li, Qingjiang; Berdan, Radu; Papavassiliou, Christos; Prodromakis, Themistoklis

2014-04-01

This work exploits the switching dynamics of nanoscale resistive random access memory (ReRAM) cells with particular emphasis on the origin of the observed variability when cells are consecutively cycled/programmed at distinct memory states. It is demonstrated that this variance is a common feature of all ReRAM elements and is ascribed to the formation and rupture of conductive filaments that expand across the active core, independently of the material employed as the active switching core, the causal physical switching mechanism, the switching mode (bipolar/unipolar) or even the unit cells' dimensions. Our hypothesis is supported through both experimental and theoretical studies on TiO2 and In2O3 : SnO2 (ITO) based ReRAM cells programmed at three distinct resistive states. Our prototypes employed TiO2 or ITO active cores over 5 × 5 µm2 and 100 × 100 µm2 cell areas, with all tested devices demonstrating both unipolar and bipolar switching modalities. In the case of TiO2-based cells, the underlying switching mechanism is based on the non-uniform displacement of ionic species that foster the formation of conductive filaments. On the other hand, the resistive switching observed in the ITO-based devices is considered to be due to a phase change mechanism. The selected experimental parameters allowed us to demonstrate that the observed programming variance is a common feature of all ReRAM devices, proving that its origin is dependent upon randomly oriented local disorders within the active core that have a substantial impact on the overall state variance, particularly for high-resistive states.

A Genetic Variant Ameliorates β-Thalassemia Severity by Epigenetic-Mediated Elevation of Human Fetal Hemoglobin Expression.

PubMed

Chen, Diyu; Zuo, Yangjin; Zhang, Xinhua; Ye, Yuhua; Bao, Xiuqin; Huang, Haiyan; Tepakhan, Wanicha; Wang, Lijuan; Ju, Junyi; Chen, Guangfu; Zheng, Mincui; Liu, Dun; Huang, Shuodan; Zong, Lu; Li, Changgang; Chen, Yajun; Zheng, Chenguang; Shi, Lihong; Zhao, Quan; Wu, Qiang; Fucharoen, Supan; Zhao, Cunyou; Xu, Xiangmin

2017-07-06

A delayed fetal-to-adult hemoglobin (Hb) switch ameliorates the severity of β-thalassemia and sickle cell disease. The molecular mechanism underlying the epigenetic dysregulation of the switch is unclear. To explore the potential cis-variants responsible for the Hb switching, we systematically analyzed an 80-kb region spanning the β-globin cluster using capture-based next-generation sequencing of 1142 Chinese β-thalassemia persons and identified 31 fetal hemoglobin (HbF)-associated haplotypes of the selected 28 tag regulatory single-nucleotide polymorphisms (rSNPs) in seven linkage disequilibrium (LD) blocks. A Ly1 antibody reactive (LYAR)-binding motif disruptive rSNP rs368698783 (G/A) from LD block 5 in the proximal promoter of hemoglobin subunit gamma 1 (HBG1) was found to be a significant predictor for β-thalassemia clinical severity by epigenetic-mediated variant-dependent HbF elevation. We found this rSNP accounted for 41.6% of β-hemoglobinopathy individuals as an ameliorating factor in a total of 2,738 individuals from southern China and Thailand. We uncovered that the minor allele of the rSNP triggers the attenuation of LYAR and two repressive epigenetic regulators DNA methyltransferase 3 alpha (DNMT3A) and protein arginine methyltransferase 5 (PRMT5) from the HBG promoters, mediating allele-biased γ-globin elevation by facilitating demethylation of HBG core promoter CpG sites in erythroid progenitor cells from β-thalassemia persons. The present study demonstrates that this common rSNP in the proximal A γ-promoter is a major genetic modifier capable of ameliorating the severity of thalassemia major through the epigenetic-mediated regulation of the delayed fetal-to-adult Hb switch and provides potential targets for the treatment of β-hemoglobinopathy. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Laser treatment of solar lentigines on dorsum of hands: QS Ruby laser versus ablative CO2 fractional laser - a randomized controlled trial.

PubMed

Schoenewolf, Nicola L; Hafner, Jürg; Dummer, Reinhard; Bogdan Allemann, Inja

2015-04-01

Lentigines solares (LS) on the dorsum of hands are often esthetically disturbing. Q-switched ruby laser treatment is highly effective in the treatment of these lesions. Ablative fractional photothermolysis may be a suitable alternative. We compared the Q-switched ruby laser with ablative CO2 fractional photothermolysis for the treatment of solar lentigines. To evaluate the efficacy and side-effects of 694nm Q-switched ruby laser (Sinon) with the ablative 10,600nm CO2 fractional laser (Quantel Excel O2) in an intra-individual side-to-side comparison in the treatment of LS on the dorsum of hands. Eleven patients were included in the study. The hands of each patient were randomized for treatment with the two laser systems. Three treatment sessions were scheduled at weeks 0, 4 and 8. Evaluations by patients, treating physician and blinded experts were scheduled at weeks 0, 4, 8, 16 and 24. The Q-switched ruby laser was significantly more efficacious than the ablative CO2 fractional laser for removing LS on the dorsum of hands (p = 0.01). In this first study on this topic, the Q-switched ruby laser was superior to the ablative CO2 fractional laser in the treatment of lentigines solares on the dorsum of hands.

Controllable Magnetization Processes Induced by Nucleation Sites in Permalloy Rings

NASA Astrophysics Data System (ADS)

Chen, Ying-Jiun; Hsu, Chia-Jung; Liao, Chun-Neng; Huang, Hao-Ting; Lee, Chiun-Peng; Chiu, Yi-Hsun; Tung, Tzu-Yun; Lai, Mei-Feng

2010-02-01

Different arrangements of notches as nucleation sites are demonstrated experimentally and numerically to effectively control the magnetization processes of permalloy rings. In the ring with notches at the same side with respect to field direction, two same-helicity vortex domain walls in the onion state lead to two-step switching going through flux-closure state; in the ring with diagonal notches two opposite-helicity vortex domain walls lead to one-step switching skipping flux-closure state. The switching processes are repeatable in contrast to rings without notches where helicites of two vortex domain walls are random so the switching processes can not be controlled.

Free Language Selection in the Bilingual Brain: An Event-Related fMRI Study

PubMed Central

Zhang, Yong; Wang, Tao; Huang, Peiyu; Li, Dan; Qiu, Jiang; Shen, Tong; Xie, Peng

2015-01-01

Bilingual speakers may select between two languages either on demand (forced language selection) or on their own volition (free language selection). However, the neural substrates underlying free and forced language selection may differ. While the neural substrates underlying forced language selection have been well-explored with language switching paradigms, those underlying free language selection have remained unclear. Using a modified digit-naming switching paradigm, we addressed the neural substrates underlying free language selection by contrasting free language switching with forced language switching. For a digit-pair trial, Chinese-English bilinguals named each digit in Chinese or English either on demand under forced language selection condition or on their own volition under free language selection condition. The results revealed activation in the frontoparietal regions that mediate volition of language selection. Furthermore, a comparison of free and forced language switching demonstrated differences in the patterns of brain activation. Additionally, free language switching showed reduced switching costs as compared to forced language switching. These findings suggest differences between the mechanism(s) underlying free and forced language switching. As such, the current study suggests interactivity between control of volition and control of language switching in free language selection, providing insights into a model of bilingual language control. PMID:26177885

SESOTHO trial ("Switch Either near Suppression Or THOusand") - switch to second-line versus WHO-guided standard of care for unsuppressed patients on first-line ART with viremia below 1000 copies/mL: protocol of a multicenter, parallel-group, open-label, randomized clinical trial in Lesotho, Southern Africa.

PubMed

Amstutz, Alain; Nsakala, Bienvenu Lengo; Vanobberghen, Fiona; Muhairwe, Josephine; Glass, Tracy Renée; Achieng, Beatrice; Sepeka, Mamorena; Tlali, Katleho; Sao, Lebohang; Thin, Kyaw; Klimkait, Thomas; Battegay, Manuel; Labhardt, Niklaus Daniel

2018-02-12

The World Health Organization (WHO) recommends viral load (VL) measurement as the preferred monitoring strategy for HIV-infected individuals on antiretroviral therapy (ART) in resource-limited settings. The new WHO guidelines 2016 continue to define virologic failure as two consecutive VL ≥1000 copies/mL (at least 3 months apart) despite good adherence, triggering switch to second-line therapy. However, the threshold of 1000 copies/mL for defining virologic failure is based on low-quality evidence. Observational studies have shown that individuals with low-level viremia (measurable but below 1000 copies/mL) are at increased risk for accumulation of resistance mutations and subsequent virologic failure. The SESOTHO trial assesses a lower threshold for switch to second-line ART in patients with sustained unsuppressed VL. In this multicenter, parallel-group, open-label, randomized controlled trial conducted in Lesotho, patients on first-line ART with two consecutive unsuppressed VL measurements ≥100 copies/mL, where the second VL is between 100 and 999 copies/mL, will either be switched to second-line ART immediately (intervention group) or not be switched (standard of care, according to WHO guidelines). The primary endpoint is viral resuppression (VL < 50 copies/mL) 9 months after randomization. We will enrol 80 patients, giving us 90% power to detect a difference of 35% in viral resuppression between the groups (assuming two-sided 5% alpha error). For our primary analysis, we will use a modified intention-to-treat set, with those lost to care, death, or crossed over considered failure to resuppress, and using logistic regression models adjusted for the prespecified stratification variables. The SESOTHO trial challenges the current WHO guidelines, assessing an alternative, lower VL threshold for patients with unsuppressed VL on first-line ART. This trial will provide data to inform future WHO guidelines on VL thresholds to recommend switch to second-line ART. ClinicalTrials.gov ( NCT03088241 ), registered May 05, 2017.

Denoising of genetic switches based on Parrondo's paradox

NASA Astrophysics Data System (ADS)

Fotoohinasab, Atiyeh; Fatemizadeh, Emad; Pezeshk, Hamid; Sadeghi, Mehdi

2018-03-01

Random decision making in genetic switches can be modeled as tossing a biased coin. In other word, each genetic switch can be considered as a game in which the reactive elements compete with each other to increase their molecular concentrations. The existence of a very small number of reactive element molecules has caused the neglect of effects of noise to be inevitable. Noise can lead to undesirable cell fate in cellular differentiation processes. In this paper, we study the robustness to noise in genetic switches by considering another switch to have a new gene regulatory network (GRN) in which both switches have been affected by the same noise and for this purpose, we will use Parrondo's paradox. We introduce two networks of games based on possible regulatory relations between genes. Our results show that the robustness to noise can increase by combining these noisy switches. We also describe how one of the switches in network II can model lysis/lysogeny decision making of bacteriophage lambda in Escherichia coli and we change its fate by another switch.

Reward Motivation Enhances Task Coding in Frontoparietal Cortex

PubMed Central

Etzel, Joset A.; Cole, Michael W.; Zacks, Jeffrey M.; Kay, Kendrick N.; Braver, Todd S.

2016-01-01

Reward motivation often enhances task performance, but the neural mechanisms underlying such cognitive enhancement remain unclear. Here, we used a multivariate pattern analysis (MVPA) approach to test the hypothesis that motivation-related enhancement of cognitive control results from improved encoding and representation of task set information. Participants underwent two fMRI sessions of cued task switching, the first under baseline conditions, and the second with randomly intermixed reward incentive and no-incentive trials. Information about the upcoming task could be successfully decoded from cue-related activation patterns in a set of frontoparietal regions typically associated with task control. More critically, MVPA classifiers trained on the baseline session had significantly higher decoding accuracy on incentive than non-incentive trials, with decoding improvement mediating reward-related enhancement of behavioral performance. These results strongly support the hypothesis that reward motivation enhances cognitive control, by improving the discriminability of task-relevant information coded and maintained in frontoparietal brain regions. PMID:25601237

An integrated reweighting theory of perceptual learning

PubMed Central

Dosher, Barbara Anne; Jeter, Pamela; Liu, Jiajuan; Lu, Zhong-Lin

2013-01-01

Improvements in performance on visual tasks due to practice are often specific to a retinal position or stimulus feature. Many researchers suggest that specific perceptual learning alters selective retinotopic representations in early visual analysis. However, transfer is almost always practically advantageous, and it does occur. If perceptual learning alters location-specific representations, how does it transfer to new locations? An integrated reweighting theory explains transfer over retinal locations by incorporating higher level location-independent representations into a multilevel learning system. Location transfer is mediated through location-independent representations, whereas stimulus feature transfer is determined by stimulus similarity at both location-specific and location-independent levels. Transfer to new locations/positions differs fundamentally from transfer to new stimuli. After substantial initial training on an orientation discrimination task, switches to a new location or position are compared with switches to new orientations in the same position, or switches of both. Position switches led to the highest degree of transfer, whereas orientation switches led to the highest levels of specificity. A computational model of integrated reweighting is developed and tested that incorporates the details of the stimuli and the experiment. Transfer to an identical orientation task in a new position is mediated via more broadly tuned location-invariant representations, whereas changing orientation in the same position invokes interference or independent learning of the new orientations at both levels, reflecting stimulus dissimilarity. Consistent with single-cell recording studies, perceptual learning alters the weighting of both early and midlevel representations of the visual system. PMID:23898204

The Innate Immune System in Acute and Chronic Wounds

PubMed Central

MacLeod, Amanda S.; Mansbridge, Jonathan N.

2016-01-01

Significance: This review article provides an overview of the critical roles of the innate immune system to wound healing. It explores aspects of dysregulation of individual innate immune elements known to compromise wound repair and promote nonhealing wounds. Understanding the key mechanisms whereby wound healing fails will provide seed concepts for the development of new therapeutic approaches. Recent Advances: Our understanding of the complex interactions of the innate immune system in wound healing has significantly improved, particularly in our understanding of the role of antimicrobials and peptides and the nature of the switch from inflammatory to reparative processes. This takes place against an emerging understanding of the relationship between human cells and commensal bacteria in the skin. Critical Issues: It is well established and accepted that early local inflammatory mediators in the wound bed function as an immunological vehicle to facilitate immune cell infiltration and microbial clearance upon injury to the skin barrier. Both impaired and excessive innate immune responses can promote nonhealing wounds. It appears that the switch from the inflammatory to the proliferative phase is tightly regulated and mediated, at least in part, by a change in macrophages. Defining the factors that initiate the switch in such macrophage phenotypes and functions is the subject of multiple investigations. Future Directions: The review highlights processes that may be useful targets for further investigation, particularly the switch from M1 to M2 macrophages that appears to be critical as dysregulation of this switch occurs during defective wound healing. PMID:26862464

Two intermediate states of the conformational switch in dual specificity phosphatase 13a.

PubMed

Wei, Chun Hwa; Min, Hee Gyeong; Kim, Myeongbin; Kim, Gwan Hee; Chun, Ha-Jung; Ryu, Seong Eon

2018-02-01

Dual specificity phosphatases (DUSPs) include MAP kinase phosphatases and atypical dual specificity phosphatases and mediate cell growth and differentiation, brain function, and immune responses. They serve as targets for drug development against cancers, diabetes and depression. Several DUSPs have non-canonical conformation of the central β-sheet and active site loops, suggesting that they may have conformational switch that is related to the regulation of enzyme activity. Here, we determined the crystal structure of DUSP13a, and identified two different structures that represent intermediates of the postulated conformational switch. Amino acid sequence of DUSP13a is not significantly homologous to DUSPs with conformational switch, indicating that the conformational switch is not sequence-dependent, but rather determined by ligand interaction. The sequence-independency suggests that other DUSPs with canonical conformation may have the conformational switch during specific cellular regulation. The conformational switch leads to significant changes in the protein surface, including a hydrophobic surface and pockets, which can be exploited for development of allosteric modulators of drug target DUSPs. Copyright © 2017 Elsevier Ltd. All rights reserved.

Prospective Randomized Phase II Parallel Study of Vinorelbine Maintenance Therapy versus Best Supportive Care in Advanced Non-Small Cell Lung Cancer.

PubMed

Khosravi, Adnan; Esfahani-Monfared, Zahra; Seifi, Sharareh; Khodadad, Kian

2017-01-01

Maintenance strategy has been used to improve survival in non-small cell lung cancer (NSCLC). We investigated whether switch maintenance therapy with vinorelbine improved progression free survival (PFS) after first-line chemotherapy with gemcitabine plus carboplatin. In this single blind, parallel, phase 2, randomized trial, patients with NSCLC pathology, age >18 years, Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0-2, and advanced stage (IIIB and IV) were treated with up to 6 cycles of gemcitabine 1250 mg/m 2 (day 1 and 8) plus carboplatin AUC 5 (day 1) every 3 weeks. Patients who did not show progression after first-line chemotherapy were randomly assigned to receive switch maintenance with vinorelbine (25 mg/m 2 , day 1, 15) or the best supportive care until disease progression. A total of 100 patients were registered, of whom 34 had a non-progressive response to first-line chemotherapy and randomly received maintenance vinorelbine (n=19) or best supportive care (n=15). The hazard ratio of PFS in the vinorelbine group relative to the best supportive care group was 1.097 (95% confidence interval = 0.479-2.510; P-value =0.827). There was no significant difference between the overall survival for the two groups (P=0.068). Switch maintenance strategies are beneficial, but defining the right candidates for treatment is a problem. Moreover, the trial designs do not always reflect the real-world considerations. Switch maintenance therapy with vinorelbine, though had tolerable toxicity, did not improve PFS in patients with NSCLC. Therefore, other agents should be considered in this setting.

Contraceptive discontinuation and switching among couples receiving integrated HIV and family planning services in Lusaka, Zambia.

PubMed

Haddad, Lisa; Wall, Kristin M; Vwalika, Bellington; Khu, Naw Htee; Brill, Ilene; Kilembe, William; Stephenson, Rob; Chomba, Elwyn; Vwalika, Cheswa; Tichacek, Amanda; Allen, Susan

2013-10-01

To describe predictors of contraceptive method discontinuation and switching behaviours among HIV-positive couples receiving couples' voluntary HIV counselling and testing services in Lusaka, Zambia. Couples were randomized in a factorial design to two-family planning educational intervention videos, received comprehensive family planning services and were assessed every 3 months for contraceptive initiation, discontinuation and switching. We modelled factors associated with contraceptive method upgrading and downgrading via multivariate Andersen-Gill models. Most women continued the initial method selected after randomization. The highest rates of discontinuation/switching were observed for injectable contraceptive and intrauterine device users. Time to discontinuing the more effective contraceptive methods or downgrading to oral contraceptives or condoms was associated with the women's younger age, desire for more children within the next year, heavy menstrual bleeding, bleeding between periods and cystitis/dysuria. Health concerns among women about contraceptive implants and male partners not wanting more children were associated with upgrading from oral contraceptives or condoms. HIV status of the woman or the couple was not predictive of switching or stopping. We found complicated patterns of contraceptive use. The predictors of contraception switching indicate that interventions targeted to younger couples that address common contraception-related misconceptions could improve effective family planning utilization. We recommend these findings be used to increase the uptake and continuation of contraception, especially long-acting reversible contraceptive (LARC) methods, and that fertility goal based, LARC-focused family planning be offered as an integral part of HIV prevention services.

TBK1 controls IgA class switching by negatively regulating noncanonical NF-κB signaling

PubMed Central

Jin, Jin; Xiao, Yichuan; Chang, Jae-Hoon; Yu, Jiayi; Hu, Hongbo; Starr, Robyn; Brittain, George C.; Chang, Mikyoung; Cheng, Xuhong; Sun, Shao-Cong

2012-01-01

Immunoglobulin (Ig) class switching is crucial for generating antibody diversity in humoral immunity and, if deregulated, also has severe pathological consequences. How the magnitude of Ig isotype switching is controlled is still poorly understood. Here we identify TANK-binding kinase 1 (TBK1) as a pivotal negative regulator of IgA class switching. B cell-specific TBK1 ablation in mice resulted in uncontrolled production of IgA and development of nephropathy-like disease symptoms. TBK1 negatively regulated IgA class switching by attenuating noncanonical NF-κB signaling, an action that involved TBK1-mediated phosphorylation and subsequent degradation of the NF-κB-inducing kinase. These findings establish TBK1 as a pivotal negative regulator of the noncanonical NF-κB pathway and highlight a unique mechanism that controls IgA production. PMID:23023393

Gold nanorod as saturable absorber for Q-switched Yb-doped fiber laser

NASA Astrophysics Data System (ADS)

Wang, Xu-De; Luo, Zhi-Chao; Liu, Hao; Zhao, Nian; Liu, Meng; Zhu, Yan-Fang; Xue, Jian-Ping; Luo, Ai-Ping; Xu, Wen-Cheng

2015-07-01

We reported on the generation of Q-switched pulse in an Yb-doped fiber laser by using a filmy polyvinyl alcohol (PVA)-based gold nanorods (GNRs) saturable absorber (SA). The GNRs are synthesized through seed-mediated method whose longitudinal surface plasmon resonance (SPR) absorption peak is located at 1038 nm. The modulation depth of the GNRs SA is ∼4.06%. By gradually increasing the pump power from 62 mW to 128 mW, the repetition rate of Q-switched pulse increases from 8.78 kHz to 20.78 kHz and the pulse duration decreases from 9.43 μs to 3.65 μs. In addition, the dual-wavelength switchable Q-switched operation was also observed. The obtained results further expand the applications of GNRs SA to the field of Q-switched pulsed fiber lasers at 1.0 μm waveband.

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…

Taper models for commercial tree species in the northeastern United States

Treesearch

James A. Westfall; Charles T. Scott

2010-01-01

A new taper model was developed based on the switching taper model of Valentine and Gregoire; the most substantial changes were reformulation to incorporate estimated join points and modification of a switching function. Random-effects parameters were included that account for within-tree correlations and allow for customized calibration to each individual tree. The...

Parkinson's Disease Is Associated with Goal Setting Deficits during Task Switching

ERIC Educational Resources Information Center

Meiran, Nachshon; Friedman, Gilad; Yehene, Eynat

2004-01-01

Ten Parkinson's Disease (PD) patients and 10 control participants were tested using a task-switching paradigm in which there was a random task sequence, and the task was cued in every trial. Five PD patients showed a unique error profile. Their performance approximated guessing when accuracy was dependent on correct task identification, and was…

Trading off switch costs and stimulus availability benefits: An investigation of voluntary task-switching behavior in a predictable dynamic multitasking environment.

PubMed

Mittelstädt, Victor; Miller, Jeff; Kiesel, Andrea

2018-03-09

In the present study, we introduce a novel, self-organized task-switching paradigm that can be used to study more directly the determinants of switching. Instead of instructing participants to randomly switch between tasks, as in the classic voluntary task-switching paradigm (Arrington & Logan, 2004), we instructed participants to optimize their task performance in a voluntary task-switching environment in which the stimulus associated with the previously selected task appeared in each trial after a delay. Importantly, the stimulus onset asynchrony (SOA) increased further with each additional repetition of this task, whereas the stimulus needed for a task switch was always immediately available. We conducted two experiments with different SOA increments (i.e., Exp. 1a = 50 ms, Exp. 1b = 33 ms) to see whether this procedure would induce switching behavior, and we explored how people trade off switch costs against the increasing availability of the stimulus needed for a task repetition. We observed that participants adapted their behavior to the different task environments (i.e., SOA increments) and that participants switched tasks when the SOA in task switches approximately matched the switch costs. Moreover, correlational analyses indicated relations between individual switch costs and individual switch rates across participants. Together, these results demonstrate that participants were sensitive to the increased availability of switch stimuli in deciding whether to switch or to repeat, which in turn demonstrates flexible adaptive task selection behavior. We suggest that performance limitations in task switching interact with the task environment to influence switching behavior.

Evolution of households’ responses to the groundwater arsenic crisis in Bangladesh: information on environmental health risks can have increasing behavioral impact over time

PubMed Central

Balasubramanya, Soumya; Pfaff, Alexander; Bennear, Lori; Tarozzi, Alessandro; Ahmed, Kazi Matin; Schoenfeld, Amy; van Geen, Alexander

2014-01-01

A national campaign of well testing through 2003 enabled households in rural Bangladesh to switch, at least for drinking, from high-arsenic wells to neighboring lower-arsenic wells. We study the well-switching dynamics over time by re-interviewing, in 2008, a randomly selected subset of households in the Araihazar region who had been interviewed in 2005. Contrary to concerns that the impact of arsenic information on switching behavior would erode over time, we find that not only was 2003–2005 switching highly persistent but also new switching by 2008 doubled the share of households at unsafe wells who had switched. The passage of time also had a cost: 22% of households did not recall test results by 2008. The loss of arsenic knowledge led to staying at unsafe wells and switching from safe wells. Our results support ongoing well testing for arsenic to reinforce this beneficial information. PMID:25383015

Additional Electrochemical Treatment Effects on the Switching Characteristics of Anodic Porous Alumina Resistive Switching Memory

NASA Astrophysics Data System (ADS)

Otsuka, Shintaro; Takeda, Ryouta; Furuya, Saeko; Shimizu, Tomohiro; Shingubara, Shouso; Iwata, Nobuyuki; Watanabe, Tadataka; Takano, Yoshiki; Takase, Kouichi

2012-06-01

We have investigated the current-voltage characteristics of a resistive switching memory (ReRAM), especially the reproducibility of the switching voltage between an insulating state and a metallic state. The poor reproducibility hinders the practical use of this memory. According to a filament model, the variation of the switching voltage may be understood in terms of the random choice of filaments with different conductivities and lengths at each switching. A limitation of the number of conductive paths is expected to lead to the suppression of the variation of switching voltage. In this study, two strategies for the limitation have been proposed using an anodic porous alumina (APA). The first is the reduction of the number of conductive paths by restriction of the contact area between the top electrodes and the insulator. The second is the lowering of the resistivity of the insulator, which makes it possible to grow filaments with the same characteristics by electrochemical treatments using a pulse-electroplating technique.

Examining age-related differences in auditory attention control using a task-switching procedure.

PubMed

Lawo, Vera; Koch, Iring

2014-03-01

Using a novel task-switching variant of dichotic selective listening, we examined age-related differences in the ability to intentionally switch auditory attention between 2 speakers defined by their sex. In our task, young (M age = 23.2 years) and older adults (M age = 66.6 years) performed a numerical size categorization on spoken number words. The task-relevant speaker was indicated by a cue prior to auditory stimulus onset. The cuing interval was either short or long and varied randomly trial by trial. We found clear performance costs with instructed attention switches. These auditory attention switch costs decreased with prolonged cue-stimulus interval. Older adults were generally much slower (but not more error prone) than young adults, but switching-related effects did not differ across age groups. These data suggest that the ability to intentionally switch auditory attention in a selective listening task is not compromised in healthy aging. We discuss the role of modality-specific factors in age-related differences.

Resistive switching mechanisms in random access memory devices incorporating transition metal oxides: TiO2, NiO and Pr0.7Ca0.3MnO3.

PubMed

Magyari-Köpe, Blanka; Tendulkar, Mihir; Park, Seong-Geon; Lee, Hyung Dong; Nishi, Yoshio

2011-06-24

Resistance change random access memory (RRAM) cells, typically built as MIM capacitor structures, consist of insulating layers I sandwiched between metal layers M, where the insulator performs the resistance switching operation. These devices can be electrically switched between two or more stable resistance states at a speed of nanoseconds, with long retention times, high switching endurance, low read voltage, and large switching windows. They are attractive candidates for next-generation non-volatile memory, particularly as a flash successor, as the material properties can be scaled to the nanometer regime. Several resistance switching models have been suggested so far for transition metal oxide based devices, such as charge trapping, conductive filament formation, Schottky barrier modulation, and electrochemical migration of point defects. The underlying fundamental principles of the switching mechanism still lack a detailed understanding, i.e. how to control and modulate the electrical characteristics of devices incorporating defects and impurities, such as oxygen vacancies, metal interstitials, hydrogen, and other metallic atoms acting as dopants. In this paper, state of the art ab initio theoretical methods are employed to understand the effects that filamentary types of stable oxygen vacancy configurations in TiO(2) and NiO have on the electronic conduction. It is shown that strong electronic interactions between metal ions adjacent to oxygen vacancy sites results in the formation of a conductive path and thus can explain the 'ON' site conduction in these materials. Implication of hydrogen doping on electroforming is discussed for Pr(0.7)Ca(0.3)MnO(3) devices based on electrical characterization and FTIR measurements.

All-Optical Switching and Two-States Light-Controlled Coherent-Incoherent Random Lasing in a Thiophene-Based Donor-Acceptor System.

PubMed

Szukalski, Adam; Ayadi, Awatef; Haupa, Karolina; El-Ghayoury, Abdelkrim; Sahraoui, Bouchta; Mysliwiec, Jaroslaw

2018-03-30

We describe herein the synthesis and characterization of a thiophene-based donor-acceptor system, namely (E)-2-(4-nitrostyryl)-5-phenylthiophene (Th-pNO 2 ), which was prepared under Horner-Wadsworth-Emmons conditions. The UV/Vis absorption bands, including the intramolecular charge transfer (ICT) band, were fully assigned using DFT and TD-DFT computations. The results of both efficient third-order nonlinear optical properties and light-amplification phenomena are presented. Investigations of photoinduced birefringence (PIB) in optical Kerr effect (OKE) experiments showed a great potential for this particular compound as an efficient, fully reversible, and fast optical switch. Time constants for the observed trans-cis-trans molecular transitions are in the range of microseconds and give a competitive experimental result for the well-known and exploited azobenzene derivatives. Random lasing (RL) investigations confirmed that this organic system is potentially useful to achieve strong light enhancement, observed as a multimode lasing action. Both RL and OKE measurements indicate that this material is a representative of thiophene derivatives, which can be utilized to fabricate fast all-optical switches or random lasers (light amplifiers). © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

New target for inhibition of bacterial RNA polymerase: 'switch region'.

PubMed

Srivastava, Aashish; Talaue, Meliza; Liu, Shuang; Degen, David; Ebright, Richard Y; Sineva, Elena; Chakraborty, Anirban; Druzhinin, Sergey Y; Chatterjee, Sujoy; Mukhopadhyay, Jayanta; Ebright, Yon W; Zozula, Alex; Shen, Juan; Sengupta, Sonali; Niedfeldt, Rui Rong; Xin, Cai; Kaneko, Takushi; Irschik, Herbert; Jansen, Rolf; Donadio, Stefano; Connell, Nancy; Ebright, Richard H

2011-10-01

A new drug target - the 'switch region' - has been identified within bacterial RNA polymerase (RNAP), the enzyme that mediates bacterial RNA synthesis. The new target serves as the binding site for compounds that inhibit bacterial RNA synthesis and kill bacteria. Since the new target is present in most bacterial species, compounds that bind to the new target are active against a broad spectrum of bacterial species. Since the new target is different from targets of other antibacterial agents, compounds that bind to the new target are not cross-resistant with other antibacterial agents. Four antibiotics that function through the new target have been identified: myxopyronin, corallopyronin, ripostatin, and lipiarmycin. This review summarizes the switch region, switch-region inhibitors, and implications for antibacterial drug discovery. Copyright © 2011 Elsevier Ltd. All rights reserved.

Switching the mode of metabolism in the yeast Saccharomyces cerevisiae

PubMed Central

Otterstedt, Karin; Larsson, Christer; Bill, Roslyn M; Ståhlberg, Anders; Boles, Eckhard; Hohmann, Stefan; Gustafsson, Lena

2004-01-01

The biochemistry of most metabolic pathways is conserved from bacteria to humans, although the control mechanisms are adapted to the needs of each cell type. Oxygen depletion commonly controls the switch from respiration to fermentation. However, Saccharomyces cerevisiae also controls that switch in response to the external glucose level. We have generated an S. cerevisiae strain in which glucose uptake is dependent on a chimeric hexose transporter mediating reduced sugar uptake. This strain shows a fully respiratory metabolism also at high glucose levels as seen for aerobic organisms, and switches to fermentation only when oxygen is lacking. These observations illustrate that manipulating a single step can alter the mode of metabolism. The novel yeast strain is an excellent tool to study the mechanisms underlying glucose-induced signal transduction. PMID:15071495

Investigation of resistive switching behaviours in WO3-based RRAM devices

NASA Astrophysics Data System (ADS)

Li, Ying-Tao; Long, Shi-Bing; Lü, Hang-Bing; Liu, Qi; Wang, Qin; Wang, Yan; Zhang, Sen; Lian, Wen-Tai; Liu, Su; Liu, Ming

2011-01-01

In this paper, a WO3-based resistive random access memory device composed of a thin film of WO3 sandwiched between a copper top and a platinum bottom electrodes is fabricated by electron beam evaporation at room temperature. The reproducible resistive switching, low power consumption, multilevel storage possibility, and good data retention characteristics demonstrate that the Cu/WO3/Pt memory device is very promising for future nonvolatile memory applications. The formation and rupture of localised conductive filaments is suggested to be responsible for the observed resistive switching behaviours.

Design approaches to experimental mediation.

PubMed

Pirlott, Angela G; MacKinnon, David P

2016-09-01

Identifying causal mechanisms has become a cornerstone of experimental social psychology, and editors in top social psychology journals champion the use of mediation methods, particularly innovative ones when possible (e.g. Halberstadt, 2010, Smith, 2012). Commonly, studies in experimental social psychology randomly assign participants to levels of the independent variable and measure the mediating and dependent variables, and the mediator is assumed to causally affect the dependent variable. However, participants are not randomly assigned to levels of the mediating variable(s), i.e., the relationship between the mediating and dependent variables is correlational. Although researchers likely know that correlational studies pose a risk of confounding, this problem seems forgotten when thinking about experimental designs randomly assigning participants to levels of the independent variable and measuring the mediator (i.e., "measurement-of-mediation" designs). Experimentally manipulating the mediator provides an approach to solving these problems, yet these methods contain their own set of challenges (e.g., Bullock, Green, & Ha, 2010). We describe types of experimental manipulations targeting the mediator (manipulations demonstrating a causal effect of the mediator on the dependent variable and manipulations targeting the strength of the causal effect of the mediator) and types of experimental designs (double randomization, concurrent double randomization, and parallel), provide published examples of the designs, and discuss the strengths and challenges of each design. Therefore, the goals of this paper include providing a practical guide to manipulation-of-mediator designs in light of their challenges and encouraging researchers to use more rigorous approaches to mediation because manipulation-of-mediator designs strengthen the ability to infer causality of the mediating variable on the dependent variable.

Cooperative light-induced molecular movements of highly ordered azobenzene self-assembled monolayers.

PubMed

Pace, Giuseppina; Ferri, Violetta; Grave, Christian; Elbing, Mark; von Hänisch, Carsten; Zharnikov, Michael; Mayor, Marcel; Rampi, Maria Anita; Samorì, Paolo

2007-06-12

Photochromic systems can convert light energy into mechanical energy, thus they can be used as building blocks for the fabrication of prototypes of molecular devices that are based on the photomechanical effect. Hitherto a controlled photochromic switch on surfaces has been achieved either on isolated chromophores or within assemblies of randomly arranged molecules. Here we show by scanning tunneling microscopy imaging the photochemical switching of a new terminally thiolated azobiphenyl rigid rod molecule. Interestingly, the switching of entire molecular 2D crystalline domains is observed, which is ruled by the interactions between nearest neighbors. This observation of azobenzene-based systems displaying collective switching might be of interest for applications in high-density data storage.

Temperature dependent characteristics of the random telegraph noise on contact resistive random access memory

NASA Astrophysics Data System (ADS)

Chang, Liang-Shun; Lin, Chrong Jung; King, Ya-Chin

2014-01-01

The temperature dependent characteristics of the random telegraphic noise (RTN) on contact resistive random access memory (CRRAM) are studied in this work. In addition to the bi-level switching, the occurrences of the middle states in the RTN signal are investigated. Based on the unique its temperature dependent characteristics, a new temperature sensing scheme is proposed for applications in ultra-low power sensor modules.

An Alternative to the Stay/Switch Equation Assessed When Using a Changeover-Delay

PubMed Central

MacDonall, James S.

2015-01-01

An alternative to the generalized matching equation for understanding concurrent performances is the stay/switch model. For the stay/switch model, the important events are the contingencies and behaviors at each alternative. The current experiment compares the descriptions by two stay/switch equations, the original, empirically derived stay/switch equation and a more theoretically derived equation based on ratios of stay to switch responses matching ratios of stay to switch reinforcers. The present experiment compared descriptions by the original stay/switch equation when using and not using a changeover delay. It also compared descriptions by the more theoretical equation with and without a changeover delay. Finally, it compared descriptions of the concurrent performances by these two equations. Rats were trained in 15 conditions on identical concurrent random-interval schedules in each component of a multiple schedule. A COD operated in only one component. There were no consistent differences in the variance accounted for by each equation of concurrent performances whether or not a COD was used. The simpler equation found greater sensitivity to stay than to switch reinforcers. It also found a COD eliminated the influence of switch reinforcers. Because estimates of parameters were more meaningful when using the more theoretical stay/switch equation it is preferred. PMID:26299548

An alternative to the stay/switch equation assessed when using a changeover-delay.

PubMed

MacDonall, James S

2015-11-01

An alternative to the generalized matching equation for understanding concurrent performances is the stay/switch model. For the stay/switch model, the important events are the contingencies and behaviors at each alternative. The current experiment compares the descriptions by two stay/switch equations, the original, empirically derived stay/switch equation and a more theoretically derived equation based on ratios of stay to switch responses matching ratios of stay to switch reinforcers. The present experiment compared descriptions by the original stay/switch equation when using and not using a changeover delay. It also compared descriptions by the more theoretical equation with and without a changeover delay. Finally, it compared descriptions of the concurrent performances by these two equations. Rats were trained in 15 conditions on identical concurrent random-interval schedules in each component of a multiple schedule. A COD operated in only one component. There were no consistent differences in the variance accounted for by each equation of concurrent performances whether or not a COD was used. The simpler equation found greater sensitivity to stay than to switch reinforcers. It also found a COD eliminated the influence of switch reinforcers. Because estimates of parameters were more meaningful when using the more theoretical stay/switch equation it is preferred. Copyright © 2015 Elsevier B.V. All rights reserved.

Stochastic switching in biology: from genotype to phenotype

NASA Astrophysics Data System (ADS)

Bressloff, Paul C.

2017-03-01

There has been a resurgence of interest in non-equilibrium stochastic processes in recent years, driven in part by the observation that the number of molecules (genes, mRNA, proteins) involved in gene expression are often of order 1-1000. This means that deterministic mass-action kinetics tends to break down, and one needs to take into account the discrete, stochastic nature of biochemical reactions. One of the major consequences of molecular noise is the occurrence of stochastic biological switching at both the genotypic and phenotypic levels. For example, individual gene regulatory networks can switch between graded and binary responses, exhibit translational/transcriptional bursting, and support metastability (noise-induced switching between states that are stable in the deterministic limit). If random switching persists at the phenotypic level then this can confer certain advantages to cell populations growing in a changing environment, as exemplified by bacterial persistence in response to antibiotics. Gene expression at the single-cell level can also be regulated by changes in cell density at the population level, a process known as quorum sensing. In contrast to noise-driven phenotypic switching, the switching mechanism in quorum sensing is stimulus-driven and thus noise tends to have a detrimental effect. A common approach to modeling stochastic gene expression is to assume a large but finite system and to approximate the discrete processes by continuous processes using a system-size expansion. However, there is a growing need to have some familiarity with the theory of stochastic processes that goes beyond the standard topics of chemical master equations, the system-size expansion, Langevin equations and the Fokker-Planck equation. Examples include stochastic hybrid systems (piecewise deterministic Markov processes), large deviations and the Wentzel-Kramers-Brillouin (WKB) method, adiabatic reductions, and queuing/renewal theory. The major aim of this review is to provide a self-contained survey of these mathematical methods, mainly within the context of biological switching processes at both the genotypic and phenotypic levels. However, applications to other examples of biological switching are also discussed, including stochastic ion channels, diffusion in randomly switching environments, bacterial chemotaxis, and stochastic neural networks.

An Acetylation Switch Regulates SUMO-Dependent Protein Interaction Networks

PubMed Central

Ullmann, Rebecca; Chien, Christopher D.; Avantaggiati, Maria Laura; Muller, Stefan

2013-01-01

SUMMARY The attachment of the SUMO modifier to proteins controls cellular signaling pathways through noncovalent binding to SUMO-interaction motifs (SIMs). Canonical SIMs contain a core of hydrophobic residues that bind to a hydrophobic pocket on SUMO. Negatively charged residues of SIMs frequently contribute to binding by interacting with a basic surface on SUMO. Here we define acetylation within this basic interface as a central mechanism for the control of SUMO-mediated interactions. The acetyl-mediated neutralization of basic charges on SUMO prevents binding to SIMs in PML, Daxx, and PIAS family members but does not affect the interaction between RanBP2 and SUMO. Acetylation is controlled by HDACs and attenuates SUMO- and PIAS-mediated gene silencing. Moreover, it affects the assembly of PML nuclear bodies and restrains the recruitment of the corepressor Daxx to these structures. This acetyl-dependent switch thus expands the regulatory repertoire of SUMO signaling and determines the selectivity and dynamics of SUMO-SIM interactions. PMID:22578841

Electrophysiological Evidence for Domain-General Processes in Task-Switching

PubMed Central

Capizzi, Mariagrazia; Ambrosini, Ettore; Arbula, Sandra; Mazzonetto, Ilaria; Vallesi, Antonino

2016-01-01

The ability to flexibly switch between tasks is a hallmark of cognitive control. Despite previous studies that have investigated whether different task-switching types would be mediated by distinct or overlapping neural mechanisms, no definitive consensus has been reached on this question yet. Here, we aimed at directly addressing this issue by recording the event-related potentials (ERPs) elicited by two types of task-switching occurring in the context of spatial and verbal cognitive domains. Source analysis was also applied to the ERP data in order to track the spatial dynamics of brain activity underlying task-switching abilities. In separate blocks of trials, participants had to perform either spatial or verbal switching tasks both of which employed the same type of stimuli. The ERP analysis, which was carried out through a channel- and time-uninformed mass univariate approach, showed no significant differences between the spatial and verbal domains in the modulation of switch and repeat trials. Specifically, relative to repeat trials, switch trials in both domains were associated with a first larger positivity developing over left parieto-occipital electrodes and with a subsequent larger negativity distributed over mid-left fronto-central sites. The source analysis reconstruction for the two ERP components complemented these findings by highlighting the involvement of left-lateralized prefrontal areas in task-switching. Overall, our results join and extend recent research confirming the existence of left-lateralized domain-general task-switching processes. PMID:27047366

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

Contextual control of instrumental actions and habits

PubMed Central

Thrailkill, Eric A.; Bouton, Mark E.

2014-01-01

After a relatively small amount of training, instrumental behavior is thought to be an action under the control of the motivational status of its goal or reinforcer. After more extended training, behavior can become habitual and insensitive to changes in reinforcer value. Recently, instrumental responding has been shown to weaken when tested outside of the training context. The present experiments compared the sensitivity of instrumental responding in rats to a context switch after training procedures that might differentially generate actions or habits. In Experiment 1, lever pressing was decremented in a new context after either short, medium, or long periods of training on either random-ratio or yoked random-interval reinforcement schedules. Experiment 2 found that more minimally-trained responding was also sensitive to a context switch. Moreover, Experiment 3 showed that when the goal-directed component of responding was removed by devaluing the reinforcer, the residual responding that remained was still sensitive to the change of context. Goal-directed responding, in contrast, transferred across contexts. Experiment 4 then found that after extensive training, a habit that was insensitive to reinforcer devaluation was still decremented by a context switch. Overall, the results suggest that a context switch primarily influences instrumental habit rather than action. In addition, even a response that has received relatively minimal training may have a habit component that is insensitive to reinforcer devaluation but sensitive to the effects of a context switch. PMID:25706547

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.

Gossip and Distributed Kalman Filtering: Weak Consensus Under Weak Detectability

NASA Astrophysics Data System (ADS)

Kar, Soummya; Moura, José M. F.

2011-04-01

The paper presents the gossip interactive Kalman filter (GIKF) for distributed Kalman filtering for networked systems and sensor networks, where inter-sensor communication and observations occur at the same time-scale. The communication among sensors is random; each sensor occasionally exchanges its filtering state information with a neighbor depending on the availability of the appropriate network link. We show that under a weak distributed detectability condition: 1. the GIKF error process remains stochastically bounded, irrespective of the instability properties of the random process dynamics; and 2. the network achieves \\emph{weak consensus}, i.e., the conditional estimation error covariance at a (uniformly) randomly selected sensor converges in distribution to a unique invariant measure on the space of positive semi-definite matrices (independent of the initial state.) To prove these results, we interpret the filtered states (estimates and error covariances) at each node in the GIKF as stochastic particles with local interactions. We analyze the asymptotic properties of the error process by studying as a random dynamical system the associated switched (random) Riccati equation, the switching being dictated by a non-stationary Markov chain on the network graph.

Comparison of oral versus rectal administration of acetaminophen with codeine in postoperative pediatric adenotonsillectomy patients.

PubMed

Owczarzak, Vicki; Haddad, Joseph

2006-08-01

To examine whether acetaminophen with codeine administered per rectum is an effective alternative for pain control compared with oral administration after an adenotonsillectomy. A prospective, randomized control study. Seventy-five children aged 1 to 5 were recruited for this study. Each child was assigned randomly to receive either rectal or oral postoperative pain medication. A journal with eight questions was kept for 10 days after the operation, and an overall survey of five questions was filled out at the first postoperative visit. Postoperative pain was adequately controlled in those patients receiving suppositories when compared with those patients receiving oral pain medication. Adverse effects and total number of doses given per day were similar. Parents found the suppositories easy to administer, and more parents would switch or consider switching from oral pain medication to suppositories if given the choice. The suppositories achieved equivalent pain control as oral medication with few side effects and good tolerance. Furthermore, many parents preferred the suppositories to oral medication in maintaining postoperative pain control because of ease of administration. If given the choice for future surgeries, many parents would switch or consider switching from oral pain medication to suppositories.

Low-power resistive random access memory by confining the formation of conducting filaments

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huang, Yi-Jen; Lee, Si-Chen, E-mail: sclee@ntu.edu.tw; Shen, Tzu-Hsien

2016-06-15

Owing to their small physical size and low power consumption, resistive random access memory (RRAM) devices are potential for future memory and logic applications in microelectronics. In this study, a new resistive switching material structure, TiO{sub x}/silver nanoparticles/TiO{sub x}/AlTiO{sub x}, fabricated between the fluorine-doped tin oxide bottom electrode and the indium tin oxide top electrode is demonstrated. The device exhibits excellent memory performances, such as low operation voltage (<±1 V), low operation power, small variation in resistance, reliable data retention, and a large memory window. The current-voltage measurement shows that the conducting mechanism in the device at the high resistancemore » state is via electron hopping between oxygen vacancies in the resistive switching material. When the device is switched to the low resistance state, conducting filaments are formed in the resistive switching material as a result of accumulation of oxygen vacancies. The bottom AlTiO{sub x} layer in the device structure limits the formation of conducting filaments; therefore, the current and power consumption of device operation are significantly reduced.« less

Hf layer thickness dependence of resistive switching characteristics of Ti/Hf/HfO2/Au resistive random access memory device

NASA Astrophysics Data System (ADS)

Nakajima, Ryo; Azuma, Atsushi; Yoshida, Hayato; Shimizu, Tomohiro; Ito, Takeshi; Shingubara, Shoso

2018-06-01

Resistive random access memory (ReRAM) devices with a HfO2 dielectric layer have been studied extensively owing to the good reproducibility of their SET/RESET switching properties. Furthermore, it was reported that a thin Hf layer next to a HfO2 layer stabilized switching properties because of the oxygen scavenging effect. In this work, we studied the Hf thickness dependence of the resistance switching characteristics of a Ti/Hf/HfO2/Au ReRAM device. It is found that the optimum Hf thickness is approximately 10 nm to obtain good reproducibility of SET/RESET voltages with a small RESET current. However, when the Hf thickness was very small (∼2 nm), the device failed after the first RESET process owing to the very large RESET current. In the case of a very thick Hf layer (∼20 nm), RESET did not occur owing to the formation of a leaky dielectric layer. We observed the occurrence of multiple resistance states in the RESET process of the device with a Hf thickness of 10 nm by increasing the RESET voltage stepwise.

Early oral switch therapy in low-risk Staphylococcus aureus bloodstream infection (SABATO): study protocol for a randomized controlled trial.

PubMed

Kaasch, Achim J; Fätkenheuer, Gerd; Prinz-Langenohl, Reinhild; Paulus, Ursula; Hellmich, Martin; Weiß, Verena; Jung, Norma; Rieg, Siegbert; Kern, Winfried V; Seifert, Harald

2015-10-09

Current guidelines recommend that patients with Staphylococcus aureus bloodstream infection (SAB) are treated with long courses of intravenous antimicrobial therapy. This serves to avoid SAB-related complications such as relapses, local extension and distant metastatic foci. However, in certain clinical scenarios, the incidence of SAB-related complications is low. Patients with a low-risk for complications may thus benefit from an early switch to oral medication through earlier discharge and fewer complications of intravenous therapy. The major objective for the SABATO trial is to demonstrate that in patients with low-risk SAB a switch from intravenous to oral antimicrobial therapy (oral switch therapy, OST) is non-inferior to a conventional course of intravenous therapy (intravenous standard therapy, IST). The trial is designed as randomized, parallel-group, observer-blinded, clinical non-inferiority trial. The primary endpoint is the occurrence of a SAB-related complication (relapsing SAB, deep-seated infection, and attributable mortality) within 90 days. Secondary endpoints are the length of hospital stay; 14-day, 30-day, and 90-day mortality; and complications of intravenous therapy. Patients with SAB who have received 5 to 7 full days of adequate intravenous antimicrobial therapy are eligible. Main exclusion criteria are polymicrobial bloodstream infection, signs and symptoms of complicated SAB (deep-seated infection, hematogenous dissemination, septic shock, and prolonged bacteremia), the presence of a non-removable foreign body, and severe comorbidity. Patients will receive either OST or IST with a protocol-approved antimicrobial and are followed up for 90 days. Four hundred thirty patients will be randomized 1:1 in two study arms. Efficacy regarding incidence of SAB-related complications is tested sequentially with a non-inferiority margin of 10 and 5 percentage points. The SABATO trial assesses whether early oral switch therapy is safe and effective for patients with low-risk SAB. Regardless of the result, this pragmatic trial will strongly influence the standard of care in SAB. ClinicalTrials.gov NCT01792804 registered 13 February 2013; German Clinical trials register DRKS00004741 registered 4 October 2013, EudraCT 2013-000577-77 . First patient randomized on 20 December 2013.

A novel 3D Cartesian random sampling strategy for Compressive Sensing Magnetic Resonance Imaging.

PubMed

Valvano, Giuseppe; Martini, Nicola; Santarelli, Maria Filomena; Chiappino, Dante; Landini, Luigi

2015-01-01

In this work we propose a novel acquisition strategy for accelerated 3D Compressive Sensing Magnetic Resonance Imaging (CS-MRI). This strategy is based on a 3D cartesian sampling with random switching of the frequency encoding direction with other K-space directions. Two 3D sampling strategies are presented. In the first strategy, the frequency encoding direction is randomly switched with one of the two phase encoding directions. In the second strategy, the frequency encoding direction is randomly chosen between all the directions of the K-Space. These strategies can lower the coherence of the acquisition, in order to produce reduced aliasing artifacts and to achieve a better image quality after Compressive Sensing (CS) reconstruction. Furthermore, the proposed strategies can reduce the typical smoothing of CS due to the limited sampling of high frequency locations. We demonstrated by means of simulations that the proposed acquisition strategies outperformed the standard Compressive Sensing acquisition. This results in a better quality of the reconstructed images and in a greater achievable acceleration.

Can task-switching training enhance executive control functioning in children with attention deficit/-hyperactivity disorder?

PubMed

Kray, Jutta; Karbach, Julia; Haenig, Susann; Freitag, Christine

2011-01-01

The key cognitive impairments of children with attention deficit/-hyperactivity disorder (ADHD) include executive control functions such as inhibitory control, task-switching, and working memory (WM). In this training study we examined whether task-switching training leads to improvements in these functions. Twenty children with combined type ADHD and stable methylphenidate medication performed a single-task and a task-switching training in a crossover training design. The children were randomly assigned to one of two groups. One group started with the single-task training and then performed the task-switching training and the other group vice versa. The effectiveness of the task-switching training was measured as performance improvements (relative to the single-task training) on a structurally similar but new switching task and on other executive control tasks measuring inhibitory control and verbal WM as well as on fluid intelligence (reasoning). The children in both groups showed improvements in task-switching, that is, a reduction of switching costs, but not in performing the single-tasks across four training sessions. Moreover, the task-switching training lead to selective enhancements in task-switching performance, that is, the reduction of task-switching costs was found to be larger after task-switching than after single-task training. Similar selective improvements were observed for inhibitory control and verbal WM, but not for reasoning. Results of this study suggest that task-switching training is an effective cognitive intervention that helps to enhance executive control functioning in children with ADHD.

Can Task-Switching Training Enhance Executive Control Functioning in Children with Attention Deficit/-Hyperactivity Disorder?

PubMed Central

Kray, Jutta; Karbach, Julia; Haenig, Susann; Freitag, Christine

2012-01-01

The key cognitive impairments of children with attention deficit/-hyperactivity disorder (ADHD) include executive control functions such as inhibitory control, task-switching, and working memory (WM). In this training study we examined whether task-switching training leads to improvements in these functions. Twenty children with combined type ADHD and stable methylphenidate medication performed a single-task and a task-switching training in a crossover training design. The children were randomly assigned to one of two groups. One group started with the single-task training and then performed the task-switching training and the other group vice versa. The effectiveness of the task-switching training was measured as performance improvements (relative to the single-task training) on a structurally similar but new switching task and on other executive control tasks measuring inhibitory control and verbal WM as well as on fluid intelligence (reasoning). The children in both groups showed improvements in task-switching, that is, a reduction of switching costs, but not in performing the single-tasks across four training sessions. Moreover, the task-switching training lead to selective enhancements in task-switching performance, that is, the reduction of task-switching costs was found to be larger after task-switching than after single-task training. Similar selective improvements were observed for inhibitory control and verbal WM, but not for reasoning. Results of this study suggest that task-switching training is an effective cognitive intervention that helps to enhance executive control functioning in children with ADHD. PMID:22291628

Differing antidepressant maintenance methodologies.

