Exploding Nitromethane in Silico, in Real Time.

PubMed

Fileti, Eudes Eterno; Chaban, Vitaly V; Prezhdo, Oleg V

2014-10-02

Nitromethane (NM) is widely applied in chemical technology as a solvent for extraction, cleaning, and chemical synthesis. NM was considered safe for a long time, until a railroad tanker car exploded in 1958. We investigate the detonation kinetics and explosion reaction mechanisms in a variety of systems consisting of NM, molecular oxygen, and water vapor. Reactive molecular dynamics allows us to simulate reactions in time-domain, as they occur in real life. High polarity of the NM molecule is shown to play a key role, driving the first exothermic step of the reaction. Rapid temperature and pressure growth stimulate the subsequent reaction steps. Oxygen is important for faster oxidation, whereas its optimal concentration is in agreement with the proposed reaction mechanism. Addition of water (50 mol %) inhibits detonation; however, water does not prevent detonation entirely. The reported results provide important insights for improving applications of NM and preserving the safety of industrial processes.

New chlorinated amphetamine-type-stimulants disinfection-by-products formed during drinking water treatment.

PubMed

Huerta-Fontela, Maria; Pineda, Oriol; Ventura, Francesc; Galceran, Maria Teresa

2012-06-15

Previous studies have demonstrated high removal rates of amphetamine-type-stimulants (ATSs) through conventional drinking water treatments; however the behaviour of these compounds through disinfection steps and their transformation into disinfection-by-products (DBPs) is still unknown. In this work, for the first time, the reactivity of some ATSs such as amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyethylamphetamine (MDEA) with chlorine has been investigated under simulated and real drinking water treatment conditions in order to evaluate their ability to give rise to transformation products. Two new DBPs from these illicit drugs have been found. A common chlorinated-by-product (3-chlorobenzo)-1,3-dioxole, was identified for both MDA and MDEA while for MDMA, 3-chlorocatechol was found. The presence of these DBPs in water samples collected through drinking water treatment was studied in order to evaluate their formation under real conditions. Both compounds were generated through treatment from raw river water samples containing ATSs at concentration levels ranging from 1 to 15 ng/L for MDA and from 2.3 to 78 ng/L for MDMA. One of them, (3-chlorobenzo)-1,3-dioxole, found after the first chlorination step, was eliminated after ozone and GAC treatment while the MDMA DBP mainly generated after the postchlorination step, showed to be recalcitrant and it was found in final treated waters at concentrations ranging from 0.5 to 5.8 ng/L. Copyright © 2012 Elsevier Ltd. All rights reserved.

Sleeping in a Brave New World: Opportunities for Improving Learning and Clinical Outcomes through Targeted Memory Reactivation.

PubMed

Paller, Ken A

2017-12-01

Neuroscientific insights into learning and memory have mostly concerned input and output, but intervening processing during the time between acquisition and retrieval is also critical. Indeed, intervening memory reactivation may regulate memory longevity, and a growing body of evidence implicates sleep in changing memory storage. For example, subtle auditory stimulation can be used experimentally to selectively encourage memory reactivation during sleep, which thereby improves learning. Much remains to be elucidated about how learning depends on sleep. Nevertheless, this methodology for modifying memory storage during sleep offers new opportunities for reinforcing learning to enhance clinical outcomes in conjunction with therapies engaged during waking. A variety of such possibilities must now be carefully investigated. Likewise, brain rhythms can be entrained to enhance sleep functions, facilitating further progress in understanding the neurophysiological basis of memory processing during sleep. Ultimately, empirical evidence may reveal the extent to which the way we behave when awake is a function of what our brains do when we are asleep. Through such research efforts, an advanced understanding of memory and sleep may allow us to both make better use of our time asleep and take steps toward better health.

Reducing proactive aggression through non-invasive brain stimulation.

PubMed

Dambacher, Franziska; Schuhmann, Teresa; Lobbestael, Jill; Arntz, Arnoud; Brugman, Suzanne; Sack, Alexander T

2015-10-01

Aggressive behavior poses a threat to human collaboration and social safety. It is of utmost importance to identify the functional mechanisms underlying aggression and to develop potential interventions capable of reducing dysfunctional aggressive behavior already at a brain level. We here experimentally shifted fronto-cortical asymmetry to manipulate the underlying motivational emotional states in both male and female participants while assessing the behavioral effects on proactive and reactive aggression. Thirty-two healthy volunteers received either anodal transcranial direct current stimulation to increase neural activity within right dorsolateral prefrontal cortex, or sham stimulation. Aggressive behavior was measured with the Taylor Aggression Paradigm. We revealed a general gender effect, showing that men displayed more behavioral aggression than women. After the induction of right fronto-hemispheric dominance, proactive aggression was reduced in men. This study demonstrates that non-invasive brain stimulation can reduce aggression in men. This is a relevant and promising step to better understand how cortical brain states connect to impulsive actions and to examine the causal role of the prefrontal cortex in aggression. Ultimately, such findings could help to examine whether the brain can be a direct target for potential supportive interventions in clinical settings dealing with overly aggressive patients and/or violent offenders. © The Author (2015). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Clinical allergy to hazelnut and peanut: identification of T cell cross-reactive allergens.

PubMed

Glaspole, Ian N; de Leon, Maria P; Prickett, Sara R; O'Hehir, Robyn E; Rolland, Jennifer M

2011-01-01

Peanut and tree nut allergies are life-threatening conditions for many affected individuals worldwide. Currently there is no cure. While co-allergy to peanut and tree nuts is a common clinical observation, and IgE cross-reactivity between peanut and tree nuts is reported, T cell cross-reactivity is poorly defined. Hazelnut-specific T cell lines were established using peripheral blood mononuclear cells from 5 subjects with co-allergy to hazelnut and peanut. These lines were stimulated with hazelnut and peanut extracts and purified major peanut allergens, Ara h 1 and Ara h 2. Proliferation was determined by (3)H-thymidine incorporation and secretion of key Th1 (IFN-γ) and Th2 (IL-5) cytokines analysed by ELISA. Hazelnut-specific T cell lines from all 5 subjects proliferated upon stimulation with both hazelnut and peanut extracts and for 4 subjects, to Ara h 1 and/or Ara h 2. Proliferating cells were mainly CD4+ T cells and produced both IL-5 and IFN-γ in response to hazelnut and peanut stimulation. Mitogenicity of extracts and allergens was excluded by their lack of stimulation of house dust mite-specific T cells. Our finding that hazelnut and peanut co-allergy is associated with cross-reactive T cell responses, driven partly by cross-reactivity to the major peanut allergens Ara h 1 and Ara h 2, points to future development of allergen immunotherapy by targeting cross-reactive T cells. Copyright © 2011 S. Karger AG, Basel.

A two-step enzymatic modification method to reduce immuno-reactivity of milk proteins.

PubMed

Damodaran, Srinivasan; Li, Yan

2017-12-15

A two-step enzymatic approach to reduce immuno-reactivity of whey protein isolate and casein has been studied. The method involves partial hydrolysis of proteins with proteases, followed by repolymerization with microbial transglutaminase. Whey protein isolate partially hydrolyzed with chymotrypsin, trypsin, or thermolysin retained about 80%, 30%, and 20% of the original immuno-reactivity, respectively. Upon repolymerization the immuno-reactivity decreased to 45%, 35%, and 5%, respectively. The immuno-reactivity of hydrolyzed and repolymerized casein was negligible compared to native casein. The repolymerized products were partially resistant to in vitro digestion. Peptides released during digestion of repolymerized thermolysin-whey protein hydrolysate had less than 5% immuno-reactivity, whereas those of whey protein control exhibited a sinusoidal immuno-reactivity ranging from 5 to 20%. Peptides released during digestion of repolymerized thermolysin-casein hydrolysates had no immuno-reactivity. These results indicated that it is possible to produce hypoallergenic milk protein products using the two-step enzymatic modification method involving thermolysin and transglutaminase. Copyright © 2017. Published by Elsevier Ltd.

Hyperactivity and reactivity of peripheral blood neutrophils in chronic periodontitis

PubMed Central

Matthews, J B; Wright, H J; Roberts, A; Cooper, P R; Chapple, I L C

2007-01-01

Some evidence exists that peripheral neutrophils from patients with chronic periodontitis generate higher levels of reactive oxygen species (ROS) after Fcγ-receptor stimulation than those from healthy controls. We hypothesized that peripheral neutrophils in periodontitis also show both hyper-reactivity to plaque organisms and hyperactivity in terms of baseline, unstimulated generation and release of ROS. Peripheral neutrophils from chronic periodontitis patients and age/sex/smoking-matched healthy controls (18 pairs) were assayed for total ROS generation and extracellular ROS release, with and without stimulation (Fcγ-receptor and Fusobacterium nucleatum), using luminol and isoluminol chemiluminescence. Assays were performed with and without priming with Escherichia coli lipopolysaccharide (LPS) and granulocyte–macrophage colony-stimulating factor (GM-CSF). Phox gene expression (p22, p47, p67, gp91) was investigated using reverse transcription–polymerase chain reaction (RT–PCR). Neutrophils from patients produced higher mean levels of ROS in all assays. Total generation and extracellular release of ROS by patients' cells were significantly greater than those from controls after FcγR-stimulation, with (P = 0·023) and without (P ≤ 0·023) priming with GM-CSF. Differences in unstimulated total ROS generation were not significant. By contrast, patients' cells demonstrated greater baseline, extracellular ROS release than those from controls (P = 0·004). This difference was maintained after priming with LPS (P = 0·028) but not GM-CSF (P = 0·217). Phox gene expression was similar in patient and control cells at baseline and stimulation with F. nucleatum (3 h) consistently reduced gp91PHOX transcripts. Our data demonstrate that peripheral neutrophils from periodontitis patients exhibit hyper-reactivity following stimulation (Fcγ-receptor and F. nucleatum) and hyperactivity in terms of excess ROS release in the absence of exogenous stimulation. This hyperactive/-reactive neutrophil phenotype is not associated with elevated phox gene expression. PMID:17223966

Perceptual Sensitivity and Response to Strong Stimuli Are Related

PubMed Central

Bolders, Anna C.; Tops, Mattie; Band, Guido P. H.; Stallen, Pieter Jan M.

2017-01-01

To shed new light on the long-standing debate about the (in)dependence of sensitivity to weak stimuli and overreactivity to strong stimuli, we examined the relation between these tendencies within the neurobehavioral framework of the Predictive and Reactive Control Systems (PARCS) theory (Tops et al., 2010, 2014). Whereas previous studies only considered overreactivity in terms of the individual tendency to experience unpleasant affect (punishment reactivity) resulting from strong sensory stimulation, we also took the individual tendency to experience pleasant affect (reward reactivity) resulting from strong sensory stimulation into account. According to PARCS theory, these temperamental tendencies overlap in terms of high reactivity toward stimulation, but oppose each other in terms of the response orientation (approach or avoid). PARCS theory predicts that both types of reactivity to strong stimuli relate to sensitivity to weak stimuli, but that these relationships are suppressed due to the opposing relationship between reward and punishment reactivity. We measured punishment and reward reactivity to strong stimuli and sensitivity to weak stimuli using scales from the Adult Temperament Questionnaire (Evans and Rothbart, 2007). Sensitivity was also measured more objectively using the masked auditory threshold. We found that sensitivity to weak stimuli (both self-reported and objectively assessed) was positively associated with self-reported punishment and reward reactivity to strong stimuli, but only when these reactivity measures were controlled for each other, implicating a mutual suppression effect. These results are in line with PARCS theory and suggest that sensitivity to weak stimuli and overreactivity are dependent, but this dependency is likely to be obscured if punishment and reward reactivity are not both taken into account. PMID:29018377

Bovine herpesvirus 1 productive infection and immediate early transcription unit 1 promoter are stimulated by the synthetic corticosteroid dexamethasone.

PubMed

Kook, Insun; Henley, Caitlin; Meyer, Florencia; Hoffmann, Federico G; Jones, Clinton

2015-10-01

The primary site for life-long latency of bovine herpesvirus 1 (BHV-1) is sensory neurons. The synthetic corticosteroid dexamethasone consistently induces reactivation from latency; however the mechanism by which corticosteroids mediate reactivation is unclear. In this study, we demonstrate for the first time that dexamethasone stimulates productive infection, in part, because the BHV-1 genome contains more than 100 potential glucocorticoid receptor (GR) response elements (GREs). Immediate early transcription unit 1 (IEtu1) promoter activity, but not IEtu2 or VP16 promoter activity, was stimulated by dexamethasone. Two near perfect consensus GREs located within the IEtu1 promoter were necessary for dexamethasone-mediated stimulation. Electrophoretic mobility shift assays and chromatin immunoprecipitation studies demonstrated that the GR interacts with IEtu1 promoter sequences containing the GREs. Although we hypothesize that DEX-mediated stimulation of IEtu1 promoter activity is important during productive infection and perhaps reactivation from latency, stress likely has pleiotropic effects on virus-infected cells. Copyright © 2015 Elsevier Inc. All rights reserved.

Activation of NOX2 by the stimulation of ionotropic and metabotropic glutamate receptors contributes to glutamate neurotoxicity in vivo through the production of reactive oxygen species and calpain activation.

PubMed

Guemez-Gamboa, Alicia; Estrada-Sánchez, Ana María; Montiel, Teresa; Páramo, Blanca; Massieu, Lourdes; Morán, Julio

2011-11-01

Prolonged activation of glutamate receptors leads to excitotoxicity. Several processes such as reactive oxygen species (ROS) production and activation of the calcium-dependent protease, calpain, contribute to glutamate-induced damage. It has been suggested that the ROS-producing enzyme, NADPH oxidase (NOX), plays a role in excitotoxicity. Studies have reported NOX activation after NMDA receptor stimulation during excitotoxic damage, but the role of non-NMDA and metabotropic receptors is unknown. We evaluated the roles of different glutamate receptor subtypes on NOX activation and neuronal death induced by the intrastriatal administration of glutamate in mice. In wild-type mice, NOX2 immunoreactivity in neurons and microglia was stimulated by glutamate administration, and it progressively increased as microglia became activated; calpain activity was also induced. By contrast, mice lacking NOX2 were less vulnerable to excitotoxicity, and there was reduced ROS production and protein nitrosylation, microglial reactivity, and calpain activation. These results suggest that NOX2 is stimulated by glutamate in neurons and reactive microglia through the activation of ionotropic and metabotropic receptors. Neuronal damage involves ROS production by NOX2, which, in turn, contributes to calpain activation.

Carbon fiber on polyimide ultra-microelectrodes

NASA Astrophysics Data System (ADS)

Gillis, Winthrop F.; Lissandrello, Charles A.; Shen, Jun; Pearre, Ben W.; Mertiri, Alket; Deku, Felix; Cogan, Stuart; Holinski, Bradley J.; Chew, Daniel J.; White, Alice E.; Otchy, Timothy M.; Gardner, Timothy J.

2018-02-01

Objective. Most preparations for making neural recordings degrade over time and eventually fail due to insertion trauma and reactive tissue response. The magnitudes of these responses are thought to be related to the electrode size (specifically, the cross-sectional area), the relative stiffness of the electrode, and the degree of tissue tolerance for the material. Flexible carbon fiber ultra-microelectrodes have a much smaller cross-section than traditional electrodes and low tissue reactivity, and thus may enable improved longevity of neural recordings in the central and peripheral nervous systems. Only two carbon fiber array designs have been described previously, each with limited channel densities due to limitations of the fabrication processes or interconnect strategies. Here, we describe a method for assembling carbon fiber electrodes on a flexible polyimide substrate that is expected to facilitate the construction of high-density recording and stimulating arrays. Approach. Individual carbon fibers were aligned using an alignment tool that was 3D-printed with sub-micron resolution using direct laser writing. Indium deposition on the carbon fibers, followed by low-temperature microsoldering, provided a robust and reliable method of electrical connection to the polyimide interconnect. Main results. Spontaneous multiunit activity and stimulation-evoked compound responses with SNR  >10 and  >120, respectively, were recorded from a small (125 µm) peripheral nerve. We also improved the typically poor charge injection capacity of small diameter carbon fibers by electrodepositing 100 nm-thick iridium oxide films, making the carbon fiber arrays usable for electrical stimulation as well as recording. Significance. Our innovations in fabrication technique pave the way for further miniaturization of carbon fiber ultra-microelectrode arrays. We believe these advances to be key steps to enable a shift from labor intensive, manual assembly to a more automated manufacturing process.

Carbon fiber on polyimide ultra-microelectrodes.

PubMed

Gillis, Winthrop F; Lissandrello, Charles A; Shen, Jun; Pearre, Ben W; Mertiri, Alket; Deku, Felix; Cogan, Stuart; Holinski, Bradley J; Chew, Daniel J; White, Alice E; Otchy, Timothy M; Gardner, Timothy J

2018-02-01

Most preparations for making neural recordings degrade over time and eventually fail due to insertion trauma and reactive tissue response. The magnitudes of these responses are thought to be related to the electrode size (specifically, the cross-sectional area), the relative stiffness of the electrode, and the degree of tissue tolerance for the material. Flexible carbon fiber ultra-microelectrodes have a much smaller cross-section than traditional electrodes and low tissue reactivity, and thus may enable improved longevity of neural recordings in the central and peripheral nervous systems. Only two carbon fiber array designs have been described previously, each with limited channel densities due to limitations of the fabrication processes or interconnect strategies. Here, we describe a method for assembling carbon fiber electrodes on a flexible polyimide substrate that is expected to facilitate the construction of high-density recording and stimulating arrays. Individual carbon fibers were aligned using an alignment tool that was 3D-printed with sub-micron resolution using direct laser writing. Indium deposition on the carbon fibers, followed by low-temperature microsoldering, provided a robust and reliable method of electrical connection to the polyimide interconnect. Spontaneous multiunit activity and stimulation-evoked compound responses with SNR  >10 and  >120, respectively, were recorded from a small (125 µm) peripheral nerve. We also improved the typically poor charge injection capacity of small diameter carbon fibers by electrodepositing 100 nm-thick iridium oxide films, making the carbon fiber arrays usable for electrical stimulation as well as recording. Our innovations in fabrication technique pave the way for further miniaturization of carbon fiber ultra-microelectrode arrays. We believe these advances to be key steps to enable a shift from labor intensive, manual assembly to a more automated manufacturing process.

Iron Mediates N-Methyl-d-aspartate Receptor-dependent Stimulation of Calcium-induced Pathways and Hippocampal Synaptic Plasticity*

PubMed Central

Muñoz, Pablo; Humeres, Alexis; Elgueta, Claudio; Kirkwood, Alfredo; Hidalgo, Cecilia; Núñez, Marco T.

2011-01-01

Iron deficiency hinders hippocampus-dependent learning processes and impairs cognitive performance, but current knowledge on the molecular mechanisms underlying the unique role of iron in neuronal function is sparse. Here, we investigated the participation of iron on calcium signal generation and ERK1/2 stimulation induced by the glutamate agonist N-methyl-d-aspartate (NMDA), and the effects of iron addition/chelation on hippocampal basal synaptic transmission and long-term potentiation (LTP). Addition of NMDA to primary hippocampal cultures elicited persistent calcium signals that required functional NMDA receptors and were independent of calcium influx through L-type calcium channels or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors; NMDA also promoted ERK1/2 phosphorylation and nuclear translocation. Iron chelation with desferrioxamine or inhibition of ryanodine receptor (RyR)-mediated calcium release with ryanodine-reduced calcium signal duration and prevented NMDA-induced ERK1/2 activation. Iron addition to hippocampal neurons readily increased the intracellular labile iron pool and stimulated reactive oxygen species production; the antioxidant N-acetylcysteine or the hydroxyl radical trapper MCI-186 prevented these responses. Iron addition to primary hippocampal cultures kept in calcium-free medium elicited calcium signals and stimulated ERK1/2 phosphorylation; RyR inhibition abolished these effects. Iron chelation decreased basal synaptic transmission in hippocampal slices, inhibited iron-induced synaptic stimulation, and impaired sustained LTP in hippocampal CA1 neurons induced by strong stimulation. In contrast, iron addition facilitated sustained LTP induction after suboptimal tetanic stimulation. Together, these results suggest that hippocampal neurons require iron to generate RyR-mediated calcium signals after NMDA receptor stimulation, which in turn promotes ERK1/2 activation, an essential step of sustained LTP. PMID:21296883

Gain suppression involving both stimulated Raman and hyper-Raman photons in two-step stimulated emissions

NASA Astrophysics Data System (ADS)

Deng, Lu; Garrett, W. R.; Payne, M. G.; Moore, M. A.

1997-05-01

We show that multiphoton destructive interference leading to gain suppression can be produced even when two different step-wise stimulated emissions, such as stimulated Raman and hyper-Raman emissions, are included in the interference loop.

Shaping memory consolidation via targeted memory reactivation during sleep.

PubMed

Cellini, Nicola; Capuozzo, Alessandra

2018-05-15

Recent studies have shown that the reactivation of specific memories during sleep can be modulated using external stimulation. Specifically, it has been reported that matching a sensory stimulus (e.g., odor or sound cue) with target information (e.g., pairs of words, pictures, and motor sequences) during wakefulness, and then presenting the cue alone during sleep, facilitates memory of the target information. Thus, presenting learned cues while asleep may reactivate related declarative, procedural, and emotional material, and facilitate the neurophysiological processes underpinning memory consolidation in humans. This paradigm, which has been named targeted memory reactivation, has been successfully used to improve visuospatial and verbal memories, strengthen motor skills, modify implicit social biases, and enhance fear extinction. However, these studies also show that results depend on the type of memory investigated, the task employed, the sensory cue used, and the specific sleep stage of stimulation. Here, we present a review of how memory consolidation may be shaped using noninvasive sensory stimulation during sleep. © 2018 New York Academy of Sciences.

Comparative efficacy of intranasal and injectable vaccines in stimulating Bordetella bronchiseptica-reactive anamnestic antibody responses in household dogs

PubMed Central

Ellis, John A.; Gow, Sheryl P.; Lee, Lindsey B.; Lacoste, Stacey; Ball, Eileen C.

2017-01-01

In order to determine the comparative efficacy of injectable and intranasal vaccines to stimulate Bordetella bronchiseptica (Bb)-reactive anamnestic antibodies, a trial was conducted using 144 adult household dogs of various breeds and ages, which had been previously administered intranasal Bb vaccine approximately 12 months before enrollment. Dogs were randomized into 2 groups and blood, nasal swabs, and pharyngeal swabs were collected prior to the administration of single component Bb vaccines intranasally or parenterally. Ten to 14 days later all dogs were resampled to measure changes in systemic and local antibody to Bb. There were no differences in the changes in Bb-reactive serum IgG and nasal IgA between the groups, whereas intranasally vaccinated dogs had significantly higher Bb-reactive serum IgA. These data indicate that both of the current generation of intranasal (modified-live) and injectable (acellular) Bb vaccines can stimulate anamnestic local and systemic antibody responses in previously vaccinated, Bb-seropositive adult household dogs. PMID:28761185

Cellular Transcription Factors Induced in Trigeminal Ganglia during Dexamethasone-Induced Reactivation from Latency Stimulate Bovine Herpesvirus 1 Productive Infection and Certain Viral Promoters

PubMed Central

Workman, Aspen; Eudy, James; Smith, Lynette; Frizzo da Silva, Leticia; Sinani, Devis; Bricker, Halie; Cook, Emily; Doster, Alan

2012-01-01

Bovine herpesvirus 1 (BHV-1), an alphaherpesvirinae subfamily member, establishes latency in sensory neurons. Elevated corticosteroid levels, due to stress, reproducibly triggers reactivation from latency in the field. A single intravenous injection of the synthetic corticosteroid dexamethasone (DEX) to latently infected calves consistently induces reactivation from latency. Lytic cycle viral gene expression is detected in sensory neurons within 6 h after DEX treatment of latently infected calves. These observations suggested that DEX stimulated expression of cellular genes leads to lytic cycle viral gene expression and productive infection. In this study, a commercially available assay—Bovine Gene Chip—was used to compare cellular gene expression in the trigeminal ganglia (TG) of calves latently infected with BHV-1 versus DEX-treated animals. Relative to TG prepared from latently infected calves, 11 cellular genes were induced more than 10-fold 3 h after DEX treatment. Pentraxin three, a regulator of innate immunity and neurodegeneration, was stimulated 35- to 63-fold after 3 or 6 h of DEX treatment. Two transcription factors, promyelocytic leukemia zinc finger (PLZF) and Slug were induced more than 15-fold 3 h after DEX treatment. PLZF or Slug stimulated productive infection 20- or 5-fold, respectively, and Slug stimulated the late glycoprotein C promoter more than 10-fold. Additional DEX-induced transcription factors also stimulated productive infection and certain viral promoters. These studies suggest that DEX-inducible cellular transcription factors and/or signaling pathways stimulate lytic cycle viral gene expression, which subsequently leads to successful reactivation from latency in a small subset of latently infected neurons. PMID:22190728

Effects of amphetamine on reactivity to emotional stimuli

PubMed Central

Wardle, Margaret C.; de Wit, Harriet

2011-01-01

Rationale Most studies of the reinforcing effects of stimulants have focused on the drugs’ capacity to induce positive mood (i.e., euphoria). However, recent findings suggest drugs may also alter emotional reactivity to external stimuli, and that this may occur independently of direct effects on mood. Objectives We aimed to examine effects of d-amphetamine, a prototypic stimulant, on self-reported and psychophysiological reactivity to emotional stimuli as well as overall subjective mood. We predicted that amphetamine would enhance reactivity to pleasant stimuli, particularly, stimuli with social content and that these effects would be independent of the drug’s direct effects on mood. Methods Over three sessions, 36 healthy normal adults received placebo, d-amphetamine 10 and 20 mg under counterbalanced double-blind conditions. At each session, emotional reactivity to standardized positive, neutral, and negative pictures with and without social content was measured in self-reports and facial muscles sensitive to emotional state. Drug effects on cardiovascular variables and subjective mood were also measured. Results Amphetamine produced euphoria, feelings of drug effect, and increased blood pressure. Most notably, amphetamine enhanced self-reported positive reactions to all pictures and psychophysiological reactions to positive pictures. These effects were not significantly related to drug-induced mood changes. Contrary to our hypothesis, effects of amphetamine on emotional reactivity were not moderated by social content. Conclusions This study demonstrates a previously unexamined and potentially reinforcing effect of stimulant drugs in humans, distinct from more typically measured euphorigenic effects, and suggests new areas of research in stimulant abuse risk and adaptations occurring during drug dependence. PMID:21947316

Detecting T-cell reactivity to whole cell vaccines

PubMed Central

Brusic, Ana; Hainz, Ursula; Wadleigh, Martha; Neuberg, Donna; Su, Mei; Canning, Christine M.; DeAngelo, Daniel J.; Stone, Richard M.; Lee, Jeng-Shin; Mulligan, Richard C.; Ritz, Jerome; Dranoff, Glenn; Sasada, Tetsuro; Wu, Catherine J.

2012-01-01

BCR-ABL+ K562 cells hold clinical promise as a component of cancer vaccines, either as bystander cells genetically modified to express immunostimulatory molecules, or as a source of leukemia antigens. To develop a method for detecting T-cell reactivity against K562 cell-derived antigens in patients, we exploited the dendritic cell (DC)-mediated cross-presentation of proteins generated from apoptotic cells. We used UVB irradiation to consistently induce apoptosis of K562 cells, which were then fed to autologous DCs. These DCs were used to both stimulate and detect antigen-specific CD8+ T-cell reactivity. As proof-of-concept, we used cross-presented apoptotic influenza matrix protein-expressing K562 cells to elicit reactivity from matrix protein-reactive T cells. Likewise, we used this assay to detect increased anti-CML antigen T-cell reactivity in CML patients that attained long-lasting clinical remissions following immunotherapy (donor lymphocyte infusion), as well as in 2 of 3 CML patients vaccinated with lethally irradiated K562 cells that were modified to secrete high levels of granulocyte macrophage colony-stimulating factor (GM-CSF). This methodology can be readily adapted to examine the effects of other whole tumor cell-based vaccines, a scenario in which the precise tumor antigens that stimulate immune responses are unknown. PMID:23170257

Surface Modified Particles By Multi-Step Michael-Type Addition And Process For The Preparation Thereof

DOEpatents

Cook, Ronald Lee; Elliott, Brian John; Luebben, Silvia DeVito; Myers, Andrew William; Smith, Bryan Matthew

2005-05-03

A new class of surface modified particles and a multi-step Michael-type addition surface modification process for the preparation of the same is provided. The multi-step Michael-type addition surface modification process involves two or more reactions to compatibilize particles with various host systems and/or to provide the particles with particular chemical reactivities. The initial step comprises the attachment of a small organic compound to the surface of the inorganic particle. The subsequent steps attach additional compounds to the previously attached organic compounds through reactive organic linking groups. Specifically, these reactive groups are activated carbon—carbon pi bonds and carbon and non-carbon nucleophiles that react via Michael or Michael-type additions.

Step-down vs. step-up noxious stimulation: differential effects on pain perception and patterns of brain activation.

PubMed

Choi, J C; Kim, J; Kang, E; Choi, J-H; Park, W Y; Choi, Y-S; Cha, J; Han, C; Park, S K; Kim, M H; Lee, G H; Do, H-J; Jung, S W; Lee, J-M

2016-01-01

We hypothesize that pain and brain responses are affected by changes in the presentation sequence of noxious stimuli that are, overall, identical in intensity and duration. During functional magnetic resonance imaging (fMRI) scanning, 21 participants experienced three patterns of noxious stimulation: Up-type (step-up noxious stimulation, 15 s), Down-type (step-down noxious stimulation, 15 s), and Down-up-type (decreasing and increasing pattern of noxious stimulation, 15 s). The total intensity and duration of the three noxious stimulation patterns were identical, but the stimulation sequences were different. Pain and unpleasantness ratings in the Down- and Down-up-type noxious stimulations were lower than in the Up-type noxious stimulation. The left prefrontal cortex [(PFC, BA (Brodmann area) 10, (-45, 50, 1)] was more highly activated in the Down- and Down-up-type noxious stimulations than in the Up-type noxious stimulation. The S1, S2, insula, bilateral PFC (BA 46), and midcingulate cortex were more highly activated in the Up-type noxious stimulation than in the Down-type noxious stimulation. PFC BA 10 was located at an inferior level compared to the bilateral PFC BA 46 (Z axis = 1 for BA 10, compared to 22 and 25 for the right and left BA 46, respectively). When cortisol level was increased, the left hippocampal cortex, along with the left parahippocampal cortex, was greatly activated for the Up-type noxious stimulation. When pain cannot be avoided in clinical practice, noxious stimuli should be applied to patients in a step-down pattern that delivers the most intense pain first and the least intense pain last. © 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Prenatal programming of emotion regulation: neonatal reactivity as a differential susceptibility factor moderating the outcome of prenatal cortisol levels.

PubMed

Bolten, Margarete; Nast, Irina; Skrundz, Marta; Stadler, Christina; Hellhammer, Dirk H; Meinlschmidt, Gunther

2013-10-01

Hypothalamic-pituitary-adrenal (HPA) activation during pregnancy is linked to dysfunctional behavioral outcomes in the offspring. According to Belsky's differential susceptibility hypothesis, individuals vary regarding their developmental plasticity. Translating the differential susceptibility hypothesis to the field of fetal programming, we hypothesize that infants' temperament, as the constitutionally based reactivity to stimulation, moderates prenatal environmental effects on postnatal emotion regulation. Maternal HPA axis activity and stress-reactivity during pregnancy was estimated, by measuring cortisol concentrations in saliva, collected at 0, 30, 45 and 60 min after awakening and in blood, collected during a laboratory stress test (Trier Social Stress Test), respectively. Newborns reactivity to stimulation was evaluated between postnatal day 10 and 14 using the Neonatal Intensive Care Unit Network Neurobehavioral Scale. Infant's self-quieting-activities, as an indicator of emotion regulation, were evaluated at the age of six months during the still face paradigm. Maternal cortisol reactivity to stress during pregnancy was associated with infant's emotion regulation at the age of six months. Whereas cortisol levels after awakening in mid and late pregnancy were not associated with emotion regulation. Furthermore, regression analyses revealed that in interaction with neonatal reactivity, both, prenatal maternal HPA activity as well as prenatal maternal HPA reactivity to stress predicted emotion regulation. The findings indicate that newborns' reactivity to stimulation is moderating the association between prenatal exposure to maternal glucocorticoids and emotion regulation in infancy. Data suggests that temperamental characteristics of the newborn are a relevant differential susceptibility factor with regard to prenatal effects on emotion regulation. © 2013.

Donor-Derived Regulatory Dendritic Cell Infusion Maintains Donor-Reactive CD4+CTLA4hi T Cells in Non-Human Primate Renal Allograft Recipients Treated with CD28 Co-Stimulation Blockade.

PubMed

Ezzelarab, Mohamed B; Lu, Lien; Shufesky, William F; Morelli, Adrian E; Thomson, Angus W

2018-01-01

Donor-derived regulatory dendritic cell (DCreg) infusion before transplantation, significantly prolongs renal allograft survival in non-human primates. This is associated with enhanced expression of the immunoregulatory molecules cytotoxic T-lymphocyte-associated antigen (Ag) 4 (CTLA4) and programmed cell death protein 1 (PD1) by host donor-reactive T cells. In rodents and humans, CD28 co-stimulatory pathway blockade with the fusion protein CTLA4:Ig (CTLA4Ig) is associated with reduced differentiation and development of regulatory T cells (Treg). We hypothesized that upregulation of CTLA4 by donor-reactive CD4 + T cells in DCreg-infused recipients treated with CTLA4Ig, might be associated with higher incidences of donor-reactive CD4 + T cells with a Treg phenotype. In normal rhesus monkeys, allo-stimulated CD4 + CTLA4 hi , but not CD4 + CTLA4 med/lo T cells exhibited a regulatory phenotype, irrespective of PD1 expression. CTLA4Ig significantly reduced the incidence of CD4 + CTLA4 hi , but not CD4 + CTLA4 med/lo T cells following allo-stimulation, associated with a significant reduction in the CD4 + CTLA4 hi /CD4 + CTLA4 med/lo T cell ratio. In CTLA4Ig-treated renal allograft recipient monkeys, there was a marked reduction in circulating donor-reactive CD4 + CTLA4 hi T cells. In contrast, in CTLA4Ig-treated monkeys with DCreg infusion, no such reduction was observed. In parallel, the donor-reactive CD4 + CTLA4 hi /CD4 + CTLA4 med/lo T cell ratio was reduced significantly in graft recipients without DCreg infusion, but increased in those given DCreg. These observations suggest that pre-transplant DCreg infusion promotes and maintains donor-reactive CD4 + CTLA4 hi T cells with a regulatory phenotype after transplantation, even in the presence of CD28 co-stimulation blockade.

Donor-Derived Regulatory Dendritic Cell Infusion Maintains Donor-Reactive CD4+CTLA4hi T Cells in Non-Human Primate Renal Allograft Recipients Treated with CD28 Co-Stimulation Blockade

PubMed Central

Ezzelarab, Mohamed B.; Lu, Lien; Shufesky, William F.; Morelli, Adrian E.; Thomson, Angus W.

2018-01-01

Donor-derived regulatory dendritic cell (DCreg) infusion before transplantation, significantly prolongs renal allograft survival in non-human primates. This is associated with enhanced expression of the immunoregulatory molecules cytotoxic T-lymphocyte-associated antigen (Ag) 4 (CTLA4) and programmed cell death protein 1 (PD1) by host donor-reactive T cells. In rodents and humans, CD28 co-stimulatory pathway blockade with the fusion protein CTLA4:Ig (CTLA4Ig) is associated with reduced differentiation and development of regulatory T cells (Treg). We hypothesized that upregulation of CTLA4 by donor-reactive CD4+ T cells in DCreg-infused recipients treated with CTLA4Ig, might be associated with higher incidences of donor-reactive CD4+ T cells with a Treg phenotype. In normal rhesus monkeys, allo-stimulated CD4+CTLA4hi, but not CD4+CTLA4med/lo T cells exhibited a regulatory phenotype, irrespective of PD1 expression. CTLA4Ig significantly reduced the incidence of CD4+CTLA4hi, but not CD4+CTLA4med/lo T cells following allo-stimulation, associated with a significant reduction in the CD4+CTLA4hi/CD4+CTLA4med/lo T cell ratio. In CTLA4Ig-treated renal allograft recipient monkeys, there was a marked reduction in circulating donor-reactive CD4+CTLA4hi T cells. In contrast, in CTLA4Ig-treated monkeys with DCreg infusion, no such reduction was observed. In parallel, the donor-reactive CD4+CTLA4hi/CD4+CTLA4med/lo T cell ratio was reduced significantly in graft recipients without DCreg infusion, but increased in those given DCreg. These observations suggest that pre-transplant DCreg infusion promotes and maintains donor-reactive CD4+CTLA4hi T cells with a regulatory phenotype after transplantation, even in the presence of CD28 co-stimulation blockade. PMID:29520267

Rapid effects of deep brain stimulation reactivation on symptoms and neuroendocrine parameters in obsessive-compulsive disorder

PubMed Central

de Koning, P P; Figee, M; Endert, E; van den Munckhof, P; Schuurman, P R; Storosum, J G; Denys, D; Fliers, E

2016-01-01

Improvement of obsessions and compulsions by deep brain stimulation (DBS) for obsessive-compulsive disorder (OCD) is often preceded by a rapid and transient mood elevation (hypomania). In a previous study we showed that improvement of mood by DBS for OCD is associated with a decreased activity of the hypothalamus–pituitary adrenal axis. The aim of our present study was to evaluate the time course of rapid clinical changes following DBS reactivation in more detail and to assess their association with additional neuroendocrine parameters. We included therapy-refractory OCD patients treated with DBS (>1 year) and performed a baseline assessment of symptoms, as well as plasma concentrations of thyroid-stimulating hormone (TSH), prolactin, growth hormone, copeptin and homovanillic acid. This was repeated after a 1-week DBS OFF condition. Next, we assessed the rapid effects of DBS reactivation by measuring psychiatric symptom changes using visual analog scales as well as repeated neuroendocrine measures after 30 min, 2 h and 6 h. OCD, anxiety and depressive symptoms markedly increased during the 1-week OFF condition and decreased again to a similar extent already 2 h after DBS reactivation. We found lower plasma prolactin (41% decrease, P=0.003) and TSH (39% decrease, P=0.003) levels during DBS OFF, which increased significantly already 30 min after DBS reactivation. The rapid and simultaneous increase in TSH and prolactin is likely to result from stimulation of hypothalamic thyrotropin-releasing hormone (TRH), which may underlie the commonly observed transient mood elevation following DBS. PMID:26812043

The Next Step in Understanding Impaired Reactive Balance Control in People With Stroke: The Role of Defective Early Automatic Postural Responses.

PubMed

de Kam, Digna; Roelofs, Jolanda M B; Bruijnes, Amber K B D; Geurts, Alexander C H; Weerdesteyn, Vivian

2017-08-01

Postural muscle responses are often impaired after stroke. We aimed to identify the contribution of deficits in very early postural responses to poorer reactive balance capacity, with a particular focus on reactive stepping as a key strategy for avoiding falls. A total of 34 chronic stroke survivors and 17 controls were subjected to translational balance perturbations in 4 directions. We identified the highest perturbation intensity that could be recovered without stepping (single stepping threshold [SST]) and with maximally 1 step (multiple stepping threshold [MST]). We determined onset latencies and response amplitudes of 7 leg muscles bilaterally and identified associations with balance capacity. People with stroke had a lower MST than controls in all directions. Side steps resulted in a higher lateral MST than crossover steps but were less common toward the paretic side. Postural responses were delayed and smaller in amplitude on the paretic side only. We observed the strongest associations between gluteus medius (GLUT) onset and amplitude and MST toward the paretic side ( R 2 = 0.33). Electromyographic variables were rather weakly associated with forward and backward MSTs ( R 2 = 0.10-0.22) and with SSTs ( R 2 = 0.08-0.15). Delayed and reduced paretic postural responses are associated with impaired reactive stepping after stroke. Particularly, fast and vigorous activity of the GLUT is imperative for overcoming large sideways perturbations, presumably because it facilitates the effective use of side steps. Because people with stroke often fall toward the paretic side, this finding indicates an important target for training.

Assessing the reactivation efficacy of hydroxylamine anion towards VX-inhibited AChE: a computational study.

PubMed

Khan, Md Abdul Shafeeuulla; Ganguly, Bishwajit

2012-05-01

Oximate anions are used as potential reactivating agents for OP-inhibited AChE because of they possess enhanced nucleophilic reactivity due to the α-effect. We have demonstrated the process of reactivating the VX-AChE adduct with formoximate and hydroxylamine anions by applying the DFT approach at the B3LYP/6-311 G(d,p) level of theory. The calculated results suggest that the hydroxylamine anion is more efficient than the formoximate anion at reactivating VX-inhibited AChE. The reaction of formoximate anion and the VX-AChE adduct is a three-step process, while the reaction of hydroxylamine anion with the VX-AChE adduct seems to be a two-step process. The rate-determining step in the process is the initial attack on the VX of the VX-AChE adduct by the nucleophile. The subsequent steps are exergonic in nature. The potential energy surface (PES) for the reaction of the VX-AChE adduct with hydroxylamine anion reveals that the reactivation process is facilitated by the lower free energy of activation (by a factor of 1.7 kcal mol(-1)) than that of the formoximate anion at the B3LYP/6-311 G(d,p) level of theory. The higher free energy of activation for the reverse reactivation reaction between hydroxylamine anion and the VX-serine adduct further suggests that the hydroxylamine anion is a very good antidote agent for the reactivation process. The activation barriers calculated in solvent using the polarizable continuum model (PCM) for the reactivation of the VX-AChE adduct with hydroxylamine anion were also found to be low. The calculated results suggest that V-series compounds can be more toxic than G-series compounds, which is in accord with earlier experimental observations.

An autonomous organic reaction search engine for chemical reactivity.

PubMed

Dragone, Vincenza; Sans, Victor; Henson, Alon B; Granda, Jaroslaw M; Cronin, Leroy

2017-06-09

The exploration of chemical space for new reactivity, reactions and molecules is limited by the need for separate work-up-separation steps searching for molecules rather than reactivity. Herein we present a system that can autonomously evaluate chemical reactivity within a network of 64 possible reaction combinations and aims for new reactivity, rather than a predefined set of targets. The robotic system combines chemical handling, in-line spectroscopy and real-time feedback and analysis with an algorithm that is able to distinguish and select the most reactive pathways, generating a reaction selection index (RSI) without need for separate work-up or purification steps. This allows the automatic navigation of a chemical network, leading to previously unreported molecules while needing only to do a fraction of the total possible reactions without any prior knowledge of the chemistry. We show the RSI correlates with reactivity and is able to search chemical space using the most reactive pathways.

An autonomous organic reaction search engine for chemical reactivity

NASA Astrophysics Data System (ADS)

Dragone, Vincenza; Sans, Victor; Henson, Alon B.; Granda, Jaroslaw M.; Cronin, Leroy

2017-06-01

The exploration of chemical space for new reactivity, reactions and molecules is limited by the need for separate work-up-separation steps searching for molecules rather than reactivity. Herein we present a system that can autonomously evaluate chemical reactivity within a network of 64 possible reaction combinations and aims for new reactivity, rather than a predefined set of targets. The robotic system combines chemical handling, in-line spectroscopy and real-time feedback and analysis with an algorithm that is able to distinguish and select the most reactive pathways, generating a reaction selection index (RSI) without need for separate work-up or purification steps. This allows the automatic navigation of a chemical network, leading to previously unreported molecules while needing only to do a fraction of the total possible reactions without any prior knowledge of the chemistry. We show the RSI correlates with reactivity and is able to search chemical space using the most reactive pathways.

An autonomous organic reaction search engine for chemical reactivity

PubMed Central

Dragone, Vincenza; Sans, Victor; Henson, Alon B.; Granda, Jaroslaw M.; Cronin, Leroy

2017-01-01

The exploration of chemical space for new reactivity, reactions and molecules is limited by the need for separate work-up-separation steps searching for molecules rather than reactivity. Herein we present a system that can autonomously evaluate chemical reactivity within a network of 64 possible reaction combinations and aims for new reactivity, rather than a predefined set of targets. The robotic system combines chemical handling, in-line spectroscopy and real-time feedback and analysis with an algorithm that is able to distinguish and select the most reactive pathways, generating a reaction selection index (RSI) without need for separate work-up or purification steps. This allows the automatic navigation of a chemical network, leading to previously unreported molecules while needing only to do a fraction of the total possible reactions without any prior knowledge of the chemistry. We show the RSI correlates with reactivity and is able to search chemical space using the most reactive pathways. PMID:28598440

Interferon-γ and interleukin-17 production from PPD-stimulated PBMCss of patients with pulmonary tuberculosis.

PubMed

Nunnari, Giuseppe; Pinzone, Marilia R; Vancheri, Carlo; Palermo, Filippo; Cacopardo, Bruno

2013-04-01

The purpose of this study was to evaluate Interferon (IFN)-γ and Interleukin(IL)-17 profiles in patients with different clinical presentations of pulmonary tuberculosis (TB) and to compare them with those of tuberculin-negative and tuberculin-reactive healthy controls Peripheral blood mononuclear cells (PBMCss), isolated from patients (n=52) and controls (n=30), were stimulated ex vivo with purified protein derivative (PPD) and IFN-γ and IL-17 levels in the supernatant were measured. At baseline, PBMCss from patients with TB released a significantly lower amount of IL-17 (p=0.043) than PBMCss from healthy controls, whereas IFN-γ levels were similar in the two groups. After PPD stimulation, a significant rise in IL-17 levels was found only among healthy controls (p=0.02). This rise in IL-17 levels was similar between tuberculin-reactive and tuberculin-negative subjects. After PPD stimulation, patients with infiltrative TB secreted higher levels of IL-17 and IFN-γ than those affected with chronic, miliary and cavitary TB (p < 0.01). IFN-γ production from patients with infiltrative TB was even higher than for healthy controls (p < 0.01). PBMCss from tuberculin-reactive patients released higher levels of IFN-γ than tuberculin-negative subjects after PPD stimulation (p < 0.01). Ex vivo PPD stimulation of PBMCs from patients with pulmonary TB does not significantly stimulate IL-17 release; however, higher IL-17 and IFN-γ levels are found in patients with infiltrative disease, in comparison with those affected with miliary, cavitary and chronic TB.

Stimulant abuser groups to engage in 12-step: a multisite trial in the National Institute on Drug Abuse Clinical Trials Network.

PubMed

Donovan, Dennis M; Daley, Dennis C; Brigham, Gregory S; Hodgkins, Candace C; Perl, Harold I; Garrett, Sharon B; Doyle, Suzanne R; Floyd, Anthony S; Knox, Patricia C; Botero, Christopher; Kelly, Thomas M; Killeen, Therese K; Hayes, Carole; Kau'i Baumhofer, Nicole; Kau'ibaumhofer, Nicole; Seamans, Cindy; Zammarelli, Lucy

2013-01-01

The study evaluated the effectiveness of an 8-week combined group plus individual 12-step facilitative intervention on stimulant drug use and 12-step meeting attendance and service. Multisite randomized controlled trial, with assessments at baseline, mid-treatment, end of treatment, and 3- and 6-month post-randomization follow-ups (FUs). Intensive outpatient substance treatment programs. Individuals with stimulant use disorders (n = 471) randomly assigned to treatment as usual (TAU) or TAU into which the Stimulant Abuser Groups to Engage in 12-Step (STAGE-12) intervention was integrated. Urinalysis and self-reports of substance use and 12-step attendance and activities. Group sessions focused on increasing acceptance of 12-step principles; individual sessions incorporated an intensive referral procedure connecting participants to 12-step volunteers. Compared with TAU, STAGE-12 participants had significantly greater odds of self-reported stimulant abstinence during the active 8-week treatment phase; however, among those who had not achieved abstinence during this period, STAGE-12 participants had more days of use. STAGE-12 participants had lower Addiction Severity Index Drug Composite scores at and a significant reduction from baseline to the 3-month FU, attended 12-step meetings on a greater number of days during the early phase of active treatment, engaged in more other types of 12-step activities throughout the active treatment phase and the entire FU period, and had more days of self-reported service at meetings from mid-treatment through the 6-month FU. The present findings are mixed with respect to the impact of integrating the STAGE-12 intervention into intensive outpatient drug treatment compared with TAU on stimulant drug use. However, the results more clearly indicate that individuals in STAGE-12 had higher rates of 12-step meeting attendance and were engaged in more related activities throughout both the active treatment phase and the entire 6-month FU period than did those in TAU. Copyright © 2013 Elsevier Inc. All rights reserved.

Fission control system for nuclear reactor

DOEpatents

Conley, G.H.; Estes, G.P.

Control system for nuclear reactor comprises a first set of reactivity modifying rods fixed in a reactor core with their upper ends stepped in height across the core, and a second set of reactivity modifying rods movable vertically within the reactor core and having their lower ends stepped to correspond with the stepped arrangement of the first set of rods, pairs of the rods of the first and second sets being in coaxial alignment.

Gp120 binding with DC-SIGN induces reactivation of HIV-1 provirus via the NF-κB signaling pathway

PubMed Central

Jin, Changzhong; Li, Jie; Cheng, Linfang; Liu, Fumin; Wu, Nanping

2016-01-01

The reactivation mechanism of latent human immunodeficiency virus type 1 (HIV-1) infection is unclear, especially in dendritic cells (DC). DC-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) binds with HIV-1 and other pathogens to activate the extracellular regulated protein kinase (ERK) and nuclear factor-kappa B (NF-κB) pathways and regulate cytokine expression. We hypothesized that DC-SIGN-induced signaling pathways may activate HIV-1 provirus. To investigate this hypothesis, we generated a model by transfecting 293T cells with a DC-SIGN expression plasmid and an HIV-1 5′ long terminal repeat (LTR) reporter plasmid, and then stimulated the 293T cells with HIV-1 gp120 protein, wild-type HIV-1 or VSV-G-pNL4.3 pseudotype virus (without gp120 protein). It was found that the HIV-1 5′LTR was reactivated by HIV-1 gp120 in DC-SIGN-expressing 293T cells. Then the HIV-1 chronically infected CEM-Bru cells were transfected with DC-SIGN expression plasmid and stimulated by HIV-1 gp120 protein. It was found that early and late HIV-1 provirus replication was reactivated by the HIV-1 gp120/DC-SIGN stimulation. We then investigated the involvement of the ERK, p38 mitogen-activated protein kinases and NF-κB signaling pathways in HIV-1 gp120/DC-SIGN-induced activation of HIV-1 provirus by inhibiting the pathways specifically. Our results indicated that HIV-1 gp120/DC-SIGN stimulation reactivates latent HIV-1 provirus via the NF-κB signal pathway. PMID:26837416

Episodic Memory Retrieval Functionally Relies on Very Rapid Reactivation of Sensory Information.

PubMed

Waldhauser, Gerd T; Braun, Verena; Hanslmayr, Simon

2016-01-06

Episodic memory retrieval is assumed to rely on the rapid reactivation of sensory information that was present during encoding, a process termed "ecphory." We investigated the functional relevance of this scarcely understood process in two experiments in human participants. We presented stimuli to the left or right of fixation at encoding, followed by an episodic memory test with centrally presented retrieval cues. This allowed us to track the reactivation of lateralized sensory memory traces during retrieval. Successful episodic retrieval led to a very early (∼100-200 ms) reactivation of lateralized alpha/beta (10-25 Hz) electroencephalographic (EEG) power decreases in the visual cortex contralateral to the visual field at encoding. Applying rhythmic transcranial magnetic stimulation to interfere with early retrieval processing in the visual cortex led to decreased episodic memory performance specifically for items encoded in the visual field contralateral to the site of stimulation. These results demonstrate, for the first time, that episodic memory functionally relies on very rapid reactivation of sensory information. Remembering personal experiences requires a "mental time travel" to revisit sensory information perceived in the past. This process is typically described as a controlled, relatively slow process. However, by using electroencephalography to measure neural activity with a high time resolution, we show that such episodic retrieval entails a very rapid reactivation of sensory brain areas. Using transcranial magnetic stimulation to alter brain function during retrieval revealed that this early sensory reactivation is causally relevant for conscious remembering. These results give first neural evidence for a functional, preconscious component of episodic remembering. This provides new insight into the nature of human memory and may help in the understanding of psychiatric conditions that involve the automatic intrusion of unwanted memories. Copyright © 2016 the authors 0270-6474/16/360251-10$15.00/0.

Age-dependent effects of acute methylphenidate on amygdala reactivity in stimulant treatment-naive patients with Attention Deficit/Hyperactivity Disorder.