PubMed

Safer, Daniel J

2017-10-01

The principle evidence that antidepressant medication (ADM) is an effective maintenance treatment for adults with major depressive disorder (MDD) is from placebo substitution trials. These trials enter responders from ADM efficacy trials into randomized, double-blind placebo-controlled (RDBPC) effectiveness trials to measure the rate of MDD relapse over time. However, other randomized maintenance trial methodologies merit consideration and comparison. A systematic review of ADM randomized maintenance trials included research reports from multiple databases. Relapse rate was the main effectiveness outcome assessed. Five ADM randomized maintenance methodologies for MDD responders are described and compared for outcome. These effectiveness trials include: placebo-substitution, ADM/placebo extension, ADM extension, ADM vs. psychotherapy, and treatment as usual. The placebo-substitution trials for those abruptly switched to placebo resulted in unusually high (46%) rates of relapse over 6-12months, twice the continuing ADM rate. These trials were characterized by selective screening, high attrition, an anxious anticipation of a switch to placebo, and a risk of drug withdrawal symptoms. Selectively screened ADM efficacy responders who entered into 4-12month extension trials experienced relapse rates averaging ~10% with a low attrition rate. Non-industry sponsored randomized trials of adults with multiple prior MDD episodes who were treated with ADM maintenance for 1-2years experienced relapse rates averaging 40%. Placebo substitution trial methodology represents only one approach to assess ADM maintenance. Antidepressant maintenance research for adults with MDD should be evaluated for industry sponsorship, attrition, the impact of the switch to placebo, and major relapse differences in MDD subpopulations. Copyright © 2017. Published by Elsevier Inc.

Contraceptive discontinuation and switching among couples receiving integrated HIV and family planning services in Lusaka, Zambia

PubMed Central

Haddad, Lisa; Wall, Kristin M; Vwalika, Bellington; Htee Khu, Naw; Brill, Ilene; Kilembe, William; Stephenson, Rob; Chomba, Elwyn; Vwalika, Cheswa; Tichacek, Amanda; Allen, Susan

2014-01-01

Objective To describe predictors of contraceptive method discontinuation and switching behaviors among HIV positive couples receiving couples' voluntary HIV counseling and testing services in Lusaka, Zambia. Design Couples were randomized in a factorial design to two family planning educational intervention videos, received comprehensive family planning services, and were assessed every 3-months for contraceptive initiation, discontinuation and switching. Methods We modeled factors associated with contraceptive method upgrading and downgrading via multivariate Andersen-Gill models. Results Most women continued the initial method selected after randomization. The highest rates of discontinuation/switching were observed for injectable contraceptive and intrauterine device users. Time to discontinuing the more effective contraceptive methods or downgrading to oral contraceptives or condoms was associated with the women's younger age, desire for more children within the next year, heavy menstrual bleeding, bleeding between periods, and cystitis/dysuria. Health concerns among women about contraceptive implants and male partners not wanting more children were associated with upgrading from oral contraceptives or condoms. HIV status of the woman or the couple was not predictive of switching or stopping. Conclusions We found complicated patterns of contraceptive use. The predictors of contraception switching indicate that interventions targeted to younger couples that address common contraception-related misconceptions could improve effective family planning utilization. We recommend these findings be used to increase the uptake and continuation of contraception, especially long acting reversible contraceptive (LARC) methods, and that fertility-goal based, LARC-focused family planning be offered as an integral part of HIV prevention services. PMID:24088689

Design approaches to experimental mediation☆

PubMed Central

Pirlott, Angela G.; MacKinnon, David P.

2016-01-01

Identifying causal mechanisms has become a cornerstone of experimental social psychology, and editors in top social psychology journals champion the use of mediation methods, particularly innovative ones when possible (e.g. Halberstadt, 2010, Smith, 2012). Commonly, studies in experimental social psychology randomly assign participants to levels of the independent variable and measure the mediating and dependent variables, and the mediator is assumed to causally affect the dependent variable. However, participants are not randomly assigned to levels of the mediating variable(s), i.e., the relationship between the mediating and dependent variables is correlational. Although researchers likely know that correlational studies pose a risk of confounding, this problem seems forgotten when thinking about experimental designs randomly assigning participants to levels of the independent variable and measuring the mediator (i.e., “measurement-of-mediation” designs). Experimentally manipulating the mediator provides an approach to solving these problems, yet these methods contain their own set of challenges (e.g., Bullock, Green, & Ha, 2010). We describe types of experimental manipulations targeting the mediator (manipulations demonstrating a causal effect of the mediator on the dependent variable and manipulations targeting the strength of the causal effect of the mediator) and types of experimental designs (double randomization, concurrent double randomization, and parallel), provide published examples of the designs, and discuss the strengths and challenges of each design. Therefore, the goals of this paper include providing a practical guide to manipulation-of-mediator designs in light of their challenges and encouraging researchers to use more rigorous approaches to mediation because manipulation-of-mediator designs strengthen the ability to infer causality of the mediating variable on the dependent variable. PMID:27570259

Stimulation of contacts in ventral but not dorsal subthalamic nucleus normalizes response switching in Parkinson's disease

PubMed Central

Greenhouse, Ian; Gould, Sherrie; Houser, Melissa; Aron, Adam R.

2014-01-01

Switching between responses is a key executive function known to rely on the frontal cortex and the basal ganglia. Here we aimed to establish with greater anatomical specificity whether such switching could be mediated via different possible frontal–basal-ganglia circuits. Accordingly, we stimulated dorsal vs. ventral contacts of electrodes in the subthalamic nucleus (STN) in Parkinson's patients during switching performance, and also studied matched controls. The patients underwent three sessions: once with bilateral dorsal contact stimulation, once with bilateral ventral contact stimulation, and once Off stimulation. Patients Off stimulation showed abnormal patterns of switching, and stimulation of the ventral contacts but not the dorsal contacts normalized the pattern of behavior relative to controls. This provides some of the first evidence in humans that stimulation of dorsal vs. ventral STN DBS contacts has differential effects on executive function. As response switching is an executive function known to rely on prefrontal cortex, these results suggest that ventral contact stimulation affected an executive/associative cortico-basal ganglia circuit. PMID:23562963

Combined deficiency of MSH2 and Sμ region abolishes class switch recombination.

PubMed

Leduc, Claire; Haddad, Dania; Laviolette-Malirat, Nathalie; Nguyen Huu, Ngoc-Sa; Khamlichi, Ahmed Amine

2010-10-01

Class switch recombination (CSR) is mediated by G-rich tandem repeated sequences termed switch regions. Transcription of switch regions generates single-stranded R loops that provide substrates for activation-induced cytidine deaminase. Mice deficient in MSH2 have a mild defect in CSR and analysis of their switch junctions has led to a model in which MSH2 is more critical for switch recombination events outside than within the tandem repeats. It is also known that deletion of the whole Sμ region severely impairs but does not abrogate CSR despite the lack of detectable R loops. Here, we demonstrate that deficiency of both MSH2 and the Sμ region completely abolishes CSR and that the abrogation occurs at the genomic level. This finding further supports the crucial role of MSH2 outside the tandem repeats. It also indicates that during CSR, MSH2 has access to activation-induced cytidine deaminase targets in R-loop-deficient Iμ-Cμ sequences rarely used in CSR, suggesting an MSH2-dependent DNA processing activity at the Iμ exon that may decrease with transcription elongation across the Sμ region.

Alpha3, a transposable element that promotes host sexual reproduction.

PubMed

Barsoum, Emad; Martinez, Paula; Aström, Stefan U

2010-01-01

Theoretical models predict that selfish DNA elements require host sex to persist in a population. Therefore, a transposon that induces sex would strongly favor its own spread. We demonstrate that a protein homologous to transposases, called alpha3, was essential for mating type switch in Kluyveromyces lactis. Mutational analysis showed that amino acids conserved among transposases were essential for its function. During switching, sequences in the 5' and 3' flanking regions of the alpha3 gene were joined, forming a DNA circle, showing that alpha3 mobilized from the genome. The sequences encompassing the alpha3 gene circle junctions in the mating type alpha (MATalpha) locus were essential for switching from MATalpha to MATa, suggesting that alpha3 mobilization was a coupled event. Switching also required a DNA-binding protein, Mating type switch 1 (Mts1), whose binding sites in MATalpha were important. Expression of Mts1 was repressed in MATa/MATalpha diploids and by nutrients, limiting switching to haploids in low-nutrient conditions. A hairpin-capped DNA double-strand break (DSB) was observed in the MATa locus in mre11 mutant strains, indicating that mating type switch was induced by MAT-specific DSBs. This study provides empirical evidence for selfish DNA promoting host sexual reproduction by mediating mating type switch.

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.

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.

Randomized, Noncomparative, Phase II Trial of Early Switch From Docetaxel to Cabazitaxel or Vice Versa, With Integrated Biomarker Analysis, in Men With Chemotherapy-Naïve, Metastatic, Castration-Resistant Prostate Cancer

PubMed Central

Tagawa, Scott T.; Galletti, Giuseppe; Worroll, Daniel; Ballman, Karla; Vanhuyse, Marie; Sonpavde, Guru; North, Scott; Albany, Costantine; Tsao, Che-Kai; Stewart, John; Zaher, Atef; Szatrowski, Ted; Zhou, Wei; Gjyrezi, Ada; Tasaki, Shinsuke; Portella, Luigi; Bai, Yang; Lannin, Timothy B.; Suri, Shalu; Gruber, Conor N.; Pratt, Erica D.; Kirby, Brian J.; Eisenberger, Mario A.; Nanus, David M.; Saad, Fred; Giannakakou, Paraskevi

2017-01-01

Purpose The TAXYNERGY trial (ClinicalTrials.gov identifier: NCT01718353) evaluated clinical benefit from early taxane switch and circulating tumor cell (CTC) biomarkers to interrogate mechanisms of sensitivity or resistance to taxanes in men with chemotherapy-naïve, metastatic, castration-resistant prostate cancer. Patients and Methods Patients were randomly assigned 2:1 to docetaxel or cabazitaxel. Men who did not achieve ≥ 30% prostate-specific antigen (PSA) decline by cycle 4 (C4) switched taxane. The primary clinical endpoint was confirmed ≥ 50% PSA decline versus historical control (TAX327). The primary biomarker endpoint was analysis of post-treatment CTCs to confirm the hypothesis that clinical response was associated with taxane drug-target engagement, evidenced by decreased percent androgen receptor nuclear localization (%ARNL) and increased microtubule bundling. Results Sixty-three patients were randomly assigned to docetaxel (n = 41) or cabazitaxel (n = 22); 44.4% received prior potent androgen receptor–targeted therapy. Overall, 35 patients (55.6%) had confirmed ≥ 50% PSA responses, exceeding the historical control rate of 45.4% (TAX327). Of 61 treated patients, 33 (54.1%) had ≥ 30% PSA declines by C4 and did not switch taxane, 15 patients (24.6%) who did not achieve ≥ 30% PSA declines by C4 switched taxane, and 13 patients (21.3%) discontinued therapy before or at C4. Of patients switching taxane, 46.7% subsequently achieved ≥ 50% PSA decrease. In 26 CTC-evaluable patients, taxane-induced decrease in %ARNL (cycle 1 day 1 v cycle 1 day 8) was associated with a higher rate of ≥ 50% PSA decrease at C4 (P = .009). Median composite progression-free survival was 9.1 months (95% CI, 4.9 to 11.7 months); median overall survival was not reached at 14 months. Common grade 3 or 4 adverse events included fatigue (13.1%) and febrile neutropenia (11.5%). Conclusion The early taxane switch strategy was associated with improved PSA response rates versus TAX327. Taxane-induced shifts in %ARNL may serve as an early biomarker of clinical benefit in patients treated with taxanes. PMID:28632486

Packet communications in satellites with multiple-beam antennas and signal processing

NASA Technical Reports Server (NTRS)

Davies, R.; Chethik, F.; Penick, M.

1980-01-01

A communication satellite with a multiple-beam antenna and onboard signal processing is considered for use in a 'message-switched' data relay system. The signal processor may incorporate demodulation, routing, storage, and remodulation of the data. A system user model is established and key functional elements for the signal processing are identified. With the throughput and delay requirements as the controlled variables, the hardware complexity, operational discipline, occupied bandwidth, and overall user end-to-end cost are estimated for (1) random-access packet switching; and (2) reservation-access packet switching. Other aspects of this network (eg, the adaptability to channel switched traffic requirements) are examined. For the given requirements and constraints, the reservation system appears to be the most attractive protocol.

Cooperative light-induced molecular movements of highly ordered azobenzene self-assembled monolayers

PubMed Central

Pace, Giuseppina; Ferri, Violetta; Grave, Christian; Elbing, Mark; von Hänisch, Carsten; Zharnikov, Michael; Mayor, Marcel; Rampi, Maria Anita; Samorì, Paolo

2007-01-01

Photochromic systems can convert light energy into mechanical energy, thus they can be used as building blocks for the fabrication of prototypes of molecular devices that are based on the photomechanical effect. Hitherto a controlled photochromic switch on surfaces has been achieved either on isolated chromophores or within assemblies of randomly arranged molecules. Here we show by scanning tunneling microscopy imaging the photochemical switching of a new terminally thiolated azobiphenyl rigid rod molecule. Interestingly, the switching of entire molecular 2D crystalline domains is observed, which is ruled by the interactions between nearest neighbors. This observation of azobenzene-based systems displaying collective switching might be of interest for applications in high-density data storage. PMID:17535889

Ga-doped indium oxide nanowire phase change random access memory cells

NASA Astrophysics Data System (ADS)

Jin, Bo; Lim, Taekyung; Ju, Sanghyun; Latypov, Marat I.; Kim, Hyoung Seop; Meyyappan, M.; Lee, Jeong-Soo

2014-02-01

Phase change random access memory (PCRAM) devices are usually constructed using tellurium based compounds, but efforts to seek other materials providing desirable memory characteristics have continued. We have fabricated PCRAM devices using Ga-doped In2O3 nanowires with three different Ga compositions (Ga/(In+Ga) atomic ratio: 2.1%, 11.5% and 13.0%), and investigated their phase switching properties. The nanowires (˜40 nm in diameter) can be repeatedly switched between crystalline and amorphous phases, and Ga concentration-dependent memory switching behavior in the nanowires was observed with ultra-fast set/reset rates of 80 ns/20 ns, which are faster than for other competitive phase change materials. The observations of fast set/reset rates and two distinct states with a difference in resistance of two to three orders of magnitude appear promising for nonvolatile information storage. Moreover, we found that increasing the Ga concentration can reduce the power consumption and resistance drift; however, too high a level of Ga doping may cause difficulty in achieving the phase transition.

Immediate movement history influences reach-to-grasp action selection in children and adults.

PubMed

Kent, Samuel W; Wilson, Andrew D; Plumb, Mandy S; Williams, Justin H G; Mon-Williams, Mark

2009-01-01

Action selection is subject to many biases. Immediate movement history is one such bias seen in young infants. Is this bias strong enough to affect adult behavior? Adult participants reached and grasped a cylinder positioned to require either pronation or supination of the hand. Successive cylinder positions changed either randomly or systematically between trials. Random positioning led to optimized economy of movement. In contrast, systematic changes in position biased action selection toward previously selected actions at the expense of movement economy. Thus, one switches to a new movement only when the savings outweigh the costs of the switch. Immediate movement history had an even larger influence on children aged 7-15 years. This suggests that switching costs are greater in children, which is consistent with their reduced grasping experience. The presence of this effect in adults suggests that immediate movement history exerts a more widespread and pervasive influence on patterns of action selection than researchers had previously recognized.

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.

Zero field reversal probability in thermally assisted magnetization reversal

NASA Astrophysics Data System (ADS)

Prasetya, E. B.; Utari; Purnama, B.

2017-11-01

This paper discussed about zero field reversal probability in thermally assisted magnetization reversal (TAMR). Appearance of reversal probability in zero field investigated through micromagnetic simulation by solving stochastic Landau-Lifshitz-Gibert (LLG). The perpendicularly anisotropy magnetic dot of 50×50×20 nm3 is considered as single cell magnetic storage of magnetic random acces memory (MRAM). Thermally assisted magnetization reversal was performed by cooling writing process from near/almost Curie point to room temperature on 20 times runs for different randomly magnetized state. The results show that the probability reversal under zero magnetic field decreased with the increase of the energy barrier. The zero-field probability switching of 55% attained for energy barrier of 60 k B T and the reversal probability become zero noted at energy barrier of 2348 k B T. The higest zero-field switching probability of 55% attained for energy barrier of 60 k B T which corespond to magnetif field of 150 Oe for switching.

Current-limiting and ultrafast system for the characterization of resistive random access memories.

PubMed

Diaz-Fortuny, J; Maestro, M; Martin-Martinez, J; Crespo-Yepes, A; Rodriguez, R; Nafria, M; Aymerich, X

2016-06-01

A new system for the ultrafast characterization of resistive switching phenomenon is developed to acquire the current during the Set and Reset process in a microsecond time scale. A new electronic circuit has been developed as a part of the main setup system, which is capable of (i) applying a hardware current limit ranging from nanoampers up to miliampers and (ii) converting the Set and Reset exponential gate current range into an equivalent linear voltage. The complete system setup allows measuring with a microsecond resolution. Some examples demonstrate that, with the developed setup, an in-depth analysis of resistive switching phenomenon and random telegraph noise can be made.

Switching from an oral dopamine receptor agonist to rotigotine transdermal patch: a review of clinical data with a focus on patient perspective.

PubMed

Chung, Sun Ju; Asgharnejad, Mahnaz; Bauer, Lars; Benitez, Arturo; Boroojerdi, Babak; Heidbrede, Tanja; Little, Allison; Kim, Han Joon

2017-07-01

Dopamine receptor agonists (DAs) are commonly used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). In certain situations, switching from oral DAs to rotigotine transdermal patch may be beneficial for the patient (e.g., optimal symptom control/side effects/perioperative management, preference for once-daily/non-oral administration, RLS augmentation treatment). Areas covered: This narrative review summarizes available data on DA dose equivalency, dose conversions, switching schedules, safety, tolerability, efficacy and patient treatment preferences of switching from oral DAs to rotigotine (and vice versa) in patients with PD/RLS. The studies were identified in a PubMed search (up to 8 November 2016) using terms ('dopamine receptor agonist' OR 'rotigotine') AND 'switch'. Expert commentary: Randomized controlled studies often do not address the challenges clinicians face in practice, e.g., switching medications within the same class when dosing is not a one-to-one ratio. The authors describe three open-label studies in PD where oral DAs were successfully switched to rotigotine, and review three studies in RLS where oral DAs/levodopa were switched to rotigotine. Finally, the authors provide a suggested tool for switching from oral DAs to rotigotine, which includes dose conversion factors and switching schedules. The authors' view is that low-dose oral DAs (equivalent to ≤8 mg/24 h rotigotine) may be switched overnight.

Slowly switching between environments facilitates reverse evolution in small populations

NASA Astrophysics Data System (ADS)

Tan, Longzhi; Gore, Jeff

2011-03-01

The rate at which a physical process occurs usually changes the behavior of a system. In thermodynamics, the reversibility of a process generally increases when it occurs at an infinitely slow rate. In biological evolution, adaptations to a new environment may be reversed by evolution in the ancestral environment. Such fluctuating environments are ubiquitous in nature, although how the rate of switching affects reverse evolution is unknown. Here we use a computational approach to quantify evolutionary reversibility as a function of the rate of switching between two environments. For small population sizes, which travel on landscapes as random walkers, we find that both genotypic and phenotypic reverse evolution increase at slow switching rates. However, slow switching of environments decreases evolutionary reversibility for a greedy walker, corresponding to large populations (extensive clonal interference). We conclude that the impact of the switching rate for biological evolution is more complicated than other common physical processes, and that a quantitative approach may yield significant insight into reverse evolution.

Ultra-low power, highly uniform polymer memory by inserted multilayer graphene electrode

NASA Astrophysics Data System (ADS)

Jang, Byung Chul; Seong, Hyejeong; Kim, Jong Yun; Koo, Beom Jun; Kim, Sung Kyu; Yang, Sang Yoon; Gap Im, Sung; Choi, Sung-Yool

2015-12-01

Filament type resistive random access memory (RRAM) based on polymer thin films is a promising device for next generation, flexible nonvolatile memory. However, the resistive switching nonuniformity and the high power consumption found in the general filament type RRAM devices present critical issues for practical memory applications. Here, we introduce a novel approach not only to reduce the power consumption but also to improve the resistive switching uniformity in RRAM devices based on poly(1,3,5-trimethyl-3,4,5-trivinyl cyclotrisiloxane) by inserting multilayer graphene (MLG) at the electrode/polymer interface. The resistive switching uniformity was thereby significantly improved, and the power consumption was markedly reduced by 250 times. Furthermore, the inserted MLG film enabled a transition of the resistive switching operation from unipolar resistive switching to bipolar resistive switching and induced self-compliance behavior. The findings of this study can pave the way toward a new area of application for graphene in electronic devices.

Switching health insurers: the role of price, quality and consumer information search.

PubMed

Boonen, Lieke H H M; Laske-Aldershof, Trea; Schut, Frederik T

2016-04-01

We examine the impact of price, service quality and information search on people's propensity to switch health insurers in the competitive Dutch health insurance market. Using panel data from annual household surveys and data on health insurers' premiums and quality ratings over the period 2006-2012, we estimate a random effects logit model of people's switching decisions. We find that switching propensities depend on health plan price and quality, and on people's age, health, education and having supplementary or group insurance. Young people (18-35 years) are more sensitive to price, whereas older people are more sensitive to quality. Searching for health plan information has a much stronger impact on peoples' sensitivity to price than to service quality. In addition, searching for health plan information has a stronger impact on the switching propensity of higher than lower educated people, suggesting that higher educated people make better use of available health plan information. Finally, having supplementary insurance significantly reduces older people's switching propensity.

No role of beta receptors in cognitive flexibility: Evidence from a task-switching paradigm in a randomized controlled trial.

PubMed

Steenbergen, L; Sellaro, R; de Rover, M; Hommel, B; Colzato, L S

2015-06-04

There is evidence that noradrenergic coeruleo-cortical projections are involved in different forms of cognitive flexibility. So far, no studies in humans have investigated the involvement of beta receptors on task-switching performance, a well-established measure of cognitive flexibility. The present study investigated whether the administration of propranolol (a central and peripheral beta-adrenergic antagonist) affected switching costs (i.e., the increase of reaction time in task-switching trials relative to task-repetition trials). Sixteen healthy adult human subjects performed a global-local task-switching paradigm in a double-blind, within-subjects design study investigating the effects of 80mg of propranolol hydrochloride (a β1 and β2 adrenergic receptor antagonist) vs. an oral dose of microcrystalline cellulose (placebo pill). The acute administration of propranolol did not affect the size of switching costs compared to the intake of the neutral placebo. Our results, corroborated by Bayesian inference, suggest that beta receptors do not modulate cognitive flexibility as measured by task-switching performance. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Non-destructive reversible resistive switching in Cr doped Mott insulator Ca2RuO4: Interface vs bulk effects

NASA Astrophysics Data System (ADS)

Shen, Shida; Williamson, Morgan; Cao, Gang; Zhou, Jianshi; Goodenough, John; Tsoi, Maxim

2017-12-01

A non-destructive reversible resistive switching is demonstrated in single crystals of Cr-doped Mott insulator Ca2RuO4. An applied electrical bias was shown to reduce the DC resistance of the crystal by as much as 75%. The original resistance of the sample could be restored by applying an electrical bias of opposite polarity. We have studied this resistive switching as a function of the bias strength, applied magnetic field, and temperature. A combination of 2-, 3-, and 4-probe measurements provide a means to distinguish between bulk and interfacial contributions to the switching and suggests that the switching is mostly an interfacial effect. The switching was tentatively attributed to electric-field driven lattice distortions which accompany the impurity-induced Mott transition. This field effect was confirmed by temperature-dependent resistivity measurements which show that the activation energy of this material can be tuned by an applied DC electrical bias. The observed resistance switching can potentially be used for building non-volatile memory devices like resistive random access memory.

Picoampere Resistive Switching Characteristics Realized with Vertically Contacted Carbon Nanotube Atomic Force Microscope Probe

NASA Astrophysics Data System (ADS)

Nakano, Haruhisa; Takahashi, Makoto; Sato, Motonobu; Kotsugi, Masato; Ohkochi, Takuo; Muro, Takayuki; Nihei, Mizuhisa; Yokoyama, Naoki

2013-11-01

The resistive switching characteristics of a TiO2/Ti structure have been investigated using a conductive atomic force microscopy (AFM) system with 5-nm-diameter carbon nanotube (CNT) probes. The resistive switching showed bipolar resistive random access memory (ReRAM) behaviors with extremely low switching currents in the order of Picoamperes when voltages were applied. From transmission electron microscopy (TEM) observation, we confirmed that filament-like nanocrystals, having a diameter of about 10 nm, existed in TiO2 films at resistive switching areas after not only set operation but also reset operation. Moreover, photoemission electron microscopy (PEEM) analysis showed that the anatase-type TiO2 structure did not change after set and reset operations. From these results, we suggested that the Picoampere resistive switching occurred at the interface between the TiO2 dielectric and conductive nanocrystal without any structural changes in the TiO2 film and nanocrystal. The resistive switching mechanism we suggested is highly promising to realize extremely low-power-consumption ReRAMs with vertically contacted CNT electrodes.

Engineering the switching dynamics of TiOx-based RRAM with Al doping

NASA Astrophysics Data System (ADS)

Trapatseli, Maria; Khiat, Ali; Cortese, Simone; Serb, Alexantrou; Carta, Daniela; Prodromakis, Themistoklis

2016-07-01

Titanium oxide (TiOx) has attracted a lot of attention as an active material for resistive random access memory (RRAM), due to its versatility and variety of possible crystal phases. Although existing RRAM materials have demonstrated impressive characteristics, like ultra-fast switching and high cycling endurance, this technology still encounters challenges like low yields, large variability of switching characteristics, and ultimately device failure. Electroforming has been often considered responsible for introducing irreversible damage to devices, with high switching voltages contributing to device degradation. In this paper, we have employed Al doping for tuning the resistive switching characteristics of titanium oxide RRAM. The resistive switching threshold voltages of undoped and Al-doped TiOx thin films were first assessed by conductive atomic force microscopy. The thin films were then transferred in RRAM devices and tested with voltage pulse sweeping, demonstrating that the Al-doped devices could on average form at lower potentials compared to the undoped ones and could support both analog and binary switching at potentials as low as 0.9 V. This work demonstrates a potential pathway for implementing low-power RRAM systems.

Spin-orbit torque induced magnetization switching in Ta/Co{sub 20}Fe{sub 60}B{sub 20}/MgO structures under small in-plane magnetic fields

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cao, Jiangwei, E-mail: caojw@lzu.edu.cn; Zheng, Yuqiang; Su, Xianpeng

2016-04-25

Spin-orbit torque (SOT)-induced magnetization switching under small in-plane magnetic fields in as-deposited and annealed Ta/CoFeB/MgO structures is studied. For the as-deposited samples, partial SOT-induced switching behavior is observed under an in-plane field of less than 100 Oe. Conversely, for the annealed samples, an in-plane field of 10 Oe is large enough to achieve full deterministic magnetization switching. The Dzyaloshinskii-Moriya interaction at the Ta/CoFeB interface is believed to be the main reason for the discrepancy of the requisite in-plane magnetic fields for switching in the as-deposited and annealed samples. In addition, asymmetric field dependence behavior of SOT-induced magnetization switching is observed in themore » annealed samples. Deterministic magnetization switching in the absence of an external magnetic field is obtained in the annealed samples, which is extremely important to develop SOT-based magnetoresistive random access memory.« less

The influence of preferred orientation and poling temperature on the polarization switching current in PZT thin films

NASA Astrophysics Data System (ADS)

Xiao, Mi; Zhang, Weikang; Zhang, Zebin; Zhang, Ping; Lan, Kuibo

2017-07-01

In this paper, Pb(Zr0.52Ti0.48)O3 (PZT) thin films with different preferred orientation were prepared on platinized silicon substrates by a modified sol-gel method. Our results indicate that the polarization switching current in PZT thin films is dependent on preferred orientation and poling temperature. In our measurements, (111)-oriented PZT has a larger polarization switching current than randomly oriented PZT, and with the increase of the degree of (111) preferred orientation and the poling temperature, the polarization switching current gradually increase. Considering the contact of PZT thin film with electrodes, the space-charged limited conduction (SCLC) combined with domain switching mechanism may be responsible for such phenomena. By analyzing the conduction data, we found the interface-limited Schottky emission (ES) and bulk-limited Poole-Frenkel hopping (PF) are not suitable for our samples.

A graphene integrated highly transparent resistive switching memory device

NASA Astrophysics Data System (ADS)

Dugu, Sita; Pavunny, Shojan P.; Limbu, Tej B.; Weiner, Brad R.; Morell, Gerardo; Katiyar, Ram S.

2018-05-01

We demonstrate the hybrid fabrication process of a graphene integrated highly transparent resistive random-access memory (TRRAM) device. The indium tin oxide (ITO)/Al2O3/graphene nonvolatile memory device possesses a high transmittance of >82% in the visible region (370-700 nm) and exhibits stable and non-symmetrical bipolar switching characteristics with considerably low set and reset voltages (<±1 V). The vertical two-terminal device shows an excellent resistive switching behavior with a high on-off ratio of ˜5 × 103. We also fabricated a ITO/Al2O3/Pt device and studied its switching characteristics for comparison and a better understanding of the ITO/Al2O3/graphene device characteristics. The conduction mechanisms in high and low resistance states were analyzed, and the observed polarity dependent resistive switching is explained based on electro-migration of oxygen ions.

Plasma-Induced Nonvolatile Resistive Switching with Extremely Low SET Voltage in TiOxFy with AgF Nanoparticles.

PubMed

Sun, Xiangyu; Wu, Chuangui; Shuai, Yao; Pan, Xinqiang; Luo, Wenbo; You, Tiangui; Bogusz, Agnieszka; Du, Nan; Li, Yanrong; Schmidt, Heidemarie

2016-12-07

Low power consumption is crucial for the application of resistive random access memory. In this work, we present the bipolar resistive switching in an Ag/TiO x F y /Ti/Pt stack with extremely low switch-on voltage of 0.07 V. Operating current as low as 10 nA was also obtained by conductive atomic force microscopy. The highly defective TiO x F y layer was fabricated by plasma treatment using helium, oxygen, and carbon tetrafluoride orderly. During the electroforming process, AgF nanoparticles were formed due to the diffusion of Ag + which reacted with the adsorbed F - in the TiO x F y layer. These nanoparticles are of great importance to resistive switching performance because they are believed to be conductive phases and become part of the conducting path when the sample is switched to a low-resistance state.

Clustering promotes switching dynamics in networks of noisy neurons

NASA Astrophysics Data System (ADS)

Franović, Igor; Klinshov, Vladimir

2018-02-01

Macroscopic variability is an emergent property of neural networks, typically manifested in spontaneous switching between the episodes of elevated neuronal activity and the quiescent episodes. We investigate the conditions that facilitate switching dynamics, focusing on the interplay between the different sources of noise and heterogeneity of the network topology. We consider clustered networks of rate-based neurons subjected to external and intrinsic noise and derive an effective model where the network dynamics is described by a set of coupled second-order stochastic mean-field systems representing each of the clusters. The model provides an insight into the different contributions to effective macroscopic noise and qualitatively indicates the parameter domains where switching dynamics may occur. By analyzing the mean-field model in the thermodynamic limit, we demonstrate that clustering promotes multistability, which gives rise to switching dynamics in a considerably wider parameter region compared to the case of a non-clustered network with sparse random connection topology.

Rapid mapping of polarization switching through complete information acquisition

NASA Astrophysics Data System (ADS)

Somnath, Suhas; Belianinov, Alex; Kalinin, Sergei V.; Jesse, Stephen

2016-12-01

Polarization switching in ferroelectric and multiferroic materials underpins a broad range of current and emergent applications, ranging from random access memories to field-effect transistors, and tunnelling devices. Switching in these materials is exquisitely sensitive to local defects and microstructure on the nanometre scale, necessitating spatially resolved high-resolution studies of these phenomena. Classical piezoresponse force microscopy and spectroscopy, although providing necessary spatial resolution, are fundamentally limited in data acquisition rates and energy resolution. This limitation stems from their two-tiered measurement protocol that combines slow (~1 s) switching and fast (~10 kHz-1 MHz) detection waveforms. Here we develop an approach for rapid probing of ferroelectric switching using direct strain detection of material response to probe bias. This approach, facilitated by high-sensitivity electronics and adaptive filtering, enables spectroscopic imaging at a rate 3,504 times faster the current state of the art, achieving high-veracity imaging of polarization dynamics in complex microstructures.

The effect of switch control site on computer skills of infants and toddlers.

PubMed

Glickman, L; Deitz, J; Anson, D; Stewart, K

1996-01-01

The purpose of this study was to determine whether switch control site (hand vs. head) affects the age at which children can successfully activate a computer to play a cause-and-effect game. The sample consisted of 72 participants randomly divided into two groups (head switch and hand switch), with stratification for gender and age (9-11 months, 12-14 months, 15-17 months). All participants were typically developing. After a maximum of 5 min of training, each participant was given five opportunities to activate a Jelly Bean switch to play a computer game. Competency was defined as four to five successful switch activations. Most participants in the 9-month to 11-month age group could successfully use a hand switch to activate a computer, and for the 15-month to 17-month age group, 100% of the participants met with success. By contrast, in the head switch condition, approximately one third of the participants in each of the three age ranges were successful in activating the computer to play a cause-and-effect game. The findings from this study provide developmental guidelines for using switches (head vs. hand) to activate computers to play cause-and-effect games and suggest that the clinician may consider introducing basic computer and switch skills to children as young as 9 months of age. However, the clinician is cautioned that the head switch may be more difficult to master than the hand switch and that additional research involving children with motor impairments is needed.

A cluster-based randomized controlled trial promoting community participation in arsenic mitigation efforts in Bangladesh.

PubMed

George, Christine Marie; van Geen, Alexander; Slavkovich, Vesna; Singha, Ashit; Levy, Diane; Islam, Tariqul; Ahmed, Kazi Matin; Moon-Howard, Joyce; Tarozzi, Alessandro; Liu, Xinhua; Factor-Litvak, Pam; Graziano, Joseph

2012-06-19

To reduce arsenic (As) exposure, we evaluated the effectiveness of training community members to perform water arsenic (WAs) testing and provide As education compared to sending representatives from outside communities to conduct these tasks. We conducted a cluster based randomized controlled trial of 20 villages in Singair, Bangladesh. Fifty eligible respondents were randomly selected in each village. In 10 villages, a community member provided As education and WAs testing. In a second set of 10 villages an outside representative performed these tasks. Overall, 53% of respondents using As contaminated wells, relative to the Bangladesh As standard of 50 μg/L, at baseline switched after receiving the intervention. Further, when there was less than 60% arsenic contaminated wells in a village, the classification used by the Bangladeshi and UNICEF, 74% of study households in the community tester villages, and 72% of households in the outside tester villages reported switching to an As safe drinking water source. Switching was more common in the outside-tester (63%) versus community-tester villages (44%). However, after adjusting for the availability of arsenic safe drinking water sources, well switching did not differ significantly by type of As tester (Odds ratio = 0.86[95% confidence interval 0.42-1.77). At follow-up, among those using As contaminated wells who switched to safe wells, average urinary As concentrations significantly decreased. The overall intervention was effective in reducing As exposure provided there were As-safe drinking water sources available. However, there was not a significant difference observed in the ability of the community and outside testers to encourage study households to use As-safe water sources. The findings of this study suggest that As education and WAs testing programs provided by As testers, irrespective of their residence, could be used as an effective, low cost approach to reduce As exposure in many As-affected areas of Bangladesh.

Efficacy and safety of repaglinide added to sitagliptin in Japanese patients with type 2 diabetes: A randomized 24-week open-label clinical trial.

PubMed

Nishimura, Akihiro; Usui, Shuki; Kumashiro, Naoki; Uchino, Hiroshi; Yamato, Azusa; Yasuda, Daijiro; Nagasawa, Kaoru; Okubo, Minoru; Mori, Yasumichi; Hirose, Takahisa

2016-12-30

Although sitagliptin and repaglinide monotherapies improve postprandial hyperglycemia, the long-term effects and safety of their combination has not been examined. In this randomized 24-week trial of Japanese patients with poor control (HbA1c 7.0-8.5%) by sitagliptin, we divided 40 patients randomly into two equal groups of the repaglinide add-on to sitagliptin (ADD-ON, n=20), or sitagliptin switched to repaglinide (SWITCH, n=20). The meal tolerance test was carried out at weeks 0 and 24. The primary outcomes were changes in HbA1c and area under the curves (AUC) of glucose from the baseline to week 24. The mean change in HbA1c from baseline to week 24 was larger in the ADD-ON (-0.87±0.63%, mean±SD), compared with the SWITCH (0.03±0.65%, p=0.000). Significant improvements were noted in the mean changes in fasting glucose and AUCs of glucose in the ADD-ON vs. SWITCH (p=0.007 and p=0.000). Insulin secretion relative to glucose elevation (ISG; defined as AUC insulin/AUC glucose) increased significantly in the ADD-ON, although the mean change in fasting insulin level was significantly decreased in the ADD-ON (p=0.015 and p=0.026). The AUC of glucagon was significantly lower at 24-week relative to baseline in the ADD-ON, but was not significant in the two groups (p=0.047 and p=0.056, respectively). The combination therapy produced significant reductions in HbA1c, AUC of glucose and fasting glucose compared with switching to repaglinide without weight gain or severe hypoglycemia. The improved glycemic control with this combination therapy may be at least in part due to augmentation of repaglinide-induced insulin secretion by sitagliptin.

Switching to lopinavir/ritonavir with or without abacavir/lamivudine in lipoatrophic patients treated with zidovudine/abacavir/lamivudine.

PubMed

Bernardino, J I; Pulido, F; Martinez, E; Arrizabalaga, J; Domingo, P; Portilla, J; Ocampo, A; Muñoz, J; Torres, R; Arribas, J R

2013-06-01

Discontinuation of thymidine nucleoside reverse transcriptase inhibitors (tNRTIs) is the only proven strategy for improving lipoatrophy. It is unclear whether switching to NRTI-sparing or to non-thymidine NRTI-containing therapy has differential effects on body fat recovery. This was a 96 week, open-label, randomized study in suppressed patients with moderate/severe lipoatrophy and no prior virological failure while receiving a protease inhibitor and who had their triple NRTI regimen (zidovudine/lamivudine/abacavir) switched to lopinavir/ritonavir plus abacavir/lamivudine for a 1 month run-in period and then randomized to lopinavir/ritonavir plus abacavir/lamivudine versus lopinavir/ritonavir monotherapy. The KRETA trial is registered with ClinicalTrials.gov (number NCT00865007). Of 95 patients included, 88 were randomized to lopinavir/ritonavir plus abacavir/lamivudine (n = 44) or lopinavir/ritonavir monotherapy (n = 44). Median (IQR) baseline limb fat was 2.5 (1.6-3.7) kg in the lopinavir/ritonavir plus abacavir/lamivudine group and 2.5 (2.0-5.4) kg in the lopinavir/ritonavir monotherapy group. Six patients in the triple therapy group and 13 in the monotherapy group had discontinued study drugs by week 96. Although there were limb fat gains in each group at weeks 48/96 (+324/+358 g in lopinavir/ritonavir plus abacavir/lamivudine, P = 0.09/0.07, versus +215/+416 g in the lopinavir/ritonavir monotherapy group, P = 0.28/0.16), differences between groups were not significant [difference +109 g (95% CI -442, +660)/-57 g (95% CI -740, +625)]. In lipoatrophic patients treated with zidovudine/lamivudine/abacavir, switching to lopinavir/ritonavir monotherapy had no additional benefit in limb fat recovery relative to switching to lopinavir/ritonavir with abacavir/lamivudine. These data suggest that non-thymidine nucleosides such as abacavir/lamivudine are not an obstacle to limb fat recovery.

Modular protein switches derived from antibody mimetic proteins.

PubMed

Nicholes, N; Date, A; Beaujean, P; Hauk, P; Kanwar, M; Ostermeier, M

2016-02-01

Protein switches have potential applications as biosensors and selective protein therapeutics. Protein switches built by fusion of proteins with the prerequisite input and output functions are currently developed using an ad hoc process. A modular switch platform in which existing switches could be readily adapted to respond to any ligand would be advantageous. We investigated the feasibility of a modular protein switch platform based on fusions of the enzyme TEM-1 β-lactamase (BLA) with two different antibody mimetic proteins: designed ankyrin repeat proteins (DARPins) and monobodies. We created libraries of random insertions of the gene encoding BLA into genes encoding a DARPin or a monobody designed to bind maltose-binding protein (MBP). From these libraries, we used a genetic selection system for β-lactamase activity to identify genes that conferred MBP-dependent ampicillin resistance to Escherichia coli. Some of these selected genes encoded switch proteins whose enzymatic activity increased up to 14-fold in the presence of MBP. We next introduced mutations into the antibody mimetic domain of these switches that were known to cause binding to different ligands. To different degrees, introduction of the mutations resulted in switches with the desired specificity, illustrating the potential modularity of these platforms. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Reputation-based partner choice promotes cooperation in social networks

NASA Astrophysics Data System (ADS)

Fu, Feng; Hauert, Christoph; Nowak, Martin A.; Wang, Long

2008-08-01

We investigate the cooperation dynamics attributed to the interplay between the evolution of individual strategies and evolution of individual partnerships. We focus on the effect of reputation on an individual’s partner-switching process. We assume that individuals can either change their strategies by imitating their partners or adjust their partnerships based on local information about reputations. We manipulate the partner switching in two ways; that is, individuals can switch from the lowest reputation partners, either to their partners’ partners who have the highest reputation (i.e., ordering in partnership) or to others randomly chosen from the entire population (i.e., randomness in partnership). We show that when individuals are able to alter their behavioral strategies and their social interaction partnerships on the basis of reputation, cooperation can prevail. We find that the larger temptation to defect and the denser the partner network, the more frequently individuals need to shift their partnerships in order for cooperation to thrive. Furthermore, an increasing tendency of switching to partners’ partners is more likely to lead to a higher level of cooperation. We show that when reputation is absent in such partner-switching processes, cooperation is much less favored than that of the reputation involved. Moreover, we investigate the effect of discounting an individual’s reputation on the evolution of cooperation. Our results highlight the importance of the consideration of reputation (indirect reciprocity) on the promotion of cooperation when individuals can adjust their partnerships.

Gold nanorods saturable absorber for Q-switched Nd:GAGG lasers at 1 μm

NASA Astrophysics Data System (ADS)

Feng, Chao; Liu, Mingyi; Li, Yanbin; Gao, Xuejian; Kang, Zhe; Qin, Guanshi; Jia, Zhitai; Tao, Xutang; Song, Teng; Dun, Yangyang; Bai, Fen; Li, Ping; Wang, Qingpu; Fang, Jiaxiong

2017-03-01

A gold nanorod saturable absorber has been synthesized by the seed-mediated growth method characterized in detail. The absorption peak wavelength was 1080 nm, and the modulation depth was measured to be 9%. The performance of its Q-switched Nd:GAGG lasers at 1061 and 1106 nm has been systematically investigated, respectively. The corresponding shortest pulsewidths were 250 and 480 ns. Our experiment results proved that the GNR-SA is a promising saturable absorber for nanosecond bulk lasers.

Patients' ability to treat anaphylaxis using adrenaline autoinjectors: a randomized controlled trial.

PubMed

Umasunthar, T; Procktor, A; Hodes, M; Smith, J G; Gore, C; Cox, H E; Marrs, T; Hanna, H; Phillips, K; Pinto, C; Turner, P J; Warner, J O; Boyle, R J

2015-07-01

Previous work has shown patients commonly misuse adrenaline autoinjectors (AAI). It is unclear whether this is due to inadequate training, or poor device design. We undertook a prospective randomized controlled trial to evaluate ability to administer adrenaline using different AAI devices. We allocated mothers of food-allergic children prescribed an AAI for the first time to Anapen or EpiPen using a computer-generated randomization list, with optimal training according to manufacturer's instructions. After one year, participants were randomly allocated a new device (EpiPen, Anapen, new EpiPen, JEXT or Auvi-Q), without device-specific training. We assessed ability to deliver adrenaline using their AAI in a simulated anaphylaxis scenario six weeks and one year after initial training, and following device switch. Primary outcome was successful adrenaline administration at six weeks, assessed by an independent expert. Secondary outcomes were success at one year, success after switching device, and adverse events. We randomized 158 participants. At six weeks, 30 of 71 (42%) participants allocated to Anapen and 31 of 73 (43%) participants allocated to EpiPen were successful - RR 1.00 (95% CI 0.68-1.46). Success rates at one year were also similar, but digital injection was more common at one year with EpiPen (8/59, 14%) than Anapen (0/51, 0%, P = 0.007). When switched to a new device without specific training, success rates were higher with Auvi-Q (26/28, 93%) than other devices (39/80, 49%; P < 0.001). AAI device design is a major determinant of successful adrenaline administration. Success rates were low with several devices, but were high using the audio-prompt device Auvi-Q. © 2015 The Authors Allergy Published by John Wiley & Sons Ltd.

Angular Random Walk Estimation of a Time-Domain Switching Micromachined Gyroscope

DTIC Science & Technology

2016-10-19

1 2. PARAMETRIC SYSTEM IDENTIFICATION BASED ON TIME-DOMAIN SWITCHING ........ 2 3. FINITE ELEMENT MODELING OF RESONATOR...8 3. FINITE ELEMENT MODELING OF RESONATOR This section details basic finite element modeling of the resonator used with the TDSMG. While it...Based on finite element simulations of the employed resonator, it is found that the effects of thermomechanical noise is on par with 10 ps of timing

Ion beam synthesis of indium-oxide nanocrystals for improvement of oxide resistive random-access memories

NASA Astrophysics Data System (ADS)

Bonafos, C.; Benassayag, G.; Cours, R.; Pécassou, B.; Guenery, P. V.; Baboux, N.; Militaru, L.; Souifi, A.; Cossec, E.; Hamga, K.; Ecoffey, S.; Drouin, D.

2018-01-01

We report on the direct ion beam synthesis of a delta-layer of indium oxide nanocrystals (In2O3-NCs) in silica matrices by using ultra-low energy ion implantation. The formation of the indium oxide phase can be explained by (i) the affinity of indium with oxygen, (ii) the generation of a high excess of oxygen recoils generated by the implantation process in the region where the nanocrystals are formed and (iii) the proximity of the indium-based nanoparticles with the free surface and oxidation from the air. Taking advantage of the selective diffusivity of implanted indium in SiO2 with respect to Si3N4, In2O3-NCs have been inserted in the SiO2 switching oxide of micrometric planar oxide-based resistive random access memory (OxRAM) devices fabricated using the nanodamascene process. Preliminary electrical measurements show switch voltage from high to low resistance state. The devices with In2O3-NCs have been cycled 5 times with identical operating voltages and RESET current meanwhile no switch has been observed for non implanted devices. This first measurement of switching is very promising for the concept of In2O3-NCs based OxRAM memories.

Improved multi-level capability in Si3N4-based resistive switching memory using continuous gradual reset switching

NASA Astrophysics Data System (ADS)

Kim, Sungjun; Park, Byung-Gook

2017-01-01

In this letter, we compare three different types of reset switching behavior in a bipolar resistive random-access memory (RRAM) system that is housed in a Ni/Si3N4/Si structure. The abrupt, step-like gradual and continuous gradual reset transitions are largely determined by the low-resistance state (LRS). For abrupt reset switching, the large conducting path shows ohmic behavior or has a weak nonlinear current-voltage (I-V) characteristics in the LRS. For gradual switching, including both the step-like and continuous reset types, trap-assisted direct tunneling is dominant in the low-voltage regime, while trap-assisted Fowler-Nordheim tunneling is dominant in the high-voltage regime, thus causing nonlinear I-V characteristics. More importantly, we evaluate the multi-level capabilities of the two different gradual switching types, including both step-like and continuous reset behavior, using identical and incremental voltage conditions. Finer control of the conductance level with good uniformity is achieved in continuous gradual reset switching when compared to that in step-like gradual reset switching. For continuous reset switching, a single conducting path, which initially has a tunneling gap, gradually responds to pulses with even and identical amplitudes, while for step-like reset switching, the multiple conducting paths only respond to incremental pulses to obtain effective multi-level states.

Antibody-Mediated Small Molecule Detection Using Programmable DNA-Switches.

PubMed

Rossetti, Marianna; Ippodrino, Rudy; Marini, Bruna; Palleschi, Giuseppe; Porchetta, Alessandro

2018-06-13

The development of rapid, cost-effective, and single-step methods for the detection of small molecules is crucial for improving the quality and efficiency of many applications ranging from life science to environmental analysis. Unfortunately, current methodologies still require multiple complex, time-consuming washing and incubation steps, which limit their applicability. In this work we present a competitive DNA-based platform that makes use of both programmable DNA-switches and antibodies to detect small target molecules. The strategy exploits both the advantages of proximity-based methods and structure-switching DNA-probes. The platform is modular and versatile and it can potentially be applied for the detection of any small target molecule that can be conjugated to a nucleic acid sequence. Here the rational design of programmable DNA-switches is discussed, and the sensitive, rapid, and single-step detection of different environmentally relevant small target molecules is demonstrated.

High-Dimensional Mutant and Modular Thermodynamic Cycles, Molecular Switching, and Free Energy Transduction

PubMed Central

Carter, Charles W.

2017-01-01

Understanding how distinct parts of proteins produce coordinated behavior has driven and continues to drive advances in protein science and enzymology. However, despite consensus about the conceptual basis for allostery, the idiosyncratic nature of allosteric mechanisms resists general approaches. Computational methods can identify conformational transition states from structural changes, revealing common switching mechanisms that impose multistate behavior. Thermodynamic cycles use factorial perturbations to measure coupling energies between side chains in molecular switches that mediate shear during domain motion. Such cycles have now been complemented by modular cycles that measure energetic coupling between separable domains. For one model system, energetic coupling between domains has been shown to be quantitatively equivalent to that between dynamic side chains. Linkages between domain motion, switching residues, and catalysis make nucleoside triphosphate hydrolysis conditional on domain movement, confirming an essential yet neglected aspect of free energy transduction and suggesting the potential generality of these studies. PMID:28375734

Intrinsic transcriptional heterogeneity in B cells controls early class switching to IgE

PubMed Central

Wu, Yee Ling; Teichmann, Sarah A.

2017-01-01

Noncoding transcripts originating upstream of the immunoglobulin constant region (I transcripts) are required to direct activation-induced deaminase to initiate class switching in B cells. Differential regulation of Iε and Iγ1 transcription in response to interleukin 4 (IL-4), hence class switching to IgE and IgG1, is not fully understood. In this study, we combine novel mouse reporters and single-cell RNA sequencing to reveal the heterogeneity in IL-4–induced I transcription. We identify an early population of cells expressing Iε but not Iγ1 and demonstrate that early Iε transcription leads to switching to IgE and occurs at lower activation levels than Iγ1. Our results reveal how probabilistic transcription with a lower activation threshold for Iε directs the early choice of IgE versus IgG1, a key physiological response against parasitic infestations and a mediator of allergy and asthma. PMID:27994069

Electrically-controlled nonlinear switching and multi-level storage characteristics in WOx film-based memory cells

NASA Astrophysics Data System (ADS)

Duan, W. J.; Wang, J. B.; Zhong, X. L.

2018-05-01

Resistive switching random access memory (RRAM) is considered as a promising candidate for the next generation memory due to its scalability, high integration density and non-volatile storage characteristics. Here, the multiple electrical characteristics in Pt/WOx/Pt cells are investigated. Both of the nonlinear switching and multi-level storage can be achieved by setting different compliance current in the same cell. The correlations among the current, time and temperature are analyzed by using contours and 3D surfaces. The switching mechanism is explained in terms of the formation and rupture of conductive filament which is related to oxygen vacancies. The experimental results show that the non-stoichiometric WOx film-based device offers a feasible way for the applications of oxide-based RRAMs.

Oxygen-modulated quantum conductance for ultrathin HfO 2 -based memristive switching devices

DOE PAGES

Zhong, Xiaoliang; Rungger, Ivan; Zapol, Peter; ...

2016-10-24

Memristive switching devices, candidates for resistive random access memory technology, have been shown to switch off through a progression of states with quantized conductance and subsequent noninteger conductance (in terms of conductance quantum G 0). We have performed calculations based on density functional theory to model the switching process for a Pt-HfO 2-Pt structure, involving the movement of one or two oxygen atoms. Oxygen atoms moving within a conductive oxygen vacancy filament act as tunneling barriers, and partition the filament into weakly coupled quantum wells. We show that the low-bias conductance decreases exponentially when one oxygen atom moves away frommore » interface. In conclusion, our results demonstrate the high sensitivity of the device conductance to the position of oxygen atoms.« less

Oxygen-modulated quantum conductance for ultrathin HfO 2 -based memristive switching devices

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhong, Xiaoliang; Rungger, Ivan; Zapol, Peter

Memristive switching devices, candidates for resistive random access memory technology, have been shown to switch off through a progression of states with quantized conductance and subsequent noninteger conductance (in terms of conductance quantum G 0). We have performed calculations based on density functional theory to model the switching process for a Pt-HfO 2-Pt structure, involving the movement of one or two oxygen atoms. Oxygen atoms moving within a conductive oxygen vacancy filament act as tunneling barriers, and partition the filament into weakly coupled quantum wells. We show that the low-bias conductance decreases exponentially when one oxygen atom moves away frommore » interface. In conclusion, our results demonstrate the high sensitivity of the device conductance to the position of oxygen atoms.« less

Oxygen-ion-migration-modulated bipolar resistive switching and complementary resistive switching in tungsten/indium tin oxide/gold memory device

NASA Astrophysics Data System (ADS)

Wu, Xinghui; Zhang, Qiuhui; Cui, Nana; Xu, Weiwei; Wang, Kefu; Jiang, Wei; Xu, Qixing

2018-06-01

In this paper, we report our investigation of room-temperature-fabricated tungsten/indium tin oxide/gold (W/ITO/Au) resistive random access memory (RRAM), which exhibits asymmetric bipolar resistive switching (BRS) behavior. The device displays good write/erase endurance and data retention properties. The device shows complementary resistive switching (CRS) characteristics after controlling the compliance current. A WO x layer electrically formed at the W/ITO in the forming process. Mobile oxygen ions within ITO migrate toward the electrode/ITO interface and produce a semiconductor-like layer that acts as a free-carrier barrier. The CRS characteristic here can be elucidated in light of the evolution of an asymmetric free-carrier blocking layer at the electrode/ITO interface.

Marginal bone response of implants with platform switching and non-platform switching abutments in posterior healed sites: a 1-year prospective study

PubMed Central

Wang, Yun-Chi; Kan, Joseph Y K; Rungcharassaeng, Kitichai; Roe, Phillip; Lozada, Jaime L

2015-01-01

Objectives This 1-year prospective study evaluated the implant success rate and marginal bone response of non-submerged implants with platform and non-platform switching abutments in posterior healed sites. Material and methods Nineteen patients (9 male, 10 female) with posterior partially edentulous spaces, between the ages of 23 and 76 (mean = 55.4 years), were included in this study. A total of 30 implants (15 implants restored with platform switching [PS] abutments [control] and 15 implants restored with non-platform switching [NPS] abutments [test]) were assigned between two groups using a randomization procedure. The definitive abutments with conical connections were placed at the time of surgery, and the definitive restorations were placed at 3 months. All patients were evaluated clinically and radiographically using standardized radiographs at time of implant placement (0), 3, 6 and 12 months after implant placement. Data were analyzed using Friedman test with post hoc pairwise comparisons, Mann–Whitney U-test, and Pearson's chi-square test at the significance level of α = 0.05. Results At 12 months, all 30 implants remained osseointegrated corresponding to a 100% success rate. The overall mean marginal bone level change at 12 months was −0.04 ± 0.08 mm for PS group and −0.19 ± 0.16 mm for NPS group. Statistically significant difference in the marginal bone level change was observed between groups at 0 to 12 months and 3 to 12 months (P < 0.05). Conclusions This 1-year randomized control study suggests that when a conical implant–abutment connection is present, similar peri-implant tissue responses can be achieved with platform switching and non-platform switching abutments. PMID:24383912

On the functional relevance of frontal cortex for passive and voluntarily controlled bistable vision.

PubMed

de Graaf, Tom A; de Jong, Maartje C; Goebel, Rainer; van Ee, Raymond; Sack, Alexander T

2011-10-01

In bistable vision, one constant ambiguous stimulus leads to 2 alternating conscious percepts. This perceptual switching occurs spontaneously but can also be influenced through voluntary control. Neuroimaging studies have reported that frontal regions are activated during spontaneous perceptual switches, leading some researchers to suggest that frontal regions causally induce perceptual switches. But the opposite also seems possible: frontal activations may themselves be caused by spontaneous switches. Classically implicated in attentional processes, these same regions are also candidates for the origins of voluntary control over bistable vision. Here too, it remains unknown whether frontal cortex is actually functionally relevant. It is even possible that spontaneous perceptual switches and voluntarily induced switches are mediated by the same top-down mechanisms. To directly address these issues, we here induced "virtual lesions," with transcranial magnetic stimulation, in frontal, parietal, and 2 lower level visual cortices using an established ambiguous structure-from-motion stimulus. We found that dorsolateral prefrontal cortex was causally relevant for voluntary control over perceptual switches. In contrast, we failed to find any evidence for an active role of frontal cortex in passive bistable vision. Thus, it seems the same pathway used for willed top-down modulation of bistable vision is not used during passive bistable viewing.

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.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lin, Chun-Cheng; Department of Mathematic and Physical Sciences, R.O.C. Air Force Academy, Kaohsiung 820, Taiwan; Tang, Jian-Fu

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.

Oleanolic acid suppresses aerobic glycolysis in cancer cells by switching pyruvate kinase type M isoforms.

PubMed

Liu, Jia; Wu, Ning; Ma, Leina; Liu, Ming; Liu, Ge; Zhang, Yuyan; Lin, Xiukun

2014-01-01

Warburg effect, one of the hallmarks for cancer cells, is characterized by metabolic switch from mitochondrial oxidative phosphorylation to aerobic glycolysis. In recent years, increased expression level of pyruvate kinase M2 (PKM2) has been found to be the culprit of enhanced aerobic glycolysis in cancer cells. However, there is no agent inhibiting aerobic glycolysis by targeting PKM2. In this study, we found that Oleanolic acid (OA) induced a switch from PKM2 to PKM1, and consistently, abrogated Warburg effect in cancer cells. Suppression of aerobic glycolysis by OA is mediated by PKM2/PKM1 switch. Furthermore, mTOR signaling was found to be inactivated in OA-treated cancer cells, and mTOR inhibition is required for the effect of OA on PKM2/PKM1 switch. Decreased expression of c-Myc-dependent hnRNPA1 and hnRNPA1 was responsible for OA-induced switch between PKM isoforms. Collectively, we identified that OA is an antitumor compound that suppresses aerobic glycolysis in cancer cells and there is potential that PKM2 may be developed as an important target in aerobic glycolysis pathway for developing novel anticancer agents.

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 competition-mediated pyrene-switching aptasensor is promising to have potential for clinical and forensic applications. PMID:21080638

Detection of single-nucleotide polymorphisms using an ON-OFF switching of regenerated biosensor based on a locked nucleic acid-integrated and toehold-mediated strand displacement reaction.

PubMed

Gao, Zhong Feng; Ling, Yu; Lu, Lu; Chen, Ning Yu; Luo, Hong Qun; Li, Nian Bing

2014-03-04

Although various strategies have been reported for single-nucleotide polymorphisms (SNPs) detection, development of a time-saving, specific, and regenerated electrochemical sensing platform still remains a realistic goal. In this study, an ON-OFF switching of a regenerated biosensor based on a locked nucleic acid (LNA)-integrated and toehold-mediated strand displacement reaction technique is constructed for detection of SNPs. The LNA-integrated and methylene blue-labeled capture probe with an external toehold is designed to switch on the sensing system. The mutant-type DNA probe completes complementary with the capture probe to trigger the strand displacement reaction, which switches off the sensing system. However, when the single-base mismatched wild-type DNA probe is presented, the strand displacement reaction cannot be achieved; therefore, the sensing system still keeps the ON state. This DNA sensor is stable over five reuses. We further testify that the LNA-integrated sequence has better recognition ability for SNPs detection compared to the DNA-integrated sequence. Moreover, this DNA senor exhibits a remarkable discrimination capability of SNPs among abundant wild-type targets and 6000-fold (m/m) excess of genomic DNA. In addition, it is selective enough in complex and contaminant-ridden samples, such as human urine, soil, saliva, and beer. Overall, these results demonstrate that this reliable DNA sensor is easy to be fabricated, simple to operate, and stable enough to be readily regenerated.

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.

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

Neural network for control of rearrangeable Clos networks.

PubMed

Park, Y K; Cherkassky, V

1994-09-01

Rapid evolution in the field of communication networks requires high speed switching technologies. This involves a high degree of parallelism in switching control and routing performed at the hardware level. The multistage crossbar networks have always been attractive to switch designers. In this paper a neural network approach to controlling a three-stage Clos network in real time is proposed. This controller provides optimal routing of communication traffic requests on a call-by-call basis by rearranging existing connections, with a minimum length of rearrangement sequence so that a new blocked call request can be accommodated. The proposed neural network controller uses Paull's rearrangement algorithm, along with the special (least used) switch selection rule in order to minimize the length of rearrangement sequences. The functional behavior of our model is verified by simulations and it is shown that the convergence time required for finding an optimal solution is constant, regardless of the switching network size. The performance is evaluated for random traffic with various traffic loads. Simulation results show that applying the least used switch selection rule increases the efficiency in switch rearrangements, reducing the network convergence time. The implementation aspects are also discussed to show the feasibility of the proposed approach.

Methods for resistive switching of memristors

DOEpatents

Mickel, Patrick R.; James, Conrad D.; Lohn, Andrew; Marinella, Matthew; Hsia, Alexander H.

2016-05-10

The present invention is directed generally to resistive random-access memory (RRAM or ReRAM) devices and systems, as well as methods of employing a thermal resistive model to understand and determine switching of such devices. In particular example, the method includes generating a power-resistance measurement for the memristor device and applying an isothermal model to the power-resistance measurement in order to determine one or more parameters of the device (e.g., filament state).

Temperature induced complementary switching in titanium oxide resistive random access memory

DOE Office of Scientific and Technical Information (OSTI.GOV)

Panda, D., E-mail: dpanda@nist.edu; Department of Electronics Engineering and Institute of Electronics, National Chiao Tung University, Hsinchu 30010, Taiwan; Simanjuntak, F. M.

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 tomore » 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.« less

Impact of ultra-thin Al2O3-y layers on TiO2-x ReRAM switching characteristics

NASA Astrophysics Data System (ADS)

Trapatseli, Maria; Cortese, Simone; Serb, Alexander; Khiat, Ali; Prodromakis, Themistoklis

2017-05-01

Transition metal-oxide resistive random access memory devices have demonstrated excellent performance in switching speed, versatility of switching and low-power operation. However, this technology still faces challenges like poor cycling endurance, degradation due to high electroforming (EF) switching voltages and low yields. Approaches such as engineering of the active layer by doping or addition of thin oxide buffer layers have been often adopted to tackle these problems. Here, we have followed a strategy that combines the two; we have used ultra-thin Al2O3-y buffer layers incorporated between TiO2-x thin films taking into account both 3+/4+ oxidation states of Al/Ti cations. Our devices were tested by DC and pulsed voltage sweeping and in both cases demonstrated improved switching voltages. We believe that the Al2O3-y layers act as reservoirs of oxygen vacancies which are injected during EF, facilitate a filamentary switching mechanism and provide enhanced filament stability, as shown by the cycling endurance measurements.

Autoshaping, random control, and omission training in the rat1

PubMed Central

Locurto, Charles; Terrace, H. S.; Gibbon, John

1976-01-01

The role of the stimulus-reinforcer contingency in the development and maintenance of lever contact responding was studied in hooded rats. In Experiment I, three groups of experimentally naive rats were trained either on autoshaping, omission training, or a random-control procedure. Subjects trained by the autoshaping procedure responded more consistently than did either random-control or omission-trained subjects. The probability of at least one lever contact per trial was slightly higher in subjects trained by the omission procedure than by the random-control procedure. However, these differences were not maintained during extended training, nor were they evident in total lever-contact frequencies. When omission and random-control subjects were switched to the autoshaping condition, lever contacts increased in all animals, but a pronounced retardation was observed in omission subjects relative to the random-control subjects. In addition, subjects originally exposed to the random-control procedure, and later switched to autoshaping, acquired more rapidly than naive subjects that were exposed only on the autoshaping procedure. In Experiment II, subjects originally trained by an autoshaping procedure were exposed either to an omission, a random-control, or an extinction procedure. No differences were observed among the groups either in the rate at which lever contacts decreased or in the frequency of lever contacts at the end of training. These data implicate prior experience in the interpretation of omission-training effects and suggest limitations in the influence of stimulus-reinforcer relations in autoshaping. PMID:16811960

Autoshaping, random control, and omission training in the rat.

PubMed

Locurto, C; Terrace, H S; Gibbon, J

1976-11-01

The role of the stimulus-reinforcer contingency in the development and maintenance of lever contact responding was studied in hooded rats. In Experiment I, three groups of experimentally naive rats were trained either on autoshaping, omission training, or a random-control procedure. Subjects trained by the autoshaping procedure responded more consistently than did either random-control or omission-trained subjects. The probability of at least one lever contact per trial was slightly higher in subjects trained by the omission procedure than by the random-control procedure. However, these differences were not maintained during extended training, nor were they evident in total lever-contact frequencies. When omission and random-control subjects were switched to the autoshaping condition, lever contacts increased in all animals, but a pronounced retardation was observed in omission subjects relative to the random-control subjects. In addition, subjects originally exposed to the random-control procedure, and later switched to autoshaping, acquired more rapidly than naive subjects that were exposed only on the autoshaping procedure. In Experiment II, subjects originally trained by an autoshaping procedure were exposed either to an omission, a random-control, or an extinction procedure. No differences were observed among the groups either in the rate at which lever contacts decreased or in the frequency of lever contacts at the end of training. These data implicate prior experience in the interpretation of omission-training effects and suggest limitations in the influence of stimulus-reinforcer relations in autoshaping.

Population density approach for discrete mRNA distributions in generalized switching models for stochastic gene expression.

PubMed

Stinchcombe, Adam R; Peskin, Charles S; Tranchina, Daniel

2012-06-01

We present a generalization of a population density approach for modeling and analysis of stochastic gene expression. In the model, the gene of interest fluctuates stochastically between an inactive state, in which transcription cannot occur, and an active state, in which discrete transcription events occur; and the individual mRNA molecules are degraded stochastically in an independent manner. This sort of model in simplest form with exponential dwell times has been used to explain experimental estimates of the discrete distribution of random mRNA copy number. In our generalization, the random dwell times in the inactive and active states, T_{0} and T_{1}, respectively, are independent random variables drawn from any specified distributions. Consequently, the probability per unit time of switching out of a state depends on the time since entering that state. Our method exploits a connection between the fully discrete random process and a related continuous process. We present numerical methods for computing steady-state mRNA distributions and an analytical derivation of the mRNA autocovariance function. We find that empirical estimates of the steady-state mRNA probability mass function from Monte Carlo simulations of laboratory data do not allow one to distinguish between underlying models with exponential and nonexponential dwell times in some relevant parameter regimes. However, in these parameter regimes and where the autocovariance function has negative lobes, the autocovariance function disambiguates the two types of models. Our results strongly suggest that temporal data beyond the autocovariance function is required in general to characterize gene switching.

Common and Distinct Neural Mechanisms of Attentional Switching and Response Conflict

PubMed Central

Kim, Chobok; Johnson, Nathan F.; Gold, Brian T.

2012-01-01

The human capacities for overcoming prepotent actions and flexibly switching between tasks represent cornerstones of cognitive control. Functional neuroimaging has implicated a diverse set of brain regions contributing to each of these cognitive control processes. However, the extent to which attentional switching and response conflict draw on shared or distinct neural mechanisms remains unclear. The current study examined the neural correlates of response conflict and attentional switching using event-related functional magnetic resonance imaging (fMRI) and a fully randomized 2×2 design. We manipulated an arrow-word version of the Stroop task to measure conflict and switching in the context of a single task decision, in response to a common set of stimuli. Under these common conditions, both behavioral and imaging data showed significant main effects of conflict and switching but no interaction. However, conjunction analyses identified frontal regions involved in both switching and response conflict, including the dorsal anterior cingulate cortex (dACC) and left inferior frontal junction. In addition, connectivity analyses demonstrated task-dependent functional connectivity patterns between dACC and inferior temporal cortex for attentional switching and between dACC and posterior parietal cortex for response conflict. These results suggest that the brain makes use of shared frontal regions, but can dynamically modulate the connectivity patterns of some of those regions, to deal with attentional switching and response conflict. PMID:22750124

Common and distinct neural mechanisms of attentional switching and response conflict.

PubMed

Kim, Chobok; Johnson, Nathan F; Gold, Brian T

2012-08-21

The human capacities for overcoming prepotent actions and flexibly switching between tasks represent cornerstones of cognitive control. Functional neuroimaging has implicated a diverse set of brain regions contributing to each of these cognitive control processes. However, the extent to which attentional switching and response conflict draw on shared or distinct neural mechanisms remains unclear. The current study examined the neural correlates of response conflict and attentional switching using event-related functional magnetic resonance imaging (fMRI) and a fully randomized 2×2 design. We manipulated an arrow-word version of the Stroop task to measure conflict and switching in the context of a single task decision, in response to a common set of stimuli. Under these common conditions, both behavioral and imaging data showed significant main effects of conflict and switching but no interaction. However, conjunction analyses identified frontal regions involved in both switching and response conflict, including the dorsal anterior cingulate cortex (dACC) and left inferior frontal junction. In addition, connectivity analyses demonstrated task-dependent functional connectivity patterns between dACC and inferior temporal cortex for attentional switching and between dACC and posterior parietal cortex for response conflict. These results suggest that the brain makes use of shared frontal regions, but can dynamically modulate the connectivity patterns of some of those regions, to deal with attentional switching and response conflict. Copyright © 2012 Elsevier B.V. All rights reserved.

Causal mediation analysis for longitudinal data with exogenous exposure

PubMed Central

Bind, M.-A. C.; Vanderweele, T. J.; Coull, B. A.; Schwartz, J. D.

2016-01-01

Mediation analysis is a valuable approach to examine pathways in epidemiological research. Prospective cohort studies are often conducted to study biological mechanisms and often collect longitudinal measurements on each participant. Mediation formulae for longitudinal data have been developed. Here, we formalize the natural direct and indirect effects using a causal framework with potential outcomes that allows for an interaction between the exposure and the mediator. To allow different types of longitudinal measures of the mediator and outcome, we assume two generalized mixed-effects models for both the mediator and the outcome. The model for the mediator has subject-specific random intercepts and random exposure slopes for each cluster, and the outcome model has random intercepts and random slopes for the exposure, the mediator, and their interaction. We also expand our approach to settings with multiple mediators and derive the mediated effects, jointly through all mediators. Our method requires the absence of time-varying confounding with respect to the exposure and the mediator. This assumption is achieved in settings with exogenous exposure and mediator, especially when exposure and mediator are not affected by variables measured at earlier time points. We apply the methodology to data from the Normative Aging Study and estimate the direct and indirect effects, via DNA methylation, of air pollution, and temperature on intercellular adhesion molecule 1 (ICAM-1) protein levels. Our results suggest that air pollution and temperature have a direct effect on ICAM-1 protein levels (i.e. not through a change in ICAM-1 DNA methylation) and that temperature has an indirect effect via a change in ICAM-1 DNA methylation. PMID:26272993

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 Central

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; Kelleher, Anthony; Merlin, Kate; Yeung, Julie; Fsadni, Bertha; Marks, Kat; Suzuki, Kazuo; Rismanto, Nick; Salomon, Horacio; Rubio, Andrea E.; Chibo, Doris; Birch, Chris; Harrigan, Richard; Swenson, Luke; Chan, Dennison; Berg, Thomas; Obermeier, Martin; Kaiser, Rolf; Schuelter, Eugen; Sierra Aragon, Saleta; Luebke, Nadine; Coughlan, Suzie; Dean, Jonathan; Sugiura, Wataru; Iwatani, Yasumasa; Reyes Teran, Gustavo; Avila, Santiago; Ruxrungtham, Kiat; Sirivichayakul, Sunee; Naphassanant, May; Ubolyam, Sasiwimol; Kaye, Steve; Land, Sally; Walker, Sarah; Haubrich, Richard; DeJesus, Edwin; Emery, Sean; Pett, Sarah L.; Tu, Elise; Silk, David; Berthon-Jones, Nisha; Amin, Janaki; Espinosa, Natalie; Courtney-Vega, Kymme; Absar, Noorul; Haskelberg, Hila; Robson, Rose; Donaldson, Anna; Losso, Marcelo; Belloso, Waldo; Guelman, Daniel; Gambardella, Luciana; Valdovinos, Mariana; Gatell, Jose; Arnaiz, Juan; Beleta, Helena; Ramos, Nuria; Targa, Marta; Rockstroh, Jurgen; Späth, Brigitta; Boesecke, Christoph; Engelhardt, Angelika; Fisher, Martin; Perry, Nicky; Clarke, Amanda; Gill, John; Beckthold, Brenda; Clark, Andrew; Drummond, Fraser; Lefevre, Eric; Corr, Sharon; Grant, Carol; Lupo, Sergio; Peroni, Luciana; Italiano, Hospital; Sanchez, Marisa; De Paz Sierra, Mariana; Mejia, Ramos; Losso, Marcelo; Viloria, Guillermo; Parlante, Angel; Bissio, Emiliano; Luchetti, Pablo; Warley, Eduardo; Vieni, Ines; Porteiro, Norma; Vilas, Cecilia; Zarate, Abel; Mayer, Gabriela; Elliot, Julian; Hagenauer, Michelle; Kelley, Mark; Rowling, Diane; Gibson, Abby; Latch, Ngaire; Tabrett, Chantal; Warzywoda, Elizabeth; Cooper, David; Pett, Sarah; MacRae, Karen; Sinclair, Brett; Sinn, Kate; Bloch, Mark; Franic, Teo; Vincent, Trina; Stewart, Natasha; Jayewardene, Avindra; Dwyer, Dominic; Kok, Jennifer; Assam, Delene; Taylor, Janette; King, Patricia; Orth, David; Youds, David; Sowden, David; Johnston, Colleen; Murray, Suzanne; Hehir, Jennifer; Wadham, Samantha; Donohue, William; Thompson, Jill; Garsia, Roger; Turnham, Geoffrey; Madden, Tracey; Woolley, Ian; Gillies, Ainsley; Bryant, Mellissa; Gill, John; Beckthold, Brenda; Walmsley, Sharon; Chan, Warmond; LeBlanc, Roger; Lanteigne, Francois; Mouawad, Rima; Rahal, Ines; Guber, Sergio; Ozturk, Sefika; Smith, Graham; Halpenny, Roberta; Reko, Tatjana; Robinette Hills, Jennifer; Wolff, Marcelo; Prazuck, Thierry; Laurent Hocqueloux, Francois; Wolfgang, Johann; Stephan, Christoph; Ebeling, Franziska; Rockstroh, Juergen; Boesecke, Christoph; Spath, Brigitta; Engelhardt, Angelika; Ole Jensen, Bjorn-Erik; Feind, Cecilie; Meyer-Olson, Dirk; Stoll, Matthias; Hoeper, Kirsten; Beider, Renata; Faetkenheur, Gerd; Thomas Baumgarten, Ellen; Baumgarten, Axel; Ingiliz, Patrick; Wienbreyer, Andreas; Behrendt, Daniela; Nienkarken, Tanja; Stein, Jessen; Jessen, Heiko; Zedlack, Carmen; Mallon, Paddy; Simelane, Sibongile; Assmann, Jennifer; Ghavami-Kia, Bijan; Sugiura, Wataru; Imahashi, Mayumi; Tanabe, Kazue; Yokomaku, Yoshiyuki; Imamura, Junji; Andrade-Villanueva, Jaime; Montes de Oca, Melva; Gonzalez, Lucero; Ponce, David; Mendoza, Andrea; Sierra-Madero, Juan; Sanchez Hernandez, Jesus Eduardo; Jaime Ruiz Ballesteros, Eduardo; del Moral Ponce, Sergio; Mosqueda, Luis; Lopez, Monica; Horban, Andrzej; Ignatowska, Anna; Bakowska, Elzbieta; Pulik, Piotr; Sanz-Moreno, Jose; Paredes, Roger; Puig, Jordi; Domingo, Pere; Gutierrez, Mar; Gatell, Jose; González-Cordón, Ana; Callau, Pili; Lopez Aldeguer, Jose; Cuellar Tovar, Sandra; Leal Noval, Manuel; Rivas, Inmaculada; Delgado-Fernandez, Marcial; Ramon Arribas, Jose; Miguel Castro, Juan; Ruxrungtham, Kiat; Avihingsanon, Anchalee; Maek-a-nantawat, Wirach; Intasan, Jintana; Charoenporn, Walairat; Cuprasitrut, Thidarat; Jaisomkom, Pachuen; Pruksakaew, Kanchana; Winston, Alan; Mullaney, Scott; Fisher, Martin; Clarke, Amanda; Barbour, Lisa; Perry, Nicky; Richardson, Celia; Fox, Julie; Murray, Tammy; Leen, Clifford; Morris, Shelia; Satyajit, Das; Sandhu, Rumun; Tucker, James

2016-01-01

Abstract Background. 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. Methods. 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. Results. 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. Conclusions. These data support MVC as a switch option for ritonavir-boosted PIs when partnered with a 2-N(t)RTI backbone, but not as part of N(t)RTI-sparing regimens comprising MVC with PI/r. Clinical Trials Registration. NCT01384682. PMID:27048747

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.

Equilibrious Strand Exchange Promoted by DNA Conformational Switching

NASA Astrophysics Data System (ADS)

Wu, Zhiguo; Xie, Xiao; Li, Puzhen; Zhao, Jiayi; Huang, Lili; Zhou, Xiang

2013-01-01

Most of DNA strand exchange reactions in vitro are based on toehold strategy which is generally nonequilibrium, and intracellular strand exchange mediated by proteins shows little sequence specificity. Herein, a new strand exchange promoted by equilibrious DNA conformational switching is verified. Duplexes containing c-myc sequence which is potentially converted into G-quadruplex are designed in this strategy. The dynamic equilibrium between duplex and G4-DNA is response to the specific exchange of homologous single-stranded DNA (ssDNA). The SER is enzyme free and sequence specific. No ATP is needed and the displaced ssDNAs are identical to the homologous ssDNAs. The SER products and exchange kenetics are analyzed by PAGE and the RecA mediated SER is performed as the contrast. This SER is a new feature of G4-DNAs and a novel strategy to utilize the dynamic equilibrium of DNA conformations.

Age differences in working memory updating: the role of interference, focus switching and substituting information.

PubMed

Lendínez, Cristina; Pelegrina, Santiago; Lechuga, M Teresa

2015-05-01

Working memory updating (WMU) tasks require different elements in working memory (WM) to be maintained simultaneously, accessing one of these elements, and substituting its content. This study examined possible developmental changes from childhood to adulthood both in focus switching and substituting information in WM. In addition, possible age-related changes in interference due to representational overlap between the different elements simultaneously held in these tasks were examined. Children (8- and 11-year-olds), adolescents (14-year-olds) and younger adults (mean age=22 years) were administered a numerical updating memory task, in which updating and focus switching were manipulated. As expected, response times decreased and recall performance increased with age. More importantly, the time needed for focus switching was longer in children than in adolescents and younger adults. On the other hand, substitution of information and interference due to representational overlap were not affected by age. These results suggest that age-related changes in focus switching might mediate developmental changes in WMU performance. Copyright © 2015 Elsevier B.V. All rights reserved.

Resistive switching mechanism of ZnO/ZrO2-stacked resistive random access memory device annealed at 300 °C by sol-gel method with forming-free operation

NASA Astrophysics Data System (ADS)

Jian, Wen-Yi; You, Hsin-Chiang; Wu, Cheng-Yen

2018-01-01

In this work, we used a sol-gel process to fabricate a ZnO-ZrO2-stacked resistive switching random access memory (ReRAM) device and investigated its switching mechanism. The Gibbs free energy in ZnO, which is higher than that in ZrO2, facilitates the oxidation and reduction reactions of filaments in the ZnO layer. The current-voltage (I-V) characteristics of the device revealed a forming-free operation because of nonlattice oxygen in the oxide layer. In addition, the device can operate under bipolar or unipolar conditions with a reset voltage of 0 to ±2 V, indicating that in this device, Joule heating dominates at reset and the electric field dominates in the set process. Furthermore, the characteristics reveal why the fabricated device exhibits a greater discrete distribution phenomenon for the set voltage than for the reset voltage. These results will enable the fabrication of future ReRAM devices with double-layer oxide structures with improved characteristics.

E-field induced resistive switch in metal/praseodymium calcium manganite interfaces: A model for future nonvolatile memory devices

NASA Astrophysics Data System (ADS)

Das, Nilanjan

Among the various candidates for non-volatile random access memory (RAM), interfacial resistive switch in Ag/Pr0.7Ca0.3 MnO3 (PCMO) configuration has drawn major attention in recent years due to its potential as a high storage density (˜ terabyte) device. However, the diverse nature of the resistive switch in different systems makes the development of a unifying model for its underlying physics very difficult. This dissertation will address both issues, namely, characterization of switches for device applications and development of a system-independent generic model, in detail. In our work, we have studied the properties electric pulse induced interfacial switch in electrode/PCMO system. A very fast speed ("write speed") of 100 ns, threshold ("programming voltage") as low as 2 V (for micro electrodes), and non-volatility ("data retention") of switched states have been achieved. A clear distinction between fast switch and sub-threshold slow quasistatic-dc switch has been made. Results obtained from time-dependence studies and impedance spectroscopy suggest that defect creation/annihilation, such as broken bonds (under very high field at interface, 107V/cm), is likely the mechanism for the sub-micros fast switching. On the other hand, slow accumulative process, such as electromigration of point defects, are responsible for the subthreshold quasi-dc switch. Scanning probe imaging has revealed the nanoscale inhomogeneity of the switched surfaces, essential for observing a resistive switch. Evolution of such structures has been observed under surface pre-training. Device scalability has been tested by creating reversible modification of surface conductivities with atomic force microscopy, thus creating the "nano-switch" (limited to a region of 10--100 nm).

Protective effects of flavanol-rich dark chocolate on endothelial function and wave reflection during acute hyperglycemia.

PubMed

Grassi, Davide; Desideri, Giovambattista; Necozione, Stefano; Ruggieri, Fabrizio; Blumberg, Jeffrey B; Stornello, Michele; Ferri, Claudio

2012-09-01

Nitric oxide plays a pivotal role in regulating vascular tone. Different studies show endothelial function is impaired during hyperglycemia. Dark chocolate increases flow-mediated dilation in healthy and hypertensive subjects with and without glucose intolerance; however, the effect of pretreatment with dark chocolate on endothelial function and other vascular responses to hyperglycemia has not been examined. Therefore, we aimed to investigate the effects of flavanol-rich dark chocolate administration on (1) flow-mediated dilation and wave reflections; (2) blood pressure, endothelin-1 and oxidative stress, before and after oral glucose tolerance test (OGTT). Twelve healthy volunteers (5 males, 28.2±2.7 years) randomly received either 100 g/d dark chocolate or flavanol-free white chocolate for 3 days. After 7 days washout period, volunteers were switched to the other treatment. Flow-mediated dilation, stiffness index, reflection index, peak-to-peak time, blood pressure, endothelin-1 and 8-iso-PGF(2α) were evaluated after each treatment phase and OGTT. Compared with white chocolate, dark chocolate ingestion improved flow-mediated dilation (P=0.03), wave reflections, endothelin-1 and 8-iso-PGF(2α) (P<0.05). After white chocolate ingestion, flow-mediated dilation was reduced after OGTT from 7.88±0.68 to 6.07±0.76 (P=0.027), 6.74±0.51 (P=0.046) at 1 and 2 h after the glucose load, respectively. Similarly, after white chocolate but not after dark chocolate, wave reflections, blood pressure, and endothelin-1 and 8-iso-PGF(2α) increased after OGTT. OGTT causes acute, transient impairment of endothelial function and oxidative stress, which is attenuated by flavanol-rich dark chocolate. These results suggest cocoa flavanols may contribute to vascular health by reducing the postprandial impairment of arterial function associated with the pathogenesis of atherosclerosis.

Atomic Layer Deposited Oxide-Based Nanocomposite Structures with Embedded CoPtx Nanocrystals for Resistive Random Access Memory Applications.

PubMed

Wang, Lai-Guo; Cao, Zheng-Yi; Qian, Xu; Zhu, Lin; Cui, Da-Peng; Li, Ai-Dong; Wu, Di

2017-02-22

Al 2 O 3 - or HfO 2 -based nanocomposite structures with embedded CoPt x nanocrystals (NCs) on TiN-coated Si substrates have been prepared by combination of thermal atomic layer deposition (ALD) and plasma-enhanced ALD for resistive random access memory (RRAM) applications. The impact of CoPt x NCs and their average size/density on the resistive switching properties has been explored. Compared to the control sample without CoPt x NCs, ALD-derived Pt/oxide/100 cycle-CoPt x NCs/TiN/SiO 2 /Si exhibits a typical bipolar, reliable, and reproducible resistive switching behavior, such as sharp distribution of RRAM parameters, smaller set/reset voltages, stable resistance ratio (≥10 2 ) of OFF/ON states, better switching endurance up to 10 4 cycles, and longer data retention over 10 5 s. The possible resistive switching mechanism based on nanocomposite structures of oxide/CoPt x NCs has been proposed. The dominant conduction mechanisms in low- and high-resistance states of oxide-based device units with embedded CoPt x NCs are Ohmic behavior and space-charge-limited current, respectively. The insertion of CoPt x NCs can effectively improve the formation of conducting filaments due to the CoPt x NC-enhanced electric field intensity. Besides excellent resistive switching performances, the nanocomposite structures also simultaneously present ferromagnetic property. This work provides a flexible pathway by combining PEALD and TALD compatible with state-of-the-art Si-based technology for multifunctional electronic devices applications containing RRAM.

Rapid mapping of polarization switching through complete information acquisition

DOE PAGES

Somnath, Suhas; Belianinov, Alex; Kalinin, Sergei V.; ...

2016-12-02

Polarization switching in ferroelectric and multiferroic materials underpins a broad range of current and emergent applications, ranging from random access memories to field-effect transistors, and tunnelling devices. Switching in these materials is exquisitely sensitive to local defects and microstructure on the nanometre scale, necessitating spatially resolved high-resolution studies of these phenomena. Classical piezoresponse force microscopy and spectroscopy, although providing necessary spatial resolution, are fundamentally limited in data acquisition rates and energy resolution. This limitation stems from their two-tiered measurement protocol that combines slow (~1 s) switching and fast (~10 kHz–1 MHz) detection waveforms. Here we develop an approach for rapidmore » probing of ferroelectric switching using direct strain detection of material response to probe bias. This approach, facilitated by high-sensitivity electronics and adaptive filtering, enables spectroscopic imaging at a rate 3,504 times faster the current state of the art, achieving high-veracity imaging of polarization dynamics in complex microstructures.« less

Effects of fundamentals acquisition and strategy switch on stock price dynamics

NASA Astrophysics Data System (ADS)

Wu, Songtao; He, Jianmin; Li, Shouwei

2018-02-01

An agent-based artificial stock market is developed to simulate trading behavior of investors. In the market, acquisition and employment of information about fundamentals and strategy switch are investigated to explain stock price dynamics. Investors could obtain the information from both market and neighbors resided on their social networks. Depending on information status and performances of different strategies, an informed investor may switch to the strategy of fundamentalist. This in turn affects the information acquisition process, since fundamentalists are more inclined to search and spread the information than chartists. Further investigation into price dynamics generated from three typical networks, i.e. regular lattice, small-world network and random graph, are conducted after general relation between network structures and price dynamics is revealed. In each network, integrated effects of different combinations of information efficiency and switch intensity are investigated. Results have shown that, along with increasing switch intensity, market and social information efficiency play different roles in the formation of price distortion, standard deviation and kurtosis of returns.

Rapid mapping of polarization switching through complete information acquisition

PubMed Central

Somnath, Suhas; Belianinov, Alex; Kalinin, Sergei V.; Jesse, Stephen

2016-01-01

Polarization switching in ferroelectric and multiferroic materials underpins a broad range of current and emergent applications, ranging from random access memories to field-effect transistors, and tunnelling devices. Switching in these materials is exquisitely sensitive to local defects and microstructure on the nanometre scale, necessitating spatially resolved high-resolution studies of these phenomena. Classical piezoresponse force microscopy and spectroscopy, although providing necessary spatial resolution, are fundamentally limited in data acquisition rates and energy resolution. This limitation stems from their two-tiered measurement protocol that combines slow (∼1 s) switching and fast (∼10 kHz–1 MHz) detection waveforms. Here we develop an approach for rapid probing of ferroelectric switching using direct strain detection of material response to probe bias. This approach, facilitated by high-sensitivity electronics and adaptive filtering, enables spectroscopic imaging at a rate 3,504 times faster the current state of the art, achieving high-veracity imaging of polarization dynamics in complex microstructures. PMID:27910941

Sphingolipid-Mediated Apoptosis and Tumor Suppression in Breast Carcinoma.

DTIC Science & Technology

1997-11-01

sodium bicarbonate . G418 at 500 jtg/ml was added to the CrmA cell line and its vector while hygromycin 150 jtg/ml was added to the Bcl-2 cell line...were switched to fresh complete medium containing [3H] choline ( 1 pCi/ml). After 48 hrs, cells were switched again to fresh medium and chased for 2 hr...1, v/v) and 0.2 ml of water. After phase separation, a portion of the upper phase containing the product [14C] choline phosphate was counted for

Electron transfer dynamics of bistable single-molecule junctions.

PubMed

Danilov, Andrey V; Kubatkin, Sergey E; Kafanov, Sergey G; Flensberg, Karsten; Bjørnholm, Thomas

2006-10-01

We present transport measurements of single-molecule junctions bridged by a molecule with three benzene rings connected by two double bonds and with thiol end-groups that allow chemical binding to gold electrodes. The I-V curves show switching behavior between two distinct states. By statistical analysis of the switching events, we show that a 300 meV mode mediates the transition between the two states. We propose that breaking and reformation of a S-H bond in the contact zone between molecule and electrode explains the observed bistability.

Receptor-like kinases as surface regulators for RAC/ROP-mediated pollen tube growth and interaction with the pistil

PubMed Central

Zou, Yanjiao; Aggarwal, Mini; Zheng, Wen-Guang; Wu, Hen-Ming; Cheung, Alice Y.

2011-01-01

Background RAC/ROPs are RHO-type GTPases and are known to play diverse signalling roles in plants. Cytoplasmic RAC/ROPs are recruited to the cell membrane and activated in response to extracellular signals perceived and mediated by cell surface-located signalling assemblies, transducing the signals to regulate cellular processes. More than any other cell types in plants, pollen tubes depend on continuous interactions with an extracellular environment produced by their surrounding tissues as they grow within the female organ pistil to deliver sperm to the female gametophyte for fertilization. Scope We review studies on pollen tube growth that provide compelling evidence indicating that RAC/ROPs are crucial for regulating the cellular processes that underlie the polarized cell growth process. Efforts to identify cell surface regulators that mediate extracellular signals also point to RAC/ROPs being the molecular switches targeted by growth-regulating female factors for modulation to mediate pollination and fertilization. We discuss a large volume of work spanning more than two decades on a family of pollen-specific receptor kinases and some recent studies on members of the FERONIA family of receptor-like kinases (RLKs). Significance The research described shows the crucial roles that two RLK families play in transducing signals from growth regulatory factors to the RAC/ROP switch at the pollen tube apex to mediate and target pollen tube growth to the female gametophyte and signal its disintegration to achieve fertilization once inside the female chamber. PMID:22476487

Programmability of nanowire networks

NASA Astrophysics Data System (ADS)

Bellew, A. T.; Bell, A. P.; McCarthy, E. K.; Fairfield, J. A.; Boland, J. J.

2014-07-01

Electrical connectivity in networks of nanoscale junctions must be better understood if nanowire devices are to be scaled up from single wires to functional material systems. We show that the natural connectivity behaviour found in random nanowire networks presents a new paradigm for creating multi-functional, programmable materials. In devices made from networks of Ni/NiO core-shell nanowires at different length scales, we discover the emergence of distinct behavioural regimes when networks are electrically stressed. We show that a small network, with few nanowire-nanowire junctions, acts as a unipolar resistive switch, demonstrating very high ON/OFF current ratios (>105). However, large networks of nanowires distribute an applied bias across a large number of junctions, and thus respond not by switching but instead by evolving connectivity. We demonstrate that these emergent properties lead to fault-tolerant materials whose resistance may be tuned, and which are capable of adaptively reconfiguring under stress. By combining these two behavioural regimes, we demonstrate that the same nanowire network may be programmed to act both as a metallic interconnect, and a resistive switch device with high ON/OFF ratio. These results enable the fabrication of programmable, multi-functional materials from random nanowire networks.Electrical connectivity in networks of nanoscale junctions must be better understood if nanowire devices are to be scaled up from single wires to functional material systems. We show that the natural connectivity behaviour found in random nanowire networks presents a new paradigm for creating multi-functional, programmable materials. In devices made from networks of Ni/NiO core-shell nanowires at different length scales, we discover the emergence of distinct behavioural regimes when networks are electrically stressed. We show that a small network, with few nanowire-nanowire junctions, acts as a unipolar resistive switch, demonstrating very high ON/OFF current ratios (>105). However, large networks of nanowires distribute an applied bias across a large number of junctions, and thus respond not by switching but instead by evolving connectivity. We demonstrate that these emergent properties lead to fault-tolerant materials whose resistance may be tuned, and which are capable of adaptively reconfiguring under stress. By combining these two behavioural regimes, we demonstrate that the same nanowire network may be programmed to act both as a metallic interconnect, and a resistive switch device with high ON/OFF ratio. These results enable the fabrication of programmable, multi-functional materials from random nanowire networks. Electronic supplementary information (ESI) available: Nanowire statistics (length, diameter statistics, and oxide thickness) are provided. Forming curves for single junctions and networks. Passive voltage contrast image demonstrating selectivity of conductive pathways in 100 μm network. See DOI: 10.1039/c4nr02338b

Introduction of Electronic Pressure Scanning at the Royal Aerospace Establishment

DTIC Science & Technology

1991-09-01

electronic pressure scanning system could offer an acciracy the same as or better than that of the mechanical pressure switch system it would replace and...described it as comparable with the kind of problem encountered with pressures in a rotating pressure switch system and suggested two ways around the...sufficient to reduce the system random noise to less than the systematic errors for data from the surface of a pressure plotted model A mechanical pressure

Track-before-detect labeled multi-bernoulli particle filter with label switching

NASA Astrophysics Data System (ADS)

Garcia-Fernandez, Angel F.

2016-10-01

This paper presents a multitarget tracking particle filter (PF) for general track-before-detect measurement models. The PF is presented in the random finite set framework and uses a labelled multi-Bernoulli approximation. We also present a label switching improvement algorithm based on Markov chain Monte Carlo that is expected to increase filter performance if targets get in close proximity for a sufficiently long time. The PF is tested in two challenging numerical examples.

Nonvolatile random access memory

NASA Technical Reports Server (NTRS)

Wu, Jiin-Chuan (Inventor); Stadler, Henry L. (Inventor); Katti, Romney R. (Inventor)

1994-01-01

A nonvolatile magnetic random access memory can be achieved by an array of magnet-Hall effect (M-H) elements. The storage function is realized with a rectangular thin-film ferromagnetic material having an in-plane, uniaxial anisotropy and inplane bipolar remanent magnetization states. The thin-film magnetic element is magnetized by a local applied field, whose direction is used to form either a 0 or 1 state. The element remains in the 0 or 1 state until a switching field is applied to change its state. The stored information is detcted by a Hall-effect sensor which senses the fringing field from the magnetic storage element. The circuit design for addressing each cell includes transistor switches for providing a current of selected polarity to store a binary digit through a separate conductor overlying the magnetic element of the cell. To read out a stored binary digit, transistor switches are employed to provide a current through a row of Hall-effect sensors connected in series and enabling a differential voltage amplifier connected to all Hall-effect sensors of a column in series. To avoid read-out voltage errors due to shunt currents through resistive loads of the Hall-effect sensors of other cells in the same column, at least one transistor switch is provided between every pair of adjacent cells in every row which are not turned on except in the row of the selected cell.

Large-eddy simulation, atmospheric measurement and inverse modeling of greenhouse gas emissions at local spatial scales

NASA Astrophysics Data System (ADS)

Nottrott, Anders Andelman

Multiferroic materials and devices have attracted intensified interests due to the demonstrated strong magnetoelectric coupling in new multiferroic materials, artificial multiferroic heterostructures and devices with unique functionalities and superior performance characteristics. This offers great opportunities for achieving compact, fast, energy-efficient and voltage tunable spintronic devices. In traditional magnetic materials based magnetic random access memories (MRAM) devices, the binary information is stored as magnetization. The high coercivity of the ferromagnetic media requires large magnetic fields for switching the magnetic states thus consuming large amount of energy. In modern MRAM information writing process, spin-torque technique is utilized for minimizing the large energy for generating magnetic field by passing through a spin-polarized current directly to the magnets. However, both methods still need large current/current density to toggle the magnetic bits which consume large amount of energy. With the presence of multiferroic or magnetoelectric materials, spin is controlled by electric field which opens new opportunities for power-efficient voltage control of magnetization in spintronic devices leading to magnetoelectric random access memories (MERAM) with ultra-low energy consumption. However, state of the art multiferroic materials still have difficulty of realizing nonvolatile 180° magnetization reversal, which is desired in realizing MERAM. In a strain-mediated multiferroic system, the typical modification of the magnetism of ferromagnetic phase as a function of bipolar electric field shows a "butterfly" like behavior. This is due to the linear piezoelectricity of ferroelectric phase which has a "butterfly" like piezostrain as a function of electric field curve resulting from ferroelectric domain wall switching. In this case, the magnetization state is volatile because of the vanishing of the piezostrain at zero electric field. However, the non-volatile switching of magnetization would be more promising for information storage or MERAM devices with lower energy consumption and the magnetic state can be further controlled by voltage impulse. In this work, we first study the equivalent of direct and converse magnetoelectric effects. The resonant direct and converse magnetoelectric (ME) effects have been investigated experimentally and theoretically in FeGa/PZT/FeGa sandwich laminate composites. The frequency responses of direct and converse magnetoelectric effects were measured under the same electric and magnetic bias conditions. The resonant direct ME effect (DME) occurs at an antiresonance frequency, while resonant converse ME effect (CME) occurs at a resonance frequency. The antiresonance and resonance frequencies have close but different values under identical bias conditions. The magnitudes of resonant effective ME coefficients for direct and converse ME effects are also not equal. Based on different sets of constitutive equations of the materials for DME and CME, a new model was developed to describe the frequency response of DME and CME in laminate composite, which was in good agreement with the experimental results. Inequivalence of resonant ME effects is ascribed to the different mechanical and electrical boundary conditions for DME and CME. On the other hand, similar bias E and H field dependence was observed for both DME and CME resonance frequencies and resonant coefficients, indicating consistency between DME and CME effects. In the study of the frequency response of DME and CME, the linear piezoelectric effect is used. However, this linear piezoelectric effect in converse magnetoelectric coupling would lead to "butter-fly" like magnetization vs. electric field curve which leads to a "volatile" behavior in magnetic memory system. In the presented study, a unique ferroelastic switching pathway in ferroelectric substrates is utilized to produce two distinct, reversible and stable lattice strain states which leads to the establish of two stable magnetization states of the ferromagnetic thin film. In this process, instead of complete 180° ferromagnetic domain switching, 71°/109° ferroelastic domain wall switching is involved, where the electric polarization is switching between in-plane and out-of-plane direction. A voltage impulse induced reversible bistable magnetization switching in FeGaB/lead zirconate titanate (PZT) multiferroic heterostructures at room temperature is first demonstrated. Two reversible and stable voltage-impulse induced mechanical strain states were obtained in the PZT by applying an electric field impulse with its amplitude smaller than the electric coercive field, which led to reversible voltage impulse induced bistable magnetization switching. Direct and converse magnetoelectric effects are carefully quantified.

Maximal feeding with active prey-switching: A kill-the-winner functional response and its effect on global diversity and biogeography

NASA Astrophysics Data System (ADS)

Vallina, S. M.; Ward, B. A.; Dutkiewicz, S.; Follows, M. J.

2014-01-01

Predators' switching towards the most abundant prey is a mechanism that stabilizes population dynamics and helps overcome competitive exclusion of species in food webs. Current formulations of active prey-switching, however, display non-maximal feeding in which the predators' total ingestion decays exponentially with the number prey species (i.e. the diet breadth) even though the total prey biomass stays constant. We analyse three previously published multi-species functional responses which have either active switching or maximal feeding, but not both. We identify the cause of this apparent incompatibility and describe a kill-the-winner formulation that combines active switching with maximal feeding. Active switching is shown to be a community response in which some predators become prey-selective and the formulations with maximal or non-maximal feeding are implicitly assuming different food web configurations. Global simulations using a marine ecosystem model with 64 phytoplankton species belonging to 4 major functional groups show that the species richness and biogeography of phytoplankton are very sensitive to the choice of the functional response for grazing. The phytoplankton biogeography reflects the balance between the competitive abilities for nutrient uptake and the degree of apparent competition which occurs indirectly between species that share a common predator species. The phytoplankton diversity significantly increases when active switching is combined with maximal feeding through predator-mediated coexistence.

A nonlinear HP-type complementary resistive switch

NASA Astrophysics Data System (ADS)

Radtke, Paul K.; Schimansky-Geier, Lutz

2016-05-01

Resistive Switching (RS) is the change in resistance of a dielectric under the influence of an external current or electric field. This change is non-volatile, and the basis of both the memristor and resistive random access memory. In the latter, high integration densities favor the anti-serial combination of two RS-elements to a single cell, termed the complementary resistive switch (CRS). Motivated by the irregular shape of the filament protruding into the device, we suggest a nonlinearity in the resistance-interpolation function, characterized by a single parameter p. Thereby the original HP-memristor is expanded upon. We numerically simulate and analytically solve this model. Further, the nonlinearity allows for its application to the CRS.

Switching from usual brand cigarettes to a tobacco-heating cigarette or snus: Part 2. Biomarkers of exposure.

PubMed

Ogden, Michael W; Marano, Kristin M; Jones, Bobbette A; Morgan, Walter T; Stiles, Mitchell F

2015-01-01

A randomized, multi-center study of adult cigarette smokers switched to tobacco-heating cigarettes, snus or ultra-low machine yield tobacco-burning cigarettes (50/group) was conducted, and subjects' experience with the products was followed for 24 weeks. Differences in biomarkers of tobacco exposure between smokers and never smokers at baseline and among groups relative to each other and over time were assessed. Results indicated reduced exposure to many potentially harmful constituents found in cigarette smoke following product switching. Findings support differences in exposure from the use of various tobacco products and are relevant to the understanding of a risk continuum among tobacco products (ClinicalTrials.gov Identifier: NCT02061917).

High-power femtosecond pulses without a modelocked laser

PubMed Central

Fu, Walter; Wright, Logan G.; Wise, Frank W.

2017-01-01

We demonstrate a fiber system which amplifies and compresses pulses from a gain-switched diode. A Mamyshev regenerator shortens the pulses and improves their coherence, enabling subsequent amplification by parabolic pre-shaping. As a result, we are able to control nonlinear effects and generate nearly transform-limited, 140-fs pulses with 13-MW peak power—an order-of-magnitude improvement over previous gain-switched diode sources. Seeding with a gain-switched diode results in random fluctuations of 2% in the pulse energy, which future work using known techniques may ameliorate. Further development may allow such systems to compete directly with sources based on modelocked oscillators in some applications while enjoying unparalleled robustness and repetition rate control. PMID:29214187

The simultaneous generation of soliton bunches and Q-switched-like pulses in a partially mode-locked fiber laser with a graphene saturable absorber

NASA Astrophysics Data System (ADS)

Wang, Zhenhong; Wang, Zhi; Liu, Yan-ge; He, Ruijing; Wang, Guangdou; Yang, Guang; Han, Simeng

2018-05-01

We experimentally report the coexistence of soliton bunches and Q-switched-like pulses in a partially mode-locked fiber laser with a microfiber-based graphene saturable absorber. The soliton bunches, like isolated spikes with extreme amplitude and ultrashort duration, randomly generate in the background of the Q-switched-like pulses. The soliton bunches have some pulse envelopes in which pulses operate at a fundamental repetition rate in the temporal domain. Further investigation shows that the composite pulses are highly correlated with the noise-like pulses. Our work can make a further contribution to enrich the understanding of the nonlinear dynamics in fiber lasers.

Causal mediation analysis for longitudinal data with exogenous exposure.

PubMed

Bind, M-A C; Vanderweele, T J; Coull, B A; Schwartz, J D

2016-01-01

Mediation analysis is a valuable approach to examine pathways in epidemiological research. Prospective cohort studies are often conducted to study biological mechanisms and often collect longitudinal measurements on each participant. Mediation formulae for longitudinal data have been developed. Here, we formalize the natural direct and indirect effects using a causal framework with potential outcomes that allows for an interaction between the exposure and the mediator. To allow different types of longitudinal measures of the mediator and outcome, we assume two generalized mixed-effects models for both the mediator and the outcome. The model for the mediator has subject-specific random intercepts and random exposure slopes for each cluster, and the outcome model has random intercepts and random slopes for the exposure, the mediator, and their interaction. We also expand our approach to settings with multiple mediators and derive the mediated effects, jointly through all mediators. Our method requires the absence of time-varying confounding with respect to the exposure and the mediator. This assumption is achieved in settings with exogenous exposure and mediator, especially when exposure and mediator are not affected by variables measured at earlier time points. We apply the methodology to data from the Normative Aging Study and estimate the direct and indirect effects, via DNA methylation, of air pollution, and temperature on intercellular adhesion molecule 1 (ICAM-1) protein levels. Our results suggest that air pollution and temperature have a direct effect on ICAM-1 protein levels (i.e. not through a change in ICAM-1 DNA methylation) and that temperature has an indirect effect via a change in ICAM-1 DNA methylation. © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Hls5 regulated erythroid differentiation by modulating GATA-1 activity.