PubMed

Bottelier, Marco A; Schrantee, Anouk; Ferguson, Bart; Tamminga, Hyke G H; Bouziane, Cheima; Kooij, J J Sandra; de Ruiter, Michiel B; Reneman, Liesbeth

2017-11-30

In the present study, we investigate whether methylphenidate (MPH) affects emotional processing and whether this effect is modulated by age. We measured amygdala reactivity with functional Magnetic Resonance Imaging (fMRI) during processing of angry and fearful facial expressions in male stimulant treatment-naive patients with ADHD (N = 35 boys; N = 46 men) and 23 healthy control subjects (N = 11 boys; N = 12 men). In ADHD patients, we also measured amygdala reactivity 90min after an acute oral challenge with MPH (0.5mg/kg). Mean amygdala reactivity was analyzed for all subjects using a repeated measures analysis of variance (ANOVA). Whole-brain maps were analyzed for the patients only. At baseline, we found a age*diagnosis effect approaching significance (p = 0.05) in the right amygdala due to lower reactivity in children with Attention Deficit/Hyperactivity Disorder (ADHD) vs. controls (-31%), but higher reactivity in adults with ADHD vs. controls (+31%). MPH significantly reduced right amygdala reactivity in all patients, resulting in further reductions in children. In the left amygdala, reduction of amygdala reactivity was confined to adult ADHD patients whereas there was no change in children with ADHD. MPH-induced decrease of amygdala reactivity in adults might be a promising avenue for managing emotional dysregulation when replicated for chronic MPH treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

Bilateral stimulation of the subthalamic nucleus has differential effects on reactive and proactive inhibition and conflict-induced slowing in Parkinson's disease.

PubMed

Obeso, Ignacio; Wilkinson, Leonora; Rodríguez-Oroz, Maria-Cruz; Obeso, Jose A; Jahanshahi, Marjan

2013-05-01

It has been proposed that the subthalamic nucleus (STN) mediates response inhibition and conflict resolution through the fronto-basal ganglia pathways. Our aim was to compare the effects of deep brain stimulation (DBS) of the STN on reactive and proactive inhibition and conflict resolution in Parkinson's disease using a single task. We used the conditional Stop signal reaction time task that provides the Stop signal reaction time (SSRT) as a measure of reactive inhibition, the response delay effect (RDE) as a measure of proactive inhibition and conflict-induced slowing (CIS) as a measure of conflict resolution. DBS of the STN significantly prolonged SSRT relative to stimulation off. However, while the RDE measure of proactive inhibition was not significantly altered by DBS of the STN, relative to healthy controls, RDE was significantly lower with DBS off but not DBS on. DBS of the STN did not alter the mean CIS but produced a significant differential effect on the slowest and fastest RTs on conflict trials, further prolonging the slowest RTs on the conflict trials relative to DBS off and to controls. These results are the first demonstration, using a single task in the same patient sample, that DBS of the STN produces differential effects on reactive and proactive inhibition and on conflict resolution, suggesting that these effects are likely to be mediated through the impact of STN stimulation on different fronto-basal ganglia pathways: hyperdirect, direct and indirect.

High heating rate decomposition dynamics of copper oxide by nanocalorimetry-coupled time-of-flight mass spectrometry

NASA Astrophysics Data System (ADS)

Yi, Feng; DeLisio, Jeffery B.; Nguyen, Nam; Zachariah, Michael R.; LaVan, David A.

2017-12-01

The thermodynamics and evolved gases were measured during the rapid decomposition of copper oxide (CuO) thin film at rates exceeding 100,000 K/s. CuO decomposes to release oxygen when heated and serves as an oxidizer in reactive composites and chemical looping combustion. Other instruments have shown either one or two decomposition steps during heating. We have confirmed that CuO decomposes by two steps at both slower and higher heating rates. The decomposition path influences the reaction course in reactive Al/CuO/Al composites, and full understanding is important in designing reactive mixtures and other new reactive materials.

Effects of Stand and Step Training with Epidural Stimulation on Motor Function for Standing in Chronic Complete Paraplegics

PubMed Central

Rejc, Enrico; Angeli, Claudia A.; Bryant, Nicole

2017-01-01

Abstract Individuals affected by motor complete spinal cord injury are unable to stand, walk, or move their lower limbs voluntarily; this diagnosis normally implies severe limitations for functional recovery. We have recently shown that the appropriate selection of epidural stimulation parameters was critical to promoting full-body, weight-bearing standing with independent knee extension in four individuals with chronic clinically complete paralysis. In the current study, we examined the effects of stand training and subsequent step training with epidural stimulation on motor function for standing in the same four individuals. After stand training, the ability to stand improved to different extents in the four participants. Step training performed afterwards substantially impaired standing ability in three of the four individuals. Improved standing ability generally coincided with continuous electromyography (EMG) patterns with constant levels of ground reaction forces. Conversely, poorer standing ability was associated with more variable EMG patterns that alternated EMG bursts and longer periods of negligible activity in most of the muscles. Stand and step training also differentially affected the evoked potentials amplitude modulation induced by sitting-to-standing transition. Finally, stand and step training with epidural stimulation were not sufficient to improve motor function for standing without stimulation. These findings show that the spinal circuitry of motor complete paraplegics can generate motor patterns effective for standing in response to task-specific training with optimized stimulation parameters. Conversely, step training can lead to neural adaptations resulting in impaired motor function for standing. PMID:27566051

Optimal design of neural stimulation current waveforms.

PubMed

Halpern, Mark

2009-01-01

This paper contains results on the design of electrical signals for delivering charge through electrodes to achieve neural stimulation. A generalization of the usual constant current stimulation phase to a stepped current waveform is presented. The electrode current design is then formulated as the calculation of the current step sizes to minimize the peak electrode voltage while delivering a specified charge in a given number of time steps. This design problem can be formulated as a finite linear program, or alternatively by using techniques for discrete-time linear system design.

Mechano-stimulated modifications in the chloroplast antioxidant system and proteome changes are associated with cold response in wheat.

PubMed

Li, Xiangnan; Hao, Chenglong; Zhong, Jianwen; Liu, Fulai; Cai, Jian; Wang, Xiao; Zhou, Qin; Dai, Tingbo; Cao, Weixing; Jiang, Dong

2015-09-11

Mechanical wounding can cause morphological and developmental changes in plants, which may affect the responses to abiotic stresses. However, the mechano-stimulation triggered regulation network remains elusive. Here, the mechano-stimulation was applied at two different times during the growth period of wheat before exposing the plants to cold stress (5.6 °C lower temperature than the ambient temperature, viz., 5.0 °C) at the jointing stage. Results showed that mechano-stimulation at the Zadoks growth stage 26 activated the antioxidant system, and substantially, maintained the homeostasis of reactive oxygen species. In turn, the stimulation improved the electron transport and photosynthetic rate of wheat plants exposed to cold stress at the jointing stage. Proteomic and transcriptional analyses revealed that the oxidative stress defense, ATP synthesis, and photosynthesis-related proteins and genes were similarly modulated by mechano-stimulation and the cold stress. It was concluded that mechano-stimulated modifications of the chloroplast antioxidant system and proteome changes are related to cold tolerance in wheat. The findings might provide deeper insights into roles of reactive oxygen species in mechano-stimulated cold tolerance of photosynthetic apparatus, and be helpful to explore novel approaches to mitigate the impacts of low temperature occurring at critical developmental stages.

An efficient unstructured WENO method for supersonic reactive flows

NASA Astrophysics Data System (ADS)

Zhao, Wen-Geng; Zheng, Hong-Wei; Liu, Feng-Jun; Shi, Xiao-Tian; Gao, Jun; Hu, Ning; Lv, Meng; Chen, Si-Cong; Zhao, Hong-Da

2018-03-01

An efficient high-order numerical method for supersonic reactive flows is proposed in this article. The reactive source term and convection term are solved separately by splitting scheme. In the reaction step, an adaptive time-step method is presented, which can improve the efficiency greatly. In the convection step, a third-order accurate weighted essentially non-oscillatory (WENO) method is adopted to reconstruct the solution in the unstructured grids. Numerical results show that our new method can capture the correct propagation speed of the detonation wave exactly even in coarse grids, while high order accuracy can be achieved in the smooth region. In addition, the proposed adaptive splitting method can reduce the computational cost greatly compared with the traditional splitting method.

Is the human mirror neuron system plastic? Evidence from a transcranial magnetic stimulation study.

PubMed

Mehta, Urvakhsh Meherwan; Waghmare, Avinash V; Thirthalli, Jagadisha; Venkatasubramanian, Ganesan; Gangadhar, Bangalore N

2015-10-01

Virtual lesions in the mirror neuron network using inhibitory low-frequency (1Hz) transcranial magnetic stimulation (TMS) have been employed to understand its spatio-functional properties. However, no studies have examined the influence of neuro-enhancement by using excitatory high-frequency (20Hz) repetitive transcranial magnetic stimulation (HF-rTMS) on these networks. We used three forms of TMS stimulation (HF-rTMS, single and paired pulse) to investigate whether the mirror neuron system facilitates the motor system during goal-directed action observation relative to inanimate motion (motor resonance), a marker of putative mirror neuron activity. 31 healthy individuals were randomized to receive single-sessions of true or sham HF-rTMS delivered to the left inferior frontal gyrus - a component of the human mirror system. Motor resonance was assessed before and after HF-rTMS using three TMS cortical reactivity paradigms: (a) 120% of resting motor threshold (RMT), (b) stimulus intensity set to evoke motor evoked potential of 1-millivolt amplitude (SI1mV) and (c) a short latency paired pulse paradigm. Two-way RMANOVA showed a significant group (true versus sham) X occasion (pre- and post-HF-rTMS motor resonance) interaction effect for SI1mV [F(df)=6.26 (1, 29), p=0.018] and 120% RMT stimuli [F(df)=7.01 (1, 29), p=0.013] indicating greater enhancement of motor resonance in the true HF-rTMS group than the sham-group. This suggests that HF-rTMS could adaptively modulate properties of the mirror neuron system. This neuro-enhancement effect is a preliminary step that can open translational avenues for novel brain stimulation therapeutics targeting social-cognition deficits in schizophrenia and autism. Copyright © 2015 Elsevier B.V. All rights reserved.

Multilevel Analysis of Locomotion in Immature Preparations Suggests Innovative Strategies to Reactivate Stepping after Spinal Cord Injury.

PubMed

Brumley, Michele R; Guertin, Pierre A; Taccola, Giuliano

2017-01-01

Locomotion is one of the most complex motor behaviors. Locomotor patterns change during early life, reflecting development of numerous peripheral and hierarchically organized central structures. Among them, the spinal cord is of particular interest since it houses the central pattern generator (CPG) for locomotion. This main command center is capable of eliciting and coordinating complex series of rhythmic neural signals sent to motoneurons and to corresponding target-muscles for basic locomotor activity. For a long-time, the CPG has been considered a black box. In recent years, complementary insights from in vitro and in vivo animal models have contributed significantly to a better understanding of its constituents, properties and ways to recover locomotion after a spinal cord injury (SCI). This review discusses key findings made by comparing the results of in vitro isolated spinal cord preparations and spinal-transected in vivo models from neonatal animals. Pharmacological, electrical, and sensory stimulation approaches largely used to further understand CPG function may also soon become therapeutic tools for potent CPG reactivation and locomotor movement induction in persons with SCI or developmental neuromuscular disorder. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Role of the epidermal growth factor receptor in signaling strain-dependent activation of the brain natriuretic peptide gene.

PubMed

Anderson, Hope D I; Wang, Feng; Gardner, David G

2004-03-05

The epidermal growth factor receptor (EGFR) and ectoshedding of heparin-binding epidermal growth factor (HBEGF), an EGFR ligand, have been linked to the development of cardiac myocyte hypertrophy. However, the precise role that the liganded EGFR plays in the transcriptional activation of the gene program that accompanies hypertrophy remains undefined. Utilizing the human (h) BNP gene as a model of hypertrophy-dependent gene activation, we show that activation of the EGFR plays an important role in mediating mechanical strain-dependent stimulation of the hBNP promoter. Strain promotes endothelin (ET) generation through NAD(P)H oxidase-dependent production of reactive oxygen species. ET in turn induces metalloproteinase-mediated cleavage of pro-HBEGF and ectoshedding of HBEGF, which activates the EGFR and stimulates hBNP promoter activity. HBEGF also stimulates other phenotypic markers of hypertrophy including protein synthesis and sarcomeric assembly. The antioxidant N-acetylcysteine or the NAD(P)H oxidase inhibitor, apocynin, inhibited strain-dependent activation of the ET-1 promoter, HBEGF shedding, and hBNP promoter activation. The metalloproteinase inhibitor, GM-6001, prevented the induction of HBEGF ectoshedding and the hBNP promoter response to strain, suggesting a critical role for the metalloproteinase-dependent cleavage event in signaling the strain response. These findings suggest that metalloproteinase activity as an essential step in this pathway may prove to be a relevant therapeutic target in the management of cardiac hypertrophy.

Comparison of Th1- and Th2-associated immune reactivities stimulated by single versus multiple vaccination of mice with irradiated Schistosoma mansoni cercariae

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

Caulada-Benedetti, Z.; Al-Zamel, F.; Sher, A.

1991-03-01

Mice immunized against Schistosoma mansoni by a single percutaneous exposure to radiation-attenuated parasite larvae demonstrate partial resistance to challenge infection that has been shown to correlate with development of cell-mediated immunity, whereas mice hyperimmunized by multiple exposure to attenuated larvae produce antibodies capable of transferring partial protection to naive recipients. Measurement of Ag-specific lymphokine responses in these animals suggested that the difference in resistance mechanisms may be due to the differential induction of Th subset response by the two immunization protocols. Thus, upon Ag stimulation, singly immunized mice predominantly demonstrated responses associated with Th1 reactivity, including IL-2 and IFN-gamma production,more » whereas multiply immunized animals showed increased IL-5, IL-4, and IgG1 antibody production associated with enhanced Th2 response. These responses demonstrated some degree of organ compartmentalization, with splenocytes demonstrating higher Th1-related lymphokine production and cells from draining lymph nodes showing stronger proliferation and Th2 type reactivity. However, hyperimmunized mice also continued to demonstrate substantial Th1-associated immune reactivity. Moreover, in vivo Ag challenge elicited activated larvacidal macrophages in hyperimmunized animals. These observations indicate that protective cell-mediated mechanisms associated with induction of CD4+ Th1 cell reactivity predominate in singly vaccinated mice. Further vaccination stimulates Th2 responses, such as enhanced IgG1 production, that may also contribute to protective immunity.« less

Asymmetry in the dorsolateral prefrontal cortex and aggressive behavior: a continuous theta-burst magnetic stimulation study.

PubMed

Perach-Barzilay, N; Tauber, A; Klein, E; Chistyakov, A; Ne'eman, R; Shamay-Tsoory, S G

2013-01-01

Aggressive behavior is aimed at causing damage or pain to another individual. Aggression has been associated with structural and functional deficits in numerous brain areas, including the dorsolateral region of the prefrontal cortex (DLPFC), typically related to inhibition and impulse control. In this study, we used inhibitory continuous theta-burst magnetic stimulation (cTBS) to explore the role of the right and left DLPFC in aggression. Sixteen healthy right-handed volunteers underwent two sessions involving random, real and sham, right and left DLPFC stimulations. These sessions were followed by the Social Orientation Paradigm (SOP), a monetary task that was specially designed to assess participants' aggressive tendencies by measuring the patterns of their reactive aggression (a response to a perceived provocation) and proactive aggression (an aggressive act with goal-oriented purposes). Results indicate that using cTBS to target the left DLPFC was associated with a greater increase in aggressive responses than right DLPFC stimulation. This pattern of results was found for both reactive and proactive types of aggressive reactions. It is concluded that DLPFC asymmetry is involved in modulating reactive and proactive aggression. Our results are in line with recent studies suggesting that the left DLPFC plays a major role in aggressive behavior.

CPEB1 modulates lipopolysaccharide-mediated iNOS induction in rat primary astrocytes

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

Kim, Ki Chan; Hyun Joo, So; Shin, Chan Young, E-mail: chanyshin@kku.ac.kr

2011-06-17

Highlights: {yields} Expression and phosphorylation of CPEB1 is increased by LPS stimulation in rat primary astrocytes. {yields} JNK regulates expression and phosphorylation of CPEB1 in reactive astrocytes. {yields} Down-regulation of CPEB1 using siRNA inhibits oxidative stress and iNOS induction by LPS stimulation. {yields} CPEB1 may play an important role in regulating inflammatory responses in reactive astrocytes induced by LPS. -- Abstract: Upon CNS damage, astrocytes undergo a series of biological changes including increased proliferation, production of inflammatory mediators and morphological changes, in a response collectively called reactive gliosis. This process is an essential part of the brains response to injury,more » yet much is unknown about the molecular mechanism(s) that induce these changes. In this study, we investigated the role of cytoplasmic polyadenylation element binding protein 1 (CPEB1) in the regulation of inflammatory responses in a model of reactive gliosis, lipopolysaccharide-stimulated astrocytes. CPEB1 is an mRNA-binding protein recently shown to be expressed in astrocytes that may play a role in astrocytes migration. After LPS stimulation, the expression and phosphorylation of CPEB1 was increased in rat primary astrocytes in a JNK-dependent process. siRNA-induced knockdown of CPEB1 expression inhibited the LPS-induced up-regulation of iNOS as well as NO and ROS production, a hallmark of immunological activation of astrocytes. The results from the study suggest that CPEB1 is actively involved in the regulation of inflammatory responses in astrocytes, which might provide new insights into the regulatory mechanism after brain injury.« less

Association of T-cell reactivity with beta-cell function in recent onset type 1 diabetes patients.

PubMed

Pfleger, Christian; Meierhoff, Guido; Kolb, Hubert; Schloot, Nanette C

2010-03-01

The aim of the current study was to investigate whether autoantigen directed T-cell reactivity relates to beta-cell function during the first 78 weeks after diagnosis of type 1 diabetes. 50 adults and 49 children (mean age 27.3 and 10.9 years respectively) with recent onset type 1 diabetes who participated in a placebo-controlled trial of immune intervention with DiaPep277 were analyzed. Secretion of interferon (IFN)-gamma, interleukin (IL)-5, IL-13 and IL-10 by single peripheral mononuclear cells (PBMC) upon stimulation with islet antigens GAD65, heat shock protein 60 (Hsp60) protein-tyrosine-phosphatase-like-antigen (pIA2) or tetanus toxoid (TT) was determined applying ELISPOT; beta-cell function was evaluated by glucagon stimulated C-peptide. Multivariate regression analysis was applied. In general, number of islet antigen-reactive cells decreased over 78 weeks in both adults and children, whereas reactivity to TT was not reduced. In addition, there was an association between the quality of immune cell responses and beta-cell function. Overall, increased responses by IFN-gamma secreting cells were associated with lower beta-cell function whereas IL-5, IL-13 and IL-10 cytokine responses were positively associated with beta-cell function in adults and children. Essentially, the same results were obtained with three different models of regression analysis. The number of detectable islet-reactive immune cells decreases within 1-2 years after diagnosis of type 1 diabetes. Cytokine production by antigen-specific PBMC reactivity is related to beta-cell function as measured by stimulated C-peptide. Cellular immunity appears to regress soon after disease diagnosis and begin of insulin therapy. Copyright 2009 Elsevier Ltd. All rights reserved.

Effects of peptides on generation of reactive oxygen species in subcellular fractions of Drosophila melanogaster.

PubMed

Khavinson, V K; Myl'nikov, S V; Oparina, T I; Arutyunyan, A V

2001-07-01

We studied the effects of Epithalon (Ala-Glu-Asp-Gly) and Vilon (Lys-Glu) on free radical processes in highly inbred HA(+)line of Drosophila melanogaster. Vilon inhibited generation of reactive oxygen species in mitochondria, but stimulated this process in the cytosol. We found sex- and age-related differences in the generation of reactive oxygen species and cytosol antioxidant activity.

Combinatorial Effects of the Glucocorticoid Receptor and Krüppel-Like Transcription Factor 15 on Bovine Herpesvirus 1 Transcription and Productive Infection.

PubMed

El-Mayet, Fouad S; Sawant, Laximan; Thunuguntla, Prasanth; Jones, Clinton

2017-11-01

Bovine herpesvirus 1 (BoHV-1), an important bovine pathogen, establishes lifelong latency in sensory neurons. Latently infected calves consistently reactivate from latency following a single intravenous injection of the synthetic corticosteroid dexamethasone. The immediate early transcription unit 1 (IEtu1) promoter, which drives bovine ICP0 (bICP0) and bICP4 expression, is stimulated by dexamethasone because it contains two glucocorticoid receptor (GR) response elements (GREs). Several Krüppel-like transcription factors (KLF), including KLF15, are induced during reactivation from latency, and they stimulate certain viral promoters and productive infection. In this study, we demonstrate that the GR and KLF15 were frequently expressed in the same trigeminal ganglion (TG) neuron during reactivation and cooperatively stimulated productive infection and IEtu1 GREs in mouse neuroblastoma cells (Neuro-2A). We further hypothesized that additional regions in the BoHV-1 genome are transactivated by the GR or stress-induced transcription factors. To test this hypothesis, BoHV-1 DNA fragments (less than 400 bp) containing potential GR and KLF binding sites were identified and examined for transcriptional activation by stress-induced transcription factors. Intergenic regions within the unique long 52 gene (UL52; a component of the DNA primase/helicase complex), bICP4, IEtu2, and the unique short region were stimulated by KLF15 and the GR. Chromatin immunoprecipitation studies revealed that the GR and KLF15 interacted with sequences within IEtu1 GREs and the UL52 fragment. Coimmunoprecipitation studies demonstrated that KLF15 and the GR were associated with each other in transfected cells. Since the GR stimulates KLF15 expression, we suggest that these two transcription factors form a feed-forward loop that stimulates viral gene expression and productive infection following stressful stimuli. IMPORTANCE Bovine herpesvirus 1 (BoHV-1) is an important viral pathogen that causes respiratory disease and suppresses immune responses in cattle; consequently, life-threatening bacterial pneumonia can occur. Following acute infection, BoHV-1 establishes lifelong latency in sensory neurons. Reactivation from latency is initiated by the synthetic corticosteroid dexamethasone. Dexamethasone stimulates lytic cycle viral gene expression in sensory neurons of calves latently infected with BoHV-1, culminating in virus shedding and transmission. Two stress-induced cellular transcription factors, Krüppel-like transcription factor 15 (KLF15) and the glucocorticoid receptor (GR), cooperate to stimulate productive infection and viral transcription. Additional studies demonstrated that KLF15 and the GR form a stable complex and that these stress-induced transcription factors bind to viral DNA sequences, which correlates with transcriptional activation. The ability of the GR and KLF15 to synergistically stimulate viral gene expression and productive infection may be critical for the ability of BoHV-1 to reactivate from latency following stressful stimuli. Copyright © 2017 American Society for Microbiology.

Combinatorial Effects of the Glucocorticoid Receptor and Krüppel-Like Transcription Factor 15 on Bovine Herpesvirus 1 Transcription and Productive Infection

PubMed Central

El-mayet, Fouad S.; Sawant, Laximan; Thunuguntla, Prasanth

2017-01-01

ABSTRACT Bovine herpesvirus 1 (BoHV-1), an important bovine pathogen, establishes lifelong latency in sensory neurons. Latently infected calves consistently reactivate from latency following a single intravenous injection of the synthetic corticosteroid dexamethasone. The immediate early transcription unit 1 (IEtu1) promoter, which drives bovine ICP0 (bICP0) and bICP4 expression, is stimulated by dexamethasone because it contains two glucocorticoid receptor (GR) response elements (GREs). Several Krüppel-like transcription factors (KLF), including KLF15, are induced during reactivation from latency, and they stimulate certain viral promoters and productive infection. In this study, we demonstrate that the GR and KLF15 were frequently expressed in the same trigeminal ganglion (TG) neuron during reactivation and cooperatively stimulated productive infection and IEtu1 GREs in mouse neuroblastoma cells (Neuro-2A). We further hypothesized that additional regions in the BoHV-1 genome are transactivated by the GR or stress-induced transcription factors. To test this hypothesis, BoHV-1 DNA fragments (less than 400 bp) containing potential GR and KLF binding sites were identified and examined for transcriptional activation by stress-induced transcription factors. Intergenic regions within the unique long 52 gene (UL52; a component of the DNA primase/helicase complex), bICP4, IEtu2, and the unique short region were stimulated by KLF15 and the GR. Chromatin immunoprecipitation studies revealed that the GR and KLF15 interacted with sequences within IEtu1 GREs and the UL52 fragment. Coimmunoprecipitation studies demonstrated that KLF15 and the GR were associated with each other in transfected cells. Since the GR stimulates KLF15 expression, we suggest that these two transcription factors form a feed-forward loop that stimulates viral gene expression and productive infection following stressful stimuli. IMPORTANCE Bovine herpesvirus 1 (BoHV-1) is an important viral pathogen that causes respiratory disease and suppresses immune responses in cattle; consequently, life-threatening bacterial pneumonia can occur. Following acute infection, BoHV-1 establishes lifelong latency in sensory neurons. Reactivation from latency is initiated by the synthetic corticosteroid dexamethasone. Dexamethasone stimulates lytic cycle viral gene expression in sensory neurons of calves latently infected with BoHV-1, culminating in virus shedding and transmission. Two stress-induced cellular transcription factors, Krüppel-like transcription factor 15 (KLF15) and the glucocorticoid receptor (GR), cooperate to stimulate productive infection and viral transcription. Additional studies demonstrated that KLF15 and the GR form a stable complex and that these stress-induced transcription factors bind to viral DNA sequences, which correlates with transcriptional activation. The ability of the GR and KLF15 to synergistically stimulate viral gene expression and productive infection may be critical for the ability of BoHV-1 to reactivate from latency following stressful stimuli. PMID:28794031

Reactive oxygen species potentiate the negative inotropic effect of cardiac M2-muscarinic receptor stimulation.

PubMed

Peters, S L; Sand, C; Batinik, H D; Pfaffendorf, M; van Zwieten, P A

2001-08-01

The aim of the present study was to investigate the influence of reactive oxygen species (ROS) on the contractile responses of rat isolated left atria to muscarinic receptor stimulation. ROS were generated by means of electrolysis (30 mA, 75 s) of the organ bath fluid. Twenty minutes after the electrolysis period, the electrically paced atria (3 Hz) were stimulated with the adenylyl cyclase activator forskolin (1 microM). Subsequently, cumulative acetylcholine concentration-response curves were constructed (0.01 nM-10 microM). In addition, phosphoinositide turnover and adenylyl cyclase activity under basal and stimulated conditions were measured. For these biochemical experiments we used the stable acetylcholine analogue carbachol. The atria exposed to reactive oxygen species were influenced more potently (pD2 control: 6.2 vs. 7.1 for electrolysis-treated atria, P<0.05) and more effectively (Emax control: 40% vs. 90% reduction of the initial amplitude, P<0.05) by acetylcholine. In contrast, ROS exposure did not alter the responses to adenosine, whose receptor is also coupled via a Gi-protein to adenylyl cyclase. The basal (40% vs. control, P<0.05) as well as the carbachol-stimulated (-85% vs. control, P<0.05) inositol-phosphate formation was reduced in atria exposed to ROS. The forskolin-stimulated adenylyl cyclase activity was identical in both groups but carbachol stimulation induced a more pronounced reduction in adenylyl cyclase activity in the electrolysis-treated atria. Accordingly we may conclude that ROS enhance the negative inotropic response of isolated rat atria to acetylcholine by both a reduction of the positive (inositide turnover) and increase of the negative (adenylyl cyclase inhibition) inotropic components of cardiac muscarinic receptor stimulation. This phenomenon is most likely M2-receptor specific, since the negative inotropic response to adenosine is unaltered by ROS exposure.

Improving TCO-Conjugated Antibody Reactivity for Bioorthogonal Pretargeting

NASA Astrophysics Data System (ADS)

Chu, Tina Tingyi

Cancer remains a major cause of death because of its unpredictable progression. Utilizing bioorthogonal chemistry between trans-cyclooctene (TCO) and tetrazine to target imaging agents to tumors in two subsequent steps offers a more versatile platform for molecular imaging. This is accomplished by pretargeting TCO-modified primary antibody to cell surface biomarkers, followed by delivery of tetrazine-modified imaging probes. In previous work, it has been established that TCO-tetrazine chemistry can be applied to in vivo imaging, resulting in precise tumor detection. However, most TCO modifications on an antibody are not reactive because they are buried within hydrophobic domains. To expose and improve the reactivity, Rahim et al. incorporated a polyethylene glycol (PEG) linker through a two-step reaction with DBCO-azide, which successfully maintained 100% TCO functionality. In this project, various types of linkers were studied to improve the reactivity in a single step. Three primary types of linkers were studied: hydrophilic PEG chains, hydrophobic short linkers, and amphiphilic linkers. Our results show that PEG chain alone can only maintain 40% TCO reactivity. Unexpectedly, a short alkyl chain (valeric acid) provided superior results, with 60% TCO reactivity. Lengthening the alkyl chain did not improve results further. Finally, an amphiphilic linker containing valeric acid and PEG performed worse than either linker type alone, at ˜30% functionality. We conclude that our previous 100% functional TCO result obtained with the two-step coupling may have stemmed from generation of the DBCO/azide cycloaddition product. Future work will explore factors such as rigidity of linker structure, polarity, or charges.

A muscle-driven approach to restore stepping with an exoskeleton for individuals with paraplegia.

PubMed

Chang, Sarah R; Nandor, Mark J; Li, Lu; Kobetic, Rudi; Foglyano, Kevin M; Schnellenberger, John R; Audu, Musa L; Pinault, Gilles; Quinn, Roger D; Triolo, Ronald J

2017-05-30

Functional neuromuscular stimulation, lower limb orthosis, powered lower limb exoskeleton, and hybrid neuroprosthesis (HNP) technologies can restore stepping in individuals with paraplegia due to spinal cord injury (SCI). However, a self-contained muscle-driven controllable exoskeleton approach based on an implanted neural stimulator to restore walking has not been previously demonstrated, which could potentially result in system use outside the laboratory and viable for long term use or clinical testing. In this work, we designed and evaluated an untethered muscle-driven controllable exoskeleton to restore stepping in three individuals with paralysis from SCI. The self-contained HNP combined neural stimulation to activate the paralyzed muscles and generate joint torques for limb movements with a controllable lower limb exoskeleton to stabilize and support the user. An onboard controller processed exoskeleton sensor signals, determined appropriate exoskeletal constraints and stimulation commands for a finite state machine (FSM), and transmitted data over Bluetooth to an off-board computer for real-time monitoring and data recording. The FSM coordinated stimulation and exoskeletal constraints to enable functions, selected with a wireless finger switch user interface, for standing up, standing, stepping, or sitting down. In the stepping function, the FSM used a sensor-based gait event detector to determine transitions between gait phases of double stance, early swing, late swing, and weight acceptance. The HNP restored stepping in three individuals with motor complete paralysis due to SCI. The controller appropriately coordinated stimulation and exoskeletal constraints using the sensor-based FSM for subjects with different stimulation systems. The average range of motion at hip and knee joints during walking were 8.5°-20.8° and 14.0°-43.6°, respectively. Walking speeds varied from 0.03 to 0.06 m/s, and cadences from 10 to 20 steps/min. A self-contained muscle-driven exoskeleton was a feasible intervention to restore stepping in individuals with paraplegia due to SCI. The untethered hybrid system was capable of adjusting to different individuals' needs to appropriately coordinate exoskeletal constraints with muscle activation using a sensor-driven FSM for stepping. Further improvements for out-of-the-laboratory use should include implantation of plantar flexor muscles to improve walking speed and power assist as needed at the hips and knees to maintain walking as muscles fatigue.

Subthalamic stimulation improves the cerebral hemodynamic response to the cold pressure test in patients with Parkinson's disease.

PubMed

Rätsep, Tõnu; Asser, Toomas

2012-01-01

Disturbances of the autonomic nervous system are common in patients with Parkinson's disease (PD) but the effect of deep brain stimulation of the subthalamic nucleus on cerebrovascular reactivity is not entirely known. Seven patients in an advanced stage of the disease and seven healthy age-matched controls participated in the study, which took place after one night of drug withdrawal. Cerebral blood flow velocity was continuously monitored on both sides with transcranial Doppler ultrasound, and cerebrovascular reactivity (CR) was evaluated with the cold pressure test. The measurements were repeated and compared during the stimulation-on and -off phases. The PD patients had significantly higher CR values in the stimulation-on than -off conditions (15.1% ± 6.9 versus 9.4% ± 6.2; p = 0.03). CR values were higher in controls than in patients in the stimulation-off condition (20.4% ± 12.5 versus 9.4% ± 6.2; p = 0.007) without a significant difference with the stimulation-on phase. CR, evaluated by the response to the cold pressure test, is impaired in patients with advanced PD and improved by subthalamic nucleus. Copyright © 2012 Wiley Periodicals, Inc.

A systematic review of gait perturbation paradigms for improving reactive stepping responses and falls risk among healthy older adults.

PubMed

McCrum, Christopher; Gerards, Marissa H G; Karamanidis, Kiros; Zijlstra, Wiebren; Meijer, Kenneth

2017-01-01

Falls are a leading cause of injury among older adults and most often occur during walking. While strength and balance training moderately improve falls risk, training reactive recovery responses following sudden perturbations during walking may be more task-specific for falls prevention. The aim of this review was to determine the variety, characteristics and effectiveness of gait perturbation paradigms that have been used for improving reactive recovery responses during walking and reducing falls among healthy older adults. A systematic search was conducted in PubMed, Web of Science, MEDLINE and CINAHL databases in December 2015, repeated in May 2016, using sets of terms relating to gait, perturbations, adaptation and training, and ageing. Inclusion criteria: studies were conducted with healthy participants of 60 years or older; repeated, unpredictable, mechanical perturbations were applied during walking; and reactive recovery responses to gait perturbations or the incidence of laboratory or daily life falls were recorded. Results were narratively synthesised. The risk of bias for each study (PEDro Scale) and the levels of evidence for each perturbation type were determined. In the nine studies that met the inclusion criteria, moveable floor platforms, ground surface compliance changes, or treadmill belt accelerations or decelerations were used to perturb the gait of older adults. Eight studies used a single session of perturbations, with two studies using multiple sessions. Eight of the studies reported improvement in the reactive recovery response to the perturbations. Four studies reported a reduction in the percentage of laboratory falls from the pre- to post-perturbation experience measurement and two studies reported a reduction in daily life falls. As well as the range of perturbation types, the magnitude and frequency of the perturbations varied between the studies. To date, a range of perturbation paradigms have been used successfully to perturb older adults' gait and stimulate reactive response adaptations. Variation also exists in the number and magnitudes of applied perturbations. Future research should examine the effects of perturbation type, magnitude and number on the extent and retention of the reactive recovery response adaptations, as well as on falls, over longer time periods among older adults.

Effects of a Stimulant Drug on Extraversion Level in Hyperactive Children.

ERIC Educational Resources Information Center

Mc Manis, Donald L.; And Others

1978-01-01

Seven hyperactive children in a pilot study, and 15 hyperactive and 15 nonhyperactive control children in a later study, were assessed for salivation to lemon juice stimulation, reactive inhibition on an audio-vigilance task, and visual-motor maze errors. (Author)

Augmentation of Voluntary Locomotor Activity by Transcutaneous Spinal Cord Stimulation in Motor-Incomplete Spinal Cord-Injured Individuals.

PubMed

Hofstoetter, Ursula S; Krenn, Matthias; Danner, Simon M; Hofer, Christian; Kern, Helmut; McKay, William B; Mayr, Winfried; Minassian, Karen

2015-10-01

The level of sustainable excitability within lumbar spinal cord circuitries is one of the factors determining the functional outcome of locomotor therapy after motor-incomplete spinal cord injury. Here, we present initial data using noninvasive transcutaneous lumbar spinal cord stimulation (tSCS) to modulate this central state of excitability during voluntary treadmill stepping in three motor-incomplete spinal cord-injured individuals. Stimulation was applied at 30 Hz with an intensity that generated tingling sensations in the lower limb dermatomes, yet without producing muscle reflex activity. This stimulation changed muscle activation, gait kinematics, and the amount of manual assistance required from the therapists to maintain stepping with some interindividual differences. The effect on motor outputs during treadmill-stepping was essentially augmentative and step-phase dependent despite the invariant tonic stimulation. The most consistent modification was found in the gait kinematics, with the hip flexion during swing increased by 11.3° ± 5.6° across all subjects. This preliminary work suggests that tSCS provides for a background increase in activation of the lumbar spinal locomotor circuitry that has partially lost its descending drive. Voluntary inputs and step-related feedback build upon the stimulation-induced increased state of excitability in the generation of locomotor activity. Thus, tSCS essentially works as an electrical neuroprosthesis augmenting remaining motor control. Copyright © 2015 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

In-cell SHAPE uncovers dynamic interactions between the untranslated regions of the foot-and-mouth disease virus RNA.

PubMed

Diaz-Toledano, Rosa; Lozano, Gloria; Martinez-Salas, Encarnacion

2017-02-17

The genome of RNA viruses folds into 3D structures that include long-range RNA–RNA interactions relevant to control critical steps of the viral cycle. In particular, initiation of translation driven by the IRES element of foot-and-mouth disease virus is stimulated by the 3΄UTR. Here we sought to investigate the RNA local flexibility of the IRES element and the 3΄UTR in living cells. The SHAPE reactivity observed in vivo showed statistically significant differences compared to the free RNA, revealing protected or exposed positions within the IRES and the 3΄UTR. Importantly, the IRES local flexibility was modified in the presence of the 3΄UTR, showing significant protections at residues upstream from the functional start codon. Conversely, presence of the IRES element in cis altered the 3΄UTR local flexibility leading to an overall enhanced reactivity. Unlike the reactivity changes observed in the IRES element, the SHAPE differences of the 3΄UTR were large but not statistically significant, suggesting multiple dynamic RNA interactions. These results were supported by covariation analysis, which predicted IRES-3΄UTR conserved helices in agreement with the protections observed by SHAPE probing. Mutational analysis suggested that disruption of one of these interactions could be compensated by alternative base pairings, providing direct evidences for dynamic long-range interactions between these distant elements of the viral genome.

Procyanidin trimer C1 derived from Theobroma cacao reactivates latent human immunodeficiency virus type 1 provirus.

PubMed

Hori, Takanori; Barnor, Jacob; Huu, Tung Nguyen; Morinaga, Osamu; Hamano, Akiko; Ndzinu, Jerry; Frimpong, Angela; Minta-Asare, Keren; Amoa-Bosompem, Mildred; Brandful, James; Odoom, John; Bonney, Joseph; Tuffour, Isaac; Owusu, Baffour-Awuah; Ofosuhene, Mark; Atchoglo, Philip; Sakyiamah, Maxwell; Adegle, Richard; Appiah-Opong, Regina; Ampofo, William; Koram, Kwadwo; Nyarko, Alexander; Okine, Laud; Edoh, Dominic; Appiah, Alfred; Uto, Takuhiro; Yoshinaka, Yoshiyuki; Uota, Shin; Shoyama, Yukihiro; Yamaoka, Shoji

2015-04-03

Despite remarkable advances in combination antiretroviral therapy (cART), human immunodeficiency virus type 1 (HIV-1) infection remains incurable due to the incomplete elimination of the replication-competent virus, which persists in latent reservoirs. Strategies for targeting HIV reservoirs for eradication that involves reactivation of latent proviruses while protecting uninfected cells by cART are urgently needed for cure of HIV infection. We screened medicinal plant extracts for compounds that could reactivate the latent HIV-1 provirus and identified a procyanidin trimer C1 derived from Theobroma cacao as a potent activator of the provirus in human T cells latently infected with HIV-1. This reactivation largely depends on the NF-κB and MAPK signaling pathways because either overexpression of a super-repressor form of IκBα or pretreatment with a MEK inhibitor U0126 diminished provirus reactivation by C1. A pan-PKC inhibitor significantly blocked the phorbol ester-induced but not the C1-induced HIV-1 reactivation. Although C1-induced viral gene expression persisted for as long as 48 h post-stimulation, NF-κB-dependent transcription peaked at 12 h post-stimulation and then quickly declined, suggesting Tat-mediated self-sustainment of HIV-1 expression. These results suggest that procyanidin C1 trimer is a potential compound for reactivation of latent HIV-1 reservoirs. Copyright © 2015 Elsevier Inc. All rights reserved.

Predictors of 12-Step Attendance and Participation for Individuals With Stimulant Use Disorders.

PubMed

Hatch-Maillette, Mary; Wells, Elizabeth A; Doyle, Suzanne R; Brigham, Gregory S; Daley, Dennis; DiCenzo, Jessica; Donovan, Dennis; Garrett, Sharon; Horigian, Viviana E; Jenkins, Lindsay; Killeen, Therese; Owens, Mandy; Perl, Harold I

2016-09-01

Few studies have examined the effectiveness of 12-step peer recovery support programs with drug use disorders, especially stimulant use, and it is difficult to know how outcomes related to 12-step attendance and participation generalize to individuals with non-alcohol substance use disorders (SUDs). A clinical trial of 12-step facilitation (N=471) focusing on individuals with cocaine or methamphetamine use disorders allowed examination of four questions: Q1) To what extent do treatment-seeking stimulant users use 12-step programs and, which ones? Q2) Do factors previously found to predict 12-step participation among those with alcohol use disorders also predict participation among stimulant users? Q3) What specific baseline "12-step readiness" factors predict subsequent 12-step participation and attendance? And Q4) Does stimulant drug of choice differentially predict 12-step participation and attendance? The four outcomes variables, attendance, speaking, duties at 12-step meetings, and other peer recovery support activities, were not related to baseline demographic or substance problem history or severity. Drug of choice was associated with differential days of Alcoholics Anonymous (AA) and Narcotics Anonymous (NA) attendance among those who reported attending, and cocaine users reported more days of attending AA or NA at 1-, 3- and 6-month follow-ups than did methamphetamine users. Pre-randomization measures of perceived benefit of 12-step groups predicted 12-step attendance at 3- and 6-month follow-ups. Pre-randomization 12-step attendance significantly predicted number of other self-help activities at end-of-treatment, 3- and 6-month follow-ups. Pre-randomization perceived benefit and problem severity both predicted number of self-help activities at end-of-treatment and 3-month follow-up. Pre-randomization perceived barriers to 12-step groups were negatively associated with self-help activities at end-of-treatment and 3-month follow-up. Whether or not one participated in any duties was predicted at all time points by pre-randomization involvement in self-help activities. The primary finding of this study is one of continuity: prior attendance and active involvement with 12-step programs were the main signs pointing to future involvement. Limitations and recommendations are discussed. Copyright © 2016 Elsevier Inc. All rights reserved.

Predictors of 12-Step Attendance and Participation for Individuals with Stimulant Use Disorders

PubMed Central

Hatch-Maillette, Mary; Wells, Elizabeth A.; Doyle, Suzanne R.; Brigham, Gregory S.; Daley, Dennis; DiCenzo, Jessica; Donovan, Dennis; Garrett, Sharon; Horigian, Viviana E.; Jenkins, Lindsay; Killeen, Therese; Owens, Mandy; Perl, Harold I.

2017-01-01

Objective Few studies have examined the effectiveness of 12-step peer recovery support programs with drug use disorders, especially stimulant use, and it is difficult to know how outcomes related to 12-step attendance and participation generalize to individuals with non-alcohol substance use disorders (SUDs). Method A clinical trial of 12-step facilitation (N=471) focusing on individuals with cocaine or methamphetamine use disorders allowed examination of four questions: Q1) To what extent do treatment-seeking stimulant users use 12-step programs and, which ones? Q2) Do factors previously found to predict 12-step participation among those with alcohol use disorders also predict participation among stimulant users? Q3) What specific baseline “12-step readiness” factors predict subsequent 12-step participation and attendance? And Q4) Does stimulant drug of choice differentially predict 12-step participation and attendance? Results The four outcomes variables, Attendance, Speaking, Duties at 12-step meetings, and other peer recovery support Activities, were not related to baseline demographic or substance problem history or severity. Drug of choice was associated with differential days of Alcoholics Anonymous (AA) and Narcotics Anonymous (NA) attendance among those who reported attending, and cocaine users reported more days of attending AA or NA at 1-, 3- and 6-month follow-ups than did methamphetamine users. Pre-randomization measures of Perceived Benefit of 12-step groups predicted 12-step Attendance at 3- and 6-month follow-ups. Pre-randomization 12-step Attendance significantly predicted number of other Self-Help Activities at end-of-treatment, 3- and 6-month follow-ups. Pre-randomization Perceived Benefit and problem severity both predicted number of Self-Help Activities at end-of-treatment and 3-month follow-up. Pre-randomization Perceived Barriers to 12-step groups were negatively associated with Self-Help Activities at end-of-treatment and 3-month follow-up. Whether or not one participated in any Duties was predicted at all time points by pre-randomization involvement in Self-Help Activities. Conclusions The primary finding of this study is one of continuity: prior attendance and active involvement with 12-step programs were the main signs pointing to future involvement. Limitations and Recommendations are discussed. PMID:27431050

Development of a multi-electrode array for spinal cord epidural stimulation to facilitate stepping and standing after a complete spinal cord injury in adult rats.

PubMed

Gad, Parag; Choe, Jaehoon; Nandra, Mandheerej Singh; Zhong, Hui; Roy, Roland R; Tai, Yu-Chong; Edgerton, V Reggie

2013-01-21

Stimulation of the spinal cord has been shown to have great potential for improving function after motor deficits caused by injury or pathological conditions. Using a wide range of animal models, many studies have shown that stimulation applied to the neural networks intrinsic to the spinal cord can result in a dramatic improvement of motor ability, even allowing an animal to step and stand after a complete spinal cord transection. Clinical use of this technology, however, has been slow to develop due to the invasive nature of the implantation procedures, the lack of versatility in conventional stimulation technology, and the difficulty of ascertaining specific sites of stimulation that would provide optimal amelioration of the motor deficits. Moreover, the development of tools available to control precise stimulation chronically via biocompatible electrodes has been limited. In this paper, we outline the development of this technology and its use in the spinal rat model, demonstrating the ability to identify and stimulate specific sites of the spinal cord to produce discrete motor behaviors in spinal rats using this array. We have designed a chronically implantable, rapidly switchable, high-density platinum based multi-electrode array that can be used to stimulate at 1-100 Hz and 1-10 V in both monopolar and bipolar configurations to examine the electrophysiological and behavioral effects of spinal cord epidural stimulation in complete spinal cord transected rats. In this paper, we have demonstrated the effectiveness of using high-resolution stimulation parameters in the context of improving motor recovery after a spinal cord injury. We observed that rats whose hindlimbs were paralyzed can stand and step when specific sets of electrodes of the array are stimulated tonically (40 Hz). Distinct patterns of stepping and standing were produced by stimulation of different combinations of electrodes on the array located at specific spinal cord levels and by specific stimulation parameters, i.e., stimulation frequency and intensity, and cathode/anode orientation. The array also was used to assess functional connectivity between the cord dorsum to interneuronal circuits and specific motor pools via evoked potentials induced at 1 Hz stimulation in the absence of any anesthesia. Therefore the high density electrode array allows high spatial resolution and the ability to selectively activate different neural pathways within the lumbosacral region of the spinal cord to facilitate standing and stepping in adult spinal rats and provides the capability to evoke motor potentials and thus a means for assessing connectivity between sensory circuits and specific motor pools and muscles.

Modification of Agility Running Technique in Reaction to a Defender in Rugby Union

PubMed Central

Wheeler, Keane W.; Sayers, Mark G.L.

2010-01-01

Three-dimensional kinematic analysis examined agility running technique during pre-planned and reactive performance conditions specific to attacking ball carries in rugby union. The variation to running technique of 8 highly trained rugby union players was compared between agility conditions (pre-planned and reactive) and also agility performance speeds (fast, moderate and slow). Kinematic measures were used to determine the velocity of the centre of mass (COM) in the anteroposterior (running speed) and mediolateral (lateral movement speed) planes. The position of foot-strike and toe-off was also examined for the step prior to the agility side- step (pre-change of direction phase) and then the side-step (change of direction phase). This study demonstrated that less lateral movement speed towards the intended direction change occurred during reactive compared to pre-planned conditions at pre-change of direction (0.08 ± 0.28 m·s-1 and 0.42 ± 0.25 m·s-1, respectively) and change of direction foot-strikes (0.25 ± 0.42 m·s-1 and 0.69 ± 0.43 m·s-1, respectively). Less lateral movement speed during reactive conditions was associated with greater lateral foot displacement (44.52 ± 6.10% leg length) at the change of direction step compared to pre-planned conditions (41.35 ± 5.85%). Importantly, the anticipation abilities during reactive conditions provided a means to differentiate between speeds of agility performance, with faster performances displaying greater lateral movement speed at the change of direction foot- strike (0.52 ± 0.34 m·s-1) compared to moderate (0.20 ± 0.37 m·s-1) and slow (-0.08 ± 0.31 m·s-1). The changes to running technique during reactive conditions highlight the need to incorporate decision-making in rugby union agility programs. Key points Changes to running technique occur when required to make a decision. Fast agility performers use different stepping strategies in reactive conditions. Decision-making must be incorporated in agility training programs. PMID:24149639

Do Gravity-Related Sensory Information Enable the Enhancement of Cortical Proprioceptive Inputs When Planning a Step in Microgravity?

PubMed Central

Saradjian, Anahid H.; Paleressompoulle, Dany; Louber, Didier; Coyle, Thelma; Blouin, Jean; Mouchnino, Laurence

2014-01-01

We recently found that the cortical response to proprioceptive stimulation was greater when participants were planning a step than when they stood still, and that this sensory facilitation was suppressed in microgravity. The aim of the present study was to test whether the absence of gravity-related sensory afferents during movement planning in microgravity prevented the proprioceptive cortical processing to be enhanced. We reestablished a reference frame in microgravity by providing and translating a horizontal support on which the participants were standing and verified whether this procedure restored the proprioceptive facilitation. The slight translation of the base of support (lateral direction), which occurred prior to step initiation, stimulated at least cutaneous and vestibular receptors. The sensitivity to proprioceptive stimulation was assessed by measuring the amplitude of the cortical somatosensory-evoked potential (SEP, over the Cz electrode) following the vibration of the leg muscle. The vibration lasted 1 s and the participants were asked to either initiate a step at the vibration offset or to remain still. We found that the early SEP (90–160 ms) was smaller when the platform was translated than when it remained stationary, revealing the existence of an interference phenomenon (i.e., when proprioceptive stimulation is preceded by the stimulation of different sensory modalities evoked by the platform translation). By contrast, the late SEP (550 ms post proprioceptive stimulation onset) was greater when the translation preceded the vibration compared to a condition without pre-stimulation (i.e., no translation). This suggests that restoring a body reference system which is impaired in microgravity allowed a greater proprioceptive cortical processing. Importantly, however, the late SEP was similarly increased when participants either produced a step or remained still. We propose that the absence of step-induced facilitation of proprioceptive cortical processing results from a decreased weight of proprioception in the absence of balance constraints in microgravity. PMID:25259838

Impact of acute exacerbations on platelet reactivity in chronic obstructive pulmonary disease patients.

PubMed

Muñoz-Esquerre, Mariana; Ferreiro, José Luis; Huertas, Daniel; Marcano, Ana Lucrecia; López-Sánchez, Marta; Roura, Gerard; Gómez-Hospital, Joan Antoni; Dorca, Jordi; Cequier, Angel; Santos, Salud

2018-01-01

A higher risk of atherothrombotic cardiovascular events, which are platelet-driven processes, has been described during acute exacerbations of chronic obstructive pulmonary disease (AECOPD). However, the relevance of platelet reactivity during AECOPD and whether this is affected by antiplatelet agents are not fully elucidated to date. This study aimed to evaluate whether platelet reactivity is augmented during an exacerbation in COPD patients with and without antiplatelet therapy and its association with systemic inflammatory parameters. Prospective, observational, ex vivo investigation was conducted in consecutive patients suffering an exacerbation of COPD. Platelet reactivity was assessed during AECOPD and at stable state. Platelet function assays included: 1) vasodilator-stimulated phosphoprotein assay expressed as P2Y 12 reactivity index (PRI), 2) multiple electrode aggregometry and 3) optical aggregometry. Systemic inflammatory parameters such as leukocyte count, interleukin-6 and fibrinogen were also assessed. Higher platelet reactivity was observed during AECOPD compared to stability measured by vasodilator-stimulated phosphoprotein (PRI: 75.2%±1.9% vs 68.8%±2.4%, p =0.001). This augmented platelet aggregability was also observed in the subset of patients on antiplatelet therapy (PRI: 72.8%±3.1% vs 61.7%±7.5%, p =0.071). Consistent findings were observed with all other platelet function tests. Patients with greater enhancement of inflammatory markers during AECOPD were more likely to present a higher increase in platelet reactivity. Platelet reactivity is increased during AECOPD, which may contribute to the augmented cardiovascular risk of these patients. Additionally, the increase in platelet reactivity might be associated with an increment in inflammatory markers during exacerbations.

Abnormal Amygdalar Activation and Connectivity in Adolescents With Attention-Deficit/Hyperactivity Disorder

PubMed Central

Posner, Jonathan; Nagel, Bonnie J.; Maia, Tiago V.; Mechling, Anna; Oh, Milim; Wang, Zhishun; Peterson, Bradley S.

2011-01-01

Objective Emotional reactivity is one of the most disabling symptoms associated with ADHD. We aimed to identify neural substrates associated with emotional reactivity and assess the effects of stimulants on those substrates. Method We used functional magnetic resonance imaging (fMRI) to assess neural activity in adolescents with (N=15) and without (N=15) ADHD while they performed a task involving the subliminal presentation of fearful faces. Using dynamic causal modeling, we also examined the effective connectivity of two regions associated with emotional reactivity — the amygdala and the lateral prefrontal cortex (LPFC). The participants with ADHD were scanned both on and off stimulant medication in a counterbalanced fashion. Results During the task, we found that activity in the right amygdala was greater in adolescents with ADHD than in controls. Additionally, in adolescents with ADHD, greater connectivity was detected between the amygdala and LPFC. Stimulants had a normalizing effect on both the activity in the right amygdala and the connectivity between the amygdala and LPFC. Conclusions Our findings demonstrate that in adolescents with ADHD, a neural substrate of fear processing is atypical, as is the connectivity between the amygdala and LPFC. These findings suggest possible neural substrates for the emotional reactivity that is often present in youths with ADHD and provide putative neural targets for the development of novel therapeutic interventions for this condition. PMID:21784302

Supramolecular reactivity in the gas phase: investigating the intrinsic properties of non-covalent complexes.