PubMed

Endersby, Raelene; Majewski, Ian J; Winteringham, Louise; Beaumont, Jennifer G; Samuels, Amy; Scaife, Robin; Lim, Esther; Crossley, Merlin; Klinken, S Peter; Lalonde, Jean-Philippe

2008-02-15

Hemopoietic lineage switch (Hls) 5 and 7 were originally isolated as genes up-regulated during an erythroid-to-myeloid lineage switch. We have shown previously that Hls7/Mlf1 imposes a monoblastoid phenotype on erythroleukemic cells. Here we show that Hls5 impedes erythroid maturation by restricting proliferation and inhibiting hemoglobin synthesis; however, Hls5 does not influence the morphology of erythroid cells. Under the influence of GATA-1, Hls5 relocates from cytoplasmic granules to the nucleus where it associates with both FOG-1 and GATA-1. In the nucleus, Hls5 is able to suppress GATA-1-mediated transactivation and reduce GATA-1 binding to DNA. We conclude that Hls5 and Hls7/Mlf1 act cooperatively to induce biochemical and phenotypic changes associated with erythroid/myeloid lineage switching.

Irreversible magnetization switching at the onset of superconductivity in a superconductor ferromagnet hybrid

DOE Office of Scientific and Technical Information (OSTI.GOV)

Curran, P. J.; Bending, S. J.; Kim, J.

2015-12-28

We demonstrate that the magnetic state of a superconducting spin valve, that is normally controlled with an external magnetic field, can also be manipulated by varying the temperature which increases the functionality and flexibility of such structures as switching elements. In this case, switching is driven by changes in the magnetostatic energy due to spontaneous Meissner screening currents forming in the superconductor below the critical temperature. Our scanning Hall probe measurements also reveal vortex-mediated pinning of the ferromagnetic domain structure due to the pinning of quantized stray fields in the adjacent superconductor. The ability to use temperature as well asmore » magnetic field to control the local magnetisation structure raises the prospect of potential applications in magnetic memory devices.« less

Once bitten, twice shy: experienced regret and non-adaptive choice switching

PubMed Central

Cosulich, Anna; Ferrante, Donatella

2015-01-01

When a good decision leads to a bad outcome, the experience of regret can bias subsequent choices: people are less likely to select the regret-producing alternative a second time, even when it is still objectively the best alternative (non-adaptive choice switching). The first study presented herein showed that nearly half of participants experiencing regret rejected a previous alternative they had recognized as the best one, and chose a non-optimal alternative instead. The second study investigated the mechanism underlying this bias, and results supported the hypothesis that this non-adaptive choice switching is caused by inhibition of the previous decision (direct effect of experienced regret), rather than by increased sensitivity to anticipated regret in subsequent choices (indirect effect of experienced regret mediated by anticipated regret). PMID:26157618

Epigenetic switch from repressive to permissive chromatin in response to cold stress.

PubMed

Park, Junghoon; Lim, Chae Jin; Shen, Mingzhe; Park, Hee Jin; Cha, Joon-Yung; Iniesto, Elisa; Rubio, Vicente; Mengiste, Tesfaye; Zhu, Jian-Kang; Bressan, Ray A; Lee, Sang Yeol; Lee, Byeong-Ha; Jin, Jing Bo; Pardo, Jose M; Kim, Woe-Yeon; Yun, Dae-Jin

2018-06-05

Switching from repressed to active status in chromatin regulation is part of the critical responses that plants deploy to survive in an ever-changing environment. We previously reported that HOS15, a WD40-repeat protein, is involved in histone deacetylation and cold tolerance in Arabidopsis However, it remained unknown how HOS15 regulates cold responsive genes to affect cold tolerance. Here, we show that HOS15 interacts with histone deacetylase 2C (HD2C) and both proteins together associate with the promoters of cold-responsive COR genes, COR15A and COR47 Cold induced HD2C degradation is mediated by the CULLIN4 (CUL4)-based E3 ubiquitin ligase complex in which HOS15 acts as a substrate receptor. Interference with the association of HD2C and the COR gene promoters by HOS15 correlates with increased acetylation levels of histone H3. HOS15 also interacts with CBF transcription factors to modulate cold-induced binding to the COR gene promoters. Our results here demonstrate that cold induces HOS15-mediated chromatin modifications by degrading HD2C. This switches the chromatin structure status and facilitates recruitment of CBFs to the COR gene promoters. This is an apparent requirement to acquire cold tolerance. Copyright © 2018 the Author(s). Published by PNAS.

Microbiota regulate the ability of lung dendritic cells to induce IgA class-switch recombination and generate protective gastrointestinal immune responses

PubMed Central

Ruane, Darren; Chorny, Alejo; Lee, Haekyung; Faith, Jeremiah; Pandey, Gaurav; Shan, Meimei; Simchoni, Noa; Rahman, Adeeb; Garg, Aakash; Weinstein, Erica G.; Oropallo, Michael; Gaylord, Michelle; Ungaro, Ryan; Cunningham-Rundles, Charlotte; Alexandropoulos, Konstantina; Mucida, Daniel; Merad, Miriam; Cerutti, Andrea

2016-01-01

Protective immunoglobulin A (IgA) responses to oral antigens are usually orchestrated by gut dendritic cells (DCs). Here, we show that lung CD103+ and CD24+CD11b+ DCs induced IgA class-switch recombination (CSR) by activating B cells through T cell–dependent or –independent pathways. Compared with lung DCs (LDC), lung CD64+ macrophages had decreased expression of B cell activation genes and induced significantly less IgA production. Microbial stimuli, acting through Toll-like receptors, induced transforming growth factor-β (TGF-β) production by LDCs and exerted a profound influence on LDC-mediated IgA CSR. After intranasal immunization with inactive cholera toxin (CT), LDCs stimulated retinoic acid–dependent up-regulation of α4β7 and CCR9 gut-homing receptors on local IgA-expressing B cells. Migration of these B cells to the gut resulted in IgA-mediated protection against an oral challenge with active CT. However, in germ-free mice, the levels of LDC-induced, CT–specific IgA in the gut are significantly reduced. Herein, we demonstrate an unexpected role of the microbiota in modulating the protective efficacy of intranasal vaccination through their effect on the IgA class-switching function of LDCs. PMID:26712806

Epigenetic switch from repressive to permissive chromatin in response to cold stress

PubMed Central

Park, Junghoon; Lim, Chae Jin; Shen, Mingzhe; Park, Hee Jin; Cha, Joon-Yung; Iniesto, Elisa; Rubio, Vicente; Mengiste, Tesfaye; Bressan, Ray A.; Lee, Sang Yeol; Lee, Byeong-ha; Kim, Woe-Yeon; Yun, Dae-Jin

2018-01-01

Switching from repressed to active status in chromatin regulation is part of the critical responses that plants deploy to survive in an ever-changing environment. We previously reported that HOS15, a WD40-repeat protein, is involved in histone deacetylation and cold tolerance in Arabidopsis. However, it remained unknown how HOS15 regulates cold responsive genes to affect cold tolerance. Here, we show that HOS15 interacts with histone deacetylase 2C (HD2C) and both proteins together associate with the promoters of cold-responsive COR genes, COR15A and COR47. Cold induced HD2C degradation is mediated by the CULLIN4 (CUL4)-based E3 ubiquitin ligase complex in which HOS15 acts as a substrate receptor. Interference with the association of HD2C and the COR gene promoters by HOS15 correlates with increased acetylation levels of histone H3. HOS15 also interacts with CBF transcription factors to modulate cold-induced binding to the COR gene promoters. Our results here demonstrate that cold induces HOS15-mediated chromatin modifications by degrading HD2C. This switches the chromatin structure status and facilitates recruitment of CBFs to the COR gene promoters. This is an apparent requirement to acquire cold tolerance. PMID:29784800

A long-term epigenetic memory switch controls bacterial virulence bimodality

PubMed Central

Ronin, Irine; Katsowich, Naama; Rosenshine, Ilan; Balaban, Nathalie Q

2017-01-01

When pathogens enter the host, sensing of environmental cues activates the expression of virulence genes. Opposite transition of pathogens from activating to non-activating conditions is poorly understood. Interestingly, variability in the expression of virulence genes upon infection enhances colonization. In order to systematically detect the role of phenotypic variability in enteropathogenic E. coli (EPEC), an important human pathogen, both in virulence activating and non-activating conditions, we employed the ScanLag methodology. The analysis revealed a bimodal growth rate. Mathematical modeling combined with experimental analysis showed that this bimodality is mediated by a hysteretic memory-switch that results in the stable co-existence of non-virulent and hyper-virulent subpopulations, even after many generations of growth in non-activating conditions. We identified the per operon as the key component of the hysteretic switch. This unique hysteretic memory switch may result in persistent infection and enhanced host-to-host spreading. DOI: http://dx.doi.org/10.7554/eLife.19599.001 PMID:28178445

Metal-centred azaphosphatriptycene gear with a photo- and thermally driven mechanical switching function based on coordination isomerism.

PubMed

Ube, Hitoshi; Yasuda, Yoshihiro; Sato, Hiroyasu; Shionoya, Mitsuhiko

2017-02-08

Metal ions can serve as a centre of molecular motions due to their coordination geometry, reversible bonding nature and external stimuli responsiveness. Such essential features of metal ions have been utilized for metal-mediated molecular machines with the ability to motion switch via metallation/demetallation or coordination number variation at the metal centre; however, motion switching based on the change in coordination geometry remain largely unexplored. Herein, we report a Pt II -centred molecular gear that demonstrates control of rotor engagement and disengagement based on photo- and thermally driven cis-trans isomerization at the Pt II centre. This molecular rotary motion transmitter has been constructed from two coordinating azaphosphatriptycene rotators and one Pt II ion as a stator. Isomerization between an engaged cis-form and a disengaged trans-form is reversibly driven by ultraviolet irradiation and heating. Such a photo- and thermally triggered motional interconversion between engaged/disengaged states on a metal ion would provide a selector switch for more complex interlocking systems.

Switchable DNA wire: deposition-stripping of copper nanoclusters as an "ON-OFF" nanoswitch.

PubMed

Zhu, Xiaoli; Liu, Siyu; Cao, Jiepei; Mao, Xiaoxia; Li, Genxi

2016-01-19

Today, a consensus that DNA working as a molecular wire shows promise in nanoscale electronics is reached. Considering that the "ON-OFF" switch is the basis of a logic circuit, the switch of DNA-mediated charge transport (DNA CT) should be conquered. Here, on the basis of chemical or electrochemical deposition and stripping of DNA-templated copper nanoclusters (CuNCs), we develop an "ON-OFF" nanoswitch for DNA CT. While CuNCs are deposited, the DNA CT is blocked, which can be also recovered after stripping the CuNCs. A switch cycle can be completed in a few seconds and can be repeated for many times. Moreover, by regulating the amount of reagents, deposition/stripping time, applied potential, etc., the switch is adjustable to make the wire at either an "ON-OFF" state or an intermediate state. We believe that this concept and the successful implementation will promote the practical application of DNA wire one step further.

Antigenic variation in malaria: in situ switching, relaxed and mutually exclusive transcription of var genes during intra-erythrocytic development in Plasmodium falciparum.

PubMed Central

Scherf, A; Hernandez-Rivas, R; Buffet, P; Bottius, E; Benatar, C; Pouvelle, B; Gysin, J; Lanzer, M

1998-01-01

Members of the Plasmodium falciparum var gene family encode clonally variant adhesins, which play an important role in the pathogenicity of tropical malaria. Here we employ a selective panning protocol to generate isogenic P.falciparum populations with defined adhesive phenotypes for CD36, ICAM-1 and CSA, expressing single and distinct var gene variants. This technique has established the framework for examining var gene expression, its regulation and switching. It was found that var gene switching occurs in situ. Ubiquitous transcription of all var gene variants appears to occur in early ring stages. However, var gene expression is tightly regulated in trophozoites and is exerted through a silencing mechanism. Transcriptional control is mutually exclusive in parasites that express defined adhesive phenotypes. In situ var gene switching is apparently mediated at the level of transcriptional initiation, as demonstrated by nuclear run-on analyses. Our results suggest that an epigenetic mechanism(s) is involved in var gene regulation. PMID:9736619

Switchable DNA wire: deposition-stripping of copper nanoclusters as an “ON-OFF” nanoswitch

PubMed Central

Zhu, Xiaoli; Liu, Siyu; Cao, Jiepei; Mao, Xiaoxia; Li, Genxi

2016-01-01

Today, a consensus that DNA working as a molecular wire shows promise in nanoscale electronics is reached. Considering that the “ON-OFF” switch is the basis of a logic circuit, the switch of DNA-mediated charge transport (DNA CT) should be conquered. Here, on the basis of chemical or electrochemical deposition and stripping of DNA-templated copper nanoclusters (CuNCs), we develop an “ON-OFF” nanoswitch for DNA CT. While CuNCs are deposited, the DNA CT is blocked, which can be also recovered after stripping the CuNCs. A switch cycle can be completed in a few seconds and can be repeated for many times. Moreover, by regulating the amount of reagents, deposition/stripping time, applied potential, etc., the switch is adjustable to make the wire at either an “ON-OFF” state or an intermediate state. We believe that this concept and the successful implementation will promote the practical application of DNA wire one step further. PMID:26781761

Immunoglobulin class-switch recombination deficiencies.

PubMed

Durandy, Anne; Kracker, Sven

2012-07-30

Immunoglobulin class-switch recombination deficiencies (Ig-CSR-Ds) are rare primary immunodeficiencies characterized by defective switched isotype (IgG/IgA/IgE) production. Depending on the molecular defect in question, the Ig-CSR-D may be combined with an impairment in somatic hypermutation (SHM). Some of the mechanisms underlying Ig-CSR and SHM have been described by studying natural mutants in humans. This approach has revealed that T cell-B cell interaction (resulting in CD40-mediated signaling), intrinsic B-cell mechanisms (activation-induced cytidine deaminase-induced DNA damage), and complex DNA repair machineries (including uracil-N-glycosylase and mismatch repair pathways) are all involved in class-switch recombination and SHM. However, several of the mechanisms required for full antibody maturation have yet to be defined. Elucidation of the molecular defects underlying the diverse set of Ig-CSR-Ds is essential for understanding Ig diversification and has prompted better definition of the clinical spectrum of diseases and the development of increasingly accurate diagnostic and therapeutic approaches.

Immunoglobulin class-switch recombination deficiencies

PubMed Central

2012-01-01

Immunoglobulin class-switch recombination deficiencies (Ig-CSR-Ds) are rare primary immunodeficiencies characterized by defective switched isotype (IgG/IgA/IgE) production. Depending on the molecular defect in question, the Ig-CSR-D may be combined with an impairment in somatic hypermutation (SHM). Some of the mechanisms underlying Ig-CSR and SHM have been described by studying natural mutants in humans. This approach has revealed that T cell-B cell interaction (resulting in CD40-mediated signaling), intrinsic B-cell mechanisms (activation-induced cytidine deaminase-induced DNA damage), and complex DNA repair machineries (including uracil-N-glycosylase and mismatch repair pathways) are all involved in class-switch recombination and SHM. However, several of the mechanisms required for full antibody maturation have yet to be defined. Elucidation of the molecular defects underlying the diverse set of Ig-CSR-Ds is essential for understanding Ig diversification and has prompted better definition of the clinical spectrum of diseases and the development of increasingly accurate diagnostic and therapeutic approaches. PMID:22894609

Poly-4-vinylphenol (PVP) and Poly(melamine-co-formaldehyde) (PMF)-Based Atomic Switching Device and Its Application to Logic Gate Circuits with Low Operating Voltage.

PubMed

Kang, Dong-Ho; Choi, Woo-Young; Woo, Hyunsuk; Jang, Sungkyu; Park, Hyung-Youl; Shim, Jaewoo; Choi, Jae-Woong; Kim, Sungho; Jeon, Sanghun; Lee, Sungjoo; Park, Jin-Hong

2017-08-16

In this study, we demonstrate a high-performance solid polymer electrolyte (SPE) atomic switching device with low SET/RESET voltages (0.25 and -0.5 V, respectively), high on/off-current ratio (10 5 ), excellent cyclic endurance (>10 3 ), and long retention time (>10 4 s), where poly-4-vinylphenol (PVP)/poly(melamine-co-formaldehyde) (PMF) is used as an SPE layer. To accomplish these excellent device performance parameters, we reduce the off-current level of the PVP/PMF atomic switching device by improving the electrical insulating property of the PVP/PMF electrolyte through adjustment of the number of cross-linked chains. We then apply a titanium buffer layer to the PVP/PMF switching device for further improvement of bipolar switching behavior and device stability. In addition, we first implement SPE atomic switch-based logic AND and OR circuits with low operating voltages below 2 V by integrating 5 × 5 arrays of PVP/PMF switching devices on the flexible substrate. In particular, this low operating voltage of our logic circuits was much lower than that (>5 V) of the circuits configured by polymer resistive random access memory. This research successfully presents the feasibility of PVP/PMF atomic switches for flexible integrated circuits for next-generation electronic applications.

Comparing the Effectiveness and Safety of the Addition of and Switching to Aripiprazole for Resolving Antipsychotic-Induced Hyperprolactinemia: A Multicenter, Open-Label, Prospective Study.

PubMed

Yoon, Hui Woo; Lee, Jung Suk; Park, Sang Jin; Lee, Seon-Koo; Choi, Won-Jung; Kim, Tae Yong; Hong, Chang Hyung; Seok, Jeong-Ho; Park, Il-Ho; Son, Sang Joon; Roh, Daeyoung; Kim, Bo-Ra; Lee, Byung Ook

Hyperprolactinemia is an important but often overlooked adverse effect of antipsychotics. Several studies have shown that switching to or adding aripiprazole normalizes antipsychotic-induced hyperprolactinemia. However, no study has directly compared the effectiveness and safety of the 2 strategies. A total of 52 patients with antipsychotic-induced hyperprolactinemia were recruited. Aripiprazole was administered to patients with mild hyperprolactinemia (serum prolactin level < 50 ng/mL). Patients with severe hyperprolactinemia (serum prolactin level > 50 ng/mL) were randomized to an aripiprazole-addition group (adding aripiprazole to previous antipsychotics) or a switching group (switching previous antipsychotics to aripiprazole). Serum prolactin level, menstrual disturbances, sexual dysfunction, psychopathologies, and quality of life were measured at weeks 0, 1, 2, 4, 6, and 8. Both the addition and switching groups showed significantly reduced serum prolactin level and menstrual disturbances and improved sexual dysfunction. In patients with severe hyperprolactinemia, the numbers of patients with hyperprolactinemia and menstrual disturbance in the switching group were significantly lower than those in the addition group at week 8. Both the addition and switching strategies were effective in resolving antipsychotic-induced hyperprolactinemia and hyperprolactinemia-related adverse events, including menstrual disturbances and sexual dysfunction. In addition, these findings suggest that switching to aripiprazole may be more effective than addition of aripiprazole for normalizing hyperprolactinemia and improving hyperprolactinemia-related adverse events in patients with schizophrenia.

Morse taper dental implants and platform switching: The new paradigm in oral implantology

PubMed Central

Macedo, José Paulo; Pereira, Jorge; Vahey, Brendan R.; Henriques, Bruno; Benfatti, Cesar A. M.; Magini, Ricardo S.; López-López, José; Souza, Júlio C. M.

2016-01-01

The aim of this study was to conduct a literature review on the potential benefits with the use of Morse taper dental implant connections associated with small diameter platform switching abutments. A Medline bibliographical search (from 1961 to 2014) was carried out. The following search items were explored: “Bone loss and platform switching,” “bone loss and implant-abutment joint,” “bone resorption and platform switching,” “bone resorption and implant-abutment joint,” “Morse taper and platform switching.” “Morse taper and implant-abutment joint,” Morse taper and bone resorption,” “crestal bone remodeling and implant-abutment joint,” “crestal bone remodeling and platform switching.” The selection criteria used for the article were: meta-analysis; randomized controlled trials; prospective cohort studies; as well as reviews written in English, Portuguese, or Spanish languages. Within the 287 studies identified, 81 relevant and recent studies were selected. Results indicated a reduced occurrence of peri-implantitis and bone loss at the abutment/implant level associated with Morse taper implants and a reduced-diameter platform switching abutment. Extrapolation of data from previous studies indicates that Morse taper connections associated with platform switching have shown less inflammation and possible bone loss with the peri-implant soft tissues. However, more long-term studies are needed to confirm these trends. PMID:27011755

Allergic inflammation induces a persistent mechanistic switch in thromboxane-mediated airway constriction in the mouse

PubMed Central

Cyphert, Jaime M.; Allen, Irving C.; Church, Rachel J.; Latour, Anne M.; Snouwaert, John N.; Coffman, Thomas M.

2012-01-01

Actions of thromboxane (TXA2) to alter airway resistance were first identified over 25 years ago. However, the mechanism underlying this physiological response has remained largely undefined. Here we address this question using a novel panel of mice in which expression of the thromboxane receptor (TP) has been genetically manipulated. We show that the response of the airways to TXA2 is complex: it depends on expression of other G protein-coupled receptors but also on the physiological context of the signal. In the healthy airway, TXA2-mediated airway constriction depends on expression of TP receptors by smooth muscle cells. In contrast, in the inflamed lung, the direct actions of TXA2 on smooth muscle cell TP receptors no longer contribute to bronchoconstriction. Instead, in allergic lung disease, TXA2-mediated airway constriction depends on neuronal TP receptors. Furthermore, this mechanistic switch persists long after resolution of pulmonary inflammation. Our findings demonstrate the powerful ability of lung inflammation to modify pathways leading to airway constriction, resulting in persistent changes in mechanisms of airway reactivity to key bronchoconstrictors. Such alterations are likely to shape the pathogenesis of asthmatic lung disease. PMID:21984570

5-Aminolevulinic Acid-Mediated Sonodynamic Therapy Inhibits RIPK1/RIPK3-Dependent Necroptosis in THP-1-Derived Foam Cells

PubMed Central

Tian, Fang; Yao, Jianting; Yan, Meng; Sun, Xin; Wang, Wei; Gao, Weiwei; Tian, Zhen; Guo, Shuyuan; Dong, Zengxiang; Li, Bicheng; Gao, Tielei; Shan, Peng; Liu, Bing; Wang, Haiyang; Cheng, Jiali; Gao, Qianping; Zhang, Zhiguo; Cao, Wenwu; Tian, Ye

2016-01-01

Necroptosis, or programmed necrosis, contributes to the formation of necrotic cores in atherosclerotic plaque in animal models. However, whether inhibition of necroptosis ameliorates atherosclerosis is largely unknown. In this study, we demonstrated that necroptosis occurred in clinical atherosclerotic samples, suggesting that it may also play an important role in human atherosclerosis. We established an in vitro necroptotic model in which necroptosis was induced in THP-1-derived foam cells by serum deprivation. With this model, we demonstrated that 5-aminolevulinic acid-mediated sonodynamic therapy (ALA-SDT) inhibited necroptosis while promoting apoptosis. ALA-SDT activated the caspase-3 and caspase-8 pathways in foam cells, which is responsible for the switch from necroptosis to apoptosis. The inhibition of either caspase-8 or caspase-3 abolished the anti-necroptotic effect of ALA-SDT. In addition, we found that caspase-3 activation peaked 4 hours after ALA-SDT treatment, 2 hours earlier than maximal caspase-8activation. Taken together, our data indicate that ALA-SDT mediates the switch from necroptosis to apoptosis by activating the caspase-3 and caspase-8 pathways and may improve the prognosis of atherosclerosis. PMID:26911899

Random laser action in bovine semen

NASA Astrophysics Data System (ADS)

Smuk, Andrei; Lazaro, Edgar; Olson, Leif P.; Lawandy, N. M.

2011-03-01

Experiments using bovine semen reveal that the addition of a high-gain water soluble dye results in random laser action when excited by a Q-switched, frequency doubled, Nd:Yag laser. The data shows that the linewidth collapse of the emission is correlated to the sperm count of the individual samples, potentially making this a rapid, low sample volume approach to count determination.

Switching From Reference Adalimumab to SB5 (Adalimumab Biosimilar) in Patients With Rheumatoid Arthritis: Fifty-Two-Week Phase III Randomized Study Results.

PubMed

Weinblatt, Michael E; Baranauskaite, Asta; Dokoupilova, Eva; Zielinska, Agnieszka; Jaworski, Janusz; Racewicz, Artur; Pileckyte, Margarita; Jedrychowicz-Rosiak, Krystyna; Baek, Inyoung; Ghil, Jeehoon

2018-06-01

The 24-week equivalent efficacy and comparable safety results of the biosimilar SB5 and reference adalimumab (ADA) from the phase III randomized study in patients with moderate-to-severe rheumatoid arthritis (RA) have been reported previously. We undertook this transition study to evaluate patients who switched from ADA to SB5 or who continued to receive SB5 or ADA up to 52 weeks. In this phase III study, patients were initially randomized 1:1 to receive SB5 or ADA (40 mg subcutaneously every other week). At 24 weeks, patients receiving ADA were rerandomized 1:1 to continue with ADA (ADA/ADA group) or to switch to SB5 (ADA/SB5 group) up to week 52; patients receiving SB5 continued with SB5 for 52 weeks (SB5 group). Efficacy, safety, and immunogenicity were evaluated up to 52 weeks. The full analysis set population consisted of 542 patients (269 in the SB5 group, 273 in the ADA overall group [patients who were randomized to receive ADA at week 0], 125 in the ADA/SB5 group, and 129 in the ADA/ADA group). The percentages of patients meeting the American College of Rheumatology 20%, 50%, or 70% improvement criteria (achieving an ACR20, ACR50, or ACR70 response) at week 24 were maintained after the transition from ADA to SB5, and these response rates were comparable across treatment groups throughout the study. ACR20 response rates ranged from 73.4% to 78.8% at week 52. Radiographic progression was minimal and comparable across treatment groups. The safety profile and the incidence of antidrug antibodies were comparable across treatment groups after transition. SB5 was well tolerated over 1 year in patients with RA, with efficacy, safety, and immunogenicity comparable to those of ADA. Switching from ADA to SB5 had no treatment-emergent issues such as increased adverse events, increased immunogenicity, or loss of efficacy. © 2018 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.

Impulse voltage control of continuously tunable bipolar resistive switching in Pt/Bi0.9Eu0.1FeO3/Nb-doped SrTiO3 heterostructures

NASA Astrophysics Data System (ADS)

Wei, Maocai; Liu, Meifeng; Wang, Xiuzhang; Li, Meiya; Zhu, Yongdan; Zhao, Meng; Zhang, Feng; Xie, Shuai; Hu, Zhongqiang; Liu, Jun-Ming

2017-03-01

Epitaxial Bi0.9Eu0.1FeO3 (BEFO) thin films are deposited on Nb-doped SrTiO3 (NSTO) substrates by pulsed laser deposition to fabricate the Pt/BEFO/NSTO (001) heterostructures. These heterostructures possess bipolar resistive switching, where the resistances versus writing voltage exhibits a distinct hysteresis loop and a memristive behavior with good retention and anti-fatigue characteristics. The local resistive switching is confirmed by the conductive atomic force microscopy (C-AFM), suggesting the possibility to scale down the memory cell size. The observed memristive behavior could be attributed to the ferroelectric polarization effect, which modulates the height of potential barrier and width of depletion region at the BEFO/NSTO interface. The continuously tunable resistive switching behavior could be useful to achieve non-volatile, high-density, multilevel random access memory with low energy consumption.

Resistive switching characteristics and mechanisms in silicon oxide memory devices

NASA Astrophysics Data System (ADS)

Chang, Yao-Feng; Fowler, Burt; Chen, Ying-Chen; Zhou, Fei; Wu, Xiaohan; Chen, Yen-Ting; Wang, Yanzhen; Xue, Fei; Lee, Jack C.

2016-05-01

Intrinsic unipolar SiOx-based resistance random access memories (ReRAM) characterization, switching mechanisms, and applications have been investigated. Device structures, material compositions, and electrical characteristics are identified that enable ReRAM cells with high ON/OFF ratio, low static power consumption, low switching power, and high readout-margin using complementary metal-oxide semiconductor transistor (CMOS)-compatible SiOx-based materials. These ideas are combined with the use of horizontal and vertical device structure designs, composition optimization, electrical control, and external factors to help understand resistive switching (RS) mechanisms. Measured temperature effects, pulse response, and carrier transport behaviors lead to compact models of RS mechanisms and energy band diagrams in order to aid the development of computer-aided design for ultralarge-v scale integration. This chapter presents a comprehensive investigation of SiOx-based RS characteristics and mechanisms for the post-CMOS device era.

Resistive switching properties and physical mechanism of cobalt ferrite thin films

NASA Astrophysics Data System (ADS)

Hu, Wei; Zou, Lilan; Chen, Ruqi; Xie, Wei; Chen, Xinman; Qin, Ni; Li, Shuwei; Yang, Guowei; Bao, Dinghua

2014-04-01

We report reproducible resistive switching performance and relevant physical mechanism of sandwiched Pt/CoFe2O4/Pt structures in which the CoFe2O4 thin films were fabricated by a chemical solution deposition method. Uniform switching voltages, good endurance, and long retention have been demonstrated in the Pt/CoFe2O4/Pt memory cells. On the basis of the analysis of current-voltage characteristic and its temperature dependence, we suggest that the carriers transport through the conducting filaments in low resistance state with Ohmic conduction behavior, and the Schottky emission and Poole-Frenkel emission dominate the conduction mechanism in high resistance state. From resistance-temperature dependence of resistance states, we believe that the physical origin of the resistive switching refers to the formation and rupture of the oxygen vacancies related filaments. The nanostructured CoFe2O4 thin films can find applications in resistive random access memory.

Observation of indium ion migration-induced resistive switching in Al/Mg{sub 0.5}Ca{sub 0.5}TiO{sub 3}/ITO

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lin, Zong-Han; Wang, Yeong-Her, E-mail: yhw@ee.ncku.edu.tw

2016-08-01

Understanding switching mechanisms is very important for resistive random access memory (RRAM) applications. This letter reports an investigation of Al/Mg{sub 0.5}Ca{sub 0.5}TiO{sub 3} (MCTO)/ITO RRAM, which exhibits bipolar resistive switching behavior. The filaments that connect Al electrodes with indium tin oxide electrodes across the MCTO layer at a low-resistance state are identified. The filaments composed of In{sub 2}O{sub 3} crystals are observed through energy-dispersive X-ray spectroscopy, high-resolution transmission electron microscopy, nanobeam diffraction, and comparisons of Joint Committee on Powder Diffraction Standards (JCPDS) cards. Finally, a switching mechanism resulting from an electrical field induced by In{sup 3+} ion migration is proposed.more » In{sup 3+} ion migration forms/ruptures the conductive filaments and sets/resets the RRAM device.« less

EFFECTS OF TiOx INTERLAYER ON RESISTANCE SWITCHING OF Pt/TiOx/ZnO/n+-Si STRUCTURES

NASA Astrophysics Data System (ADS)

Li, Hongxia; Lv, Xiaojun; Xi, Junhua; Wu, Xin; Mao, Qinan; Liu, Qingmin; Ji, Zhenguo

2014-08-01

In this paper, we fabricated Pt/TiOx/ZnO/n+-Si structures by inserting TiOx interlayer between Pt top electrode (TE) and ZnO thin film for non-volatile resistive random access memory (ReRAM) applications. Effects of TiOx interlayer with different thickness on the resistance switching of Pt/TiOx/ZnO/n+-Si structures were investigated. Conduction behaviors in high and low resistance state (HRS and LRS) fit well with the trap-controlled space-charge-limited conduction (SCLC) and Ohmic behavior, respectively. Variations of set and reset voltages and HRS and LRS resistances of Pt/TiOx/ZnO/n+-Si structures were investigated as a function of TiOx thickness. Switching cycling tests were attempted to evaluate the endurance reliability of Pt/TiOx/ZnO/n+-Si structures. Additionally, the switching mechanism was analyzed by the filament model.

Impacts of Co doping on ZnO transparent switching memory device characteristics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Simanjuntak, Firman Mangasa; Wei, Kung-Hwa; Prasad, Om Kumar

2016-05-02

The resistive switching characteristics of indium tin oxide (ITO)/Zn{sub 1−x}Co{sub x}O/ITO transparent resistive memory devices were investigated. An appropriate amount of cobalt dopant in ZnO resistive layer demonstrated sufficient memory window and switching stability. In contrast, pure ZnO devices demonstrated a poor memory window, and using an excessive dopant concentration led to switching instability. To achieve suitable memory performance, relying only on controlling defect concentrations is insufficient; the grain growth orientation of the resistive layer must also be considered. Stable endurance with an ON/OFF ratio of more than one order of magnitude during 5000 cycles confirmed that the Co-doped ZnOmore » device is a suitable candidate for resistive random access memory application. Additionally, fully transparent devices with a high transmittance of up to 90% at wavelength of 550 nm have been fabricated.« less

Selective attention to perceptual dimensions and switching between dimensions.

PubMed

Meiran, Nachshon; Dimov, Eduard; Ganel, Tzvi

2013-02-01

In the present experiments, the question being addressed was whether switching attention between perceptual dimensions and selective attention to dimensions are processes that compete over a common resource? Attention to perceptual dimensions is usually studied by requiring participants to ignore a never-relevant dimension. Selection failure (Garner's Interference, GI) is indicated by poorer performance in the filtering condition (when this dimension varies) as compared with baseline (when it is fixed). Switching between perceptual dimensions is usually studied with the task switching paradigm. In the present experiments, attention switching was manipulated by using single-task blocks and blocks in which participants switched between tasks or dimensions in reaction to task cues, and attention to dimensions was assessed by including a third, never-relevant dimension that was either fixed or varied randomly. In Experiments 1 (long cue-target interval, CTI) and 2 (short CTI), the tasks involved shape and color and the never-relevant dimension (texture) was chosen to be separable from them. In Experiments 3 (long CTI) and 4 (short CTI), the tasks involved shape and brightness and the never-relevant dimension, saturation, was chosen to be separable from shape and integral with brightness. Task switching did not generate GI but a short CTI did. Thus, switching and filtering generally do not compete over central limited resources unless under tight time pressure. Experiment 3 shows GI in the brightness task but not in the shape task, suggesting that participants switched their attention between brightness and shape when they switched tasks. PsycINFO Database Record (c) 2013 APA, all rights reserved.

Phase IV study of retention on fingolimod versus injectable multiple sclerosis therapies: a randomized clinical trial.

PubMed

Cree, Bruce A C; Arnold, Douglas L; Cascione, Mark; Fox, Edward J; Williams, Ian M; Meng, Xiangyi; Schofield, Lesley; Tenenbaum, Nadia

2018-01-01

In relapsing-remitting multiple sclerosis (RRMS), suboptimal adherence to injectable disease-modifying therapies (iDMTs; interferon β-1a/b, glatiramer acetate) is common, reducing their effectiveness. Patient retention on oral fingolimod and iDMTs was evaluated in PREFER MS , a randomized, parallel-group, active-controlled, open-label, 48-week study. Patients were included if they had RRMS, were aged 18-65 years and had Expanded Disability Status Scale score up to 6, enrolled at 117 US study sites, were treatment naïve or had received only one iDMT class. Patients were randomized 1:1 (fingolimod 0.5 mg/day; preselected iDMT) by interactive voice-and-web-response system without blinding, followed up quarterly, and allowed one study-approved treatment switch after 12 weeks, or earlier for efficacy or safety reasons. The primary outcome was patient retention on randomized treatment over 48 weeks. Secondary endpoints included patient-reported outcomes, brain volume loss (BVL), and cognitive function. Analysis of 433/436 patients receiving fingolimod and 428/439 receiving iDMTs showed that patient retention rate was significantly higher with fingolimod than with iDMTs [352 (81.3%) versus 125 (29.2%); 95% confidence interval 46.4-57.8%; p < 0.0001]. The most common treatment switch was from iDMT to fingolimod for injection-related reasons. Patient satisfaction was greater and BVL less with fingolimod than with iDMTs, with no difference in cognitive function. Adverse events were consistent with established tolerability profiles for each treatment. In RRMS, fingolimod was associated with better treatment retention, patient satisfaction and BVL outcomes than iDMTs. Patients may persist with iDMTs, but many may switch treatment if permitted. Treatment satisfaction fosters adherence, a prerequisite for optimal outcomes.

Coformulated bictegravir, Emtricitabine (F), tenofovir alafenamide (TAF) after initial treatment with bictegravir or dolutegravir plus F/TAF.

PubMed

Sax, Paul E; Dejesus, Edwin; Crofoot, Gordon; Ward, Douglas; Benson, Paul; Dretler, Robin; Mills, Anthony; Brinson, Cynthia; Wei, Xuelian; Collins, Sean E; Cheng, Andrew

2018-05-22

: A phase 2, randomized, active-controlled study of initial antiretroviral therapy with bictegravir or dolutegravir in combination with emtricitabine and tenofovir alafenamide showed excellent efficacy. After 60 weeks of blinded treatment, participants switched to a single tablet regimen of bictegravir, emtricitabine and tenofovir alafenamide. Switching maintained viral suppression in all participants who chose to remain on the study through at least 12 weeks in the open-label phase, was safe and well tolerated.

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

NASA Astrophysics Data System (ADS)

Devulder, Wouter; Opsomer, Karl; Franquet, Alexis; Meersschaut, Johan; Belmonte, Attilio; Muller, Robert; De Schutter, Bob; Van Elshocht, Sven; Jurczak, Malgorzata; Goux, Ludovic; Detavernier, Christophe

2014-02-01

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 Cu0.6Te0.4 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/Cu0.6Te0.4-C/Al2O3/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 Al2O3 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 Al2O3 before and after annealing, showing a higher Cu, Te, and C migration for high carbon contents.

Changes in Liver Steatosis After Switching From Efavirenz to Raltegravir Among Human Immunodeficiency Virus-Infected Patients With Nonalcoholic Fatty Liver Disease.

PubMed

Macías, Juan; Mancebo, María; Merino, Dolores; Téllez, Francisco; Montes-Ramírez, M Luisa; Pulido, Federico; Rivero-Juárez, Antonio; Raffo, Miguel; Pérez-Pérez, Montserrat; Merchante, Nicolás; Cotarelo, Manuel; Pineda, Juan A

2017-09-15

Antiretroviral drugs with a lower potential to induce hepatic steatosis in human immunodeficiency virus (HIV) infection need to be identified. We compared the effect of switching efavirenz (EFV) to raltegravir (RAL) on hepatic steatosis among HIV-infected patients with nonalcoholic fatty liver disease (NAFLD) receiving EFV plus 2 nucleoside analogues. HIV-infected patients on EFV plus tenofovir/emtricitabine or abacavir/lamivudine with NAFLD were randomized 1:1 to switch from EFV to RAL (400 mg twice daily), maintaining nucleoside analogues unchanged, or to continue with EFV plus 2 nucleoside analogues. At baseline, eligible patients should show controlled attenuation parameter (CAP) values ≥238 dB/m. Changes in hepatic steatosis at 48 weeks of follow-up over baseline levels were measured by CAP. Overall, 39 patients were included, and 19 of them were randomized to switch to RAL. At week 48, median CAP for the RAL group was 250 (Q1-Q3, 221-277) dB/m and 286 (Q1-Q3, 269-314) dB/m for the EFV group (P = .035). The median decrease in CAP values was -20 (Q1-Q3, -67 to 15) dB/m for the RAL arm and 30 (Q1-Q3, -17 to 49) dB/m for the EFV group (P = .011). CAP values <238 dB/m at week 48 were observed in 9 (47%) patients on RAL and 3 (15%) individuals on EFV (P = .029). After 48 weeks, HIV-infected individuals switching EFV to RAL showed decreases in the degree of hepatic steatosis, as measured by CAP, compared with those continuing with EFV. In addition, the proportion of patients without significant hepatic steatosis after 48 weeks was greater for those who switched to RAL. NCT01900015. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

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

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.

Highly uniform resistive switching properties of amorphous InGaZnO thin films prepared by a low temperature photochemical solution deposition method.

PubMed

Hu, Wei; Zou, Lilan; Chen, Xinman; Qin, Ni; Li, Shuwei; Bao, Dinghua

2014-04-09

We report on highly uniform resistive switching properties of amorphous InGaZnO (a-IGZO) thin films. The thin films were fabricated by a low temperature photochemical solution deposition method, a simple process combining chemical solution deposition and ultraviolet (UV) irradiation treatment. The a-IGZO based resistive switching devices exhibit long retention, good endurance, uniform switching voltages, and stable distribution of low and high resistance states. Electrical conduction mechanisms were also discussed on the basis of the current-voltage characteristics and their temperature dependence. The excellent resistive switching properties can be attributed to the reduction of organic- and hydrogen-based elements and the formation of enhanced metal-oxide bonding and metal-hydroxide bonding networks by hydrogen bonding due to UV irradiation, based on Fourier-transform-infrared spectroscopy, X-ray photoelectron spectroscopy, and Field emission scanning electron microscopy analysis of the thin films. This study suggests that a-IGZO thin films have potential applications in resistive random access memory and the low temperature photochemical solution deposition method can find the opportunity for further achieving system on panel applications if the a-IGZO resistive switching cells were integrated with a-IGZO thin film transistors.

A randomized comparative trial of continued abacavir/lamivudine plus efavirenz or replacement with efavirenz/emtricitabine/tenofovir DF in hypercholesterolemic HIV-1 infected individuals.

PubMed

Moyle, Graeme J; Orkin, Chloe; Fisher, Martin; Dhar, Jyoti; Anderson, Jane; Wilkins, Edmund; Ewan, Jacqueline; Ebrahimi, Ramin; Wang, Hui

2015-01-01

Drug choice and metabolic changes with antiretroviral therapy contribute to cardiovascular risk in persons with HIV-1 infection. A randomized, 12 week, open-label, comparative study of the impact on lipids of continuation of abacavir/lamivudine (ABC/3TC) plus efavirenz (EFV) or replacement with the single tablet regimen of EFV/emtricitabine/tenofovir DF (EFV/FTC/TDF) in hypercholesterolaemic subjects on successful antiretroviral therapy, with a 12-week extension with all subjects on EFV/FTC/TDF. 157 subjects received study drug, 79 switched to EFV/FTC/TDF and 78 subjects continued ABC/3TC+EFV. At Week 12, 73 subjects on ABC/3TC+EFV switched to EFV/FTC/TDF. The switch was well tolerated and no subject experienced viral rebound. Median baseline fasting total cholesterol was 6.32 mmol/L. 12 weeks following switch, the difference in the means (LSM) between treatment groups (EFV/FTC/TDF minus ABC/3TC+EFV) in total cholesterol change from baseline was -0.74 mmol/l (95% CI -1.00, -0.47, p < 0.001). The median change from baseline in total cholesterol following switch in the EFV/FTC/TDF arm was -0.86 mmol/l (p < 0.001) compared with +0.01 mmol/l (p = 0.45) in the continuation arm at Week 12. Significant (p < 0.001) differences between treatment groups following switch were seen for all lipid fractions from baseline to Week 12: LDL cholesterol (-0.47 mmol/L [-0.70, -0.25]), HDL cholesterol (-0.15 mmol/L [-0.21, -0.08]), triglycerides (-0.43 mmol/L [-0.75, -0.11]), and non HDL cholesterol (-0.56 mmol/L [-0.80, -0.31]). In the extension phase, similar declines in total cholesterol were observed with a median change from Week 12 to Week 24 of -0.73 mmol/L (p < 0.001). Switching from ABC/3TC+EFV to EFV/FTC/TDF in persons with hypercholesterolemia maintains virological control and significantly improves key lipid parameters. ClinicalTrials.gov NCT00615810.

Adherence to Positive Airway Therapy After Switching From CPAP to ASV: A Big Data Analysis.

PubMed

Pépin, Jean-Louis D; Woehrle, Holger; Liu, Dongquan; Shao, Shiyun; Armitstead, Jeff P; Cistulli, Peter A; Benjafield, Adam V; Malhotra, Atul

2018-01-15

There is a lack of data regarding adherence trajectories when switching from continuous positive airway pressure (CPAP) to adaptive servoventilation (ASV) in the context of persistent or treatment-emergent central sleep apnea (CSA). This study investigated 90-day adherence rates in patients with sleep apnea based on the type of positive airway pressure (PAP) device used and any switching of PAP modality over time. Telemonitoring data were obtained from a United States PAP database. Eligible patients were a 30% random sample who started PAP, plus all who started ASV, from January 1, 2015 to October 2, 2015. All received PAP and had at least one session with usage of 1 hour or more. Adherence and device usage were determined in three groups: started on CPAP and stayed on CPAP (CPAP only); started on ASV and stayed on ASV (ASV only); started on CPAP, switched to ASV (Switch). The United States Medicare definition of adherence was used. The study included 198,890 patients; 189,724 (CPAP only), 8,957 (ASV only) and 209 (Switch). In the Switch group, average apnea-hypopnea index decreased significantly on ASV versus CPAP. At 90 days, adherence rates were 73.8% and 73.2% in the CPAP only and ASV only groups. In the Switch group, CPAP adherence was 62.7%, improving to 76.6% after the switch to ASV. Mean device usage at 90 days was 5.27, 5.31, and 5.73 h/d in the CPAP only, ASV only, and Switch groups, respectively. Treatment-emergent or persistent CSA during CPAP reduced therapy adherence, but adherence improved early after switching from CPAP to ASV. © 2018 American Academy of Sleep Medicine

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, 1.04-1.23]). No significant treatment differences were observed for relapse. Anxiety was more frequent in the 2 bupropion groups (24.3% in the switch group [n = 124] vs 16.6% in the augment-aripiprazole group [n = 84]; and 22.5% in augment-bupropion group [n = 114]). Adverse effects more frequent in the augment-aripiprazole group included somnolence, akathisia, and weight gain. Among a predominantly male population with major depressive disorder unresponsive to antidepressant treatment, augmentation with aripiprazole resulted in a statistically significant but only modestly increased likelihood of remission during 12 weeks of treatment compared with switching to bupropion monotherapy. Given the small effect size and adverse effects associated with aripiprazole, further analysis including cost-effectiveness is needed to understand the net utility of this approach. clinicaltrials.gov Identifier: NCT01421342.

Mediating Parent Learning to Promote Social Communication for Toddlers with Autism: Effects from a Randomized Controlled Trial

ERIC Educational Resources Information Center

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

2018-01-01

A randomized controlled trial was conducted to evaluate effects of the Joint Attention Mediated Learning (JAML) intervention. Toddlers with autism spectrum disorders (ASD) aged 16-30 months (n = 144) were randomized to intervention and community control conditions. Parents, who participated in 32 weekly home-based sessions, followed a mediated…

The effect of transcutaneous application of carbon dioxide (CO{sub 2}) on skeletal muscle

DOE Office of Scientific and Technical Information (OSTI.GOV)

Oe, Keisuke; Ueha, Takeshi; Sakai, Yoshitada, E-mail: sakai.yoshitada@gm.himeji-du.ac.jp

2011-04-01

Highlights: {yields} PGC-1{alpha} is up-regulated as a result of exercise such as mitochondrial biogenesis and muscle fiber-type switching, and up-regulation of VEGF. {yields} We demonstrated transcutaneous application of CO{sub 2} up-regulated the gene expression of PGC-1{alpha}, SIRT1 and VEGF, and instance of muscle fiber switching. {yields} Transcutaneous application of CO{sub 2} may cause similar effect to aerobic exercise in skeletal muscle. -- Abstract: In Europe, carbon dioxide therapy has been used for cardiac disease and skin problems for a long time. However there have been few reports investigating the effects of carbon dioxide therapy on skeletal muscle. Peroxisome proliferators-activated receptormore » (PPAR)-gamma coactivator-1 (PGC-1{alpha}) is up-regulated as a result of exercise and mediates known responses to exercise, such as mitochondrial biogenesis and muscle fiber-type switching, and neovascularization via up-regulation of vascular endothelial growth factor (VEGF). It is also known that silent mating type information regulation 2 homologs 1 (SIRT1) enhances PGC-1{alpha}-mediated muscle fiber-type switching. Previously, we demonstrated transcutaneous application of CO{sub 2} increased blood flow and a partial increase of O{sub 2} pressure in the local tissue known as the Bohr effect. In this study, we transcutaneously applied CO{sub 2} to the lower limbs of rats, and investigated the effect on the fast muscle, tibialis anterior (TA) muscle. The transcutaneous CO{sub 2} application caused: (1) the gene expression of PGC-1{alpha}, silent mating type information regulation 2 homologs 1 (SIRT1) and VEGF, and increased the number of mitochondria, as proven by real-time PCR and immunohistochemistry, (2) muscle fiber switching in the TA muscle, as proven by isolation of myosin heavy chain and ATPase staining. Our results suggest the transcutaneous application of CO{sub 2} may have therapeutic potential for muscular strength recovery resulting from disuse atrophy in post-operative patients and the elderly population.« less

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.

Markov and semi-Markov switching linear mixed models used to identify forest tree growth components.

PubMed

Chaubert-Pereira, Florence; Guédon, Yann; Lavergne, Christian; Trottier, Catherine

2010-09-01

Tree growth is assumed to be mainly the result of three components: (i) an endogenous component assumed to be structured as a succession of roughly stationary phases separated by marked change points that are asynchronous among individuals, (ii) a time-varying environmental component assumed to take the form of synchronous fluctuations among individuals, and (iii) an individual component corresponding mainly to the local environment of each tree. To identify and characterize these three components, we propose to use semi-Markov switching linear mixed models, i.e., models that combine linear mixed models in a semi-Markovian manner. The underlying semi-Markov chain represents the succession of growth phases and their lengths (endogenous component) whereas the linear mixed models attached to each state of the underlying semi-Markov chain represent-in the corresponding growth phase-both the influence of time-varying climatic covariates (environmental component) as fixed effects, and interindividual heterogeneity (individual component) as random effects. In this article, we address the estimation of Markov and semi-Markov switching linear mixed models in a general framework. We propose a Monte Carlo expectation-maximization like algorithm whose iterations decompose into three steps: (i) sampling of state sequences given random effects, (ii) prediction of random effects given state sequences, and (iii) maximization. The proposed statistical modeling approach is illustrated by the analysis of successive annual shoots along Corsican pine trunks influenced by climatic covariates. © 2009, The International Biometric Society.

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 option for ritonavir-boosted PIs when partnered with a 2-N(t)RTI backbone, but not as part of N(t)RTI-sparing regimens comprising MVC with PI/r. NCT01384682. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Inhibition of Poliovirus-Induced Cleavage of Cellular Protein PCBP2 Reduces the Levels of Viral RNA Replication

PubMed Central

Chase, Amanda J.; Daijogo, Sarah

2014-01-01

ABSTRACT Due to their small genome size, picornaviruses must utilize host proteins to mediate cap-independent translation and viral RNA replication. The host RNA-binding protein poly(rC) binding protein 2 (PCBP2) is involved in both processes in poliovirus infected cells. It has been shown that the viral proteinase 3CD cleaves PCBP2 and contributes to viral translation inhibition. However, cleaved PCBP2 remains active in viral RNA replication. This would suggest that both cleaved and intact forms of PCBP2 have a role in the viral RNA replication cycle. The picornavirus genome must act as a template for both translation and RNA replication. However, a template that is actively being translated cannot function as a template for RNA replication, suggesting that there is a switch in template usage from translation to RNA replication. We demonstrate that the cleavage of PCBP2 by the poliovirus 3CD proteinase is a necessary step for efficient viral RNA replication and, as such, may be important for mediating a switch in template usage from translation to RNA replication. IMPORTANCE Poliovirus, like all positive-strand RNA viruses that replicate in the cytoplasm of eukaryotic cells, uses its genomic RNA as a template for both viral protein synthesis and RNA replication. Given that these processes cannot occur simultaneously on the same template, poliovirus has evolved a mechanism(s) to facilitate the switch from using templates for translation to using them for RNA synthesis. This study explores one possible scenario for how the virus alters the functions of a host cell RNA binding protein to mediate, in part, this important transition. PMID:24371074

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

Phenobarbital mediates an epigenetic switch at the constitutive androstane receptor (CAR) target gene Cyp2b10 in the liver of B6C3F1 mice.

PubMed

Lempiäinen, Harri; Müller, Arne; 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

2011-03-24

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.

Quantum random access memory.

PubMed

Giovannetti, Vittorio; Lloyd, Seth; Maccone, Lorenzo

2008-04-25

A random access memory (RAM) uses n bits to randomly address N=2(n) distinct memory cells. A quantum random access memory (QRAM) uses n qubits to address any quantum superposition of N memory cells. We present an architecture that exponentially reduces the requirements for a memory call: O(logN) switches need be thrown instead of the N used in conventional (classical or quantum) RAM designs. This yields a more robust QRAM algorithm, as it in general requires entanglement among exponentially less gates, and leads to an exponential decrease in the power needed for addressing. A quantum optical implementation is presented.

Switching from usual brand cigarettes to a tobacco-heating cigarette or snus: Part 2. Biomarkers of exposure

PubMed Central

Ogden, Michael W.; Marano, Kristin M.; Jones, Bobbette A.; Morgan, Walter T.; Stiles, Mitchell F.

2015-01-01

Abstract A randomized, multi-center study of adult cigarette smokers switched to tobacco-heating cigarettes, snus or ultra-low machine yield tobacco-burning cigarettes (50/group) was conducted, and subjects’ experience with the products was followed for 24 weeks. Differences in biomarkers of tobacco exposure between smokers and never smokers at baseline and among groups relative to each other and over time were assessed. Results indicated reduced exposure to many potentially harmful constituents found in cigarette smoke following product switching. Findings support differences in exposure from the use of various tobacco products and are relevant to the understanding of a risk continuum among tobacco products (ClinicalTrials.gov Identifier: NCT02061917). PMID:26554277

Magnetic domain wall engineering in a nanoscale permalloy junction

NASA Astrophysics Data System (ADS)

Wang, Junlin; Zhang, Xichao; Lu, Xianyang; Zhang, Jason; Yan, Yu; Ling, Hua; Wu, Jing; Zhou, Yan; Xu, Yongbing

2017-08-01

Nanoscale magnetic junctions provide a useful approach to act as building blocks for magnetoresistive random access memories (MRAM), where one of the key issues is to control the magnetic domain configuration. Here, we study the domain structure and the magnetic switching in the Permalloy (Fe20Ni80) nanoscale magnetic junctions with different thicknesses by using micromagnetic simulations. It is found that both the 90-° and 45-° domain walls can be formed between the junctions and the wire arms depending on the thickness of the device. The magnetic switching fields show distinct thickness dependencies with a broad peak varying from 7 nm to 22 nm depending on the junction sizes, and the large magnetic switching fields favor the stability of the MRAM operation.

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…

Reversible susceptibility studies of magnetization switching in FeCoB synthetic antiferromagnets

NASA Astrophysics Data System (ADS)

Radu, Cosmin; Cimpoesu, Dorin; Girt, Erol; Ju, Ganping; Stancu, Alexandru; Spinu, Leonard

2007-05-01

In this paper we present a study of switching characteristics of a series of synthetic antiferromagnet (SAF) structures using reversible susceptibility experiments. Three series of SAF samples were considered in our study with (t1, t2), the thickness of the FeCoB layers of (80nm, 80nm), (50nm, 50nm), and (80nm, 20nm) and with the interlayer of Ru ranging from 0to2nm. A vector vibrating sample magnetometer was used to measure the hysteresis loops along the different directions in the plane of the samples. The reversible susceptibility experiments were performed using a resonant method based on a tunnel diode oscillator. We showed that the switching peaks in the susceptibility versus field plots obtained for different orientations of the applied dc field can be used to construct the switching diagram of the SAF structure. The critical curve constitutes the fingerprint of the switching behavior and provides information about micromagnetic and structural properties of SAF which is an essential component of modern magnetic random access memories.

Enhancement of switching stability of tunneling magnetoresistance system with artificial ferrimagnet

NASA Astrophysics Data System (ADS)

You, Chun-Yeol; Bader, Sam. D.; Scheinfein, M. R.

2002-03-01

In the study of spin dependent magnetic tunneling junctions, the switching stability of the magnetically hard layer is a crucial issue in magnetic random access memory applications[1]. After repeated cycling of the soft layer, the magnetization of the hard layer is demagnetized by the stray field from the domain wall created during the switching[2]. The magnitude of the stray field from the soft layer is large enough to switch a domain in the hard layer. Therefore, reducing this stray field is necessary to increase the switching stability. In this study, we explore an artificial ferrimagnet to replace the usual soft layer in order to reduce stray field. The ferrimagnet consists of an antiferromagnetically coupled trilayer that has two ferromagnetic layers of unequal thickness and opposite magnetization orientation. Since the sign of stray field of the two ferromagnetic layers is opposed, the total stray field is greatly reduced. [Supported by the US DOE, BES-MS, under Contract W-31-109-ENG-38.] [1] S. Gider et al. Science 281, 797 (1998). [2] L. Thomas et al. Phys. Rev. Lett. 84, 1816 (2000).

Resistive switching characteristics of HfO2-based memory devices on flexible plastics.

PubMed

Han, Yong; Cho, Kyoungah; Park, Sukhyung; Kim, Sangsig

2014-11-01

In this study, we examine the characteristics of HfO2-based resistive switching random access memory (ReRAM) devices on flexible plastics. The Pt/HfO2/Au ReRAM devices exhibit the unipolar resistive switching behaviors caused by the conducting filaments. From the Auger depth profiles of the HfO2 thin film, it is confirmed that the relatively lower oxygen content in the interface of the bottom electrode is responsible for the resistive switching by oxygen vacancies. And the unipolar resistive switching behaviors are analyzed from the C-V characteristics in which negative and positive capacitances are measured in the low-resistance state and the high-resistance state, respectively. The devices have a high on/off ratio of 10(4) and the excellent retention properties even after a continuous bending test of two thousand cycles. The correlation between the device size and the memory characteristics is investigated as well. A relatively smaller-sized device having a higher on/off ratio operates at a higher voltage than a relatively larger-sized device.

Resistive Switching of Ta2O5-Based Self-Rectifying Vertical-Type Resistive Switching Memory

NASA Astrophysics Data System (ADS)

Ryu, Sungyeon; Kim, Seong Keun; Choi, Byung Joon

2018-01-01

To efficiently increase the capacity of resistive switching random-access memory (RRAM) while maintaining the same area, a vertical structure similar to a vertical NAND flash structure is needed. In addition, the sneak-path current through the half-selected neighboring memory cell should be mitigated by integrating a selector device with each RRAM cell. In this study, an integrated vertical-type RRAM cell and selector device was fabricated and characterized. Ta2O5 as the switching layer and TaOxNy as the selector layer were used to preliminarily study the feasibility of such an integrated device. To make the side contact of the bottom electrode with active layers, a thick Al2O3 insulating layer was placed between the Pt bottom electrode and the Ta2O5/TaOxNy stacks. Resistive switching phenomena were observed under relatively low currents (below 10 μA) in this vertical-type RRAM device. The TaOxNy layer acted as a nonlinear resistor with moderate nonlinearity. Its low-resistance-state and high-resistance-state were well retained up to 1000 s.

Conduction Channel Formation and Dissolution Due to Oxygen Thermophoresis/Diffusion in Hafnium Oxide Memristors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kumar, Suhas; Wang, Ziwen; Huang, Xiaopeng

Due to the favorable operating power, endurance, speed, and density., transition-metal-oxide memristors, or resistive random-access memory (RRAM) switches, are under intense development for storage-class memory. Their commercial deployment critically depends on predictive compact models based on understanding nanoscale physiocochemical forces, which remains elusive and controversial owing to the difficulties in directly observing atomic motions during resistive switching, Here, using scanning transmission synchrotron X-ray spectromicroscopy to study in situ switching of hafnium oxide memristors, we directly observed the formation of a localized oxygen-deficiency-derived conductive channel surrounded by a low-conductivity ring of excess oxygen. Subsequent thermal annealing homogenized the segregated oxygen, resettingmore » the cells toward their as-grown resistance state. We show that the formation and dissolution of the conduction channel are successfully modeled by radial thermophoresis and Fick diffusion of oxygen atoms driven by Joule heating. This confirmation and quantification of two opposing nanoscale radial forces that affect bipolar memristor switching are important components for any future physics-based compact model for the electronic switching of these devices.« less

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

Soft and Hard Tissue Changes around Tissue-Oriented Tulip-Design Implant Abutments: A 1-Year Randomized Prospective Clinical Trial.

PubMed

Gutmacher, Zvi; Levi, Guy; Blumenfeld, Israel; Machtei, Eli E

2015-10-01

The advantages of platform switching using narrower abutments remain controversial. Many researchers suggest that platform switching can yield enhanced clinical results, while others remain skeptical. We hypothesize that the effectiveness of platform switching might be associated with the degree of reduction in size of the abutment. To radiographically and clinically examine a new abutment design created to move the implant-abutment interface farther medially. This was a prospective, randomized controlled clinical trial that included 27 patients (41 MIS Lance Plus® implants; MIS Implant Technologies, Karmiel, Israel). The patients' age ranged from 39 to 75 years. At the second stage of the surgery, the implants were randomly assigned to either the new platform switch Tulip abutment (TA) design or to the standard platform abutment (SA). Implant probing depth (IPD) and bleeding on probing (BOP) were recorded at baseline and after 12 months. Standardized periapical radiographs were taken (at baseline and at 12 months) and the marginal bone height measured. All implants were successfully integrated. The mean IPD at 1 year post-op was 2.91 mm for the SA group and 2.69 mm for the TA group (p > .05). Similarly, the BOP at 1 year was almost identical in both groups. The mean values of bone resorption at baseline were 0.98 ± 0.37 mm and 0.69 ± 0.20 for the TA and SA groups, respectively (p > .05). Bone loss (baseline to 12 months) was significantly greater in the SA group compared with the TA group. Use of the new TA, with its significantly downsized diameter, resulted in reduced bone loss at 1 year. Further research will be required to assess the long-term effect of this abutment on peri-implant health. © 2014 Wiley Periodicals, Inc.

Efficacy and safety of emtricitabine/tenofovir alafenamide (FTC/TAF) vs. emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) as a backbone for treatment of HIV-1 infection in virologically suppressed adults: subgroup analysis by third agent of a randomized, double-blind, active-controlled phase 3 trial^.

PubMed

Post, Frank A; Yazdanpanah, Yazdan; Schembri, Gabriel; Lazzarin, Adriano; Reynes, Jacques; Maggiolo, Franco; Yan, Mingjin; Abram, Michael E; Tran-Muchowski, Cecilia; Cheng, Andrew; Rhee, Martin S

2017-05-01

FTC/TAF was shown to be noninferior to FTC/TDF with advantages in markers of renal and bone safety. To evaluate the efficacy and safety of switching to FTC/TAF from FTC/TDF by third agent (boosted protease inhibitor [PI] vs. unboosted third agent). We conducted a 48-week subgroup analysis based on third agent from a randomized, double blind study in virologically suppressed adults on a FTC/TDF-containing regimen who switched to FTC/TAF vs. continued FTC/TDF while remaining on the same third agent. We randomized (1:1) 663 participants to either switch to FTC/TAF (N = 333) or continue FTC/TDF (N = 330), each with baseline third agent stratifying by class of third agent in the prior treatment regimen (boosted PI 46%, unboosted third agent 54%). At week 48, significant differences in renal biomarkers and bone mineral density were observed favoring FTC/TAF over FTC/TDF (p < 0.05 for all), with similar improvements in the FTC/TAF arm in those who received boosted PI vs. unboosted third agents. At week 48, virologic success rates were similar between treatment groups for those who received a boosted PI (FTC/TAF 92%, FTC/TDF 93%) and for those who received an unboosted third agent (97% vs. 93%). In virologically suppressed patients switching to FTC/TAF from FTC/TDF, high rates of virologic suppression were maintained, while renal and bone safety parameters improved, regardless of whether participants were receiving a boosted PI or an unboosted third agent. FTC/TAF offers safety advantages over FTC/TDF and can be an important option as an NRTI backbone given with a variety of third agents.

Failure and recovery in dynamical networks.

PubMed

Böttcher, L; Luković, M; Nagler, J; Havlin, S; Herrmann, H J

2017-02-03

Failure, damage spread and recovery crucially underlie many spatially embedded networked systems ranging from transportation structures to the human body. Here we study the interplay between spontaneous damage, induced failure and recovery in both embedded and non-embedded networks. In our model the network's components follow three realistic processes that capture these features: (i) spontaneous failure of a component independent of the neighborhood (internal failure), (ii) failure induced by failed neighboring nodes (external failure) and (iii) spontaneous recovery of a component. We identify a metastable domain in the global network phase diagram spanned by the model's control parameters where dramatic hysteresis effects and random switching between two coexisting states are observed. This dynamics depends on the characteristic link length of the embedded system. For the Euclidean lattice in particular, hysteresis and switching only occur in an extremely narrow region of the parameter space compared to random networks. We develop a unifying theory which links the dynamics of our model to contact processes. Our unifying framework may help to better understand controllability in spatially embedded and random networks where spontaneous recovery of components can mitigate spontaneous failure and damage spread in dynamical networks.

Motivational intensity modulates the effects of positive emotions on set shifting after controlling physiological arousal.

PubMed

Zhou, Ya; Siu, Angela F Y

2015-12-01

Recent research on the construct of emotion suggests the integration of a motivational dimension into the traditional two-dimension (subjective valence and physiological arousal) model. The motivational intensity of an emotional state should be taken into account while investigating the emotion-cognition relationship. This study examined how positive emotional states varying in motivational intensity influenced set shifting, after controlling the potential confounding impacts of physiological arousal. In Experiment 1, 155 volunteers performed a set-shifting task after being randomly assigned to five states: high- vs. low-motivating positive affect (interest vs. serenity), high- vs. low-motivating negative affect (disgust vs. anxiety), and neutral state. Eighty-five volunteers participated in Experiment 2, which further examined the effects of higher vs. lower degree of interest. Both experiments measured and compared participants' physiological arousal (blood pressure and pulse rate) under the normal and experimental conditions as the covariate. Results showed no difference in switching performance between the neutral and serenity groups. As compared with the neutral state, the high-motivating positive affect significantly increased set-switching reaction time costs, but reduced error rate costs; the higher the motivational intensity, the greater the time-costs impairment. This indicates a role of the high-motivating positive affect in regulating the balance between the flexible and stable cognitive control. Motivational intensity also modulated the effects of negative emotional states, i.e., disgust caused a larger increase in time costs than anxiety. Further exploration into neurobiological mechanisms that may mediate the emotional effects on set shifting is warranted. © 2015 Scandinavian Psychological Associations and John Wiley & Sons Ltd.

Determinants of Method Switching among Social Franchise Clients Who Discontinued the Use of Intrauterine Contraceptive Device

PubMed Central

Hameed, Waqas; Ali, Moazzam; Hussain, Wajahat; Mustafa, Ghulam; Ishaque, Muhammad; Ali, Safdar; Ahmed, Aftab; Temmerman, Marleen

2015-01-01

Introduction. Women who do not switch to alternate methods after contraceptive discontinuation, for reasons other than the desire to get pregnant or not needing it, are at obvious risk for unplanned pregnancies or unwanted births. This paper examines the factors that influence women to switch from Intrauterine Contraceptive Device (IUCD) to other methods instead of terminating contraceptive usage altogether. Methods. The data used for this study comes from a larger cross-sectional survey conducted in nine (9) randomly selected districts of Sindh and Punjab provinces of Pakistan, during January 2011. Using Stata 11.2, we analyzed data on 333 women, who reported the removal of IUCDs due to reasons other than the desire to get pregnant. Results. We found that 39.9% of the women do not switch to another method of contraception within one month after IUCD discontinuation. Use of contraception before IUCD insertion increases the odds for method switching by 2.26 times after removal. Similarly, postremoval follow-up by community health worker doubles (OR = 2.0) the chances of method switching. Compared with women who received free IUCD service (via voucher scheme), the method switching is 2.01 times higher among women who had paid for IUCD insertion. Conclusion. To increase the likelihood of method switching among IUCD discontinuers this study emphasizes the need for postremoval client counseling, follow-up by healthcare provider, improved choices to a wider range of contraceptives for poor clients, and user satisfaction. PMID:26576454

Determinants of Method Switching among Social Franchise Clients Who Discontinued the Use of Intrauterine Contraceptive Device.

PubMed

Hameed, Waqas; Azmat, Syed Khurram; Ali, Moazzam; Hussain, Wajahat; Mustafa, Ghulam; Ishaque, Muhammad; Ali, Safdar; Ahmed, Aftab; Temmerman, Marleen

2015-01-01

Introduction. Women who do not switch to alternate methods after contraceptive discontinuation, for reasons other than the desire to get pregnant or not needing it, are at obvious risk for unplanned pregnancies or unwanted births. This paper examines the factors that influence women to switch from Intrauterine Contraceptive Device (IUCD) to other methods instead of terminating contraceptive usage altogether. Methods. The data used for this study comes from a larger cross-sectional survey conducted in nine (9) randomly selected districts of Sindh and Punjab provinces of Pakistan, during January 2011. Using Stata 11.2, we analyzed data on 333 women, who reported the removal of IUCDs due to reasons other than the desire to get pregnant. Results. We found that 39.9% of the women do not switch to another method of contraception within one month after IUCD discontinuation. Use of contraception before IUCD insertion increases the odds for method switching by 2.26 times after removal. Similarly, postremoval follow-up by community health worker doubles (OR = 2.0) the chances of method switching. Compared with women who received free IUCD service (via voucher scheme), the method switching is 2.01 times higher among women who had paid for IUCD insertion. Conclusion. To increase the likelihood of method switching among IUCD discontinuers this study emphasizes the need for postremoval client counseling, follow-up by healthcare provider, improved choices to a wider range of contraceptives for poor clients, and user satisfaction.

The Monty Hall dilemma in pigeons: effect of investment in initial choice.

PubMed

Stagner, Jessica P; Rayburn-Reeves, Rebecca; Zentall, Thomas R

2013-10-01

In the Monty Hall dilemma, humans are initially given a choice among three alternatives, one of which has a hidden prize. After choosing, but before it is revealed whether they have won the prize, they are shown that one of the remaining alternatives does not have the prize. They are then asked whether they want to stay with their original choice or switch to the remaining alternative. Although switching results in obtaining the prize two thirds of the time, humans consistently fail to adopt the optimal strategy of switching even after considerable training. Interestingly, there is evidence that pigeons show more optimal switching performance with this task than humans. Because humans often view even random choices already made as being more valuable than choices not made, we reasoned that if pigeons made a greater investment, it might produce an endowment or ownership effect resulting in more human-like suboptimal performance. On the other hand, the greater investment in the initial choice by the pigeons might facilitate switching behavior by helping them to better discriminate their staying versus switching behavior. In Experiment 1, we examined the effect of requiring pigeons to make a greater investment in their initial choice (20 pecks rather than the usual 1 peck). We found that the increased response requirement facilitated acquisition of the switching response. In Experiment 2, we showed that facilitation of switching due to the increased response requirement did not result from extinction of responding to the initially chosen location.

Fabry disease under enzyme replacement therapy-new insights in efficacy of different dosages.

PubMed

Krämer, Johannes; Lenders, Malte; Canaan-Kühl, Sima; Nordbeck, Peter; Üçeyler, Nurcan; Blaschke, Daniela; Duning, Thomas; Reiermann, Stefanie; Stypmann, Jörg; Brand, Stefan-Martin; Gottschling, Timo; Störk, Stefan; Wanner, Christoph; Sommer, Claudia; Brand, Eva; Weidemann, Frank

2017-11-23

Fabry patients on reduced dose of agalsidase-beta or after switch to agalsidase-alfa show a decline in estimated glomerular filtration rate (eGFR) and an increase of the Mainz Severity Score Index. In this prospective observational study, we assessed end-organ damage and clinical symptoms in 112 patients who had received agalsidase-beta (1.0 mg/kg) for >1 year, who were (i) non-randomly assigned to continue this treatment regime (regular-dose group, n = 37); (ii) received a reduced dose of agalsidase-beta and subsequent switch to agalsidase-alfa (0.2 mg/kg) or a direct switch to 0.2 mg/kg agalsidase-alfa (switch group, n = 38); or (iii) were re-switched to agalsidase-beta after receiving agalsidase-alfa for at least 12 months (re-switch group, n = 37) with a median follow-up of 53 (38-57) months. eGFR of patients in the regular-dose group remained stable. Patients in the switch group showed an annual eGFR loss of - 4.6  ±  9.1 mL/min/1.73 m2 (P < 0.05). Patients in the re-switch group also had an eGFR loss of - 2.2  ±  4.4 mL/min/1.73 m2 after re-switch to agalsidase-beta, but to a lower degree compared with the switch group (P < 0.05). Patients in the re-switch group suffered less frequently from diarrhoea (relative risk 0.42; 95% confidence interval 0.19-0.93; P = 0.02). Lyso-Gb3 remained stable in the switch (P = 0.97) and the regular-dose (P = 0.48) groups, but decreased in the re-switch group after change of the therapy regimen (P < 0.05). After switch to agalsidase-alfa, Fabry patients experienced a continuous decline in eGFR, while this decline was attenuated in patients who were re-switched to agalsidase-beta. Decreasing lyso-Gb3 levels may indicate a better treatment response in the latter group. © The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Reversible switching of fluorophore property based on intrinsic conformational transition of adenylate kinase during its catalytic cycle.

PubMed

Fujii, Akira; Hirota, Shun; Matsuo, Takashi

2013-07-17

Adenylate kinase shows a conformational transition (OPEN and CLOSED forms) during substrate binding and product release to mediate the phosphoryl transfer between ADP and ATP/AMP. The protein motional characteristics will be useful to construct switching systems of fluorophore properties caused by the catalytic cycle of the enzyme. This paper demonstrates in situ reversible switching of a fluorophore property driven by the conformational transition of the enzyme. The pyrene-conjugated mutant adenylate kinase is able to switch the monomer/excimer emission property of pyrene on addition of ADP or P(1)P(5)-di(adenosine-5')pentaphosphate (Ap5A, a transition state analog). The observation under the dilute condition (~0.1 μM) indicates that the emission spectral change was caused by the motion of a protein molecule and not led by protein-protein interactions through π-π stacking of pyrene rings. The switching can be reversibly conducted by using hexokinase-coupling reaction. The fashion of the changes in emission intensities at various ligand concentrations is different between ADP, Mg(2+)-bound ADP, and Mg(2+)-bound Ap5A. The emission property switching is repeatable by a sequential addition of a substrate in a one-pot process. It is proposed that the property of a synthetic molecule on the enzyme surface is switchable in response to the catalytic cycle of adenylate kinase.

Abacus Training Affects Math and Task Switching Abilities and Modulates Their Relationships in Chinese Children

PubMed Central

Yao, Yuan; Weng, Jian; Hu, Yuzheng; Chen, Feiyan

2015-01-01

Our previous work demonstrated that abacus-based mental calculation (AMC), a traditional Chinese calculation method, could help children improve their math abilities (e.g. basic arithmetical ability) and executive function (e.g. working memory). This study further examined the effects of long-term AMC training on math ability in visual-spatial domain and the task switching component of executive function. More importantly, this study investigated whether AMC training modulated the relationship between math abilities and task switching. The participants were seventy 7-year-old children who were randomly assigned into AMC and control groups at primary school entry. Children in AMC group received 2-hour AMC training every week since primary school entry. On the contrary, children in the control group had never received any AMC training. Math and task switching abilities were measured one year and three years respectively after AMC training began. The results showed that AMC children performed better than their peers on math abilities in arithmetical and visual-spatial domains. In addition, AMC group responded faster than control group in the switching task, while no group difference was found in switch cost. Most interestingly, group difference was present in the relationships between math abilities and switch cost. These results implied the effect of AMC training on math abilities as well as its relationship with executive function. PMID:26444689

Abacus Training Affects Math and Task Switching Abilities and Modulates Their Relationships in Chinese Children.

PubMed

Wang, Chunjie; Geng, Fengji; Yao, Yuan; Weng, Jian; Hu, Yuzheng; Chen, Feiyan

2015-01-01

Our previous work demonstrated that abacus-based mental calculation (AMC), a traditional Chinese calculation method, could help children improve their math abilities (e.g. basic arithmetical ability) and executive function (e.g. working memory). This study further examined the effects of long-term AMC training on math ability in visual-spatial domain and the task switching component of executive function. More importantly, this study investigated whether AMC training modulated the relationship between math abilities and task switching. The participants were seventy 7-year-old children who were randomly assigned into AMC and control groups at primary school entry. Children in AMC group received 2-hour AMC training every week since primary school entry. On the contrary, children in the control group had never received any AMC training. Math and task switching abilities were measured one year and three years respectively after AMC training began. The results showed that AMC children performed better than their peers on math abilities in arithmetical and visual-spatial domains. In addition, AMC group responded faster than control group in the switching task, while no group difference was found in switch cost. Most interestingly, group difference was present in the relationships between math abilities and switch cost. These results implied the effect of AMC training on math abilities as well as its relationship with executive function.

Effectiveness of Parent-Child Mediation in Improving Family Functioning and Reducing Adolescent Problem Behavior: Results from a Pilot Randomized Controlled Trial.

PubMed

Tucker, Joan S; Edelen, Maria Orlando; Huang, Wenjing

2017-03-01

Parent-child mediation programs are intended to resolve or manage disputes and improve family functioning, but rigorous evaluations of their effectiveness are lacking. Families referred to a community-based mediation program (N = 111) were randomized to an intervention or wait-list control group, and completed three surveys over a 12-week period. With the exception of parent-reported child delinquency (which decreased more in the intervention group), this evaluation provides little support for the short-term effectiveness of parent-child mediation for improving family functioning and reducing child problem behaviors in general. Given that this is the first randomized controlled trial of a parent-child mediation program, additional evaluations involving larger samples and longer follow-ups are needed before firm conclusions can be drawn about the effectiveness of this intervention.

Effectiveness of Parent-Child Mediation in Improving Family Functioning and Reducing Adolescent Problem Behavior: Results from a Pilot Randomized Controlled Trial

PubMed Central

Tucker, Joan S.; Edelen, Maria Orlando; Huang, Wenjing

2016-01-01

Parent-child mediation programs are intended to resolve or manage disputes and improve family functioning, but rigorous evaluations of their effectiveness are lacking. Families referred to a community-based mediation program (N=111) were randomized to an intervention or wait-list control group, and completed three surveys over a 12-week period. With the exception of parent-reported child delinquency (which decreased more in the intervention group), this evaluation provides little support for the short-term effectiveness of parent-child mediation for improving family functioning and reducing child problem behaviors in general. Given that this is the first randomized controlled trial of a parent-child mediation program, additional evaluations involving larger samples and longer follow-ups are needed before firm conclusions can be drawn about the effectiveness of this intervention. PMID:26762375

Hypoxic Switch in Mitochondrial Myeloid Cell Leukemia Factor-1/Mtd Apoptotic Rheostat Contributes to Human Trophoblast Cell Death in Preeclampsia

PubMed Central

Soleymanlou, Nima; Jurisicova, Andrea; Wu, Yuanhong; Chijiiwa, Mari; Ray, Jocelyn E.; Detmar, Jacqui; Todros, Tullia; Zamudio, Stacy; Post, Martin; Caniggia, Isabella

2007-01-01

Preeclampsia, a disorder of pregnancy, is characterized by increased trophoblast cell death and altered trophoblast-mediated remodeling of myometrial spiral arteries resulting in reduced uteroplacental perfusion. Mitochondria-associated Bcl-2 family members are important regulators of programed cell death. The mechanism whereby hypoxia alters the mitochondrial apoptotic rheostat is essential to our understanding of placental disease. Herein, myeloid cell leukemia factor-1 (Mcl-1) isoform expression was examined in physiological/pathological models of placental hypoxia. Preeclamptic placentae were characterized by caspase-dependent cleavage of death-suppressing Mcl-1L and switch toward cell death-inducing Mcl-1S. In vitro, Mcl-1L cleavage was induced by hypoxia-reoxygenation in villous explants, whereas Mcl-1L overexpression under hypoxia-reoxygenation rescued trophoblast cells from undergoing apoptosis. Cleavage was mediated by caspase-3/-7 because pharmacological caspase inhibition prevented this process. Altitude-induced chronic hypoxia was characterized by expression of Mcl-1L; resulting in a reduction of apoptotic markers (cleaved caspase-3/-8 and p85 poly-ADP-ribose polymerase). Moreover, in both physiological (explants and high altitude) and pathological (preeclampsia) placental hypoxia, decreased trophoblast syncytin expression was observed. Hence, although both pathological and physiological placental hypoxia are associated with slowed trophoblast differentiation, trophoblast apoptosis is only up-regulated in preeclampsia, because of a hypoxia-reoxygenation-induced switch in generation of proapoptotic Mcl-1 isoforms. PMID:17600131

Inorganic Nitrate Mimics Exercise-Stimulated Muscular Fiber-Type Switching and Myokine and γ-Aminobutyric Acid Release.

PubMed

Roberts, Lee D; Ashmore, Tom; McNally, Ben D; Murfitt, Steven A; Fernandez, Bernadette O; Feelisch, Martin; Lindsay, Ross; Siervo, Mario; Williams, Elizabeth A; Murray, Andrew J; Griffin, Julian L

2017-03-01

Exercise is an effective intervention for the prevention and treatment of type 2 diabetes. Skeletal muscle combines multiple signals that contribute to the beneficial effects of exercise on cardiometabolic health. Inorganic nitrate increases exercise efficiency, tolerance, and performance. The transcriptional regulator peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) coordinates the exercise-stimulated skeletal muscle fiber-type switch from glycolytic fast-twitch (type IIb) to oxidative slow-twitch (type I) and intermediate (type IIa) fibers, an effect reversed in insulin resistance and diabetes. We found that nitrate induces PGC1α expression and a switch toward type I and IIa fibers in rat muscle and myotubes in vitro. Nitrate induces the release of exercise/PGC1α-dependent myokine FNDC5/irisin and β-aminoisobutyric acid from myotubes and muscle in rats and humans. Both exercise and nitrate stimulated PGC1α-mediated γ-aminobutyric acid (GABA) secretion from muscle. Circulating GABA concentrations were increased in exercising mice and nitrate-treated rats and humans; thus, GABA may function as an exercise/PGC1α-mediated myokine-like small molecule. Moreover, nitrate increased circulating growth hormone levels in humans and rodents. Nitrate induces physiological responses that mimic exercise training and may underlie the beneficial effects of this metabolite on exercise and cardiometabolic health. © 2017 by the American Diabetes Association.

Multiferroic YCrO3 thin films grown on glass substrate: Resistive switching characteristics

NASA Astrophysics Data System (ADS)

Seo, Jeongdae; Ahn, Yoonho; Son, Jong Yeog

2016-01-01

Polycrystalline YCrO3 thin films were deposited on (111) Pt/Ta/glass substrates by pulsed laser deposition. The YCrO3 thin films exhibited good ferroelectric properties with remnant polarization of about 5 µC/cm2. Large leakage current was observed by I- V curve and ferroelectric hysteresis loop. The YCrO3 resistive random access memory (RRAM) capacitor showed unipolar switching behaviors with SET and RESET voltages higher than those of general NiO RRAM capacitors. [Figure not available: see fulltext.

TiO2-based memristors and ReRAM: materials, mechanisms and models (a review)

NASA Astrophysics Data System (ADS)

Gale, Ella

2014-10-01

The memristor is the fundamental nonlinear circuit element, with uses in computing and computer memory. Resistive Random Access Memory (ReRAM) is a resistive switching memory proposed as a non-volatile memory. In this review we shall summarize the state of the art for these closely-related fields, concentrating on titanium dioxide, the well-utilized and archetypal material for both. We shall cover material properties, switching mechanisms and models to demonstrate what ReRAM and memristor scientists can learn from each other and examine the outlook for these technologies.

Multiphasic On/Off Pheromone Signalling in Moths as Neural Correlates of a Search Strategy

PubMed Central

Martinez, Dominique; Chaffiol, Antoine; Voges, Nicole; Gu, Yuqiao; Anton, Sylvia; Rospars, Jean-Pierre; Lucas, Philippe

2013-01-01

Insects and robots searching for odour sources in turbulent plumes face the same problem: the random nature of mixing causes fluctuations and intermittency in perception. Pheromone-tracking male moths appear to deal with discontinuous flows of information by surging upwind, upon sensing a pheromone patch, and casting crosswind, upon losing the plume. Using a combination of neurophysiological recordings, computational modelling and experiments with a cyborg, we propose a neuronal mechanism that promotes a behavioural switch between surge and casting. We show how multiphasic On/Off pheromone-sensitive neurons may guide action selection based on signalling presence or loss of the pheromone. A Hodgkin-Huxley-type neuron model with a small-conductance calcium-activated potassium (SK) channel reproduces physiological On/Off responses. Using this model as a command neuron and the antennae of tethered moths as pheromone sensors, we demonstrate the efficiency of multiphasic patterning in driving a robotic searcher toward the source. Taken together, our results suggest that multiphasic On/Off responses may mediate olfactory navigation and that SK channels may account for these responses. PMID:23613816

Multiphasic on/off pheromone signalling in moths as neural correlates of a search strategy.

PubMed

Martinez, Dominique; Chaffiol, Antoine; Voges, Nicole; Gu, Yuqiao; Anton, Sylvia; Rospars, Jean-Pierre; Lucas, Philippe

2013-01-01

Insects and robots searching for odour sources in turbulent plumes face the same problem: the random nature of mixing causes fluctuations and intermittency in perception. Pheromone-tracking male moths appear to deal with discontinuous flows of information by surging upwind, upon sensing a pheromone patch, and casting crosswind, upon losing the plume. Using a combination of neurophysiological recordings, computational modelling and experiments with a cyborg, we propose a neuronal mechanism that promotes a behavioural switch between surge and casting. We show how multiphasic On/Off pheromone-sensitive neurons may guide action selection based on signalling presence or loss of the pheromone. A Hodgkin-Huxley-type neuron model with a small-conductance calcium-activated potassium (SK) channel reproduces physiological On/Off responses. Using this model as a command neuron and the antennae of tethered moths as pheromone sensors, we demonstrate the efficiency of multiphasic patterning in driving a robotic searcher toward the source. Taken together, our results suggest that multiphasic On/Off responses may mediate olfactory navigation and that SK channels may account for these responses.

Reward Motivation Enhances Task Coding in Frontoparietal Cortex.

PubMed

Etzel, Joset A; Cole, Michael W; Zacks, Jeffrey M; Kay, Kendrick N; Braver, Todd S

2016-04-01

Reward motivation often enhances task performance, but the neural mechanisms underlying such cognitive enhancement remain unclear. Here, we used a multivariate pattern analysis (MVPA) approach to test the hypothesis that motivation-related enhancement of cognitive control results from improved encoding and representation of task set information. Participants underwent two fMRI sessions of cued task switching, the first under baseline conditions, and the second with randomly intermixed reward incentive and no-incentive trials. Information about the upcoming task could be successfully decoded from cue-related activation patterns in a set of frontoparietal regions typically associated with task control. More critically, MVPA classifiers trained on the baseline session had significantly higher decoding accuracy on incentive than non-incentive trials, with decoding improvement mediating reward-related enhancement of behavioral performance. These results strongly support the hypothesis that reward motivation enhances cognitive control, by improving the discriminability of task-relevant information coded and maintained in frontoparietal brain regions. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

“Off with the Old”: Mindfulness Practice Improves Backward Inhibition

PubMed Central

Greenberg, Jonathan; Reiner, Keren; Meiran, Nachshon

2013-01-01

Mindfulness practice has been linked to reduced depressive rumination and described as involving inhibition of information that has been relevant in the past and is no longer relevant in the present moment. Backward inhibition (BI) is considered to be one of the purest measures of task set inhibition, and impaired BI has been linked to depressive rumination. BI was contrasted with Competitor Rule Suppression (CRS), which is another phenomenon observed in task switching, yet one which involves episodic memory tagging of information that is currently conflicting rather than active inhibition. Although similar at baseline level, a randomly assigned group (n = 38) who underwent an eight session mindfulness training program exhibited improved BI but not CRS compared to a waiting list group (n = 38). Findings indicate that mindfulness improves the specific component of task set inhibition, which has previously been linked to reduced rumination. Implications regarding the potential role of task set inhibition in mediating between mindfulness and reduced rumination, as well as the role of mindfulness in “being in the present moment” are discussed. PMID:23335909

Optimal switching between geocentric and egocentric strategies in navigation

PubMed Central

Mahadevan, L.

2016-01-01

Animals use a combination of egocentric navigation driven by the internal integration of environmental cues, interspersed with geocentric course correction and reorientation. These processes are accompanied by uncertainty in sensory acquisition of information, planning and execution. Inspired by observations of dung beetle navigational strategies that show switching between geocentric and egocentric strategies, we consider the question of optimal reorientation rates for the navigation of an agent moving along a preferred direction in the presence of multiple sources of noise. We address this using a model that takes the form of a correlated random walk at short time scales that is punctuated by reorientation events leading to a biased random walks at long time scales. This allows us to identify optimal alternation schemes and characterize their robustness in the context of noisy sensory acquisition as well as performance errors linked with variations in environmental conditions and agent–environment interactions. PMID:27493769

Activation-induced deoxycytidine deaminase (AID) co-transcriptional scanning at single-molecule resolution

NASA Astrophysics Data System (ADS)

Senavirathne, Gayan; Bertram, Jeffrey G.; Jaszczur, Malgorzata; Chaurasiya, Kathy R.; Pham, Phuong; Mak, Chi H.; Goodman, Myron F.; Rueda, David

2015-12-01

Activation-induced deoxycytidine deaminase (AID) generates antibody diversity in B cells by initiating somatic hypermutation (SHM) and class-switch recombination (CSR) during transcription of immunoglobulin variable (IgV) and switch region (IgS) DNA. Using single-molecule FRET, we show that AID binds to transcribed dsDNA and translocates unidirectionally in concert with RNA polymerase (RNAP) on moving transcription bubbles, while increasing the fraction of stalled bubbles. AID scans randomly when constrained in an 8 nt model bubble. When unconstrained on single-stranded (ss) DNA, AID moves in random bidirectional short slides/hops over the entire molecule while remaining bound for ~5 min. Our analysis distinguishes dynamic scanning from static ssDNA creasing. That AID alone can track along with RNAP during transcription and scan within stalled transcription bubbles suggests a mechanism by which AID can initiate SHM and CSR when properly regulated, yet when unregulated can access non-Ig genes and cause cancer.

Sonic Hedgehog switches on Wnt/planar cell polarity signaling in commissural axon growth cones by reducing levels of Shisa2

PubMed Central

Onishi, Keisuke

2017-01-01

Commissural axons switch on responsiveness to Wnt attraction during midline crossing and turn anteriorly only after exiting the floor plate. We report here that Sonic Hedgehog (Shh)-Smoothened signaling downregulates Shisa2, which inhibits the glycosylation and cell surface presentation of Frizzled3 in rodent commissural axon growth cones. Constitutive Shisa2 expression causes randomized turning of post-crossing commissural axons along the anterior–posterior (A–P) axis. Loss of Shisa2 led to precocious anterior turning of commissural axons before or during midline crossing. Post-crossing commissural axon turning is completely randomized along the A–P axis when Wntless, which is essential for Wnt secretion, is conditionally knocked out in the floor plate. This regulatory link between Shh and planar cell polarity (PCP) signaling may also occur in other developmental processes. PMID:28885142

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

Coevolution between positive reciprocity, punishment, and partner switching in repeated interactions.

PubMed

Wubs, Matthias; Bshary, Redouan; Lehmann, Laurent

2016-06-15

Cooperation based on mutual investments can occur between unrelated individuals when they are engaged in repeated interactions. Individuals then need to use a conditional strategy to deter their interaction partners from defecting. Responding to defection such that the future payoff of a defector is reduced relative to cooperating with it is called a partner control mechanism. Three main partner control mechanisms are (i) to switch from cooperation to defection when being defected ('positive reciprocity'), (ii) to actively reduce the payoff of a defecting partner ('punishment'), or (iii) to stop interacting and switch partner ('partner switching'). However, such mechanisms to stabilize cooperation are often studied in isolation from each other. In order to better understand the conditions under which each partner control mechanism tends to be favoured by selection, we here analyse by way of individual-based simulations the coevolution between positive reciprocity, punishment, and partner switching. We show that random interactions in an unstructured population and a high number of rounds increase the likelihood that selection favours partner switching. In contrast, interactions localized in small groups (without genetic structure) increase the likelihood that selection favours punishment and/or positive reciprocity. This study thus highlights the importance of comparing different control mechanisms for cooperation under different conditions. © 2016 The Author(s).

Chaos control of Hastings-Powell model by combining chaotic motions.

PubMed

Danca, Marius-F; Chattopadhyay, Joydev

2016-04-01

In this paper, we propose a Parameter Switching (PS) algorithm as a new chaos control method for the Hastings-Powell (HP) system. The PS algorithm is a convergent scheme that switches the control parameter within a set of values while the controlled system is numerically integrated. The attractor obtained with the PS algorithm matches the attractor obtained by integrating the system with the parameter replaced by the averaged value of the switched parameter values. The switching rule can be applied periodically or randomly over a set of given values. In this way, every stable cycle of the HP system can be approximated if its underlying parameter value equalizes the average value of the switching values. Moreover, the PS algorithm can be viewed as a generalization of Parrondo's game, which is applied for the first time to the HP system, by showing that losing strategy can win: "losing + losing = winning." If "loosing" is replaced with "chaos" and, "winning" with "order" (as the opposite to "chaos"), then by switching the parameter value in the HP system within two values, which generate chaotic motions, the PS algorithm can approximate a stable cycle so that symbolically one can write "chaos + chaos = regular." Also, by considering a different parameter control, new complex dynamics of the HP model are revealed.

Chaos control of Hastings-Powell model by combining chaotic motions

NASA Astrophysics Data System (ADS)

Danca, Marius-F.; Chattopadhyay, Joydev

2016-04-01

In this paper, we propose a Parameter Switching (PS) algorithm as a new chaos control method for the Hastings-Powell (HP) system. The PS algorithm is a convergent scheme that switches the control parameter within a set of values while the controlled system is numerically integrated. The attractor obtained with the PS algorithm matches the attractor obtained by integrating the system with the parameter replaced by the averaged value of the switched parameter values. The switching rule can be applied periodically or randomly over a set of given values. In this way, every stable cycle of the HP system can be approximated if its underlying parameter value equalizes the average value of the switching values. Moreover, the PS algorithm can be viewed as a generalization of Parrondo's game, which is applied for the first time to the HP system, by showing that losing strategy can win: "losing + losing = winning." If "loosing" is replaced with "chaos" and, "winning" with "order" (as the opposite to "chaos"), then by switching the parameter value in the HP system within two values, which generate chaotic motions, the PS algorithm can approximate a stable cycle so that symbolically one can write "chaos + chaos = regular." Also, by considering a different parameter control, new complex dynamics of the HP model are revealed.

Progress with infliximab biosimilars for inflammatory bowel disease.

PubMed

Kurti, Zsuzsanna; Gonczi, Lorant; Lakatos, Peter L

2018-04-29

Biological therapies have revolutionized the treatment of inflammatory bowel diseases (IBD) in the last two decades. Though biological drugs are effective, their use is associated with high costs and access to biological agents varies among countries. As the patent for the reference products expired, the advent of biosimilar monoclonal antibodies has been expected. Biosimilars represent less expensive alternatives compared to the reference product. Areas covered: In this review, authors will review the literature on the clinical efficacy, safety and immunogenicity of current and future biosimilar infliximabs. Short- and medium-term data from real-life cohorts and from randomized-clinical trials in IBD demonstrated similar outcomes in terms of efficacy, safety and immunogenicity as the reference product for CT-P13. Switch data from the reference to the biosimilar product are also accumulating (including the NOR-SWITCH and the CT-P13 3.4 study). Expert opinion: The use of biosimilar infliximab in IBD is increasing worldwide. Its use may be associated with budget savings leading to better access to biological therapies and consequently improved health outcomes. Switching from the originator to a biosimilar in patients with IBD is acceptable, although scientific and clinical evidence is lacking regarding reverse switching, multiple switching, and cross-switching among biosimilars in IBD patients.

A complex molecular switch directs stress-induced cyclin C nuclear release through SCFGrr1-mediated degradation of Med13

PubMed Central

Stieg, David C.; Willis, Stephen D.; Ganesan, Vidyaramanan; Ong, Kai Li; Scuorzo, Joseph; Song, Mia; Grose, Julianne; Strich, Randy; Cooper, Katrina F.

2018-01-01

In response to oxidative stress, cells decide whether to mount a survival or cell death response. The conserved cyclin C and its kinase partner Cdk8 play a key role in this decision. Both are members of the Cdk8 kinase module, which, with Med12 and Med13, associate with the core mediator complex of RNA polymerase II. In Saccharomyces cerevisiae, oxidative stress triggers Med13 destruction, which thereafter releases cyclin C into the cytoplasm. Cytoplasmic cyclin C associates with mitochondria, where it induces hyperfragmentation and regulated cell death. In this report, we show that residues 742–844 of Med13’s 600–amino acid intrinsic disordered region (IDR) both directs cyclin C-Cdk8 association and serves as the degron that mediates ubiquitin ligase SCFGrr1-dependent destruction of Med13 following oxidative stress. Here, cyclin C-Cdk8 phosphorylation of Med13 most likely primes the phosphodegron for destruction. Next, pro-oxidant stimulation of the cell wall integrity pathway MAP kinase Slt2 initially phosphorylates cyclin C to trigger its release from Med13. Thereafter, Med13 itself is modified by Slt2 to stimulate SCFGrr1-mediated destruction. Taken together, these results support a model in which this IDR of Med13 plays a key role in controlling a molecular switch that dictates cell fate following exposure to adverse environments. PMID:29212878

Switching Transient Generation in Surface Interrogation Scanning Electrochemical Microscopy and Time-of-Flight Techniques.

PubMed

Ahn, Hyun S; Bard, Allen J

2015-12-15

In surface interrogation scanning electrochemical microscopy (SI-SECM), fine and accurate control of the delay time between substrate generation and tip interrogation (tdelay) is crucial because tdelay defines the decay time of the reactive intermediate. In previous applications of the SI-SECM, the resolution in the control of tdelay has been limited to several hundreds of milliseconds due to the slow switching of the bipotentiostat. In this work, we have improved the time resolution of tdelay control up to ca. 1 μs, enhancing the SI-SECM to be competitive in the time domain with the decay of many reactive intermediates. The rapid switching SI-SECM has been implemented in a substrate generation-tip collection time-of-flight (SG-TC TOF) experiment of a solution redox mediator, and the results obtained from the experiment exhibited good agreement with that obtained from digital simulation. The reaction rate constant of surface Co(IV) on oxygen-evolving catalyst film, which was inaccessible thus far due to the lack of tdelay control, has been measured by the rapid switching SI-SECM.

The AID enzyme induces class switch recombination in fibroblasts.

PubMed

Okazaki, Il-mi; Kinoshita, Kazuo; Muramatsu, Masamichi; Yoshikawa, Kiyotsugu; Honjo, Tasuku

2002-03-21

The switch of the immunoglobulin isotype from IgM to IgG, IgE or IgA is mediated by class switch recombination (CSR). CSR changes the immunoglobulin heavy chain constant region (CH) gene from Cmu to one of the other CH genes. Somatic hypermutation introduces massive numbers of point mutations in the immunoglobulin variable (V) region gene, giving rise to immunoglobulin with higher affinity. Activation-induced cytidine deaminase (AID), a putative RNA-editing cytidine deaminase, is expressed strictly in activated B cells and is indispensable in both CSR and somatic hypermutation. But the exact function of AID is unknown. Here we show that ectopic expression of AID induces CSR in an artificial switch construct in fibroblasts at a level comparable to that in stimulated B cells. Sequences around recombination junctions in the artificial substrate have features similar to endogenous CSR junctions. Furthermore, AID-induced CSR in fibroblasts is dependent on transcription of the target S region, as shown in endogenous CSR in B cells. The results show that AID is the only B-cell-specific factor required for initiation of the CSR reaction in the activated locus.

Transcription factor YY1 can control AID-mediated mutagenesis in mice.

PubMed

Zaprazna, Kristina; Basu, Arindam; Tom, Nikola; Jha, Vibha; Hodawadekar, Suchita; Radova, Lenka; Malcikova, Jitka; Tichy, Boris; Pospisilova, Sarka; Atchison, Michael L

2018-02-01

Activation-induced cytidine deminase (AID) is crucial for controlling the immunoglobulin (Ig) diversification processes of somatic hypermutation (SHM) and class switch recombination (CSR). AID initiates these processes by deamination of cytosine, ultimately resulting in mutations or double strand DNA breaks needed for SHM and CSR. Levels of AID control mutation rates, and off-target non-Ig gene mutations can contribute to lymphomagenesis. Therefore, factors that control AID levels in the nucleus can regulate SHM and CSR, and may contribute to disease. We previously showed that transcription factor YY1 can regulate the level of AID in the nucleus and Ig CSR. Therefore, we hypothesized that conditional knock-out of YY1 would lead to reduction in AID localization at the Ig locus, and reduced AID-mediated mutations. Using mice that overexpress AID (IgκAID yy1 f/f ) or that express normal AID levels (yy1 f/f ), we found that conditional knock-out of YY1 results in reduced AID nuclear levels, reduced localization of AID to the Sμ switch region, and reduced AID-mediated mutations. We find that the mechanism of YY1 control of AID nuclear accumulation is likely due to YY1-AID physical interaction which blocks AID ubiquitination. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Eukaryotic Translation Initiation Factor 4E Availability Controls the Switch between Cap-Dependent and Internal Ribosomal Entry Site-Mediated Translation†

PubMed Central

Svitkin, Yuri V.; Herdy, Barbara; Costa-Mattioli, Mauro; Gingras, Anne-Claude; Raught, Brian; Sonenberg, Nahum

2005-01-01

Translation of m7G-capped cellular mRNAs is initiated by recruitment of ribosomes to the 5′ end of mRNAs via eukaryotic translation initiation factor 4F (eIF4F), a heterotrimeric complex comprised of a cap-binding subunit (eIF4E) and an RNA helicase (eIF4A) bridged by a scaffolding molecule (eIF4G). Internal translation initiation bypasses the requirement for the cap and eIF4E and occurs on viral and cellular mRNAs containing internal ribosomal entry sites (IRESs). Here we demonstrate that eIF4E availability plays a critical role in the switch from cap-dependent to IRES-mediated translation in picornavirus-infected cells. When both capped and IRES-containing mRNAs are present (as in intact cells or in vitro translation extracts), a decrease in the amount of eIF4E associated with the eIF4F complex elicits a striking increase in IRES-mediated viral mRNA translation. This effect is not observed in translation extracts depleted of capped mRNAs, indicating that capped mRNAs compete with IRES-containing mRNAs for translation. These data explain numerous reported observations where viral mRNAs are preferentially translated during infection. PMID:16287867

Eukaryotic translation initiation factor 4E availability controls the switch between cap-dependent and internal ribosomal entry site-mediated translation.

PubMed

Svitkin, Yuri V; Herdy, Barbara; Costa-Mattioli, Mauro; Gingras, Anne-Claude; Raught, Brian; Sonenberg, Nahum

2005-12-01

Translation of m7G-capped cellular mRNAs is initiated by recruitment of ribosomes to the 5' end of mRNAs via eukaryotic translation initiation factor 4F (eIF4F), a heterotrimeric complex comprised of a cap-binding subunit (eIF4E) and an RNA helicase (eIF4A) bridged by a scaffolding molecule (eIF4G). Internal translation initiation bypasses the requirement for the cap and eIF4E and occurs on viral and cellular mRNAs containing internal ribosomal entry sites (IRESs). Here we demonstrate that eIF4E availability plays a critical role in the switch from cap-dependent to IRES-mediated translation in picornavirus-infected cells. When both capped and IRES-containing mRNAs are present (as in intact cells or in vitro translation extracts), a decrease in the amount of eIF4E associated with the eIF4F complex elicits a striking increase in IRES-mediated viral mRNA translation. This effect is not observed in translation extracts depleted of capped mRNAs, indicating that capped mRNAs compete with IRES-containing mRNAs for translation. These data explain numerous reported observations where viral mRNAs are preferentially translated during infection.

The HILDA Complex Coordinates a Conditional Switch in the 3′-Untranslated Region of the VEGFA mRNA

PubMed Central

Yao, Peng; Potdar, Alka A.; Ray, Partho Sarothi; Eswarappa, Sandeepa M.; Flagg, Andrew C.; Willard, Belinda; Fox, Paul L.

2013-01-01

Cell regulatory circuits integrate diverse, and sometimes conflicting, environmental cues to generate appropriate, condition-dependent responses. Here, we elucidate the components and mechanisms driving a protein-directed RNA switch in the 3′UTR of vascular endothelial growth factor (VEGF)-A. We describe a novel HILDA (hypoxia-inducible hnRNP L–DRBP76–hnRNP A2/B1) complex that coordinates a three-element RNA switch, enabling VEGFA mRNA translation during combined hypoxia and inflammation. In addition to binding the CA-rich element (CARE), heterogeneous nuclear ribonucleoprotein (hnRNP) L regulates switch assembly and function. hnRNP L undergoes two previously unrecognized, condition-dependent posttranslational modifications: IFN-γ induces prolyl hydroxylation and von Hippel-Lindau (VHL)-mediated proteasomal degradation, whereas hypoxia stimulates hnRNP L phosphorylation at Tyr359, inducing binding to hnRNP A2/B1, which stabilizes the protein. Also, phospho-hnRNP L recruits DRBP76 (double-stranded RNA binding protein 76) to the 3′UTR, where it binds an adjacent AU-rich stem-loop (AUSL) element, “flipping” the RNA switch by disrupting the GAIT (interferon-gamma-activated inhibitor of translation) element, preventing GAIT complex binding, and driving robust VEGFA mRNA translation. The signal-dependent, HILDA complex coordinates the function of a trio of neighboring RNA elements, thereby regulating translation of VEGFA and potentially other mRNA targets. The VEGFA RNA switch might function to ensure appropriate angiogenesis and tissue oxygenation during conflicting signals from combined inflammation and hypoxia. We propose the VEGFA RNA switch as an archetype for signal-activated, protein-directed, multi-element RNA switches that regulate posttranscriptional gene expression in complex environments. PMID:23976881

Omni-Directional Viewing-Angle Switching through Control of the Beam Divergence Angle in a Liquid Crystal Panel

NASA Astrophysics Data System (ADS)

Baek, Jong-In; Kim, Ki-Han; Kim, Jae Chang; Yoon, Tae-Hoon

2010-01-01

This paper proposes a method of omni-directional viewing-angle switching by controlling the beam diverging angle (BDA) in a liquid crystal (LC) panel. The LCs aligned randomly by in-cell polymer structures diffuse the collimated backlight for the bright state of the wide viewing-angle mode. We align the LCs homogeneously by applying an in-plane field for the narrow viewing-angle mode. By doing this the scattering is significantly reduced so that the small BDA is maintained as it passes through the LC layer. The dark state can be obtained by aligning the LCs homeotropically with a vertical electric field. We demonstrated experimentally the omni-directional switching of the viewing-angle, without an additional panel or backlighting system.