PubMed

Cera, Luca; Schalley, Christoph A

2014-03-21

The high vacuum inside a mass spectrometer offers unique conditions to broaden our view on the reactivity of supramolecules. Because dynamic exchange processes between complexes are efficiently suppressed, the intrinsic and intramolecular reactivity of the complexes of interest is observed. Besides this, the significantly higher strength of non-covalent interactions in the absence of competing solvent allows processes to occur that are unable to compete in solution. The present review highlights a series of examples illustrating different aspects of supramolecular gas-phase reactivity ranging from the dissociation and formation of covalent bonds in non-covalent complexes through the reactivity in the restricted inner phase of container molecules and step-by-step mechanistic studies of organocatalytic reaction cycles to cage contraction reactions, processes induced by electron capture, and finally dynamic molecular motion within non-covalent complexes as unravelled by hydrogen-deuterium exchange processes performed in the gas phase.

Modification of existing human motor memories is enabled by primary cortical processing during memory reactivation.

PubMed

Censor, Nitzan; Dimyan, Michael A; Cohen, Leonardo G

2010-09-14

One of the most challenging tasks of the brain is to constantly update the internal neural representations of existing memories. Animal studies have used invasive methods such as direct microfusion of protein inhibitors to designated brain areas, in order to study the neural mechanisms underlying modification of already existing memories after their reactivation during recall [1-4]. Because such interventions are not possible in humans, it is not known how these neural processes operate in the human brain. In a series of experiments we show here that when an existing human motor memory is reactivated during recall, modification of the memory is blocked by virtual lesion [5] of the related primary cortical human brain area. The virtual lesion was induced by noninvasive repetitive transcranial magnetic stimulation guided by a frameless stereotactic brain navigation system and each subject's brain image. The results demonstrate that primary cortical processing in the human brain interacting with pre-existing reactivated memory traces is critical for successful modification of the existing related memory. Modulation of reactivated memories by noninvasive cortical stimulation may have important implications for human memory research and have far-reaching clinical applications. Copyright © 2010 Elsevier Ltd. All rights reserved.

Cytokine Response to Subclinical Cytomegalovirus Reactivation as a Cause of Severe Fatigue in Women Undergoing Chemotherapy for Breast Cancer

DTIC Science & Technology

2013-09-01

herpesvirus cytomegalovirus (CMV) might contribute to severe cancer treatment related fatigue (CTRF) in women undergoing chemotherapy for breast cancer...reactivation of the latent herpesvirus CMV, which would stimulate inflammatory cytokines. We predicted that women harboring latent CMV (CMV positives) would

Inorganic Polyphosphates Regulate Hexokinase Activity and Reactive Oxygen Species Generation in Mitochondria of Rhipicephalus (Boophilus) microplus Embryo

PubMed Central

Fraga, Amanda; Moraes, Jorge; da Silva, José Roberto; Costa, Evenilton P.; Menezes, Jackson; da Silva Vaz Jr, Itabajara; Logullo, Carlos; da Fonseca, Rodrigo Nunes; Campos, Eldo

2013-01-01

The physiological roles of polyphosphates (poly P) recently found in arthropod mitochondria remain obscure. Here, the possible involvement of poly P with reactive oxygen species generation in mitochondria of Rhipicephalus microplus embryos was investigated. Mitochondrial hexokinase and scavenger antioxidant enzymes, such as superoxide dismutase, catalase, and glutathione reductase were assayed during embryogenesis of R. microplus. The influence of poly P3 and poly P15 were analyzed during the period of higher enzymatic activity during embryogenesis. Both poly Ps inhibited hexokinase activity by up to 90% and, interestingly, the mitochondrial membrane exopolyphosphatase activity was stimulated by the hexokinase reaction product, glucose-6-phosphate. Poly P increased hydrogen peroxide generation in mitochondria in a situation where mitochondrial hexokinase is also active. The superoxide dismutase, catalase and glutathione reductase activities were higher during embryo cellularization, at the end of embryogenesis and during embryo segmentation, respectively. All of the enzymes were stimulated by poly P3. However, superoxide dismutase was not affected by poly P15, catalase activity was stimulated only at high concentrations and glutathione reductase was the only enzyme that was stimulated in the same way by both poly Ps. Altogether, our results indicate that inorganic polyphosphate and mitochondrial membrane exopolyphosphatase regulation can be correlated with the generation of reactive oxygen species in the mitochondria of R. microplus embryos. PMID:23983617

Weight Bearing Over-ground Stepping in an Exoskeleton with Non-invasive Spinal Cord Neuromodulation after Motor Complete Paraplegia.

PubMed

Gad, Parag; Gerasimenko, Yury; Zdunowski, Sharon; Turner, Amanda; Sayenko, Dimitry; Lu, Daniel C; Edgerton, V Reggie

2017-01-01

We asked whether coordinated voluntary movement of the lower limbs could be regained in an individual having been completely paralyzed (>4 year) and completely absent of vision (>15 year) using two novel strategies-transcutaneous electrical spinal cord stimulation at selected sites over the spine as well as pharmacological neuromodulation by buspirone. We also asked whether these neuromodulatory strategies could facilitate stepping assisted by an exoskeleton (EKSO, EKSO Bionics, CA) that is designed so that the subject can voluntarily complement the work being performed by the exoskeleton. We found that spinal cord stimulation and drug enhanced the level of effort that the subject could generate while stepping in the exoskeleton. In addition, stimulation improved the coordination patterns of the lower limb muscles resulting in a more continuous, smooth stepping motion in the exoskeleton along with changes in autonomic functions including cardiovascular and thermoregulation. Based on these data from this case study it appears that there is considerable potential for positive synergistic effects after complete paralysis by combining the over-ground step training in an exoskeleton, combined with transcutaneous electrical spinal cord stimulation either without or with pharmacological modulation.

Insect-computer hybrid legged robot with user-adjustable speed, step length and walking gait.

PubMed

Cao, Feng; Zhang, Chao; Choo, Hao Yu; Sato, Hirotaka

2016-03-01

We have constructed an insect-computer hybrid legged robot using a living beetle (Mecynorrhina torquata; Coleoptera). The protraction/retraction and levation/depression motions in both forelegs of the beetle were elicited by electrically stimulating eight corresponding leg muscles via eight pairs of implanted electrodes. To perform a defined walking gait (e.g., gallop), different muscles were individually stimulated in a predefined sequence using a microcontroller. Different walking gaits were performed by reordering the applied stimulation signals (i.e., applying different sequences). By varying the duration of the stimulation sequences, we successfully controlled the step frequency and hence the beetle's walking speed. To the best of our knowledge, this paper presents the first demonstration of living insect locomotion control with a user-adjustable walking gait, step length and walking speed. © 2016 The Author(s).

Insect–computer hybrid legged robot with user-adjustable speed, step length and walking gait

PubMed Central

Cao, Feng; Zhang, Chao; Choo, Hao Yu

2016-01-01

We have constructed an insect–computer hybrid legged robot using a living beetle (Mecynorrhina torquata; Coleoptera). The protraction/retraction and levation/depression motions in both forelegs of the beetle were elicited by electrically stimulating eight corresponding leg muscles via eight pairs of implanted electrodes. To perform a defined walking gait (e.g. gallop), different muscles were individually stimulated in a predefined sequence using a microcontroller. Different walking gaits were performed by reordering the applied stimulation signals (i.e. applying different sequences). By varying the duration of the stimulation sequences, we successfully controlled the step frequency and hence the beetle's walking speed. To the best of our knowledge, this paper presents the first demonstration of living insect locomotion control with a user-adjustable walking gait, step length and walking speed. PMID:27030043

Mechanisms of acetylcholine- and bradykinin-induced preconditioning.

PubMed

Critz, Stuart D; Cohen, Michael V; Downey, James M

2005-01-01

Acetylcholine (ACh) and bradykinin (BK) are potent pharmacological agents which mimic ischemic preconditioning (IPC) enabling hearts to resist infarction during a subsequent period of ischemia. The cardioprotective pathways activated by BK but not ACh may also protect when activated at reperfusion. ACh and BK stimulate Gi/o-linked receptors and ultimately mediate protection by opening mitochondrial ATP-sensitive potassium channels with the generation of reactive oxygen species that act as second messengers to activate protein kinase C (PKC). There appear to be key differences, however, in the pathways prior to potassium channel opening for these two receptors. This review aims to summarize what is currently known about pharmacological preconditioning by ACh and BK with an emphasis on differences that are seen in the signal transduction cascades. Understanding the cellular basis of protection by ACh and BK is a critical step towards developing pharmacological agents that will prevent infarction during ischemia resulting from coronary occlusion or heart attack.

Mammalian DNA single-strand break repair: an X-ra(y)ted affair.

PubMed

Caldecott, K W

2001-05-01

The genetic stability of living cells is continuously threatened by the presence of endogenous reactive oxygen species and other genotoxic molecules. Of particular threat are the thousands of DNA single-strand breaks that arise in each cell, each day, both directly from disintegration of damaged sugars and indirectly from the excision repair of damaged bases. If un-repaired, single-strand breaks can be converted into double-strand breaks during DNA replication, potentially resulting in chromosomal rearrangement and genetic deletion. Consequently, cells have adopted multiple pathways to ensure the rapid and efficient removal of single-strand breaks. A general feature of these pathways appears to be the extensive employment of protein-protein interactions to stimulate both the individual component steps and the overall repair reaction. Our current understanding of DNA single-strand break repair is discussed, and testable models for the architectural coordination of this important process are presented. Copyright 2001 John Wiley & Sons, Inc.

Cytotoxic Effects of Re-Activated Lunar Dust Stimulant on Human Lung Cells

NASA Technical Reports Server (NTRS)

Upadhyaya, Krishna

2009-01-01

Lunar dust has been of significant concern due to various problems observed on the Apollo missions. Reports from astronauts have shown that the dust may have caused eye and nasal irritation as well as possible hay fever like symptoms. As NASA hopes to go to the Moon within the next few years, we hope to understand the possible toxic effects the dust might have. In these studies, we are looking at the effect of "re-activated" lunar dust stimulant on human bronchial cells. A simple grinding analog as a method of simulating micrometeorite crushing on the moon is used to "activate" the dust stimulant, i.e. capable of producing hydroxyl radicals. These radicals could then interact with human cells and may lead to a loss in membrane integrity and cell death. (Castranova, 1994) Cells are exposed to the dust for 6 and 24 hour intervals to assess cytotoxicity. Cytotoxicity is measured by looking at the production of inflammatory cytokines. Cells are exposed to ground and unground stimulant and compared to cytokine production from cells exposed to quartz which have a known toxicity. Here we look at the cytotoxicity of the lunar dust stimulant relative to quartz by measuring the production of inflammatory cytokines.

Abnormal Amygdalar Activation and Connectivity in Adolescents with Attention-Deficit/Hyperactivity Disorder

ERIC Educational Resources Information Center

Posner, Jonathan; Nagel, Bonnie J.; Maia, Tiago V.; Mechling, Anna; Oh, Milim; Wang, Zhishun; Peterson, Bradley S.

2011-01-01

Objective: Emotional reactivity is one of the most disabling symptoms associated with attention-deficit/hyperactivity disorder (ADHD). We aimed to identify neural substrates associated with emotional reactivity and to assess the effects of stimulants on those substrates. Method: We used functional magnetic resonance imaging (fMRI) to assess neural…

Cardiac Reactivity and Stimulant Use in Adolescents with Autism Spectrum Disorders with Comorbid ADHD Versus ADHD

ERIC Educational Resources Information Center

Bink, M.; Popma, A.; Bongers, I. L.; van Boxtel, G. J. M.; Denissen, A.; van Nieuwenhuizen, Ch.

2015-01-01

A large number of youngsters with autism spectrum disorders (ASD) display comorbid attention deficit/hyperactivity disorder (ADHD) symptoms. However, previous studies are not conclusive whether psychophysiological correlates, like cardiac reactivity, are different for ASD with comorbid ADHD (ASD+) compared to ADHD. Therefore, the current study…

Repetitive Visual Stimulation Enhances Recovery from Severe Amblyopia

ERIC Educational Resources Information Center

Montey, Karen L.; Eaton, Nicolette C.; Quinlan, Elizabeth M.

2013-01-01

Severe amblyopia, characterized by a significant reduction in visual acuity through the affected eye, is highly resistant to reversal in adulthood. We have previously shown that synaptic plasticity can be reactivated in the adult rat visual cortex by dark exposure, and the reactivated plasticity can be harnessed to promote the recovery from severe…

Analysis of sensory processing in preterm infants.

PubMed

Cabral, Thais Invenção; da Silva, Louise Gracelli Pereira; Martinez, Cláudia Maria Simões; Tudella, Eloisa

2016-12-01

Premature birth suggests condition of biological vulnerability, predisposing to neurological injuries, requiring hospitalization in Neonatal Intensive Care Units, which, while contributing to increase the survival rates, expose infants to sensory stimuli harmful to the immature organism. To evaluate the sensory processing at 4 and 6months' corrected age. This was a descriptive cross-sectional study with a sample of 30 infants divided into an experimental group composed of preterm infants (n=15), and a control group composed of full-term infants (n=15). The infants were assessed using the Test of Sensory Functions in Infants. The preterm infants showed poor performance in the total score of the test in reactivity to tactile deep pressure and reactivity to vestibular stimulation. When groups were compared, significant differences in the total score (p=0.0113) and in the reactivity to tactile deep pressure (p<0.0001) were found. At 4 and 6months of corrected age, the preterm infants showed alterations in sensory processing. These changes were most evident in reactivity to tactile deep pressure and vestibular stimulation. Copyright © 2016. Published by Elsevier Ireland Ltd.

Transcriptional Elongation Control of Hepatitis B Virus Covalently Closed Circular DNA Transcription by Super Elongation Complex and BRD4.

PubMed

Francisco, Joel Celio; Dai, Qian; Luo, Zhuojuan; Wang, Yan; Chong, Roxanne Hui-Heng; Tan, Yee Joo; Xie, Wei; Lee, Guan-Huei; Lin, Chengqi

2017-10-01

Chronic hepatitis B virus (HBV) infection can lead to liver cirrhosis and hepatocellular carcinoma. HBV reactivation during or after chemotherapy is a potentially fatal complication for cancer patients with chronic HBV infection. Transcription of HBV is a critical intermediate step of the HBV life cycle. However, factors controlling HBV transcription remain largely unknown. Here, we found that different P-TEFb complexes are involved in the transcription of the HBV viral genome. Both BRD4 and the super elongation complex (SEC) bind to the HBV genome. The treatment of bromodomain inhibitor JQ1 stimulates HBV transcription and increases the occupancy of BRD4 on the HBV genome, suggesting the bromodomain-independent recruitment of BRD4 to the HBV genome. JQ1 also leads to the increased binding of SEC to the HBV genome, and SEC is required for JQ1-induced HBV transcription. These findings reveal a novel mechanism by which the HBV genome hijacks the host P-TEFb-containing complexes to promote its own transcription. Our findings also point out an important clinical implication, that is, the potential risk of HBV reactivation during therapy with a BRD4 inhibitor, such as JQ1 or its analogues, which are a potential treatment for acute myeloid leukemia. Copyright © 2017 American Society for Microbiology.

The effect of rTMS over the inferior parietal lobule on EEG sensorimotor reactivity differs according to self-reported traits of autism in typically developing individuals.

PubMed

Puzzo, Ignazio; Cooper, Nicholas R; Cantarella, Simona; Fitzgerald, Paul B; Russo, Riccardo

2013-12-06

Previous research suggested that EEG markers of mirror neuron system activation may differ, in the normal population as a function of different levels of the autistic spectrum quotient; (AQ). The present study aimed at modulating the EEG sensorimotor reactivity induced by hand movement observation by means of repetitive transcranial magnetic stimulation (rTMS) applied to the inferior parietal lobule. We examined how the resulting rTMS modulation differed in relation to the self-reported autistic traits in the typically developing population. Results showed that during sham stimulation, all participants had significantly greater sensorimotor alpha reactivity (motor cortex-C electrodes) when observing hand movements compared to static hands. This sensorimotor alpha reactivity difference was reduced during active rTMS stimulation. Results also revealed that in the average AQ group at sham there was a significant increase in low beta during hand movement than static hand observation (pre-motor areas-FC electrodes) and that (like alpha over the C electrodes) this difference is abolished when active rTMS is delivered. Participants with high AQ scores showed no significant difference in low beta sensorimotor reactivity between active and sham rTMS during static hand or hand movement observation. These findings suggest that unlike sham, active rTMS over the IPL modulates the oscillatory activity of the low beta frequency of a distal area, namely the anterior sector of the sensorimotor cortex, when participants observe videos of static hand. Importantly, this modulation differs according to the degree of self-reported traits of autism in a typically developing population. © 2013 Elsevier B.V. All rights reserved.

Step training improves reaction time, gait and balance and reduces falls in older people: a systematic review and meta-analysis.

PubMed

Okubo, Yoshiro; Schoene, Daniel; Lord, Stephen R

2017-04-01

To examine the effects of stepping interventions on fall risk factors and fall incidence in older people. Electronic databases (PubMed, EMBASE, CINAHL, Cochrane, CENTRAL) and reference lists of included articles from inception to March 2015. Randomised (RCT) or clinical controlled trials (CCT) of volitional and reactive stepping interventions that included older (minimum age 60) people providing data on falls or fall risk factors. Meta-analyses of seven RCTs (n=660) showed that the stepping interventions significantly reduced the rate of falls (rate ratio=0.48, 95% CI 0.36 to 0.65, p<0.0001, I 2 =0%) and the proportion of fallers (risk ratio=0.51, 95% CI 0.38 to 0.68, p<0.0001, I 2 =0%). Subgroup analyses stratified by reactive and volitional stepping interventions revealed a similar efficacy for rate of falls and proportion of fallers. A meta-analysis of two RCTs (n=62) showed that stepping interventions significantly reduced laboratory-induced falls, and meta-analysis findings of up to five RCTs and CCTs (n=36-416) revealed that stepping interventions significantly improved simple and choice stepping reaction time, single leg stance, timed up and go performance (p<0.05), but not measures of strength. The findings indicate that both reactive and volitional stepping interventions reduce falls among older adults by approximately 50%. This clinically significant reduction may be due to improvements in reaction time, gait, balance and balance recovery but not in strength. Further high-quality studies aimed at maximising the effectiveness and feasibility of stepping interventions are required. CRD42015017357. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Generation of B-cell chronic lymphocytic leukemia (B-CLL)-reactive T-cell lines and clones from HLA class I-matched donors using modified B-CLL cells as stimulators: implications for adoptive immunotherapy.

PubMed

Hoogendoorn, M; Wolbers, J Olde; Smit, W M; Schaafsma, M R; Barge, R M Y; Willemze, R; Falkenburg, J H F

2004-07-01

Allogeneic stem cell transplantation following reduced-intensity conditioning is being evaluated in patients with advanced B-cell chronic lymphocytic leukemia (B-CLL). The curative potential of this procedure is mediated by donor-derived alloreactive T cells, resulting in a graft-versus-leukemia effect. However, B-CLL may escape T-cell-mediated immune reactivity since these cells lack expression of costimulatory molecules. We examined the most optimal method to transform B-CLL cells into efficient antigen-presenting cells (APC) using activating cytokines, by triggering toll-like receptors (TLRs) using microbial pathogens and by CD40 stimulation with CD40L-transfected fibroblasts. CD40 activation in the presence of IL-4 induced strongest upregulation of costimulatory and adhesion molecules on B-CLL cells and induced the production of high amounts of IL-12 by the leukemic cells. In contrast to primary B-CLL cells as stimulator cells, these malignant APCs were capable of inducing the generation of B-CLL-reactive CD8(+) CTL lines and clones from HLA class I-matched donors. These CTL lines and clones recognized and killed primary B-CLL as well as patient-derived lymphoblasts, but not donor cells. These results show the feasibility of ex vivo generation of B-CLL-reactive CD8(+) CTLs. This opens new perspectives for adoptive immunotherapy, following allogeneic stem cell transplantation in patients with advanced B-CLL.

Highly Human Immunodeficiency Virus-Exposed Seronegative Men Have Lower Mucosal Innate Immune Reactivity.

PubMed

Fulcher, Jennifer A; Romas, Laura; Hoffman, Jennifer C; Elliott, Julie; Saunders, Terry; Burgener, Adam D; Anton, Peter A; Yang, Otto O

2017-08-01

Risk of HIV acquisition varies, and some individuals are highly HIV-1-exposed, yet, persistently seronegative (HESN). The immunologic mechanisms contributing to this phenomenon are an area of intense interest. As immune activation and inflammation facilitate disease progression in HIV-1-infected persons and gastrointestinal-associated lymphoid tissue is a highly susceptible site for transmission, we hypothesized that reduced gut mucosal immune reactivity may contribute to reduced HIV-1 susceptibility in HESN men with a history of numerous rectal sexual exposures. To test this, we used ex vivo mucosal explants from freshly acquired colorectal biopsies from healthy control and HESN subjects who were stimulated with specific innate immune ligands and inactivated whole pathogens. Immune reactivity was then assessed via cytokine arrays and proteomic analysis. Mucosal immune cell compositions were quantified via immunohistochemistry. We found that explants from HESN subjects produced less proinflammatory cytokines compared with controls following innate immune stimulation; while noninflammatory cytokines were similar between groups. Proteomic analysis identified several immune response proteins to be differentially expressed between HIV-1-stimulated HESN and control explants. Immunohistochemical examination of colorectal mucosa showed similar amounts of T cells, macrophages, and dendritic cells between groups. The results of this pilot study suggest that mucosal innate immune reactivity is dampened in HESN versus control groups, despite presence of similar densities of immune cells in the colorectal mucosa. This observed modulation of the rectal mucosal immune response may contribute to lower risk of mucosal HIV-1 transmission in these individuals.

One-Step Chromatographic Purification of Helicobacter pylori Neutrophil-Activating Protein Expressed in Bacillus subtilis

PubMed Central

Shih, Kuo-Shun; Lin, Chih-Chang; Hung, Hsiao-Fang; Yang, Yu-Chi; Wang, Chung-An; Jeng, Kee-Ching; Fu, Hua-Wen

2013-01-01

Helicobacter pylori neutrophil-activating protein (HP-NAP), a major virulence factor of Helicobacter pylori (H. pylori), is capable of activating human neutrophils to produce reactive oxygen species (ROS) and secrete inammatory mediators. HP-NAP is a vaccine candidate, a possible drug target, and a potential in vitro diagnostic marker for H. pylori infection. HP-NAP has also been shown to be a novel therapeutic agent for the treatment of allergic asthma and bladder cancer. Hence, an efficient way to obtain pure HP-NAP needs to be developed. In this study, one-step anion-exchange chromatography in negative mode was applied to purify the recombinant HP-NAP expressed in Bacillus subtilis (B. subtilis). This purification technique was based on the binding of host cell proteins and/or impurities other than HP-NAP to DEAE Sephadex resins. At pH 8.0, almost no other proteins except HP-NAP passed through the DEAE Sephadex column. More than 60% of the total HP-NAP with purity higher than 91% was recovered in the flow-through fraction from this single-step DEAE Sephadex chromatography. The purified recombinant HP-NAP was further demonstrated to be a multimeric protein with a secondary structure of α-helix and capable of activating human neutrophils to stimulate ROS production. Thus, this one-step negative chromatography using DEAE Sephadex resin can efficiently yield functional HP-NAP from B. subtilis in its native form with high purity. HP-NAP purified by this method could be further utilized for the development of new drugs, vaccines, and diagnostics for H. pylori infection. PMID:23577158

Facile fabrication of HDPE-g-MA/nanodiamond nanocomposites via one-step reactive blending.

PubMed

Song, Ping'an; Yu, Youming; Wu, Qiang; Fu, Shenyuan

2012-06-29

In this letter, nanocomposites based on maleic anhydride grafted high density polyethylene (HDPE-g-MA) and amine-functionalized nanodiamond (ND) were fabricated via one-step reactive melt-blending, generating a homogeneous dispersion of ND, as evidenced by transmission electron microscope observations. Thermal analysis results suggest that addition of ND does not affect significantly thermal stability of polymer matrix in nitrogen. However, it was interestingly found that incorporating pure ND decreases the thermal oxidation degradation stability temperature, but blending amino-functionalized ND via reactive processing significantly enhances it of HDPE in air condition. Most importantly, cone tests revealed that both ND additives and reactive blending greatly reduce the heat release rate of HDPE. The results suggest that ND has a potential application as flame retardant alternative for polymers. Tensile results show that adding ND considerably enhances Young's modulus, and reactive blending leads to further improvement in Young's modulus while hardly reducing the elongation at break of HDPE.

Facile fabrication of HDPE-g-MA/nanodiamond nanocomposites via one-step reactive blending

PubMed Central

2012-01-01

In this letter, nanocomposites based on maleic anhydride grafted high density polyethylene (HDPE-g-MA) and amine-functionalized nanodiamond (ND) were fabricated via one-step reactive melt-blending, generating a homogeneous dispersion of ND, as evidenced by transmission electron microscope observations. Thermal analysis results suggest that addition of ND does not affect significantly thermal stability of polymer matrix in nitrogen. However, it was interestingly found that incorporating pure ND decreases the thermal oxidation degradation stability temperature, but blending amino-functionalized ND via reactive processing significantly enhances it of HDPE in air condition. Most importantly, cone tests revealed that both ND additives and reactive blending greatly reduce the heat release rate of HDPE. The results suggest that ND has a potential application as flame retardant alternative for polymers. Tensile results show that adding ND considerably enhances Young’s modulus, and reactive blending leads to further improvement in Young’s modulus while hardly reducing the elongation at break of HDPE. PMID:22747773

The effect of single and repeated prefrontal intermittent theta burst stimulation on cortical reactivity and working memory.

PubMed

Chung, Sung Wook; Rogasch, Nigel C; Hoy, Kate E; Fitzgerald, Paul B

With an increasing interest in the use of theta burst stimulation (TBS) as a cognitive enhancer and a potential therapeutic tool for psychiatric disorders, there is a need to identify optimal parameters of TBS in the prefrontal cortex. This study examined the effect of two blocks of prefrontal intermittent TBS (iTBS) on cortical reactivity and working memory performance, compared to one block of iTBS and sham stimulation. We hypothesized that greater cortical effects would be obtained with two blocks of iTBS. Eighteen healthy participants attended three experimental sessions and received either sham, one block or two blocks of iTBS with a 15-min interval. Concurrent transcranial magnetic stimulation with electroencephalography (TMS-EEG) was used to assess the change in cortical reactivity via TMS-evoked potentials. Working memory performance was assessed using the N-back task. Cluster-based permutation statistics and two-way ANOVAs were used for neurophysiological and behavioural data, respectively. Both single and two blocks of iTBS resulted in a significant increase in the amplitude of TMS-evoked N100 and P200. No significant differences were observed between active conditions in either neurophysiological changes or working memory performance, and both failed to improve working memory performance relative to sham. Two blocks of iTBS did not result in stronger measured effects as compared to one block of iTBS. Future studies are needed to identify the optimal stimulation pattern in order to achieve a desired effect. It is also important to establish the best approach in quantifying neuromodulatory effects targeting the prefrontal cortex. Copyright © 2018 Elsevier Inc. All rights reserved.

PBMC are as good a source of tumor-reactive T lymphocytes as TIL after selection by Melan-A/A2 multimer immunomagnetic sorting.

PubMed

Labarrière, Nathalie; Gervois, Nadine; Bonnin, Annabelle; Bouquié, Régis; Jotereau, Francine; Lang, François

2008-02-01

Choosing a reliable source of tumor-specific T lymphocytes and an efficient method to isolate these cells still remains a critical issue in adoptive cellular therapy (ACT). In this study, we assessed the capacity of MHC/peptide based immunomagnetic sorting followed by polyclonal T cell expansion to derive pure polyclonal and tumor-reactive Melan-A specific T cell populations from melanoma patient's PBMC and TIL. We first demonstrated that this approach was extremely efficient and reproducible. We then used this procedure to compare PBMC and TIL-derived cells from three melanoma patients in terms of avidity for Melan-A A27L analog, Melan-A(26-35)and Melan-A(27-35), tumor reactivity (lysis and cytokine production) and repertoire. Regardless of their origin, i.e., fresh PBMC, peptide stimulated PBMC or TIL, all sorted populations (from the three patients) were cytotoxic against HLA-A2+ melanoma cell lines expressing Melan-A. Although some variability in peptide avidity, lytic activity and cytokine production was observed between populations of different origins in a given patient, it differed from one patient to another and thus no correlation could be drawn between T cell source and reactivity. Analysis of Vbeta usage within the sorted populations showed the recurrence of Vbeta3 and Vbeta14 subfamilies in the three patients but differences in the rest of the Melan-A repertoire. In addition, in two patients, we observed major repertoire differences between populations sorted from the three sources. We especially documented that in vitro peptide stimulation of PBMC, used to facilitate the sort by enriching in specific T lymphocytes, could significantly alter their repertoire and reactivity towards tumor cells. We conclude that PBMC which are easily obtained from all melanoma patients, can be as good a source as TIL to derive high amounts of tumor-reactive Melan-A specific T cells, with this selection/amplification procedure. However, the conditions of peptide stimulation should be improved to prevent a possible loss of reactive clonotypes.

Mechanism of short-term ERK activation by electromagnetic fields at mobile phone frequencies.

PubMed

Friedman, Joseph; Kraus, Sarah; Hauptman, Yirmi; Schiff, Yoni; Seger, Rony

2007-08-01

The exposure to non-thermal microwave electromagnetic fields generated by mobile phones affects the expression of many proteins. This effect on transcription and protein stability can be mediated by the MAPK (mitogen-activated protein kinase) cascades, which serve as central signalling pathways and govern essentially all stimulated cellular processes. Indeed, long-term exposure of cells to mobile phone irradiation results in the activation of p38 as well as the ERK (extracellular-signal-regulated kinase) MAPKs. In the present study, we have studied the immediate effect of irradiation on the MAPK cascades, and found that ERKs, but not stress-related MAPKs, are rapidly activated in response to various frequencies and intensities. Using signalling inhibitors, we delineated the mechanism that is involved in this activation. We found that the first step is mediated in the plasma membrane by NADH oxidase, which rapidly generates ROS (reactive oxygen species). These ROS then directly stimulate MMPs (matrix metalloproteinases) and allow them to cleave and release Hb-EGF [heparin-binding EGF (epidermal growth factor)]. This secreted factor activates the EGF receptor, which in turn further activates the ERK cascade. Thus this study demonstrates for the first time a detailed molecular mechanism by which electromagnetic irradiation from mobile phones induces the activation of the ERK cascade and thereby induces transcription and other cellular processes.

A Three-Step Atomic Layer Deposition Process for SiN x Using Si2Cl6, CH3NH2, and N2 Plasma.

PubMed

Ovanesyan, Rafaiel A; Hausmann, Dennis M; Agarwal, Sumit

2018-06-06

We report a novel three-step SiN x atomic layer deposition (ALD) process using Si 2 Cl 6 , CH 3 NH 2 , and N 2 plasma. In a two-step process, nonhydrogenated chlorosilanes such as Si 2 Cl 6 with N 2 plasmas lead to poor-quality SiN x films that oxidize rapidly. The intermediate CH 3 NH 2 step was therefore introduced in the ALD cycle to replace the NH 3 plasma step with a N 2 plasma, while using Si 2 Cl 6 as the Si precursor. This three-step process lowers the atomic H content and improves the film conformality on high-aspect-ratio nanostructures as Si-N-Si bonds are formed during a thermal CH 3 NH 2 step in addition to the N 2 plasma step. During ALD, the reactive surface sites were monitored using in situ surface infrared spectroscopy. Our infrared spectra show that, on the post-N 2 plasma-treated SiN x surface, Si 2 Cl 6 reacts primarily with the surface -NH 2 species to form surface -SiCl x ( x = 1, 2, or 3) bonds, which are the reactive sites during the CH 3 NH 2 cycle. In the N 2 plasma step, reactive -NH 2 surface species are created because of the surface H available from the -CH 3 groups. At 400 °C, the SiN x films have a growth per cycle of ∼0.9 Å with ∼12 atomic percent H. The films grown on high-aspect-ratio nanostructures have a conformality of ∼90%.

A spectral radius scaling semi-implicit iterative time stepping method for reactive flow simulations with detailed chemistry

NASA Astrophysics Data System (ADS)

Xie, Qing; Xiao, Zhixiang; Ren, Zhuyin

2018-09-01

A spectral radius scaling semi-implicit time stepping scheme has been developed for simulating unsteady compressible reactive flows with detailed chemistry, in which the spectral radius in the LUSGS scheme has been augmented to account for viscous/diffusive and reactive terms and a scalar matrix is proposed to approximate the chemical Jacobian using the minimum species destruction timescale. The performance of the semi-implicit scheme, together with a third-order explicit Runge-Kutta scheme and a Strang splitting scheme, have been investigated in auto-ignition and laminar premixed and nonpremixed flames of three representative fuels, e.g., hydrogen, methane, and n-heptane. Results show that the minimum species destruction time scale can well represent the smallest chemical time scale in reactive flows and the proposed scheme can significantly increase the allowable time steps in simulations. The scheme is stable when the time step is as large as 10 μs, which is about three to five orders of magnitude larger than the smallest time scales in various tests considered. For the test flames considered, the semi-implicit scheme achieves second order of accuracy in time. Moreover, the errors in quantities of interest are smaller than those from the Strang splitting scheme indicating the accuracy gain when the reaction and transport terms are solved coupled. Results also show that the relative efficiency of different schemes depends on fuel mechanisms and test flames. When the minimum time scale in reactive flows is governed by transport processes instead of chemical reactions, the proposed semi-implicit scheme is more efficient than the splitting scheme. Otherwise, the relative efficiency depends on the cost in sub-iterations for convergence within each time step and in the integration for chemistry substep. Then, the capability of the compressible reacting flow solver and the proposed semi-implicit scheme is demonstrated for capturing the hydrogen detonation waves. Finally, the performance of the proposed method is demonstrated in a two-dimensional hydrogen/air diffusion flame.

Computerized fetal heart rate monitoring after vibroacoustic stimulation in the anencephalic fetus.

PubMed

Park, Yong-Jin; Park, Seon-Hye; Kim, Young-Jae; Hoh, Jeong-Kyu; Park, Young-Sun; Park, Moon-Il

2010-09-01

To quantify changes in fetal heart rate (FHR) parameters after vibroacoustic stimulation (VAS) and to evaluate the usefulness of VAS testing (VAST) in anencephalic fetuses. Our findings may also help to clarify the route(s) of vibration and sound transmission during VAST. We obtained the antepartum FHR tracings of 16 anencephalic fetuses, including both the nonstress test (NST) and VAST. Using a computerized monitoring system, HYFM, we determined all FHR parameters from data collected for 10 min before and 10 min after VAS, at successive gestational stages. We observed three false reactive responses at term. The false reactive rate for VAST (3/16) was higher than that for NST (1/16). No FHR parameters increased significantly after VAS except for the number of fetal movements (FM), which increased significantly in all gestational groups (25th-32nd and 33rd-40th weeks). These findings call attention to an increased probability of a false reactive response in VAST analysis, when the fetus is affected by a CNS disorder. Increased numbers of FM after VAS suggest that the vibratory pathway is more likely to elicit fetal response than the auditory pathway in this setting, and that the vibratory stimulation travels by subcortical rather than by cortical pathways. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Stimulation of NADH-dependent microsomal DNA strand cleavage by rifamycin SV.

PubMed

Kukiełka, E; Cederbaum, A I

1995-04-15

Rifamycin SV is an antibiotic anti-bacterial agent used in the treatment of tuberculosis. This drug can autoxidize, especially in the presence of metals, and generate reactive oxygen species. A previous study indicated that rifamycin SV can increase NADH-dependent microsomal production of reactive oxygen species. The current study evaluated the ability of rifamycin SV to interact with iron and increase microsomal production of hydroxyl radical, as detected by conversion of supercoiled plasmid DNA into the relaxed open circular state. The plasmid used was pBluescript II KS(-), and the forms of DNA were separated by agarose-gel electrophoresis. Incubation of rat liver microsomes with plasmid plus NADH plus ferric-ATP caused DNA strand cleavage. The addition of rifamycin SV produced a time- and concentration-dependent increase in DNA-strand cleavage. No stimulation by rifamycin SV occurred in the absence of microsomes, NADH or ferric-ATP. Stimulation occurred with other ferric complexes besides ferric-ATP, e.g. ferric-histidine, ferric-citrate, ferric-EDTA, and ferric-(NH4)2SO4. Rifamycin SV did not significantly increase the high rates of DNA strand cleavage found with NADPH as the microsomal reductant. The stimulation of NADH-dependent microsomal DNA strand cleavage was completely blocked by catalase, superoxide dismutase, GSH and a variety of hydroxyl-radical-scavenging agents, but not by anti-oxidants that prevent microsomal lipid peroxidation. Redox cycling agents, such as menadione and paraquat, in contrast with rifamycin SV, stimulated the NADPH-dependent reaction; menadione and rifamycin SV were superior to paraquat in stimulating the NADH-dependent reaction. These results indicate that rifamycin SV can, in the presence of an iron catalyst, increase microsomal production of reactive oxygen species which can cause DNA-strand cleavage. In contrast with other redox cycling agents, the stimulation by rifamycin SV is more pronounced with NADH than with NADPH as the microsomal reductant. Interactions between rifamycin SV, iron and NADH generating hydroxyl-radical-like species may play a role in some of the hepatotoxic effects associated with the use of this antibacterial antibiotic.

CD4+ T-Cell Reactivity to Orexin/Hypocretin in Patients With Narcolepsy Type 1.

PubMed

Ramberger, Melanie; Högl, Birgit; Stefani, Ambra; Mitterling, Thomas; Reindl, Markus; Lutterotti, Andreas

2017-03-01

Narcolepsy type 1 is accompanied by a selective loss of orexin/hypocretin (hcrt) neurons in the lateral hypothalamus caused by yet unknown mechanisms. Epidemiologic and genetic associations strongly suggest an immune-mediated pathogenesis of the disease. We compared specific T-cell reactivity to orexin/hcrt peptides in peripheral blood mononuclear cells of narcolepsy type 1 patients to healthy controls by a carboxyfluorescein succinimidyl ester proliferation assay. Orexin/hcrt-specific T-cell reactivity was also determined by cytokine (interferon gamma and granulocyte-macrophage colony-stimulating factor) analysis. Individuals were considered as responders if the cell division index of CD3+CD4+ T cells and both stimulation indices of cytokine secretion exceeded the cutoff 3. Additionally, T-cell reactivity to orexin/hcrt had to be confirmed by showing reactivity to single peptides present in different peptide pools. Using these criteria, 3/15 patients (20%) and 0/13 controls (0%) showed orexin/hcrt-specific CD4+ T-cell proliferation (p = .2262). The heterogeneous reactivity pattern did not allow the identification of a preferential target epitope. A significant role of orexin/hcrt-specific T cells in narcolepsy type 1 patients could not be confirmed in this study. Further studies are needed to assess the exact role of CD4+ T cells and possible target antigens in narcolepsy type 1 patients. © Sleep Research Society 2016. Published by Oxford University Press [on behalf of the Sleep Research Society].

Cytomegalovirus Reinfections Stimulate CD8 T-Memory Inflation.

PubMed

Trgovcich, Joanne; Kincaid, Michelle; Thomas, Alicia; Griessl, Marion; Zimmerman, Peter; Dwivedi, Varun; Bergdall, Valerie; Klenerman, Paul; Cook, Charles H

2016-01-01

Cytomegalovirus (CMV) has been shown to induce large populations of CD8 T-effector memory cells that unlike central memory persist in large quantities following infection, a phenomenon commonly termed "memory inflation". Although murine models to date have shown very large and persistent CMV-specific T-cell expansions following infection, there is considerable variability in CMV-specific T-memory responses in humans. Historically such memory inflation in humans has been assumed a consequence of reactivation events during the life of the host. Because basic information about CMV infection/re-infection and reactivation in immune competent humans is not available, we used a murine model to test how primary infection, reinfection, and reactivation stimuli influence memory inflation. We show that low titer infections induce "partial" memory inflation of both mCMV specific CD8 T-cells and antibody. We show further that reinfection with different strains can boost partial memory inflation. Finally, we show preliminary results suggesting that a single strong reactivation stimulus does not stimulate memory inflation. Altogether, our results suggest that while high titer primary infections can induce memory inflation, reinfections during the life of a host may be more important than previously appreciated.

Pathogen stimulation history impacts donor-specific CD8+ T cell susceptibility to costimulation/integrin blockade-based therapy

PubMed Central

Badell, IR; Kitchens, WH; Wagener, ME; Lukacher, AE; Larsen, CP; Ford, ML

2017-01-01

Recent studies have shown that the quantity of donor-reactive memory T cells is an important factor in determining the relative heterologous immunity barrier posed during transplantation. Here, we hypothesized that the quality of T cell memory also potently influences the response to costimulation blockade-based immunosuppression. Using a murine skin graft model of CD8+ memory T cell-mediated costimulation blockade resistance, we elicited donor-reactive memory T cells using three distinct types of pathogen infections. Strikingly, we observed differential efficacy of a costimulation and integrin blockade regimen based on the type of pathogen used to elicit the donor-reactive memory T cell response. Intriguingly, the most immunosuppression-sensitive memory T cell populations were composed primarily of central memory cells that possessed greater recall potential, exhibited a less differentiated phenotype, and contained more multi-cytokine producers. These data therefore demonstrate that the memory T cell barrier is dependent on the specific type of pathogen infection via which the donor-reactive memory T cells are elicited, and suggest that the immune stimulation history of a given transplant patient may profoundly influence the relative barrier posed by heterologous immunity during transplantation. PMID:26228897

A comparison of African American and Caucasian stimulant users in 12-step facilitation treatment

PubMed Central

Peavy, K. Michelle; Garrett, Sharon; Doyle, Suzanne; Donovan, Dennis

2017-01-01

Engagement in 12-step meetings and activities has been shown to be a powerful aid to recovery from substance use disorders. However, only limited attention has been given to ethnic and racial differences in attitudes toward 12-step and involvement. This study utilized data from a large multisite trial testing the effectiveness of a 12-step facilitation therapy with stimulant-dependent treatment seekers. We compared baseline differences and treatment outcomes between African American and Caucasian participants. A select few baseline differences were found (i.e., African Americans reported higher levels of spirituality than Caucasians; African American participants indicated more perceived benefits of 12-step involvement; Caucasians were more likely to endorse future involvement in 12-step). There were no outcome differences (e.g., substance use outcomes, 12-step meeting attendance). The tested intervention produced similar outcomes for both groups, indicating that it may be useful across racial categories. PMID:27294812

A comparison of African American and Caucasian stimulant users in 12-step facilitation treatment.

PubMed

Peavy, K Michelle; Garrett, Sharon; Doyle, Suzanne; Donovan, Dennis

2017-01-01

Engagement in 12-step meetings and activities has been shown to be a powerful aid to recovery from substance use disorders. However, only limited attention has been given to ethnic and racial differences in attitudes toward 12-step and involvement. This study utilized data from a large multisite trial testing the effectiveness of a 12-step facilitation therapy with stimulant-dependent treatment seekers. We compared baseline differences and treatment outcomes between African American and Caucasian participants. A select few baseline differences were found (i.e., African Americans reported higher levels of spirituality than Caucasians; African American participants indicated more perceived benefits of 12-step involvement; Caucasians were more likely to endorse future involvement in 12-step). There were no outcome differences (e.g., substance use outcomes, 12-step meeting attendance). The tested intervention produced similar outcomes for both groups, indicating that it may be useful across racial categories.

Frequency steps and compositions determine properties of nee- dling sensation during electroacupuncture.

PubMed

Xuan, Chen; Xiaoran, Ye; Suying, Ge; Zhifang, Yao; Xiaoqing, Huang

2015-04-01

To investigate the relationship of electro-parameters and the electroacupuncture sensation (EAS), which is thought to be an important factor for optimal treatment. The frequency steps and compositions of three frequently used electrical stimulations were set when the switch of the electroacupuncture apparatus was turned to the second or third grade of the dense-disperse frequency wave (DD2 and DD3, respectively) or the second grade of the continuous wave (C2). Three groups of patients according to the three electroacupuncture stimulations were divided again into three sub-groups according to the stimulated acupoints: the face acupoint Quanliao (SI 18), the upper-limb acupoint Quchi (LI 11) and the back acupoint Dachangshu (BL 25). The EAS values were measured every 5 min during 30 min electroacupuncture treatments using a visual analogue scale. The frequency compositions of the three electroacupuncture stimulations were 3.3 and 33 Hz, 12.5 and 66.7 Hz, and 3.3 and 3.3 Hz; each frequency step was 30, 54 and 0 Hz, respectively. In each sub-group of the C2 group, the EAS values from 10 to 30 min were significantly weaker than at 0 min. The sensation fluctuations in the DD2 and DD3 groups were different during the 30 min. The greater the frequency step of the electroacupuncture stimulation, the longer the needling sensation lasted. The electroacupuncture stimulations of the DD3 group were unsuitable for the facial acupoint because of its painful and uncomfortable EAS, but more suitable for the back acupoint.

Follow-up of congenital heart disease patients with subclinical hypothyroidism.

PubMed

Martínez-Quintana, Efrén; Rodríguez-González, Fayna

2015-08-01

Subclinical hypothyroidism or mild thyroid failure is a common problem in patients without known thyroid disease. Demographic and analytical data were collected in 309, of which 181 were male and 128 were female, congenital heart disease (CHD) patients. CHD patients with thyroid-stimulating hormone above 5.5 mIU/L were also followed up from an analytical point of view to determine changes in serum glucose, cholesterol, N-terminal pro b-type natriuretic peptide, and C-reactive protein concentrations. Of the CHD patients, 35 (11.3%) showed thyroid-stimulating hormone concentration above 5.5 mIU/L. Of them, 27 were followed up during 2.4±1.2 years - 10 were under thyroid hormone replacement treatment, and 17 were not. Of the 27 patients (25.9%), 7 with subclinical hypothyroidism had positive anti-thyroid peroxidase, and 3 of them (42.8%) with positive anti-thyroid peroxidase had Down syndrome. Down syndrome and hypoxaemic CHD patients showed higher thyroid-stimulating hormone concentrations than the rest of the congenital patients (p<0.001). No significant differences were observed in serum thyroxine, creatinine, uric acid, lipids, C-reactive protein, or N-terminal pro b-type natriuretic peptide concentrations before and after the follow-up in those CHD patients with thyroid-stimulating hormone above 5.5 mIU/L whether or not they received levothyroxine therapy. CHD patients with subclinical hypothyroidism showed no significant changes in serum thyroxine, cholesterol, C-reactive protein, or N-terminal pro b-type natriuretic peptide concentrations whether or not they were treated with thyroid hormone replacement therapy.

Platelet reactivity and mean platelet volume as risk markers of thrombogenesis in atrial fibrillation.

PubMed

Makowski, Marcin; Smorag, Ireneusz; Makowska, Joanna; Bissinger, Andrzej; Grycewicz, Tomasz; Paśnik, Jarek; Kidawa, Michal; Lubiński, Andrzej; Zielińska, Marzenna; Baj, Zbigniew

2017-05-15

Atrial fibrillation (AF) is associated with increased risk of thromboembolic complications. One of the markers of the increased risk of hypercoagulable state is platelet hyperreactivity. The aim of the study was to assess impact of arrhythmia on platelet reactivity. The study included 36 (mean age 48,3; range 21-60) male patients with lone atrial fibrillation, with exclusion of concomitant diseases known to trigger hypercoagulable state. The AF patients underwent cardioversion to restore sinus rhythm and were subsequently under observation for 1month. Echocardiography, ECG and blood collection was performed before cardioversion (T0) and 4weeks after successful cardioversion (T1). During the study period patients have been contacted and examined every week and 24h ECG monitoring was performed. Platelet reactivity was assessed based on changes of CD62 and CD42b expression on platelet surface after stimulation with thrombin. Also changes in MPV were assessed. In all patients sinus rhythm was maintained at the end of the study period, however in 14 patients recurrences of AF were observed, confirmed by 24h ECG monitoring (atrial fibrillation recurrence group - AFR) and 22 patients maintained sinus rhythm throughout the whole study period (SR group). Mean fluorescence intensity (MFI) of CD62 on thrombin stimulated platelets decreased significantly 4weeks after electrical cardioversion as compared to T0 (48.04±22.42 vs 41.47±16.03; p<0.01). Also MFI of CD42b on thrombin stimulated platelets decreased significantly 4weeks after electrical cardioversion as compared to T0 (22.16±10.82 vs 12.06±5.99; p<0.0001). Platelets reactivity estimated by CD 62 expression in SR group decreased significantly after 4weeks observation (58.01±15.26 vs 46.57±13.44; p<0.001) opposite to AFR group 35.66±21.87 vs 34.54±16.4; p-ns). Moreover there were significant differences between basal reactivity during AF between SR and AFR groups (58.01±15.26 vs 35.66±21.87; p-0.01). MFI of CD42b on thrombin stimulated platelets decreased significantly both in AFR and SR groups (22.05±11.36 vs 13.8±6.03; p<0.001 and 21.87±14.18 vs 10.04±5.09; p<0005). MPV decreased significantly 4weeks after electrical cardioversion as compared to T0 (8.81±0.19 vs 8.42±0.14; p<0.0001). The changes of platelet reactivity to thrombin observed after restoration of sinus rhythm in patients prove that arrhythmia intrinsically leads to increased reactivity of platelets. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Loss of Xist RNA from the inactive X during B cell development is restored in a dynamic YY1-dependent two-step process in activated B cells

PubMed Central

Syrett, Camille M.; Sindhava, Vishal; Hodawadekar, Suchita; Myles, Arpita; Liang, Guanxiang; Zhang, Yue; Nandi, Satabdi; Cancro, Michael; Atchison, Michael

2017-01-01

X-chromosome inactivation (XCI) in female lymphocytes is uniquely regulated, as the inactive X (Xi) chromosome lacks localized Xist RNA and heterochromatin modifications. Epigenetic profiling reveals that Xist RNA is lost from the Xi at the pro-B cell stage and that additional heterochromatic modifications are gradually lost during B cell development. Activation of mature B cells restores Xist RNA and heterochromatin to the Xi in a dynamic two-step process that differs in timing and pattern, depending on the method of B cell stimulation. Finally, we find that DNA binding domain of YY1 is necessary for XCI in activated B cells, as ex-vivo YY1 deletion results in loss of Xi heterochromatin marks and up-regulation of X-linked genes. Ectopic expression of the YY1 zinc finger domain is sufficient to restore Xist RNA localization during B cell activation. Together, our results indicate that Xist RNA localization is critical for maintaining XCI in female lymphocytes, and that chromatin changes on the Xi during B cell development and the dynamic nature of YY1-dependent XCI maintenance in mature B cells predisposes X-linked immunity genes to reactivation. PMID:28991910

STEP activation by Gαq coupled GPCRs opposes Src regulation of NMDA receptors containing the GluN2A subunit

PubMed Central

Tian, Meng; Xu, Jian; Lei, Gang; Lombroso, Paul J.; Jackson, Michael F.; MacDonald, John F.

2016-01-01

N-methyl-D-aspartate receptors (NMDARs) are necessary for the induction of synaptic plasticity and for the consolidation of learning and memory. NMDAR function is tightly regulated by functionally opposed families of kinases and phosphatases. Herein we show that the striatal-enriched protein tyrosine phosphatase (STEP) is recruited by Gαq-coupled receptors, including the M1 muscarinic acetylcholine receptor (M1R), and opposes the Src tyrosine kinase-mediated increase in the function of NMDARs composed of GluN2A. STEP activation by M1R stimulation requires IP3Rs and can depress NMDA-evoked currents with modest intracellular Ca2+ buffering. Src recruitment by M1R stimulation requires coincident NMDAR activation and can augment NMDA-evoked currents with high intracellular Ca2+ buffering. Our findings suggest that Src and STEP recruitment is contingent on differing intracellular Ca2+ dynamics that dictate whether NMDAR function is augmented or depressed following M1R stimulation. PMID:27857196

Airway reactivity in response to repeated emotional film clip presentation in asthma.

PubMed

Janssens, Thomas; Steele, Ashton M; Rosenfield, David; Ritz, Thomas

2017-02-01

Emotional stimuli elicit airway constriction in individuals with asthma and in healthy individuals, but little is known about effects of repeated stimulation. We therefore explored the effect of repeated emotion induction on respiratory resistance (R rs ) using unpleasant, high-arousal surgery films and investigated effects of respiration and emotional reactivity. Twenty-six participants (13 with asthma) watched a series of 12 short, 45-s surgery films followed by 2-min recovery periods. R rs assessed with impulse oscillometry was significantly elevated during films in both groups compared to baseline and recovered quickly after that. No habituation of airway responses occurred. R rs was higher in participants who felt more aroused and less in control when watching the films. Changes in R rs remained significant when controlling for changes in respiration or emotional experience. Thus, although unpleasant stimuli lead to elevated R rs , airway obstruction is not exacerbated with repeated stimulation due to a fast return to baseline after stimulation. Copyright © 2016 Elsevier B.V. All rights reserved.