Interaction of clopidogrel and statins in secondary prevention after cerebral ischaemia – a randomized, double-blind, double-dummy crossover study

PubMed Central

Siepmann, Timo; Heinke, Denise; Kepplinger, Jessica; Barlinn, Kristian; Gehrisch, Siegmund; Grählert, Xina; Schwanebeck, Uta; Reichmann, Heinz; Puetz, Volker; Bodechtel, Ulf; Gahn, Georg

2014-01-01

Aims Variability in responsiveness to clopidogrel is a clinical problem in secondary prevention after cerebral ischaemia which has been suggested to be linked to competitive metabolization of clopidogrel and cytochrome P450 (CYP) 3A4-oxidated statins such as simvastatin. We assessed the hypothesis that simvastatin, in contrast to CYP 2C9-metabolized fluvastatin, reduces clopidogrel-mediated platelet inhibition. Methods We performed a randomized, double-blind, double-dummy, two period crossover study in 13 patients with cerebral ischaemia (8F, 5 M), aged 64.1 ± 8.0 years (mean ± SD). After a 14 day period in which all patients received 75 mg clopidogrel day−1, patients additionally received either 20 mg simvastatin day−1 or 80 mg fluvastatin day−1 for 14 days. Regimens were crossed over after a 14 day wash-out period and switched regimens were continued for another 14 days. Platelet aggregation, clopidogrel active metabolite (CAM) plasma concentrations and routine laboratory parameters including prothrombin time (PT) Quick percent value were assessed at baseline and following each treatment phase. Results Clopidogrel reduced platelet aggregation in all patients as expected. Platelet aggregation and CAM plasma concentrations were unaltered when simvastatin or fluvastatin was added to clopidogrel. Simvastatin decreased PT Quick percent value (decrease from 109 ± 10.5% to 103 ± 11%, P < 0.05) when combined with clopidogrel but there was no such change following treatment with fluvastatin and clopidogrel. Conclusions Our data indicate that treatment with CYP 3A4-metabolized simvastatin does not jeopardize clopidogrel-mediated inhibition of platelet aggregation. After co-administration of simvastatin and clopidogrel we observed a decrease in the PT Quick percent value which could be due to simvastatin-induced reduction of activity of prothrombin fragment 1 + 2. PMID:24803100

The Role of Work Function and Band Gap in Resistive Switching Behaviour of ZnTe Thin Films

NASA Astrophysics Data System (ADS)

Rowtu, Srinu; Sangani, L. D. Varma; Krishna, M. Ghanashyam

2018-02-01

Resistive switching behavior by engineering the electrode work function and band gap of ZnTe thin films is demonstrated. The device structures Au/ZnTe/Au, Au/ZnTe/Ag, Al/ZnTe/Ag and Pt/ZnTe/Ag were fabricated. ZnTe was deposited by thermal evaporation and the stoichiometry and band gap were controlled by varying the source-substrate distance. Band gap could be varied between 1.0 eV to approximately 4.0 eV with the larger band gap being attributed to the partial oxidation of ZnTe. The transport characteristics reveal that the low-resistance state is ohmic in nature which makes a transition to Poole-Frenkel defect-mediated conductivity in the high-resistance states. The highest R off-to- R on ratio achieved is 109. Interestingly, depending on stoichiometry, both unipolar and bipolar switching can be realized.

Multirate parallel distributed compensation of a cluster in wireless sensor and actor networks

NASA Astrophysics Data System (ADS)

Yang, Chun-xi; Huang, Ling-yun; Zhang, Hao; Hua, Wang

2016-01-01

The stabilisation problem for one of the clusters with bounded multiple random time delays and packet dropouts in wireless sensor and actor networks is investigated in this paper. A new multirate switching model is constructed to describe the feature of this single input multiple output linear system. According to the difficulty of controller design under multi-constraints in multirate switching model, this model can be converted to a Takagi-Sugeno fuzzy model. By designing a multirate parallel distributed compensation, a sufficient condition is established to ensure this closed-loop fuzzy control system to be globally exponentially stable. The solution of the multirate parallel distributed compensation gains can be obtained by solving an auxiliary convex optimisation problem. Finally, two numerical examples are given to show, compared with solving switching controller, multirate parallel distributed compensation can be obtained easily. Furthermore, it has stronger robust stability than arbitrary switching controller and single-rate parallel distributed compensation under the same conditions.

Forming free and ultralow-power erase operation in atomically crystal TiO2 resistive switching

NASA Astrophysics Data System (ADS)

Dai, Yawei; Bao, Wenzhong; Hu, Linfeng; Liu, Chunsen; Yan, Xiao; Chen, Lin; Sun, Qingqing; Ding, Shijin; Zhou, Peng; Zhang, David Wei

2017-06-01

Two-dimensional layered materials (2DLMs) have attracted broad interest from fundamental sciences to industrial applications. Their applications in memory devices have been demonstrated, yet much still remains to explore optimal materials and device structure for practical application. In this work, a forming-free, bipolar resistive switching behavior are demonstrated in 2D TiO2-based resistive random access memory (RRAM). Physical adsorption method is adopted to achieve high quality, continuous 2D TiO2 network efficiently. The 2D TiO2 RRAM devices exhibit superior properties such as fast switching capability (20 ns of erase operation) and extremely low erase energy consumption (0.16 fJ). Furthermore, the resistive switching mechanism is attributed to the formation and rupture of oxygen vacancies-based percolation path in 2D TiO2 crystals. Our results pave the way for the implementation of high performance 2DLMs-based RRAM in the next generation non-volatile memory (NVM) application.

Nudging Leads Consumers In Colorado To Shop But Not Switch ACA Marketplace Plans.

PubMed

Marzilli Ericson, Keith M; Kingsdale, Jon; Layton, Tim; Sacarny, Adam

2017-02-01

The Affordable Care Act (ACA) dramatically expanded the use of regulated marketplaces in health insurance, but consumers often fail to shop for plans during open enrollment periods. Typically these consumers are automatically reenrolled in their old plans, which potentially exposes them to unexpected increases in their insurance premiums and cost sharing. We conducted a randomized intervention to encourage enrollees in an ACA Marketplace to shop for plans. We tested the effect of letters and e-mails with personalized information about the savings on insurance premiums that they could realize from switching plans and the effect of generic communications that simply emphasized the possibility of saving. The personalized and generic messages both increased shopping on the Marketplace's website by 23 percent, but neither type of message had a significant effect on plan switching. These findings show that simple "nudges" with even generic information can promote shopping in health insurance marketplaces, but whether they can lead to switching remains an open question. Project HOPE—The People-to-People Health Foundation, Inc.

A biphasic epigenetic switch controls immunoevasion, virulence and niche adaptation in non-typeable Haemophilus influenzae.

PubMed

Atack, John M; Srikhanta, Yogitha N; Fox, Kate L; Jurcisek, Joseph A; Brockman, Kenneth L; Clark, Tyson A; Boitano, Matthew; Power, Peter M; Jen, Freda E-C; McEwan, Alastair G; Grimmond, Sean M; Smith, Arnold L; Barenkamp, Stephen J; Korlach, Jonas; Bakaletz, Lauren O; Jennings, Michael P

2015-07-28

Non-typeable Haemophilus influenzae contains an N(6)-adenine DNA-methyltransferase (ModA) that is subject to phase-variable expression (random ON/OFF switching). Five modA alleles, modA2, modA4, modA5, modA9 and modA10, account for over two-thirds of clinical otitis media isolates surveyed. Here, we use single molecule, real-time (SMRT) methylome analysis to identify the DNA-recognition motifs for all five of these modA alleles. Phase variation of these alleles regulates multiple proteins including vaccine candidates, and key virulence phenotypes such as antibiotic resistance (modA2, modA5, modA10), biofilm formation (modA2) and immunoevasion (modA4). Analyses of a modA2 strain in the chinchilla model of otitis media show a clear selection for ON switching of modA2 in the middle ear. Our results indicate that a biphasic epigenetic switch can control bacterial virulence, immunoevasion and niche adaptation in an animal model system.

Influence of thermal agitation on the electric field induced precessional magnetization reversal with perpendicular easy axis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cheng, Hongguang, E-mail: chenghg7932@gmail.com; Deng, Ning

2013-12-15

We investigated the influence of thermal agitation on the electric field induced precessional magnetization switching probability with perpendicular easy axis by solving the Fokker-Planck equation numerically with finite difference method. The calculated results show that the thermal agitation during the reversal process crucially influences the switching probability. The switching probability can be achieved is only determined by the thermal stability factor Δ of the free layer, it is independent on the device dimension, which is important for the high density device application. Ultra-low error rate down to the order of 10{sup −9} can be achieved for the device of thermalmore » stability factor Δ of 40. Low damping factor α material should be used for the free layer for high reliability device applications. These results exhibit potential of electric field induced precessional magnetization switching with perpendicular easy axis for ultra-low power, high speed and high density magnetic random access memory (MRAM) applications.« less

Theoretical implications of quantitative properties of interval timing and probability estimation in mouse and rat.

PubMed

Kheifets, Aaron; Freestone, David; Gallistel, C R

2017-07-01

In three experiments with mice ( Mus musculus ) and rats (Rattus norvigicus), we used a switch paradigm to measure quantitative properties of the interval-timing mechanism. We found that: 1) Rodents adjusted the precision of their timed switches in response to changes in the interval between the short and long feed latencies (the temporal goalposts). 2) The variability in the timing of the switch response was reduced or unchanged in the face of large trial-to-trial random variability in the short and long feed latencies. 3) The adjustment in the distribution of switch latencies in response to changes in the relative frequency of short and long trials was sensitive to the asymmetry in the Kullback-Leibler divergence. The three results suggest that durations are represented with adjustable precision, that they are timed by multiple timers, and that there is a trial-by-trial (episodic) record of feed latencies in memory. © 2017 Society for the Experimental Analysis of Behavior.

Evaluation of the feasibility of switching from immediate release quetiapine to extended release quetiapine fumarate in stable outpatients with schizophrenia.

PubMed

Möller, Hans-Jürgen; Johnson, Sunny; Mateva, Temenuzhka; Brecher, Martin; Svensson, Ola; Miller, Frank; Meulien, Didier

2008-03-01

This double-blind, double-dummy study (D1444C00146) evaluated the efficacy and safety of switching patients with clinically stable schizophrenia from quetiapine immediate release (IR) to the same dose of once-daily extended release quetiapine fumarate (quetiapine XR). Patients received quetiapine IR 400-800 mg/day twice daily for 4 weeks, and were then randomized (2 : 1) to a once-daily equivalent dose of quetiapine XR or maintained on IR for 6 weeks. The primary variable was the proportion of patients who discontinued treatment owing to lack of efficacy or whose Positive and Negative Syndrome Scale scores increased by at least 20% from randomization to any visit. In total, 497 patients were randomized to quetiapine XR (n=331) or IR (n=166). Noninferiority (6% margin; one-sided test, 2.5% significance level) was narrowly missed for the primary efficacy variable for the modified intention-to-treat population (9.1%, quetiapine XR; 7.2%, quetiapine IR; difference 1.86%; 95% confidence interval: -3.78, 6.57; P=0.0431), but was shown for the per-protocol population (5.3%, quetiapine XR; 6.2%, quetiapine IR; difference: -0.83%; 95% confidence interval: -6.75, 3.71; P=0.0017). Serious adverse event incidence was low for quetiapine XR and IR; there were no unexpected adverse events. In conclusion, efficacy was maintained without compromising safety/tolerability when switching patients with stable schizophrenia from twice-daily quetiapine IR to once-daily quetiapine XR (400-800 mg/day).

Bipolar resistive switching in Cu/AlN/Pt nonvolatile memory device

NASA Astrophysics Data System (ADS)

Chen, C.; Yang, Y. C.; Zeng, F.; Pan, F.

2010-08-01

Highly stable and reproducible bipolar resistive switching effects are reported on Cu/AlN/Pt devices. Memory characteristics including large memory window of 103, long retention time of >106 s and good endurance of >103 were demonstrated. It is concluded that the reset current decreases as compliance current decreases, which provides an approach to suppress power consumption. The dominant conduction mechanisms of low resistance state and high resistance state were verified by Ohmic behavior and trap-controlled space charge limited current, respectively. The memory effect is explained by the model concerning redox reaction mediated formation and rupture of the conducting filament in AlN films.

Inversion of ferrimagnetic magnetization by ferroelectric switching via a novel magnetoelectric coupling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weng, Yakui; Lin, Lingfang; Dagotto, Elbio

2016-07-12

Although several multiferroic materials or heterostructures have been extensively studied, finding strong magnetoelectric couplings for the electric field control of the magnetization remains challenging. Here, a novel interfacial magnetoelectric coupling based on three components (ferroelectric dipole, magnetic moment, and antiferromagnetic order) is analytically formulated. As an extension of carrier-mediated magnetoelectricity, the new coupling is shown to induce an electric-magnetic hysteresis loop. In addition, realizations employing BiFeO 3 bilayers grown along the [111] axis are proposed. Without involving magnetic phase transitions, the magnetization orientation can be switched by the carrier modulation driven by the field effect, as confirmed using first-principles calculations.

Switching bonds in a DNA gel: an all-DNA vitrimer.

PubMed

Romano, Flavio; Sciortino, Francesco

2015-02-20

We design an all-DNA system that behaves like vitrimers, innovative plastics with self-healing and stress-releasing properties. The DNA sequences are engineered to self-assemble first into tetra- and bifunctional units which, upon further cooling, bind to each other forming a fully bonded network gel. An innovative design of the binding regions of the DNA sequences, exploiting a double toehold-mediated strand displacement, generates a network gel which is able to reshuffle its bonds, retaining at all times full bonding. As in vitrimers, the rate of bond switching can be controlled via a thermally activated catalyst, which in the present design is very short DNA strands.

Alterations in neural systems mediating cognitive flexibility and inhibition in mood disorders.

PubMed

Piguet, Camille; Cojan, Yann; Sterpenich, Virginie; Desseilles, Martin; Bertschy, Gilles; Vuilleumier, Patrik

2016-04-01

Impairment in mental flexibility may be a key component contributing to cardinal cognitive symptoms among mood disorders patients, particularly thought control disorders. Impaired ability to switch from one thought to another might reflect difficulties in either generating new mental states, inhibiting previous states, or both. However, the neural underpinnings of impaired cognitive flexibility in mood disorders remain largely unresolved. We compared a group of mood disorders patients (n = 29) and a group of matched healthy subjects (n = 32) on a novel task-switching paradigm involving happy and sad faces, that allowed us to separate generation of a new mental set (Switch Cost) and inhibition of the previous set during switching (Inhibition Cost), using fMRI. Behavioral data showed a larger Switch Cost in patients relative to controls, but the average Inhibition Cost did not differ between groups. At the neural level, a main effect of group was found with stronger activation of the subgenual cingulate cortex in patients. The larger Switch Cost in patients was reflected by a stronger recruitment of brain regions involved in attention and executive control, including the left intraparietal sulcus, precuneus, left inferior fontal gyrus, and right anterior cingulate. Critically, activity in the subgenual cingulate cortex was not downregulated by inhibition in patients relative to controls. In conclusion, mood disorder patients have exaggerated Switch Cost relative to controls, and this deficit in cognitive flexibility is associated with increased activation of the fronto-parietal attention networks, combined with impaired modulation of the subgenual cingulate cortex when inhibition of previous mental states is needed. © 2016 Wiley Periodicals, Inc.

Ribozyme-based aminoglycoside switches of gene expression engineered by genetic selection in S. cerevisiae.

PubMed

Klauser, Benedikt; Atanasov, Janina; Siewert, Lena K; Hartig, Jörg S

2015-05-15

Systems for conditional gene expression are powerful tools in basic research as well as in biotechnology. For future applications, it is of great importance to engineer orthogonal genetic switches that function reliably in diverse contexts. RNA-based switches have the advantage that effector molecules interact immediately with regulatory modules inserted into the target RNAs, getting rid of the need of transcription factors usually mediating genetic control. Artificial riboswitches are characterized by their simplicity and small size accompanied by a high degree of modularity. We have recently reported a series of hammerhead ribozyme-based artificial riboswitches that allow for post-transcriptional regulation of gene expression via switching mRNA, tRNA, or rRNA functions. A more widespread application was so far hampered by moderate switching performances and a limited set of effector molecules available. Here, we report the re-engineering of hammerhead ribozymes in order to respond efficiently to aminoglycoside antibiotics. We first established an in vivo selection protocol in Saccharomyces cerevisiae that enabled us to search large sequence spaces for optimized switches. We then envisioned and characterized a novel strategy of attaching the aptamer to the ribozyme catalytic core, increasing the design options for rendering the ribozyme ligand-dependent. These innovations enabled the development of neomycin-dependent RNA modules that switch gene expression up to 25-fold. The presented aminoglycoside-responsive riboswitches belong to the best-performing RNA-based genetic regulators reported so far. The developed in vivo selection protocol should allow for sampling of large sequence spaces for engineering of further optimized riboswitches.

Healthcare resource use and costs of privately insured patients who switch, discontinue, or persist on anti-muscarinic therapy for overactive bladder.

PubMed

Ivanova, Jasmina I; Hayes-Larson, Eleanor; Sorg, Rachael A; Birnbaum, Howard G; Berner, Todd

2014-10-01

To compare the healthcare costs of patients with overactive bladder (OAB) who switch vs persist on anti-muscarinic agents (AMs), describe resource use and costs among OAB patients who discontinue AMs, and assess factors associated with persisting vs switching or discontinuing. OAB patients initiating an AM between January 1, 2007 and March 31, 2012 were identified from a claims database of US privately insured beneficiaries (n ≈ 16 million) and required to have no AM claims in the 12 months before AM initiation (baseline period). Patients were classified as persisters, switchers, or discontinuers, and assigned a study index date based on their AM use in the 6 months following initiation. Baseline characteristics, resource use, and costs were compared between persisters and the other groups. Resource use and costs in the 1 month before and 6 months after the study index date (for switchers, the date of index AM switching; for persisters, a randomly assigned date to reflect the distribution of the time from AM initiation to switching among switchers) were also compared between persisters and switchers in unadjusted and adjusted analyses. Factors associated with persisting vs switching or discontinuing were assessed. After controlling for baseline characteristics and costs, persisters vs switchers had significantly lower all-cause and OAB-related costs in both the month before (all-cause $1222 vs $1759, OAB-related $142 vs $170) and 6 months after the study index date (all-cause $7017 vs $8806, OAB-related $642 vs $797). Factors associated with switching or discontinuing vs persisting included index AM, younger age, and history of UTI. A large proportion of OAB patients discontinue or switch AMs shortly after initiation, and switching is associated with higher costs.

In-hospital switching between adenosine diphosphate receptor inhibitors in patients with acute myocardial infarction treated with percutaneous coronary intervention: Insights into contemporary practice from the TRANSLATE-ACS study.

PubMed

Bagai, Akshay; Peterson, Eric D; Honeycutt, Emily; Effron, Mark B; Cohen, David J; Goodman, Shaun G; Anstrom, Kevin J; Gupta, Anjan; Messenger, John C; Wang, Tracy Y

2015-12-01

While randomized clinical trials have compared clopidogrel with higher potency adenosine diphosphate (ADP) receptor inhibitors among patients with acute myocardial infarction, little is known about the frequency, effectiveness and safety of switching between ADP receptor inhibitors in routine clinical practice. We studied 11,999 myocardial infarction patients treated with percutaneous coronary intervention at 230 hospitals from April 2010 to October 2012 in the TRANSLATE-ACS study. Multivariable Cox regression was used to compare six-month post-discharge risks of major adverse cardiovascular events (MACE: death, myocardial infarction, stroke, or unplanned revascularization) and Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO)-defined bleeding between in-hospital ADP receptor inhibitor switching versus continuation of the initially selected therapy. Among 8715 patients treated initially with clopidogrel, 994 (11.4%) were switched to prasugrel or ticagrelor; switching occurred primarily after percutaneous coronary intervention (60.9%) and at the time of hospital discharge (26.7%). Among 3284 patients treated initially with prasugrel or ticagrelor, 448 (13.6%) were switched to clopidogrel; 48.2% of switches occurred after percutaneous coronary intervention and 48.0% at hospital discharge. Switching to prasugrel or ticagrelor was not associated with increased bleeding when compared with continuation on clopidogrel (2.7% vs. 3.3%, adjusted hazard ratio 0.96, 95% confidence interval 0.64-1.42, p=0.82). Switching from prasugrel or ticagrelor to clopidogrel was not associated with increased MACE (8.9% vs. 7.7%, adjusted hazard ratio 1.06, 95% confidence interval 0.75-1.49, p=0.76) when compared with continuation on the higher potency agent. In-hospital ADP receptor inhibitor switching occurs in more than one in 10 myocardial infarction patients in contemporary practice. In this observational study, ADP receptor inhibitor switching does not appear to be significantly associated with increased hazard of MACE or bleeding. © The European Society of Cardiology 2014.

Afternoon nap and bright light exposure improve cognitive flexibility post lunch.

PubMed

Slama, Hichem; Deliens, Gaétane; Schmitz, Rémy; Peigneux, Philippe; Leproult, Rachel

2015-01-01

Beneficial effects of napping or bright light exposure on cognitive performance have been reported in participants exposed to sleep loss. Nonetheless, few studies investigated the effect of these potential countermeasures against the temporary drop in performance observed in mid-afternoon, and even less so on cognitive flexibility, a crucial component of executive functions. This study investigated the impact of either an afternoon nap or bright light exposure on post-prandial alterations in task switching performance in well-rested participants. Twenty-five healthy adults participated in two randomized experimental conditions, either wake versus nap (n=15), or bright light versus placebo (n=10). Participants were tested on a switching task three times (morning, post-lunch and late afternoon sessions). The interventions occurred prior to the post-lunch session. In the nap/wake condition, participants either stayed awake watching a 30-minute documentary or had the opportunity to take a nap for 30 minutes. In the bright light/placebo condition, participants watched a documentary under either bright blue light or dim orange light (placebo) for 30 minutes. The switch cost estimates cognitive flexibility and measures task-switching efficiency. Increased switch cost scores indicate higher difficulties to switch between tasks. In both control conditions (wake or placebo), accuracy switch-cost score increased post lunch. Both interventions (nap or bright light) elicited a decrease in accuracy switch-cost score post lunch, which was associated with diminished fatigue and decreased variability in vigilance. Additionally, there was a trend for a post-lunch benefit of bright light with a decreased latency switch-cost score. In the nap group, improvements in accuracy switch-cost score were associated with more NREM sleep stage N1. Thus, exposure to bright light during the post-lunch dip, a countermeasure easily applicable in daily life, results in similar beneficial effects as a short nap on performance in the cognitive flexibility domain with possible additional benefits on latency switch-cost scores.

Afternoon Nap and Bright Light Exposure Improve Cognitive Flexibility Post Lunch

PubMed Central

Schmitz, Rémy; Peigneux, Philippe; Leproult, Rachel

2015-01-01

Beneficial effects of napping or bright light exposure on cognitive performance have been reported in participants exposed to sleep loss. Nonetheless, few studies investigated the effect of these potential countermeasures against the temporary drop in performance observed in mid-afternoon, and even less so on cognitive flexibility, a crucial component of executive functions. This study investigated the impact of either an afternoon nap or bright light exposure on post-prandial alterations in task switching performance in well-rested participants. Twenty-five healthy adults participated in two randomized experimental conditions, either wake versus nap (n=15), or bright light versus placebo (n=10). Participants were tested on a switching task three times (morning, post-lunch and late afternoon sessions). The interventions occurred prior to the post-lunch session. In the nap/wake condition, participants either stayed awake watching a 30-minute documentary or had the opportunity to take a nap for 30 minutes. In the bright light/placebo condition, participants watched a documentary under either bright blue light or dim orange light (placebo) for 30 minutes. The switch cost estimates cognitive flexibility and measures task-switching efficiency. Increased switch cost scores indicate higher difficulties to switch between tasks. In both control conditions (wake or placebo), accuracy switch-cost score increased post lunch. Both interventions (nap or bright light) elicited a decrease in accuracy switch-cost score post lunch, which was associated with diminished fatigue and decreased variability in vigilance. Additionally, there was a trend for a post-lunch benefit of bright light with a decreased latency switch-cost score. In the nap group, improvements in accuracy switch-cost score were associated with more NREM sleep stage N1. Thus, exposure to bright light during the post-lunch dip, a countermeasure easily applicable in daily life, results in similar beneficial effects as a short nap on performance in the cognitive flexibility domain with possible additional benefits on latency switch-cost scores. PMID:26016658

Absence of Activation-induced Cytidine Deaminase, a Regulator of Class Switch Recombination and Hypermutation in B Cells, Suppresses Aorta Allograft Vasculopathy in Mice.

PubMed

Nakanishi, Tomonori; Xu, Xiaoyan; Wynn, Carmen; Yamada, Toshiko; Pan, Fan; Erickson, Laurie; Teo, Haeman; Nakagawa, Terry; Masunaga, Taro; Abe, Jumpei; Akamatsu, Masahiko; Tamura, Kouichi; Jiang, Hongsi

2015-08-01

Antibody-mediated rejection is caused in part by increasing circulation/production of donor-specific antibody (DSA). Activation-induced cytidine deaminase (AID) is a key regulator of class switch recombination and somatic hypermutation of immunoglobulin in B cells, yet its role in antibody-mediated transplant rejection remains unclear. We show here that AID deficiency in mice enables suppression of allograft vasculopathy (AV) after aorta transplantation, a DSA-mediated process. Splenocytes from C57BL/6 J (B6) AID(−/−) mice were used for determining in vitro proliferation responses, alloreactivity, cell surface marker expression, and antibody production. BALB/c mouse aortas were transplanted into B6 AID(−/−) mice with or without FK506 treatment. Blood and aorta grafts were harvested on day 30 after transplantation and were subjected to DSA, histological, and immunohistological analyses. The AID(−/−) splenocytes were comparable to wild type splenocytes in proliferation responses, alloreactivity, and expression of cell surface markers in vitro. However, they completely failed to produce immunoglobulin G, although they were not impaired in immunoglobulin M production relative to controls. Furthermore, BALB/c aorta grafts from B6 AID(−/−) recipient mice on day 30 after transplantation showed reduced signs of AV compared to the grafts from B6 wild type recipient mice which had severe vascular intimal hyperplasia, interstitial fibrosis, and inflammation. Treatment with FK506 produced a synergistic effect in the grafts from AID(−/−) recipients with further reduction of intimal hyperplasia and fibrosis scores. The AID deficiency inhibits DSA-mediated AV after aorta transplantation in mice. We propose that AID could be a novel molecular target for controlling antibody-mediated rejection in organ transplantation.

SWIFT: Prospective 48-Week Study to Evaluate Efficacy and Safety of Switching to Emtricitabine/Tenofovir From Lamivudine/Abacavir in Virologically Suppressed HIV-1 Infected Patients on a Boosted Protease Inhibitor Containing Antiretroviral Regimen

PubMed Central

Campo, R.; DeJesus, E.; Bredeek, U. F.; Henry, K.; Khanlou, H.; Logue, K.; Brinson, C.; Benson, P.; Dau, L.; Wang, H.; White, K.; Flaherty, J.; Fralich, T.; Guyer, B.; Piontkowsky, D.

2013-01-01

Background. In the United States, emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) is a preferred nucleoside reverse transcriptase inhibitor (NRTI) backbone with lamivudine/abacavir (3TC/ABC) as a commonly used alternative. For patients infected with human immunodeficiency virus (HIV-1) virologically suppressed on a boosted protease inhibitor (PI) + 3TC/ABC regimen, the merits of switching to FTC/TDF as the NRTI backbone are unknown. Methods. SWIFT was a prospective, randomized, open-label 48-week study to evaluate efficacy and safety of switching to FTC/TDF. Subjects receiving 3TC/ABC + PI + ritonavir (RTV) with HIV-1 RNA < 200 c/mL ≥3 months were randomized to continue 3TC/ABC or switch to FTC/TDF. The primary endpoint was time to loss of virologic response (TLOVR) with noninferiority measured by delta of 12%. Virologic failure (VF) was defined as confirmed rebound or the last HIV-1 RNA measurement on study drug ≥200 c/mL. Results. In total, 311 subjects were treated in this study (155 to PI + RTV + FTC/TDF, 156 to PI + RTV + 3TC/ABC). Baseline characteristics were similar between the arms: 85% male, 28% black, median age, 46 years; and median CD4 532 cells/mm3. By TLOVR through week 48, switching to FTC/TDF was noninferior compared to continued 3TC/ABC (86.4% vs 83.3%, treatment difference 3.0% (95% confidence interval, −5.1% to 11.2%). Fewer subjects on FTC/TDF experienced VF (3 vs 11; P = .034). FTC/TDF showed greater declines in fasting low-density lipoproteins (LDL), total cholesterol (TC), and triglycerides (TG) with significant declines in LDL and TC beginning at week 12 with no TC/HDL ratio change. Switching to FTC/TDF showed improved NCEP thresholds for TC and TG and improved 10-year Framingham TC calculated scores. Decreased epidermal growth factor receptor (eGFR) was observed in both arms with a larger decrease in the FTC/TDF arm. Conclusions. Switching to FTC/TDF from 3TC/ABC maintained virologic suppression, had fewer VFs, improved lipid parameters and Framingham scores but decreased eGFR. ClinicalTrials.gov identifier. NCT00724711. PMID:23362296

Open- and Closed-Skill Exercise Interventions Produce Different Neurocognitive Effects on Executive Functions in the Elderly: A 6-Month Randomized, Controlled Trial

PubMed Central

Tsai, Chia-Liang; Pan, Chien-Yu; Chen, Fu-Chen; Tseng, Yu-Ting

2017-01-01

This study aimed to explore the effects of open- and closed-skill exercise interventions on the neurocognitive performance of executive functions in the elderly. Sixty-four healthy elderly males were randomly assigned to either a closed-skill (bike riding or brisk walking/jogging, n = 22), open-skill (table tennis, n = 21), or control (n = 21) group. Various neuropsychological [e.g., accuracy rates (AR) and reaction time (RT)] and electrophysiological [e.g., event-related potential (ERP) P3 component] measures were assessed during a variant of the task-switching paradigm, as well as an N-back task at baseline and after either a 6-month exercise intervention or control period. The results showed that, when performing the task-switching paradigm, the two exercise groups relative to control group showed significantly faster RTs in the switch trials after the exercise intervention. However, the RT facilitation in the non-switch and switch trials post-exercise relative to pre-exercise only emerged in the open-skill group. In terms of the N-back task, the two exercise groups significantly increased ARs in the 1-back condition after the exercise intervention, and the beneficial AR effect on the 2-back condition only emerged in the closed-skill group. In addition, the two exercise groups exhibited significantly larger P3 amplitudes on the frontal-to-parietal cortex areas after the exercise intervention relative to the baseline when performing the two cognitive tasks. These neurocognitive results still remained unchanged even when the confounding factors (e.g., cardiorespiratory fitness, social participation, and BMI) were controlled for. The present study concluded that, although 6-month open- and closed-skill exercise interventions facilitate overall electrophysiological effects (i.e., increased ERP P3 amplitudes) on the frontal-to-parietal cortices in the elderly, the two exercise modes produced different levels of neuropsychologically beneficial effects on RTs of the task-switching paradigm (i.e., lessened RTs) and ARs of the N-back task (i.e., enhanced ARs). The distinctive neurocognitive changes induced by open- and closed-skill exercise have implications for task switching and working memory in elderly individuals, especially with such cognitive functioning impairments. PMID:28959200

Reactive molecular dynamics simulations of switching processes of azobenzene-based monolayer on surface

NASA Astrophysics Data System (ADS)

Tian, Ziqi; Wen, Jin; Ma, Jing

2013-07-01

It is a challenge to simulate the switching process of functional self-assembled monolayers (SAMs) on metal surfaces, since the systems consist of thousands of atoms and the switching is triggered by quantum-mechanical events. Herein a molecular dynamics simulation with a reactive rotation potential of N=N bond is implemented to investigate the dynamic conformational changes and packing effects on the stimuli-responsive isomerization of the terminally thiol functionalized azobiphenyls (AZOs), which are bound on the Au(111) surface. To, respectively, distinguish the time evolutions that start from cis and trans initial configurations, two different functions are established to model the potential energy curves for cis-to-trans and trans-to-cis transitions, instead of the only one cosine function used in the conventional non-reactive force fields. In order to simulate the conformation transitions of the AZO film on surface, a random switching function, depending on the N=N twisting angle, is constructed to consider both forward and backward cis/trans isomerization events and to trigger the reaction by changing the N atom types automatically. The factors that will influence the isomerization process, including the choice of ensembles and thermostat algorithms, the time intervals separating each switching, and the forms of the switching function, are systematically tested. Most AZO molecules switch from the cis to trans configuration with a coverage of 5.76 × 10-6 mol/m2 on a picosecond time scale, and a low coverage might make the switching irreversible, which is in agreement with the experiments.

Antiplatelet Regimen for Patients With Breakthrough Strokes While on Aspirin: A Systematic Review and Meta-Analysis.

PubMed

Lee, Meng; Saver, Jeffrey L; Hong, Keun-Sik; Rao, Neal M; Wu, Yi-Ling; Ovbiagele, Bruce

2017-09-01

Optimal antiplatelet therapy after an ischemic stroke or transient ischemic attack while on aspirin is uncertain. We, therefore, conducted a systematic review and meta-analysis. We searched PubMed (1966 to August 2016) and bibliographies of relevant published original studies to identify randomized trials and cohort studies reporting patients who were on aspirin at the time of an index ischemic stroke or transient ischemic attack and reported hazard ratio for major adverse cardiovascular events or recurrent stroke associated with a switch to or addition of another antiplatelet agent versus maintaining aspirin monotherapy. Estimates were combined using a random effects model. Five studies with 8723 patients with ischemic stroke or transient ischemic attack were identified. Clopidogrel was used in 4 cohorts, and ticagrelor was used in 1 cohort. Pooling results showed that addition of or a switch to another antiplatelet agent, versus aspirin monotherapy, was associated with reduced risks of major adverse cardiovascular events (hazard ratio, 0.68; 95% confidence interval, 0.54-0.85) and recurrent stroke (hazard ratio, 0.70; 95% confidence interval, 0.54-0.92). Each of the strategies of addition of and switching another antiplatelet agent showed benefit versus continued aspirin monotherapy, and studies with regimen initiation in the first days after index event showed more homogenous evidence of benefit. Among patients who experience an ischemic stroke or transient ischemic attack while on aspirin monotherapy, the addition of or a switch to another antiplatelet agent, especially in the first days after index event, is associated with fewer future vascular events, including stroke. © 2017 American Heart Association, Inc.

Tri-state resistive switching characteristics of MnO/Ta2O5 resistive random access memory device by a controllable reset process

NASA Astrophysics Data System (ADS)

Lee, N. J.; Kang, T. S.; Hu, Q.; Lee, T. S.; Yoon, T.-S.; Lee, H. H.; Yoo, E. J.; Choi, Y. J.; Kang, C. J.

2018-06-01

Tri-state resistive switching characteristics of bilayer resistive random access memory devices based on manganese oxide (MnO)/tantalum oxide (Ta2O5) have been studied. The current–voltage (I–V) characteristics of the Ag/MnO/Ta2O5/Pt device show tri-state resistive switching (RS) behavior with a high resistance state (HRS), intermediate resistance state (IRS), and low resistance state (LRS), which are controlled by the reset process. The MnO/Ta2O5 film shows bipolar RS behavior through the formation and rupture of conducting filaments without the forming process. The device shows reproducible and stable RS both from the HRS to the LRS and from the IRS to the LRS. In order to elucidate the tri-state RS mechanism in the Ag/MnO/Ta2O5/Pt device, transmission electron microscope (TEM) images are measured in the LRS, IRS and HRS. White lines like dendrites are observed in the Ta2O5 film in both the LRS and the IRS. Poole–Frenkel conduction, space charge limited conduction, and Ohmic conduction are proposed as the dominant conduction mechanisms for the Ag/MnO/Ta2O5/Pt device based on the obtained I–V characteristics and TEM images.

Effect of dysprosium and lutetium metal buffer layers on the resistive switching characteristics of Cu-Sn alloy-based conductive-bridge random access memory.

PubMed

Vishwanath, Sujaya Kumar; Woo, Hyunsuk; Jeon, Sanghun

2018-06-18

Conductive-bridge random access memory (CBRAM) has become one of the most suitable candidates for non-volatile memory in next-generation information and communication technology. The resistive switching mechanism of CBRAM depends on the formation/annihilation of the conductive filament (CF) between the active metal electrode and the inert electrode. However, excessive ion injection from the active electrode into the solid electrolyte is reduces the uniformity and reliability of the resistive switching devices. To solve this problem, we investigated the resistive switching characteristics of a modified active electrode with different compositions of Cu_x-Sn_{_1-x}(0.13 < X < 0.55). The resistive switching characteristics were further improved by inserting a dysprosium (Dy) or lutetium (Lu) buffer layer at the interface of Cu_x-Sn_1-x/Al₂O₃. Electrical analysis of the optimal Cu_0.27-Sn_0.73/Lu-based CBRAM exhibited stable resistive switching behavior with low operation voltage (SET: 0.7 V and RESET: -0.3 V), a high on/off resistive ratio (10⁶), cyclic endurance (>10⁴), and long-term retention (85℃/10 years). To achieve these performance parameters, CFs were locally formed inside the electrolyte using a modified CuSn active electrode, and the amount of Cu-ion injection was reduced by inserting the Dy or Lu buffer layer between the CuSn active electrode and the electrolyte. In particular, conductive-atomic force microscopy results at the Dy/ or Lu/Al₂O₃ interface directly showed and defined the diameter of the CF. © 2018 IOP Publishing Ltd.

Adiponectin and the steatosis marker Chi3L1 decrease following switch to raltegravir compared to continued PI/NNRTI-based antiretroviral therapy.

PubMed

Offor, Obiageli; Utay, Netanya; Reynoso, David; Somasunderam, Anoma; Currier, Judith; Lake, Jordan

2018-01-01

People with HIV are at for metabolic syndrome (MetS) and fatty liver disease, but the role of Antiretroviral therapy (ART) is poorly understood. MetS and fatty liver disease been associated with changes in adiponectin, soluble ST2 (sST2), chitinase 3-like 1 (Chi3L1), hyaluronic acid (HA), tissue inhibitor of metalloproteinase-1 (TIMP-1), lysyl oxidase-like-2 (LOXL2) and transforming growth factor β (TGF-β) concentrations in HIV-uninfected populations. Protease (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) may contribute to these comorbidities, but the effects of switching from PI- or NNRTI to raltegravir (RAL) on these biomarkers is unknown. Cryopreserved plasma was obtained from a completed, prospective trial of HIV-infected women with central adiposity on NNRTI- or PI-based ART during which they were randomized to remain on their current ART or switch to a RAL based regimen. Biomarker concentrations were quantified using ELISA and Multiplex assays at baseline and 24 weeks after randomization. Wilcoxon-signed rank test evaluated within-group changes, Spearman and linear regression models evaluated correlations between biomarkers and clinical covariates. Participants had a median age of 43 years, CD4+ T lymphocyte count 558 cells/mm3 and BMI 32 kg/m2; 35% met criteria for MetS. At baseline, higher adiponectin levels correlated with higher Chi3L1 levels (r = 0.42, p = 0.02), as did declines after 24 weeks (r = 0.40, p = 0.03). Changes in sST2 correlated with changes in Chi3L1 (r = 0.43, p = 0.02) and adiponectin (r = 0.40, p = 0.03). Adiponectin and Chi3L1 levels decreased significantly in women switched to RAL vs continue PI/NNRTI. In women with HIV and central obesity, the hepatic steatosis/fibrosis marker Chi3L1 and adiponectin decrease in conjunction with sST2 decreases following switch to RAL. Whether switching from NNRTI/PI-based regimens to RAL can improve hepatic steatosis and dysmetabolism requires further study. Clinicaltrials.gov NCT00656175.

Stable Caloric Intake and Continued Virologic Suppression for HIV-Positive Antiretroviral Treatment-Experienced Women After Switching to a Single-Tablet Regimen of Emtricitabine, Rilpivirine, and Tenofovir Disoproxil Fumarate.

PubMed

Menezes, Prema; Mollan, Katie; Hoffman, Erin; Xie, Zimeng; Wills, Jennifer; Marcus, Cheryl; Rublein, John; Hudgens, Michael; Eron, Joseph J

2018-05-02

Benefits of switching to a single-tablet regimen (STR) of emtricitabine/rilpivirine/tenofovir (FTC/RPV/TDF) in virologically suppressed antiretroviral treatment (ART) experienced HIV-positive women include pregnancy category B rating and lack of clinically significant drug interactions between RPV and oral contraceptives. Unfortunately, studies involving switching to FTC/RPV/TDF enrolled fewer than 25% women. We undertook this 48-week study to assess the ability of virologically suppressed HIV-positive women switching to RPV STR to remain virologically suppressed and comply with the caloric intake requirement. HIV-positive women on ART with viral load <50 c/mL for 6 months before study entry and no known resistance to FTC, TDF, or RPV were enrolled and switched to STR RPV/FTC/TDF. Caloric intake (≥400 kcal) compliance and concurrency with oral STR RPV/FTC/TDF were evaluated with a 3-day food diary, which was validated by obtaining participant's caloric consumption through phone calls on randomly chosen dates. For each 3-day food diary, the daily median caloric intake and median value for each macronutrient consumed concurrent with FTC/RPV/TDF were computed. Medication adherence was measured using a visual analog scale. We enrolled 33 women, 73% of whom were African American. At week 48, virologic suppression (HIV RNA <40 c/mL) was maintained in 96% of women, including those (n = 4) who reported imperfect ART adherence. The daily median caloric intake concurrent with FTC/RPV/TDF was 820 kcal by food diary and 677 kcal by random phone call. Median kcal intake (food diary) did not change significantly from baseline (684 kcal) to week 48 (820 kcal); median change 102 kcal, p = .15. Women who reported noncompliance with a ≥400 kcal meal did not experience virologic failure. Significant concordance between caloric adherence and virologic suppression was not detected. Our study demonstrated that HIV-positive women who switched to STR FTC/RPV/TDF continued to experience virologic suppression and were readily able to comply with the recommended caloric intake requirement.

Uniting Gradual and Abrupt set Processes in Resistive Switching Oxides

NASA Astrophysics Data System (ADS)

Fleck, Karsten; La Torre, Camilla; Aslam, Nabeel; Hoffmann-Eifert, Susanne; Böttger, Ulrich; Menzel, Stephan

2016-12-01

Identifying limiting factors is crucial for a better understanding of the dynamics of the resistive switching phenomenon in transition-metal oxides. This improved understanding is important for the design of fast-switching, energy-efficient, and long-term stable redox-based resistive random-access memory devices. Therefore, this work presents a detailed study of the set kinetics of valence change resistive switches on a time scale from 10 ns to 104 s , taking Pt /SrTiO3/TiN nanocrossbars as a model material. The analysis of the transient currents reveals that the switching process can be subdivided into a linear-degradation process that is followed by a thermal runaway. The comparison with a dynamical electrothermal model of the memory cell allows the deduction of the physical origin of the degradation. The origin is an electric-field-induced increase of the oxygen-vacancy concentration near the Schottky barrier of the Pt /SrTiO3 interface that is accompanied by a steadily rising local temperature due to Joule heating. The positive feedback of the temperature increase on the oxygen-vacancy mobility, and thereby on the conductivity of the filament, leads to a self-acceleration of the set process.

Next generation communications satellites: Multiple access and network studies

NASA Technical Reports Server (NTRS)

Stern, T. E.; Schwartz, M.; Meadows, H. E.; Ahmadi, H. K.; Gadre, J. G.; Gopal, I. S.; Matsmo, K.

1980-01-01

Following an overview of issues involved in the choice of promising system architectures for efficient communication with multiple small inexpensive Earth stations serving hetergeneous user populations, performance evaluation via analysis and simulation for six SS/TDMA (satellite-switched/time-division multiple access) system architectures is discussed. These configurations are chosen to exemplify the essential alternatives available in system design. Although the performance evaluation analyses are of fairly general applicability, whenever possible they are considered in the context of NASA's 30/20 GHz studies. Packet switched systems are considered, with the assumption that only a part of transponder capacit is devoted to packets, the integration of circuit and packet switched traffic being reserved for further study. Three types of station access are distinguished: fixed (FA), demand (DA), and random access (RA). Similarly, switching in the satellite can be assigned on a fixed (FS) or demand (DS) basis, or replaced by a buffered store-and-forward system (SF) onboard the satellite. Since not all access/switching combinations are practical, six systems are analyzed in detail: three FS SYSTEMS, FA/FS, DA/ES, RA/FS; one DS system, DA/DS; and two SF systems, FA/SF, DA/SF. Results are presented primarily in terms of delay-throughput characteristics.

Resistive switching characteristics of manganese oxide thin film and nanoparticle assembly hybrid devices

NASA Astrophysics Data System (ADS)

Abbas, Haider; Park, Mi Ra; Abbas, Yawar; Hu, Quanli; Kang, Tae Su; Yoon, Tae-Sik; Kang, Chi Jung

2018-06-01

Improved resistive switching characteristics are demonstrated in a hybrid device with Pt/Ti/MnO (thin film)/MnO (nanoparticle)/Pt structure. The hybrid devices of MnO thin film and nanoparticle assembly were fabricated. MnO nanoparticles with an average diameter of ∼30 nm were chemically synthesized and assembled as a monolayer on a Pt bottom electrode. A MnO thin film of ∼40 nm thickness was deposited on the nanoparticle assembly to form the hybrid structure. Resistive switching could be induced by the formation and rupture of conducting filaments in the hybrid oxide layers. The hybrid device exhibited very stable unipolar switching with good endurance and retention characteristics. It showed a larger and stable memory window with a uniform distribution of SET and RESET voltages. Moreover, the conduction mechanisms of ohmic conduction, space-charge-limited conduction, Schottky emission, and Poole–Frenkel emission have been investigated as possible conduction mechanisms for the switching of the devices. Using MnO nanoparticles in the thin film and nanoparticle heterostructures enabled the appropriate control of resistive random access memory (RRAM) devices and markedly improved their memory characteristics.

Analysis of switch and examine combining with post-examining selection in cognitive radio

NASA Astrophysics Data System (ADS)

Agarwal, Rupali; Srivastava, Neelam; Katiyar, Himanshu

2018-06-01

To perform spectrum sensing in fading environment is one of the most challenging tasks for a CR system. Diversity combining schemes are used to combat the effect of fading and hence detection probability of CR gets improved. Among many diversity combining techniques, switched diversity offers one of the lowest complexity solutions. The receiver embedded with switched diversity looks for an acceptable diversity path (having signal to noise ratio (SNR) above the required threshold) to receive the data. In conventional switch and examine combining (SEC) scheme, when no acceptable path is found after all the paths are examined, the receiver randomly chooses an unacceptable path. Switch and examine combining with post-examining selection (SECp) is a modified version of conventional SEC. In SECp, the conventional SEC scheme is altered in a way that it selects the best path when no acceptable path is found after all paths have been examined. In this paper, formula for probability of detection ( ?) is derived using SECp and SEC diversity combining technique over Rayleigh fading channel. Also the performance of SECp is compared with SEC and no diversity case. Performance comparison is done with the help of SNR vs. ? and complementary receiver operating characteristic curves.

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…

Correlated resistive/capacitive state variability in solid TiO2 based memory devices

NASA Astrophysics Data System (ADS)

Li, Qingjiang; Salaoru, Iulia; Khiat, Ali; Xu, Hui; Prodromakis, Themistoklis

2017-05-01

In this work, we experimentally demonstrated the correlated resistive/capacitive switching and state variability in practical TiO2 based memory devices. Based on filamentary functional mechanism, we argue that the impedance state variability stems from the randomly distributed defects inside the oxide bulk. Finally, our assumption was verified via a current percolation circuit model, by taking into account of random defects distribution and coexistence of memristor and memcapacitor.

Conception, fabrication and characterization of a silicon based MEMS inertial switch with a threshold value of 5 g

NASA Astrophysics Data System (ADS)

Zhang, Fengtian; Wang, Chao; Yuan, Mingquan; Tang, Bin; Xiong, Zhuang

2017-12-01

Most of the MEMS inertial switches developed in recent years are intended for shock and impact sensing with a threshold value above 50 g. In order to follow the requirement of detecting linear acceleration signal at low-g level, a silicon based MEMS inertial switch with a threshold value of 5 g was designed, fabricated and characterized. The switch consisted of a large proof mass, supported by circular spiral springs. An analytical model of the structure stiffness of the proposed switch was derived and verified by finite-element simulation. The structure fabrication was based on a customized double-buried layer silicon-on-insulator wafer and encapsulated by glass wafers. The centrifugal experiment and nanoindentation experiment were performed to measure the threshold value as well as the structure stiffness. The actual threshold values were measured to be 0.1-0.3 g lower than the pre-designed value of 5 g due to the dimension loss during non-contact lithography processing. Concerning the reliability assessment, a series of environmental experiments were conducted and the switches remained operational without excessive errors. However, both the random vibration and the shock tests indicate that the metal particles generated during collision of contact parts might affect the contact reliability and long-time stability. According to the conclusion reached in this report, an attentive study on switch contact behavior should be included in future research.

Design, conduct, and analyses of Breast International Group (BIG) 1-98: a randomized, double-blind, phase-III study comparing letrozole and tamoxifen as adjuvant endocrine therapy for postmenopausal women with receptor-positive, early breast cancer.

PubMed

Giobbie-Hurder, Anita; Price, Karen N; Gelber, Richard D

2009-06-01

Aromatase inhibitors provide superior disease control when compared with tamoxifen as adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer. To present the design, history, and analytic challenges of the Breast International Group (BIG) 1-98 trial: an international, multicenter, randomized, double-blind, phase-III study comparing the aromatase inhibitor letrozole with tamoxifen in this clinical setting. From 1998-2003, BIG 1-98 enrolled 8028 women to receive monotherapy with either tamoxifen or letrozole for 5 years, or sequential therapy of 2 years of one agent followed by 3 years of the other. Randomization to one of four treatment groups permitted two complementary analyses to be conducted several years apart. The first, reported in 2005, provided a head-to-head comparison of letrozole versus tamoxifen. Statistical power was increased by an enriched design, which included patients who were assigned sequential treatments until the time of the treatment switch. The second, reported in late 2008, used a conditional landmark approach to test the hypothesis that switching endocrine agents at approximately 2 years from randomization for patients who are disease-free is superior to continuing with the original agent. The 2005 analysis showed the superiority of letrozole compared with tamoxifen. The patients who were assigned tamoxifen alone were unblinded and offered the opportunity to switch to letrozole. Results from other trials increased the clinical relevance about whether or not to start treatment with letrozole or tamoxifen, and analysis plans were expanded to evaluate sequential versus single-agent strategies from randomization. Due to the unblinding of patients assigned tamoxifen alone, analysis of updated data will require ascertainment of the influence of selective crossover from tamoxifen to letrozole. BIG 1-98 is an example of an enriched design, involving complementary analyses addressing different questions several years apart, and subject to evolving analytic plans influenced by new data that emerge over time.

Psilocybin links binocular rivalry switch rate to attention and subjective arousal levels in humans.

PubMed

Carter, Olivia L; Hasler, Felix; Pettigrew, John D; Wallis, Guy M; Liu, Guang B; Vollenweider, Franz X

2007-12-01

Binocular rivalry occurs when different images are simultaneously presented to each eye. During continual viewing of this stimulus, the observer will experience repeated switches between visual awareness of the two images. Previous studies have suggested that a slow rate of perceptual switching may be associated with clinical and drug-induced psychosis. The objective of the study was to explore the proposed relationship between binocular rivalry switch rate and subjective changes in psychological state associated with 5-HT2A receptor activation. This study used psilocybin, the hallucinogen found naturally in Psilocybe mushrooms that had previously been found to induce psychosis-like symptoms via the 5-HT2A receptor. The effects of psilocybin (215 microg/kg) were considered alone and after pretreatment with the selective 5-HT2A antagonist ketanserin (50 mg) in ten healthy human subjects. Psilocybin significantly reduced the rate of binocular rivalry switching and increased the proportion of transitional/mixed percept experience. Pretreatment with ketanserin blocked the majority of psilocybin's "positive" psychosis-like hallucinogenic symptoms. However, ketanserin had no influence on either the psilocybin-induced slowing of binocular rivalry or the drug's "negative-type symptoms" associated with reduced arousal and vigilance. Together, these findings link changes in binocular rivalry switching rate to subjective levels of arousal and attention. In addition, it suggests that psilocybin's effect on binocular rivalry is unlikely to be mediated by the 5-HT2A receptor.

A Randomized Controlled Trial of Vildagliptin Versus Alogliptin: Effective Switch From Sitagliptin in Patients With Type 2 Diabetes.

PubMed

Shigematsu, Erina; Yamakawa, Tadashi; Oba, Mari S; Suzuki, Jun; Nagakura, Jo; Kadonosono, Kazuaki; Terauchi, Yasuo

2017-07-01

We investigated the effects of vildagliptin or alogliptin on blood glucose and hemoglobin A1c (HbA1c) in patients with type 2 diabetes inadequately controlled by sitagliptin. In a single-center open-label trial, 35 patients with inadequate glycemic control on sitagliptin therapy (50 mg once daily) were randomly switched to treatment with vildagliptin (50 mg twice daily) or alogliptin (25 mg once daily). After 12 weeks, patients who failed to achieve the target HbA1c level of < 7.0% with vildagliptin or alogliptin treatment were switched to high-dose sitagliptin (100 mg once daily) and the effect on glycemic control was assessed. Vildagliptin did not significantly alter the mean plasma glucose level (175.5 ± 54.4 mg/dL vs. 179.1 ± 73.4 mg/dL) or HbA1c (8.01% vs. 8.02%) after 12 weeks. With alogliptin, mean plasma glucose increased from 175.4 ± 50.9 mg/dL to 195.3 ± 55.0 mg/dL after 12 weeks and HbA1c increased significantly from 8.0% to 8.3% (P < 0.05). At 12 weeks after switching from vildagliptin to high-dose sitagliptin (100 mg daily), HbA1c was increased to 8.3%, but it was significantly (P < 0.05) reduced to the baseline level of 8.0% after switching from alogliptin. The reduction of HbA1c was significantly greater in the vildagliptin group than the alogliptin group (P = 0.008), but the response rate (achieving the target HbA1c < 7.0%) did not differ significantly between the two groups. The glucose-lowering effects of these three dipeptidyl peptidase-4 (DPP-4) inhibitors (vildagliptin, alogliptin, and sitagliptin) were different, and the effects of vildagliptin and sitagliptin were stronger than that of alogliptin.