EEG Brain Wave Activity at Rest and during Evoked Attention in Children with Attention-Deficit/Hyperactivity Disorder and Effects of Methylphenidate.

PubMed

Thomas, Bianca Lee; Viljoen, Margaretha

2016-01-01

The aim of this study was to assess baseline EEG brain wave activity in children with attention-deficit/hyperactivity disorder (ADHD) and to examine the effects of evoked attention and methylphenidate on this activity. Children with ADHD (n = 19) were tested while they were stimulant free and during a period in which they were on stimulant (methylphenidate) medication. Control subjects (n = 18) were tested once. EEG brain wave activity was tested both at baseline and during focussed attention. Attention was evoked and EEG brain wave activity was determined by means of the BioGraph Infiniti biofeedback apparatus. The main finding of this study was that control subjects and stimulant-free children with ADHD exhibited the expected reactivity in high alpha-wave activity (11-12 Hz) from baseline to focussed attention; however, methylphenidate appeared to abolish this reactivity. Methylphenidate attenuates the normal cortical response to a cognitive challenge. © 2016 S. Karger AG, Basel.

Detection of proliferating cell nuclear antigens and interleukin-2 beta receptor molecules on mitogen- and antigen-stimulated lymphocytes.

PubMed Central

Hesketh, J; Dobbelaere, D; Griffin, J F; Buchan, G

1993-01-01

The expression of interleukin-2 receptors (IL-2R) and proliferating cell nuclear antigens (PCNA) were compared for their usefulness as markers of lymphocyte activation. Heterologous polyclonal (anti-bovine IL-2R) and monoclonal (anti-human PCNA) antibodies were used to detect the expression of these molecules on activated deer lymphocytes. Both molecules were co-expressed on blast cells which had been activated with mitogen [concanavalin A (Con A)]. There was detectable up-regulation of IL-2R expression in response to antigen [Mycobacterium bovis-derived purified protein derivative (PPD)] stimulation while PCNA expression mimicked lymphocyte transformation (LT) reactivity. PCNA expression was found to more accurately reflect both antigen- and mitogen-activated lymphocyte activation, as estimated by LT activity. The expression of PCNA was used to identify antigen reactive cells from animals exposed to M. bovis. A very low percentage (1.1 +/- 0.4%) of peripheral blood lymphocytes from non-infected animals could be stimulated to express PCNA by in vitro culture with antigen (PPD). Within the infected group both diseased and healthy, 'in-contact', animals expressed significantly higher levels of PCNA upon antigen stimulation. PMID:8104884

Patterned sensory nerve stimulation enhances the reactivity of spinal Ia inhibitory interneurons.

PubMed

Kubota, Shinji; Hirano, Masato; Morishita, Takuya; Uehara, Kazumasa; Funase, Kozo

2015-03-25

Patterned sensory nerve stimulation has been shown to induce plastic changes in the reciprocal Ia inhibitory circuit. However, the mechanisms underlying these changes have not yet been elucidated in detail. The aim of the present study was to determine whether the reactivity of Ia inhibitory interneurons could be altered by patterned sensory nerve stimulation. The degree of reciprocal Ia inhibition, the conditioning effects of transcranial magnetic stimulation (TMS) on the soleus (SOL) muscle H-reflex, and the ratio of the maximum H-reflex amplitude versus maximum M-wave (H(max)/M(max)) were examined in 10 healthy individuals. Patterned electrical nerve stimulation was applied to the common peroneal nerve every 1 s (100 Hz-5 train) at the motor threshold intensity of tibialis anterior muscle to induce activity changes in the reciprocal Ia inhibitory circuit. Reciprocal Ia inhibition, the TMS-conditioned H-reflex amplitude, and H(max)/M(max) were recorded before, immediately after, and 15 min after the electrical stimulation. The patterned electrical nerve stimulation significantly increased the degree of reciprocal Ia inhibition and decreased the amplitude of the TMS-conditioned H-reflex in the short-latency inhibition phase, which was presumably mediated by Ia inhibitory interneurons. However, it had no effect on H(max)/M(max). Our results indicated that patterned sensory nerve stimulation could modulate the activity of Ia inhibitory interneurons, and this change may have been caused by the synaptic modification of Ia inhibitory interneuron terminals. These results may lead to a clearer understanding of the spinal cord synaptic plasticity produced by repetitive sensory inputs. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Effects of transcranial direct current stimulation on craving, heart-rate variability and prefrontal hemodynamics during smoking cue exposure.

PubMed

Kroczek, A M; Häußinger, F B; Rohe, T; Schneider, S; Plewnia, C; Batra, A; Fallgatter, A J; Ehlis, A-C

2016-11-01

Drug-related cue exposure elicits craving and risk for relapse during recovery. Transcranial direct current stimulation is a promising research tool and possible treatment for relapse prevention. Enhanced functional neuroconnectivity is discussed as a treatment target. The goal of this research was to examine whether transcranial direct current stimulation affected cortical hemodynamic indicators of functional connectivity, craving, and heart rate variability during smoking-related cue exposure in non-treatment-seeking smokers. In vivo smoking cue exposure supported by a 2mA transcranial direct current stimulation (anode: dorsolateral prefrontal cortex, cathode: orbitofrontal cortex; placebo-controlled, randomized, double-blind) in 29 (age: M=25, SD=5) German university students (smoking at least once a week). Cue reactivity was assessed on an autonomous (heart rate variability) and a subjective level (craving ratings). Functional near-infrared spectroscopy measured changes in the concentration of deoxygenated hemoglobin, and seed-based correlation analysis was used to quantify prefrontal connectivity of brain regions involved in cue reactivity. Cue exposure elicited increased subjective craving and heart rate variability changes in smokers. Connectivity between the orbitofrontal and dorsolateral prefrontal cortex was increased in subjects receiving verum compared to placebo stimulation (d=0.66). Hemodynamics in the left dorsolateral prefrontal cortex, however, increased in the group receiving sham stimulation (η 2 =0.140). Transcranial direct current stimulation did not significantly alter craving or heart rate variability during cue exposure. Prefrontal connectivity - between regions involved in the processing of reinforcement value and cognitive control - was increased by anodal transcranial direct current stimulation during smoking cue exposure. Possible clinical implications should be considered in future studies. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

CMV retinitis recurs after stopping treatment in virological and immunological failures of potent antiretroviral therapy.

PubMed

Torriani, F J; Freeman, W R; Macdonald, J C; Karavellas, M P; Durand, D M; Jeffrey, D D; Meylan, P R; Schrier, R D

2000-01-28

To determine predictors of clinical relapse of cytomegalovirus (CMV) end-organ disease in a cohort of 17 HIV-infected patients with healed and treated CMV retinitis (CMVR) who responded to HAART with an increase in CD4 cell counts to above 70 cells/mm3 and discontinued CMV maintenance therapy (MT). Seventeen patients were monitored for reactivation of retinitis. The CD4 cell counts, HIV RNA and peripheral blood mononuclear cell (PBMC) lymphoproliferative assays to CMV at 3 month intervals were compared between patients with and without reactivation of CMVR. Positive lymphoproliferative responses were defined as a stimulation index of 3 or greater. Five out of 17 (29%) patients experienced a recurrence of CMVR a mean of 14.5 months after stopping CMV MT and between 8 days and 10 months after CD4 cell counts fell below 50 cells/mm3. Median CD4 cell counts and plasma HIV RNA at reactivation were 37 cells/mm3 and 5.3 log10 copies/ml. Three patients recurred at a previously active site of the retina, one had contralateral CMVR, and one a recurrence of retinitis and pancreatitis simultaneously. Mean lymphoproliferative responses to CMV were 2.4 in patients with reactivation versus 21.0 stimulation index (SI) in patients without reactivation (P= 0.01). A model incorporating four variables (CD4 cell counts and HIV RNA at maintenance discontinuation, highest CD4 cell count, nadir HIV RNA and median lymphoproliferative responses) identified correctly 88% of patients with and without reactivation. CMV disease recurs after virological and immunological failure of HAART if CD4 cell counts drop below 50. In this situation, anti-CMV agents should be resumed before clinical reactivation ensues, because of the risk of contralateral retinal involvement and systemic disease.

Stimulation of the human auditory nerve with optical radiation

NASA Astrophysics Data System (ADS)

Fishman, Andrew; Winkler, Piotr; Mierzwinski, Jozef; Beuth, Wojciech; Izzo Matic, Agnella; Siedlecki, Zygmunt; Teudt, Ingo; Maier, Hannes; Richter, Claus-Peter

2009-02-01

A novel, spatially selective method to stimulate cranial nerves has been proposed: contact free stimulation with optical radiation. The radiation source is an infrared pulsed laser. The Case Report is the first report ever that shows that optical stimulation of the auditory nerve is possible in the human. The ethical approach to conduct any measurements or tests in humans requires efficacy and safety studies in animals, which have been conducted in gerbils. This report represents the first step in a translational research project to initiate a paradigm shift in neural interfaces. A patient was selected who required surgical removal of a large meningioma angiomatum WHO I by a planned transcochlear approach. Prior to cochlear ablation by drilling and subsequent tumor resection, the cochlear nerve was stimulated with a pulsed infrared laser at low radiation energies. Stimulation with optical radiation evoked compound action potentials from the human auditory nerve. Stimulation of the auditory nerve with infrared laser pulses is possible in the human inner ear. The finding is an important step for translating results from animal experiments to human and furthers the development of a novel interface that uses optical radiation to stimulate neurons. Additional measurements are required to optimize the stimulation parameters.

[The effect of body immunological reactivity on the persistence of rickettsiae].

PubMed

Klimchuk, M D; Kurganova, I I; Kos, E T; Basarab, N I

1996-01-01

Correlation between the rate of seeding of organs by rickettsiae and duration of the exciter persistence and condition of immunological reactivity was established using the experimental rickettsial infection as a model. When using the preparation which stimulates the immunity indices, we have revealed that the number of rickettsiae in organs was less and the release from them was faster than under immunodepression.

Electroencephalographic reactivity testing in unconscious patients: a systematic review of methods and definitions.

PubMed

Admiraal, M M; van Rootselaar, A-F; Horn, J

2017-02-01

Electroencephalographic (EEG) reactivity testing is often presented as a clear-cut element of electrophysiological testing. Absence of EEG reactivity is generally considered an indicator of poor outcome, especially in patients after cardiac arrest. However, guidelines do not clearly describe how to test for reactivity and how to evaluate the results. In a quest for clear guidelines, we performed a systematic review aimed at identifying testing methods and definitions of EEG reactivity. We systematically searched the literature between 1970 and May 2016. Methodological quality of the studies was assessed using the QUality In Prognostic Studies tool. Quality of the descriptions of stimulus protocol and reactivity definition was rated on a four-category grading scale based on reproducibility. We found that protocols for EEG reactivity testing vary greatly and descriptions of protocols are almost never replicable. Furthermore, replicable definitions of presence or absence of EEG reactivity are never provided. In order to draw firm conclusions on EEG reactivity as a prognostic factor, future studies should include a precise stimulation protocol and reactivity definition to facilitate guideline formation. © 2016 EAN.

In situ formation of magnetite reactive barriers in soil for waste stabilization

DOEpatents

Moore, Robert C.

2003-01-01

Reactive barriers containing magnetite and methods for making magnetite reactive barriers in situ in soil for sequestering soil contaminants including actinides and heavy metals, organic materials, iodine and technetium are disclosed. According to one embodiment, a two-step reagent introduction into soil takes place. In the first step, free oxygen is removed from the soil by separately injecting into the soil aqueous solutions of iron (II) salt, for example FeCl.sub.2, and base, for example NaOH or NH.sub.3 in about a 1:1 volume ratio. Then, in the second step, similar reagents are injected a second time (however, according to about a 1:2 volume ratio, iron to salt) to form magnetite. The magnetite formation is facilitated, in part, due to slow intrusion of oxygen into the soil from the surface. The invention techniques are suited to injection of reagents into soil in proximity to a contamination plume or source allowing in situ formation of the reactive barrier at the location of waste or hazardous material. Mixing of reagents to form. precipitate is mediated and enhanced through movement of reagents in soil as a result of phenomena including capillary action, movement of groundwater, soil washing and reagent injection pressure.

Reactive Balance in Individuals With Chronic Stroke: Biomechanical Factors Related to Perturbation-Induced Backward Falling.

PubMed

Salot, Pooja; Patel, Prakruti; Bhatt, Tanvi

2016-03-01

An effective compensatory stepping response is the first line of defense for preventing a fall during sudden large external perturbations. The biomechanical factors that contribute to heightened fall risk in survivors of stroke, however, are not clearly understood. It is known that impending sensorimotor and balance deficits poststroke predispose these individuals to a risk of fall during sudden external perturbations. The purpose of this study was to examine the mechanism of fall risk in survivors of chronic stroke when exposed to sudden, slip-like forward perturbations in stance. This was a cross-sectional study. Fourteen individuals with stroke, 14 age-matched controls (AC group), and 14 young controls (YC group) were exposed to large-magnitude forward stance perturbations. Postural stability was computed as center of mass (COM) position (XCOM/BOS) and velocity (ẊCOM/BOS) relative to the base of support (BOS) at first step lift-off (LO) and touch-down (TD) and at second step TD. Limb support was quantified as vertical hip descent (Zhip) from baseline after perturbation onset. All participants showed a backward balance loss, with 71% of the stroke group experiencing a fall compared with no falls in the control groups (AC and YC groups). At first step LO, no between-group differences in XCOM/BOS and ẊCOM/BOS were noted. At first step TD, however, the stroke group had a significantly posterior XCOM/BOS and backward ẊCOM/BOS compared with the control groups. At second step TD, individuals with stroke were still more unstable (more posterior XCOM/BOS and backward ẊCOM/BOS) compared with the AC group. Individuals with stroke also showed greater peak Zhip compared with the control groups. Furthermore, the stroke group took a larger number of steps with shorter step length and delayed step initiation compared with the control groups. Although the study highlights the reactive balance deficits increasing fall risk in survivors of stroke compared with healthy adults, the study was restricted to individuals with chronic stroke only. It is likely that comparing compensatory stepping responses across different stages of recovery would enable clinicians to identify reactive balance deficits related to a specific stage of recovery. These findings suggest the inability of the survivors of stroke to regain postural stability with one or more compensatory steps, unlike their healthy counterparts. Such a response may expose them to a greater fall risk resulting from inefficient compensatory stepping and reduced vertical limb support. Therapeutic interventions for fall prevention, therefore, should focus on improving both reactive stepping and limb support. © 2016 American Physical Therapy Association.

Mechanical design and driving mechanism of an isokinetic functional electrical stimulation-based leg stepping trainer.

PubMed

Hamzaid, N A; Fornusek, C; Ruys, A; Davis, G M

2007-12-01

The mechanical design of a constant velocity (isokinetic) leg stepping trainer driven by functional electrical stimulation-evoked muscle contractions was the focus of this paper. The system was conceived for training the leg muscles of neurologically-impaired patients. A commercially available slider crank mechanism for elliptical stepping exercise was adapted to a motorized isokinetic driving mechanism. The exercise system permits constant-velocity pedalling at cadences of 1-60 rev x min(-1). The variable-velocity feature allows low pedalling forces for individuals with very weak leg muscles, yet provides resistance to higher pedalling effort in stronger patients. In the future, the system will be integrated with a computer-controlled neuromuscular stimulator and a feedback control unit to monitor training responses of spinal cord-injured, stroke and head injury patients.

[Supportive amblyopia treatment by means of computer games with background stimulation; a placebo controlled pilot study of 10 days].

PubMed

Kämpf, U; Muchamedjarow, F; Seiler, T

2001-04-01

Computer programmes for visual stimulation may give new impulses to the field of amblyopia treatment by offering an option to shift the apparative visual training into the domestic sphere. Regarding this aspect we report on a placebo controlled study on a newly developed vision training consisting of a background stimulation by a drifting sinusoidal grating combined with a foreground game aimed to maintain the attention. Fourteen amblyopia patients aged from 6 to 13 years participated in the study. Seven were allocated to a placebo and seven to a treatment group. Both groups had to train at the computer for a period of 10 working days by two sessions of about 20 minutes daily. Whilst the placebo group played in front of a neutral background, the treatment group did this with a drifting sinusoidal grating in the background. The treatment condition resulted in a greater increase of visual acuity than the placebo condition. Near vision improved in the treatment group from 0.20 (SD +/- 4.51 steps) to 0.39 (SD +/- 3.06 steps), i.e. by 3.0 steps of visual acuity (SD +/- 1.8 steps), in the placebo group from 0.14 (SD +/- 6.02 steps) to 0.17 (SD +/- 5.85 steps), i.e. by 0.8 steps of visual acuity (SD +/- 1.6 steps). Far vision improved in the treatment group from 0.29 (SD +/- 2.57 steps) to 0.44 (SD +/- 3.16 steps), i.e. by 1.9 steps of visual acuity (SD +/- 1.3 steps), in the placebo group from 0.24 (SD +/- 5.20 steps) to 0.28 (SD +/- 5.51 steps), i.e. by 0.7 steps of visual acuity (SD +/- 1.1 steps). Stimulation with drifting sinusoidal gratings improves the visual acuity of amblyopic eyes in a specific way. The effect might be accounted for by a synergy of spatial and temporal frequency in form vs. motion channels. A preliminary hypothesis is discussed and will be the subject of ongoing research. The presented method has been developed for the treatment of "delayed" amblyopia in the elder child. It is aimed to support and complement occlusion therapy. However, the reported results obtained over 10 days should be estimated only within the context of evaluation. By no means should the results be interpreted as a renewed pledge for a short-term treatment of amblyopia.

Reactivation and upgrade of the NASA Ames 16-Inch Shock Tunnel - Status report

NASA Technical Reports Server (NTRS)

Bogdanoff, David W.; Zambrana, Horacio A.; Cavolowsky, John A.; Newfield, Mark E.; Cornelison, Charles J.; Miller, Robert J.

1992-01-01

The NASA Ames 16-Inch Shock Tunnel has been reactivated after seventeen years of inactivity. In the years before deactivating the facility, it was operated at enthalpies of 4,700 J/gm and pressures up to 260 atm or at enthalpies of 1900 J/gm over a wide pressure range. Since reactivating, the facility has been operated at enthalpies up to 12,000 J/gm and pressures up to 408 atm. The present paper describes the steps taken in upgrading the facility and summarizes the currently achievable conditions. The selection of the driver gas, the steps taken to improve the driver burn, and the diaphragm opening techniques are described. The pressure and heat flux instrumentation, the optical diagnostics and the data acquisition system are also described.

tif-Stimulated deoxyribonucleic acid repair in Escherichia coli K-12.

PubMed Central

Castellazzi, M; Jacques, M; George, J

1980-01-01

Bacterial survival is significantly increased after ultraviolet irradiation in tif sfi cells, provided that the thermosensitive tif mutation has been expressed at 41 degrees C before irradiation. This tif-mediated "reactivation of ultraviolet irradiated bacteria" needs de novo protein synthesis, as is the case for the tif-mediated reactivation of ultraviolet-irradiated phage lambda. However, in striking contrast to the phage reactivation process, this tif-mediated reactivation is no longer associated with mutagenesis. It also requires the presence of the uvrA+ excision function. These results strongly suggest the existence in Escherichia coli K-12 of a repair pathway acting on bacterial deoxyribonucleic acid which is inducible, error free, and uvr dependent. PMID:6451614

Using cheminformatics to predict cross reactivity of “designer drugs” to their currently available immunoassays

PubMed Central

2014-01-01

Background A challenge for drug of abuse testing is presented by ‘designer drugs’, compounds typically discovered by modifications of existing clinical drug classes such as amphetamines and cannabinoids. Drug of abuse screening immunoassays directed at amphetamine or methamphetamine only detect a small subset of designer amphetamine-like drugs, and those immunoassays designed for tetrahydrocannabinol metabolites generally do not cross-react with synthetic cannabinoids lacking the classic cannabinoid chemical backbone. This suggests complexity in understanding how to detect and identify whether a patient has taken a molecule of one class or another, impacting clinical care. Methods Cross-reactivity data from immunoassays specifically targeting designer amphetamine-like and synthetic cannabinoid drugs was collected from multiple published sources, and virtual chemical libraries for molecular similarity analysis were built. The virtual library for synthetic cannabinoid analysis contained a total of 169 structures, while the virtual library for amphetamine-type stimulants contained 288 compounds. Two-dimensional (2D) similarity for each test compound was compared to the target molecule of the immunoassay undergoing analysis. Results 2D similarity differentiated between cross-reactive and non-cross-reactive compounds for immunoassays targeting mephedrone/methcathinone, 3,4-methylenedioxypyrovalerone, benzylpiperazine, mephentermine, and synthetic cannabinoids. Conclusions In this study, we applied 2D molecular similarity analysis to the designer amphetamine-type stimulants and synthetic cannabinoids. Similarity calculations can be used to more efficiently decide which drugs and metabolites should be tested in cross-reactivity studies, as well as to design experiments and potentially predict antigens that would lead to immunoassays with cross reactivity for a broader array of designer drugs. PMID:24851137

Measurement of Reactive Oxygen Species in the Culture Media Using Acridan Lumigen PS-3 Assay

PubMed Central

Uy, Benedict; McGlashan, Susan R.; Shaikh, Shamim B.

2011-01-01

Reactive oxygen species (ROS) are generated continuously during aerobic metabolism. ROS are highly reactive molecules and in excessive amounts, can lead to protein and DNA oxidation, protein cross-linking, and cell death. Cell-culture models provide a valuable tool in understanding the mechanisms that lead to cell death. Accumulation of ROS within cells and/or their release into the culture media are highly cell type-specific. The ability to estimate ROS levels in the culture media is an important step in understanding the mechanisms contributing to disease processes. In this paper, we describe the optimization of a simple method to estimate ROS levels in the culture media using the Acridan Lumigen PS-3 reagent provided in the Amersham ECL Plus kit (GE Healthcare, UK). We have shown that the Acridan Lumigen PS-3 assay generates ROS-specific chemiluminescence in fresh as well as media stored at −20°C, in as little as 10–20 μl of samples. The method was able to detect the dose (of stimulants)- and time (acute and chronic)-dependent changes in ROS levels in media collected from various cell types. Our results suggest that the kit reagents, PBS buffer, and various media did not contribute significantly to the overall chemiluminescence generated in the assay; however, we suggest that the unused medium specific for each cell type should be used as blanks and final readings of test samples normalized against these readings. As this method uses commonly available laboratory equipment and commercially available reagents, we believe this assay is convenient, economical, and specific in estimating ROS released extracellularly into the culture media. PMID:21966257

Measurement of reactive oxygen species in the culture media using Acridan Lumigen PS-3 assay.

PubMed

Uy, Benedict; McGlashan, Susan R; Shaikh, Shamim B

2011-09-01

Reactive oxygen species (ROS) are generated continuously during aerobic metabolism. ROS are highly reactive molecules and in excessive amounts, can lead to protein and DNA oxidation, protein cross-linking, and cell death. Cell-culture models provide a valuable tool in understanding the mechanisms that lead to cell death. Accumulation of ROS within cells and/or their release into the culture media are highly cell type-specific. The ability to estimate ROS levels in the culture media is an important step in understanding the mechanisms contributing to disease processes. In this paper, we describe the optimization of a simple method to estimate ROS levels in the culture media using the Acridan Lumigen PS-3 reagent provided in the Amersham ECL Plus kit (GE Healthcare, UK). We have shown that the Acridan Lumigen PS-3 assay generates ROS-specific chemiluminescence in fresh as well as media stored at -20°C, in as little as 10-20 μl of samples. The method was able to detect the dose (of stimulants)- and time (acute and chronic)-dependent changes in ROS levels in media collected from various cell types. Our results suggest that the kit reagents, PBS buffer, and various media did not contribute significantly to the overall chemiluminescence generated in the assay; however, we suggest that the unused medium specific for each cell type should be used as blanks and final readings of test samples normalized against these readings. As this method uses commonly available laboratory equipment and commercially available reagents, we believe this assay is convenient, economical, and specific in estimating ROS released extracellularly into the culture media.

Association of BDNF Val66Met polymorphism with HPA and SAM axis reactivity to psychological and physical stress.

PubMed

Tsuru, Jusen; Tanaka, Yoshihiro; Ishitobi, Yoshinobu; Maruyama, Yoshihiro; Inoue, Ayako; Kawano, Aimi; Ikeda, Rie; Ando, Tomoko; Oshita, Harumi; Aizawa, Saeko; Masuda, Koji; Higuma, Haruka; Kanehisa, Masayuki; Ninomiya, Taiga; Akiyoshi, Jotaro

2014-01-01

Decreased expression of brain-derived neurotrophic factor (BDNF) is implicated in enhanced stress responses. The BDNF Val66Met polymorphism is associated with psychological changes; for example, carriers of the Met allele exhibit increased harm avoidance as well as a higher prevalence of depression and anxiety disorder. To analyze the effects of BDNF Val66Met on stress responses, we tested 226 university students (88 women and 138 men) using a social stress procedure (Trier Social Stress Test [TSST]) and an electrical stimulation stress test. Stress indices were derived from repeated measurements of salivary α-amylase, salivary cortisol, heart rate, and psychological testing during the stress tests. All subjects were genotyped for the Val66Met polymorphism (G196A). A significant three-way interaction (time [3 levels] × BDNF [Val/Val, Val/Met, Met/Met]; P<0.05) was demonstrated that revealed different salivary cortisol responses in the TSST but not in electrical stimulation. Met/Met women had stronger cortisol responses than Val/Met and Val/Val individuals in the TSST. Met/Met men exhibited stronger salivary cortisol responses than Val/Met and Val/Val individuals in the TSST. These results indicate that a common, functionally significant polymorphism in BDNF had different effects on hypothalamic-pituitary-adrenocortical axis reactivity but not on sympathetic adrenomedullary reactivity in TSST and electrical stimulation tests.

BEARKIMPE-2: A VBA Excel program for characterizing granular iron in treatability studies

NASA Astrophysics Data System (ADS)

Firdous, R.; Devlin, J. F.

2014-02-01

The selection of a suitable kinetic model to investigate the reaction rate of a contaminant with granular iron (GI) is essential to optimize the permeable reactive barrier (PRB) performance in terms of its reactivity. The newly developed Kinetic Iron Model (KIM) determines the surface rate constant (k) and sorption parameters (Cmax &J) which were not possible to uniquely identify previously. The code was written in Visual Basic (VBA), within Microsoft Excel, was adapted from earlier command line FORTRAN codes, BEARPE and KIMPE. The program is organized with several user interface screens (UserForms) that guide the user step by step through the analysis. BEARKIMPE-2 uses a non-linear optimization algorithm to calculate transport and chemical kinetic parameters. Both reactive and non-reactive sites are considered. A demonstration of the functionality of BEARKIMPE-2, with three nitroaromatic compounds showed that the differences in reaction rates for these compounds could be attributed to differences in their sorption behavior rather than their propensities to accept electrons in the reduction process.

Responsive behavior of regenerated cellulose in hydrolysis under microwave radiation.

PubMed

Ni, Jinping; Na, Haining; She, Zhen; Wang, Jinggang; Xue, Wenwen; Zhu, Jin

2014-09-01

This work studied the responsive behavior of regenerated cellulose (RC) in hydrolysis under microwave radiation. Four types of RC with different crystallinity (Cr) and degree of polymerization (DP) are produced to evaluate the reactivity of RC by step-by-step hydrolysis. Results show Cr is the key factor to affect the reactivity of RCs. With hydrolysis of amorphous region and the formation of recrystallization, the Cr of RC reaches a high value and thus weakens the reactivity. As a result, the increment of cellulose conversion and sugar yield gradually reduces. Decrease of the DP of RC is helpful to increase the speed at the onset of hydrolysis and produce high sugar yield. But, there is no direct influence with the reactivity of RC to prolong the time of pretreatment. This research provides an accurate understanding to guide the RC preparation for sugar formation with relative high efficiency under mild reaction conditions. Copyright © 2014 Elsevier Ltd. All rights reserved.

Gain of postural responses increases in response to real and anticipated pain.

PubMed

Hodges, Paul W; Tsao, Henry; Sims, Kevin

2015-09-01

This study tested two contrasting theories of adaptation of postural control to pain. One proposes alteration to the postural strategy including inhibition of muscles that produce painful movement; another proposes amplification of the postural adjustment to recruit strategies normally reserved for higher load. This study that aimed to determine which of these alternatives best explains pain-related adaptation of the hip muscle activity associated with stepping down from steps of increasing height adaptation of postural control to increasing load was evaluated from hip muscle electromyography (fine-wire and surface electrodes) as ten males stepped from steps of increasing height (i.e. increasing load). In one set of trials, participants stepped from a low step (5 cm) and pain was induced by noxious electrical stimulation over the sacrum triggered from foot contact with a force plate or was anticipated. Changes in EMG amplitude and onset timing were compared between conditions. Hip muscle activation was earlier and larger when stepping from higher steps. Although ground reaction forces (one of the determinants of joint load) were unchanged before, during and after pain, trials with real or anticipated noxious stimulation were accompanied by muscle activity indistinguishable from that normally reserved for higher steps (EMG amplitude increased from 9 to 17 % of peak). These data support the notion that muscle activation for postural control is augmented when challenged by real/anticipated noxious stimulation. Muscle activation was earlier and greater than that required for the task and is likely to create unnecessary joint loading. This could have long-term consequences if maintained.

Activation of sperm EGFR by light irradiation is mediated by reactive oxygen species.

PubMed

Shahar, Shiran; Hillman, Pnina; Lubart, Rachel; Ickowicz, Debby; Breitbart, Haim

2014-01-01

To acquire fertilization competence, spermatozoa must undergo several biochemical and motility changes in the female reproductive tract, collectively called capacitation. Actin polymerization and the development of hyperactivated motility (HAM) are part of the capacitation process. In a recent study, we showed that irradiation of human sperm with visible light stimulates HAM through a mechanism involving reactive-oxygen-species (ROS), Ca(2+) influx, protein kinases A (PKA), and sarcoma protein kinase (Src). Here, we showed that this effect of light on HAM is mediated by ROS-dependent activation of the epidermal growth factor receptor (EGFR). Interestingly, ROS-mediated HAM even when the EGFR was activated by EGF, the physiological ligand of EGFR. Light irradiation stimulated ROS-dependent actin polymerization, and this effect was abrogated by PBP10, a peptide which activates the actin-severing protein, gelsolin, and causes actin-depolymerization in human sperm. Light-stimulated tyrosine phosphorylation of Src-dependent gelsolin, resulting in enhanced HAM. Thus, light irradiation stimulates HAM through a mechanism involving Src-mediated actin polymerization. Light-stimulated HAM and in vitro-fertilization (IVF) rate in mouse sperm, and these effects were mediated by ROS and EGFR. In conclusion, we show here that irradiation of sperm with visible light, enhances their fertilization capacity via a mechanism requiring ROS, EGFR and HAM. © 2014 The American Society of Photobiology.

EVOLUTION OF THE IMMUNE RESPONSE

PubMed Central

Papermaster, Ben W.; Condie, Richard M.; Finstad, Joanne; Good, Robert A.

1964-01-01

1. The California hagfish, Eptatretus stoutii, seems to be completely lacking in adaptive immunity: it forms no detectable circulating antibody despite intensive stimulation with a range of antigens; it does not show reactivity to old tuberculin following sensitization with BCG; and gives no evidence of homograft immunity. 2. Studies on the sea lamprey, Petromyzon marinus, have been limited to the response to bacteriophage T2 and hemocyanin in small groups of spawning animals. They suggest that the lamprey may have a low degree of immunologic reactivity. 3. One holostean, the bowfin (Amia calva) and the guitarfish (Rhinobatos productus), an elasmobranch, showed a low level of primary response to phage and hemocyanin. The response is slow and antibody levels low. Both the bowfin and the guitarfish showed a vigorous secondary response to phage, but neither showed much enhancement of reactivity to hemocyanin in the secondary response. The bowfin formed precipitating antibody to hemocyanin, but the guitarfish did not. Both hemagglutinating and precipitating antibody to hemocyanin were also observed in the primary response of the black bass. 4. The bowfin was successfully sensitized to Ascaris antigen, and lesions of the delayed type developed after challenge at varying intervals following sensitization. 5. The horned shark (Heterodontus franciscii) regularly cleared hemocyanin from the circulation after both primary and secondary antigenic stimulation, and regularly formed hemagglutinating antibody, but not precipitating antibody, after both primary and secondary stimulation with this antigen. These animals regularly cleared bacteriophage from the circulation after both the primary and secondary stimulation with bacteriophage T2. Significant but small amounts of antibody were produced in a few animals in the primary response, and larger amounts in the responding animals after secondary antigenic stimulation. 6. Studies by starch gel and immunoelectrophoresis show that the hagfish has no bands with mobilities of mammalian gamma globulins; that the lamprey has a single, relatively faint band of this type; and that multiple gamma bands are characteristic of the holostean, elasmobranchs, and teleosts studied. By this method of study, the bowfin appeared to have substantial amounts of gamma2 globulin. 7. We conclude that adaptive immunity and its cellular and humoral correlates developed in the lowest vertebrates, and that a rising level of immunologic reactivity and an increasingly differentiated and complex immunologic mechanism are observed going up the phylogenetic scale from the hagfish, to the lamprey, to the elasmobranchs, to the holosteans, and finally the teleosts. PMID:14113107

Generation of reactive oxygen species (ROS) is a key factor for stimulation of macrophage proliferation by ceramide 1-phosphate

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

Arana, Lide; Gangoiti, Patricia; Ouro, Alberto

2012-02-15

We previously demonstrated that ceramide 1-phosphate (C1P) is mitogenic for fibroblasts and macrophages. However, the mechanisms involved in this action were only partially described. Here, we demonstrate that C1P stimulates reactive oxygen species (ROS) formation in primary bone marrow-derived macrophages, and that ROS are required for the mitogenic effect of C1P. ROS production was dependent upon prior activation of NADPH oxidase by C1P, which was determined by measuring phosphorylation of the p40phox subunit and translocation of p47phox from the cytosol to the plasma membrane. In addition, C1P activated cytosolic calcium-dependent phospholipase A{sub 2} and protein kinase C-{alpha}, and NADPH oxidasemore » activation was blocked by selective inhibitors of these enzymes. These inhibitors, and inhibitors of ROS production, blocked the mitogenic effect of C1P. By using BHNB-C1P (a photolabile caged-C1P analog), we demonstrate that all of these C1P actions are caused by intracellular C1P. It can be concluded that the enzyme responsible for C1P-stimulated ROS generation in bone marrow-derived macrophages is NADPH oxidase, and that this enzyme is downstream of PKC-{alpha} and cPLA{sub 2}-{alpha} in this pathway. -- Highlights: Black-Right-Pointing-Pointer Ceramide 1-phosphate (C1P) stimulates reactive oxygen species (ROS) formation. Black-Right-Pointing-Pointer The enzyme responsible for ROS generation by C1P in macrophages is NADPH oxidase. Black-Right-Pointing-Pointer NADPH oxidase lies downstream of cPLA{sub 2}-{alpha} and PKC-{alpha} in this pathway. Black-Right-Pointing-Pointer ROS generation is essential for the stimulation of macrophage proliferation by C1P.« less

Low cytomegalovirus-specific T-cell counts at reactivation are associated with progression to high-level viremia or disease in seropositive recipients of hematopoietic cell grafts from seropositive but not seronegative donors.

PubMed

Hoegh-Petersen, Mette; Roa, Lina; Liu, Yiping; Zhou, Feng; Ugarte-Torres, Alejandra; Louie, Polly; Fonseca, Kevin; Khan, Faisal; Russell, James A; Storek, Jan

2012-02-01

Identifying patients who spontaneously resolve cytomegalovirus (CMV) reactivation could spare these patients from the toxicity of antiviral drugs such as ganciclovir. The role of CMV-specific T cells in clearing CMV viremia in patients who do not receive ganciclovir has not been evaluated. We assessed this in patients with CMV viremia between 50 and 50 000 genome copies/mL, because our threshold for initiating ganciclovir is 50 000 copies/mL. We enumerated CMV-specific T cells in 39 CMV seropositive hematopoietic cell transplantation (HCT) recipients within 4 days of the first positive CMV polymerase chain reaction (PCR). CMV-specific T cells were defined as cells that upon stimulation with CMV lysate or pp65 overlapping peptides produced interferon (IFN)-γ, tumor necrosis factor (TNF)-α or interleukin (IL)-2, alone or in combination. Among Donor (D+), Recipient (R+) patients, unifunctional CMV-specific CD4 T-cells were higher in patients who spontaneously resolved CMV viremia (did not receive ganciclovir) versus those who progressed (received ganciclovir) (median 0.20 versus 0.02/μL lysate-stimulated cells, P < 0.05, and 0.26 versus 0.05/μL pp65 peptide-stimulated cells, P<0.05). Among D- R+ patients, there was no difference between patients with spontaneous resolution or progression; all subsets of CMV-specific T cells measured were barely detectable, in both patients with spontaneous resolution and those with progression. Among D+ R+ patients (but not D- R+ patients), high CMV-specific CD4 T-cell counts identify patients who can spontaneously resolve CMV reactivation. In D- R+ patients, immune mechanisms other than T cells may control the progression from reactivation to high-level viremia/disease.

Reactive hyperemia is not responsible for stimulating muscle protein synthesis following blood flow restriction exercise

PubMed Central

Gundermann, David M.; Fry, Christopher S.; Dickinson, Jared M.; Walker, Dillon K.; Timmerman, Kyle L.; Drummond, Micah J.; Volpi, Elena

2012-01-01

Blood flow restriction (BFR) to contracting skeletal muscle during low-intensity resistance exercise training increases muscle strength and size in humans. However, the mechanism(s) underlying these effects are largely unknown. We have previously shown that mammalian target of rapamycin complex 1 (mTORC1) signaling and muscle protein synthesis (MPS) are stimulated following an acute bout of BFR exercise. The purpose of this study was to test the hypothesis that reactive hyperemia is the mechanism responsible for stimulating mTORC1 signaling and MPS following BFR exercise. Six young men (24 ± 2 yr) were used in a randomized crossover study consisting of two exercise trials: low-intensity resistance exercise with BFR (BFR trial) and low-intensity resistance exercise with sodium nitroprusside (SNP), a pharmacological vasodilator infusion into the femoral artery immediately after exercise to simulate the reactive hyperemia response after BFR exercise (SNP trial). Postexercise mixed-muscle fractional synthetic rate from the vastus lateralis increased by 49% in the BFR trial (P < 0.05) with no change in the SNP trial (P > 0.05). BFR exercise increased the phosphorylation of mTOR, S6 kinase 1, ribosomal protein S6, ERK1/2, and Mnk1-interacting kinase 1 (P < 0.05) with no changes in mTORC1 signaling in the SNP trial (P > 0.05). We conclude that reactive hyperemia is not a primary mechanism for BFR exercise-induced mTORC1 signaling and MPS. Further research is necessary to elucidate the cellular mechanism(s) responsible for the increase in mTOR signaling, MPS, and hypertrophy following acute and chronic BFR exercise. PMID:22362401

Reactive hyperemia is not responsible for stimulating muscle protein synthesis following blood flow restriction exercise.

PubMed

Gundermann, David M; Fry, Christopher S; Dickinson, Jared M; Walker, Dillon K; Timmerman, Kyle L; Drummond, Micah J; Volpi, Elena; Rasmussen, Blake B

2012-05-01

Blood flow restriction (BFR) to contracting skeletal muscle during low-intensity resistance exercise training increases muscle strength and size in humans. However, the mechanism(s) underlying these effects are largely unknown. We have previously shown that mammalian target of rapamycin complex 1 (mTORC1) signaling and muscle protein synthesis (MPS) are stimulated following an acute bout of BFR exercise. The purpose of this study was to test the hypothesis that reactive hyperemia is the mechanism responsible for stimulating mTORC1 signaling and MPS following BFR exercise. Six young men (24 ± 2 yr) were used in a randomized crossover study consisting of two exercise trials: low-intensity resistance exercise with BFR (BFR trial) and low-intensity resistance exercise with sodium nitroprusside (SNP), a pharmacological vasodilator infusion into the femoral artery immediately after exercise to simulate the reactive hyperemia response after BFR exercise (SNP trial). Postexercise mixed-muscle fractional synthetic rate from the vastus lateralis increased by 49% in the BFR trial (P < 0.05) with no change in the SNP trial (P > 0.05). BFR exercise increased the phosphorylation of mTOR, S6 kinase 1, ribosomal protein S6, ERK1/2, and Mnk1-interacting kinase 1 (P < 0.05) with no changes in mTORC1 signaling in the SNP trial (P > 0.05). We conclude that reactive hyperemia is not a primary mechanism for BFR exercise-induced mTORC1 signaling and MPS. Further research is necessary to elucidate the cellular mechanism(s) responsible for the increase in mTOR signaling, MPS, and hypertrophy following acute and chronic BFR exercise.

Stability of gas atomized reactive powders through multiple step in-situ passivation

DOEpatents

Anderson, Iver E.; Steinmetz, Andrew D.; Byrd, David J.

2017-05-16

A method for gas atomization of oxygen-reactive reactive metals and alloys wherein the atomized particles are exposed as they solidify and cool in a very short time to multiple gaseous reactive agents for the in-situ formation of a protective reaction film on the atomized particles. The present invention is especially useful for making highly pyrophoric reactive metal or alloy atomized powders, such as atomized magnesium and magnesium alloy powders. The gaseous reactive species (agents) are introduced into the atomization spray chamber at locations downstream of a gas atomizing nozzle as determined by the desired powder or particle temperature for the reactions and the desired thickness of the reaction film.

Fracture Evolution Following a Hydraulic Stimulation within an EGS Reservoir

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

Mella, Michael

The objective of this project was to develop and demonstrate an approach for tracking the evolution of circulation immediately following a hydraulic stimulation in an EGS reservoir. Series of high-resolution tracer tests using conservative and thermally reactive tracers were designed at recently created EGS reservoirs in order to track changes in fluid flow parameters such as reservoir pore volume, flow capacity, and effective reservoir temperature over time. Data obtained from the project would be available for the calibration of reservoir models that could serve to predict EGS performance following a hydraulic stimulation.

[Metronome therapy in patients with Parkinson disease].

PubMed

Enzensberger, W; Oberländer, U; Stecker, K

1997-12-01

We studied 10 patients with Parkinson's disease and 12 patients with Parkinson-plus-syndrome, trying to improve patients' gait by application of various external rhythmic stimuli, including metronome stimulation (96 beats per minute = middle andante). The test course of the patients was 4 x 10 meters and 3 U-turns. The patients' gait quality under stimulation was compared with their free walk (velocity, number of steps, number of freezing episodes). Metronome stimulation significantly reduced the time and number of steps needed for the test course and also diminished the number of freezing episodes. March music stimulation was less effective and tactile stimulation (rhythmically tapping on the patient's shoulder) even produced negative results. The positive effect of metronome stimulation was also found, when the tests were not performed inside the hospital building, but outside in the hospital parc. Metronome stimulation was comparably effective in both patient sub-groups examined in this study (M. Parkinson, Parkinson-plus-syndrome) and seems to be an important additional help in the treatment of these patients. Electronical metronomes are not expensive, easy in handling, and portable. A theoretical explanation of metronome stimulation effectivity in patients with Parkinson's disease still needs to be elucidated.

Two-step tunneling technique of deep brain stimulation extension wires-a description.

PubMed

Fontaine, Denys; Vandersteen, Clair; Saleh, Christian; von Langsdorff, Daniel; Poissonnet, Gilles

2013-12-01

While a significant body of literature exists on the intracranial part of deep brain stimulation surgery, the equally important second part of the intervention related to the subcutaneous tunneling of deep brain stimulation extension wires is rarely described. The tunneling strategy can consist of a single passage of the extension wires from the frontal incision site to the subclavicular area, or of a two-step approach that adds a retro-auricular counter-incision. Each technique harbors the risk of intraoperative and postoperative complications. At our center, we perform a two-step tunneling procedure that we developed based on a cadaveric study. In 125 consecutive patients operated since 2002, we did not encounter any complication related to our tunneling method. Insufficient data exist to fully evaluate the advantages and disadvantages of each tunneling technique. It is of critical importance that authors detail their tunneling modus operandi and report the presence or absence of complications. This gathered data pool may help to formulate a definitive conclusions on the safest method for subcutaneous tunneling of extension wires in deep brain stimulation.

Investigating the Role of TNF-α and IFN-γ Activation on the Dynamics of iNOS Gene Expression in LPS Stimulated Macrophages.

PubMed

Salim, Taha; Sershen, Cheryl L; May, Elebeoba E

2016-01-01

Macrophage produced inducible nitric oxide synthase (iNOS) is known to play a critical role in the proinflammatory response against intracellular pathogens by promoting the generation of bactericidal reactive nitrogen species. Robust and timely production of nitric oxide (NO) by iNOS and analogous production of reactive oxygen species are critical components of an effective immune response. In addition to pathogen associated lipopolysaccharides (LPS), iNOS gene expression is dependent on numerous proinflammatory cytokines in the cellular microenvironment of the macrophage, two of which include interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α). To understand the synergistic effect of IFN-γ and TNF-α activation, and LPS stimulation on iNOS expression dynamics and NO production, we developed a systems biology based mathematical model. Using our model, we investigated the impact of pre-infection cytokine exposure, or priming, on the system. We explored the essentiality of IFN-γ priming to the robustness of initial proinflammatory response with respect to the ability of macrophages to produce reactive species needed for pathogen clearance. Results from our theoretical studies indicated that IFN-γ and subsequent activation of IRF1 are essential in consequential production of iNOS upon LPS stimulation. We showed that IFN-γ priming at low concentrations greatly increases the effector response of macrophages against intracellular pathogens. Ultimately the model demonstrated that although TNF-α contributed towards a more rapid response time, measured as time to reach maximum iNOS production, IFN-γ stimulation was significantly more significant in terms of the maximum expression of iNOS and the concentration of NO produced.

Effects of Pseudomonas aeruginosa virulence factor pyocyanin on human urothelial cell function and viability.

PubMed

McDermott, Catherine; Chess-Williams, Russ; Grant, Gary D; Perkins, Anthony V; McFarland, Amelia J; Davey, Andrew K; Anoopkumar-Dukie, Shailendra

2012-03-01

We determined the effects of Pseudomonas aeruginosa virulence factor pyocyanin on human urothelial cell viability and function in vitro. RT4 urothelial cells were treated with pyocyanin (1 to 100 μM) for 24 hours. After exposure the treatment effects were measured according to certain end points, including changes in urothelial cell viability, reactive oxygen species formation, caspase-3 activity, basal and stimulated adenosine triphosphate release, SA-β-gal activity and detection of acidic vesicular organelles. The 24-hour pyocyanin treatment resulted in a concentration dependent decrease in cell viability at concentrations of 25 μM or greater, and increases in reactive oxygen species formation and caspase-3 activity at 25 μM or greater. Basal adenosine triphosphate release was significantly decreased at all tested pyocyanin concentrations while stimulated adenosine triphosphate release was significantly inhibited at pyocyanin concentrations of 12.5 μM or greater with no significant stimulated release at 100 μM. Pyocyanin treated RT4 cells showed morphological characteristics associated with cellular senescence, including SA-β-gal expression. This effect was not evident at 100 μM pyocyanin and may have been due to apoptotic cell death, as indicated by increased caspase-3 activity. An increase in acridine orange stained vesicular-like organelles was observed in RT4 urothelial cells after pyocyanin treatment. Exposure to pyocyanin alters urothelial cell viability, reactive oxygen species production and caspase-3 activity. Treatment also results in cellular senescence, which may affect the ability of urothelium to repair during infection. The virulence factor depressed stimulated adenosine triphosphate release, which to our knowledge is a novel finding with implications for awareness of bladder filling in patients with P. aeruginosa urinary tract infection. Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Photovoltaic retinal prosthesis for restoring sight to the blind: implant design and fabrication

NASA Astrophysics Data System (ADS)

Wang, Lele; Mathieson, Keith; Kamins, Theodore I.; Loudin, James; Galambos, Ludwig; Harris, James S.; Palanker, Daniel

2012-03-01

We have designed and fabricated a silicon photodiode array for use as a subretinal prosthesis aimed at restoring sight to patients who lost photoreceptors due to retinal degeneration. The device operates in photovoltaic mode. Each pixel in the two-dimensional array independently converts pulsed infrared light into biphasic electric current to stimulate remaining retinal neurons without a wired power connection. To enhance the maximum voltage and charge injection levels, each pixel contains three photodiodes connected in series. An active and return electrode in each pixel ensure localized current flow and are sputter coated with iridium oxide to provide high charge injection. The fabrication process consists of eight mask layers and includes deep reactive ion etching, oxidation, and a polysilicon trench refill for in-pixel photodiode separation and isolation of adjacent pixels. Simulation of design parameters included TSUPREM4 computation of doping profiles for n+ and p+ doped regions and MATLAB computation of the anti-reflection coating layers thicknesses. The main process steps are illustrated in detail, and problems encountered are discussed. The IV characterization of the device shows that the dark reverse current is on the order of 10-100 pA-negligible compared to the stimulation current; the reverse breakdown voltage is higher than 20 V. The measured photo-responsivity per photodiode is about 0.33A/W at 880 nm.

Mechanism of short-term ERK activation by electromagnetic fields at mobile phone frequencies

PubMed Central

Friedman, Joseph; Kraus, Sarah; Hauptman, Yirmi; Schiff, Yoni; Seger, Rony

2007-01-01

The exposure to non-thermal microwave electromagnetic fields generated by mobile phones affects the expression of many proteins. This effect on transcription and protein stability can be mediated by the MAPK (mitogen-activated protein kinase) cascades, which serve as central signalling pathways and govern essentially all stimulated cellular processes. Indeed, long-term exposure of cells to mobile phone irradiation results in the activation of p38 as well as the ERK (extracellular-signal-regulated kinase) MAPKs. In the present study, we have studied the immediate effect of irradiation on the MAPK cascades, and found that ERKs, but not stress-related MAPKs, are rapidly activated in response to various frequencies and intensities. Using signalling inhibitors, we delineated the mechanism that is involved in this activation. We found that the first step is mediated in the plasma membrane by NADH oxidase, which rapidly generates ROS (reactive oxygen species). These ROS then directly stimulate MMPs (matrix metalloproteinases) and allow them to cleave and release Hb-EGF [heparin-binding EGF (epidermal growth factor)]. This secreted factor activates the EGF receptor, which in turn further activates the ERK cascade. Thus this study demonstrates for the first time a detailed molecular mechanism by which electromagnetic irradiation from mobile phones induces the activation of the ERK cascade and thereby induces transcription and other cellular processes. PMID:17456048

Involvement of mitogen-activated protein kinase activation in the signal-transduction pathways of the soya bean oxidative burst.

PubMed Central

Taylor, A T; Kim, J; Low, P S

2001-01-01

The oxidative burst constitutes one of the most rapid defence responses characterized in the Plant Kingdom. We have observed that four distinct elicitors of the soya bean oxidative burst activate kinases of masses approximately 44 kDa and approximately 47 kDa. Evidence that these kinases regulate production of reactive oxygen species include: (i) their rapid activation by oxidative burst elicitors, (ii) their tight temporal correlation between activation/deactivation of the kinases and activation/deactivation of the oxidative burst, (iii) the identical pharmacological profile of kinase activation and oxidant production for 13 commonly used inhibitors, and (iv) the autologous activation of both kinases and oxidant production by calyculin A and cantharidin, two phosphatase inhibitors. Immunological and biochemical studies reveal that the activated 44 kDa and 47 kDa kinases are mitogen-activated protein (MAP) kinase family members. The kinases prefer myelin basic protein as a substrate, and they phosphorylate primarily on threonine residues. The kinases are themselves phosphorylated on tyrosine residues, and this phosphorylation is required for activity. Finally, both kinases are recognized by an antibody against activated MAP kinase immediately after (but not before) cell stimulation by elicitors. Based on these and other observations, a preliminary sequence of signalling steps linking elicitor stimulation, kinase activation and Ca(2+) entry, to initiation of oxidant production, is proposed. PMID:11311144

Lactobacillus delbrueckii subsp. lactis (strain CIDCA 133) stimulates murine macrophages infected with Citrobacter rodentium.

PubMed

Hugo, Ayelén A; Rolny, Ivanna S; Romanin, David; Pérez, Pablo F

2017-03-01

Citrobacter rodentium is a specific murine enteropathogen which causes diarrheal disease characterized by colonic hyperplasia and intestinal inflammation. Recruitment of neutrophils and macrophages constitute a key step to control the infection. Since modulation of the activity of professional phagocytic cells could contribute to improve host´s defences against C. rodentium, we investigated the effect of Lactobacillus delbrueckii subsp. lactis (strain CIDCA 133) on the interaction between murine macrophages (RAW 264.7) and C. rodentium. Phagocytosis, surface molecules and inducible nitric oxide synthase (iNOs) expression were determined by flow cytometry. Reactive oxygen species (ROS) were assessed by fluorescence microscopy. The presence of lactobacilli increased phagocytosis of C. rodentium whereas C. rodentium had no effect on lactobacilli internalization. Survival of internalized C. rodentium diminished when strain CIDCA 133 was present. CD-86, MHCII, iNOs expression and nitrite production were increased when C. rodentium and lactobacilli were present even though strain CIDCA 133 alone had no effect. Strain CIDCA 133 led to a strong induction of ROS activity which was not modified by C. rodentium. Lactobacillus delbrueckii subsp. lactis (strain CIDCA 133) is able to increase the activation of murine macrophages infected with C. rodentium. The sole presence of lactobacilli is enough to modify some stimulation markers (e.g. ROS induction) whereas other markers require the presence of both bacteria; thus, indicating a synergistic effect.