Asynchronous State Estimation for Discrete-Time Switched Complex Networks With Communication Constraints.

PubMed

Zhang, Dan; Wang, Qing-Guo; Srinivasan, Dipti; Li, Hongyi; Yu, Li

2018-05-01

This paper is concerned with the asynchronous state estimation for a class of discrete-time switched complex networks with communication constraints. An asynchronous estimator is designed to overcome the difficulty that each node cannot access to the topology/coupling information. Also, the event-based communication, signal quantization, and the random packet dropout problems are studied due to the limited communication resource. With the help of switched system theory and by resorting to some stochastic system analysis method, a sufficient condition is proposed to guarantee the exponential stability of estimation error system in the mean-square sense and a prescribed performance level is also ensured. The characterization of the desired estimator gains is derived in terms of the solution to a convex optimization problem. Finally, the effectiveness of the proposed design approach is demonstrated by a simulation example.

Large magnetoresistance and sharp switching in FexTiS2

NASA Astrophysics Data System (ADS)

Choe, Jesse; Morosan, Emilia

Large magnetoresistance materials are suitable for applications in sensors, read heads, and random access memories. Most metals, though having excellent ductility which is important for manufacturing processes, have changes of magnetoresistance on the order of only 1 % . Very large magnetoresistances in Fe0.30TaS2 ( 140 %) have been attributed to misalignment of magnetic moments causing spin disorder scattering. We performed measurements of the magnetic field dependence of resistivity and magnetization of FexTiS2 single crystals (x = 0 . 1 - 0 . 5), which show both the large magnetoresistance, as well as the sharp switching in magnetization as those reported in the Ta analogue. By comparing and contrasting these two materials, we can gain deeper understanding of the underlying physics, allowing us to strategically search for materials with higher transition temperature, lower switching fields, and larger magnetoresistances. NSF DMREF 1629374.

Brief Report: Long-Term (96-Week) Efficacy and Safety After Switching From Tenofovir Disoproxil Fumarate to Tenofovir Alafenamide in HIV-Infected, Virologically Suppressed Adults

PubMed Central

Raffi, François; Orkin, Chloe; Clarke, Amanda; Slama, Laurence; Gallant, Joel; Daar, Eric; Henry, Keith; Santana-Bagur, Jorge; Stein, David K.; Bellos, Nicholaos; Scarsella, Anthony; Yan, Mingjin; Abram, Michael E.; Cheng, Andrew

2017-01-01

Abstract: In a double-blind, phase 3 trial, 663 HIV-infected, virologically suppressed adults were randomized to switch to tenofovir alafenamide (TAF; n = 333) vs. remain on tenofovir disoproxil fumarate (TDF; n = 330), each coformulated with emtricitabine (FTC), while continuing their third agent (boosted protease inhibitor or unboosted third agent). At week 96, 88.6% on FTC/TAF and 89.1% on FTC/TDF had HIV-1 RNA <50 copies per milliliter [adjusted difference −0.5% (95% confidence interval: −5.3 to 4.4%)]. Proteinuria, albuminuria, proximal renal tubular function, and bone mineral density improved after switching to TAF- from TDF-containing regimens. These longer-term data support FTC/TAF as a safe, well-tolerated, and durable nucleotide reverse transcriptase inhibitor backbone. PMID:28272164

High-performance flexible resistive memory devices based on Al2O3:GeOx composite

NASA Astrophysics Data System (ADS)

Behera, Bhagaban; Maity, Sarmistha; Katiyar, Ajit K.; Das, Samaresh

2018-05-01

In this study a resistive switching random access memory device using Al2O3:GeOx composite thin films on flexible substrate is presented. A bipolar switching characteristic was observed for the co-sputter deposited Al2O3:GeOx composite thin films. Al/Al2O3:GeOx/ITO/PET memory device shows excellent ON/OFF ratio (∼104) and endurance (>500 cycles). GeOx nanocrystals embedded in the Al2O3 matrix have been found to play a significant role in enhancing the switching characteristics by facilitating oxygen vacancy formation. Mechanical endurance was retained even after several bending. The conduction mechanism of the device was qualitatively discussed by considering Ohmic and SCLC conduction. This flexible device is a potential candidate for next-generation electronics device.

Internal filament modulation in low-dielectric gap design for built-in selector-less resistive switching memory application

NASA Astrophysics Data System (ADS)

Chen, Ying-Chen; Lin, Chih-Yang; Huang, Hui-Chun; Kim, Sungjun; Fowler, Burt; Chang, Yao-Feng; Wu, Xiaohan; Xu, Gaobo; Chang, Ting-Chang; Lee, Jack C.

2018-02-01

Sneak path current is a severe hindrance for the application of high-density resistive random-access memory (RRAM) array designs. In this work, we demonstrate nonlinear (NL) resistive switching characteristics of a HfO x /SiO x -based stacking structure as a realization for selector-less RRAM devices. The NL characteristic was obtained and designed by optimizing the internal filament location with a low effective dielectric constant in the HfO x /SiO x structure. The stacking HfO x /SiO x -based RRAM device as the one-resistor-only memory cell is applicable without needing an additional selector device to solve the sneak path issue with a switching voltage of ~1 V, which is desirable for low-power operating in built-in nonlinearity crossbar array configurations.

Modeling and experimental study of resistive switching in vertically aligned carbon nanotubes

NASA Astrophysics Data System (ADS)

Ageev, O. A.; Blinov, Yu F.; Ilina, M. V.; Ilin, O. I.; Smirnov, V. A.

2016-08-01

Model of the resistive switching in vertically aligned carbon nanotube (VA CNT) taking into account the processes of deformation, polarization and piezoelectric charge accumulation have been developed. Origin of hysteresis in VA CNT-based structure is described. Based on modeling results the VACNTs-based structure has been created. The ration resistance of high-resistance to low-resistance states of the VACNTs-based structure amounts 48. The correlation the modeling results with experimental studies is shown. The results can be used in the development nanoelectronics devices based on VA CNTs, including the nonvolatile resistive random-access memory.

A sweep algorithm for massively parallel simulation of circuit-switched networks

NASA Technical Reports Server (NTRS)

Gaujal, Bruno; Greenberg, Albert G.; Nicol, David M.

1992-01-01

A new massively parallel algorithm is presented for simulating large asymmetric circuit-switched networks, controlled by a randomized-routing policy that includes trunk-reservation. A single instruction multiple data (SIMD) implementation is described, and corresponding experiments on a 16384 processor MasPar parallel computer are reported. A multiple instruction multiple data (MIMD) implementation is also described, and corresponding experiments on an Intel IPSC/860 parallel computer, using 16 processors, are reported. By exploiting parallelism, our algorithm increases the possible execution rate of such complex simulations by as much as an order of magnitude.

Spin torque switching of 20 nm magnetic tunnel junctions with perpendicular anisotropy

NASA Astrophysics Data System (ADS)

Gajek, M.; Nowak, J. J.; Sun, J. Z.; Trouilloud, P. L.; O'Sullivan, E. J.; Abraham, D. W.; Gaidis, M. C.; Hu, G.; Brown, S.; Zhu, Y.; Robertazzi, R. P.; Gallagher, W. J.; Worledge, D. C.

2012-03-01

Spin-transfer torque magnetic random access memory (STT-MRAM) is one of the most promising emerging non-volatile memory technologies. MRAM has so far been demonstrated with a unique combination of density, speed, and non-volatility in a single chip, however, without the capability to replace any single mainstream memory. In this paper, we demonstrate the basic physics of spin torque switching in 20 nm diameter magnetic tunnel junctions with perpendicular magnetic anisotropy materials. This deep scaling capability clearly indicates the STT MRAM device itself may be suitable for integration at much higher densities than previously proven.

Chaos control of Hastings–Powell model by combining chaotic motions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Danca, Marius-F., E-mail: danca@rist.ro; Chattopadhyay, Joydev, E-mail: joydev@isical.ac.in

2016-04-15

In this paper, we propose a Parameter Switching (PS) algorithm as a new chaos control method for the Hastings–Powell (HP) system. The PS algorithm is a convergent scheme that switches the control parameter within a set of values while the controlled system is numerically integrated. The attractor obtained with the PS algorithm matches the attractor obtained by integrating the system with the parameter replaced by the averaged value of the switched parameter values. The switching rule can be applied periodically or randomly over a set of given values. In this way, every stable cycle of the HP system can bemore » approximated if its underlying parameter value equalizes the average value of the switching values. Moreover, the PS algorithm can be viewed as a generalization of Parrondo's game, which is applied for the first time to the HP system, by showing that losing strategy can win: “losing + losing = winning.” If “loosing” is replaced with “chaos” and, “winning” with “order” (as the opposite to “chaos”), then by switching the parameter value in the HP system within two values, which generate chaotic motions, the PS algorithm can approximate a stable cycle so that symbolically one can write “chaos + chaos = regular.” Also, by considering a different parameter control, new complex dynamics of the HP model are revealed.« less

Voltage-controlled magnetization switching in MRAMs in conjunction with spin-transfer torque and applied magnetic field

NASA Astrophysics Data System (ADS)

Munira, Kamaram; Pandey, Sumeet C.; Kula, Witold; Sandhu, Gurtej S.

2016-11-01

Voltage-controlled magnetic anisotropy (VCMA) effect has attracted a significant amount of attention in recent years because of its low cell power consumption during the anisotropy modulation of a thin ferromagnetic film. However, the applied voltage or electric field alone is not enough to completely and reliably reverse the magnetization of the free layer of a magnetic random access memory (MRAM) cell from anti-parallel to parallel configuration or vice versa. An additional symmetry-breaking mechanism needs to be employed to ensure the deterministic writing process. Combinations of voltage-controlled magnetic anisotropy together with spin-transfer torque (STT) and with an applied magnetic field (Happ) were evaluated for switching reliability, time taken to switch with low error rate, and energy consumption during the switching process. In order to get a low write error rate in the MRAM cell with VCMA switching mechanism, a spin-transfer torque current or an applied magnetic field comparable to the critical current and field of the free layer is necessary. In the hybrid processes, the VCMA effect lowers the duration during which the higher power hungry secondary mechanism is in place. Therefore, the total energy consumed during the hybrid writing processes, VCMA + STT or VCMA + Happ, is less than the energy consumed during pure spin-transfer torque or applied magnetic field switching.

Stochastic models for regulatory networks of the genetic toggle switch.

PubMed

Tian, Tianhai; Burrage, Kevin

2006-05-30

Bistability arises within a wide range of biological systems from the lambda phage switch in bacteria to cellular signal transduction pathways in mammalian cells. Changes in regulatory mechanisms may result in genetic switching in a bistable system. Recently, more and more experimental evidence in the form of bimodal population distributions indicates that noise plays a very important role in the switching of bistable systems. Although deterministic models have been used for studying the existence of bistability properties under various system conditions, these models cannot realize cell-to-cell fluctuations in genetic switching. However, there is a lag in the development of stochastic models for studying the impact of noise in bistable systems because of the lack of detailed knowledge of biochemical reactions, kinetic rates, and molecular numbers. In this work, we develop a previously undescribed general technique for developing quantitative stochastic models for large-scale genetic regulatory networks by introducing Poisson random variables into deterministic models described by ordinary differential equations. Two stochastic models have been proposed for the genetic toggle switch interfaced with either the SOS signaling pathway or a quorum-sensing signaling pathway, and we have successfully realized experimental results showing bimodal population distributions. Because the introduced stochastic models are based on widely used ordinary differential equation models, the success of this work suggests that this approach is a very promising one for studying noise in large-scale genetic regulatory networks.

Stochastic models for regulatory networks of the genetic toggle switch

PubMed Central

Tian, Tianhai; Burrage, Kevin

2006-01-01

Bistability arises within a wide range of biological systems from the λ phage switch in bacteria to cellular signal transduction pathways in mammalian cells. Changes in regulatory mechanisms may result in genetic switching in a bistable system. Recently, more and more experimental evidence in the form of bimodal population distributions indicates that noise plays a very important role in the switching of bistable systems. Although deterministic models have been used for studying the existence of bistability properties under various system conditions, these models cannot realize cell-to-cell fluctuations in genetic switching. However, there is a lag in the development of stochastic models for studying the impact of noise in bistable systems because of the lack of detailed knowledge of biochemical reactions, kinetic rates, and molecular numbers. In this work, we develop a previously undescribed general technique for developing quantitative stochastic models for large-scale genetic regulatory networks by introducing Poisson random variables into deterministic models described by ordinary differential equations. Two stochastic models have been proposed for the genetic toggle switch interfaced with either the SOS signaling pathway or a quorum-sensing signaling pathway, and we have successfully realized experimental results showing bimodal population distributions. Because the introduced stochastic models are based on widely used ordinary differential equation models, the success of this work suggests that this approach is a very promising one for studying noise in large-scale genetic regulatory networks. PMID:16714385

Engineering amorphous-crystalline interfaces in TiO2-x/TiO2-y-based bilayer structures for enhanced resistive switching and synaptic properties

NASA Astrophysics Data System (ADS)

Bousoulas, P.; Asenov, P.; Karageorgiou, I.; Sakellaropoulos, D.; Stathopoulos, S.; Tsoukalas, D.

2016-10-01

The operating principle of resistive random access memories (RRAMs) relies on the distribution of ionic species and their influence on the electron transport. Taking into account that formation and annihilation of conducting filaments (CFs) is the driving mechanism for the switching effect, it is very important to control the regions where these filaments will evolve. Thus, homolayers of titanium oxide with different oxygen contents were fabricated in order to tune the local electrical and thermal properties of the CFs and narrow down the potential percolation paths. We show that the oxygen content in the top layer of the TiO2-x/TiO2-y bilayer memristors can directly influence the morphology of the layers which affect the diffusion barrier and consequently the diffusivity and drift velocity of oxygen vacancies, yielding in important enhancement of switching characteristics, in terms of spatial uniformity (σ/μ < 0.2), enlarged switching ratio (˜104), and synaptic learning. In order to address the experimental data, a physical model was applied, divulging the crucial role of temperature, electric potential and oxygen vacancy density on the switching effect and offering physical insights to the SET/RESET transitions and the analog switching. The forming free nature of all the devices in conjunction with the self-rectifying behavior, should also be regarded as important assets towards RRAM device optimization.

Switching and augmentation strategies for antipsychotic medications in acute-phase schizophrenia: latest evidence and place in therapy

PubMed Central

Hatta, Kotaro; Sugiyama, Naoya; Ito, Hiroto

2018-01-01

In terms of effectiveness of antipsychotics in schizophrenia, discrepancy often exists between results from double-blind randomized controlled trials and observations in emergency or acute-phase clinical practice. For instance, the antipsychotic switching strategy is not always applicable in emergency or acute-phase situations, and augmentation of another antipsychotic is occasionally done instead. In this review, we discuss strategies for early nonresponse to an antipsychotic drug such as switching and augmentation from the perspective of emergency and acute-phase treatment. We searched PubMed for the latest evidence on switching and augmentation strategies of antipsychotics for an emergency or acute-phase period. For risperidone and olanzapine, there is some evidence on switching and augmentation strategies in the management of acute-phase schizophrenia. There may be responders to olanzapine alone among early nonresponders to risperidone, whereas there may be few responders to risperidone alone among early nonresponders to olanzapine. However, there is still insufficient evidence at this time for application of these findings to routine clinical practice. For other antipsychotics, there is little evidence for their augmentation in acute-phase practice. We should be wary of polypharmacy, as multiple agents are too often prescribed by clinicians when not warranted. Considering current evidence, we propose how to switch antipsychotics in the acute phase of schizophrenia in routine practice. PMID:29854396

In-operando hard X-ray photoelectron spectroscopy study on the impact of current compliance and switching cycles on oxygen and carbon defects in resistive switching Ti/HfO{sub 2}/TiN cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sowinska, Malgorzata, E-mail: sowinska@ihp-microelectronics.com; Bertaud, Thomas; Walczyk, Damian

2014-05-28

In this study, direct experimental materials science evidence of the important theoretical prediction for resistive random access memory (RRAM) technologies that a critical amount of oxygen vacancies is needed to establish stable resistive switching in metal-oxide-metal samples is presented. In detail, a novel in-operando hard X-ray photoelectron spectroscopy technique is applied to non-destructively investigates the influence of the current compliance and direct current voltage sweep cycles on the Ti/HfO{sub 2} interface chemistry and physics of resistive switching Ti/HfO{sub 2}/TiN cells. These studies indeed confirm that current compliance is a critical parameter to control the amount of oxygen vacancies in themore » conducting filaments in the oxide layer during the RRAM cell operation to achieve stable switching. Furthermore, clear carbon segregation towards the Ti/HfO{sub 2} interface under electrical stress is visible. Since carbon impurities impact the oxygen vacancy defect population under resistive switching, this dynamic carbon segregation to the Ti/HfO{sub 2} interface is suspected to negatively influence RRAM device endurance. Therefore, these results indicate that the RRAM materials engineering needs to include all impurities in the dielectric layer in order to achieve reliable device performance.« less

Messing with Mendel.

PubMed

Birchler, James A

2012-10-16

Paramutation, a phenomenon of epigenetic switching that violates Mendel's Law of Segregation, was first discovered in maize and later observed in other plants. In a recent report in Nature, de Vanssay and colleagues (2012) describe in Drosophila an operationally analogous phenomenon to paramutation that is mediated by piwi-interacting RNAs. Copyright © 2012 Elsevier Inc. All rights reserved.

S-nitrosylation mediates nitric oxide -auxin crosstalk in auxin signaling and polar auxin transport

USDA-ARS?s Scientific Manuscript database

Nitric oxide (NO) and auxin phytohormone cross talk has been implicated in plant development and growth. Addition and removal of NO moieties to cysteine residues of proteins, is termed S-nitrosylation and de-nitrosylation, respectively and functions as an on/off switch of protein activity. This dyna...

Plurilingual Proficiency as a Learning Objective for a Multilingual Curriculum in the Study of Business in Finland

ERIC Educational Resources Information Center

Schlabach, Joachim

2016-01-01

Plurilingual skills are among the key skills required in international business communication. Employees working in international business operations use multiple languages concurrently, switch between them, and mediate between different languages and cultures. Up until now however, the language teaching accompanying business studies at…

A Coincidence Detection Mechanism Controls PX-BAR Domain-Mediated Endocytic Membrane Remodeling via an Allosteric Structural Switch.

PubMed

Lo, Wen-Ting; Vujičić Žagar, Andreja; Gerth, Fabian; Lehmann, Martin; Puchkov, Dymtro; Krylova, Oxana; Freund, Christian; Scapozza, Leonardo; Vadas, Oscar; Haucke, Volker

2017-11-20

Clathrin-mediated endocytosis occurs by bending and remodeling of the membrane underneath the coat. Bin-amphiphysin-rvs (BAR) domain proteins are crucial for endocytic membrane remodeling, but how their activity is spatiotemporally controlled is largely unknown. We demonstrate that the membrane remodeling activity of sorting nexin 9 (SNX9), a late-acting endocytic PX-BAR domain protein required for constriction of U-shaped endocytic intermediates, is controlled by an allosteric structural switch involving coincident detection of the clathrin adaptor AP2 and phosphatidylinositol-3,4-bisphosphate (PI(3,4)P 2 ) at endocytic sites. Structural, biochemical, and cell biological data show that SNX9 is autoinhibited in solution. Binding to PI(3,4)P 2 via its PX-BAR domain, and concomitant association with AP2 via sequences in the linker region, releases SNX9 autoinhibitory contacts to enable membrane constriction. Our results reveal a mechanism for restricting the latent membrane remodeling activity of BAR domain proteins to allow spatiotemporal coupling of membrane constriction to the progression of the endocytic pathway. Copyright © 2017 Elsevier Inc. All rights reserved.

Switch-like Arp2/3 activation upon WASP and WIP recruitment to an apparent threshold level by multivalent linker proteins in vivo.

PubMed

Sun, Yidi; Leong, Nicole T; Jiang, Tommy; Tangara, Astou; Darzacq, Xavier; Drubin, David G

2017-08-16

Actin-related protein 2/3 (Arp2/3) complex activation by nucleation promoting factors (NPFs) such as WASP, plays an important role in many actin-mediated cellular processes. In yeast, Arp2/3-mediated actin filament assembly drives endocytic membrane invagination and vesicle scission. Here we used genetics and quantitative live-cell imaging to probe the mechanisms that concentrate NPFs at endocytic sites, and to investigate how NPFs regulate actin assembly onset. Our results demonstrate that SH3 (Src homology 3) domain-PRM (proline-rich motif) interactions involving multivalent linker proteins play central roles in concentrating NPFs at endocytic sites. Quantitative imaging suggested that productive actin assembly initiation is tightly coupled to accumulation of threshold levels of WASP and WIP, but not to recruitment kinetics or release of autoinhibition. These studies provide evidence that WASP and WIP play central roles in establishment of a robust multivalent SH3 domain-PRM network in vivo, giving actin assembly onset at endocytic sites a switch-like behavior.

Extracellular microvesicles and invadopodia mediate non-overlapping modes of tumor cell invasion

PubMed Central

Sedgwick, Alanna E.; Clancy, James W.; Olivia Balmert, M.; D’Souza-Schorey, Crislyn

2015-01-01

Tumor cell invasion requires the molecular and physical adaptation of both the cell and its microenvironment. Here we show that tumor cells are able to switch between the use of microvesicles and invadopodia to facilitate invasion through the extracellular matrix. Invadopodia formation accompanies the mesenchymal mode of migration on firm matrices and is facilitated by Rac1 activation. On the other hand, during invasion through compliant and deformable environments, tumor cells adopt an amoeboid phenotype and release microvesicles. Notably, firm matrices do not support microvesicle release, whereas compliant matrices are not conducive to invadopodia biogenesis. Furthermore, Rac1 activation is required for invadopodia function, while its inactivation promotes RhoA activation and actomyosin contractility required for microvesicle shedding. Suppression of RhoA signaling blocks microvesicle formation but enhances the formation of invadopodia. Finally, we describe Rho-mediated pathways involved in microvesicle biogenesis through the regulation of myosin light chain phosphatase. Our findings suggest that the ability of tumor cells to switch between the aforementioned qualitatively distinct modes of invasion may allow for dissemination across different microenvironments. PMID:26458510

Neural computations mediating one-shot learning in the human brain.

PubMed

Lee, Sang Wan; O'Doherty, John P; Shimojo, Shinsuke

2015-04-01

Incremental learning, in which new knowledge is acquired gradually through trial and error, can be distinguished from one-shot learning, in which the brain learns rapidly from only a single pairing of a stimulus and a consequence. Very little is known about how the brain transitions between these two fundamentally different forms of learning. Here we test a computational hypothesis that uncertainty about the causal relationship between a stimulus and an outcome induces rapid changes in the rate of learning, which in turn mediates the transition between incremental and one-shot learning. By using a novel behavioral task in combination with functional magnetic resonance imaging (fMRI) data from human volunteers, we found evidence implicating the ventrolateral prefrontal cortex and hippocampus in this process. The hippocampus was selectively "switched" on when one-shot learning was predicted to occur, while the ventrolateral prefrontal cortex was found to encode uncertainty about the causal association, exhibiting increased coupling with the hippocampus for high-learning rates, suggesting this region may act as a "switch," turning on and off one-shot learning as required.

The Ubiquitin Ligase SCF(Ucc1) Acts as a Metabolic Switch for the Glyoxylate Cycle.

PubMed

Nakatsukasa, Kunio; Nishimura, Takashi; Byrne, Stuart D; Okamoto, Michiyo; Takahashi-Nakaguchi, Azusa; Chibana, Hiroji; Okumura, Fumihiko; Kamura, Takumi

2015-07-02

Despite the crucial role played by the glyoxylate cycle in the virulence of pathogens, seed germination in plants, and sexual development in fungi, we still have much to learn about its regulation. Here, we show that a previously uncharacterized SCF(Ucc1) ubiquitin ligase mediates proteasomal degradation of citrate synthase in the glyoxylate cycle to maintain metabolic homeostasis in glucose-grown cells. Conversely, transcription of the F box subunit Ucc1 is downregulated in C2-compound-grown cells, which require increased metabolic flux for gluconeogenesis. Moreover, in vitro analysis demonstrates that oxaloacetate regenerated through the glyoxylate cycle induces a conformational change in citrate synthase and inhibits its recognition and ubiquitination by SCF(Ucc1), suggesting the existence of an oxaloacetate-dependent positive feedback loop that stabilizes citrate synthase. We propose that SCF(Ucc1)-mediated regulation of citrate synthase acts as a metabolic switch for the glyoxylate cycle in response to changes in carbon source, thereby ensuring metabolic versatility and flexibility. Copyright © 2015 Elsevier Inc. All rights reserved.

Ventral tegmental area GABA neurons and opiate motivation

PubMed Central

Vargas-Perez, Hector; Mabey, Jennifer K.; Shin, Samuel I.; Steffensen, Scott C.; van der Kooy, Derek

2013-01-01

Rational Past research has demonstrated that when an animal changes from a previously drug-naive to an opiate-dependent and withdrawn state, morphine’s motivational effects are switched from a tegmental pedunculopontine nucleus (TPP)-dependent to a dopamine-dependent pathway. Interestingly, a corresponding change is observed in ventral tegmental area (VTA) GABAA receptors, which change from mediating hyperpolarization of VTA GABA neurons to mediating depolarization. Objectives The present study investigated whether pharmacological manipulation of VTA GABAA receptor activity could directly influence the mechanisms underlying opiate motivation. Results Using an unbiased place conditioning procedure, we demonstrated that in Wistar rats, intra-VTA administration of furosemide, a Cl− cotransporter inhibitor, was able to promote a switch in the mechanisms underlying morphine’s motivational properties, one which is normally observed only after chronic opiate exposure. This behavioral switch was prevented by intra-VTA administration of acetazolamide, an inhibitor of the bicarbonate ion-producing carbonic anhydrase enzyme. Electrophysiological recordings of mouse VTA showed that furosemide reduced the sensitivity of VTA GABA neurons to inhibition by the GABAA receptor agonist muscimol, instead increasing the firing rate of a significant subset of these GABA neurons. Conclusion Our results suggest that the carbonic anhydrase enzyme may constitute part of a common VTA GABA neuron-based biological pathway responsible for controlling the mechanisms underlying opiate motivation, supporting the hypothesis that VTA GABAA receptor hyperpolarization or depolarization is responsible for selecting TPP- or dopamine-dependent motivational outputs, respectively. PMID:23392354

Tandem alternative polyadenylation events of genes in non-eosinophilic nasal polyp tissue identified by high-throughput sequencing analysis

PubMed Central

TIAN, PENG; LI, JIE; LIU, XIANG; LI, YUXI; CHEN, MEIHENG; MA, YUN; ZHENG, YI QING; FU, YONGGUI; ZOU, HUA

2014-01-01

Nasal polyps (NP) is highly associated with the disorder of immune cells. Alternative polyadenylation (APA) produces mRNA isoforms with different length of 3′-untranslated region (UTR) and regulates gene expression. It has been proven that this APA-mediated regulation of 3′UTR length is an immune-associated phenomenon. The aim of this study was to investigate the genome-wide alternative tandem 3′UTR length switching events in non-eosinophilic nasal polyp tissue. Thirteen patients diagnosed as having non-eosinophilic nasal polyps were included in this study. Nasal polyp tissue and control mucosa were collected during surgery. The 3′ end library of cDNA was constructed. The recovered libraries were sequenced with second sequencing technology, and the sequencing data were analyzed by an in-house bioinformatics pipeline. Tandem 3′UTR length switching between samples was detected by a test of linear trend alternative to independence. We found a significant alteration in the tandem 3′UTR length in 1,920 genes in nasal polyp samples. Functional annotation results showed that several gene ontology (GO) terms were enriched in the list of genes with switched APA sites, including regulation of transcription, macromolecule catabolic localization and mRNA processing. The results suggested that APA-mediated alternative 3′UTR regulation plays an important role in the post-transcriptional regulation of gene expression in non-eosinophilic nasal polyps. PMID:24715051

A pink mouse reports the switch from red to green fluorescence upon Cre-mediated recombination.

PubMed

Hartwich, Heiner; Satheesh, Somisetty V; Nothwang, Hans Gerd

2012-06-14

Targeted genetic modification in the mouse becomes increasingly important in biomedical and basic science. This goal is most often achieved by use of the Cre/loxP system and numerous Cre-driver mouse lines are currently generated. Their initial characterization requires reporter mouse lines to study the in vivo spatiotemporal activity of Cre. Here, we report a dual fluorescence reporter mouse line, which switches expression from the red fluorescent protein mCherry to eGFP after Cre-mediated recombination. Both fluorescent proteins are expressed from the ubiquitously active and strong CAGGS promoter. Among the founders, we noticed a pink mouse line, expressing high levels of the red fluorescent protein mCherry throughout the entire body. Presence of mCherry in the living animal as well as in almost all organs was clearly visible without optical equipment. Upon Cre-activity, mCherry expression was switched to eGFP, demonstrating functionality of this reporter mouse line. The pink mouse presented here is an attractive novel reporter line for fluorescence-based monitoring of Cre-activity. The high expression of mCherry, which is visible to the naked eye, facilitates breeding and crossing, as no genotyping is required to identify mice carrying the reporter allele. The presence of two fluorescent proteins allows in vivo monitoring of recombined and non-recombined cells. Finally, the pink mouse is an eye-catching animal model to demonstrate the power of transgenic techniques in teaching courses.

Niacin supplementation increases the number of oxidative type I fibers in skeletal muscle of growing pigs

PubMed Central

2013-01-01

Background A recent study showed that niacin supplementation counteracts the obesity-induced muscle fiber switching from oxidative type I to glycolytic type II and increases the number of type I fibers in skeletal muscle of obese Zucker rats. These effects were likely mediated by the induction of key regulators of fiber transition, PGC-1α and PGC-1β, leading to muscle fiber switching and up-regulation of genes involved in mitochondrial fatty acid import and oxidation, citrate cycle, oxidative phosphorylation, mitochondrial biogenesis. The aim of the present study was to investigate whether niacin supplementation causes type II to type I muscle and changes the metabolic phenotype of skeletal muscles in growing pigs. Results 25 male, 11 wk old crossbred pigs (Danzucht x Pietrain) with an average body weight of 32.8 ± 1.3 (mean ± SD) kg were randomly allocated to two groups of 12 (control group) and 13 pigs (niacin group) which were fed either a control diet or a diet supplemented with 750 mg niacin/kg diet. After 3 wk, the percentage number of type I fibers in three different muscles (M. longissismus dorsi, M. quadriceps femoris, M. gastrocnemius) was greater in the niacin group and the percentage number of type II fibers was lower in the niacin group than in the control group (P < 0.05). The mRNA levels of PGC-1β and genes involved in mitochondrial fatty acid catabolism (CACT, FATP1, OCTN2), citrate cycle (SDHA), oxidative phosphorylation (COX4/1, COX6A1), and thermogenesis (UCP3) in M. longissimus dorsi were greater in the niacin group than in the control group (P < 0.05). Conclusions The study demonstrates that niacin supplementation induces type II to type I muscle fiber switching, and thereby an oxidative metabolic phenotype of skeletal muscle in pigs. Given that oxidative muscle types tend to develop dark, firm and dry pork in response to intense physical activity and/or high psychological stress levels preslaughter, a niacin-induced change in the muscle´s fiber type distribution may influence meat quality of pigs. PMID:24010567

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…

Neural substrates of cognitive switching and inhibition in a face processing task.

PubMed

Piguet, Camille; Sterpenich, Virginie; Desseilles, Martin; Cojan, Yann; Bertschy, Gilles; Vuilleumier, Patrik

2013-11-15

We frequently need to change our current occupation, an operation requiring additional effortful cognitive demands. Switching from one task to another may involve two distinct processes: inhibition of the previously relevant task-set, and initiation of a new one. Here we tested whether these two processes are underpinned by separate neural substrates, and whether they differ depending on the nature of the task and the emotional content of stimuli. We used functional magnetic resonance imaging in healthy human volunteers who categorize emotional faces according to three different judgment rules (color, gender, or emotional expression). Our paradigm allowed us to separate neural activity associated with inhibition and switching based on the sequence of the tasks required on successive trials. We found that the bilateral medial superior parietal lobule and left intraparietal sulcus showed consistent activation during switching regardless of the task. On the other hand, no common region was activated (or suppressed) as a consequence of inhibition across all tasks. Rather, task-specific effects were observed in brain regions that were more activated when switching to a particular task but less activated after inhibition of the same task. In addition, compared to other conditions, the emotional task elicited a similar switching cost but lower inhibition cost, accompanied by selective decrease in the anterior cingulate cortex when returning to this task shortly after inhibiting it. These results demonstrate that switching relies on domain-general processes mediated by postero-medial parietal areas, engaged across all tasks, but also provide novel evidence that task inhibition produces domain-specific decreases as a function of particular task demands, with only the latter inhibition component being modulated by emotional information. Copyright © 2013 Elsevier Inc. All rights reserved.

Adjusting survival time estimates to account for treatment switching in randomized controlled trials--an economic evaluation context: methods, limitations, and recommendations.

PubMed

Latimer, Nicholas R; Abrams, Keith R; Lambert, Paul C; Crowther, Michael J; Wailoo, Allan J; Morden, James P; Akehurst, Ron L; Campbell, Michael J

2014-04-01

Treatment switching commonly occurs in clinical trials of novel interventions in the advanced or metastatic cancer setting. However, methods to adjust for switching have been used inconsistently and potentially inappropriately in health technology assessments (HTAs). We present recommendations on the use of methods to adjust survival estimates in the presence of treatment switching in the context of economic evaluations. We provide background on the treatment switching issue and summarize methods used to adjust for it in HTAs. We discuss the assumptions and limitations associated with adjustment methods and draw on results of a simulation study to make recommendations on their use. We demonstrate that methods used to adjust for treatment switching have important limitations and often produce bias in realistic scenarios. We present an analysis framework that aims to increase the probability that suitable adjustment methods can be identified on a case-by-case basis. We recommend that the characteristics of clinical trials, and the treatment switching mechanism observed within them, should be considered alongside the key assumptions of the adjustment methods. Key assumptions include the "no unmeasured confounders" assumption associated with the inverse probability of censoring weights (IPCW) method and the "common treatment effect" assumption associated with the rank preserving structural failure time model (RPSFTM). The limitations associated with switching adjustment methods such as the RPSFTM and IPCW mean that they are appropriate in different scenarios. In some scenarios, both methods may be prone to bias; "2-stage" methods should be considered, and intention-to-treat analyses may sometimes produce the least bias. The data requirements of adjustment methods also have important implications for clinical trialists.

Valley filters, accumulators, and switches induced in graphene quantum dots by lines of adsorbed hydrogen atoms

NASA Astrophysics Data System (ADS)

Azari, Mohammadhadi; Kirczenow, George

2018-06-01

We present electronic structure and quantum transport calculations that predict conducting channels induced in graphene quantum dots by lines of adsorbed hydrogen atoms to function as highly efficient, experimentally realizable valley filters, accumulators, and switches. The underlying physics is an interesting property of graphene Dirac point resonances (DPRs) that is revealed here, namely, that an electric current passing through a DPR-mediated conducting channel in a given direction is carried by electrons of only one of the two graphene valleys. Our predictions apply to lines of hydrogen atoms adsorbed on graphene quantum dots that are either free standing or supported on a hexagonal boron nitride substrate.

Improvement in bone mineral density after switching from tenofovir to abacavir in HIV-1-infected patients with low bone mineral density: two-centre randomized pilot study (OsteoTDF study).

PubMed

Negredo, Eugènia; Domingo, Pere; Pérez-Álvarez, Núria; Gutiérrez, Mar; Mateo, Gracia; Puig, Jordi; Escrig, Roser; Echeverría, Patricia; Bonjoch, Anna; Clotet, Bonaventura

2014-12-01

Tenofovir has been associated with a decrease in bone mineral density (BMD). However, data on changes in BMD after discontinuing tenofovir are lacking. We performed a two-centre randomized pilot study in virologically suppressed HIV-infected patients receiving tenofovir with osteopenia/osteoporosis (OsteoTDF study, ClinicalTrials.gov number NCT 01153217). Fifty-four patients were randomly assigned to switch from tenofovir to abacavir (n = 26) or to continue with tenofovir (n = 28). Changes in lumbar and total hip BMD were evaluated at Week 48 from baseline. Five patients discontinued the study (three from the tenofovir group and two from the abacavir group). No significant differences were detected between the groups at Week 48 (P = 0.229 for total hip and P = 0.312 for lumbar spine). However, hip BMD improved by 2.1% (95% CI -0.6 to 4.7) (P = 0.043) in the abacavir group and 0.7% (95% CI -0.9 to 2.4) (P = 0.372) in the tenofovir group. Lumbar spine BMD varied by -0.7% (95% CI -3.8 to 3.3) (P ≤ 0.001) in the abacavir group and -1.2% (95% CI -3.8 to 0.4) (P < 0.001) in the tenofovir group. Switching from tenofovir to abacavir led to a slight improvement in femoral BMD although no differences were detected between groups. Larger studies are necessary before firm recommendations can be made on the discontinuation of tenofovir in patients with a low BMD. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Superior Efficacy and Improved Renal and Bone Safety After Switching from a Tenofovir Disoproxil Fumarate- to a Tenofovir Alafenamide-Based Regimen Through 96 Weeks of Treatment.

PubMed

DeJesus, Edwin; Haas, Bernard; Segal-Maurer, Sorana; Ramgopal, Moti N; Mills, Anthony; Margot, Nicolas; Liu, Ya-Pei; Makadzange, Tariro; McCallister, Scott

2018-04-01

We previously demonstrated superior efficacy and safety advantages in HIV-infected, virologically suppressed adults switched to a regimen containing tenofovir alafenamide (TAF) as compared with those remaining on a tenofovir disoproxil fumarate (TDF) regimen through week 48. We now report long-term data through week 96. In this randomized, active-controlled, multicenter, open-label, noninferiority trial (ClinicalTrials.gov No. NCT01815736), we randomized virologically suppressed (HIV-1 RNA <50 copies/ml) adults (2:1) to receive a once-daily, single-tablet regimen containing elvitegravir (EVG), cobicistat (COBI), emtricitabine (FTC), and TAF group or to continue one of four TDF-containing regimens (TDF group) for 96 weeks. We evaluated efficacy (HIV-1 RNA <50 copies/ml using the FDA snapshot algorithm) and prespecified bone and renal endpoints at week 96. We randomized and treated 1,436 participants in this study (TAF n = 959, TDF n = 477). At week 96, TAF was superior to TDF in virologic efficacy, with 93% on TAF and 89% on TDF having HIV-1 RNA <50 copies/ml (difference 3.7%, 95% confidence interval: 0.4%-7.0%). Improvements in hip and spine bone mineral density for those assigned to TAF versus TDF continued through week 96 (p < .001). Significant improvements in urine protein or albumin to creatinine ratios were also seen among those in the TAF group versus TDF through week 96 (p < .001). There were no cases of investigator-reported proximal renal tubulopathy in the TAF group as compared with one case in the TDF group. Switching to EVG/COBI/FTC/TAF (E/C/F/TAF) was associated with statistically significant efficacy and safety advantages over remaining on a standard-of-care TDF-based regimen.

Postsynaptic density 95 (PSD-95) serine 561 phosphorylation regulates a conformational switch and bidirectional dendritic spine structural plasticity.

PubMed

Wu, Qian; Sun, Miao; Bernard, Laura P; Zhang, Huaye

2017-09-29

Postsynaptic density 95 (PSD-95) is a major synaptic scaffolding protein that plays a key role in bidirectional synaptic plasticity, which is a process important for learning and memory. It is known that PSD-95 shows increased dynamics upon induction of plasticity. However, the underlying structural and functional changes in PSD-95 that mediate its role in plasticity remain unclear. Here we show that phosphorylation of PSD-95 at Ser-561 in its guanylate kinase (GK) domain, which is mediated by the partitioning-defective 1 (Par1) kinases, regulates a conformational switch and is important for bidirectional plasticity. Using a fluorescence resonance energy transfer (FRET) biosensor, we show that a phosphomimetic mutation of Ser-561 promotes an intramolecular interaction between GK and the nearby Src homology 3 (SH3) domain, leading to a closed conformation, whereas a non-phosphorylatable S561A mutation or inhibition of Par1 kinase activity decreases SH3-GK interaction, causing PSD-95 to adopt an open conformation. In addition, S561A mutation facilitates the interaction between PSD-95 and its binding partners. Fluorescence recovery after photobleaching imaging reveals that the S561A mutant shows increased stability, whereas the phosphomimetic S561D mutation increases PSD-95 dynamics at the synapse. Moreover, molecular replacement of endogenous PSD-95 with the S561A mutant blocks dendritic spine structural plasticity during chemical long-term potentiation and long-term depression. Endogenous Ser-561 phosphorylation is induced by synaptic NMDA receptor activation, and the SH3-GK domains exhibit a Ser-561 phosphorylation-dependent switch to a closed conformation during synaptic plasticity. Our results provide novel mechanistic insight into the regulation of PSD-95 in dendritic spine structural plasticity through phosphorylation-mediated regulation of protein dynamics and conformation. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Distinct polymer architecture mediates switching of complement activation pathways at the nanosphere-serum interface: implications for stealth nanoparticle engineering.

PubMed

Hamad, Islam; Al-Hanbali, Othman; Hunter, A Christy; Rutt, Kenneth J; Andresen, Thomas L; Moghimi, S Moein

2010-11-23

Nanoparticles with surface projected polyethyleneoxide (PEO) chains in "mushroom-brush" and "brush" configurations display stealth properties in systemic circulation and have numerous applications in site-specific targeting for controlled drug delivery and release as well as diagnostic imaging. We report on the "structure-activity" relationship pertaining to surface-immobilized PEO of various configurations on model nanoparticles, and the initiation of complement cascade, which is the most ancient component of innate human immunity, and its activation may induce clinically significant adverse reactions in some individuals. Conformational states of surface-projected PEO chains, arising from the block copolymer poloxamine 908 adsorption, on polystyrene nanoparticles trigger complement activation differently. Alteration of copolymer architecture on nanospheres from mushroom to brush configuration not only switches complement activation from C1q-dependent classical to lectin pathway but also reduces the level of generated complement activation products C4d, Bb, C5a, and SC5b-9. Also, changes in adsorbed polymer configuration trigger alternative pathway activation differently and through different initiators. Notably, the role for properdin-mediated activation of alternative pathway was only restricted to particles displaying PEO chains in a transition mushroom-brush configuration. Since nanoparticle-mediated complement activation is of clinical concern, our findings provide a rational basis for improved surface engineering and design of immunologically safer stealth and targetable nanosystems with polymers for use in clinical medicine.

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.

Heat-Assisted Multiferroic Solid-State Memory

PubMed Central

2017-01-01

A heat-assisted multiferroic solid-state memory design is proposed and analysed, based on a PbNbZrSnTiO3 antiferroelectric layer and Ni81Fe19 magnetic free layer. Information is stored as magnetisation direction in the free layer of a magnetic tunnel junction element. The bit writing process is contactless and relies on triggering thermally activated magnetisation switching of the free layer towards a strain-induced anisotropy easy axis. A stress is generated using the antiferroelectric layer by voltage-induced antiferroelectric to ferroelectric phase change, and this is transmitted to the magnetic free layer by strain-mediated coupling. The thermally activated strain-induced magnetisation switching is analysed here using a three-dimensional, temperature-dependent magnetisation dynamics model, based on simultaneous evaluation of the stochastic Landau-Lifshitz-Bloch equation and heat flow equation, together with stochastic thermal fields and magnetoelastic contributions. The magnetisation switching probability is calculated as a function of stress magnitude and maximum heat pulse temperature. An operating region is identified, where magnetisation switching always occurs, with stress values ranging from 80 to 180 MPa, and maximum temperatures normalised to the Curie temperature ranging from 0.65 to 0.99. PMID:28841185

XRCC1 suppresses somatic hypermutation and promotes alternative nonhomologous end joining in Igh genes.

PubMed

Saribasak, Huseyin; Maul, Robert W; Cao, Zheng; McClure, Rhonda L; Yang, William; McNeill, Daniel R; Wilson, David M; Gearhart, Patricia J

2011-10-24

Activation-induced deaminase (AID) deaminates cytosine to uracil in immunoglobulin genes. Uracils in DNA can be recognized by uracil DNA glycosylase and abasic endonuclease to produce single-strand breaks. The breaks are repaired either faithfully by DNA base excision repair (BER) or mutagenically to produce somatic hypermutation (SHM) and class switch recombination (CSR). To unravel the interplay between repair and mutagenesis, we decreased the level of x-ray cross-complementing 1 (XRCC1), a scaffold protein involved in BER. Mice heterozygous for XRCC1 showed a significant increase in the frequencies of SHM in Igh variable regions in Peyer's patch cells, and of double-strand breaks in the switch regions during CSR. Although the frequency of CSR was normal in Xrcc1(+/-) splenic B cells, the length of microhomology at the switch junctions decreased, suggesting that XRCC1 also participates in alternative nonhomologous end joining. Furthermore, Xrcc1(+/-) B cells had reduced Igh/c-myc translocations during CSR, supporting a role for XRCC1 in microhomology-mediated joining. Our results imply that AID-induced single-strand breaks in Igh variable and switch regions become substrates simultaneously for BER and mutagenesis pathways.

Switch from type II to I Fas/CD95 death signaling upon in vitro culturing of primary hepatocytes

PubMed Central

Walter, Dorothée; Schmich, Kathrin; Vogel, Sandra; Pick, Robert; Kaufmann, Thomas; Hochmuth, Florian Christoph; Haber, Angelika; Neubert, Karin; McNelly, Sabine; von Weizsäcker, Fritz; Merfort, Irmgard; Maurer, Ulrich; Strasser, Andreas; Borner, Christoph

2010-01-01

Fas/CD95-induced apoptosis of hepatocytes in vivo proceeds through the so-called type II pathway, requiring the pro-apoptotic BH3-only Bcl-2 family member Bid for mitochondrial death signaling. Consequently, Bid-deficient mice are protected from anti-Fas antibody injection induced fatal hepatitis. Here we report the unexpected finding that freshly isolated mouse hepatocytes, cultured on collagen or Matrigel™, become independent of Bid for Fas-induced apoptosis, thereby switching death signaling from type II to type I. In such in vitro cultures, FasL activates caspase-3 without Bid cleavage, Bax/Bak activation or cytochrome c release, and neither Bid ablation nor Bcl-2 overexpression is protective. The type II to type I switch depends on extracellular matrix adhesion, as primary hepatocytes in suspension die in a Bid-dependent manner. Moreover, the switch is specific for FasL-induced apoptosis as collagen-plated Bid-deficient hepatocytes are protected from TNFα/ActD-induced apoptosis. Conclusion Our data suggest a selective crosstalk between extracellular matrix and Fas-mediated signaling which favours mitochondria-independent type I apoptosis induction. PMID:19003879

Switch from type II to I Fas/CD95 death signaling on in vitro culturing of primary hepatocytes.

PubMed

Walter, Dorothée; Schmich, Kathrin; Vogel, Sandra; Pick, Robert; Kaufmann, Thomas; Hochmuth, Florian Christoph; Haber, Angelika; Neubert, Karin; McNelly, Sabine; von Weizsäcker, Fritz; Merfort, Irmgard; Maurer, Ulrich; Strasser, Andreas; Borner, Christoph

2008-12-01

Fas/CD95-induced apoptosis of hepatocytes in vivo proceeds through the so-called type II pathway, requiring the proapoptotic BH3-only Bcl-2 family member Bid for mitochondrial death signaling. Consequently, Bid-deficient mice are protected from anti-Fas antibody injection induced fatal hepatitis. We report the unexpected finding that freshly isolated mouse hepatocytes, cultured on collagen or Matrigel, become independent of Bid for Fas-induced apoptosis, thereby switching death signaling from type II to type I. In such in vitro cultures, Fas ligand (FasL) activates caspase-3 without Bid cleavage, Bax/Bak activation or cytochrome c release, and neither Bid ablation nor Bcl-2 overexpression is protective. The type II to type I switch depends on extracellular matrix adhesion, as primary hepatocytes in suspension die in a Bid-dependent manner. Moreover, the switch is specific for FasL-induced apoptosis as collagen-plated Bid-deficient hepatocytes are protected from tumor necrosis factor alpha/actinomycin D (TNFalpha/ActD)-induced apoptosis. Our data suggest a selective crosstalk between extracellular matrix and Fas-mediated signaling that favors mitochondria-independent type I apoptosis induction.

Heat-Assisted Multiferroic Solid-State Memory.

PubMed

Lepadatu, Serban; Vopson, Melvin M

2017-08-25

A heat-assisted multiferroic solid-state memory design is proposed and analysed, based on a PbNbZrSnTiO₃ antiferroelectric layer and Ni 81 Fe 19 magnetic free layer. Information is stored as magnetisation direction in the free layer of a magnetic tunnel junction element. The bit writing process is contactless and relies on triggering thermally activated magnetisation switching of the free layer towards a strain-induced anisotropy easy axis. A stress is generated using the antiferroelectric layer by voltage-induced antiferroelectric to ferroelectric phase change, and this is transmitted to the magnetic free layer by strain-mediated coupling. The thermally activated strain-induced magnetisation switching is analysed here using a three-dimensional, temperature-dependent magnetisation dynamics model, based on simultaneous evaluation of the stochastic Landau-Lifshitz-Bloch equation and heat flow equation, together with stochastic thermal fields and magnetoelastic contributions. The magnetisation switching probability is calculated as a function of stress magnitude and maximum heat pulse temperature. An operating region is identified, where magnetisation switching always occurs, with stress values ranging from 80 to 180 MPa, and maximum temperatures normalised to the Curie temperature ranging from 0.65 to 0.99.

Comparison of switching bipolar ablation with multiple cooled wet electrodes and switching monopolar ablation with separable clustered electrode in treatment of small hepatocellular carcinoma: A randomized controlled trial

PubMed Central

Chang, Won; Lee, Dong Ho; Yoon, Jeong Hee; Kim, Yoon Jun; Yoon, Jung Hwan; Han, Joon Koo

2018-01-01

Objective A randomized controlled trial was conducted to prospectively compare the therapeutic effectiveness of switching bipolar (SB) radiofrequency ablation (RFA) using cooled-wet electrodes and switching monopolar (SM) RFA using separable clustered (SC) electrodes in patients with hepatocellular carcinomas (HCCs). Materials and methods This prospective study was approved by our Institutional Review Board. Between April 2014 and January 2015, sixty-nine patients with 74 HCCs were randomly treated with RFA using either internally cooled-wet (ICW) electrodes in SB mode (SB-RFA, n = 36) or SC electrodes in SM mode (SM-RFA, n = 38). Technical parameters including the number of ablations, ablation time, volume, energy delivery, and complications were evaluated. Thereafter, 1-year and 2-year local tumor progression (LTP) free survival rates were compared between the two groups using the Kaplan-Meier method. Results In the SB-RFA group, less number of ablations were required (1.72±0.70 vs. 2.31±1.37, P = 0.039), the ablation time was shorter (10.9±3.9 vs.14.3±5.0 min, p = 0.004), and energy delivery was smaller (13.1±6.3 vs.23.4±12.8 kcal, p<0.001) compared to SM-RFA. Ablation volume was not significantly different between SB-RFA and SM-RFA groups (61.8±24.3 vs.54.9±23.7 cm3, p = 0.229). Technical failure occurred in one patient in the SM-RFA group, and major complications occurred in one patient in each group. The 1-year and 2-year LTP free survival rates were 93.9% and 84.3% in the SB-RFA group and 94.4% and 88.4% in the SM-RFA group (p = 0.687). Conclusion Both SB-RFA using ICW electrodes and SM-RFA using SC electrodes provided comparable LTP free survival rates although SB-RFA required less ablations and shorter ablation time. PMID:29420589

High-speed true random number generation based on paired memristors for security electronics

NASA Astrophysics Data System (ADS)

Zhang, Teng; Yin, Minghui; Xu, Changmin; Lu, Xiayan; Sun, Xinhao; Yang, Yuchao; Huang, Ru

2017-11-01

True random number generator (TRNG) is a critical component in hardware security that is increasingly important in the era of mobile computing and internet of things. Here we demonstrate a TRNG using intrinsic variation of memristors as a natural source of entropy that is otherwise undesirable in most applications. The random bits were produced by cyclically switching a pair of tantalum oxide based memristors and comparing their resistance values in the off state, taking advantage of the more pronounced resistance variation compared with that in the on state. Using an alternating read scheme in the designed TRNG circuit, the unbiasedness of the random numbers was significantly improved, and the bitstream passed standard randomness tests. The Pt/TaO x /Ta memristors fabricated in this work have fast programming/erasing speeds of ˜30 ns, suggesting a high random number throughput. The approach proposed here thus holds great promise for physically-implemented random number generation.

High-speed true random number generation based on paired memristors for security electronics.

PubMed

Zhang, Teng; Yin, Minghui; Xu, Changmin; Lu, Xiayan; Sun, Xinhao; Yang, Yuchao; Huang, Ru

2017-11-10

True random number generator (TRNG) is a critical component in hardware security that is increasingly important in the era of mobile computing and internet of things. Here we demonstrate a TRNG using intrinsic variation of memristors as a natural source of entropy that is otherwise undesirable in most applications. The random bits were produced by cyclically switching a pair of tantalum oxide based memristors and comparing their resistance values in the off state, taking advantage of the more pronounced resistance variation compared with that in the on state. Using an alternating read scheme in the designed TRNG circuit, the unbiasedness of the random numbers was significantly improved, and the bitstream passed standard randomness tests. The Pt/TaO x /Ta memristors fabricated in this work have fast programming/erasing speeds of ∼30 ns, suggesting a high random number throughput. The approach proposed here thus holds great promise for physically-implemented random number generation.