[Activation of the alternative oxidase of Yarrowia lipolytica by adenosine 5'-monophosphate].

PubMed

Medentsev, A G; Arinbasarova, A Iu; Smirnova, N M; Akimenko, V K

2004-01-01

The study of the effect of nucleoside phosphates on the activity of cyanide-resistant oxidase in the mitochondria and the submitochondrial particles of Yarrowia lipolytica showed that adenosine monophosphate (5'-AMP, AMP) did not stimulate the respiration of the intact mitochondria. The incubation of the mitochondria at room temperature (25 degrees C) for 3-5 h or their treatment with ultrasound, phospholipase A, and detergent Triton X-100 at a low temperature inactivated the cyanide-resistant alternative oxidase. The inactivated alternative oxidase could be reactivated by AMP. The reactivating effect of AMP was enhanced by azolectin. Some other nucleoside phosphates also showed reactivating ability in the following descending order. AMP = GMP > GDP > GTP > XMP > IMP. The apparent reaction rate constant Km for AMP upon the reactivation of the alternative oxidase of mitochondria treated with Triton X-100 or incubated at 25 degrees C was 12.5 and 20 microM, respectively. The Km for AMP upon the reactivation of the alternative oxidase of submitochondrial particles was 15 microM. During the incubation of yeast cells under conditions promoting the development of alternative oxidase, the content of adenine nucleotides (AMP, ADP, and ATP) in the cells and their respiration tended to decrease. The subsequent addition of cyanide to the cells activated their respiration, diminished the intracellular content of ATP three times, and augmented the content of AMP five times. These data suggest that the stimulation of cell respiration by cyanide may be due to the activation of alternative oxidase by AMP.

Non-Invasive Electrical Brain Stimulation Montages for Modulation of Human Motor Function.

PubMed

Curado, Marco; Fritsch, Brita; Reis, Janine

2016-02-04

Non-invasive electrical brain stimulation (NEBS) is used to modulate brain function and behavior, both for research and clinical purposes. In particular, NEBS can be applied transcranially either as direct current stimulation (tDCS) or alternating current stimulation (tACS). These stimulation types exert time-, dose- and in the case of tDCS polarity-specific effects on motor function and skill learning in healthy subjects. Lately, tDCS has been used to augment the therapy of motor disabilities in patients with stroke or movement disorders. This article provides a step-by-step protocol for targeting the primary motor cortex with tDCS and transcranial random noise stimulation (tRNS), a specific form of tACS using an electrical current applied randomly within a pre-defined frequency range. The setup of two different stimulation montages is explained. In both montages the emitting electrode (the anode for tDCS) is placed on the primary motor cortex of interest. For unilateral motor cortex stimulation the receiving electrode is placed on the contralateral forehead while for bilateral motor cortex stimulation the receiving electrode is placed on the opposite primary motor cortex. The advantages and disadvantages of each montage for the modulation of cortical excitability and motor function including learning are discussed, as well as safety, tolerability and blinding aspects.

Characterization of sputtered iridium oxide thin films on planar and laser micro-structured platinum thin film surfaces for neural stimulation applications

NASA Astrophysics Data System (ADS)

Thanawala, Sachin

Electrical stimulation of neurons provides promising results for treatment of a number of diseases and for restoration of lost function. Clinical examples include retinal stimulation for treatment of blindness and cochlear implants for deafness and deep brain stimulation for treatment of Parkinsons disease. A wide variety of materials have been tested for fabrication of electrodes for neural stimulation applications, some of which are platinum and its alloys, titanium nitride, and iridium oxide. In this study iridium oxide thin films were sputtered onto laser micro-structured platinum thin films by pulsed-DC reactive sputtering of iridium metal in oxygen-containing atmosphere, to obtain high charge capacity coatings for neural stimulation applications. The micro-structuring of platinum films was achieved by a pulsed-laser-based technique (KrF excimer laser emitting at lambda=248nm). The surface morphology of the micro-structured films was studied using different surface characterization techniques. In-vitro biocompatibility of these laser micro-structured films coated with iridium oxide thin films was evaluated using cortical neurons isolated from rat embryo brain. Characterization of these laser micro-structured films coated with iridium oxide, by cyclic voltammetry and impedance spectroscopy has revealed a considerable decrease in impedance and increase in charge capacity. A comparison between amorphous and crystalline iridium oxide thin films as electrode materials indicated that amorphous iridium oxide has significantly higher charge capacity and lower impedance making it preferable material for neural stimulation application. Our biocompatibility studies show that neural cells can grow and differentiate successfully on our laser micro-structured films coated with iridium oxide. This indicates that reactively sputtered iridium oxide (SIROF) is biocompatible.

Primed tumor-reactive multifunctional CD62L+ human CD8+T-cells for immunotherapy

PubMed Central

Wölfl, Matthias; Merker, Katharina; Morbach, Henner; Van Gool, Stefaan W.; Eyrich, Matthias; Greenberg, Philip D.; Schlegel, Paul G.

2011-01-01

T-cell mediated immunotherapy against malignancies has been shown to be effective for certain types of cancer. However ex vivo expansion of tumor-reactive T-cells has been hindered by the low precursor frequency of such cells, often requiring multiple rounds of stimulation, resulting in full differentiation, loss of homing receptors and potential exhaustion of the expanded T-cells. Here we show that when using highly purified naïve CD8+ T-cells, a single stimulation with peptide pulsed, IFNγ/LPS-matured dendritic cells in combination with the sequential use of IL-21, IL-7 and IL-15 is sufficient for extensive expansion of antigen-specific T-cells. Short-term expanded T-cells were tumor-reactive, multifunctional and retained a central memory-like phenotype (CD62L+, CCR7+, CD28+). The procedure is highly reproducible and robust as demonstrated for different healthy donors and for cancer patients. Such short-term tumor-antigen-primed, multifunctional T-cells may therefore serve as a platform to target different malignancies accessible to immunotherapy. PMID:20972785

Expansion of tumor-infiltrating lymphocytes (TIL) from human pancreatic tumors.

PubMed

Hall, MacLean; Liu, Hao; Malafa, Mokenge; Centeno, Barbara; Hodul, Pamela J; Pimiento, José; Pilon-Thomas, Shari; Sarnaik, Amod A

2016-01-01

We evaluated whether tumor infiltrating lymphocytes (TIL) could be expanded from surgically resected tumors from pancreatic cancer patients. Tumors were resected from pancreatic cancer patients. Tumors were minced into fragments and cultured in media containing high dose interleukin-2 (IL-2) for up to 6 weeks. T cell phenotype, activation markers, and reactivity were measured. TIL expansion was measured in 19 patient samples. The majority of these TIL were CD4 + T cells and were highly activated. Purified CD8 + T cells produced IFN-γ in response to HLA-matched pancreatic tumor targets. PD-1 blockade and 4-1BB stimulation were demonstrated as effective strategies to improve effective TIL yield, including the production of tumor-reactive pancreatic TIL. TIL expanded from pancreatic tumors are functional and able to respond to pancreatic tumor associated antigens. PD-1 blockade, 41BB stimulation, and CD8 + T cell enrichment are effective strategies to improve TIL yield and tumor reactivity. These results support the development of adoptive cell therapy strategies using TIL for the treatment of pancreatic cancer.

Neutrophil hyper-responsiveness in periodontitis.

PubMed

Matthews, J B; Wright, H J; Roberts, A; Ling-Mountford, N; Cooper, P R; Chapple, I L C

2007-08-01

Peripheral neutrophil hyper-responsiveness in chronic periodontitis leads to excessive reactive oxygen species (ROS) production. We aimed to determine whether neutrophil hyper-responsiveness was constitutive or reactive, and to discover the effect of non-surgical therapy. Peripheral blood neutrophils from patients (n = 19), before and 3 months after therapy, and matched control individuals were Fc gamma-receptor-stimulated with/without priming with P. gingivalis and F. nucleatum. Total and extracellular ROS were determined by luminol/isoluminol chemiluminescence. The high total ROS generation of patients' neutrophils compared with that of control individuals (P = 0.016) continued at a reduced level post-therapy (P = 0.059). Reduced activity post-therapy was also seen with priming. Unstimulated total ROS levels did not differ between patients and control individuals before or after therapy. However, the high unstimulated, extracellular ROS production by patients' neutrophils compared with control individuals (P < 0.05) continued post-therapy and was unaffected by priming. Therapy reduced Fc gamma-receptor-stimulated total ROS production, but not unstimulated extracellular radical release, suggesting that constitutive and reactive mechanisms underlie neutrophil hyper-responsiveness.

Eicosanoids up-regulate production of reactive oxygen species by NADPH-dependent oxidase in Spodoptera exigua phagocytic hemocytes

USDA-ARS?s Scientific Manuscript database

Eicosanoids mediate cellular immune responses in insects, including phagocytosis of invading microbes. Phagocytosis entails two major steps, the internalization of microbes and the subsequent killing of them via formation of reactive oxygen species (ROS). Here, we posed the hypothesis that eicosanoi...

A Reactive, Radical Approach to Engaged Scholarship

ERIC Educational Resources Information Center

Smith, Malcolm

2011-01-01

While exploring the current challenges facing academic institutions and the needs of their scholars to make their work relevant in the lives of university constituents, the author advocates for a reactive and radical approach to engaged scholarship by outlining an 8-step process that considers the importance of transformation, immediacy, and…

Estimating the Reactivation Potential of Pre-Existing Fractures in Subsurface Granitoids from Outcrop Analogues and in-Situ Stress Modeling: Implications for EGS Reservoir Stimulation with an Example from Thuringia (Central Germany)

NASA Astrophysics Data System (ADS)

Kasch, N.; Ustaszewski, K. M.; Siegburg, M.; Navabpour, P.; Hesse, G.

2014-12-01

The Mid-German Crystalline Rise (MGCR) in Thuringia (central Germany) is part of the European Variscan orogen and hosts large extents of Visean granites (c. 350 Ma), locally overlain by up to 3 km of Early Permian to Mid-Triassic volcanic and sedimentary rocks. A geothermal gradient of 36°C km-1 suggests that such subsurface granites form an economically viable hot dry rock reservoir at > 4 km depth. In order to assess the likelihood of reactivating any pre-existing fractures during hydraulic reservoir stimulation, slip and dilation tendency analyses (Morris et al. 1996) were carried out. For this purpose, we determined orientations of pre-existing fractures in 14 granite exposures along the southern border fault of an MGCR basement high. Additionally, the strike of 192 Permian magmatic dikes affecting the granite was considered. This analysis revealed a prevalence of NW-SE-striking fractures (mainly joints, extension veins, dikes and subordinately brittle faults) with a maximum at 030/70 (dip azimuth/dip). Borehole data and earthquake focal mechanisms reveal a maximum horizontal stress SHmax trending N150°E and a strike-slip regime. Effective in-situ stress magnitudes at 4.5 km depth, assuming hydrostatic conditions and frictional equilibrium along pre-existing fractures with a friction coefficient of 0.85 yielded 230 and 110 MPa for SHmax and Shmin, respectively. In this stress field, fractures with the prevailing orientations show a high tendency of becoming reactivated as dextral strike-slip faults if stimulated hydraulically. To ensure that a stimulation well creates fluid connectivity on a reservoir volume as large as possible rather than dissipating fluids along existing fractures, it should follow a trajectory at the highest possible angle to the orientation of prevailing fractures, i.e. subhorizontal and NE-SW-oriented. References: Morris, A., D. A. Ferrill, and D. B. Henderson (1996), Slip-tendency analysis and fault reactivation, Geology, 24, 275-278.

Quantification of EEG reactivity in comatose patients

PubMed Central

Hermans, Mathilde C.; Westover, M. Brandon; van Putten, Michel J.A.M.; Hirsch, Lawrence J.; Gaspard, Nicolas

2016-01-01

Objective EEG reactivity is an important predictor of outcome in comatose patients. However, visual analysis of reactivity is prone to subjectivity and may benefit from quantitative approaches. Methods In EEG segments recorded during reactivity testing in 59 comatose patients, 13 quantitative EEG parameters were used to compare the spectral characteristics of 1-minute segments before and after the onset of stimulation (spectral temporal symmetry). Reactivity was quantified with probability values estimated using combinations of these parameters. The accuracy of probability values as a reactivity classifier was evaluated against the consensus assessment of three expert clinical electroencephalographers using visual analysis. Results The binary classifier assessing spectral temporal symmetry in four frequency bands (delta, theta, alpha and beta) showed best accuracy (Median AUC: 0.95) and was accompanied by substantial agreement with the individual opinion of experts (Gwet’s AC1: 65–70%), at least as good as inter-expert agreement (AC1: 55%). Probability values also reflected the degree of reactivity, as measured by the inter-experts’ agreement regarding reactivity for each individual case. Conclusion Automated quantitative EEG approaches based on probabilistic description of spectral temporal symmetry reliably quantify EEG reactivity. Significance Quantitative EEG may be useful for evaluating reactivity in comatose patients, offering increased objectivity. PMID:26183757

CO oxidation on stepped-Pt(111) under electrochemical conditions: insights from theory and experiment.

PubMed

Busó-Rogero, C; Herrero, E; Bandlow, J; Comas-Vives, A; Jacob, Timo

2013-11-14

The co-adsorption of CO and OH on two Pt stepped surfaces vicinal to the (111) orientation has been evaluated by means of density functional theory (DFT) calculations. Focusing on Pt(533) and Pt(221), which contain (100) and (111)-steps, respectively, we find that (111)-steps should be more reactive towards CO oxidation than surfaces containing (100)-steps. The DFT results are compared with electrochemical experiments on the CO adsorption and oxidation on these vicinal surfaces.

Triggering co-stimulation directly in melanoma tumor fragments drives CD8+ tumor-infiltrating lymphocyte expansion with improved effector-memory properties.

PubMed

Chacon, Jessica Ann; Sarnaik, Amod A; Pilon-Thomas, Shari; Radvanyi, Laszlo

2015-12-01

TIL from solid tumors can express activation/co-stimulatory molecules like 4-1BB/CD137, a sign of recent antigenic stimulation in the tumor microenvironment (TME). This activated state can be exploited ex vivo to enhance the expansion of tumor-reactive CD8 + TIL for adoptive cell therapy through direct addition of immunomodulators to tumor fragments in culture.

CRH-stimulated cortisol release and food intake in healthy, non-obese adults.

PubMed

George, Sophie A; Khan, Samir; Briggs, Hedieh; Abelson, James L

2010-05-01

There is considerable anecdotal and some scientific evidence that stress triggers eating behavior, but underlying physiological mechanisms remain uncertain. The hypothalamic-pituitary-adrenal (HPA) axis is a key mediator of physiological stress responses and may play a role in the link between stress and food intake. Cortisol responses to laboratory stressors predict consumption but it is unclear whether such responses mark a vulnerability to stress-related eating or whether cortisol directly stimulates eating in humans. We infused healthy adults with corticotropin-releasing hormone (CRH) at a dose that is subjectively undetectable but elicits a robust endogenous cortisol response, and measured subsequent intake of snack foods, allowing analysis of HPA reactivity effects on food intake without the complex psychological effects of a stress paradigm. CRH elevated cortisol levels relative to placebo but did not impact subjective anxious distress. Subjects ate more following CRH than following placebo and peak cortisol response to CRH was strongly related to both caloric intake and total consumption. These data show that HPA axis reactivity to pharmacological stimulation predicts subsequent food intake and suggest that cortisol itself may directly stimulate food consumption in humans. Understanding the physiological mechanisms that underlie stress-related eating may prove useful in efforts to attack the public health crises created by obesity. Copyright 2009 Elsevier Ltd. All rights reserved.

Ascorbate and α-tocopherol differentially modulate reactive oxygen species generation by neutrophils in response to FcγR and TLR agonists.

PubMed

Chapple, Iain Lc; Matthews, John B; Wright, Helen J; Scott, Ann E; Griffiths, Helen R; Grant, Melissa M

2013-01-01

Periodontitis, a ubiquitous chronic inflammatory disease, is associated with reduced antioxidant defences and neutrophil hyperactivity in terms of reactive oxygen species (ROS) generation. Its phenotype is thus characterized by oxidative stress. We have determined the effect of antioxidant micronutrients ascorbate and α-tocopherol on neutrophil ROS generation. Peripheral neutrophils from periodontally-healthy individuals (n = 20) were challenged with phorbol myristate acetate, IgG-opsonised Staphylococcus aureus, Fusobacterium nucleatum or PBS in the presence and absence of micronutrients (50 µM). Total and extracellular ROS were measured by luminol and isoluminol chemiluminescence respectively. Total and extracellular unstimulated, baseline ROS generation was unaffected by α-tocopherol, but inhibited by ascorbate and a combination of both micronutrients. Fcγ-receptor (Fcγ-R)-stimulated total or extracellular ROS generation was not affected by the presence of individual micronutrients. However, the combination significantly reduced extracellular FcγR-stimulated ROS release. Neither micronutrient inhibited TLR-stimulated total ROS, but the combination caused inhibition. Ascorbate and the micronutrient combination, but not α-tocopherol, inhibited extracellular ROS release by TLR-stimulated cells. Such micronutrient effects in vivo could be beneficial in reducing collateral tissue damage in chronic inflammatory diseases, such as periodontitis, while retaining immune-mediated neutrophil function.

The effect of light on lake herring (Coregonus artedi) reactive volume

USGS Publications Warehouse

Link, Jason; Edsall, Thomas A.

1996-01-01

The lake herring (Coregonus artedi) is an important coldwater planktivore in the Laurentian Great Lakes and in smaller inland lakes in portions of Canada and the northern United States. Lake herring cruise the pelagia and feed selectively in both gulping and particulate modes. They are visual predators in environments with adequate illumination. Visual predation by fish consists of a series of discrete steps. We studied the first step in the predation sequence, reaction to prey, at light intensities of 2–1500 Lx in a simulated pelagic environment at 10–13°C. We measured lake herring reactive distances, the distance at which a prey item will be detected and attacked, to liveLimnocalanus macrurus, a natural prey of lake herring in Lake Superior. We used the reactive distances and associated angles of bearing and elevation, which described the location of the prey relative to the lake herring, to calculate reactive volume. This reactive volume can be envisioned as an irregular sphere surrounding the fish, within which prey are detected and attacked. All of the attacks on prey occurred in the anterior portions of the sagittal and lateral planes of the lake herring, as would be expected for a pelagic, cruising fish. The reactive volume surrounding the lake herring was generally spherical, but was more irregular than the simple spheres, hemispheres, cylinders, cones or other geometries assumed in previous studies. The reactive distances and the reactive volume changed with light intensity and were significantly smaller at 2–10 Lx than at 40–1500 Lx. At 40–1500 Lx, the reactive volume was expanded over that observed at 2–10 Lx laterally and caudally. Collectively our results indicate that lake herring can visually forage most effectively in environments with light levels >10 Lx.

Baccharis trimera inhibits reactive oxygen species production through PKC and down-regulation p47 phox phosphorylation of NADPH oxidase in SK Hep-1 cells.

PubMed

de Araújo, Glaucy Rodrigues; Rabelo, Ana Carolina Silveira; Meira, Janaína Serenato; Rossoni-Júnior, Joamyr Victor; Castro-Borges, William de; Guerra-Sá, Renata; Batista, Maurício Azevedo; Silveira-Lemos, Denise da; Souza, Gustavo Henrique Bianco de; Brandão, Geraldo Célio; Chaves, Míriam Martins; Costa, Daniela Caldeira

2017-02-01

Baccharis trimera, popularly known as "carqueja", is a native South-American plant possessing a high concentration of polyphenolic compounds and therefore high antioxidant potential. Despite the antioxidant potential described for B. trimera, there are no reports concerning the signaling pathways involved in this process. So, the aim of the present study was to assess the influence of B. trimera on the modulation of PKC signaling pathway and to characterize the effect of the nicotinamide adenine dinucleotide phosphate oxidase enzyme (NOX) on the generation of reactive oxygen species in SK Hep-1 cells. SK-Hep 1 cells were treated with B. trimera, quercetin, or rutin and then stimulated or not with PMA/ionomycin and labeled with carboxy H 2 DCFDA for detection of reactive oxygen species by flow cytometer. The PKC expression by Western blot and enzyme activity was performed to evaluate the influence of B. trimera and quercetin on PKC signaling pathway. p47 phox and p47 phox phosphorylated expression was performed by Western blot to evaluate the influence of B. trimera on p47 phox phosphorylation. The results showed that cells stimulated with PMA/ionomycin (activators of PKC) showed significantly increased reactive oxygen species production, and this production returned to baseline levels after treatment with DPI (NOX inhibitor). Both B. trimera and quercetin modulated reactive oxygen species production through the inhibition of PKC protein expression and enzymatic activity, also with inhibition of p47 phox phosphorylation. Taken together, these results suggest that B. trimera has a potential mechanism for inhibiting reactive oxygen species production through the PKC signaling pathway and inhibition subunit p47 phox phosphorylation of nicotinamide adenine dinucleotide phosphate oxidase.

The Role of the Reactive Oxygen Species and Oxidative Stress in the Pathomechanism of the Age-Related Ocular Diseases and Other Pathologies of the Anterior and Posterior Eye Segments in Adults

PubMed Central

Nita, Małgorzata; Grzybowski, Andrzej

2016-01-01

The reactive oxygen species (ROS) form under normal physiological conditions and may have both beneficial and harmful role. We search the literature and current knowledge in the aspect of ROS participation in the pathogenesis of anterior and posterior eye segment diseases in adults. ROS take part in the pathogenesis of keratoconus, Fuchs endothelial corneal dystrophy, and granular corneal dystrophy type 2, stimulating apoptosis of corneal cells. ROS play a role in the pathogenesis of glaucoma stimulating apoptotic and inflammatory pathways on the level of the trabecular meshwork and promoting retinal ganglion cells apoptosis and glial dysfunction in the posterior eye segment. ROS play a role in the pathogenesis of Leber's hereditary optic neuropathy and traumatic optic neuropathy. ROS induce apoptosis of human lens epithelial cells. ROS promote apoptosis of vascular and neuronal cells and stimulate inflammation and pathological angiogenesis in the course of diabetic retinopathy. ROS are associated with the pathophysiological parainflammation and autophagy process in the course of the age-related macular degeneration. PMID:26881021

Mitochondrial reactive oxygen species (ROS) as signaling molecules of intracellular pathways triggered by the cardiac renin-angiotensin II-aldosterone system (RAAS)

PubMed Central

De Giusti, V. C.; Caldiz, C. I.; Ennis, I. L.; Pérez, N. G.; Cingolani, H. E.; Aiello, E. A.

2013-01-01

Mitochondria represent major sources of basal reactive oxygen species (ROS) production of the cardiomyocyte. The role of ROS as signaling molecules that mediate different intracellular pathways has gained increasing interest among physiologists in the last years. In our lab, we have been studying the participation of mitochondrial ROS in the intracellular pathways triggered by the renin-angiotensin II-aldosterone system (RAAS) in the myocardium during the past few years. We have demonstrated that acute activation of cardiac RAAS induces mitochondrial ATP-dependent potassium channel (mitoKATP) opening with the consequent enhanced production of mitochondrial ROS. These oxidant molecules, in turn, activate membrane transporters, as sodium/hydrogen exchanger (NHE-1) and sodium/bicarbonate cotransporter (NBC) via the stimulation of the ROS-sensitive MAPK cascade. The stimulation of such effectors leads to an increase in cardiac contractility. In addition, it is feasible to suggest that a sustained enhanced production of mitochondrial ROS induced by chronic cardiac RAAS, and hence, chronic NHE-1 and NBC stimulation, would also result in the development of cardiac hypertrophy. PMID:23755021

Mitochondrial reactive oxygen species (ROS) as signaling molecules of intracellular pathways triggered by the cardiac renin-angiotensin II-aldosterone system (RAAS).

PubMed

De Giusti, V C; Caldiz, C I; Ennis, I L; Pérez, N G; Cingolani, H E; Aiello, E A

2013-01-01

Mitochondria represent major sources of basal reactive oxygen species (ROS) production of the cardiomyocyte. The role of ROS as signaling molecules that mediate different intracellular pathways has gained increasing interest among physiologists in the last years. In our lab, we have been studying the participation of mitochondrial ROS in the intracellular pathways triggered by the renin-angiotensin II-aldosterone system (RAAS) in the myocardium during the past few years. We have demonstrated that acute activation of cardiac RAAS induces mitochondrial ATP-dependent potassium channel (mitoKATP) opening with the consequent enhanced production of mitochondrial ROS. These oxidant molecules, in turn, activate membrane transporters, as sodium/hydrogen exchanger (NHE-1) and sodium/bicarbonate cotransporter (NBC) via the stimulation of the ROS-sensitive MAPK cascade. The stimulation of such effectors leads to an increase in cardiac contractility. In addition, it is feasible to suggest that a sustained enhanced production of mitochondrial ROS induced by chronic cardiac RAAS, and hence, chronic NHE-1 and NBC stimulation, would also result in the development of cardiac hypertrophy.

The angiotensin II-AT1 receptor stimulates reactive oxygen species within the cell nucleus

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

Pendergrass, Karl D.; Gwathmey, TanYa M.; Michalek, Ryan D.

2009-06-26

We and others have reported significant expression of the Ang II Type 1 receptor (AT1R) on renal nuclei; thus, the present study assessed the functional pathways and distribution of the intracellular AT1R on isolated nuclei. Ang II (1 nM) stimulated DCF fluorescence, an intranuclear indicator of reactive oxygen species (ROS), while the AT1R antagonist losartan or the NADPH oxidase (NOX) inhibitor DPI abolished the increase in ROS. Dual labeling of nuclei with antibodies against nucleoporin 62 (Nup62) and AT1R or the NADPH oxidase isoform NOX4 revealed complete overlap of the Nup62 and AT1R (99%) by flow cytometry, while NOX4 wasmore » present on 65% of nuclei. Treatment of nuclei with a PKC agonist increased ROS while the PKC inhibitor GF109203X or PI3 kinase inhibitor LY294002 abolished Ang II stimulation of ROS. We conclude that the Ang II-AT1R-PKC axis may directly influence nuclear function within the kidney through a redox sensitive pathway.« less

Toll-like receptor prestimulation increases phagocytosis of Escherichia coli DH5alpha and Escherichia coli K1 strains by murine microglial cells.

PubMed

Ribes, Sandra; Ebert, Sandra; Czesnik, Dirk; Regen, Tommy; Zeug, Andre; Bukowski, Stephanie; Mildner, Alexander; Eiffert, Helmut; Hanisch, Uwe-Karsten; Hammerschmidt, Sven; Nau, Roland

2009-01-01

Meningitis and meningoencephalitis caused by Escherichia coli are associated with high rates of mortality. When an infection occurs, Toll-like receptors (TLRs) expressed by microglial cells can recognize pathogen-associated molecular patterns and activate multiple steps in the inflammatory response that coordinate the brain's local defense, such as phagocytosis of invading pathogens. An upregulation of the phagocytic ability of reactive microglia could improve the host defense in immunocompromised patients against pathogens such as E. coli. Here, murine microglial cultures were stimulated with the TLR agonists Pam(3)CSK(4) (TLR1/TLR2), lipopolysaccharide (TLR4), and CpG oligodeoxynucleotide (TLR9) for 24 h. Upon stimulation, levels of tumor necrosis factor alpha and the neutrophil chemoattractant CXCL1 were increased, indicating microglial activation. Phagocytic activity was studied after adding either E. coli DH5alpha or E. coli K1 strains. After 60 and 90 min of bacterial exposure, the number of ingested bacteria was significantly higher in cells prestimulated with TLR agonists than in unstimulated controls (P < 0.01). Addition of cytochalasin D, an inhibitor of actin polymerization, blocked >90% of phagocytosis. We also analyzed the ability of microglia to kill the ingested E. coli strains. Intracellularly surviving bacteria were quantified at different time points (90, 150, 240, and 360 min) after 90 min of phagocytosis. The number of bacteria killed intracellularly after 6 h was higher in cells primed with the different TLR agonists than in unstimulated microglia. Our data suggest that microglial stimulation by the TLR system can increase bacterial phagocytosis and killing. This approach could improve central nervous system resistance to infections in immunocompromised patients.

Milder is better? advantages and disadvantages of "mild" ovarian stimulation for human in vitro fertilization

PubMed Central

2011-01-01

In the last decades, several steps have been made aiming at rendering human IVF more successful on one side, more tolerable on the other side. The "mild" ovarian stimulation approach, in which a lower-than-average dose of exogenous gonadotropins is given and gonadotropin treatment is started from day 2 to 7 of the cycle, represents a significant step toward a more patient's friendly IVF. However, a clear view of its virtues and defects is still lacking, because only a few prospective randomized trials comparing "mild" vs. conventional stimulation exist, and they do not consider some important aspects, such as, e.g., thawing cycles. This review gives a complete panorama of the "mild" stimulation philosophy, showing its advantages vs. conventional ovarian stimulation, but also discussing its disadvantages. Both patients with a normal ovarian responsiveness to exogenous gonadotropins and women with a poor ovarian reserve are considered. Overall, we conclude that the level of evidence supporting the use of "mild" stimulation protocols is still rather poor, and further, properly powered prospective studies about "mild" treatment regimens are required. PMID:21324155

Effect of thermal processing on T cell reactivity of shellfish allergens - Discordance with IgE reactivity.

PubMed

Abramovitch, Jodie B; Lopata, Andreas L; O'Hehir, Robyn E; Rolland, Jennifer M

2017-01-01

Crustacean allergy is a major cause of food-induced anaphylaxis. We showed previously that heating increases IgE reactivity of crustacean allergens. Here we investigate the effects of thermal processing of crustacean extracts on cellular immune reactivity. Raw and cooked black tiger prawn, banana prawn, mud crab and blue swimmer crab extracts were prepared and IgE reactivity assessed by ELISA. Mass spectrometry revealed a mix of several allergens in the raw mud crab extract but predominant heat-stable tropomyosin in the cooked extract. PBMC from crustacean-allergic and non-atopic control subjects were cultured with the crab and prawn extracts and proliferation of lymphocyte subsets was analysed by CFSE labelling and flow cytometry. Effector responses were assessed by intracellular IL-4 and IFN-γ, and regulatory T (CD4+CD25+CD127loFoxp3+) cell proportions in cultures were also compared by flow cytometry. For each crustacean species, the cooked extract had greater IgE reactivity than the raw (mud crab p<0.05, other species p<0.01). In contrast, there was a trend for lower PBMC proliferative responses to cooked compared with raw extracts. In crustacean-stimulated PBMC cultures, dividing CD4+ and CD56+ lymphocytes showed higher IL-4+/IFN-γ+ ratios for crustacean-allergic subjects than for non-atopics (p<0.01), but there was no significant difference between raw and cooked extracts. The percentage IL-4+ of dividing CD4+ cells correlated with total and allergen-specific IgE levels (prawns p<0.01, crabs p<0.05). Regulatory T cell proportions were lower in cultures stimulated with cooked compared with raw extracts (mud crab p<0.001, banana prawn p<0.05). In conclusion, cooking did not substantially alter overall T cell proliferative or cytokine reactivity of crustacean extracts, but decreased induction of Tregs. In contrast, IgE reactivity of cooked extracts was increased markedly. These novel findings have important implications for improved diagnostics, managing crustacean allergy and development of future therapeutics. Assessment of individual allergen T cell reactivity is required.

Responses to vertical vestibular stimulation of neurons in the nucleus reticularis gigantocellularis in rabbits.

PubMed

Fagerson, M H; Barmack, N H

1995-06-01

1. Because the nucleus reticularis gigantocellularis (NRGc) receives a substantial descending projection from the caudal vestibular nuclei, we used extracellular single-unit recording combined with natural vestibular stimulation to examine the possible peripheral origins of the vestibularly modulated activity of caudal NRGc neurons located within 500 microns of the midline. Chloralose-urethan anesthetized rabbits were stimulated with an exponential "step" and/or static head-tilt stimulus, as well as sinusoidal rotation about the longitudinal or interaural axes providing various combinations of roll or pitch, respectively. Recording sites were reconstructed from electrolytic lesions confirmed histologically. 2. More than 85% of the 151 neurons, in the medial aspect of the caudal NRGc, responded to vertical vestibular stimulation. Ninety-six percent of these responded to rotation onto the contralateral side (beta responses). Only a few also responded to horizontal stimulation. Seventy-eight percent of the neurons that responded to vestibular stimulation responded during static roll-tilt. One-half of these neurons also responded transiently to the change in head position during exponential "step" stimulation, suggesting input mediated by otolith and semicircular canal receptors or tonic-phasic otolith neurons. 3. Seventy-five percent of the responsive neurons had a "null plane." The planes of stimulation resulting in maximal responses, for cells that responded to static stimulation, were distributed throughout 150 degrees in both roll and pitch quadrants. Five of these cells responded only transiently during exponential "step" stimulation and responded maximally when stimulated in the plane of one of the vertical semicircular canals. 4. The phase of the response of the 25% of medial NRGc neurons that lacked "null planes" gradually shifted approximately 180 degrees during sinusoidal vestibular stimulation as the plane of stimulation was shifted about the vertical axis. These neurons likely received convergent input with differing spatial and temporal properties. 5. The activity of neurons in the medial aspect of the caudal NRGc of rabbits was modulated by both otolithic macular and vertical semicircular canal receptor stimulation. This vestibular information may be important for controlling the intensity of the muscle activity in muscles such as neck muscles where the load on the muscle is affected by the position of the head with respect to gravity. Some of these neurons may also shift muscle function from an agonist to an antagonist as the direction of head tilt changes.

Investigation of infrared radiation in rubidium vapor upon two-photon and step-by-step excitations of the initial level

NASA Astrophysics Data System (ADS)

Bimagambetov, T. S.

2011-12-01

Stimulated infrared (IR) 5.231-μm line radiation is obtained upon two-photon and step-by-step excitations of the initial level. Dependences of the line power on the concentration of atoms and laser frequency are investigated. The mechanism of initial level occupation is explained.

Acute exposure of mercury chloride stimulates the tissue regeneration program and reactive oxygen species production in the Drosophila midgut.

PubMed

Chen, Zhi; Wu, Xiaochun; Luo, Hongjie; Zhao, Lingling; Ji, Xin; Qiao, Xianfeng; Jin, Yaping; Liu, Wei

2016-01-01

We used Drosophila as an animal model to study the digestive tract in response to the exposure of inorganic mercury (HgCl2). We found that after oral administration, mercury was mainly sequestered within the midgut. This resulted in increased cell death, which in turn stimulated the tissue regeneration program, including accelerated proliferation and differentiation of the intestinal stem cells (ISCs). We further demonstrated that these injuries correlate closely with the excessive production of the reactive oxygen species (ROS), as vitamin E, an antioxidant reagent, efficiently suppressed the HgCl2-induced phenotypes of midgut and improved the viability. We propose that the Drosophila midgut could serve as a suitable model to study the treatment of acute hydrargyrism on the digestive systems. Copyright © 2015 Elsevier B.V. All rights reserved.

Application of point kinetics equations to the design of a reactivity meter

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

Binney, S.E.; Bakir, A.J.M.

1988-01-01

The time-dependent reactivity of a nuclear reactor is obviously one of the most important reactor parameters that describes the state of the reactor. Although several different types of techniques exist to measure reactivity, only the kinetic method is described here. The paper illustrates the measured reactor power and calculated reactivity for a 70 cents step change in reactivity. These data were taken at 1-s time intervals. It is seen that the reactivity, initially at zero, rises rapidly to a predetermined value (determined by the reactivity change induced in the system) and then returns to zero as the reactor is reestablishedmore » in a critical situation by insertion of another control rod. It is concluded that the method of Tuttle has been adapted to produce a reliable, on-line calculation of reactivity from a time-dependent reactor power signal.« less

beta-Aminoalcohols as Potential Reactivators of Aged Sarin-/Soman-Inhibited Acetylcholinesterase

DTIC Science & Technology

2017-02-08

This approach includes high - quality quantum mechanical/molecular mechanical calcula- tions, providing reliable reactivation steps and energetics...I. V. Khavrutskii Department of Defense Biotechnology High Performance Computing Software Applications Institute Telemedicine and Advanced...b] Dr. A. Wallqvist Department of Defense Biotechnology High Performance Computing Software Applications Institute Telemedicine and Advanced

Oxygen reduction reaction on stepped platinum surfaces in alkaline media.

PubMed

Rizo, Ruben; Herrero, Enrique; Feliu, Juan M

2013-10-07

The oxygen reduction reaction (ORR) in 0.1 M NaOH on platinum single crystal electrodes has been studied using hanging meniscus rotating disk electrode configuration. Basal planes and stepped surfaces with (111) and (100) terraces have been employed. The results indicate that the Pt(111) electrode has the highest electrocatalytic activity among all the studied surfaces. The addition of steps on this electrode surface significantly diminishes the reactivity of the surface towards the ORR. In fact, the reactivity of the steps on the surfaces with wide terraces can be considered negligible with respect to that measured for the terrace. On the other hand, Pt(100) and Pt(110) electrodes have much lower activity than the Pt(111) electrode. These results have been compared with those obtained in acid media to understand the effect of the pH and the adsorbed OH on the mechanism. It is proposed that the surface covered by adsorbed OH is active for the reduction of the oxygen molecules.

Adsorption of pentacene on (100) vicinal surfaces: role of coordination, surface chemistry and vdWs effects

NASA Astrophysics Data System (ADS)

Matos, Jeronimo; Kara, Abdelkader

2015-03-01

In contrast to low miller index surfaces, vicinal surfaces are characterized by steps and step edges that not only present an interesting atomic landscape for the adsorption organic molecules, but also a unique electronic structure resulting in part from the low coordinated atoms at the step edges. The adsorption of pentacene on the stepped (511), (711), (911) surfaces (respectively 3, 4 and 5-atom wide terraces) of Cu and Ag (coinage transition metals); Pt (reactive transition metal); and Ni (reactive, magnetic transition metal) are studied using density functional theory, in order to investigate the support effects arising from differing surface chemistry. We compare the adsorption energy, adsorption geometry and electronic structure predicted by the PBE functional with those obtained from one of the optimized vdW-DF methods: optB88-vdW. Work supported by the U.S. Department of Energy Basic Energy Science under Contract No. DE-FG02-11ER16243.

2,4-dinitrophenylhydrazine carbonyl assay in metal-catalysed protein glycoxidation.

PubMed

Stefek, M; Trnkova, Z; Krizanova, L

1999-01-01

Using an experimental in vitro glycation model, long-term incubations of bovine serum albumin with glucose (fructose) resulted in a significant increase in protein content of 2,4-dinitrophenylhydrazine (DNPH)-reactive carbonyl groups, which could be strongly inhibited by anaerobiosis and metal chelation. The pattern of yields of the protein-bound DNPH was not in accordance with that of the sugar-derived carbonyls determined as the ketoamine Amadori product. In spite of the fact that the contribution of the final advanced glycation end-products to the total DNPH-reactivity of glycation-altered protein remains unclear, the present results stress the need of oxidative steps in formation of most of the DNPH-reactive carbonyl compounds generated by glycation. The results provide evidence that, in protein glycoxidation, the DNPH assay is selective enough to discriminate between protein-bound carbonyls produced by metal-catalysed oxidations and those formed in the early glycation steps.

Preparation and properties of poly HTBN-based urethane-urea/organo reactive montmorillonite nanocomposites

NASA Astrophysics Data System (ADS)

Li, Zai-Feng; Wu, Yuan; Zhang, Fu-Tao; Cao, Yu-Yang; Wu, Shou-Peng; Wang, Ting

2012-12-01

With ultrasonic assistant mixing way, an intercalated mixture of polyol/organo reactive montmorillonite (ORMMT) was pretreated. The prepolymer composed MMT clay was prepared by reaction of polyol/ORMMT mixture with toluene diisocyanate (TDI). The resultant prepolymer reacted with extender (DMTDA) and then the polyurethane-urea/organo reactive montmorillonite (PUU/ORMMT) nanocomposites were obtained. The structure, morphology and properties of PUU/ORMMT nanocomposites were characterized by FT-IR, TEM, AFM, strain-stress machine, TGA, and dynamic mechanical analysis (DMA). The results showed that when the OMMT content is 3%, the PUU/ORMMT nanocomposities performed super mechanical properties. Because of the presence of ORMMT, both T g of the soft segment and tan δ of the PUU increased, and the decomposition temperature for the first step and the second step increased respectively. TEM images showed that the organophilic MMT particles in the PUU composite exhibit a high degree of intercalation and exfoliation.

Photoluminescent silicon nanocrystals with chlorosilane surfaces - synthesis and reactivity

NASA Astrophysics Data System (ADS)

Höhlein, Ignaz M. D.; Kehrle, Julian; Purkait, Tapas K.; Veinot, Jonathan G. C.; Rieger, Bernhard

2014-12-01

We present a new efficient two-step method to covalently functionalize hydride terminated silicon nanocrystals with nucleophiles. First a reactive chlorosilane layer was formed via diazonium salt initiated hydrosilylation of chlorodimethyl(vinyl)silane which was then reacted with alcohols, silanols and organolithium reagents. With organolithium compounds a side reaction is observed in which a direct functionalization of the silicon surface takes place.We present a new efficient two-step method to covalently functionalize hydride terminated silicon nanocrystals with nucleophiles. First a reactive chlorosilane layer was formed via diazonium salt initiated hydrosilylation of chlorodimethyl(vinyl)silane which was then reacted with alcohols, silanols and organolithium reagents. With organolithium compounds a side reaction is observed in which a direct functionalization of the silicon surface takes place. Electronic supplementary information (ESI) available: Detailed experimental procedures and additional NMR, PL, EDX, DLS and TEM data. See DOI: 10.1039/C4NR05888G

Auditory feedback blocks memory benefits of cueing during sleep

PubMed Central

Schreiner, Thomas; Lehmann, Mick; Rasch, Björn

2015-01-01

It is now widely accepted that re-exposure to memory cues during sleep reactivates memories and can improve later recall. However, the underlying mechanisms are still unknown. As reactivation during wakefulness renders memories sensitive to updating, it remains an intriguing question whether reactivated memories during sleep also become susceptible to incorporating further information after the cue. Here we show that the memory benefits of cueing Dutch vocabulary during sleep are in fact completely blocked when memory cues are directly followed by either correct or conflicting auditory feedback, or a pure tone. In addition, immediate (but not delayed) auditory stimulation abolishes the characteristic increases in oscillatory theta and spindle activity typically associated with successful reactivation during sleep as revealed by high-density electroencephalography. We conclude that plastic processes associated with theta and spindle oscillations occurring during a sensitive period immediately after the cue are necessary for stabilizing reactivated memory traces during sleep. PMID:26507814

Detection of ABCB5 tumour antigen-specific CD8+ T cells in melanoma patients and implications for immunotherapy.

PubMed

Borchers, S; Maβlo, C; Müller, C A; Tahedl, A; Volkind, J; Nowak, Y; Umansky, V; Esterlechner, J; Frank, M H; Ganss, C; Kluth, M A; Utikal, J

2018-01-01

ATP binding cassette subfamily B member 5 (ABCB5) has been identified as a tumour-initiating cell marker and is expressed in various malignancies, including melanoma. Moreover, treatment with anti-ABCB5 monoclonal antibodies has been shown to inhibit tumour growth in xenotransplantation models. Therefore, ABCB5 represents a potential target for cancer immunotherapy. However, cellular immune responses against ABCB5 in humans have not been described so far. Here, we investigated whether ABCB5-reactive T cells are present in human melanoma patients and tested the applicability of ABCB5-derived peptides for experimental induction of human T cell responses. Peripheral blood mononuclear cells (PBMNC) isolated from blood samples of melanoma patients (n = 40) were stimulated with ABCB5 peptides, followed by intracellular cytokine staining (ICS) for interferon (IFN)-γ and tumour necrosis factor (TNF)-α. To evaluate immunogenicity of ABCB5 peptides in naive healthy donors, CD8 T cells were co-cultured with ABCB5 antigen-loaded autologous dendritic cells (DC). ABCB5 reactivity in expanded T cells was assessed similarly by ICS. ABCB5-reactive CD8 + T cells were detected ex vivo in 19 of 29 patients, melanoma antigen recognised by T cells (MART-1)-reactive CD8 + T cells in six of 21 patients. In this small, heterogeneous cohort, reactivity against ABCB5 was significantly higher than against MART-1. It occurred significantly more often and independently of clinical characteristics. Reactivity against ABCB5 could be induced in 14 of 16 healthy donors in vitro by repeated stimulation with peptide-loaded autologous DC. As ABCB5-reactive CD8 T cells can be found in the peripheral blood of melanoma patients and an ABCB5-specific response can be induced in vitro in naive donors, ABCB5 could be a new target for immunotherapies in melanoma. © 2017 British Society for Immunology.

Triggering co-stimulation directly in melanoma tumor fragments drives CD8+ tumor-infiltrating lymphocyte expansion with improved effector-memory properties

PubMed Central

Chacon, Jessica Ann; Sarnaik, Amod A; Pilon-Thomas, Shari; Radvanyi, Laszlo

2015-01-01

TIL from solid tumors can express activation/co-stimulatory molecules like 4–1BB/CD137, a sign of recent antigenic stimulation in the tumor microenvironment (TME). This activated state can be exploited ex vivo to enhance the expansion of tumor-reactive CD8+ TIL for adoptive cell therapy through direct addition of immunomodulators to tumor fragments in culture. PMID:26587314

T cell reactivity with allergoids: influence of the type of APC.

PubMed

Kahlert, H; Grage-Griebenow, E; Stüwe, H T; Cromwell, O; Fiebig, H

2000-08-15

The use of allergoids for allergen-specific immunotherapy has been established for many years. The characteristic features of these chemically modified allergens are their strongly reduced IgE binding activity compared with the native form and the retained immunogenicity. T cell reactivity of chemically modified allergens is documented in animals, but in humans indirect evidence of reactivity has been concluded from the induction of allergen-specific IgG during immunotherapy. Direct evidence of T cell reactivity was obtained recently using isolated human T cells. To obtain further insight into the mechanism of action of allergoids, we compared the Ag-presenting capacity of different APC types, including DC and macrophages, generated from CD14+ precursor cells from the blood of grass pollen allergic subjects, autologous PBMC, and B cells. These APC were used in experiments together with Phl p 5-specific T cell clones under stimulation with grass pollen allergen extract, rPhl p 5b, and the respective allergoids. Using DC and macrophages, allergoids exhibited a pronounced and reproducible T cell-stimulating capacity. Responses were superior to those with PBMC, and isolated B cells failed to present allergoids. Considerable IL-12 production was observed only when using the DC for Ag presentation of both allergens and allergoids. The amount of IL-10 in supernatants was dependent on the phenotype of the respective T cell clone. High IL-10 production was associated with suppressed IL-12 production from the DC in most cases. In conclusion, the reactivity of Th cells with allergoids is dependent on the type of the APC.

Apparatus for measurements of thermal and optical stimulated exo-electron emission and luminescence

NASA Astrophysics Data System (ADS)

Pokorný, P.; Novotný, M.; Fitl, P.; Zuklín, J.; Vlček, J.; Nikl, J.; Marešová, E.; Hruška, P.; Bulíř, J.; Drahokoupil, J.; Čerňanský, M.; Lančok, J.

2018-06-01

The purpose of the design, construction and implementation of vacuum apparatus for measuring simultaneously three or more stimulated phenomena in dielectrics and eventually semiconductors is to investigate those phenomena as a function of temperature and wavelength. The test of equipment and its functionality were carried out step by step (apparatus, components and control sample) and associated with the calculation of the main physical parameters. The tests of individual parts of the apparatus clearly confirmed that the design, construction and selected components fulfil or even exceed the required properties. On the basis of the measurement of selected sample, it was shown that even weak signals from the material can be detected from both thermally stimulated luminescence and thermally stimulated exo-electron emission moreover transmission and desorption can be measured. NaCl:Ni (0.2%) was chosen as the test material. The activation energies and frequency factor were calculated using the methods of different authors.

Formation of simple nitrogen hydrides NH and NH2 at cryogenic temperatures through N + NH3→ NH + NH2 reaction: dark cloud chemistry of nitrogen.

PubMed

Nourry, Sendres; Krim, Lahouari

2016-07-21

Although NH3 molecules interacting with ground state nitrogen atoms N((4)S) seem not to be a very reactive system without providing additional energy to initiate the chemical process, we show through this study that, in the solid phase, at very low temperature, NH3 + N((4)S) reaction leads to the formation of the amidogen radical NH2. Such a dissociation reaction previously thought to occur exclusively through UV photon or energetic particle irradiation is in this work readily occurring just by stimulating the mobility of N((4)S)-atoms in the 3-10 K temperature range in the solid sample. The N((4)S)-N((4)S) recombination may be the source of metastable molecular nitrogen N2(A), a reactive species which might trigger the NH3 dissociation or react with ground state nitrogen atoms N((4)S) to form excited nitrogen atoms N((4)P/(2)D) through energy transfer processes. Based on our obtained results, it is possible to propose reaction pathways to explain the NH2 radical formation which is the first step in the activation of stable species such as NH3, a chemical induction process that, in addition to playing an important role in the origin of molecular complexity in interstellar space, is known to require external energy supplies to occur in the gas phase.

Adolescent pedometer protocols: examining reactivity, tampering and participants' perceptions.

PubMed

Scott, Joseph John; Morgan, Philip James; Plotnikoff, Ronald Cyril; Trost, Stewart Graeme; Lubans, David Revalds

2014-01-01

The aim of this study was to investigate adolescents' potential reactivity and tampering while wearing pedometers by comparing different monitoring protocols to accelerometer output. The sample included adolescents (N = 123, age range = 14-15 years) from three secondary schools in New South Wales, Australia. Schools were randomised to one of the three pedometer monitoring protocols: (i) daily sealed (DS) pedometer group, (ii) unsealed (US) pedometer group or (iii) weekly sealed (WS) pedometer group. Participants wore pedometers (Yamax Digi-Walker CW700, Yamax Corporation, Kumamoto City, Japan) and accelerometers (Actigraph GT3X+, Pensacola, USA) simultaneously for seven days. Repeated measures analysis of variance was used to examine potential reactivity. Bivariate correlations between step counts and accelerometer output were calculated to explore potential tampering. The correlation between accelerometer output and pedometer steps/day was strongest among participants in the WS group (r = 0.82, P ≤ 0.001), compared to the US (r = 0.63, P ≤ 0.001) and DS (r = 0.16, P = 0.324) groups. The DS (P ≤ 0.001) and US (P = 0.003), but not the WS (P = 0.891), groups showed evidence of reactivity. The results suggest that reactivity and tampering does occur in adolescents and contrary to existing research, pedometer monitoring protocols may influence participant behaviour.

Reactivity of bromoselenophenes in palladium-catalyzed direct arylations.

PubMed

Skhiri, Aymen; Ben Salem, Ridha; Soulé, Jean-François; Doucet, Henri

2017-01-01

The reactivity of 2-bromo- and 2,5-dibromoselenophenes in Pd-catalyzed direct heteroarylation was investigated. From 2-bromoselenophene, only the most reactive heteroarenes could be employed to prepare 2-heteroarylated selenophenes; whereas, 2,5-dibromoselenophene generally gave 2,5-di(heteroarylated) selenophenes in high yields using both thiazole and thiophene derivatives. Moreover, sequential catalytic C2 heteroarylation, bromination, catalytic C5 arylation reactions allowed the synthesis of unsymmetrical 2,5-di(hetero)arylated selenophene derivatives in three steps from selenophene.

The effects of pulsed auditory stimulation on various gait measurements in persons with Parkinson's Disease.

PubMed

Freedland, Robert L; Festa, Carmel; Sealy, Marita; McBean, Andrew; Elghazaly, Paul; Capan, Ariel; Brozycki, Lori; Nelson, Arthur J; Rothman, Jeffrey

2002-01-01

The purpose of this study was to examine the Functional Ambulation Performance Score (FAP; a quantitative gait measure) in persons with Parkinson's Disease (PD) using the auditory stimulation of a metronome (ASM). Participants (n = 16; 5F/11M; range 60--84 yrs.) had a primary diagnosis of PD and were all independent ambulators. Footfall data were collected while participants walked multiple times on an electronic walkway under the following conditions: 1) PRETEST: establishing baseline cadence, 2) ASM: metronome set to baseline cadence, 3) 10ASM: metronome set to 10% FAP scores increased between PRETEST and POSTTEST. PRE/POSTTEST comparisons also indicated decreases in cycle time and double support and increases in step length and step-extremity ratio (step length/leg length). The results confirm prior findings that auditory stimulation can be used to positively influence the gait of persons with PD and suggest beneficial effects of ASM as an adjunct to dopaminergic therapy to treat gait dysfunctions in PD.

A speculated ribozyme site in the herpes simplex virus type 1 latency-associated transcript gene is not essential for a wild-type reactivation phenotype

PubMed Central

Carpenter, Dale; Singh, Sukhpreet; Osorio, Nelson; Hsiang, Chinhui; Jiang, Xianzhi; Jin, Ling; Jones, Clinton; Wechsler, Steven L

2010-01-01

During herpes simplex virus-1 (HSV-1) latency in sensory neurons, LAT (latency-associated transcript) is the only abundantly expressed viral gene. LAT plays an important role in the HSV-1 latency-reactivation cycle, because LAT deletion mutants have a significantly decreased reactivation phenotype. Based solely on sequence analysis, it was speculated that LAT encodes a ribozyme that plays an important role in how LAT enhances the virus’ reactivation phenotype. Because LAT ribozyme activity has never been reported, we decided to test the converse hypothesis, namely, that this region of LAT does not encode a ribozyme function important for LAT’s ability to enhance the reactivation phenotype. We constructed a viral mutant (LAT-Rz) in which the speculated ribozyme consensus sequence was altered such that no ribozyme was encoded. We report here that LAT-Rz had a wild-type reactivation phenotype in mice, confirming the hypothesis that the speculated LAT ribozyme is not a dominant factor in stimulating the latency-reactivation cycle in mice. PMID:18982533

Reactive stepping behaviour in response to forward loss of balance predicts future falls in community-dwelling older adults.

PubMed

Carty, Christopher P; Cronin, Neil J; Nicholson, Deanne; Lichtwark, Glen A; Mills, Peter M; Kerr, Graham; Cresswell, Andrew G; Barrett, Rod S

2015-01-01

a fall occurs when an individual experiences a loss of balance from which they are unable to recover. Assessment of balance recovery ability in older adults may therefore help to identify individuals at risk of falls. The purpose of this 12-month prospective study was to assess whether the ability to recover from a forward loss of balance with a single step across a range of lean magnitudes was predictive of falls. two hundred and one community-dwelling older adults, aged 65-90 years, underwent baseline testing of sensori-motor function and balance recovery ability followed by 12-month prospective falls evaluation. Balance recovery ability was defined by whether participants required either single or multiple steps to recover from forward loss of balance from three lean magnitudes, as well as the maximum lean magnitude participants could recover from with a single step. forty-four (22%) participants experienced one or more falls during the follow-up period. Maximal recoverable lean magnitude and use of multiple steps to recover at the 15% body weight (BW) and 25%BW lean magnitudes significantly predicted a future fall (odds ratios 1.08-1.26). The Physiological Profile Assessment, an established tool that assesses variety of sensori-motor aspects of falls risk, was also predictive of falls (Odds ratios 1.22 and 1.27, respectively), whereas age, sex, postural sway and timed up and go were not predictive. reactive stepping behaviour in response to forward loss of balance and physiological profile assessment are independent predictors of a future fall in community-dwelling older adults. Exercise interventions designed to improve reactive stepping behaviour may protect against future falls. © The Author 2014. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Reactive oxygen species and fatigue-induced prolonged low-frequency force depression in skeletal muscle fibres of rats, mice and SOD2 overexpressing mice.

PubMed

Bruton, Joseph D; Place, Nicolas; Yamada, Takashi; Silva, José P; Andrade, Francisco H; Dahlstedt, Anders J; Zhang, Shi-Jin; Katz, Abram; Larsson, Nils-Göran; Westerblad, Håkan

2008-01-01

Skeletal muscle often shows a delayed force recovery after fatiguing stimulation, especially at low stimulation frequencies. In this study we focus on the role of reactive oxygen species (ROS) in this fatigue-induced prolonged low-frequency force depression. Intact, single muscle fibres were dissected from flexor digitorum brevis (FDB) muscles of rats and wild-type and superoxide dismutase 2 (SOD2) overexpressing mice. Force and myoplasmic free [Ca(2+)] ([Ca(2+)](i)) were measured. Fibres were stimulated at different frequencies before and 30 min after fatigue induced by repeated tetani. The results show a marked force decrease at low stimulation frequencies 30 min after fatiguing stimulation in all fibres. This decrease was associated with reduced tetanic [Ca(2+)](i) in wild-type mouse fibres, whereas rat fibres and mouse SOD2 overexpressing fibres instead displayed a decreased myofibrillar Ca(2+) sensitivity. The SOD activity was approximately 50% lower in wild-type mouse than in rat FDB muscles. Myoplasmic ROS increased during repeated tetanic stimulation in rat fibres but not in wild-type mouse fibres. The decreased Ca(2+) sensitivity in rat fibres could be partially reversed by application of the reducing agent dithiothreitol, whereas the decrease in tetanic [Ca(2+)](i) in wild-type mouse fibres was not affected by dithiothreitol or the antioxidant N-acetylcysteine. In conclusion, we describe two different causes of fatigue-induced prolonged low-frequency force depression, which correlate to differences in SOD activity and ROS metabolism. These findings may have clinical implications since ROS-mediated impairments in myofibrillar function can be counteracted by reductants and antioxidants, whereas changes in SR Ca(2+) handling appear more resistant to interventions.

Quantification of EEG reactivity in comatose patients.

PubMed

Hermans, Mathilde C; Westover, M Brandon; van Putten, Michel J A M; Hirsch, Lawrence J; Gaspard, Nicolas

2016-01-01

EEG reactivity is an important predictor of outcome in comatose patients. However, visual analysis of reactivity is prone to subjectivity and may benefit from quantitative approaches. In EEG segments recorded during reactivity testing in 59 comatose patients, 13 quantitative EEG parameters were used to compare the spectral characteristics of 1-minute segments before and after the onset of stimulation (spectral temporal symmetry). Reactivity was quantified with probability values estimated using combinations of these parameters. The accuracy of probability values as a reactivity classifier was evaluated against the consensus assessment of three expert clinical electroencephalographers using visual analysis. The binary classifier assessing spectral temporal symmetry in four frequency bands (delta, theta, alpha and beta) showed best accuracy (Median AUC: 0.95) and was accompanied by substantial agreement with the individual opinion of experts (Gwet's AC1: 65-70%), at least as good as inter-expert agreement (AC1: 55%). Probability values also reflected the degree of reactivity, as measured by the inter-experts' agreement regarding reactivity for each individual case. Automated quantitative EEG approaches based on probabilistic description of spectral temporal symmetry reliably quantify EEG reactivity. Quantitative EEG may be useful for evaluating reactivity in comatose patients, offering increased objectivity. Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Quantum mechanical calculations suggest that lytic polysaccharide monooxygenases use a copper-oxyl, oxygen-rebound mechanism

PubMed Central

Kim, Seonah; Ståhlberg, Jerry; Sandgren, Mats; Paton, Robert S.; Beckham, Gregg T.

2014-01-01

Lytic polysaccharide monooxygenases (LPMOs) exhibit a mononuclear copper-containing active site and use dioxygen and a reducing agent to oxidatively cleave glycosidic linkages in polysaccharides. LPMOs represent a unique paradigm in carbohydrate turnover and exhibit synergy with hydrolytic enzymes in biomass depolymerization. To date, several features of copper binding to LPMOs have been elucidated, but the identity of the reactive oxygen species and the key steps in the oxidative mechanism have not been elucidated. Here, density functional theory calculations are used with an enzyme active site model to identify the reactive oxygen species and compare two hypothesized reaction pathways in LPMOs for hydrogen abstraction and polysaccharide hydroxylation; namely, a mechanism that employs a η1-superoxo intermediate, which abstracts a substrate hydrogen and a hydroperoxo species is responsible for substrate hydroxylation, and a mechanism wherein a copper-oxyl radical abstracts a hydrogen and subsequently hydroxylates the substrate via an oxygen-rebound mechanism. The results predict that oxygen binds end-on (η1) to copper, and that a copper-oxyl–mediated, oxygen-rebound mechanism is energetically preferred. The N-terminal histidine methylation is also examined, which is thought to modify the structure and reactivity of the enzyme. Density functional theory calculations suggest that this posttranslational modification has only a minor effect on the LPMO active site structure or reactivity for the examined steps. Overall, this study suggests the steps in the LPMO mechanism for oxidative cleavage of glycosidic bonds. PMID:24344312

A pelvic motion driven electrical stimulator for drop-foot treatment.

PubMed

Chen, Shih-Wei; Chen, Shih-Ching; Chen, Chiun-Fan; Lai, Jin-Shin; Kuo, Te-Son

2009-01-01

Foot switches operating with force sensitive resistors placed in the shoe sole were considered as an effective way for driving FES assisted walking systems in gait restoration. However, the reliability and durability of the foot switches run down after a certain number of steps. As an alternative for foot switches, a simple, portable, and easy to handle motion driven electrical stimulator (ES) is provided for drop foot treatment. The device is equipped with a single tri-axis accelerometer worn on the pelvis, a commercial dual channel electrical stimulator, and a controller unit. By monitoring the pelvic rotation and acceleration during a walking cycle, the events including heel strike and toe off of each step is thereby predicted by a post-processing neural network model.

Vision restoration after brain and retina damage: the "residual vision activation theory".

PubMed

Sabel, Bernhard A; Henrich-Noack, Petra; Fedorov, Anton; Gall, Carolin

2011-01-01

Vision loss after retinal or cerebral visual injury (CVI) was long considered to be irreversible. However, there is considerable potential for vision restoration and recovery even in adulthood. Here, we propose the "residual vision activation theory" of how visual functions can be reactivated and restored. CVI is usually not complete, but some structures are typically spared by the damage. They include (i) areas of partial damage at the visual field border, (ii) "islands" of surviving tissue inside the blind field, (iii) extrastriate pathways unaffected by the damage, and (iv) downstream, higher-level neuronal networks. However, residual structures have a triple handicap to be fully functional: (i) fewer neurons, (ii) lack of sufficient attentional resources because of the dominant intact hemisphere caused by excitation/inhibition dysbalance, and (iii) disturbance in their temporal processing. Because of this resulting activation loss, residual structures are unable to contribute much to everyday vision, and their "non-use" further impairs synaptic strength. However, residual structures can be reactivated by engaging them in repetitive stimulation by different means: (i) visual experience, (ii) visual training, or (iii) noninvasive electrical brain current stimulation. These methods lead to strengthening of synaptic transmission and synchronization of partially damaged structures (within-systems plasticity) and downstream neuronal networks (network plasticity). Just as in normal perceptual learning, synaptic plasticity can improve vision and lead to vision restoration. This can be induced at any time after the lesion, at all ages and in all types of visual field impairments after retinal or brain damage (stroke, neurotrauma, glaucoma, amblyopia, age-related macular degeneration). If and to what extent vision restoration can be achieved is a function of the amount of residual tissue and its activation state. However, sustained improvements require repetitive stimulation which, depending on the method, may take days (noninvasive brain stimulation) or months (behavioral training). By becoming again engaged in everyday vision, (re)activation of areas of residual vision outlasts the stimulation period, thus contributing to lasting vision restoration and improvements in quality of life. Copyright © 2011 Elsevier B.V. All rights reserved.

Potential of adult mammalian lumbosacral spinal cord to execute and acquire improved locomotion in the absence of supraspinal input

NASA Technical Reports Server (NTRS)

Edgerton, V. R.; Roy, R. R.; Hodgson, J. A.; Prober, R. J.; de Guzman, C. P.; de Leon, R.

1992-01-01

The neural circuitry of the lumbar spinal cord can generate alternating extension and flexion of the hindlimbs. The hindlimbs of adult cats with complete transection of the spinal cord at a low thoracic level (T12-T13) can perform full weight-supporting locomotion on a treadmill belt moving at a range of speeds. Some limitations in the locomotor capacity can be associated with a deficit in the recruitment level of the fast extensors during the stance phase and the flexors during the swing phase of a step cycle. The level of locomotor performance, however, can be enhanced by daily training on a treadmill while emphasizing full weight-support stepping and by providing appropriately timed sensory stimulation, loading, and/or pharmacologic stimulation of the hindlimb neuromuscular apparatus. Furthermore, there appears to be an interactive effect of these interventions. For example, the maximum treadmill speed that a spinal adult cat can attain and maintain is significantly improved with daily full weight-supporting treadmill training, but progressive recruitment of fast extensors becomes apparent only when the hindlimbs are loaded by gently pulling down on the tail during the stepping. Stimulation of the sural nerve at the initiation of the flexion phase of the step cycle can likewise markedly improve the locomotor capability. Administration of clonidine, in particular in combination with an elevated load, resulted in the most distinct and consistent alternating bursts of electromyographic activity during spinal stepping. These data indicate that the spinal cord has the ability to execute alternating activation of the extensor and flexor musculature of the hindlimbs (stepping) and that this ability can be improved by several interventions such as training, sensory stimulation, and use of some pharmacologic agents. Thus, it appears that the spinal cord, without supraspinal input, is highly plastic and has the potential to "learn," that is, to acquire and improve its ability to execute full weight-supporting locomotion on a treadmill belt.

Treatment of both native and deamidated gluten peptides with an endo-peptidase from Aspergillus niger prevents stimulation of gut-derived gluten-reactive T cells from either children or adults with celiac disease.

PubMed

Toft-Hansen, Henrik; Rasmussen, Karina S; Staal, Anne; Roggen, Erwin L; Sollid, Ludvig M; Lillevang, Søren T; Barington, Torben; Husby, Steffen

2014-08-01

Celiac disease (CD) is characterized by an inappropriate immunological reaction against gluten driven by gluten-specific CD4+ T cells. We screened 25 proteases and tested 10 for their potential to degrade gluten in vitro. Five proteases were further tested for their ability to prevent the proliferative response by a gluten-specific CD4+ T cell clone and seven gluten-reactive T cell lines to protease-digested gluten peptides. A proline-specific endo-peptidase from Aspergillus niger (AnP2) was particularly efficient at diminishing proliferation after stimulation with cleaved antigen, and could completely block the response against both native and deamidated gluten peptides. We found that AnP2 was efficient down to a 1:64 protease:substrate ratio (w:w). When AnP2 was tested in assays using seven gluten-reactive T cell lines from individual CD patients (three adults and four children), the response to gluten was diminished in all cases. Our study indicates a therapeutic benefit of AnP2 to CD patients. Copyright © 2014 Elsevier Inc. All rights reserved.

Principles of using Cold Atmospheric Plasma Stimulated Media for Cancer Treatment

PubMed Central

Yan, Dayun; Talbot, Annie; Nourmohammadi, Niki; Cheng, Xiaoqian; Canady, Jerome; Sherman, Jonathan; Keidar, Michael

2015-01-01

To date, the significant anti-cancer capacity of cold atmospheric plasma (CAP) on dozens of cancer cell lines has been demonstrated in vitro and in mice models. Conventionally, CAP was directly applied to irradiate cancer cells or tumor tissue. Over past three years, the CAP irradiated media was also found to kill cancer cells as effectively as the direct CAP treatment. As a novel strategy, using the CAP stimulated (CAPs) media has become a promising anti-cancer tool. In this study, we demonstrated several principles to optimize the anti-cancer capacity of the CAPs media on glioblastoma cells and breast cancer cells. Specifically, using larger wells on a multi-well plate, smaller gaps between the plasma source and the media, and smaller media volume enabled us to obtain a stronger anti-cancer CAPs media composition without increasing the treatment time. Furthermore, cysteine was the main target of effective reactive species in the CAPs media. Glioblastoma cells were more resistant to the CAPs media than breast cancer cells. Glioblastoma cells consumed the effective reactive species faster than breast cancer cells did. In contrast to nitric oxide, hydrogen peroxide was more likely to be the effective reactive species. PMID:26677750

Feeling worse to feel better: pain-offset relief simultaneously stimulates positive affect and reduces negative affect.

PubMed

Franklin, Joseph C; Lee, Kent M; Hanna, Eleanor K; Prinstein, Mitchell J

2013-04-01

Although pain itself induces negative affect, the removal (or offset) of pain induces a powerful state of relief. Despite being implicated in a wide range of psychological and behavioral phenomena, relief remains a poorly understood emotion. In particular, some theorists associate relief with increased positive affect, whereas others associate relief with diminished negative affect. In the present study, we examined the affective nature of relief in a pain-offset paradigm with psychophysiological measures that were specific to negative valence (startle eyeblink reactivity) and positive valence (startle postauricular reactivity). Results revealed that pain offset simultaneously stimulates positive affect and diminishes negative affect for at least several seconds. Results also indicated that pain intensity differentially affects the positive and negative valence aspects of relief. These findings clarify the affective nature of relief and provide insight into why people engage in both normal and abnormal behaviors associated with relief.

Effects of permafrost microorganisms on skin wound reparation.

PubMed

Kalenova, L F; Novikova, M A; Subbotin, A M

2015-02-01

Local application of ointment with Bacillus spp. strain MG8 (15,000-20,000 living bacterial cells), isolated from permafrost specimens, on the skin wound of about 60 mm(2) stimulated the reparation processes in experimental mice. A possible mechanism stimulating the regeneration of the damaged tissues under the effect of MG8 could be modulation of the immune system reactivity with more rapid switchover to humoral immunity anti-inflammatory mechanisms aimed at de novo synthesis of protein.

Deep brain stimulation reveals emotional impact processing in ventromedial prefrontal cortex.

PubMed

Gjedde, Albert; Geday, Jacob

2009-12-07

We tested the hypothesis that modulation of monoaminergic tone with deep-brain stimulation (DBS) of subthalamic nucleus would reveal a site of reactivity in the ventromedial prefrontal cortex that we previously identified by modulating serotonergic and noradrenergic mechanisms by blocking serotonin-noradrenaline reuptake sites. We tested the hypothesis in patients with Parkinson's disease in whom we had measured the changes of blood flow everywhere in the brain associated with the deep brain stimulation of the subthalamic nucleus. We determined the emotional reactivity of the patients as the average impact of emotive images rated by the patients off the DBS. We then searched for sites in the brain that had significant correlation of the changes of blood flow with the emotional impact rated by the patients. The results indicate a significant link between the emotional impact when patients are not stimulated and the change of blood flow associated with the DBS. In subjects with a low emotional impact, activity measured as blood flow rose when the electrode was turned on, while in subjects of high impact, the activity at this site in the ventromedial prefrontal cortex declined when the electrode was turned on. We conclude that changes of neurotransmission in the ventromedial prefrontal cortex had an effect on the tissue that depends on changes of monoamine concentration interacting with specific combinations of inhibitory and excitatory monoamine receptors.

Intermittent theta-burst stimulation induces correlated changes in cortical and corticospinal excitability in healthy older subjects.

PubMed

Gedankien, Tamara; Fried, Peter J; Pascual-Leone, Alvaro; Shafi, Mouhsin M

2017-12-01

We studied the correlation between motor evoked potentials (MEPs) and early TMS-evoked EEG potentials (TEPs) from single-pulse TMS before and after intermittent Theta Burst Stimulation (iTBS) to the left primary motor cortex (M1) in 17 healthy older participants. TMS was targeted to the hand region of M1 using a MRI-guided navigated brain stimulation system and a figure-of-eight biphasic coil. MEPs were recorded from the right first dorsal interosseous muscle using surface EMG. TEPs were extracted from a 61-channel EEG recording. Participants received 90 single TMS pulses at 120% of resting motor threshold before and after iTBS. Across all participants, the change in N15-P30 TEP and MEP amplitudes were significantly correlated (r=0.69; p<0.01). Average TEP responses did not change significantly after iTBS, whereas MEP amplitudes showed a significant increase. Changes in corticospinal reactivity and cortical reactivity induced by iTBS are related. However, the effect of iTBS on TEPs, unlike MEPs, is not straightforward. Our findings help elucidate the relationship between changes in cortical and corticospinal excitability in healthy older individuals. Going forward, TEPs may be used to evaluate the effects of theta-burst stimulation in non-motor brain regions. Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

Comparison between treadmill training with rhythmic auditory stimulation and ground walking with rhythmic auditory stimulation on gait ability in chronic stroke patients: A pilot study.

PubMed

Park, Jin; Park, So-yeon; Kim, Yong-wook; Woo, Youngkeun

2015-01-01

Generally, treadmill training is very effective intervention, and rhythmic auditory stimulation is designed to feedback during gait training in stroke patients. The purpose of this study was to compare the gait abilities in chronic stroke patients following either treadmill walking training with rhythmic auditory stimulation (TRAS) or over ground walking training with rhythmic auditory stimulation (ORAS). Nineteen subjects were divided into two groups: a TRAS group (9 subjects) and an ORAS group (10 subjects). Temporal and spatial gait parameters and motor recovery ability were measured before and after the training period. Gait ability was measured by the Biodex Gait trainer treadmill system, Timed up and go test (TUG), 6 meter walking distance (6MWD) and Functional gait assessment (FGA). After the training periods, the TRAS group showed a significant improvement in walking speed, step cycle, step length of the unaffected limb, coefficient of variation, 6MWD, and, FGA when compared to the ORAS group (p <  0.05). Treadmill walking training during the rhythmic auditory stimulation may be useful for rehabilitation of patients with chronic stroke.

Spatiotemporal trajectories of reactivation of somatosensory cortex by direct and secondary pathways after dorsal column lesions in squirrel monkeys

PubMed Central

Qi, Hui-Xin; Wang, Feng; Liao, Chia-Chi; Friedman, Robert M.; Tang, Chaohui; Kaas, Jon H.; Avison, Malcolm J.

2016-01-01

After lesions of the somatosensory dorsal column (DC) pathway, the cortical hand representation can become unresponsive to tactile stimuli, but considerable responsiveness returns over weeks of post-lesion recovery. The reactivation suggests that preserved subthreshold sensory inputs become potentiated and axon sprouting occurs over time to mediate recovery. Here, we studied the recovery process in 3 squirrel monkeys, using high-resolution fMRI CBV-fMRI mapping of contralateral somatosensory cortex responsiveness to stimulation of distal finger pads with low and high level electrocutaneous stimulation (ES) before and 2, 4, and 6 weeks after a high cervical level contralateral DC lesion. Both low and high intensity ES of digits revealed the expected somatotopy of the area 3b hand representation in pre-lesion monkeys, while in areas 1 and 3a, high intensity stimulation was more effective in activating somatotopic patterns. Six weeks post-lesion, and irrespective of the severity of loss of direct DC inputs (98%, 79%, 40%), somatosensory cortical area 3b of all three animals showed near complete recovery in terms of somatotopy and responsiveness to low and high intensity ES. However there was significant variability in the patterns and amplitudes of reactivation of individual digit territories within and between animals, reflecting differences in the degree of permanent and/or transient silencing of primary DC and secondary inputs 2 weeks post-lesion, and their spatio-temporal trajectories of recovery between 2 and 6 weeks. Similar variations in the silencing and recovery of somatotopy and responsiveness to high intensity ES in areas 3a and 1 are consistent with inter-individual differences in collateral damage to and recovery of secondary (e.g. spinothalamic) pathways. Thus, cortical deactivation and subsequent reactivation depends not only on the degree of DC lesion, but also on the severity and duration of loss of secondary as well as primary inputs revealed by low and high intensity ES. PMID:27523450

Biclustering of gene expression data using reactive greedy randomized adaptive search procedure.

PubMed

Dharan, Smitha; Nair, Achuthsankar S

2009-01-30

Biclustering algorithms belong to a distinct class of clustering algorithms that perform simultaneous clustering of both rows and columns of the gene expression matrix and can be a very useful analysis tool when some genes have multiple functions and experimental conditions are diverse. Cheng and Church have introduced a measure called mean squared residue score to evaluate the quality of a bicluster and has become one of the most popular measures to search for biclusters. In this paper, we review basic concepts of the metaheuristics Greedy Randomized Adaptive Search Procedure (GRASP)-construction and local search phases and propose a new method which is a variant of GRASP called Reactive Greedy Randomized Adaptive Search Procedure (Reactive GRASP) to detect significant biclusters from large microarray datasets. The method has two major steps. First, high quality bicluster seeds are generated by means of k-means clustering. In the second step, these seeds are grown using the Reactive GRASP, in which the basic parameter that defines the restrictiveness of the candidate list is self-adjusted, depending on the quality of the solutions found previously. We performed statistical and biological validations of the biclusters obtained and evaluated the method against the results of basic GRASP and as well as with the classic work of Cheng and Church. The experimental results indicate that the Reactive GRASP approach outperforms the basic GRASP algorithm and Cheng and Church approach. The Reactive GRASP approach for the detection of significant biclusters is robust and does not require calibration efforts.

Stepping Stones to Evaluating Your Own School Literacy Program

ERIC Educational Resources Information Center

Levesque, Jeri; Carnahan, Danielle

2005-01-01

Stepping Stones to Literacy is a tool for elementary school improvement teams to evaluate and strengthen their reading programs. Each Stepping Stone is a guided activity to stimulate reflection and guide systematic inquiry. It is a collaborative, active research approach to evaluation (Levesque & Hinton 2001). The goal is to eliminate the gap…

Highly specific detection of H2O2-dependent luminol chemiluminescence in stimulated human leukocytes using polyvinyl films.

PubMed

Moriguchi, K; Ohno, N; Ogawa, T; Hirai, K

1999-01-01

When human polymorphonuclear leukocytes (PMN) were attached to glass coverslips, cells always spread and formed reactive oxygen species prior to any experimental stimulation. To avoid this, a polyvinylidine chloride film was used as an inactive substance to place the cells. Cells engaged in phagocytosis on the film exhibited a specific H2O2-mediated luminol chemiluminescence (LCL) at the cell-particle interface; the cells stimulated with 12-O-tetradecanoylphorbol-13-acetate became aggregated and the LCL was observed at the cell-cell contact. These results corresponded well with those obtained by an electron microscopic H2O2-demonstration method.

Single-Run Single-Mask Inductively-Coupled-Plasma Reactive-Ion-Etching Process for Fabricating Suspended High-Aspect-Ratio Microstructures

NASA Astrophysics Data System (ADS)

Yang, Yao-Joe; Kuo, Wen-Cheng; Fan, Kuang-Chao

2006-01-01

In this work, we present a single-run single-mask (SRM) process for fabricating suspended high-aspect-ratio structures on standard silicon wafers using an inductively coupled plasma-reactive ion etching (ICP-RIE) etcher. This process eliminates extra fabrication steps which are required for structure release after trench etching. Released microstructures with 120 μm thickness are obtained by this process. The corresponding maximum aspect ratio of the trench is 28. The SRM process is an extended version of the standard process proposed by BOSCH GmbH (BOSCH process). The first step of the SRM process is a standard BOSCH process for trench etching, then a polymer layer is deposited on trench sidewalls as a protective layer for the subsequent structure-releasing step. The structure is released by dry isotropic etching after the polymer layer on the trench floor is removed. All the steps can be integrated into a single-run ICP process. Also, only one mask is required. Therefore, the process complexity and fabrication cost can be effectively reduced. Discussions on each SRM step and considerations for avoiding undesired etching of the silicon structures during the release process are also presented.

Toxocara canis adult worm antigen induces proliferative response of healthy human peripheral blood mononuclear cells.

PubMed

Inuo, G; Akao, N; Kohsaka, H; Saito, I; Miyasaka, N; Fujita, K

1995-02-01

The proliferative response of human peripheral blood mononuclear cells (PBMC) from healthy donors to Toxocara canis adult worm antigens (TcA) was examined. PBMC from all donors examined (n = 7) strongly responded to TcA in a dose-dependent fashion after six days of culture, irrespective of their serological reactivity. In contrast, cord blood mononuclear cells did not react to TcA. The proliferation of PBMC in response to TcA was completely inhibited by anti-HLA-DR antibody. Purified CD4+ T cells reconstituted with autologous irradiated antigen presenting cells (APC) vigorously proliferated in response to TcA, but this was abrogated by pretreatment of APC with paraformaldehyde. Significant IL-2, IL-3, IL-4, IL-5 and IFN-gamma mRNA expression was detected in PBMC stimulated with TcA, with expression peaking at 72 h after stimulation. IL-1 beta, IL-6, IL-10 and GM-CSF mRNA expression was also upregulated, peaking at 24 h after stimulation. Taken together, these results suggest that adult T. canis-derived antigens have the ability to activate human PBMC as conventional antigens, possibly due to their cross-reactivity, which may be involved in the host defence against helminth infection.

Structural and kinetic insights into stimulation of RppH-dependent RNA degradation by the metabolic enzyme DapF.

PubMed

Gao, Ang; Vasilyev, Nikita; Luciano, Daniel J; Levenson-Palmer, Rose; Richards, Jamie; Marsiglia, William M; Traaseth, Nathaniel J; Belasco, Joel G; Serganov, Alexander

2018-05-04

Vitally important for controlling gene expression in eukaryotes and prokaryotes, the deprotection of mRNA 5' termini is governed by enzymes whose activity is modulated by interactions with ancillary factors. In Escherichia coli, 5'-end-dependent mRNA degradation begins with the generation of monophosphorylated 5' termini by the RNA pyrophosphohydrolase RppH, which can be stimulated by DapF, a diaminopimelate epimerase involved in amino acid and cell wall biosynthesis. We have determined crystal structures of RppH-DapF complexes and measured rates of RNA deprotection. These studies show that DapF potentiates RppH activity in two ways, depending on the nature of the substrate. Its stimulatory effect on the reactivity of diphosphorylated RNAs, the predominant natural substrates of RppH, requires a substrate long enough to reach DapF in the complex, while the enhanced reactivity of triphosphorylated RNAs appears to involve DapF-induced changes in RppH itself and likewise increases with substrate length. This study provides a basis for understanding the intricate relationship between cellular metabolism and mRNA decay and reveals striking parallels with the stimulation of decapping activity in eukaryotes.

Effects of different frequencies of transcutaneous electrical nerve stimulation on venous vascular reactivity

PubMed Central

Franco, O.S.; Paulitsch, F.S.; Pereira, A.P.C.; Teixeira, A.O.; Martins, C.N.; Silva, A.M.V.; Plentz, R.D.M.; Irigoyen, M.C.; Signori, L.U.

2014-01-01

Transcutaneous electrical nerve stimulation (TENS) is a type of therapy used primarily for analgesia, but also presents changes in the cardiovascular system responses; its effects are dependent upon application parameters. Alterations to the cardiovascular system suggest that TENS may modify venous vascular response. The objective of this study was to evaluate the effects of TENS at different frequencies (10 and 100 Hz) on venous vascular reactivity in healthy subjects. Twenty-nine healthy male volunteers were randomized into three groups: placebo (n=10), low-frequency TENS (10 Hz, n=9) and high-frequency TENS (100 Hz, n=10). TENS was applied for 30 min in the nervous plexus trajectory from the superior member (from cervical to dorsal region of the fist) at low (10 Hz/200 μs) and high frequency (100 Hz/200 μs) with its intensity adjusted below the motor threshold and intensified every 5 min, intending to avoid accommodation. Venous vascular reactivity in response to phenylephrine, acetylcholine (endothelium-dependent) and sodium nitroprusside (endothelium-independent) was assessed by the dorsal hand vein technique. The phenylephrine effective dose to achieve 70% vasoconstriction was reduced 53% (P<0.01) using low-frequency TENS (10 Hz), while in high-frequency stimulation (100 Hz), a 47% increased dose was needed (P<0.01). The endothelium-dependent (acetylcholine) and independent (sodium nitroprusside) responses were not modified by TENS, which modifies venous responsiveness, and increases the low-frequency sensitivity of α1-adrenergic receptors and shows high-frequency opposite effects. These changes represent an important vascular effect caused by TENS with implications for hemodynamics, inflammation and analgesia. PMID:24820225

Heterobimetallic Catalysis: Platinum-Gold-Catalyzed Tandem Cyclization/C-X Coupling Reaction of (Hetero)Arylallenes with Nucleophiles.

PubMed

Alonso, José Miguel; Muñoz, María Paz

2018-04-16

Heterobimetallic catalysis offers new opportunities for reactivity and selectivity but still presents challenges, and only a few metal combinations have been explored so far. Reported here is a Pt-Au heterobimetallic catalyst system for the synthesis of a family of multi-heteroaromatic structures through tandem cyclization/C-X coupling reaction. Au-catalyzed 6-endo-cyclization takes place as the first fast step. Pt-Au clusters are proposed to be responsible for the increased reactivity in the second step, that is, the intermolecular nucleophilic addition which occurs through an outer-sphere mechanism by hybrid homogeneous-heterogeneous catalysis. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Prostaglandin E2 induces expression of P-selectin (CD62P) on cultured human umbilical vein endothelial cells and enhances endothelial binding of CD4-T-cells.

PubMed

Hailer, N P; Oppermann, E; Leckel, K; Cinatl, J; Markus, B H; Blaheta, R A

2000-07-15

Interaction of endothelial P-selectin with sialyl Lewis(x)-glycoprotein or P-selectin glycoprotein ligand (PSGL)-1 on leukocytes represents an early step in leukocyte recruitment. Redistribution of P-selectin to the endothelial cell surface occurs rapidly after challenge with several proinflammatory agents, for example, histamine, leucopterins, or lipopolysaccharide. We present evidence that prostaglandin E2 (PGE2) is an efficient inductor of surface P-selectin on cultured human umbilical vein endothelial cells (HUVEC). The increase in P-selectin-immunoreactivity coincided with redistribution of cytoplasmic P-selectin-reactive granulae to the endothelial cell surface, as visualized by confocal laser microscopic examination. CD4-T-cell adhesion to PGE2-stimulated HUVEC was also enhanced by a factor of 4, and blocking mAb directed against the binding site of P-selectin almost completely abrogated this increase in CD4-T-cell adhesion. In summary, our findings show that liberation of PGE2 is an important inductor of P-selectin surface expression on endothelial cells, resulting in enhanced recruitment of inflammatory cells.

Measuring Physical Activity with Pedometers in Older Adults with Intellectual Disability: Reactivity and Number of Days

ERIC Educational Resources Information Center

Hilgenkamp, Thessa; Van Wijck, Ruud; Evenhuis, Heleen

2012-01-01

The minimum number of days of pedometer monitoring needed to estimate valid average weekly step counts and reactivity was investigated for older adults with intellectual disability. Participants (N = 268) with borderline to severe intellectual disability ages 50 years and older were instructed to wear a pedometer for 14 days. The outcome measure…

Problematic Alcohol Use and Mild Intellectual Disability: Standardization of Pictorial Stimuli for an Alcohol Cue Reactivity Task

ERIC Educational Resources Information Center

van Duijvenbode, Neomi; Didden, Robert; Bloemsaat, Gijs; Engels, Rutger C. M. E.

2012-01-01

The present study focused on the first step in developing a cue reactivity task for studying cognitive biases in individuals with mild to borderline intellectual disability (ID) and alcohol use-related problems: the standardization of pictorial stimuli. Participants (N = 40), both with and without a history of alcohol use-related problems and…

A concise synthesis of optically active solanacol, the germination stimulant for seeds of root parasitic weeds.

PubMed

Kumagai, Hiroshi; Fujiwara, Mami; Kuse, Masaki; Takikawa, Hirosato

2015-01-01

Solanacol, isolated from tobacco (Nicotiana tabacum L.), is a germination stimulant for seeds of root parasitic weeds. A concise synthesis of optically active solanacol has been achieved by employing enzymatic resolution as a key step.

Cardiac parasympathetic reactivation following exercise: implications for training prescription.

PubMed

Stanley, Jamie; Peake, Jonathan M; Buchheit, Martin

2013-12-01

The objective of exercise training is to initiate desirable physiological adaptations that ultimately enhance physical work capacity. Optimal training prescription requires an individualized approach, with an appropriate balance of training stimulus and recovery and optimal periodization. Recovery from exercise involves integrated physiological responses. The cardiovascular system plays a fundamental role in facilitating many of these responses, including thermoregulation and delivery/removal of nutrients and waste products. As a marker of cardiovascular recovery, cardiac parasympathetic reactivation following a training session is highly individualized. It appears to parallel the acute/intermediate recovery of the thermoregulatory and vascular systems, as described by the supercompensation theory. The physiological mechanisms underlying cardiac parasympathetic reactivation are not completely understood. However, changes in cardiac autonomic activity may provide a proxy measure of the changes in autonomic input into organs and (by default) the blood flow requirements to restore homeostasis. Metaboreflex stimulation (e.g. muscle and blood acidosis) is likely a key determinant of parasympathetic reactivation in the short term (0-90 min post-exercise), whereas baroreflex stimulation (e.g. exercise-induced changes in plasma volume) probably mediates parasympathetic reactivation in the intermediate term (1-48 h post-exercise). Cardiac parasympathetic reactivation does not appear to coincide with the recovery of all physiological systems (e.g. energy stores or the neuromuscular system). However, this may reflect the limited data currently available on parasympathetic reactivation following strength/resistance-based exercise of variable intensity. In this review, we quantitatively analyse post-exercise cardiac parasympathetic reactivation in athletes and healthy individuals following aerobic exercise, with respect to exercise intensity and duration, and fitness/training status. Our results demonstrate that the time required for complete cardiac autonomic recovery after a single aerobic-based training session is up to 24 h following low-intensity exercise, 24-48 h following threshold-intensity exercise and at least 48 h following high-intensity exercise. Based on limited data, exercise duration is unlikely to be the greatest determinant of cardiac parasympathetic reactivation. Cardiac autonomic recovery occurs more rapidly in individuals with greater aerobic fitness. Our data lend support to the concept that in conjunction with daily training logs, data on cardiac parasympathetic activity are useful for individualizing training programmes. In the final sections of this review, we provide recommendations for structuring training microcycles with reference to cardiac parasympathetic recovery kinetics. Ultimately, coaches should structure training programmes tailored to the unique recovery kinetics of each individual.

Therapeutic Effects of Caloric Stimulation and Optokinetic Stimulation on Hemispatial Neglect

PubMed Central

Moon, SY; Lee, BH

2006-01-01

Hemispatial neglect refers to a cognitive disorder in which patients with unilateral brain injury cannot recognize or respond to stimuli located in the contralesional hemispace. Hemispatial neglect in stroke patients is an important predictor for poor functional outcome. Therefore, there is a need for effective treatment for this condition. A number of interventions for hemispatial neglect have been proposed, although an approach resulting in persistent improvement is not available. Of these interventions, our review is focused on caloric stimulation and optokinetic stimulation. These lateralized or direction-specific stimulations of peripheral sensory systems can temporarily improve hemispatial neglect. According to recent functional MRI and PET studies, this improvement might result from the partial (re)activation of a distributed, multisensory vestibular network in the lesioned hemisphere, which is a part of a system that codes ego-centered space. However, much remain unknown regarding exact signal timing and directional selectivity of the network. PMID:20396481

Surface Modified Particles By Multi-Step Addition And Process For The Preparation Thereof

DOEpatents

Cook, Ronald Lee; Elliott, Brian John; Luebben, Silvia DeVito; Myers, Andrew William; Smith, Bryan Matthew

2006-01-17

The present invention relates to a new class of surface modified particles and to a multi-step surface modification process for the preparation of the same. The multi-step surface functionalization process involves two or more reactions to produce particles that are compatible with various host systems and/or to provide the particles with particular chemical reactivities. The initial step comprises the attachment of a small organic compound to the surface of the inorganic particle. The subsequent steps attach additional compounds to the previously attached organic compounds through organic linking groups.

Structure reactivity and thermodynamic analysis on the oxidation of ampicillin drug by copper(III) complex in aqueous alkaline medium (stopped-flow technique)

NASA Astrophysics Data System (ADS)

Shetti, Nagaraj P.; Hegde, Rajesh N.; Nandibewoor, Sharanappa T.

2009-07-01

Oxidation of penicillin derivative, ampicillin (AMP) by diperiodatocuprate(III) (DPC) in alkaline medium at a constant ionic strength of 0.01-mol dm -3 was studied spectrophotometrically. The reaction between DPC and ampicillin in alkaline medium exhibits 1:4 stoichiometry (ampicillin:DPC). Intervention of free radicals was observed in the reaction. Based on the observed orders and experimental evidences, a mechanism involving the protonated form of DPC as the reactive oxidant species has been proposed. The oxidation reaction in alkaline medium has been shown to proceed via a DPC-AMP complex, which decomposes slowly in a rate determining step to yield phenyl glycine (PG) and free radical species of 6-aminopenicillanic acid (6-APA), followed by other fast steps to give the products. The two major products were characterized by IR, NMR, LC-MS and Spot test. The reaction constants involved in the different steps of the mechanism were calculated. The activation parameters with respect to slow step of the mechanism were computed and discussed and thermodynamic quantities were also determined.

Electronic bypass of spinal lesions: activation of lower motor neurons directly driven by cortical neural signals.

PubMed

Li, Yan; Alam, Monzurul; Guo, Shanshan; Ting, K H; He, Jufang

2014-07-03

Lower motor neurons in the spinal cord lose supraspinal inputs after complete spinal cord injury, leading to a loss of volitional control below the injury site. Extensive locomotor training with spinal cord stimulation can restore locomotion function after spinal cord injury in humans and animals. However, this locomotion is non-voluntary, meaning that subjects cannot control stimulation via their natural "intent". A recent study demonstrated an advanced system that triggers a stimulator using forelimb stepping electromyographic patterns to restore quadrupedal walking in rats with spinal cord transection. However, this indirect source of "intent" may mean that other non-stepping forelimb activities may false-trigger the spinal stimulator and thus produce unwanted hindlimb movements. We hypothesized that there are distinguishable neural activities in the primary motor cortex during treadmill walking, even after low-thoracic spinal transection in adult guinea pigs. We developed an electronic spinal bridge, called "Motolink", which detects these neural patterns and triggers a "spinal" stimulator for hindlimb movement. This hardware can be head-mounted or carried in a backpack. Neural data were processed in real-time and transmitted to a computer for analysis by an embedded processor. Off-line neural spike analysis was conducted to calculate and preset the spike threshold for "Motolink" hardware. We identified correlated activities of primary motor cortex neurons during treadmill walking of guinea pigs with spinal cord transection. These neural activities were used to predict the kinematic states of the animals. The appropriate selection of spike threshold value enabled the "Motolink" system to detect the neural "intent" of walking, which triggered electrical stimulation of the spinal cord and induced stepping-like hindlimb movements. We present a direct cortical "intent"-driven electronic spinal bridge to restore hindlimb locomotion after complete spinal cord injury.

Neutrophil extracellular traps release induced by Leishmania: role of PI3Kγ, ERK, PI3Kσ, PKC, and [Ca2+

PubMed Central

DeSouza-Vieira, Thiago; Guimarães-Costa, Anderson; Rochael, Natalia C.; Lira, Maria N.; Nascimento, Michelle T.; Lima-Gomez, Phillipe de Souza; Mariante, Rafael M.; Persechini, Pedro M.; Saraiva, Elvira M.

2016-01-01

Upon in vitro stimulation, neutrophils undergo a cell death named netosis. This process is characterized by extracellular release of chromatin scaffold associated with granular and cytoplasmic proteins, which together, ensnare and kill microbes. We have previously described that interaction of Leishmania amazonensis with human neutrophils leads to the release of neutrophil extracellular traps, which trap and kill the parasite. However, the signaling leading to Leishmania induced netosis is still unknown. Thus, we sought to evaluate signaling events that drive L. amazonensis induced neutrophil extracellular trap release from human neutrophils. Here, we found that PI3K, independently of protein kinase B, has a role in parasite-induced netosis. We also described that the main isoforms involved are PI3Kγ and PI3Kδ, which work in reactive oxygen species-dependent and -independent ways, respectively. We demonstrated that activation of ERK downstream of PI3Kγ is important to trigger reactive oxygen species-dependent, parasite-induced netosis. Pharmacological inhibition of protein kinase C also significantly decreased parasite-induced neutrophil extracellular trap release. Intracellular calcium, regulated by PI3Kδ, represents an alternative reactive oxygen species-independent pathway of netosis stimulated by L. amazonensis. Finally, intracellular calcium mobilization and reactive oxygen species generation are the major regulators of parasite-induced netosis. Our results contribute to a better understanding of the signaling behind netosis induced by interactions between Leishmania and neutrophils. PMID:27154356

Cortisol Reactivity in Two-Year-Old Children Prenatally Exposed to Methamphetamine

PubMed Central

Kirlic, Namik; Newman, Elana; LaGasse, Linda L.; Derauf, Chris; Shah, Rizwan; Smith, Lynne M.; Arria, Amelia M.; Huestis, Marilyn A.; Haning, William; Strauss, Arthur; Dellagrotta, Sheri; Dansereau, Lynne M.; Abar, Beau; Neal, Charles R.; Lester, Barry M.

2013-01-01

Objective: Until now, the functioning of the hypothalamic–pituitary–adrenal (HPA) axis in children with prenatal methamphetamine exposure (PME) had been unexamined. Previous research indicates that prenatal exposure to stimulant drugs is associated with dose-response alterations in neural growth and connectivity and consequent neurobehavioral deficits. In addition, children of drug-using parents are at an increased risk for exposure to chronic postnatal stress. In this preliminary study, we examined the associations of PME and postnatal environmental stress with cortisol stress reactivity in children with PME. Method: Participants were 2-year-old children (N = 123; 55.3% male) with PME from a multicenter longitudinal Infant, Development, Environment, and Lifestyle Study. Saliva samples were obtained before and after a stress-inducing separation task. Hierarchical multiple regression analyses examined prenatal drug exposure, methodological and postnatal stress covariates, and interactions between levels of PME and postnatal stress. Results: Mild to moderate potential for child physical abuse moderated increased cortisol reactivity in high exposed children with PME. Blunted cortisol reactivity was associated with caregiver’s postnatal alcohol use, child’s behavioral dysregulation, and the interaction between higher levels of PME and caregiver’s psychopathology. Conclusions: Consistent with the known effects of stimulant drugs and chronically stressful environments on the HPA axis and, thus, the toxic stress and allostatic load phenomena, our results imply that elevated PME may be associated with alterations in the programming of the HPA axis reflecting hyperactivity, which under significant and chronic environmental stress then may become hypoactive. PMID:23490574

Characterisation of vaccine-induced, broadly cross-reactive IFN-γ secreting T cell responses that correlate with rapid protection against classical swine fever virus.

PubMed

Graham, Simon P; Haines, Felicity J; Johns, Helen L; Sosan, Olubukola; La Rocca, S Anna; Lamp, Benjamin; Rümenapf, Till; Everett, Helen E; Crooke, Helen R

2012-04-05

Live attenuated C-strain classical swine fever viruses (CSFV) provide a rapid onset of protection, but the lack of a serological test that can differentiate vaccinated from infected animals limits their application in CSF outbreaks. Since immunity may precede antibody responses, we examined the kinetics and specificity of peripheral blood T cell responses from pigs vaccinated with a C-strain vaccine and challenged after five days with a genotypically divergent CSFV isolate. Vaccinated animals displayed virus-specific IFN-γ responses from day 3 post-challenge, whereas, unvaccinated challenge control animals failed to mount a detectable response. Both CD4(+) and cytotoxic CD8(+) T cells were identified as the cellular source of IFN-γ. IFN-γ responses showed extensive cross-reactivity when T cells were stimulated with CSFV isolates spanning the major genotypes. To determine the specificity of these responses, T cells were stimulated with recombinant CSFV proteins and a proteome-wide peptide library from a related virus, BVDV. Major cross-reactive peptides were mapped on the E2 and NS3 proteins. Finally, IFN-γ was shown to exert potent antiviral effects on CSFV in vitro. These data support the involvement of broadly cross-reactive T cell IFN-γ responses in the rapid protection conferred by the C-strain vaccine and this information should aid the development of the next generation of CSFV vaccines. Crown Copyright © 2012. Published by Elsevier Ltd. All rights reserved.

Decreased dopamine brain reactivity in marijuana abusers is associated with negative emotionality and addiction severity

PubMed Central

Volkow, Nora D.; Wang, Gene-Jack; Telang, Frank; Fowler, Joanna S.; Alexoff, David; Logan, Jean; Jayne, Millard; Wong, Christopher; Tomasi, Dardo

2014-01-01

Moves to legalize marijuana highlight the urgency to investigate effects of chronic marijuana in the human brain. Here, we challenged 48 participants (24 controls and 24 marijuana abusers) with methylphenidate (MP), a drug that elevates extracellular dopamine (DA) as a surrogate for probing the reactivity of the brain to DA stimulation. We compared the subjective, cardiovascular, and brain DA responses (measured with PET and [11C]raclopride) to MP between controls and marijuana abusers. Although baseline (placebo) measures of striatal DA D2 receptor availability did not differ between groups, the marijuana abusers showed markedly blunted responses when challenged with MP. Specifically, compared with controls, marijuana abusers had significantly attenuated behavioral (“self-reports” for high, drug effects, anxiety, and restlessness), cardiovascular (pulse rate and diastolic blood pressure), and brain DA [reduced decreases in distribution volumes (DVs) of [11C]raclopride, although normal reductions in striatal nondisplaceable binding potential (BPND)] responses to MP. In ventral striatum (key brain reward region), MP-induced reductions in DVs and BPND (reflecting DA increases) were inversely correlated with scores of negative emotionality, which were significantly higher for marijuana abusers than controls. In marijuana abusers, DA responses in ventral striatum were also inversely correlated with addiction severity and craving. The attenuated responses to MP, including reduced decreases in striatal DVs, are consistent with decreased brain reactivity to the DA stimulation in marijuana abusers that might contribute to their negative emotionality (increased stress reactivity and irritability) and addictive behaviors. PMID:25024177

Interactions of cervico-ocular and vestibulo-ocular fast-phase signals in the control of eye position in rabbits.

PubMed Central

Barmack, N H; Errico, P; Ferraresi, A; Pettorossi, V E

1989-01-01

1. Eye movements in unanaesthetized rabbits were studied during horizontal neck-proprioceptive stimulation (movement of the body with respect to the fixed head), when this stimulation was given alone and when it was given simultaneously with vestibular stimulation (rotation of the head-body). The effect of neck-proprioceptive stimulation on modifying the anticompensatory fast-phase eye movements (AFPs) evoked by vestibular stimulation was studied with a 'conditioning-test' protocol; the 'conditioning' stimulus was a neck-proprioceptive signal evoked by a step-like change in body position with respect to the head and the 'test' stimulus was a vestibular signal evoked by a step rotation of the head-body. 2. The influence of eye position and direction of slow eye movements on the occurrence of compensatory fast-phase eye movements (CFPs) evoked by neck-proprioceptive stimulation was also examined. 3. The anticompensatory fast phase (AFP) evoked by vestibular stimulation was attenuated by a preceding neck-proprioceptive stimulus which when delivered alone evoked compensatory slow-phase eye movements (CSP) in the same direction as the CSP evoked by vestibular stimulation. Conversely, the vestibularly evoked AFP was potentiated by a neck-proprioceptive stimulus which evoked CSPs opposite to that of vestibularly evoked CSPs. 4. Eccentric initial eye positions increased the probability of occurrence of midline-directed compensatory fast-phase eye movements (CFPs) evoked by appropriate neck-proprioceptive stimulation. 5. The gain of the horizontal cervico-ocular reflex (GHCOR) was measured from the combined changes in eye position resulting from AFPs and CSPs. GHCOR was potentiated during simultaneous vestibular stimulation. This enhancement of GHCOR occurred at neck-proprioceptive stimulus frequencies which, in the absence of conjoint vestibular stimulation, do not evoke CSPs. PMID:2795479

Mechanisms of deep benzene oxidation on the Pt(1 1 1) surface using temperature-programmed reaction methods

NASA Astrophysics Data System (ADS)

Marsh, Anderson L.; Gland, John L.

2003-06-01

The catalytic oxidation of benzene on the Pt(1 1 1) surface has been characterized using temperature-programmed reaction spectroscopy (TPRS) over a wide range of benzene and oxygen coverages. Coadsorbed atomic oxygen and benzene are the primary reactants on the surface during the initial oxidation step. Benzene is oxidized over the 300-500 K range to produce carbon dioxide and water. Carbon-hydrogen and carbon-carbon bond activation are clearly rate-limiting steps for these reactions. Preferential oxidation causes depletion of bridge-bonded benzene, suggesting enhanced reactivity in this bonding configuration. When oxygen is in excess on the surface, all of the surface carbon and hydrogen is oxidized. When benzene is in excess on the surface, hydrogen produced by dehydrogenation is desorbed after all of the surface oxygen has been consumed. Repulsive interactions between benzene and molecular oxygen dominate at low temperatures. Preadsorption of oxygen inhibits adsorption of less reactive benzene in threefold hollow sites. The desorption temperature of this non-reactive chemisorbed benzene decreases and overlaps with the multilayer desorption peak with increasing oxygen exposure. The results presented here provide a clear picture of rate-limiting steps during deep oxidation of benzene on the Pt(1 1 1) surface.

Accelerometer-based step initiation control for gait-assist neuroprostheses.

PubMed

Foglyano, Kevin M; Schnellenberger, John R; Kobetic, Rudi; Lombardo, Lisa; Pinault, Gilles; Selkirk, Stephen; Makowski, Nathaniel S; Triolo, Ronald J

2016-01-01

Electrical activation of paralyzed musculature can generate or augment joint movements required for walking after central nervous system trauma. Proper timing of stimulation relative to residual volitional control is critical to usefully affecting ambulation. This study evaluates three-dimensional accelerometers and customized algorithms to detect the intent to step from voluntary movements to trigger stimulation during walking in individuals with significantly different etiologies, mobility limitations, manual dexterities, and walking aids. Three individuals with poststroke hemiplegia or partial spinal cord injury exhibiting varying gait deficits were implanted with multichannel pulse generators to provide joint motions at the hip, knee, and ankle. An accelerometer integrated into the external control unit was used to detect heel strike or walker movement, and wireless accelerometers were used to detect crutch strike. Algorithms were developed for each sensor location to detect intent to step to progress through individualized stimulation patterns. Testing these algorithms produced detection accuracies of at least 90% on both level ground and uneven terrain. All participants use their accelerometer-triggered implanted gait systems in the community; the validation/system testing was completed in the hospital. The results demonstrated that safe, reliable, and convenient accelerometer-based step initiation can be achieved regardless of specific gait deficits, manual dexterities, and walking aids.