Morphine induced exacerbation of sepsis is mediated by tempering endotoxin tolerance through modulation of miR-146a

PubMed Central

Banerjee, Santanu; Meng, Jingjing; Das, Subhas; Krishnan, Anitha; Haworth, Justin; Charboneau, Richard; Zeng, Yan; Ramakrishnan, Sundaram; Roy, Sabita

2013-01-01

Development of tolerance to endotoxin prevents sustained hyper inflammation during systemic infections. Here we report for the first time that chronic morphine treatment tempers endotoxin tolerance resulting in persistent inflammation, septicemia and septic shock. Morphine was found to down-regulate endotoxin/LPS induced miR-146a and 155 in macrophages. However, only miR-146a over expression, but not miR-155 abrogates morphine mediated hyper-inflammation. Conversely, antagonizing miR-146a (but not miR-155) heightened the severity of morphine-mediated hyper-inflammation. These results suggest that miR-146a acts as a molecular switch controlling hyper-inflammation in clinical and/or recreational use of morphine. PMID:23756365

Mechanisms of bicarbonate secretion: lessons from the airways.

PubMed

Bridges, Robert J

2012-08-01

Early studies showed that airway cells secrete HCO(3)(-) in response to cAMP-mediated agonists and HCO(3)(-) secretion was impaired in cystic fibrosis (CF). Studies with Calu-3 cells, an airway serous model with high expression of CFTR, also show the secretion of HCO(3)(-) when cells are stimulated with cAMP-mediated agonists. Activation of basolateral membrane hIK-1 K(+) channels inhibits HCO(3)(-) secretion and stimulates Cl(-) secretion. CFTR mediates the exit of both HCO(3)(-) and Cl(-) across the apical membrane. Entry of HCO(3)(-) on a basolateral membrane NBC or Cl(-) on the NKCC determines which anion is secreted. Switching between these two secreted anions is determined by the activity of hIK-1 K(+) channels.

General Slowing and Education Mediate Task Switching Performance Across the Life-Span

PubMed Central

Moretti, Luca; Semenza, Carlo; Vallesi, Antonino

2018-01-01

Objective: This study considered the potential role of both protective factors (cognitive reserve, CR) and adverse ones (general slowing) in modulating cognitive flexibility in the adult life-span. Method: Ninety-eight individuals performed a task-switching (TS) paradigm in which we adopted a manipulation concerning the timing between the cue and the target. Working memory demands were minimized by using transparent cues. Additionally, indices of cognitive integrity, depression, processing speed and different CR dimensions were collected and used in linear models accounting for TS performance under the different time constraints. Results: The main results showed similar mixing costs and higher switching costs in older adults, with an overall age-dependent effect of general slowing on these costs. The link between processing speed and TS performance was attenuated when participants had more time to prepare. Among the different CR indices, formal education only was associated with reduced switch costs under time pressure. Discussion: Even though CR is often operationalized as a unitary construct, the present research confirms the benefits of using tools designed to distinguish between different CR dimensions. Furthermore, our results provide empirical support to the assumption that processing speed influence on executive performance depends on time constraints. Finally, it is suggested that whether age differences appear in terms of switch or mixing costs depends on working memory demands (which were low in our tasks with transparent cues). PMID:29780341

Forming-free bipolar resistive switching in nonstoichiometric ceria films

NASA Astrophysics Data System (ADS)

Ismail, Muhammad; Huang, Chun-Yang; Panda, Debashis; Hung, Chung-Jung; Tsai, Tsung-Ling; Jieng, Jheng-Hong; Lin, Chun-An; Chand, Umesh; Rana, Anwar Manzoor; Ahmed, Ejaz; Talib, Ijaz; Nadeem, Muhammad Younus; Tseng, Tseung-Yuen

2014-01-01

The mechanism of forming-free bipolar resistive switching in a Zr/CeO x /Pt device was investigated. High-resolution transmission electron microscopy and energy-dispersive spectroscopy analysis indicated the formation of a ZrO y layer at the Zr/CeO x interface. X-ray diffraction studies of CeO x films revealed that they consist of nano-polycrystals embedded in a disordered lattice. The observed resistive switching was suggested to be linked with the formation and rupture of conductive filaments constituted by oxygen vacancies in the CeO x film and in the nonstoichiometric ZrO y interfacial layer. X-ray photoelectron spectroscopy study confirmed the presence of oxygen vacancies in both of the said regions. In the low-resistance ON state, the electrical conduction was found to be of ohmic nature, while the high-resistance OFF state was governed by trap-controlled space charge-limited mechanism. The stable resistive switching behavior and long retention times with an acceptable resistance ratio enable the device for its application in future nonvolatile resistive random access memory (RRAM).

A theoretical and experimental study of neuromorphic atomic switch networks for reservoir computing.

PubMed

Sillin, Henry O; Aguilera, Renato; Shieh, Hsien-Hang; Avizienis, Audrius V; Aono, Masakazu; Stieg, Adam Z; Gimzewski, James K

2013-09-27

Atomic switch networks (ASNs) have been shown to generate network level dynamics that resemble those observed in biological neural networks. To facilitate understanding and control of these behaviors, we developed a numerical model based on the synapse-like properties of individual atomic switches and the random nature of the network wiring. We validated the model against various experimental results highlighting the possibility to functionalize the network plasticity and the differences between an atomic switch in isolation and its behaviors in a network. The effects of changing connectivity density on the nonlinear dynamics were examined as characterized by higher harmonic generation in response to AC inputs. To demonstrate their utility for computation, we subjected the simulated network to training within the framework of reservoir computing and showed initial evidence of the ASN acting as a reservoir which may be optimized for specific tasks by adjusting the input gain. The work presented represents steps in a unified approach to experimentation and theory of complex systems to make ASNs a uniquely scalable platform for neuromorphic computing.

A theoretical and experimental study of neuromorphic atomic switch networks for reservoir computing

NASA Astrophysics Data System (ADS)

Sillin, Henry O.; Aguilera, Renato; Shieh, Hsien-Hang; Avizienis, Audrius V.; Aono, Masakazu; Stieg, Adam Z.; Gimzewski, James K.

2013-09-01

Atomic switch networks (ASNs) have been shown to generate network level dynamics that resemble those observed in biological neural networks. To facilitate understanding and control of these behaviors, we developed a numerical model based on the synapse-like properties of individual atomic switches and the random nature of the network wiring. We validated the model against various experimental results highlighting the possibility to functionalize the network plasticity and the differences between an atomic switch in isolation and its behaviors in a network. The effects of changing connectivity density on the nonlinear dynamics were examined as characterized by higher harmonic generation in response to AC inputs. To demonstrate their utility for computation, we subjected the simulated network to training within the framework of reservoir computing and showed initial evidence of the ASN acting as a reservoir which may be optimized for specific tasks by adjusting the input gain. The work presented represents steps in a unified approach to experimentation and theory of complex systems to make ASNs a uniquely scalable platform for neuromorphic computing.

Brownmillerite thin films as fast ion conductors for ultimate-performance resistance switching memory.

PubMed

Acharya, Susant Kumar; Jo, Janghyun; Raveendra, Nallagatlla Venkata; Dash, Umasankar; Kim, Miyoung; Baik, Hionsuck; Lee, Sangik; Park, Bae Ho; Lee, Jae Sung; Chae, Seung Chul; Hwang, Cheol Seong; Jung, Chang Uk

2017-07-27

An oxide-based resistance memory is a leading candidate to replace Si-based flash memory as it meets the emerging specifications for future memory devices. The non-uniformity in the key switching parameters and low endurance in conventional resistance memory devices are preventing its practical application. Here, a novel strategy to overcome the aforementioned challenges has been unveiled by tuning the growth direction of epitaxial brownmillerite SrFeO 2.5 thin films along the SrTiO 3 [111] direction so that the oxygen vacancy channels can connect both the top and bottom electrodes rather directly. The controlled oxygen vacancy channels help reduce the randomness of the conducting filament (CF). The resulting device displayed high endurance over 10 6 cycles, and a short switching time of ∼10 ns. In addition, the device showed very high uniformity in the key switching parameters for device-to-device and within a device. This work demonstrates a feasible example for improving the nanoscale device performance by controlling the atomic structure of a functional oxide layer.

An Element of Determinism in a Stochastic Flagellar Motor Switch

PubMed Central

Xie, Li; Altindal, Tuba; Wu, Xiao-Lun

2015-01-01

Marine bacterium Vibrio alginolyticus uses a single polar flagellum to navigate in an aqueous environment. Similar to Escherichia coli cells, the polar flagellar motor has two states; when the motor is counter-clockwise, the cell swims forward and when the motor is clockwise, the cell swims backward. V. alginolyticus also incorporates a direction randomization step at the start of the forward swimming interval by flicking its flagellum. To gain an understanding on how the polar flagellar motor switch is regulated, distributions of the forward Δf and backward Δb intervals are investigated herein. We found that the steady-state probability density functions, P(Δf) and P(Δb), of freely swimming bacteria are strongly peaked at a finite time, suggesting that the motor switch is not Poissonian. The short-time inhibition is sufficiently strong and long lasting, i.e., several hundred milliseconds for both intervals, which is readily observed and characterized. Treating motor reversal dynamics as a first-passage problem, which results from conformation fluctuations of the motor switch, we calculated P(Δf) and P(Δb) and found good agreement with the measurements. PMID:26554590

An Element of Determinism in a Stochastic Flagellar Motor Switch.

PubMed

Xie, Li; Altindal, Tuba; Wu, Xiao-Lun

2015-01-01

Marine bacterium Vibrio alginolyticus uses a single polar flagellum to navigate in an aqueous environment. Similar to Escherichia coli cells, the polar flagellar motor has two states; when the motor is counter-clockwise, the cell swims forward and when the motor is clockwise, the cell swims backward. V. alginolyticus also incorporates a direction randomization step at the start of the forward swimming interval by flicking its flagellum. To gain an understanding on how the polar flagellar motor switch is regulated, distributions of the forward Δf and backward Δb intervals are investigated herein. We found that the steady-state probability density functions, P(Δf) and P(Δb), of freely swimming bacteria are strongly peaked at a finite time, suggesting that the motor switch is not Poissonian. The short-time inhibition is sufficiently strong and long lasting, i.e., several hundred milliseconds for both intervals, which is readily observed and characterized. Treating motor reversal dynamics as a first-passage problem, which results from conformation fluctuations of the motor switch, we calculated P(Δf) and P(Δb) and found good agreement with the measurements.

Efficacy and safety of extended- versus immediate-release pramipexole in Japanese patients with advanced and L-dopa-undertreated Parkinson disease: a double-blind, randomized trial.

PubMed

Mizuno, Yoshikuni; Yamamoto, Mitsutoshi; Kuno, Sadako; Hasegawa, Kazuko; Hattori, Nobutaka; Kagimura, Tatsuro; Sarashina, Akiko; Rascol, Olivier; Schapira, Anthony H V; Barone, Paolo; Hauser, Robert A; Poewe, Werner

2012-01-01

To compare the efficacy, safety, tolerability, and trough plasma levels of pramipexole extended-release (ER) and pramipexole immediate-release (IR), and to assess the effects of overnight switching from an IR to an ER formulation, in L-dopa-treated patients with Parkinson disease (PD). After a 1- to 4-week screening/enrollment, 112 patients who had exhibited L-dopa-related problems or were receiving suboptimal L-dopa dosage were randomized in double-blind, double-dummy, 1:1 fashion to pramipexole ER once daily or pramipexole IR 2 to 3 times daily for 12 weeks, both titrated to a maximum daily dose of 4.5 mg. Successful completers of double-blind treatment were switched to open-label pramipexole ER, beginning with a 4-week dose-adjustment phase. Among the double-blind treatment patients (n = 56 in each group), Unified Parkinson's Disease Rating Scale Parts II+III total scores decreased significantly from baseline and to a similar degree with pramipexole ER and IR formulations. In each group, 47 double-blind patients (83.9%) reported adverse events (AEs), requiring withdrawal of 3 ER patients (5.4%) and 2 IR patients (3.6%). Trough plasma levels at steady state (at the same doses and dose-normalized concentrations) were also similar with both formulations. Among open-label treatment patients (n = 53 from IR to ER), 83% were successfully switched (no worsening of PD symptoms) to pramipexole ER. In L-dopa-treated patients, pramipexole ER and pramipexole IR demonstrated similar efficacy, safety, tolerability, and trough plasma levels. Patients can be safely switched overnight from pramipexole IR to pramipexole ER with no impact on efficacy.

Brief Report: Efficacy and Safety of Switching to Coformulated Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide (E/C/F/TAF) in Virologically Suppressed Women.

PubMed

Hodder, Sally; Squires, Kathleen; Kityo, Cissy; Hagins, Debbie; Avihingsanon, Anchalee; Kido, Anna; Jiang, Shuping; Kulkarni, Rima; Cheng, Andrew; Cao, Huyen

2018-06-01

The integrase inhibitor regimen [elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (TDF)] demonstrated superior efficacy when compared with a protease inhibitor regimen [ritonavir-boosted atazanavir (ATV + RTV) and FTC/TDF] in 575 treatment-naive women at week 48. We investigated the efficacy, safety, and tolerability of switching to a TAF-based, single-tablet regimen containing elvitegravir, cobicistat, FTC, and tenofovir alafenamide (E/C/F/TAF) versus remaining on ATV + RTV plus FTC/TDF. After completing the initial randomized, blinded phase, virologically suppressed (HIV-1 RNA <50 copies/mL) women on ATV + RTV plus FTC/TDF were rerandomized (3:1) to receive open-label E/C/F/TAF versus remaining on their current regimen. The primary end point was proportion of participants with plasma HIV-1 RNA <50 copies per milliliter at week 48 (U.S. FDA snapshot algorithm), with a prespecified noninferiority margin of 12%. Safety [adverse events (AEs)] and tolerability were also assessed. Of 575 women originally randomized and treated in the blinded phase, 159 were rerandomized to switch to E/C/F/TAF and 53 to remain on ATV + RTV plus FTC/TDF. At week 48, virologic suppression was maintained in 150 (94%) of women on E/C/F/TAF and 46 (87%) on ATV + RTV plus FTC/TDF [difference 7.5% (95% confidence interval -1.2% to 19.4%)], demonstrating noninferiority of E/C/F/TAF to ATV + RTV and FTC/TDF. Incidence of AEs was similar between groups; study drug-related AEs were more common with E/C/F/TAF (11% versus 4%). Switching to E/C/F/TAF was noninferior to continuing ATV + RTV plus FTC/TDF in maintaining virologic suppression and was well tolerated at 48 weeks.

Acceptability of randomization to levonorgestrel versus copper intrauterine device among women requesting IUD insertion for contraception

PubMed Central

Achilles, Sharon L.; Chen, Beatrice A.; Lee, Jessica K.; Gariepy, Aileen M.; Creinin, Mitchell D.

2015-01-01

Objective Assess feasibility of randomizing women to intrauterine device (IUD) type. Study Design Women enrolling in a 2-month study who desired an IUD for contraception were randomized 1:1 to receive a levonorgestrel 52mg IUD (LNG-IUD) or copper T380A (Cu-IUD), understanding they could switch IUD type at the end of the study. Results Randomization to IUD type was acceptable to 54/55 (98%) women who screened. All 32 enrolled participants completed follow-up. Two women exchanged their IUD (Cu-IUD to LNG-IUD) and 2 requested removal (1 LNG-IUD, 1 Cu-IUD). Overall, 88% continued their assigned IUD. Conclusions Randomization to IUD type is feasible and few women change their IUD. PMID:26297203

A Novel Ni/WOX/W Resistive Random Access Memory with Excellent Retention and Low Switching Current

NASA Astrophysics Data System (ADS)

Chien, Wei-Chih; Chen, Yi-Chou; Lee, Feng-Ming; Lin, Yu-Yu; Lai, Erh-Kun; Yao, Yeong-Der; Gong, Jeng; Horng, Sheng-Fu; Yeh, Chiao-Wen; Tsai, Shih-Chang; Lee, Ching-Hsiung; Huang, Yu-Kai; Chen, Chun-Fu; Kao, Hsiao-Feng; Shih, Yen-Hao; Hsieh, Kuang-Yeu; Lu, Chih-Yuan

2011-04-01

The behavior of WOX resistive random access memory (ReRAM) is a strong function of the top electrode material, which controls the conduction mechanism and the forming process. When using a top electrode with low work function, the current conduction is limited by space charges. On the other hand, the mechanism becomes thermionic emission for devices with a high work function top electrode. These (thermionic) devices are also found to have higher initial resistance, reduced forming current, and larger resistance window. Based on these insights and considering the compatibility to complementary metal-oxide-semiconductor (CMOS) process, we proposed to use Ni as the top electrode for high performance WOX ReRAM devices. The new Ni/WOX/W device can be switched at a low current density less than 8×105 A/cm2, with RESET/SET resistance ratio greater than 100, and extremely good data retention of more than 300 years at 85 °C.

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.

Activation-induced deoxycytidine deaminase (AID) co-transcriptional scanning at single-molecule resolution

PubMed Central

Senavirathne, Gayan; Bertram, Jeffrey G.; Jaszczur, Malgorzata; Chaurasiya, Kathy R.; Pham, Phuong; Mak, Chi H.; Goodman, Myron F.; Rueda, David

2015-01-01

Activation-induced deoxycytidine deaminase (AID) generates antibody diversity in B cells by initiating somatic hypermutation (SHM) and class-switch recombination (CSR) during transcription of immunoglobulin variable (IgV) and switch region (IgS) DNA. Using single-molecule FRET, we show that AID binds to transcribed dsDNA and translocates unidirectionally in concert with RNA polymerase (RNAP) on moving transcription bubbles, while increasing the fraction of stalled bubbles. AID scans randomly when constrained in an 8 nt model bubble. When unconstrained on single-stranded (ss) DNA, AID moves in random bidirectional short slides/hops over the entire molecule while remaining bound for ∼5 min. Our analysis distinguishes dynamic scanning from static ssDNA creasing. That AID alone can track along with RNAP during transcription and scan within stalled transcription bubbles suggests a mechanism by which AID can initiate SHM and CSR when properly regulated, yet when unregulated can access non-Ig genes and cause cancer. PMID:26681117

Engineering of ribozyme-based aminoglycoside switches of gene expression by in vivo genetic selection in Saccharomyces cerevisiae.

PubMed

Klauser, Benedikt; Rehm, Charlotte; Summerer, Daniel; Hartig, Jörg S

2015-01-01

Synthetic RNA-based switches are a growing class of genetic controllers applied in synthetic biology to engineer cellular functions. In this chapter, we detail a protocol for the selection of posttranscriptional controllers of gene expression in yeast using the Schistosoma mansoni hammerhead ribozyme as a central catalytic unit. Incorporation of a small molecule-sensing aptamer domain into the ribozyme renders its activity ligand-dependent. Aptazymes display numerous advantages over conventional protein-based transcriptional controllers, namely, the use of little genomic space for encryption, their modular architecture allowing for easy reprogramming to new inputs, the physical linkage to the message to be controlled, and the ability to function without protein cofactors. Herein, we describe the method to select ribozyme-based switches of gene expression in Saccharomyces cerevisiae that we successfully implemented to engineer neomycin- and theophylline-responsive switches. We also highlight how to adapt the protocol to screen for switches responsive to other ligands. Reprogramming of the sensor unit and incorporation into any RNA of interest enables the fulfillment of a variety of regulatory functions. However, proper functioning of the aptazyme is largely dependent on optimal connection between the aptamer and the catalytic core. We obtained functional switches from a pool of variants carrying randomized connection sequences by an in vivo selection in MaV203 yeast cells that allows screening of a large sequence space of up to 1×10(9) variants. The protocol given explains how to construct aptazyme libraries, carry out the in vivo selection and characterize novel ON- and OFF-switches. © 2015 Elsevier Inc. All rights reserved.

Interallelic class switch recombination contributes significantly to class switching in mouse B cells.

PubMed

Reynaud, Stéphane; Delpy, Laurent; Fleury, Laurence; Dougier, Hei-Lanne; Sirac, Christophe; Cogné, Michel

2005-05-15

Except for the expression of IgM and IgD, DNA recombination is constantly needed for the expression of other Ig classes and subclasses. The predominant path of class switch recombination (CSR) is intrachromosomal, and the looping-out and deletion model has been abundantly documented. However, switch regions also occasionally constitute convenient substrates for interchromosomal recombination, since it is noticeably the case in a number of chromosomal translocations causing oncogene deregulation in the course of lymphoma and myeloma. Although asymmetric accessibility of Ig alleles should theoretically limit its occurrence, interallelic CSR was shown to occur at low levels during IgA switching in rabbit, where the definition of allotypes within both V and C regions helped identify interchromosomally derived Ig. Thus, we wished to evaluate precisely interallelic CSR frequency in mouse B cells, by using a system in which only one allele (of b allotype) could express a functional VDJ region, whereas only interallelic CSR could restore expression of an excluded (a allotype) allele. In our study, we show that interchromosomal recombination of V(H) and Cgamma or Calpha occurs in vivo in B cells at a frequency that makes a significant contribution to physiological class switching: trans-association of V(H) and C(H) genes accounted for 7% of all alpha mRNA, and this frequency was about twice higher for the gamma3 transcripts, despite the much shorter distance between the J(H) region and the Cgamma3 gene, thus confirming that this phenomenon corresponded to site-specific switching and not to random recombination between long homologous loci.

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…

Assessing Mediation Using Marginal Structural Models in the Presence of Confounding and Moderation

ERIC Educational Resources Information Center

Coffman, Donna L.; Zhong, Wei

2012-01-01

This article presents marginal structural models with inverse propensity weighting (IPW) for assessing mediation. Generally, individuals are not randomly assigned to levels of the mediator. Therefore, confounders of the mediator and outcome may exist that limit causal inferences, a goal of mediation analysis. Either regression adjustment or IPW…

Flipping the Metabolic Switch: Understanding and Applying Health Benefits of Fasting

PubMed Central

Anton, Stephen D.; Moehl, Keelin; Donahoo, William T.; Marosi, Krisztina; Lee, Stephanie; Mainous, Arch G.; Leeuwenburgh, Christiaan; Mattson, Mark P.

2017-01-01

Intermittent fasting (IF) is a term used to describe a variety of eating patterns in which no or few calories are consumed for time periods that can range from 12 hours to several days, on a recurring basis. Here we focus on the physiological responses of major organ systems, including the musculoskeletal system, to the onset of the metabolic switch – the point of negative energy balance at which liver glycogen stores are depleted and fatty acids are mobilized (typically beyond 12 hours after cessation of food intake). Emerging findings suggest the metabolic switch from glucose to fatty acid-derived ketones represents an evolutionarily conserved trigger point that shifts metabolism from lipid/cholesterol synthesis and fat storage to mobilization of fat through fatty acid oxidation and fatty-acid derived ketones, which serve to preserve muscle mass and function. Thus, IF regimens that induce the metabolic switch have the potential to improve body composition in overweight individuals. Moreover, IF regimens also induce the coordinated activation of signaling pathways that optimize physiological function, enhance performance, and slow aging and disease processes. Future randomized controlled IF trials should use biomarkers of the metabolic switch (e.g., plasma ketone levels) as a measure of compliance and the magnitude of negative energy balance during the fasting period. PMID:29086496

Flipping the Metabolic Switch: Understanding and Applying the Health Benefits of Fasting.

PubMed

Anton, Stephen D; Moehl, Keelin; Donahoo, William T; Marosi, Krisztina; Lee, Stephanie A; Mainous, Arch G; Leeuwenburgh, Christiaan; Mattson, Mark P

2018-02-01

Intermittent fasting (IF) is a term used to describe a variety of eating patterns in which no or few calories are consumed for time periods that can range from 12 hours to several days, on a recurring basis. This review is focused on the physiological responses of major organ systems, including the musculoskeletal system, to the onset of the metabolic switch: the point of negative energy balance at which liver glycogen stores are depleted and fatty acids are mobilized (typically beyond 12 hours after cessation of food intake). Emerging findings suggest that the metabolic switch from glucose to fatty acid-derived ketones represents an evolutionarily conserved trigger point that shifts metabolism from lipid/cholesterol synthesis and fat storage to mobilization of fat through fatty acid oxidation and fatty acid-derived ketones, which serve to preserve muscle mass and function. Thus, IF regimens that induce the metabolic switch have the potential to improve body composition in overweight individuals. Moreover, IF regimens also induce the coordinated activation of signaling pathways that optimize physiological function, enhance performance, and slow aging and disease processes. Future randomized controlled IF trials should use biomarkers of the metabolic switch (e.g., plasma ketone levels) as a measure of compliance and of the magnitude of negative energy balance during the fasting period. © 2017 The Obesity Society.

Light-activated resistance switching in SiOx RRAM devices

NASA Astrophysics Data System (ADS)

Mehonic, A.; Gerard, T.; Kenyon, A. J.

2017-12-01

We report a study of light-activated resistance switching in silicon oxide (SiOx) resistive random access memory (RRAM) devices. Our devices had an indium tin oxide/SiOx/p-Si Metal/Oxide/Semiconductor structure, with resistance switching taking place in a 35 nm thick SiOx layer. The optical activity of the devices was investigated by characterising them in a range of voltage and light conditions. Devices respond to illumination at wavelengths in the range of 410-650 nm but are unresponsive at 1152 nm, suggesting that photons are absorbed by the bottom p-type silicon electrode and that generation of free carriers underpins optical activity. Applied light causes charging of devices in the high resistance state (HRS), photocurrent in the low resistance state (LRS), and lowering of the set voltage (required to go from the HRS to LRS) and can be used in conjunction with a voltage bias to trigger switching from the HRS to the LRS. We demonstrate negative correlation between set voltage and applied laser power using a 632.8 nm laser source. We propose that, under illumination, increased electron injection and hence a higher rate of creation of Frenkel pairs in the oxide—precursors for the formation of conductive oxygen vacancy filaments—reduce switching voltages. Our results open up the possibility of light-triggered RRAM devices.

Markov switching of the electricity supply curve and power prices dynamics

NASA Astrophysics Data System (ADS)

Mari, Carlo; Cananà, Lucianna

2012-02-01

Regime-switching models seem to well capture the main features of power prices behavior in deregulated markets. In a recent paper, we have proposed an equilibrium methodology to derive electricity prices dynamics from the interplay between supply and demand in a stochastic environment. In particular, assuming that the supply function is described by a power law where the exponent is a two-state strictly positive Markov process, we derived a regime switching dynamics of power prices in which regime switches are induced by transitions between Markov states. In this paper, we provide a dynamical model to describe the random behavior of power prices where the only non-Brownian component of the motion is endogenously introduced by Markov transitions in the exponent of the electricity supply curve. In this context, the stochastic process driving the switching mechanism becomes observable, and we will show that the non-Brownian component of the dynamics induced by transitions from Markov states is responsible for jumps and spikes of very high magnitude. The empirical analysis performed on three Australian markets confirms that the proposed approach seems quite flexible and capable of incorporating the main features of power prices time-series, thus reproducing the first four moments of log-returns empirical distributions in a satisfactory way.

Methodological issues in assessing changes in costs pre- and post-medication switch: a schizophrenia study example.

PubMed

Faries, Douglas E; Nyhuis, Allen W; Ascher-Svanum, Haya

2009-05-27

Schizophrenia is a severe, chronic, and costly illness that adversely impacts patients' lives and health care payer budgets. Cost comparisons of treatment regimens are, therefore, important to health care payers and researchers. Pre-Post analyses ("mirror-image"), where outcomes prior to a medication switch are compared to outcomes post-switch, are commonly used in such research. However, medication changes often occur during a costly crisis event. Patients may relapse, be hospitalized, have a medication change, and then spend a period of time with intense use of costly resources (post-medication switch). While many advantages and disadvantages of Pre-Post methodology have been discussed, issues regarding the attributability of costs incurred around the time of medication switching have not been fully investigated. Medical resource use data, including medications and acute-care services (hospitalizations, partial hospitalizations, emergency department) were collected for patients with schizophrenia who switched antipsychotics (n = 105) during a 1-year randomized, naturalistic, antipsychotic cost-effectiveness schizophrenia trial. Within-patient changes in total costs per day were computed during the pre- and post-medication change periods. In addition to the standard Pre-Post analysis comparing costs pre- and post-medication change, we investigated the sensitivity of results to varying assumptions regarding the attributability of acute care service costs occurring just after a medication switch that were likely due to initial medication failure. Fifty-six percent of all costs incurred during the first week on the newly initiated antipsychotic were likely due to treatment failure with the previous antipsychotic. Standard analyses suggested an average increase in cost-per-day for each patient of $2.40 after switching medications. However, sensitivity analyses removing costs incurred post-switch that were potentially due to the failure of the initial medication suggested decreases in costs in the range of $4.77 to $9.69 per day post-switch. Pre-Post cost analyses are sensitive to the approach used to handle acute-service costs occurring just after a medication change. Given the importance of quality economic research on the cost of switching treatments, thorough sensitivity analyses should be performed to identify the impact of crisis events around the time of medication change.

A study on the resistance switching of Ag2Se and Ta2O5 heterojunctions using structural engineering

NASA Astrophysics Data System (ADS)

Lee, Tae Sung; Lee, Nam Joo; Abbas, Haider; Hu, Quanli; Yoon, Tae-Sik; Lee, Hyun Ho; Le Shim, Ee; Kang, Chi Jung

2018-01-01

The resistive random access memory (RRAM) devices with heterostuctures have been investigated due to cycling stability, nonlinear switching, complementary resistive switching and self-compliance. The heterostructured devices can modulate the resistive switching (RS) behavior appropriately by bilayer structure with a variety of materials. In this study, the bipolar resistive switching characteristics of the bilayer structures composed of Ta2O5 and Ag2Se, which are transition-metal oxide (TMO) and silver chalcogenide, were investigated. The bilayer devices of Ta2O5 deposited on Ag2Se (Ta2O5/Ag2Se) and Ag2Se deposited on Ta2O5 (Ag2Se/Ta2O5) were fabricated for investigation of the RS characteristics by stacking sequence of Ta2O5 and Ag2Se. All operating voltages were applied to the Ag top electrode with the Pt bottom electrode grounded. The Ta2O5/Ag2Se device showed that a negative voltage sweep switched the device from high resistance state (HRS) to low resistance state (LRS) and a positive voltage sweep switched the device from LRS to HRS. On the contrary, for the Ag2Se/Ta2O5 device a positive voltage sweep switched the device from HRS to LRS, and a negative voltage sweep switched it from LRS to HRS. The polarity dependence of RS was attributed to the stacking sequence of Ta2O5 and Ag2Se. In addition, the combined heterostructured device of both bilayer stacks, Ta2O5/Ag2Se and Ag2Se/Ta2O5, exhibited the complementary switching characteristics. By using threshold switching devices, sneak path leakage can be reduced without additional selectors. The bilayer heterostructures of Ta2O5 and Ag2Se have various advantages such as self-compliance, reproducibility and forming-free stable RS. It confirms the possible applications of TMO and silver chalcogenide heterostructures in RRAM.

Electron holography on HfO2/HfO2-x bilayer structures with multilevel resistive switching properties

NASA Astrophysics Data System (ADS)

Niu, G.; Schubert, M. A.; Sharath, S. U.; Zaumseil, P.; Vogel, S.; Wenger, C.; Hildebrandt, E.; Bhupathi, S.; Perez, E.; Alff, L.; Lehmann, M.; Schroeder, T.; Niermann, T.

2017-05-01

Unveiling the physical nature of the oxygen-deficient conductive filaments (CFs) that are responsible for the resistive switching of the HfO2-based resistive random access memory (RRAM) devices represents a challenging task due to the oxygen vacancy related defect nature and nanometer size of the CFs. As a first important step to this goal, we demonstrate in this work direct visualization and a study of physico-chemical properties of oxygen-deficient amorphous HfO2-x by carrying out transmission electron microscopy electron holography as well as energy dispersive x-ray spectroscopy on HfO2/HfO2-x bilayer heterostructures, which are realized by reactive molecular beam epitaxy. Furthermore, compared to single layer devices, Pt/HfO2/HfO2-x /TiN bilayer devices show enhanced resistive switching characteristics with multilevel behavior, indicating their potential as electronic synapses in future neuromorphic computing applications.

Switching non-local median filter

NASA Astrophysics Data System (ADS)

Matsuoka, Jyohei; Koga, Takanori; Suetake, Noriaki; Uchino, Eiji

2015-06-01

This paper describes a novel image filtering method for removal of random-valued impulse noise superimposed on grayscale images. Generally, it is well known that switching-type median filters are effective for impulse noise removal. In this paper, we propose a more sophisticated switching-type impulse noise removal method in terms of detail-preserving performance. Specifically, the noise detector of the proposed method finds out noise-corrupted pixels by focusing attention on the difference between the value of a pixel of interest (POI) and the median of its neighboring pixel values, and on the POI's isolation tendency from the surrounding pixels. Furthermore, the removal of the detected noise is performed by the newly proposed median filter based on non-local processing, which has superior detail-preservation capability compared to the conventional median filter. The effectiveness and the validity of the proposed method are verified by some experiments using natural grayscale images.

Finite-time synchronization of stochastic coupled neural networks subject to Markovian switching and input saturation.

PubMed

Selvaraj, P; Sakthivel, R; Kwon, O M

2018-06-07

This paper addresses the problem of finite-time synchronization of stochastic coupled neural networks (SCNNs) subject to Markovian switching, mixed time delay, and actuator saturation. In addition, coupling strengths of the SCNNs are characterized by mutually independent random variables. By utilizing a simple linear transformation, the problem of stochastic finite-time synchronization of SCNNs is converted into a mean-square finite-time stabilization problem of an error system. By choosing a suitable mode dependent switched Lyapunov-Krasovskii functional, a new set of sufficient conditions is derived to guarantee the finite-time stability of the error system. Subsequently, with the help of anti-windup control scheme, the actuator saturation risks could be mitigated. Moreover, the derived conditions help to optimize estimation of the domain of attraction by enlarging the contractively invariant set. Furthermore, simulations are conducted to exhibit the efficiency of proposed control scheme. Copyright © 2018 Elsevier Ltd. All rights reserved.

Filamentary model in resistive switching materials

NASA Astrophysics Data System (ADS)

Jasmin, Alladin C.

2017-12-01

The need for next generation computer devices is increasing as the demand for efficient data processing increases. The amount of data generated every second also increases which requires large data storage devices. Oxide-based memory devices are being studied to explore new research frontiers thanks to modern advances in nanofabrication. Various oxide materials are studied as active layers for non-volatile memory. This technology has potential application in resistive random-access-memory (ReRAM) and can be easily integrated in CMOS technologies. The long term perspective of this research field is to develop devices which mimic how the brain processes information. To realize such application, a thorough understanding of the charge transport and switching mechanism is important. A new perspective in the multistate resistive switching based on current-induced filament dynamics will be discussed. A simple equivalent circuit of the device gives quantitative information about the nature of the conducting filament at different resistance states.

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

PubMed Central

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

2013-01-01

SUMMARY 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 comprised of the U2 and U6 snRNAs and includes a metal bound by U6 snRNA. The precise architecture of the splicesome active site however, including 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 promoting 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. PMID:23686287

Tip-induced domain structures and polarization switching in ferroelectric amino acid glycine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Seyedhosseini, E., E-mail: Seyedhosseini@ua.pt; Ivanov, M.; Bdikin, I.

2015-08-21

Bioorganic ferroelectrics and piezoelectrics are becoming increasingly important in view of their intrinsic compatibility with biological environment and biofunctionality combined with strong piezoelectric effect and a switchable polarization at room temperature. Here, we study tip-induced domain structures and polarization switching in the smallest amino acid β-glycine, representing a broad class of non-centrosymmetric amino acids. We show that β-glycine is indeed a room-temperature ferroelectric and polarization can be switched by applying a bias to non-polar cuts via a conducting tip of atomic force microscope (AFM). Dynamics of these in-plane domains is studied as a function of an applied voltage and pulsemore » duration. The domain shape is dictated by polarization screening at the domain boundaries and mediated by growth defects. Thermodynamic theory is applied to explain the domain propagation induced by the AFM tip. Our findings suggest that the properties of β-glycine are controlled by the charged domain walls which in turn can be manipulated by an external bias.« less

Global increase in replication fork speed during a p57KIP2-regulated erythroid cell fate switch

PubMed Central

Hwang, Yung; Futran, Melinda; Hidalgo, Daniel; Pop, Ramona; Iyer, Divya Ramalingam; Scully, Ralph; Rhind, Nicholas; Socolovsky, Merav

2017-01-01

Cell cycle regulators are increasingly implicated in cell fate decisions, such as the acquisition or loss of pluripotency and self-renewal potential. The cell cycle mechanisms that regulate these cell fate decisions are largely unknown. We studied an S phase–dependent cell fate switch, in which murine early erythroid progenitors transition in vivo from a self-renewal state into a phase of active erythroid gene transcription and concurrent maturational cell divisions. We found that progenitors are dependent on p57KIP2-mediated slowing of replication forks for self-renewal, a novel function for cyclin-dependent kinase inhibitors. The switch to differentiation entails rapid down-regulation of p57KIP2 with a consequent global increase in replication fork speed and an abruptly shorter S phase. Our work suggests that cell cycles with specialized global DNA replication dynamics are integral to the maintenance of specific cell states and to cell fate decisions. PMID:28560351

Spatial Phosphoprotein Profiling Reveals a Compartmentalized Extracellular Signal-regulated Kinase Switch Governing Neurite Growth and Retraction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Yingchun; Yang, Feng; Fu, Yi

Abstract - Brain development and spinal cord regeneration require neurite sprouting and growth cone navigation in response to extension and collapsing factors present in the extracellular environment. These external guidance cues control neurite growth cone extension and retraction processes through intracellular protein phosphorylation of numerous cytoskeletal, adhesion, and polarity complex signaling proteins. However, the complex kinase/substrate signaling networks that mediate neuritogenesis have not been investigated. Here, we compare the neurite phosphoproteome under growth and retraction conditions using neurite purification methodology combined with mass spectrometry. More than 4000 non-redundant phosphorylation sites from 1883 proteins have been annotated and mapped to signalingmore » pathways that control kinase/phosphatase networks, cytoskeleton remodeling, and axon/dendrite specification. Comprehensive informatics and functional studies revealed a compartmentalized ERK activation/deactivation cytoskeletal switch that governs neurite growth and retraction, respectively. Our findings provide the first system-wide analysis of the phosphoprotein signaling networks that enable neurite growth and retraction and reveal an important molecular switch that governs neuritogenesis.« less

Sigma-1 receptor ligands control a switch between passive and active threat responses

PubMed Central

Rennekamp, Andrew J.; Huang, Xi-Ping; Wang, You; Patel, Samir; Lorello, Paul J.; Cade, Lindsay; Gonzales, Andrew P. W.; Yeh, Jing-Ruey Joanna; Caldarone, Barbara J.; Roth, Bryan L.; Kokel, David; Peterson, Randall T.

2016-01-01

Humans and many animals exhibit freezing behavior in response to threatening stimuli. In humans, inappropriate threat responses are fundamental characteristics of several mental illnesses. To identify small molecules that modulate threat responses, we developed a high-throughput behavioral assay in zebrafish (Danio rerio) and characterized the effects of 10,000 compounds on freezing behavior. We found three classes of compounds that switch the threat response from freezing to escape-like behavior. We then screened these for binding activity across 45 candidate targets. Using target profile clustering we implicated the sigma-1 receptor in the mechanism of behavioral switching and confirmed that known sigma-1 ligands also disrupt freezing behavior. Furthermore, mutation of the sigma-1 gene prevented the behavioral effect of escape-inducing compounds. The compound ‘finazine’ potently bound mammalian sigma-1 and altered rodent threat response behavior. Thus, pharmacological and genetic interrogation of the freezing response revealed sigma-1 as a mediator of vertebrate threat responses. PMID:27239788

A Mutation Directs the Structural Switch of DNA Binding Proteins under Starvation to a Ferritin-like Protein Cage.

PubMed

Williams, Sunanda Margrett; Chandran, Anu Vijayakumari; Prakash, Sunita; Vijayan, Mamannamana; Chatterji, Dipankar

2017-09-05

Proteins of the ferritin family are ubiquitous in living organisms. With their spherical cage-like structures they are the iron storehouses in cells. Subfamilies of ferritins include 24-meric ferritins and bacterioferritins (maxiferritins), and 12-meric Dps (miniferritins). Dps safeguards DNA by direct binding, affording physical protection and safeguards from free radical-mediated damage by sequestering iron in its core. The maxiferritins can oxidize and store iron but cannot bind DNA. Here we show that a mutation at a critical interface in Dps alters its assembly from the canonical 12-mer to a ferritin-like 24-mer under crystallization. This structural switch was attributed to the conformational alteration of a highly conserved helical loop and rearrangement of the C-terminus. Our results demonstrate a novel concept of mutational switch between related protein subfamilies and corroborate the popular model for evolution by which subtle substitutions in an amino acid sequence lead to diversification among proteins. Copyright © 2017 Elsevier Ltd. All rights reserved.

Community interactions govern host-switching with implications for host–parasite coevolutionary history

PubMed Central

Harbison, Christopher W.; Clayton, Dale H.

2011-01-01

Reciprocal selective effects between coevolving species are often influenced by interactions with the broader ecological community. Community-level interactions may also influence macroevolutionary patterns of coevolution, such as cospeciation, but this hypothesis has received little attention. We studied two groups of ecologically similar feather lice (Phthiraptera: Ischnocera) that differ in their patterns of association with a single group of hosts. The two groups, “body lice” and “wing lice,” are both parasites of pigeons and doves (Columbiformes). Body lice are more host-specific and show greater population genetic structure than wing lice. The macroevolutionary history of body lice also parallels that of their columbiform hosts more closely than does the evolutionary history of wing lice. The closer association of body lice with hosts, compared with wing lice, can be explained if body lice are less capable of switching hosts than wing lice. Wing lice sometimes disperse phoretically on parasitic flies (Diptera: Hippoboscidae), but body lice seldom engage in this behavior. We tested the hypothesis that wing lice switch host species more often than body lice, and that the difference is governed by phoresis. Our results show that, where flies are present, wing lice switch to novel host species in sufficient numbers to establish viable populations on the new host. Body lice do not switch hosts, even where flies are present. Thus, differences in the coevolutionary history of wing and body lice can be explained by differences in host-switching, mediated by a member of the broader parasite community. PMID:21606369

Effects of language of assessment on the measurement of acculturation: measurement equivalence and cultural frame switching.

PubMed

Schwartz, Seth J; Benet-Martínez, Verónica; Knight, George P; Unger, Jennifer B; Zamboanga, Byron L; Des Rosiers, Sabrina E; Stephens, Dionne P; Huang, Shi; Szapocznik, José

2014-03-01

The present study used a randomized design, with fully bilingual Hispanic participants from the Miami area, to investigate 2 sets of research questions. First, we sought to ascertain the extent to which measures of acculturation (Hispanic and U.S. practices, values, and identifications) satisfied criteria for linguistic measurement equivalence. Second, we sought to examine whether cultural frame switching would emerge--that is, whether latent acculturation mean scores for U.S. acculturation would be higher among participants randomized to complete measures in English and whether latent acculturation mean scores for Hispanic acculturation would be higher among participants randomized to complete measures in Spanish. A sample of 722 Hispanic students from a Hispanic-serving university participated in the study. Participants were first asked to complete translation tasks to verify that they were fully bilingual. Based on ratings from 2 independent coders, 574 participants (79.5% of the sample) qualified as fully bilingual and were randomized to complete the acculturation measures in either English or Spanish. Theoretically relevant criterion measures--self-esteem, depressive symptoms, and personal identity--were also administered in the randomized language. Measurement equivalence analyses indicated that all of the acculturation measures--Hispanic and U.S. practices, values, and identifications-met criteria for configural, weak/metric, strong/scalar, and convergent validity equivalence. These findings indicate that data generated using acculturation measures can, at least under some conditions, be combined or compared across languages of administration. Few latent mean differences emerged. These results are discussed in terms of the measurement of acculturation in linguistically diverse populations. 2014 APA

Effects of Language of Assessment on the Measurement of Acculturation: Measurement Equivalence and Cultural Frame Switching

PubMed Central

Schwartz, Seth J.; Benet-Martínez, Verónica; Knight, George P.; Unger, Jennifer B.; Zamboanga, Byron L.; Des Rosiers, Sabrina E.; Stephens, Dionne; Huang, Shi; Szapocznik, José

2014-01-01

The present study used a randomized design, with fully bilingual Hispanic participants from the Miami area, to investigate two sets of research questions. First, we sought to ascertain the extent to which measures of acculturation (heritage and U.S. practices, values, and identifications) satisfied criteria for linguistic measurement equivalence. Second, we sought to examine whether cultural frame switching would emerge – that is, whether latent acculturation mean scores for U.S. acculturation would be higher among participants randomized to complete measures in English, and whether latent acculturation mean scores for Hispanic acculturation would be higher among participants randomized to complete measures in Spanish. A sample of 722 Hispanic students from a Hispanic-serving university participated in the study. Participants were first asked to complete translation tasks to verify that they were fully bilingual. Based on ratings from two independent coders, 574 participants (79.5% of the sample) qualified as fully bilingual and were randomized to complete the acculturation measures in either English or Spanish. Theoretically relevant criterion measures – self-esteem, depressive symptoms, and personal identity – were also administered in the randomized language. Measurement equivalence analyses indicated that all of the acculturation measures – Hispanic and U.S. practices, values, and identifications – met criteria for configural, weak/metric, strong/scalar, and convergent validity equivalence. These findings indicate that data generated using acculturation measures can, at least under some conditions, be combined or compared across languages of administration. Few latent mean differences emerged. These results are discussed in terms of the measurement of acculturation in linguistically diverse populations. PMID:24188146

Switch to maraviroc with darunavir/r, both QD, in patients with suppressed HIV-1 was well tolerated but virologically inferior to standard antiretroviral therapy: 48-week results of a randomized trial

PubMed Central

Gagliardini, Roberta; Meini, Genny; Sterrantino, Gaetana; Colangeli, Vincenzo; Re, Maria Carla; Latini, Alessandra; Colafigli, Manuela; Vignale, Francesca; Rusconi, Stefano; Micheli, Valeria; Di Biagio, Antonio; Orofino, Giancarlo; Ghisetti, Valeria; Fantauzzi, Alessandra; Vullo, Vincenzo; Grima, Pierfrancesco; Francisci, Daniela; Mastroianni, Claudio; Antinori, Andrea; Trezzi, Michele; Lisi, Lucia; Navarra, Pierluigi; Canovari, Benedetta; D’Arminio Monforte, Antonella; Lamonica, Silvia; D’Avino, Alessandro; Zazzi, Maurizio; Di Giambenedetto, Simona; De Luca, Andrea

2017-01-01

Objectives Primary study outcome was absence of treatment failure (virological failure, VF, or treatment interruption) per protocol at week 48. Methods Patients on 3-drug ART with stable HIV-1 RNA <50 copies/mL and CCR5-tropic virus were randomized 1:1 to maraviroc with darunavir/ritonavir qd (study arm) or continue current ART (continuation arm). Results In June 2015, 115 patients were evaluable for the primary outcome (56 study, 59 continuation arm). The study was discontinued due to excess of VF in the study arm (7 cases, 12.5%, vs 0 in the continuation arm, p = 0.005). The proportion free of treatment failure was 73.2% in the study and 59.3% in the continuation arm. Two participants in the study and 10 in the continuation arm discontinued therapy due to adverse events (p = 0.030). At VF, no emergent drug resistance was detected. Co-receptor tropism switched to non-R5 in one patient. Patients with VF reported lower adherence and had lower plasma drug levels. Femoral bone mineral density was significantly improved in the study arm. Conclusion Switching to maraviroc with darunavir/ritonavir qd in virologically suppressed patients was associated with improved tolerability but was virologically inferior to 3-drug therapy. PMID:29161288

Mechanisms of behavioural maintenance: Long-term effects of theory-based interventions to promote safe water consumption.

PubMed

Inauen, Jennifer; Mosler, Hans-Joachim

2016-01-01

Theory-based interventions can enhance people's safe water consumption, but the sustainability of these interventions and the mechanisms of maintenance remain unclear. We investigated these questions based on an extended theory of planned behaviour. Seven hundred and ten (445 analysed) randomly selected households participated in two cluster-randomised controlled trials in Bangladesh. Study 1 promoted switching to neighbours' arsenic-safe wells, and Study 2 promoted switching to arsenic-safe deep wells. Both studies included two intervention phases. Structured interviews were conducted at baseline (T1), and at 1-month (T2), 2-month (T3) and 9-month (T4) follow-ups. In intervention phase 1 (between T1 and T2), commitment-based behaviour change techniques--reminders, implementation intentions and public commitment--were combined with information and compared to an information-only control group. In phase 2 (between T2 and T3), half of each phase 1 intervention group was randomly assigned to receive either commitment-based techniques once more or coping planning with reminders and information. Initial well-switching rates of up to 60% significantly declined by T4: 38.3% of T2 safe water users stopped consuming arsenic-safe water. The decline depended on the intervention. Perceived behavioural control, intentions, commitment strength and coping planning were associated with maintenance. In line with previous studies, the results indicate that commitment and reminders engender long-term behavioural change.

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 Central

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.

2017-01-01

Background 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. Method 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). Results 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). Interpretation In subjects 60 years and over, free from CV disease and taking prescribed chronic nsNSAIDs, CV events were infrequent and similar on celecoxib and nsNSAIDs. There was no advantage of a strategy of switching prescribed nsNSAIDs to prescribed celecoxib. This study excluded an increased risk of the primary endpoint of more than two events per 1000 patient-years associated with switching to prescribed celecoxib. Clinical Trial Registration https://clinicaltrials.gov/show/NCT00447759; Unique identifier: NCT00447759. PMID:27705888

Suppression of PLCβ2 by Endotoxin Plays a Role in the Adenosine A2A Receptor-Mediated Switch of Macrophages from an Inflammatory to an Angiogenic Phenotype

PubMed Central

Grinberg, Stan; Hasko, Gyorgy; Wu, Dianqing; Leibovich, Samuel Joseph

2009-01-01

Toll-like receptor (TLR) 2, 4, 7, and 9 agonists, together with adenosine A2A receptor (A2AR) agonists, switch macrophages from an inflammatory (M1) to an angiogenic (M2-like) phenotype. This switch involves induction of A2ARs by TLR agonists, down-regulation of tumor necrosis factor α (TNFα) and interleukin-12, and up-regulation of vascular endothelial growth factor (VEGF) and interleukin-10 expression. We show here that the TLR4 agonist lipopolysaccharide (LPS) induces rapid and specific post-transcriptional down-regulation of phospholipase C(PLC)β1 and β2 expression in macrophages by de-stabilizing their mRNAs. The PLCβ inhibitor U73122 down-regulates TNFα expression by macrophages, and in the presence of A2AR agonists, up-regulates VEGF, mimicking the synergistic action of LPS with A2AR agonists. Selective down-regulation of PLCβ2, but not PLCβ1, using small-interfering RNA resulted in increased VEGF expression in response to A2AR agonists, but did not suppress TNFα expression. Macrophages from PLCβ2−/− mice also expressed increased VEGF in response to A2AR agonists. LPS-mediated suppression of PLCβ1 and β2 is MyD88-dependent. In a model of endotoxic shock, LPS (35 μg/mouse, i.p.) suppressed PLCβ1 and β2 expression in spleen, liver, and lung of wild-type but not MyD88−/− mice. These studies indicate that LPS suppresses PLCβ1 and β2 expression in macrophages in vitro and in several tissues in vivo. These results suggest that suppression of PLCβ2 plays an important role in switching M1 macrophages into an M2-like state. PMID:19850892

DNA double-strand break response factors influence end-joining features of IgH class switch and general translocation junctions.

PubMed

Panchakshari, Rohit A; Zhang, Xuefei; Kumar, Vipul; Du, Zhou; Wei, Pei-Chi; Kao, Jennifer; Dong, Junchao; Alt, Frederick W

2018-01-23

Ig heavy chain (IgH) class switch recombination (CSR) in B lymphocytes switches IgH constant regions to change antibody functions. CSR is initiated by DNA double-strand breaks (DSBs) within a donor IgH switch (S) region and a downstream acceptor S region. CSR is completed by fusing donor and acceptor S region DSB ends by classical nonhomologous end-joining (C-NHEJ) and, in its absence, by alternative end-joining that is more biased to use longer junctional microhomologies (MHs). Deficiency for DSB response (DSBR) factors, including ataxia telangiectasia-mutated (ATM) and 53BP1, variably impair CSR end-joining, with 53BP1 deficiency having the greatest impact. However, studies of potential impact of DSBR factor deficiencies on MH-mediated CSR end-joining have been technically limited. We now use a robust DSB joining assay to elucidate impacts of deficiencies for DSBR factors on CSR and chromosomal translocation junctions in primary mouse B cells and CH12F3 B-lymphoma cells. Compared with wild-type, CSR and c-myc to S region translocation junctions in the absence of 53BP1, and, to a lesser extent, other DSBR factors, have increased MH utilization; indeed, 53BP1-deficient MH profiles resemble those associated with C-NHEJ deficiency. However, translocation junctions between c-myc DSB and general DSBs genome-wide are not MH-biased in ATM-deficient versus wild-type CH12F3 cells and are less biased in 53BP1- and C-NHEJ-deficient cells than CSR junctions or c-myc to S region translocation junctions. We discuss potential roles of DSBR factors in suppressing increased MH-mediated DSB end-joining and features of S regions that may render their DSBs prone to MH-biased end-joining in the absence of DSBR factors.