Initial antibodies binding to HIV-1 gp41 in acutely infected subjects are polyreactive and highly mutated

PubMed Central

Chen, Xi; Munshaw, Supriya; Zhang, Ruijun; Marshall, Dawn J.; Vandergrift, Nathan; Whitesides, John F.; Lu, Xiaozhi; Yu, Jae-Sung; Hwang, Kwan-Ki; Gao, Feng; Markowitz, Martin; Heath, Sonya L.; Bar, Katharine J.; Goepfert, Paul A.; Montefiori, David C.; Shaw, George C.; Alam, S. Munir; Margolis, David M.; Denny, Thomas N.; Boyd, Scott D.; Marshal, Eleanor; Egholm, Michael; Simen, Birgitte B.; Hanczaruk, Bozena; Fire, Andrew Z.; Voss, Gerald; Kelsoe, Garnett; Tomaras, Georgia D.; Moody, M. Anthony; Kepler, Thomas B.

2011-01-01

The initial antibody response to HIV-1 is targeted to envelope (Env) gp41, and is nonneutralizing and ineffective in controlling viremia. To understand the origins and characteristics of gp41-binding antibodies produced shortly after HIV-1 transmission, we isolated and studied gp41-reactive plasma cells from subjects acutely infected with HIV-1. The frequencies of somatic mutations were relatively high in these gp41-reactive antibodies. Reverted unmutated ancestors of gp41-reactive antibodies derived from subjects acutely infected with HIV-1 frequently did not react with autologous HIV-1 Env; however, these antibodies were polyreactive and frequently bound to host or bacterial antigens. In one large clonal lineage of gp41-reactive antibodies, reactivity to HIV-1 Env was acquired only after somatic mutations. Polyreactive gp41-binding antibodies were also isolated from uninfected individuals. These data suggest that the majority of gp41-binding antibodies produced after acute HIV-1 infection are cross-reactive responses generated by stimulating memory B cells that have previously been activated by non–HIV-1 antigens. PMID:21987658

Low indoleamine 2,3-dioxygenase activity in persistent food allergy in children.

PubMed

Buyuktiryaki, B; Sahiner, U M; Girgin, G; Birben, E; Soyer, O U; Cavkaytar, O; Cetin, C; Arik Yilmaz, E; Yavuz, S T; Kalayci, O; Baydar, T; Sackesen, C

2016-02-01

Indoleamine 2,3-dioxygenase (IDO), which degrades tryptophan (Trp) to kynurenine (Kyn), has been demonstrated to contribute to modulation of allergic responses. However, the role of IDO in food allergy has not yet been elucidated. Serum Trp and Kyn concentrations were analyzed by high-pressure liquid chromatography. Expression of IDO gene was measured by real-time PCR. The levels of interleukin (IL)-4, IL-10, and interferon (IFN)-γ in cell culture supernatants were measured by ELISA. Kyn/Trp (IDO activity) was significantly lower in subjects with food allergy (n = 100) than in aged-matched healthy controls (n = 112) (P = 0.004). Kyn/Trp was decreased from healthy through completely tolerant, partially tolerant, and reactive ones [LN transformation (mean ± SEM) healthy: 3.9 ± 0.02 μM/mM; completely tolerant: 3.83 ± 0.04; partially tolerant: 3.8 ± 0.06; reactive: 3.7 ± 0.04] (P = 0.008). The frequency of genetic polymorphisms of IDO did not reveal a significant association with Trp, Kyn, and Kyn/Trp in healthy and food-allergic cases. Culture of PBMC experiments yielded that IDO mRNA expression was not different between tolerant and reactive groups. IL-4 synthesis when stimulated with casein increased significantly in subjects who are reactive and tolerant to foods (P = 0.042, P = 0.006, respectively). Increase in IL-10 synthesis was observed only in children tolerant to milk, but not in reactive ones. IFN-γ synthesis, when stimulated with IL-2 and β-lactoglobulin in cell culture, was significantly higher in subjects tolerant to milk than in the reactive ones (P = 0.005 and P = 0.029, respectively). Our results imply the probability of involvement of IDO in development of tolerance process, and we presume that high IDO activity is associated with nonresponsiveness to food allergens despite allergen sensitization. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Integration of advanced preparation with coal liquefaction. Second quarterly technical progress report, January 1-March 31, 1984

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

Steedman, W.G.; Longanbach, J.R.; Muralidhara, H.S.

Standard reaction conditions of 427 C, 5 minutes reaction time, 2:1 solvent/coal ratio and 1000 psig (r.t.) hydrogen overpressure result in good, but not maximum, conversions to THF soluble with both Illinois No. 6 and Wyodak (upper seam) coals. The cumulative effects of the pretreatment steps were also examined using feedstocks which were dried in a vacuum oven at room temperature under nitrogen before liquefaction to remove the effects of moisture. Chloride removal followed by drying had a positive effect on liquefaction. Oil agglomeration followed by drying also improved liquefaction reactivity significantly. Solvent drying also resulted in a small increasemore » in liquefaction reactivity. The overall reactivity of coal treated in sequence with each pretreatment step was slightly less than that of the dry ground coal. Liquefaction under a high partial pressure of hydrogen sulfide in hydrogen also results in a significant increase in conversion to THF solubles. 1 reference, 12 figures, 7 tables.« less

Mutation analysis of the fusion domain region of St. Louis encephalitis virus envelope protein

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

Trainor, Nicole B.; Crill, Wayne D.; Roberson, Jill A.

2007-04-10

The immune response to flavivirus infections produces both species-specific and flavivirus cross-reactive antibodies. The presence of cross-reactive antibodies complicates serodiagnosis of flavivirus infections, especially secondary infections caused by a heterologous virus. A successful public health response to the growing global threat posed by flaviviruses necessitates the development of virus-specific diagnostic antigens. The flavivirus envelope (E) glycoprotein is the principle antigen stimulating protective immunity during infection. Using recombinant St. Louis encephalitis virus-like particles (VLPs), we have identified amino acid residues involved in flavivirus cross-reactive epitope determinants. Most significant among the residues studied are three highly conserved amino acids in the fusionmore » peptide: Gly104, Gly106, and Leu107. Substitutions of these residues dramatically influenced VLP secretion and cross-reactive monoclonal antibody reactivity. These results provide critical insight into the antigenic structure of the flaviviral E protein and toward development of species-specific diagnostic antigens that should improve both flavivirus diagnosis and estimates of disease burden.« less

Cognitive Therapy Skills Predict Cognitive Reactivity to Sad Mood Following Cognitive Therapy for Depression

PubMed Central

Strunk, Daniel R.; Adler, Abby D.; Hollars, Shannon N.

2013-01-01

Both patients’ competence in the coping skills taught in Cognitive Therapy (CT) and patients’ endorsement of dysfunctional cognitions following a sad mood induction (i.e., their cognitive reactivity) have been found to predict risk of relapse following a successful course of CT for depression. We examined the relationship between these constructs, specifically whether CT skills would be related to less cognitive reactivity following a mood induction among patients who responded to a course of CT. In a sample of 28 depressed patients, post-treatment CT skills were significantly related to less cognitive reactivity in response to a sad mood induction procedure (β = −.29). This relation was not accounted for by individual differences in mood reactivity. We discuss these findings as a key step in developing a more complete understanding of the role of CT coping skills and cognitive reactivity as markers of patients’ vulnerability to relapse. PMID:24363473

Developmental expression of the glutathione S-transferase Yo subunit in the rat testis and epididymis using light microscope immunocytochemistry.

PubMed

Papp, S; Robaire, B; Hermo, L

1994-11-01

Glutathione S-transferases (GSTs) are a family of isozymes that catalyze the conjugation of glutathione with various toxic electrophilic compounds. GSTs are composed of several classes based on the degree of sequence homology of their subunits. The Yo subunit, a member of the mu class, is expressed at high levels in the testis and epididymis. The purpose of this study was to immunolocalize the GST-Yo in these tissues during development. The testes and epididymides of rats aged 7, 15, 21, 28, 39, 42, 45, 49, and 56 days were fixed in Bouin's fixative, and immunostained for light microscopic analysis. In the testis the cytoplasm of all germ cells was unreactive until day 39. At that time, step 18 spermatids appeared moderately reactive, while the few observed step 19 spermatids were intensely reactive as were their residual bodies. The presence of residual bodies indicates that spermiation takes place as early as day 39; however, the number of step 19 spermatids is low at this age. A progressive increase in the size of the tubule and number of elongating spermatids was seen between days 42 and 49. In addition, by day 49, a weak staining was observed in steps 12-15, moderate in steps 16-17, and intense in steps 18-19 spermatids. In terms of the intensity of staining, cell types stained, size of the tubules, and number of elongating spermatids, no difference was noted between day 49, 56, and adult animals. Thus Yo protein expression in germ cells reached maturity by day 49. The epithelial cells of the rete testis were intensely reactive at day 7 and remained so throughout development. In contrast, while the epithelial cells of the efferent ducts at day 7 were intensely reactive, they were weakly reactive by day 39 and remained so at later ages. Along the entire epididymis, the columnar epithelial cells showed a moderate apical/supranuclear reaction from day 7 to 28. By day 39 principal cells of the initial segment became weakly reactive, while those in the caput and corpus were moderately stained, a situation seen at later ages including adults. Only by day 49 did principal cells of the proximal cauda become moderately stained as seen in adult animals. Thus the expression of the Yo protein in the principal cells of the proximal cauda may be regulated by different factors than those of the caput and corpus epididymidis. Alternatively, the expression of the Yo subunit in principal cells of the proximal cauda may develop later since this region would be the last to receive luminally derived testicular products. In the initial segment, the decrease in staining of principal cells at day 39 may be due to an inhibiting factor emanating from the testis. Spermatozoa appeared in the lumen of each epididymal region well after the expression of Yo had reached its adult staining pattern indicating that they are not a factor. Overall these results suggest that the expression of GST-Yo in the various cells of the testis and epididymis are controlled by different factors during postnatal development.

Comparison of Gait Aspects According to FES Stimulation Position Applied to Stroke Patients

PubMed Central

Mun, Byeong-mu; Kim, Tae-ho; Lee, Jin-hwan; Lim, Jin-youg; Seo, Dong-kwon; Lee, Dong-jin

2014-01-01

[Purpose] This study sought to identify the gait aspects according to the FES stimulation position in stroke patients during gait training. [Subjects and Methods] To perform gait analysis, ten stroke patients were grouped based on 4 types of gait conditions: gait without FES stimulation (non-FES), gait with FES stimulation on the tibialis anterior (Ta), gait with FES stimulation on the tibialis anterior and quadriceps (TaQ), and gait with FES stimulation on the tibialis anterior and gluteus medius (TaGm). [Results] Based on repeated measures analysis of variance of measurements of gait aspects comprised of gait speed, gait cycle, and step length according to the FES stimulation position, the FES stimulation significantly affected gait aspects. [Conclusion] In conclusion, stimulating the tibialis anterior and quadriceps and stimulating the tibialis anterior and gluteus medius are much more effective than stimulating only the tibialis anterior during gait training in stroke patients using FES. PMID:24764634

Stimulated Brillouin scattering continuous wave phase conjugation in step-index fiber optics.

PubMed

Massey, Steven M; Spring, Justin B; Russell, Timothy H

2008-07-21

Continuous wave (CW) stimulated Brillouin scattering (SBS) phase conjugation in step-index optical fibers was studied experimentally and modeled as a function of fiber length. A phase conjugate fidelity over 80% was measured from SBS in a 40 m fiber using a pinhole technique. Fidelity decreases with fiber length, and a fiber with a numerical aperture (NA) of 0.06 was found to generate good phase conjugation fidelity over longer lengths than a fiber with 0.13 NA. Modeling and experiment support previous work showing the maximum interaction length which yields a high fidelity phase conjugate beam is inversely proportional to the fiber NA(2), but find that fidelity remains high over much longer fiber lengths than previous models calculated. Conditions for SBS beam cleanup in step-index fibers are discussed.

Feed forward and feedback control for over-ground locomotion in anaesthetized cats

NASA Astrophysics Data System (ADS)

Mazurek, K. A.; Holinski, B. J.; Everaert, D. G.; Stein, R. B.; Etienne-Cummings, R.; Mushahwar, V. K.

2012-04-01

The biological central pattern generator (CPG) integrates open and closed loop control to produce over-ground walking. The goal of this study was to develop a physiologically based algorithm capable of mimicking the biological system to control multiple joints in the lower extremities for producing over-ground walking. The algorithm used state-based models of the step cycle each of which produced different stimulation patterns. Two configurations were implemented to restore over-ground walking in five adult anaesthetized cats using intramuscular stimulation (IMS) of the main hip, knee and ankle flexor and extensor muscles in the hind limbs. An open loop controller relied only on intrinsic timing while a hybrid-CPG controller added sensory feedback from force plates (representing limb loading), and accelerometers and gyroscopes (representing limb position). Stimulation applied to hind limb muscles caused extension or flexion in the hips, knees and ankles. A total of 113 walking trials were obtained across all experiments. Of these, 74 were successful in which the cats traversed 75% of the 3.5 m over-ground walkway. In these trials, the average peak step length decreased from 24.9 ± 8.4 to 21.8 ± 7.5 (normalized units) and the median number of steps per trial increased from 7 (Q1 = 6, Q3 = 9) to 9 (8, 11) with the hybrid-CPG controller. Moreover, within these trials, the hybrid-CPG controller produced more successful steps (step length ≤ 20 cm ground reaction force ≥ 12.5% body weight) than the open loop controller: 372 of 544 steps (68%) versus 65 of 134 steps (49%), respectively. This supports our previous preliminary findings, and affirms that physiologically based hybrid-CPG approaches produce more successful stepping than open loop controllers. The algorithm provides the foundation for a neural prosthetic controller and a framework to implement more detailed control of locomotion in the future.

Feed forward and feedback control for over-ground locomotion in anaesthetized cats

PubMed Central

Mazurek, K A; Holinski, B J; Everaert, D G; Stein, R B; Etienne-Cummings, R; Mushahwar, V K

2012-01-01

The biological central pattern generator (CPG) integrates open and closed loop control to produce over-ground walking. The goal of this study was to develop a physiologically based algorithm capable of mimicking the biological system to control multiple joints in the lower extremities for producing over-ground walking. The algorithm used state-based models of the step cycle each of which produced different stimulation patterns. Two configurations were implemented to restore over-ground walking in five adult anaesthetized cats using intramuscular stimulation (IMS) of the main hip, knee and ankle flexor and extensor muscles in the hind limbs. An open loop controller relied only on intrinsic timing while a hybrid-CPG controller added sensory feedback from force plates (representing limb loading), and accelerometers and gyroscopes (representing limb position). Stimulation applied to hind limb muscles caused extension or flexion in the hips, knees and ankles. A total of 113 walking trials were obtained across all experiments. Of these, 74 were successful in which the cats traversed 75% of the 3.5 m over-ground walkway. In these trials, the average peak step length decreased from 24.9 ± 8.4 to 21.8 ± 7.5 (normalized units) and the median number of steps per trial increased from 7 (Q1=6, Q3 = 9) to 9 (8, 11) with the hybrid-CPG controller. Moreover, these trials, the hybrid-CPG controller produced more successful steps (step length ≤ 20 cm; ground reaction force ≥ 12.5% body weight) than the open loop controller: 372 of 544 steps (68%) versus 65 of 134 steps (49%), respectively. This supports our previous preliminary findings, and affirms that physiologically based hybrid-CPG approaches produce more successful stepping than open loop controllers. The algorithm provides the foundation for a neural prosthetic controller and a framework to implement more detailed control of locomotion in the future. PMID:22328615

A Hybrid Neuromechanical Ambulatory Assist System

DTIC Science & Technology

2016-08-01

provide real- time closed-loop control using brace mounted sensors to deliver the stimulation needed to stand up and walk while coordinating exoskeletal...target PC during real- time implementation. The muscle stimulator unit delivered the NES to target paralyzed muscles to drive limb motion. The activity...manual adjustment of thresholds used in the GED and stimulation pattern lengths (Figure 26b). The time for a right or left step could be decreased

Biclustering of gene expression data using reactive greedy randomized adaptive search procedure

PubMed Central

Dharan, Smitha; Nair, Achuthsankar S

2009-01-01

Background Biclustering algorithms belong to a distinct class of clustering algorithms that perform simultaneous clustering of both rows and columns of the gene expression matrix and can be a very useful analysis tool when some genes have multiple functions and experimental conditions are diverse. Cheng and Church have introduced a measure called mean squared residue score to evaluate the quality of a bicluster and has become one of the most popular measures to search for biclusters. In this paper, we review basic concepts of the metaheuristics Greedy Randomized Adaptive Search Procedure (GRASP)-construction and local search phases and propose a new method which is a variant of GRASP called Reactive Greedy Randomized Adaptive Search Procedure (Reactive GRASP) to detect significant biclusters from large microarray datasets. The method has two major steps. First, high quality bicluster seeds are generated by means of k-means clustering. In the second step, these seeds are grown using the Reactive GRASP, in which the basic parameter that defines the restrictiveness of the candidate list is self-adjusted, depending on the quality of the solutions found previously. Results We performed statistical and biological validations of the biclusters obtained and evaluated the method against the results of basic GRASP and as well as with the classic work of Cheng and Church. The experimental results indicate that the Reactive GRASP approach outperforms the basic GRASP algorithm and Cheng and Church approach. Conclusion The Reactive GRASP approach for the detection of significant biclusters is robust and does not require calibration efforts. PMID:19208127

Reactivity of propene, n-butene, and isobutene in the hydrogen transfer steps of n-hexane cracking over zeolites of different structure

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

Lukyanov, D.B.

The reaction of n-hexane cracking over HZSM-5, HY zeolite and mordenite (HM) was studied in accordance with the procedure of the [beta]-test recently proposed for quantitative characterization of zeolite hydrogen transfer activity. It is shown that this procedure allows one to obtain quantitative data on propene, n-butene, and isobutene reactivities in the hydrogen transfer steps of the reaction. The results demonstrate that in the absence of steric constraints (large pore HY and HM zeolites) isobutene is approximately 5 times more reactive in hydrogen transfer than n-butene. The latter, in turn, is about 1.3 times more reactive than propene. With mediummore » pore HZSM-5, steric inhibition of the hydrogen transfer between n-hexane and isobutene is observed. This results in a sharp decrease in the isobutene reactivity: over HZSM-5 zeolites isobutene is only 1.2 times more reactive in hydrogen transfer than n-butene. On the basis of these data it is concluded that the [beta]-test measures the [open quotes]real[close quotes] hydrogen transfer activity of zeolites, i.e., the activity that summarizes the effects of the acidic and structural properties of zeolites. An attempt is made to estimate the [open quotes]ideal[close quotes] zeolite hydrogen transfer activity, i.e., the activity determined by the zeolite acidic properties only. The estimations obtained show that this activity is approximately 1.8 and 1.6 times higher for HM zeolite in comparison with HZSM-5 and HY zeolites, respectively. 16 refs., 4 figs., 2 tabs.« less

Phenotypic modulation of auto-reactive cells by insertion of tolerogenic molecules via MSC-derived exosomes.

PubMed

Mokarizadeh, Aram; Delirezh, Nowruz; Morshedi, Ahhmad; Mosayebi, Ghasem; Farshid, Amir-Abbas; Dalir-Naghadeh, Bahram

2012-01-01

Auto-reactive cells-mediated immune responses are responsible for the current tissue damages during autoimmunity. Accordingly, functional modulation of auto-reactive cells has been a pivotal aim in many of recent studies. In the current study, we investigated the possibility for insertion of regulatory molecules onto auto-reactive cells through exosomal nano-shuttles as a novel approach for phenotype modification of auto-reactive cells. The exosomes were isolated from supernatant of mesenchymal stem cells culture. Resultant exosomes co-cultured with lymphocytes were harvested from established EAE mice in the presence of antigenic MOG35-55 peptide. After 24 hr, insertion of exosomal tolerogenic molecules (PD-L1, TGF-β, galectin-1) onto auto-reactive cells were explored through flow cytometry. The potency of exosomal inserted membrane molecules to modulate phenotype of auto-reactive lymphocytes was assessed upon ELISA test for their-derived cytokines IFN-γ and IL-17. Incorporation of exosomal molecules into lymohocytes' membrane was confirmed by flow cytometric analyses for surface levels of mentioned molecules. Additionally, the decreased secretion of IFN-γ and IL-17 were detected in exosome pre-treated lymphocytes upon stimulation with MOG peptide. Mesenchymal stem cells -derived exosomes showed to be efficient organelles for insertion of bioactive tolerogenic molecules onto auto-reactive cells and modulation of their phenotypes.

Effect of stimulus type and temperature on EEG reactivity in cardiac arrest.

PubMed

Fantaneanu, Tadeu A; Tolchin, Benjamin; Alvarez, Vincent; Friolet, Raymond; Avery, Kathleen; Scirica, Benjamin M; O'Brien, Molly; Henderson, Galen V; Lee, Jong Woo

2016-11-01

Electroencephalogram (EEG) background reactivity is a reliable outcome predictor in cardiac arrest patients post therapeutic hypothermia. However, there is no consensus on modality testing and prior studies reveal only fair to moderate agreement rates. The aim of this study was to explore different stimulus modalities and report interrater agreements. We studied a multicenter, prospectively collected cohort of cardiac arrest patients who underwent therapeutic hypothermia between September 2014 and December 2015. We identified patients with reactivity data and evaluated interrater agreements of different stimulus modalities tested in hypothermia and normothermia. Of the 60 patients studied, agreement rates were moderate to substantial during hypothermia and fair to moderate during normothermia. Bilateral nipple pressure is more sensitive (80%) when compared to other modalities in eliciting a reactive background in hypothermia. Auditory, nasal tickle, nailbed pressure and nipple pressure reactivity were associated with good outcomes in both hypothermia and normothermia. EEG reactivity varies depending on the stimulus testing modality as well as the temperature during which stimulation is performed, with nipple pressure emerging as the most sensitive during hypothermia for reactivity and outcome determination. This highlights the importance of multiple stimulus testing modalities in EEG reactivity determination to reduce false negatives and optimize prognostication. Copyright © 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

In vitro effects of the small-molecule protein kinase C agonists on HIV latency reactivation.

PubMed

Brogdon, Jessica; Ziani, Widade; Wang, Xiaolei; Veazey, Ronald S; Xu, Huanbin

2016-12-12

The persistence of latently HIV-infected cellular reservoirs represents the major obstacle to virus eradication in patients under antiretroviral therapy (ART). Cure strategies to eliminate these reservoirs are thus needed to reactivate proviral gene expression in latently infected cells. In this study, we tested optimal concentrations of PKC agonist candidates (PEP005/Ingenol-3-angelate, prostratin, bryostatin-1, and JQ1) to reactivate HIV latency in vitro, and examined their effects on cell survival, activation and epigenetic histone methylation after treatment alone or in combination in cell line and isolated CD4 T cells from SIV-infected macaques. The results showed that PKC agonists increased cell activation with different degrees of latency reactivation, concomitant with reduced levels of histone methylation. With increasing concentrations, prostratin and byrostain-1 treatment rapidly reduced cell survival and cell activation. The PKC agonist combinations, or in combination with JQ1, led to modest levels of synergistic reactivation of HIV. Remarkably, PEP005 treatment alone caused marked reactivation of HIV latency, similar to PMA stimulation. These findings suggested that PEP005 alone, as indicated its lower cytotoxicity and lower effective dose inducing maximal reactivation, might be a candidate for effectively reactivating HIV latency as part of a therapeutic strategy for HIV infection.

Gap Junction Proteins in the Blood-Brain Barrier Control Nutrient-Dependent Reactivation of Drosophila Neural Stem Cells

PubMed Central

Spéder, Pauline; Brand, Andrea H.

2014-01-01

Summary Neural stem cells in the adult brain exist primarily in a quiescent state but are reactivated in response to changing physiological conditions. How do stem cells sense and respond to metabolic changes? In the Drosophila CNS, quiescent neural stem cells are reactivated synchronously in response to a nutritional stimulus. Feeding triggers insulin production by blood-brain barrier glial cells, activating the insulin/insulin-like growth factor pathway in underlying neural stem cells and stimulating their growth and proliferation. Here we show that gap junctions in the blood-brain barrier glia mediate the influence of metabolic changes on stem cell behavior, enabling glia to respond to nutritional signals and reactivate quiescent stem cells. We propose that gap junctions in the blood-brain barrier are required to translate metabolic signals into synchronized calcium pulses and insulin secretion. PMID:25065772

Reaction to background stimulation of preschool children who do and do not stutter.

PubMed

Schwenk, Krista A; Conture, Edward G; Walden, Tedra A

2007-01-01

This study investigated the maintenance of attention and adaptation to background stimuli of preschool children who do (CWS) and do not stutter (CWNS). Participants were 13 monolingual, Standard American English speaking, 3-5-year-old CWS and 14 CWNS. Results indicated that CWS were significantly more apt than CWNS to attend to or look at changes in background stimuli, although there were no significant differences between groups in duration and latency of these looks. Findings suggest that preschool CWS are more reactive to, distracted by, and slower to adapt and habituate to environmental stimuli than their CWNS counterparts. The reader should be able to: (1) recognize the temperamental differences between CWS and CWNS, (2) define attention reactivity and regulation, (3) explain how attention reactivity and regulation are associated with preschool stuttering, and (4) understand recent empirical evidence relating reactivity and regulation to preschool stuttering.

Controlling plasma stimulated media in cancer treatment application

NASA Astrophysics Data System (ADS)

Yan, Dayun; Sherman, Jonathan H.; Cheng, Xiaoqian; Ratovitski, Edward; Canady, Jerome; Keidar, Michael

2014-12-01

Cold atmospheric plasma (CAP) constitutes a "cocktail" of various reactive species. Accumulating evidence shows the effectiveness of CAP in killing cancer cells and decreasing the tumor size, which provides a solid basis for its potential use in cancer treatment. Currently, CAP is mainly used to directly treat cancer cells and trigger the death of cancer cells via apoptosis or necrosis. By altering the concentration of fetal bovine serum in Dulbecco's modified Eagle's medium and the temperature to store CAP stimulated media, we demonstrated controllable strategies to harness the stimulated media to kill glioblastoma cells in vitro. This study demonstrated the significant role of media in killing cancer cells via the CAP treatment.

CHEMOKINE RECEPTOR 7 (CCR7)-EXPRESSION AND IFNγ PRODUCTION DEFINE VACCINE-SPECIFIC CANINE T CELL SUBSETS

PubMed Central

Hartley, Ashley N.; Tarleton, Rick L.

2015-01-01

Canines suffer from and serve as strong translational animals models for many immunological disorders and infectious diseases. Routine vaccination has been a mainstay of protecting dogs through the stimulation of robust antibody responses and expansion of memory T cell populations. Commercially available reagents and described techniques are limited for identifying and characterizing canine T cell subsets and evaluating T cell-specific effector function. To define reagents for delineating naïve versus activated T cells and identify antigen-specific T cells, we tested anti-human and anti-bovine T-cell specific cell surface marker reagents for cross-reactivity with canine peripheral blood mononuclear cells (PBMCs. Both CD4+ and CD8+ T cells from healthy canine donors showed reactivity to CCL19-Ig, a CCR7 ligand, and coexpression with CD62L. An in vitro stimulation with concanavalin A validated downregulation of CCR7 and CD62L expression on stimulated healthy control PBMCs, consistent with an activated T cell phenotype. Anti-IFNγ antibodies identified antigen-specific IFNγ-producing CD4+ and CD8+ T cells upon in vitro vaccine antigen PBMC stimulation. PBMC isolation within 24 hours of sample collection allowed for efficient cell recovery and accurate T cell effector function characterization. These data provide a reagent and techniques platform via flow cytometry for identifying canine T cell subsets and characterizing circulating antigen-specific canine T cells for potential use in diagnostic and field settings. PMID:25758065

Effects of 20 Hz Repetitive Transcranial Magnetic Stimulation on Disorders of Consciousness: A Resting-State Electroencephalography Study.

PubMed

He, Fangping; Wu, Min; Meng, Fanxia; Hu, Yangfan; Gao, Jian; Chen, Zhongqin; Bao, Wangxiao; Liu, Kehong; Luo, Benyan; Pan, Gang

2018-01-01

Repetitive transcranial magnetic stimulation (rTMS) has been proposed as an experimental approach for the treatment of disorders of consciousness (DOC). To date, there has been little research into the use of rTMS in DOC and the therapeutic effects have been variously documented. This study aimed to examine the effects of 20 Hz rTMS on the electroencephalography (EEG) reactivity and clinical response in patients with DOC and to explore the neuromodulatory effects of high-frequency rTMS. In this randomized, sham-controlled, crossover study, real or sham 20 Hz rTMS was applied to the left primary motor cortex (M1) of patients with DOC for 5 consecutive days. Evaluations were blindly performed at the baseline (T0), immediately after the end of the 5 days of treatment (T1) and 1 week after the treatment (T2) using the JFK coma recovery scale-revised (CRS-R) and resting-state EEG. Only one patient, with a history of 2 months of traumatic brain injury, showed long-lasting (T1, T2) behavioral and neurophysiological modifications after the real rTMS stimulation. The 5 remaining patients presented brain reactivity localized at several electrodes, and the EEG modification was not significant. rTMS stimulation may improve awareness and arousal of DOC. Additionally, EEG represents a potential biomarker for the therapeutic efficacy of rTMS. This trial is registered with (NCT03385278).

Ursolic acid isolated from guava leaves inhibits inflammatory mediators and reactive oxygen species in LPS-stimulated macrophages.

PubMed

Kim, Min-Hye; Kim, Jin Nam; Han, Sung Nim; Kim, Hye-Kyeong

2015-06-01

Psidium guajava (guava) leaves have been frequently used for the treatment of rheumatism, fever, arthritis and other inflammatory conditions. The purpose of this study was to identify major anti-inflammatory compounds from guava leaf extract. The methanol extract and its hexane-, dichloromethane-, ethylacetate-, n-butanol- and water-soluble phases derived from guava leaves were evaluated to determine their inhibitory activity on nitric oxide (NO) production by RAW 264.7 cells stimulated with lipopolysaccharide (LPS). The methanol extract decreased NO production in a dose-dependent manner without cytotoxicity at a concentration range of 0-100 μg/mL. The n-butanol soluble phase was the most potent among the five soluble phases. Four compounds were isolated by reversed-phase HPLC from the n-butanol soluble phase and identified to be avicularin, guaijaverin, leucocyanidin and ursolic acid by their NMR spectra. Among these compounds, ursolic acid inhibited LPS-induced NO production in a dose-dependent manner without cytotoxity at a concentration range of 1-10 µM, but the other three compounds had no effect. Ursolic acid also inhibited LPS-induced prostaglandin E2 production. A western blot analysis showed that ursolic acid decreased the LPS-stimulated inducible nitric oxide synthase and cyclooxygenase protein levels. In addition, ursolic acid suppressed the production of intracellular reactive oxygen species in LPS-stimulated RAW 264.7 cells, as measured by flow cytometry. Taken together, these results identified ursolic acid as a major anti-inflammatory compound in guava leaves.

Sampangine inhibits heme biosynthesis in both yeast and human

USDA-ARS?s Scientific Manuscript database

The azaoxoaporphine alkaloid sampangine exhibits strong antiproliferation activity in various organisms. Previous studies suggested that it somehow affects heme metabolism and stimulates production of reactive oxygen species (ROS). In this study, we show that inhibition of heme biosynthesis is the p...

Effects of rhythmic stimulus presentation on oscillatory brain activity: the physiology of cueing in Parkinson’s disease

PubMed Central

te Woerd, Erik S.; Oostenveld, Robert; Bloem, Bastiaan R.; de Lange, Floris P.; Praamstra, Peter

2015-01-01

The basal ganglia play an important role in beat perception and patients with Parkinson’s disease (PD) are impaired in perception of beat-based rhythms. Rhythmic cues are nonetheless beneficial in gait rehabilitation, raising the question how rhythm improves movement in PD. We addressed this question with magnetoencephalography recordings during a choice response task with rhythmic and non-rhythmic modes of stimulus presentation. Analyses focused on (i) entrainment of slow oscillations, (ii) the depth of beta power modulation, and (iii) whether a gain in modulation depth of beta power, due to rhythmicity, is of predictive or reactive nature. The results show weaker phase synchronisation of slow oscillations and a relative shift from predictive to reactive movement-related beta suppression in PD. Nonetheless, rhythmic stimulus presentation increased beta modulation depth to the same extent in patients and controls. Critically, this gain selectively increased the predictive and not reactive movement-related beta power suppression. Operation of a predictive mechanism, induced by rhythmic stimulation, was corroborated by a sensory gating effect in the sensorimotor cortex. The predictive mode of cue utilisation points to facilitation of basal ganglia-premotor interactions, contrasting with the popular view that rhythmic stimulation confers a special advantage in PD, based on recruitment of alternative pathways. PMID:26509117

3,4,5-Tricaffeoylquinic acid inhibits tumor necrosis factor-α-stimulated production of inflammatory mediators in keratinocytes via suppression of Akt- and NF-κB-pathways.

PubMed

Lee, Chung Soo; Lee, Seon Ae; Kim, Yun Jeong; Seo, Seong Jun; Lee, Min Won

2011-11-01

Keratinocytes may play an important role in the pathogenesis of skin disease in atopic dermatitis. Caffeoyl derivatives are demonstrated to have anti-inflammatory and anti-oxidant effects. However, the effect of 3,4,5-tricaffeoylquinic acid prepared from Aconium koreanum on the pro-inflammatory cytokine-stimulated keratinocyte responses remains uncertain. In human keratinocytes, we investigated the effect of 3,4,5-tricaffeoylquinic acid on the tumor necrosis factor (TNF)-α-stimulated production of inflammatory mediators in relation to the nuclear factor (NF)-κB and cell signaling Akt, which regulates the transcription genes involved in immune and inflammatory responses. 3,4,5-Tricaffeoylquinic acid inhibited the TNF-α-stimulated production of cytokines (IL-1β and IL-8) and chemokine (CCL17 and CCL27) in keratinocytes. Bay 11-7085 (an inhibitor of NF-κB activation) and Akt inhibitor attenuated the TNF-α-induced formation of inflammatory mediators. 3,4,5-Tricaffeoylquinic acid, Bay 11-7085, Akt inhibitor and N-acetylcysteine inhibited the TNF-α-induced activation of NF-κB, activation of Akt, and formation of reactive oxygen and nitrogen species. The results show that 3,4,5-tricaffeoylquinic acid seems to attenuate the TNF-α-stimulated inflammatory mediator production in keratinocytes by suppressing the activation of Akt and NF-κB pathways which may be mediated by reactive oxygen species. The findings suggest that 3,4,5-tricaffeoylquinic acid may exert an inhibitory effect against the pro-inflammatory mediator-induced skin disease. Copyright © 2011 Elsevier B.V. All rights reserved.

Investigation of the chemical pathway of gaseous nitrogen dioxide formation during flue gas desulfurization with dry sodium bicarbonate injection

NASA Astrophysics Data System (ADS)

Stein, Antoinette Weil

The chemical reaction pathway for the viable flue gas desulfurization process, dry sodium bicarbonate injection, was investigated to mitigate undesirable plume discoloration. Based on a foundation of past findings, a simplified three-step reaction pathway was hypothesized for the formation of the plume-discoloring constituent, NO2. As the first step, it was hypothesized that sodium sulfite formed by sodium bicarbonate reaction with flue gas SO 2. As the second step, it was hypothesized that sodium nitrate formed by sodium sulfite reaction with flue gas NO. And as the third step, it was hypothesized that NO2 and sodium sulfate formed by sodium nitrate reaction with SO2. The second and third hypothesized steps were experimentally investigated using an isothermal fixed bed reactor. As reported in the past, technical grade sodium sulfite was found to be un-reactive with NO and O2. Freshly prepared sodium sulfite, maintained unexposed to moist air, was shown to react with NO and O2 resulting in a mixture of sodium nitrite and sodium nitrate together with a significant temperature rise. This reaction was found to proceed only when oxygen was present in the flue gas. As reported in the past, technical grade sodium nitrate was shown to be un-reactive with SO2. But freshly formed sodium nitrate kept unexposed to humidity was found to be reactive with SO2 and O 2 resulting in the formation of NO2 and sodium sulfate polymorphic Form I. The NO2 formation by this reaction was shown to be temperature dependent with maximum formation at 175°C. Plume mitigation methods were studied based on the validated three-step reaction pathway. Mitigation of NO2 was exhibited by limiting oxygen concentration in the flue gas to a level below 5%. It was also shown that significant NO2 mitigation was achieved by operating below 110°C or above 250°C. An innovative NO2 mitigation method was patented as a result of the findings of this study. The patented process incorporated a process step of sodium sulfite injection to remove flue gas NO prior to sodium bicarbonate injection.

DEFICIENT LIMB SUPPORT IS A MAJOR CONTRIBUTOR TO AGE-DIFFERENCES IN FALLING

PubMed Central

Pavol, Michael J.; Pai, Yi-Chung

2010-01-01

Older adults are more likely than young to fall upon a loss of balance, yet the factors responsible for this difference are not well understood. This study investigated whether age-related differences in movement stability, limb support, and reactive stepping contribute to the greater likelihood of falling among older adults. Sixty young and 41 older, safety-harnessed, healthy adults were exposed to a novel and unexpected forward slip during a sit-to-stand task. More older than young adults fell (76% vs. 30%). Falls in both age groups were related to lesser stability and lower hip height at first step touchdown, with 97.1% of slip outcomes correctly classified based on these variables. Decreases in hip height at touchdown had over 20 times greater effect on the odds of falling than equivalent decreases in stability. Three age-differences placed older adults at greater risk of falling: older adults had lower and more slowly rising hips at slip onset, they were less likely to respond to slipping with forceful limb extension, and they placed their stepping foot less posterior to their center of mass. The first two differences, each associated with deficient limb support, reduced hip ascent and increased hip descent. The third difference resulted in lesser stability at step touchdown. These results suggest that deficient limb support in normal movement patterns and in the reactive response to a perturbation is a major contributor to the high incidence of falls in older adults. Improving proactive and reactive limb support should be a focus of fall prevention efforts. PMID:16876174

Peptide-independent Recognition by Alloreactive Cytotoxic T Lymphocytes (CTL)

PubMed Central

Smith, Pamela A.; Brunmark, Anders; Jackson, Michael R.; Potter, Terry A.

1997-01-01

We have isolated several H-2Kb–alloreactive cytotoxic T cell clones and analyzed their reactivity for several forms of H-2Kb. These cytotoxic T lymphocytes (CTL) were elicited by priming with a skin graft followed by in vitro stimulation using stimulator cells that express an H-2Kb molecule unable to bind CD8. In contrast to most alloreactive T cells, these CTL were able to recognize H-2Kb on the surface of the antigen processing defective cell lines RMA-S and T2. Furthermore, this reactivity was not increased by the addition of an extract containing peptides from C57BL/6 (H-2b) spleen cells, nor was the reactivity decreased by treating the target cells with acid to remove peptides bound to MHC molecules. The CTL were also capable of recognizing targets expressing the mutant H-2Kbm8 molecule. These findings suggested that the clones recognized determinants on H-2Kb that were independent of peptide. Further evidence for this hypothesis was provided by experiments in which H-2Kb produced in Drosophila melanogaster cells and immobilized on the surface of a tissue culture plate was able to stimulate hybridomas derived from these alloreactive T cells. Precursor frequency analysis demonstrated that skin graft priming, whether with skin expressing the wild-type or the mutant H-2Kb molecule, is a strong stimulus to elicit peptide-independent CTL. Moreover, reconstitution experiments demonstrated that the peptide-independent CTL clones were capable of mediating rapid and complete rejection of H-2–incompatible skin grafts. These findings provide evidence that not all allorecognition is peptide dependent. PMID:9091576

Development of an intervention to stimulate physical activity in hard-to-reach physically disabled people and design of a pilot implementation: an intervention mapping approach.

PubMed

Krops, Leonie A; Dekker, Rienk; Geertzen, Jan H B; Dijkstra, Pieter U

2018-03-16

Physically disabled people are less physically active compared with healthy people. Existing physical activity (PA) interventions are limited in reach, since they are primarily rehabilitation or school based. The current study aims to develop a community-based intervention for stimulating PA in hard-to-reach physically disabled people. To systematically develop a PA-stimulating intervention, intervention mapping (six steps) was applied. PA level and health-related quality of life of patients after rehabilitation was determined using questionnaires (step 1). Qualitative research was performed to study professionals' and physically disabled people's ideas about intervention objectives, determinants and design (steps 2 and 3). Since experts expressed no need for a new intervention, the existing intervention 'Activity coach' was adapted to the specific target population. The adapted intervention 'Activity coach+' composes a network of intermediate organisations that refers participants to an activity coach, who coaches participants during 1 year. After a preintervention physical assessment by a physiotherapist, participants will be individually guided to existing organised or non-organised activities. An activity tracker will be used to monitor and stimulate PA in daily life (step 4). To support adoption and implementation, meetings between involved parties are organised (step 5). 'Activity coach+' is implemented in community in March 2017, and will be evaluated using a mixed-method analysis. Quantitative evaluation of intervention effects on PA, health and social participation takes place after 0, 2, 4, 6 and 12 months. The implementation process and experiences with the intervention will be determined using qualitative research (step 6). Insights from this study will be used for dissemination and further development of the intervention. The Medical Ethical Committee of the University Medical Center Groningen confirmed that formal ethical approval was not required (METc 2016/630). NTR6858. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Estimulacion Precoz para Ninos Minusvalidos (Early Stimulation for Disabled Children).

ERIC Educational Resources Information Center

Lumpkin, Garren

Written as a first step to improve early stimulation services to developmentally disabled and retarded preschool aged children in Costa Rica, the manual, in Spanish, seeks to attain the following objectives: raise consciousness and understanding of health service personnel, primary and special educators, rehabilitation personnel, and parents;…

Unifying Model-Based and Reactive Programming within a Model-Based Executive

NASA Technical Reports Server (NTRS)

Williams, Brian C.; Gupta, Vineet; Norvig, Peter (Technical Monitor)

1999-01-01

Real-time, model-based, deduction has recently emerged as a vital component in AI's tool box for developing highly autonomous reactive systems. Yet one of the current hurdles towards developing model-based reactive systems is the number of methods simultaneously employed, and their corresponding melange of programming and modeling languages. This paper offers an important step towards unification. We introduce RMPL, a rich modeling language that combines probabilistic, constraint-based modeling with reactive programming constructs, while offering a simple semantics in terms of hidden state Markov processes. We introduce probabilistic, hierarchical constraint automata (PHCA), which allow Markov processes to be expressed in a compact representation that preserves the modularity of RMPL programs. Finally, a model-based executive, called Reactive Burton is described that exploits this compact encoding to perform efficIent simulation, belief state update and control sequence generation.

Electrophilic and free radical nitration of benzene and toluene with various nitrating agents*

PubMed Central

Olah, George A.; Lin, Henry C.; Olah, Judith A.; Narang, Subhash C.

1978-01-01

Electrophilic nitration of toluene and benzene was studied under various conditions with several nitrating systems. It was found that high orthopara regioselectivity is prevalent in all reactions and is independent of the reactivity of the nitrating agent. The methyl group of toluene is predominantly ortho-para directing under all reaction conditions. Steric factors are considered to be important but not the sole reason for the variation in the ortho/para ratio. The results reinforce our earlier views that, in electrophilic aromatic nitrations with reactive nitrating agents, substrate and positional selectivities are determined in two separate steps. The first step involves a π-aromatic-NO2+ ion complex or encounter pair, whereas the subsequent step is of arenium ion nature (separate for the ortho, meta, and para positions). The former determines substrate selectivity, whereas the latter determines regioselectivity. Thermal free radical nitration of benzene and toluene with tetranitromethane in sharp contrast gave nearly statistical product distributions. PMID:16592503

Shikonin Isolated from Lithospermum erythrorhizon Downregulates Proinflammatory Mediators in Lipopolysaccharide-Stimulated BV2 Microglial Cells by Suppressing Crosstalk between Reactive Oxygen Species and NF-κB.

PubMed

Prasad, Rajapaksha Gedara; Choi, Yung Hyun; Kim, Gi-Young

2015-03-01

According to the expansion of lifespan, neuronal disorder based on inflammation has been social problem. Therefore, we isolated shikonin from Lithospermum erythrorhizon and evaluated anti-inflammatory effects of shikonin in lipopolysaccharide (LSP)-stimulated BV2 microglial cells. Shikonin dose-dependently inhibits the expression of the proinflammatory mediators, nitric oxide (NO), prostaglandin E2 (PGE2), and tumor necrosis factor-α (TNF-α) as well as their main regulatory genes and products such as inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), and TNF-α in LPS-stimulated BV2 microglial cells. Additionally, shikonin suppressed the LPS-induced DNA-binding activity of nuclear factor-κB (NF-κB) to regulate the key regulatory genes of the proinflammatory mediators, such as iNOS, COX-2, and TNF-α, accompanied with downregulation of reactive oxygen species (ROS) generation. The results indicate that shikonin may downregulate the expression of proinflammatory genes involved in the synthesis of NO, PGE2, and TNF-α in LPS-treated BV2 microglial cells by suppressing ROS and NF-κB. Taken together, our results revealed that shikonin exerts downregulation of proinflammatory mediators by interference the ROS and NF-κB signaling pathway.

Shikonin Isolated from Lithospermum erythrorhizon Downregulates Proinflammatory Mediators in Lipopolysaccharide-Stimulated BV2 Microglial Cells by Suppressing Crosstalk between Reactive Oxygen Species and NF-κB

PubMed Central

Prasad, Rajapaksha Gedara; Choi, Yung Hyun; Kim, Gi-Young

2015-01-01

According to the expansion of lifespan, neuronal disorder based on inflammation has been social problem. Therefore, we isolated shikonin from Lithospermum erythrorhizon and evaluated anti-inflammatory effects of shikonin in lipopolysaccharide (LSP)-stimulated BV2 microglial cells. Shikonin dose-dependently inhibits the expression of the proinflammatory mediators, nitric oxide (NO), prostaglandin E2 (PGE2), and tumor necrosis factor-α (TNF-α) as well as their main regulatory genes and products such as inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), and TNF-α in LPS-stimulated BV2 microglial cells. Additionally, shikonin suppressed the LPS-induced DNA-binding activity of nuclear factor-κB (NF-κB) to regulate the key regulatory genes of the proinflammatory mediators, such as iNOS, COX-2, and TNF-α, accompanied with downregulation of reactive oxygen species (ROS) generation. The results indicate that shikonin may downregulate the expression of proinflammatory genes involved in the synthesis of NO, PGE2, and TNF-α in LPS-treated BV2 microglial cells by suppressing ROS and NF-κB. Taken together, our results revealed that shikonin exerts downregulation of proinflammatory mediators by interference the ROS and NF-κB signaling pathway. PMID:25767678

Ethanol stimulates epithelial sodium channels by elevating reactive oxygen species

PubMed Central

Bao, Hui-Fang; Song, John Z.; Duke, Billie J.; Ma, He-Ping; Denson, Donald D.

2012-01-01

Alcohol affects total body sodium balance, but the molecular mechanism of its effect remains unclear. We used single-channel methods to examine how ethanol affects epithelial sodium channels (ENaC) in A6 distal nephron cells. The data showed that ethanol significantly increased both ENaC open probability (Po) and the number of active ENaC in patches (N). 1-Propanol and 1-butanol also increased ENaC activity, but iso-alcohols did not. The effects of ethanol were mimicked by acetaldehyde, the first metabolic product of ethanol, but not by acetone, the metabolic product of 2-propanol. Besides increasing open probability and apparent density of active channels, confocal microscopy and surface biotinylation showed that ethanol significantly increased α-ENaC protein in the apical membrane. The effects of ethanol on ENaC Po and N were abolished by a superoxide scavenger, 4-hydroxy-2,2,6,6-tetramethylpiperidinyloxy (TEMPOL) and blocked by the phosphatidylinositol 3-kinase inhibitor LY294002. Consistent with an effect of ethanol-induced reactive oxygen species (ROS) on ENaC, primary alcohols and acetaldehyde elevated intracellular ROS, but secondary alcohols did not. Taken together with our previous finding that ROS stimulate ENaC, the current results suggest that ethanol stimulates ENaC by elevating intracellular ROS probably via its metabolic product acetaldehyde. PMID:22895258

An antigen receptor-driven, interleukin 2-independent pathway for proliferation of murine cytolytic T lymphocyte clones

PubMed Central

1986-01-01

Proliferation of T lymphocytes can be induced by IL-2, either through an autocrine pathway in which the responding cell produces its own IL-2 or through an exocrine pathway in which IL-2 secreted by Th stimulates proliferation of IL-2-dependent CTL. However, proliferation of at least some CTL clones, such as CTL L3 and CTL dB45, also can be induced by stimulation of the antigen receptor in the absence of IL-2. Stimulation of these cloned CTL with T cell-depleted allogeneic spleen cells, allogeneic tumor cells, or immobilized mAb reactive with the T cell antigen receptor (TCR) induced thymidine incorporation, entry into cell cycle, and secretion of macrophage activating factor, but these stimuli did not induce the secretion of IL-2. Several observations indicated that such proliferation of cloned CTL induced by stimulation of the TCR was independent of IL-2; IL-2 could not be detected in supernatants from stimulated CTL cells. mAbs reactive with the murine IL-2-R efficiently blocked IL-2-mediated thymidine incorporation in cloned CTL and Th, but had no inhibitory effect on TCR-driven thymidine incorporation in the CTL clones. TCR-driven thymidine incorporation in cloned Th L2 cells was profoundly inhibited by these antibodies, indicating the operation of an IL-2-mediated autocrine pathway for proliferation in this cloned Th. When antibodies to the TCR were used to stimulate cloned CTL and Th, IFN-gamma mRNA was easily shown in the cloned CTL and Th. Although IL-2 mRNA could be detected in the cloned Th, it was never observed in the cloned CTL. These findings provide evidence for the existence of a TCR-mediated, IL-2-independent pathway for induction of cellular proliferation in cloned murine CTL. PMID:3486939

Intestinal T cell responses to cereal proteins in celiac disease.

PubMed

Kilmartin, C; Wieser, H; Abuzakouk, M; Kelly, J; Jackson, J; Feighery, C

2006-01-01

Celiac disease is caused by sensitivity to wheat gluten in genetically susceptible individuals. The etiological role of the other wheat-related cereals, barley, rye, and oats, is still debated. In order to investigate this issue further, in this study we examined the immune response of celiac mucosal T cell lines to fractions from all four cereals. Cell stimulation was assessed by measuring proliferation (employing (3)H-thymidine incorporation) or cytokine (IL-2, IFN-gamma) production. All five T cell lines demonstrated immunoreactivity to protein fractions from the four related cereals. In some cell lines, reactivity to wheat, barley, and rye was only evident when these cereal fractions had been pretreated with tissue transglutaminase. This study confirms the similar T cell antigenic reactivity of these four related cereals and has implications for their exclusion in the gluten-free diet. However, despite oats stimulation of T cell lines, this cereal does not activate a mucosal lesion in most celiac patients.

Uncoupling protein-2 attenuates glucose-stimulated insulin secretion in INS-1E insulinoma cells by lowering mitochondrial reactive oxygen species

PubMed Central

Affourtit, Charles; Jastroch, Martin; Brand, Martin D.

2011-01-01

Glucose-stimulated insulin secretion (GSIS) by pancreatic β cells is regulated by mitochondrial uncoupling protein-2 (UCP2), but opposing phenotypes, GSIS improvement and impairment, have been reported for different Ucp2-ablated mouse models. By measuring mitochondrial bioenergetics in attached INS-1E insulinoma cells with and without UCP2, we show that UCP2 contributes to proton leak and attenuates glucose-induced rises in both respiratory activity and the coupling efficiency of oxidative phosphorylation. Strikingly, the GSIS improvement seen upon UCP2 knockdown in INS-1E cells is annulled completely by the cell-permeative antioxidant MnTMPyP. Consistent with this observation, UCP2 lowers mitochondrial reactive oxygen species at high glucose levels. We conclude that UCP2 plays both regulatory and protective roles in β cells by acutely lowering GSIS and chronically preventing oxidative stress. Our findings thus provide a mechanistic explanation for the apparently discrepant findings in the field. PMID:21172424

Role of the Human Polyomavirus, BKV, in Prostate Cancer

DTIC Science & Technology

2004-08-01

can be reactivated upon immunosuppression, often leading to hemorrhagic cystitis or nephritis. Previous studies have found BKV to be tumorigenic in...reactivated upon immunosuppression of the host and is The BKV genome is divided into regulatory, early, associated with hemorrhagic cystitis and...life cycle is replication of its urinary tract, which can lead to hemorrhagic cystitis and DNA. To assess this step, we isolated low molecular weight

Sleeping on the rubber-hand illusion: Memory reactivation during sleep facilitates multisensory recalibration.

PubMed

Honma, Motoyasu; Plass, John; Brang, David; Florczak, Susan M; Grabowecky, Marcia; Paller, Ken A

2016-01-01

Plasticity is essential in body perception so that physical changes in the body can be accommodated and assimilated. Multisensory integration of visual, auditory, tactile, and proprioceptive signals contributes both to conscious perception of the body's current state and to associated learning. However, much is unknown about how novel information is assimilated into body perception networks in the brain. Sleep-based consolidation can facilitate various types of learning via the reactivation of networks involved in prior encoding or through synaptic down-scaling. Sleep may likewise contribute to perceptual learning of bodily information by providing an optimal time for multisensory recalibration. Here we used methods for targeted memory reactivation (TMR) during slow-wave sleep to examine the influence of sleep-based reactivation of experimentally induced alterations in body perception. The rubber-hand illusion was induced with concomitant auditory stimulation in 24 healthy participants on 3 consecutive days. While each participant was sleeping in his or her own bed during intervening nights, electrophysiological detection of slow-wave sleep prompted covert stimulation with either the sound heard during illusion induction, a counterbalanced novel sound, or neither. TMR systematically enhanced feelings of bodily ownership after subsequent inductions of the rubber-hand illusion. TMR also enhanced spatial recalibration of perceived hand location in the direction of the rubber hand. This evidence for a sleep-based facilitation of a body-perception illusion demonstrates that the spatial recalibration of multisensory signals can be altered overnight to stabilize new learning of bodily representations. Sleep-based memory processing may thus constitute a fundamental component of body-image plasticity.

Gypenoside IX Suppresses p38 MAPK/Akt/NFκB Signaling Pathway Activation and Inflammatory Responses in Astrocytes Stimulated by Proinflammatory Mediators.

PubMed

Wang, Xiaoshuang; Yang, Liu; Yang, Li; Xing, Faping; Yang, Hua; Qin, Liyue; Lan, Yunyi; Wu, Hui; Zhang, Beibei; Shi, Hailian; Lu, Cheng; Huang, Fei; Wu, Xiaojun; Wang, Zhengtao

2017-12-01

Gypenoside IX (GP IX) is a pure compound isolated from Panax notoginseng. Gypenosides have been implicated to benefit the recovery of enormous neurological disorders. By suppressing the activation of astrocytes, gypenosides can improve the cognitive impairment. However, so far, little is known about whether GP IX could restrain the inflammatory responses in astrocytes or reactive astrogliosis. In present study, the anti-inflammatory effects of GP IX were investigated in reactive astrocytes induced by proinflammatory mediators both in vitro and in vivo. GP IX significantly reduced the production of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) at either protein or mRNA level in glial cell line C6 cells stimulated by lipopolysaccharide (LPS)/TNF-α combination. It also alleviated the astrogliosis and decreased the production of inflammatory mediators in brain cortex of LPS-treated mice. Further study disclosed that GP IX inhibited nuclear translocation of nuclear factor kappa B (NFκB) and reduced its transcriptional activity. Meanwhile, GP IX significantly attenuated the phosphorylation of NFκB, inhibitor of kappa B (IκB), Akt, and p38 mitogen-activated protein kinase (MAPK) under inflammatory conditions both in vitro and in vivo. These findings indicated that GP IX might suppress reactive astrogliosis by suppressing Akt/p38 MAPK/NFκB signaling pathways. And GP IX might be a promising drug candidate or prodrug for the therapy of neuroinflammatory disorders characterized with reactive astrogliosis.

Attentional bias mediates the effect of neurostimulation on emotional vulnerability.

PubMed

Chen, Nigel T M; Basanovic, Julian; Notebaert, Lies; MacLeod, Colin; Clarke, Patrick J F

2017-10-01

Transcranial direct current stimulation (tDCS) is a neuromodulatory technique which has garnered recent interest in the potential treatment for emotion-based psychopathology. While accumulating evidence suggests that tDCS may attenuate emotional vulnerability, critically, little is known about underlying mechanisms of this effect. The present study sought to clarify this by examining the possibility that tDCS may affect emotional vulnerability via its capacity to modulate attentional bias towards threatening information. Fifty healthy participants were randomly assigned to receive either anodal tDCS (2 mA/min) stimulation to the left dorsolateral prefrontal cortex (DLPFC), or sham. Participants were then eye tracked during a dual-video stressor task designed to elicit emotional reactivity, while providing a concurrent in-vivo measure of attentional bias. Greater attentional bias towards threatening information was associated with greater emotional reactivity to the stressor task. Furthermore, the active tDCS group showed reduced attentional bias to threat, compared to the sham group. Importantly, attentional bias was found to statistically mediate the effect of tDCS on emotional reactivity, while no direct effect of tDCS on emotional reactivity was observed. The findings are consistent with the notion that the effect of tDCS on emotional vulnerability may be mediated by changes in attentional bias, holding implications for the application of tDCS in emotion-based psychopathology. The findings also highlight the utility of in-vivo eye tracking measures in the examination of the mechanisms associated with DLPFC neuromodulation in emotional vulnerability. Copyright © 2017 Elsevier Ltd. All rights reserved.

Redox and Reactive Oxygen Species Regulation of Mitochondrial Cytochrome c Oxidase Biogenesis

PubMed Central

Bourens, Myriam; Fontanesi, Flavia; Soto, Iliana C.; Liu, Jingjing

2013-01-01

Abstract Significance: Cytochrome c oxidase (COX), the last enzyme of the mitochondrial respiratory chain, is the major oxygen consumer enzyme in the cell. COX biogenesis involves several redox-regulated steps. The process is highly regulated to prevent the formation of pro-oxidant intermediates. Recent Advances: Regulation of COX assembly involves several reactive oxygen species and redox-regulated steps. These include: (i) Intricate redox-controlled machineries coordinate the expression of COX isoenzymes depending on the environmental oxygen concentration. (ii) COX is a heme A-copper metalloenzyme. COX copper metallation involves the copper chaperone Cox17 and several other recently described cysteine-rich proteins, which are oxidatively folded in the mitochondrial intermembrane space. Copper transfer to COX subunits 1 and 2 requires concomitant transfer of redox power. (iii) To avoid the accumulation of reactive assembly intermediates, COX is regulated at the translational level to minimize synthesis of the heme A-containing Cox1 subunit when assembly is impaired. Critical Issues: An increasing number of regulatory pathways converge to facilitate efficient COX assembly, thus preventing oxidative stress. Future Directions: Here we will review on the redox-regulated COX biogenesis steps and will discuss their physiological relevance. Forthcoming insights into the precise regulation of mitochondrial COX biogenesis in normal and stress conditions will likely open future perspectives for understanding mitochondrial redox regulation and prevention of oxidative stress. Antioxid. Redox Signal. 19, 1940–1952. PMID:22937827

Rapid expansion of T cells: Effects of culture and cryopreservation and importance of short-term cell recovery.

PubMed

Sadeghi, Arian; Ullenhag, Gustav; Wagenius, Gunnar; Tötterman, Thomas H; Eriksson, Fredrik

2013-06-01

Successful cell therapy relies on the identification and mass expansion of functional cells for infusion. Cryopreservation of cells is an inevitable step in most cell therapies which also entails consequences for the frozen cells. This study assessed the impact of cryopreservation and the widely used protocol for rapid expansion of T lymphocytes. The effects on cell viability, immunocompetence and the impact on apoptotic and immunosuppressive marker expression were analyzed using validated assays. Cryopreservation of lymphocytes during the rapid expansion protocol did not affect cell viability. Lymphocytes that underwent mass expansion or culture in high dose IL-2 were unable to respond to PHA stimulation by intracellular ATP production immediately after thawing (ATP = 16 ± 11 ng/ml). However, their reactivity to PHA was regained within 48 hours of recovery (ATP = 356 ± 61 ng/ml). Analysis of mRNA levels revealed downregulation of TGF-β and IL-10 at all time points. Culture in high dose IL-2 led to upregulation of p73 and BCL-2 mRNA levels while FoxP3 expression was elevated after culture in IL-2 and artificial TCR stimuli. FoxP3 levels decreased after short-term recovery without IL-2 or stimulation. Antigen specificity, as determined by IFNγ secretion, was unaffected by cryopreservation but was completely lost after addition of high dose IL-2 and artificial TCR stimuli. In conclusion, allowing short-time recovery of mass expanded and cryopreserved cells before reinfusion could enhance the outcome of adoptive cell therapy as the cells regain immune competence and specificity.

Reactivity loss validation of high burn-up PWR fuels with pile-oscillation experiments in MINERVE

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

Leconte, P.; Vaglio-Gaudard, C.; Eschbach, R.

2012-07-01

The ALIX experimental program relies on the experimental validation of the spent fuel inventory, by chemical analysis of samples irradiated in a PWR between 5 and 7 cycles, and also on the experimental validation of the spent fuel reactivity loss with bum-up, obtained by pile-oscillation measurements in the MINERVE reactor. These latter experiments provide an overall validation of both the fuel inventory and of the nuclear data responsible for the reactivity loss. This program offers also unique experimental data for fuels with a burn-up reaching 85 GWd/t, as spent fuels in French PWRs never exceeds 70 GWd/t up to now.more » The analysis of these experiments is done in two steps with the APOLLO2/SHEM-MOC/CEA2005v4 package. In the first one, the fuel inventory of each sample is obtained by assembly calculations. The calculation route consists in the self-shielding of cross sections on the 281 energy group SHEM mesh, followed by the flux calculation by the Method Of Characteristics in a 2D-exact heterogeneous geometry of the assembly, and finally a depletion calculation by an iterative resolution of the Bateman equations. In the second step, the fuel inventory is used in the analysis of pile-oscillation experiments in which the reactivity of the ALIX spent fuel samples is compared to the reactivity of fresh fuel samples. The comparison between Experiment and Calculation shows satisfactory results with the JEFF3.1.1 library which predicts the reactivity loss within 2% for burn-up of {approx}75 GWd/t and within 4% for burn-up of {approx}85 GWd/t. (authors)« less

NANOSIZE TITANIA STIMULATES REACTIVE OXYGEN SPECIES IN BRAIN MICROGLIA AND DAMAGES NEURONS.

EPA Science Inventory

Research that addresses the environmental impact and biological consequences of widely distributed, commonly used nanoparticles is needed. Nanosize titanium dioxide (i.e., titania, TiO2) is used in air and water remediation and in numerous products designed for direct human us...

Deciphering drought-induced metabolic responses and regulation in developing maize kernels

USDA-ARS?s Scientific Manuscript database

Aspergillus flavus is a facultative pathogen of crops such as maize and peanut which produces carcinogenic aflatoxins during infection, particularly in drought stressed host plants. Reactive oxygen species (ROS) have been shown to both accumulate in host plant tissues during drought and to stimulate...

Kinetics of HIV-1 Latency Reversal Quantified on the Single-Cell Level Using a Novel Flow-Based Technique.

PubMed

Martrus, G; Niehrs, A; Cornelis, R; Rechtien, A; García-Beltran, W; Lütgehetmann, M; Hoffmann, C; Altfeld, M

2016-10-15

HIV-1 establishes a pool of latently infected cells early following infection. New therapeutic approaches aiming at diminishing this persisting reservoir by reactivation of latently infected cells are currently being developed and tested. However, the reactivation kinetics of viral mRNA and viral protein production, and their respective consequences for phenotypical changes in infected cells that might enable immune recognition, remain poorly understood. We adapted a novel approach to assess the dynamics of HIV-1 mRNA and protein expression in latently and newly infected cells on the single-cell level by flow cytometry. This technique allowed the simultaneous detection of gagpol mRNA, intracellular p24 Gag protein, and cell surface markers. Following stimulation of latently HIV-1-infected J89 cells with human tumor necrosis factor alpha (hTNF-α)/romidepsin (RMD) or HIV-1 infection of primary CD4(+) T cells, four cell populations were detected according to their expression levels of viral mRNA and protein. gagpol mRNA in J89 cells was quantifiable for the first time 3 h after stimulation with hTNF-α and 12 h after stimulation with RMD, while p24 Gag protein was detected for the first time after 18 h poststimulation. HIV-1-infected primary CD4(+) T cells downregulated CD4, BST-2, and HLA class I expression at early stages of infection, proceeding Gag protein detection. In conclusion, here we describe a novel approach allowing quantification of the kinetics of HIV-1 mRNA and protein synthesis on the single-cell level and phenotypic characterization of HIV-1-infected cells at different stages of the viral life cycle. Early after infection, HIV-1 establishes a pool of latently infected cells, which hide from the immune system. Latency reversal and immune-mediated elimination of these latently infected cells are some of the goals of current HIV-1 cure approaches; however, little is known about the HIV-1 reactivation kinetics following stimulation with latency-reversing agents. Here we describe a novel approach allowing for the first time quantification of the kinetics of HIV-1 mRNA and protein synthesis after latency reactivation or de novo infection on the single-cell level using flow cytometry. This new technique furthermore enabled the phenotypic characterization of latently infected and de novo-infected cells dependent on the presence of viral RNA or protein. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Combined process automation for large-scale EEG analysis.

PubMed

Sfondouris, John L; Quebedeaux, Tabitha M; Holdgraf, Chris; Musto, Alberto E

2012-01-01

Epileptogenesis is a dynamic process producing increased seizure susceptibility. Electroencephalography (EEG) data provides information critical in understanding the evolution of epileptiform changes throughout epileptic foci. We designed an algorithm to facilitate efficient large-scale EEG analysis via linked automation of multiple data processing steps. Using EEG recordings obtained from electrical stimulation studies, the following steps of EEG analysis were automated: (1) alignment and isolation of pre- and post-stimulation intervals, (2) generation of user-defined band frequency waveforms, (3) spike-sorting, (4) quantification of spike and burst data and (5) power spectral density analysis. This algorithm allows for quicker, more efficient EEG analysis. Copyright © 2011 Elsevier Ltd. All rights reserved.

Quantifying stimulus-response rehabilitation protocols by auditory feedback in Parkinson's disease gait pattern

NASA Astrophysics Data System (ADS)

Pineda, Gustavo; Atehortúa, Angélica; Iregui, Marcela; García-Arteaga, Juan D.; Romero, Eduardo

2017-11-01

External auditory cues stimulate motor related areas of the brain, activating motor ways parallel to the basal ganglia circuits and providing a temporary pattern for gait. In effect, patients may re-learn motor skills mediated by compensatory neuroplasticity mechanisms. However, long term functional gains are dependent on the nature of the pathology, follow-up is usually limited and reinforcement by healthcare professionals is crucial. Aiming to cope with these challenges, several researches and device implementations provide auditory or visual stimulation to improve Parkinsonian gait pattern, inside and outside clinical scenarios. The current work presents a semiautomated strategy for spatio-temporal feature extraction to study the relations between auditory temporal stimulation and spatiotemporal gait response. A protocol for auditory stimulation was built to evaluate the integrability of the strategy in the clinic practice. The method was evaluated in transversal measurement with an exploratory group of people with Parkinson's (n = 12 in stage 1, 2 and 3) and control subjects (n =6). The result showed a strong linear relation between auditory stimulation and cadence response in control subjects (R=0.98 +/-0.008) and PD subject in stage 2 (R=0.95 +/-0.03) and stage 3 (R=0.89 +/-0.05). Normalized step length showed a variable response between low and high gait velocity (0.2> R >0.97). The correlation between normalized mean velocity and stimulus was strong in all PD stage 2 (R>0.96) PD stage 3 (R>0.84) and controls (R>0.91) for all experimental conditions. Among participants, the largest variation from baseline was found in PD subject in stage 3 (53.61 +/-39.2 step/min, 0.12 +/- 0.06 in step length and 0.33 +/- 0.16 in mean velocity). In this group these values were higher than the own baseline. These variations are related with direct effect of metronome frequency on cadence and velocity. The variation of step length involves different regulation strategies and could need others specific external cues. In conclusion the current protocol (and their selected parameters, kind of sound time for training, step of variation, range of variation) provide a suitable gait facilitation method specially for patients with the highest gait disturbance (stage 2 and 3). The method should be adjusted for initial stages and evaluated in a rehabilitation program.

Functionalized polymer nanofibre membranes for protection from chemical warfare stimulants

NASA Astrophysics Data System (ADS)

Ramaseshan, Ramakrishnan; Sundarrajan, Subramanian; Liu, Yingjun; Barhate, R. S.; Lala, Neeta L.; Ramakrishna, S.

2006-06-01

A catalyst for the detoxification of nerve agents is synthesized from β-cyclodextrin (β-CD) and o-iodosobenzoic acid (IBA). Functionalized polymer nanofibre membranes from PVC polymer are fabricated with β-CD, IBA, a blend of β-CD+IBA, and the synthesized catalyst. These functionalized nanofibres are then tested for the decontamination of paraoxon, a nerve agent stimulant, and it is observed that the stimulant gets hydrolysed. The kinetics of hydrolysis is investigated using UV spectroscopy. The rates of hydrolysis for different organophosphate hydrolyzing agents are compared. The reactivity and amount of adsorption of these catalysts are of higher capacity than the conventionally used activated charcoal. A new design for protective wear is proposed based on the functionalized nanofibre membrane.

Laser stimulation can activate autophagy in HeLa cells

NASA Astrophysics Data System (ADS)

Wang, Yisen; Lan, Bei; He, Hao; Hu, Minglie; Cao, Youjia; Wang, Chingyue

2014-10-01

For decades, lasers have been a daily tool in most biological research for fluorescent excitation by confocal or multiphoton microscopy. More than 20 years ago, cell photodamage caused by intense laser stimulation was noticed by generating reactive oxygen species, which was then thought as the main damage effect by photons. In this study, we show that laser stimulation can induce autophagy, an important cell lysosomal pathway responding to immune stimulation and starvation, without any biochemical treatment. Two different types of laser stimulations are found to be capable of activating autophagy: continuous scanning by continuous-wave visible lasers and a short-time flash of femtosecond laser irradiation. The autophagy generation is independent from wavelength, power, and scanning duration of the visible lasers. In contrast, the power of femtosecond laser is very critical to autophagy because the multiphoton excited Ca2+ dominates autophagy signaling. In general, we show here the different mechanisms of autophagy generation by such laser stimulation, which correspond to confocal microscopy and cell surgery, respectively. Those results can help further understanding of photodamage and autophagy signaling.

Laser stimulation can activate autophagy in HeLa cells

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

Wang, Yisen; Hu, Minglie; Wang, Chingyue

For decades, lasers have been a daily tool in most biological research for fluorescent excitation by confocal or multiphoton microscopy. More than 20 years ago, cell photodamage caused by intense laser stimulation was noticed by generating reactive oxygen species, which was then thought as the main damage effect by photons. In this study, we show that laser stimulation can induce autophagy, an important cell lysosomal pathway responding to immune stimulation and starvation, without any biochemical treatment. Two different types of laser stimulations are found to be capable of activating autophagy: continuous scanning by continuous-wave visible lasers and a short-time flashmore » of femtosecond laser irradiation. The autophagy generation is independent from wavelength, power, and scanning duration of the visible lasers. In contrast, the power of femtosecond laser is very critical to autophagy because the multiphoton excited Ca{sup 2+} dominates autophagy signaling. In general, we show here the different mechanisms of autophagy generation by such laser stimulation, which correspond to confocal microscopy and cell surgery, respectively. Those results can help further understanding of photodamage and autophagy signaling.« less

[Individual variability of immunological markers, radiosensitivity and oxidative status in blood lymphocytes of Moscow residents].

PubMed

Pelevina, I I; Aleshchenko, A V; Antoshchina, M M; Kudriashova, O M; Nikonova, M F; Riabchenko, N I; Serebrianyĭ, A M; Iarilin, A A

2013-01-01

Expression of activation (CD69) and proliferation (Ki67) markers, their connection with each other, with the oxidative status (reactive oxygen species--ROS) and with radiosensitivity (determined by micronucleus test) have been studied on stimulated blood lymphocytes from Moscow inhabitants. It was shown that the content of T-lymphocytes with the expressed CD69 and the content of T-lymphocytes with the expressed Ki67 markers correlate (r = 0.571; p = 0.0004). We can suppose that expression of the CD69 marker (24 h after PHA stimulation) is needed for the cell cycle progression, but it is not enough for the high expression of Ki67 markers 48 h after stimulation (DNA synthesis phase). It was discovered that T-lymphocytes with the CD69 marker or T-lymphocytes with the Ki67 marker are connected by the negative correlation with the frequency of irradiated cell with micronucleus (MN) r = -0.487; p = 0.010; r = -0.440; p = 0.008, respectively. So we can suppose that lymphocyte radiosensitivity decreased with the increase of expression activation and proliferation markers. It was shown that radiosensitivity determined by MN test is not connected with the oxidative status determined by the reactive oxygen species content including superoxide anion radicals. It is possible to explain by the fact that the ROS concentration has been determined in non-stimulated lymphocytes, but frequencies of cells with MN - in the stimulated cells 48 h after stimulation. Using separate analysis of individual differences by the studied parameters that were determined in the same people, it was shown that individual differences are high enough in the same cases. For example, the radiosensitivity when cells were irradiated 48 h after stimulation, ROS concentration, cell content with activation and proliferation markers. In conclusion, we can say that we failed to find important correlation between the parameters studied. However, the presence of individual differences in the marker expression, the frequency of MN cells, the oxidative status in the usual inhabitants, typical donors in Moscow, is very important.

Tempering Proactive Cognitive Control by Transcranial Direct Current Stimulation of the Right (but Not the Left) Lateral Prefrontal Cortex

PubMed Central

Gómez-Ariza, Carlos J.; Martín, María C.; Morales, Julia

2017-01-01

Behavioral and neuroimaging data support the distinction of two different modes of cognitive control: proactive, which involves the active and sustained maintenance of task-relevant information to bias behavior in accordance with internal goals; and reactive, which entails the detection and resolution of interference at the time it occurs. Both control modes may be flexibly deployed depending on a variety of conditions (i.e., age, brain alterations, motivational factors, prior experience). Critically, and in line with specific predictions derived from the dual mechanisms of control account (Braver, 2012), findings from neuroimaging studies indicate that the same lateral prefrontal regions (i.e., left dorsolateral cortex and right inferior frontal junction) may implement different control modes on the basis of temporal dynamics of activity, which would be modulated in response to external or internal conditions. In the present study, we aimed to explore whether transcraneal direct current stimulation over either the left dorsolateral prefrontal cortex or the right inferior frontal junction would differentially modulate performance on the AX-CPT, a well-validated task that provides sensitive and reliable behavioral indices of proactive/reactive control. The study comprised six conditions of real stimulation [3 (site: left dorsolateral, right dorsolateral and right inferior frontal junction) × 2 (polarity: anodal and cathodal)], and one sham condition. The reference electrode was always placed extracephalically. Performance on the AX-CPT was assessed through two blocks of trials. The first block took place while stimulation was being delivered, whereas the second block was administered after stimulation completion. The results indicate that both offline cathodal stimulation of the right dorsolateral prefrontal cortex and online anodal stimulation of the right inferior frontal junction led participants to be much less proactive, with such a dissociation suggesting that both prefrontal regions differentially contribute to the adjustment of cognitive control modes. tDCS of the left-DLPFC failed to modulate cognitive control. These results partially support the predictions derived from the dual mechanisms of control account. PMID:28588441

In vitro P-glycoprotein activity does not completely explain in vivo efficacy of novel centrally effective oxime acetylcholinesterase reactivators.

PubMed

Dail, Mary Beth; Meek, Edward Caldwell; Chambers, Howard Wayne; Chambers, Janice Elaine

2018-05-03

Novel-substituted phenoxyalkyl pyridinium oxime acetylcholinesterase (AChE) reactivators (US patent 9,227,937) that showed convincing evidence of penetration into the brains of intact rats were developed by our laboratories. The oximes separated into three groups based on their levels of brain AChE reactivation following exposure of rats to the sarin surrogate nitrophenyl isopropyl methylphosphonate (NIMP). P-glycoprotein (P-gp) is a major blood-brain barrier (BBB) transporter and requires ATP for efflux. To determine if P-gp affinity screening could be used to reduce animal use, we measured in vitro oxime-stimulated ATPase activity to see if the in vivo reactivation efficacies related to the oximes' functions as P-gp substrates. High efficacy oximes were expected to be poor P-gp substrates, thus remaining in the brain longer. The high efficacy oximes (24-35% brain AChE reactivation) were worse P-gp substrates than the low efficacy oximes (0-7% brain AChE reactivation). However, the oxime group with medium in vivo reactivation of 10-17% were even worse P-gp substrates than the high efficacy group so their reactivation ability was not reflected by P-gp export. The results suggest that in vitro P-gp ATPase activity can remove the low efficacy oximes from in vivo testing, but is not sufficient to differentiate between the top two tiers.

The Tat Inhibitor Didehydro-Cortistatin A Prevents HIV-1 Reactivation from Latency

PubMed Central

Mousseau, Guillaume; Kessing, Cari F.; Fromentin, Rémi; Trautmann, Lydie; Chomont, Nicolas

2015-01-01

ABSTRACT Antiretroviral therapy (ART) inhibits HIV-1 replication, but the virus persists in latently infected resting memory CD4+ T cells susceptible to viral reactivation. The virus-encoded early gene product Tat activates transcription of the viral genome and promotes exponential viral production. Here we show that the Tat inhibitor didehydro-cortistatin A (dCA), unlike other antiretrovirals, reduces residual levels of viral transcription in several models of HIV latency, breaks the Tat-mediated transcriptional feedback loop, and establishes a nearly permanent state of latency, which greatly diminishes the capacity for virus reactivation. Importantly, treatment with dCA induces inactivation of viral transcription even after its removal, suggesting that the HIV promoter is epigenetically repressed. Critically, dCA inhibits viral reactivation upon CD3/CD28 or prostratin stimulation of latently infected CD4+ T cells from HIV-infected subjects receiving suppressive ART. Our results suggest that inclusion of a Tat inhibitor in current ART regimens may contribute to a functional HIV-1 cure by reducing low-level viremia and preventing viral reactivation from latent reservoirs. PMID:26152583

Selective adsorption of toluene-3,4-dithiol on Si(553)-Au surfaces

NASA Astrophysics Data System (ADS)

Suchkova, Svetlana; Hogan, Conor; Bechstedt, Friedhelm; Speiser, Eugen; Esser, Norbert

2018-01-01

The adsorption of small organic molecules onto vicinal Au-stabilized Si(111) surfaces is shown to be a versatile route towards controlled growth of ordered organic-metal hybrid one-dimensional nanostructures. Density functional theory is used to investigate the site-specific adsorption of toluene-3,4-dithiol (TDT) molecules onto the clean Si(553)-Au surface and onto a co-doped surface whose steps are passivated by hydrogen. We find that the most reactive sites involve bonding to silicon at the step edge or on the terraces, while gold sites are relatively unfavored. H passivation and TDT adsorption both induce a controlled charge redistribution within the surface layer, causing the surface metallicity, electronic structure, and chemical reactivity of individual adsorption sites to be substantially altered.

Molecular salt effects in the gas phase: tuning the kinetic basicity of [HCCLiCl]⁻ and [HCCMgCl₂]⁻ by LiCl and MgCl₂.

PubMed

Khairallah, George N; da Silva, Gabriel; O'Hair, Richard A J

2014-10-06

A combination of gas-phase ion-molecule reaction experiments and theoretical kinetic modeling is used to examine how a salt can influence the kinetic basicity of organometallates reacting with water. [HC≡CLiCl](-) reacts with water more rapidly than [HC≡CMgCl2](-), consistent with the higher reactivity of organolithium versus organomagnesium reagents. Addition of LiCl to [HC≡CLiCl](-) or [HC≡CMgCl2](-) enhances their reactivity towards water by a factor of about 2, while addition of MgCl2 to [HC≡CMgCl2](-) enhances its reactivity by a factor of about 4. Ab initio calculations coupled with master equation/RRKM theory kinetic modeling show that these reactions proceed via a mechanism involving formation of a water adduct followed by rearrangement, proton transfer, and acetylene elimination as either discrete or concerted steps. Both the energy and entropy requirements for these elementary steps need to be considered in order to explain the observed kinetics. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Internal and external atomic steps in graphite exhibit dramatically different physical and chemical properties.

PubMed

Lee, Hyunsoo; Lee, Han-Bo-Ram; Kwon, Sangku; Salmeron, Miquel; Park, Jeong Young

2015-04-28

We report on the physical and chemical properties of atomic steps on the surface of highly oriented pyrolytic graphite (HOPG) investigated using atomic force microscopy. Two types of step edges are identified: internal (formed during crystal growth) and external (formed by mechanical cleavage of bulk HOPG). The external steps exhibit higher friction than the internal steps due to the broken bonds of the exposed edge C atoms, while carbon atoms in the internal steps are not exposed. The reactivity of the atomic steps is manifested in a variety of ways, including the preferential attachment of Pt nanoparticles deposited on HOPG when using atomic layer deposition and KOH clusters formed during drop casting from aqueous solutions. These phenomena imply that only external atomic steps can be used for selective electrodeposition for nanoscale electronic devices.

Categorization of multiple sclerosis relapse subtypes by B cell profiling in the blood.

PubMed

Hohmann, Christopher; Milles, Bianca; Schinke, Michael; Schroeter, Michael; Ulzheimer, Jochen; Kraft, Peter; Kleinschnitz, Christoph; Lehmann, Paul V; Kuerten, Stefanie

2014-09-16

B cells are attracting increasing attention in the pathogenesis of multiple sclerosis (MS). B cell-targeted therapies with monoclonal antibodies or plasmapheresis have been shown to be successful in a subset of patients. Here, patients with either relapsing-remitting (n = 24) or secondary progressive (n = 6) MS presenting with an acute clinical relapse were screened for their B cell reactivity to brain antigens and were re-tested three to nine months later. Enzyme-linked immunospot technique (ELISPOT) was used to identify brain-reactive B cells in peripheral blood mononuclear cells (PBMC) directly ex vivo and after 96 h of polyclonal stimulation. Clinical severity of symptoms was determined using the Expanded Disability Status Scale (EDSS). Nine patients displayed B cells in the blood producing brain-specific antibodies directly ex vivo. Six patients were classified as B cell positive donors only after polyclonal B cell stimulation. In 15 patients a B cell response to brain antigens was absent. Based on the autoreactive B cell response we categorized MS relapses into three different patterns. Patients who displayed brain-reactive B cell responses both directly ex vivo and after polyclonal stimulation (pattern I) were significantly younger than patients in whom only memory B cell responses were detectable or entirely absent (patterns II and III; p = 0.003). In one patient a conversion to a positive B cell response as measured directly ex vivo and subsequently also after polyclonal stimulation was associated with the development of a clinical relapse. The evaluation of the predictive value of a brain antigen-specific B cell response showed that seven of eight patients (87.5%) with a pattern I response encountered a clinical relapse during the observation period of 10 months, compared to two of five patients (40%) with a pattern II and three of 14 patients (21.4%) with a pattern III response (p = 0.0005; hazard ratio 6.08 (95% confidence interval 1.87-19.77). Our data indicate actively ongoing B cell-mediated immunity against brain antigens in a subset of MS patients that may be causative of clinical relapses and provide new diagnostic and therapeutic options for a subset of patients.

An optimized IFN-γ ELISpot assay for the sensitive and standardized monitoring of CMV protein-reactive effector cells of cell-mediated immunity.

PubMed

Barabas, Sascha; Spindler, Theresa; Kiener, Richard; Tonar, Charlotte; Lugner, Tamara; Batzilla, Julia; Bendfeldt, Hanna; Rascle, Anne; Asbach, Benedikt; Wagner, Ralf; Deml, Ludwig

2017-03-07

In healthy individuals, Cytomegalovirus (CMV) infection is efficiently controlled by CMV-specific cell-mediated immunity (CMI). Functional impairment of CMI in immunocompromized individuals however can lead to uncontrolled CMV replication and severe clinical complications. Close monitoring of CMV-specific CMI is therefore clinically relevant and might allow a reliable prognosis of CMV disease as well as assist personalized therapeutic decisions. Objective of this work was the optimization and technical validation of an IFN-γ ELISpot assay for a standardized, sensitive and reliable quantification of CMV-reactive effector cells. T-activated® immunodominant CMV IE-1 and pp65 proteins were used as stimulants. All basic assay parameters and reagents were tested and optimized to establish a user-friendly protocol and maximize the signal-to-noise ratio of the ELISpot assay. Optimized and standardized ELISpot revealed low intra-assay, inter-assay and inter-operator variability (coefficient of variation CV below 22%) and CV inter-site was lower than 40%. Good assay linearity was obtained between 6 × 10 4 and 2 × 10 5 PBMC per well upon stimulation with T-activated® IE-1 (R 2  = 0.97) and pp65 (R 2  = 0.99) antigens. Remarkably, stimulation of peripheral blood mononuclear cells (PBMC) with T-activated® IE-1 and pp65 proteins resulted in the activation of a broad range of CMV-reactive effector cells, including CD3 + CD4 + (Th), CD3 + CD8 + (CTL), CD3 - CD56 + (NK) and CD3 + CD56 + (NKT-like) cells. Accordingly, the optimized IFN-γ ELISpot assay revealed very high sensitivity (97%) in a cohort of 45 healthy donors, of which 32 were CMV IgG-seropositive. The combined use of T-activated® IE-1 and pp65 proteins for the stimulation of PBMC with the optimized IFN-γ ELISpot assay represents a highly standardized, valuable tool to monitor the functionality of CMV-specific CMI with great sensitivity and reliability.

Iron oxidation stimulates organic matter decomposition in humid tropical forest soils.

PubMed

Hall, Steven J; Silver, Whendee L

2013-09-01

Humid tropical forests have the fastest rates of organic matter decomposition globally, which often coincide with fluctuating oxygen (O2 ) availability in surface soils. Microbial iron (Fe) reduction generates reduced iron [Fe(II)] under anaerobic conditions, which oxidizes to Fe(III) under subsequent aerobic conditions. We demonstrate that Fe (II) oxidation stimulates organic matter decomposition via two mechanisms: (i) organic matter oxidation, likely driven by reactive oxygen species; and (ii) increased dissolved organic carbon (DOC) availability, likely driven by acidification. Phenol oxidative activity increased linearly with Fe(II) concentrations (P < 0.0001, pseudo R(2)  = 0.79) in soils sampled within and among five tropical forest sites. A similar pattern occurred in the absence of soil, suggesting an abiotic driver of this reaction. No phenol oxidative activity occurred in soils under anaerobic conditions, implying the importance of oxidants such as O2 or hydrogen peroxide (H2 O2 ) in addition to Fe(II). Reactions between Fe(II) and H2 O2 generate hydroxyl radical, a strong nonselective oxidant of organic compounds. We found increasing consumption of H2 O2 as soil Fe(II) concentrations increased, suggesting that reactive oxygen species produced by Fe(II) oxidation explained variation in phenol oxidative activity among samples. Amending soils with Fe(II) at field concentrations stimulated short-term C mineralization by up to 270%, likely via a second mechanism. Oxidation of Fe(II) drove a decrease in pH and a monotonic increase in DOC; a decline of two pH units doubled DOC, likely stimulating microbial respiration. We obtained similar results by manipulating soil acidity independently of Fe(II), implying that Fe(II) oxidation affected C substrate availability via pH fluctuations, in addition to producing reactive oxygen species. Iron oxidation coupled to organic matter decomposition contributes to rapid rates of C cycling across humid tropical forests in spite of periodic O2 limitation, and may help explain the rapid turnover of complex C molecules in these soils. © 2013 John Wiley & Sons Ltd.

Falls-risk post-stroke: Examining contributions from paretic versus non paretic limbs to unexpected forward gait slips.

PubMed

Kajrolkar, Tejal; Bhatt, Tanvi

2016-09-06

Community-dwelling stroke survivors show a high incidence of falls with unexpected external perturbations during dynamic activities like walking. Previous evidence has demonstrated the importance of compensatory stepping to restore dynamic stability in response to perturbations in hemiparetic stroke survivors. However, these studies were limited to either stance perturbations or perturbation induced under the unaffected limb. This study aimed to compare the differences, if any, between the non-paretic and paretic sides in dynamic stability and protective stepping strategies when exposed to unexpected external perturbation during walking. Twenty hemiparetic subjects experienced an unexpected forward slip during walking on the laboratory walkway either on the paretic (n=10) or the nonparetic limb (n=10). Both groups demonstrated a backward loss of balance with a compensatory stepping response, with the nonparetic-side slip group resorting mainly to an aborted step response (60%) and the paretic-side slip group mainly exhibiting a recovery step response (90%). Although both groups showed an equal incidence of falls, the nonparetic-side slip group demonstrated a higher stability at recovery step touchdown, resulting from lower perturbation magnitudes (slip displacement and velocity) compared to the paretic-side slip group. The results indicate that the paretic side had difficulty initiating and executing a successful stepping response (nonparetic-side slip) and also in reactive limb control while in stance (paretic-side slip). Based on these results it is suggested that intervention strategies for fall-prevention in chronic stroke survivors should focus on paretic limb training for both reactive stepping and weight bearing for improving balance control for recovery from unpredictable perturbations during dynamic activities such as walking. Copyright © 2016. Published by Elsevier Ltd.

Reactive transport in fractured porous media

NASA Astrophysics Data System (ADS)

Adler, P.; Jasinski, L.; Thovert, J.-F.; Mourzenko, V. V.

2012-04-01

Reactive flow through geological formations occurs in many situations due to human intervention or during natural processes. For instance, chemical dissolution and precipitation play a major role in diagenesis or in the formation of karsts. The quantitative description of the injection of a reacting fluid from a well into a fractured porous medium is also a subject of high interest. It can be provoked, as in the acidization stimulation technique for increasing well productivity, or accidental, in CO2 sequestration. Ideally, one wishes to analyze the improvements or damages caused by the fluid to the well itself and to its immediate surroundings. To this end, a coupled system of equations has to be solved. It includes the description of the flow in the porous matrix and in the fracture network by Darcy-like equations, and the description of the reactive solute transport and of the reactions which occur in the two structures. In addition, constitutive equations are required for the evolution of these two structures, such as evolution laws for permeability and reactivity as functions of porosity. Our discrete fracture numerical model involves three major steps. First, an unstructured tetrahedral mesh of the fractures and of the porous matrix is built. Second, the Darcy equations are discretized and solved, in a finite volume formulation. Third, the evolution of the solute concentration has to be calculated. This is the most difficult point if one wants to avoid numerical diffusion and accurately describe the transfers between the fractures and the matrix. A non linear flux limiting scheme of the Superbee type coupled with a systematic use of triple control volumes proved to be the most efficient. Various simple model situations have been considered, for validation purposes or to illustrate some physical points. In particular, it is shown that even when the matrix permeability is small and the flow is predominantly carried by the fracture network, convective exchanges still exist between the fractures and the matrix which can widely exceed diffusive ones and strongly affect the solute transport and its residence time distribution. Finally, simulations of passive and reactive solute transport have been performed in large samples containing percolating or non percolating fracture networks. Various parameters have been systematically investigated, including the transmissivity of the fractures, the flow regime characterized by Péclet numbers in the fractures and in the matrix, and the Damköhler numbers of the reaction process in the matrix and fractures. The passive transport behavior and the effect of the gradual clogging of the fractures and/or matrix pore space in the case of a precipitation process are analyzed.

Reactive flow in fractured porous media

NASA Astrophysics Data System (ADS)

Jasinski, L.; Thovert, J.; Mourzenko, V.; Adler, P. M.

2011-12-01

Reactive flow through geological formations occurs in many situations due to human intervention or during natural processes. For instance, chemical dissolution and precipitation play a major role in diagenesis or in the formation of karsts. The quantitative description of the injection of a reacting fluid from a well into a fractured porous medium is also a subject of high interest. It can be provoked, as in the acidization stimulation technique for increasing well productivity, or accidental, in CO2 sequestration. Ideally, one wishes to analyze the improvements or damages caused by the fluid to the well itself and to its immediate surroundings. To this end, a coupled system of equations has to be solved. It includes the description of the flow in the porous matrix and in the fracture network by Darcy-like equations, and the description of the reactive solute transport and of the reactions which occur in the two structures. In addition, constitutive equations are required for the evolution of these two structures, such as evolution laws for permeability and reactivity as functions of porosity. Our discrete fracture numerical model involves three major steps. First, an unstructured tetrahedral mesh of the fractures and of the porous matrix is built. Second, the Darcy equations are discretized and solved, in a finite volume formulation. Third, the evolution of the solute concentration has to be calculated. This is the most difficult point if one wants to avoid numerical diffusion and accurately describe the transfers between the fractures and the matrix. A non linear flux limiting scheme of the Superbee type coupled with a systematic use of triple control volumes proved to be the most efficient. Various simple model situations have been considered, for validation purposes or to illustrate some physical points. In particular, it is shown that even when the matrix permeability is small and the flow is predominantly carried by the fracture network, convective exchanges still exist between the fractures and the matrix which can widely exceed diffusive ones and strongly affect the solute transport and its residence time distribution. Finally, simulations of passive and reactive solute transport have been performed in large samples containing percolating or non percolating fracture networks. Various parameters have been systematically investigated, including the transmissivity of the fractures, the flow regime characterized by Péclet numbers in the fractures and in the matrix, and the Damköhler numbers of the reaction process in the matrix and fractures. The passive transport behavior and the effect of the gradual clogging of the fractures and/or matrix pore space in the case of a precipitation process are analyzed.

Method for bonding thin film thermocouples to ceramics

DOEpatents

Kreider, Kenneth G.

1993-01-01

A method is provided for adhering a thin film metal thermocouple to a ceramic substrate used in an environment up to 700 degrees Centigrade, such as at a cylinder of an internal combustion engine. The method includes the steps of: depositing a thin layer of a reactive metal on a clean ceramic substrate; and depositing thin layers of platinum and a platinum-10% rhodium alloy forming the respective legs of the thermocouple on the reactive metal layer. The reactive metal layer serves as a bond coat between the thin noble metal thermocouple layers and the ceramic substrate. The thin layers of noble metal are in the range of 1-4 micrometers thick. Preferably, the ceramic substrate is selected from the group consisting of alumina and partially stabilized zirconia. Preferably, the thin layer of reactive metal is in the range of 0.015-0.030 micrometers (15-30 nanometers) thick. The preferred reactive metal is chromium. Other reactive metals may be titanium or zirconium. The thin layer of reactive metal may be deposited by sputtering in ultra high purity argon in a vacuum of approximately 2 milliTorr (0.3 Pascals).

Emotional reactivity to valence-loaded stimuli are related to treatment response of neurocognitive therapy.

PubMed

Vanderhasselt, Marie-Anne; De Raedt, Rudi; Namur, Victoria; Valiengo, Leandro C L; Lotufo, Paulo A; Bensenor, Isabela M; Baeken, Chris; Boggio, Paulo S; Brunoni, Andre R

2016-01-15

Emotional Context Insensitivity (ECI) is a psychological feature observed in depressed patients characterized by a decreased emotional reactivity when presented to positive- and negative valence-loaded stimuli. Given that fronto-cingulate-limbic circuits are implicated in abnormal reactivity to valence-loaded stimuli, neurocognitive treatments engaging the prefrontal cortex may be able to modulate this emotional blunting observed in MDD. Therefore, our goal was to evaluate emotional reactivity in depressed patients before and after a combination of neurocognitive interventions that engage the prefrontal cortex (cognitive control training and/or transcranial direct current stimulation). In line with the premises of the ECI framework, before the start of the antidepressant intervention, patients showed blunted emotional reactivity after exposure to negative valence-loaded stimuli. This emotional reactivity pattern changed after 9 sessions of the intervention: positive affect decreased and negative affect increased after watching a series of negative valence-loaded stimuli (i.e. images). Interestingly, higher emotional reactivity (as indexed by a larger increase in negative affect after watching the valence-loaded stimuli) at baseline predicted reductions in depression symptoms after the intervention. On the other hand, higher emotional reactivity (as indexed by a decrease in positive affect) after the intervention was marginally associated with reductions in depression symptoms. To conclude, emotional reactivity increased after the neurocognitive antidepressant intervention and it was directly associated to the degree of depression improvement. Copyright © 2015 Elsevier B.V. All rights reserved.

Environmental enrichment and social interaction improve cognitive function and decrease reactive oxidative species in normal adult mice.

PubMed

Doulames, Vanessa; Lee, Sangmook; Shea, Thomas B

2014-05-01

Environmental stimulation and increased social interactions stimulate cognitive performance, while decrease in these parameters can exacerbate cognitive decline as a function of illness, injury, or age. We examined the impact of environmental stimulation and social interactions on cognitive performance in healthy adult C57B1/6J mice. Mice were housed for 1 month individually or in groups of three (to prevent or allow social interaction) in either a standard environment (SE) or an enlarged cage containing nesting material and items classically utilized to stimulate exploration and activity ("enriched environment"; EE). Cognitive performance was tested by Y maze navigation and Novel Object Recognition (NOR; which compares the relative amount of time mice spent investigating a novel vs. a familiar object). Mice maintained for 1 month under isolated conditions in the SE statistically declined in performance versus baseline in the Y maze (p < 0.02; ANOVA). Performance under all other conditions did not change from baseline. Maintenance in groups in the SE statistically improved NOR (p < 0.01), whereas maintenance in isolation in the SE did not alter performance from baseline. Maintenance in the EE statistically improved performance in NOR for mice housed in groups and individually (p < 0.01). Maintenance under isolated conditions slightly increased reactive oxygen/nitrogen species (ROS/RNS) in brain. Environmental enrichment did not influence ROS/RNS. These findings indicate that environmental and social enrichment can positively influence cognitive performance in healthy adult mice, and support the notion that proactive approaches may delay age-related cognitive decline.

The Impact of Morphine After a Spinal Cord Injury

PubMed Central

Hook, Michelle A.; Liu, Grace T.; Washburn, Stephanie N.; Ferguson, Adam R.; Bopp, Anne C.; Huie, John R.; Grau, James W.

2007-01-01

Nociceptive stimulation, at an intensity that elicits pain-related behavior, attenuates recovery of locomotor and bladder functions, and increases tissue loss after a contusion injury. These data imply that nociceptive input (e.g., from tissue damage) can enhance the loss of function after injury, and that potential clinical treatments, such pretreatment with an analgesic, may protect the damaged system from further secondary injury. The current study examined this hypothesis and showed that a potential treatment (morphine) did not have a protective effect. In fact, morphine appeared to exacerbate the effects of nociceptive stimulation. Experiment 1 showed that after spinal cord injury 20 mg/kg of systemic morphine was necessary to induce strong antinociception and block behavioral reactivity to shock treatment, a dose that was much higher than that needed for sham controls. In Experiment 2, contused rats were given one of three doses of morphine (Vehicle, 10, 20 mg/kg) prior to exposure to uncontrollable electrical stimulation or restraint alone. Despite decreasing nociceptive reactivity, morphine did not attenuate the long-term consequences of shock. Rats treated with morphine and shock had higher mortality rates, and displayed allodynic responses to innocuous sensory stimuli three weeks later. Independent of shock, morphine per se undermined recovery of sensory function. Rats treated with morphine alone also had significantly larger lesions than those treated with saline. These results suggest that nociceptive stimulation affects recovery despite a blockade of pain-elicited behavior. The results are clinically important because they suggest that opiate treatment may adversely affect the recovery of function after injury. PMID:17383022

Bupropion hydrochloride produces conditioned hyperactivity in rats.

PubMed

Wilkinson, Jamie L; Bevins, Rick A

2007-04-23

Bupropion is marketed as an antidepressant, Wellbutrin and smoking cessation aid, Zyban. Although the therapeutic neurological mechanisms of bupropion have not been fully elucidated, bupropion shares some behavioral similarities with classic psychomotor stimulants. The present study sought to further investigate these psychomotor stimulant effects of bupropion by assessing whether repeated administration of bupropion in a distinct environment produced conditioned hyperactivity. Paired rats received 10 daily i.p. injections of bupropion (2.5-30 mg/kg) before placement in locomotor chambers for 30 min. Bupropion (10-30 mg/kg) produced acute locomotor hyperactivity compared to Unpaired controls. After repeated administration, there was no progressive increase or decrease in bupropion-induced activity. In a subsequent drug-free session conditioned hyperactivity was observed at 5-30 mg/kg doses. In a follow-up experiment, we examined whether responsiveness to novelty predicted the subsequent unconditioned and conditioned locomotor effect of bupropion. Reactivity to inescapable novelty, novel environment approach, and novel-object interaction were measured before locomotor conditioning with 30 mg/kg bupropion. We replicated the previous experiment, but scores on the novelty screens did not predict locomotor response to bupropion. This study extends the literature by demonstrating that environmental cues repeatedly paired with the stimulant effects of bupropion come to evoke elevated activity in the absence of drug (i.e., conditioned hyperactivity). This finding is consistent with the literature suggesting that bupropion shares many behavioral similarities with other psychomotor stimulants which also produce conditioned hyperactivity. However, a predictive relation between reactivity to forced novelty and the subsequent locomotor effect of bupropion may not be one of these similarities.

Reactive oxygen species are involved in regulating alpha1-adrenoceptor-activated vascular smooth muscle contraction.

PubMed

Tsai, Ming-Ho; Jiang, Meei Jyh

2010-08-23

Reactive oxygen species (ROS) were shown to mediate aberrant contractility in hypertension, yet the physiological roles of ROS in vascular smooth muscle contraction have remained elusive. This study aimed to examine whether ROS regulate alpha1-adrenoceptor-activated contraction by altering myosin phosphatase activities. Using endothelium-denuded rat tail artery (RTA) strips, effects of anti-oxidants on isometric force, ROS production, phosphorylation of the 20-kDa myosin light chain (MLC20), and myosin phosphatase stimulated by alpha1-adrenoceptor agonist phenylephrine were examined. An antioxidant, N-acetyl-L-cysteine (NAC), and two NADPH oxidase inhibitors, apocynin and VAS2870, dose-dependently inhibited contraction activated by phenylephrine. Phenylephrine stimulated superoxide anion production that was diminished by the pretreatment of apocynin, VAS2870, superoxide scavenger tiron or mitochondria inhibitor rotenone, but not by xanthine oxidase inhibitor allopurinol or cyclooxygenase inhibitor indomethacin. Concurrently, NADPH oxidase activity in RTA homogenates increased within 1 min upon phenylephrine stimulation, sustained for 10 min, and was abolished by the co-treatment with apocynin, but not allopurinol or rotenone. Phenylephrine-induced MLC20 phosphorylation was dose-dependently decreased by apocynin. Furthermore, apocynin inhibited phenylephrine-stimulated RhoA translocation to plasma membrane and phosphorylation of both myosin phosphatase regulatory subunit MYPT1Thr855 and myosin phosphatase inhibitor CPI-17Thr38. ROS, probably derived from NADPH oxidase and mitochondria, partially regulate alpha1-adrenoceptor-activated smooth muscle contraction by altering myosin phosphatase-mediated MLC20 phosphorylation through both RhoA/Rho kinase- and CPI-17-dependent pathways.

Algorithms of GPU-enabled reactive force field (ReaxFF) molecular dynamics.

PubMed

Zheng, Mo; Li, Xiaoxia; Guo, Li

2013-04-01

Reactive force field (ReaxFF), a recent and novel bond order potential, allows for reactive molecular dynamics (ReaxFF MD) simulations for modeling larger and more complex molecular systems involving chemical reactions when compared with computation intensive quantum mechanical methods. However, ReaxFF MD can be approximately 10-50 times slower than classical MD due to its explicit modeling of bond forming and breaking, the dynamic charge equilibration at each time-step, and its one order smaller time-step than the classical MD, all of which pose significant computational challenges in simulation capability to reach spatio-temporal scales of nanometers and nanoseconds. The very recent advances of graphics processing unit (GPU) provide not only highly favorable performance for GPU enabled MD programs compared with CPU implementations but also an opportunity to manage with the computing power and memory demanding nature imposed on computer hardware by ReaxFF MD. In this paper, we present the algorithms of GMD-Reax, the first GPU enabled ReaxFF MD program with significantly improved performance surpassing CPU implementations on desktop workstations. The performance of GMD-Reax has been benchmarked on a PC equipped with a NVIDIA C2050 GPU for coal pyrolysis simulation systems with atoms ranging from 1378 to 27,283. GMD-Reax achieved speedups as high as 12 times faster than Duin et al.'s FORTRAN codes in Lammps on 8 CPU cores and 6 times faster than the Lammps' C codes based on PuReMD in terms of the simulation time per time-step averaged over 100 steps. GMD-Reax could be used as a new and efficient computational tool for exploiting very complex molecular reactions via ReaxFF MD simulation on desktop workstations. Copyright © 2013 Elsevier Inc. All rights reserved.

Tutorial: Reactive high power impulse magnetron sputtering (R-HiPIMS)

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

Anders, André

High Power Impulse Magnetron Sputtering (HiPIMS) is a coating technology that combines magnetron sputtering with pulsed power concepts. Furthermore, by applying power in pulses of high amplitude and a relatively low duty cycle, large fractions of sputtered atoms and near-target gases are ionized. In contrast to conventional magnetron sputtering, HiPIMS is characterized by self-sputtering or repeated gas recycling for high and low sputter yield materials, respectively, and both for most intermediate materials. The dense plasma in front of the target has the dual function of sustaining the discharge and providing plasma-assistance to film growth, affecting the microstructure of growing films.more » Many technologically interesting thin films are compound films, which are composed of one or more metals and a reactive gas, most often oxygen or nitrogen. When reactive gas is added, non-trivial consequences arise for the system because the target may become “poisoned,” i.e., a compound layer forms on the target surface affecting the sputtering yield and the yield of secondary electron emission and thereby all other parameters. It is emphasized that the target state depends not only on the reactive gas' partial pressure (balanced via gas flow and pumping) but also on the ion flux to the target, which can be controlled by pulse parameters. This is a critical technological opportunity for reactive HiPIMS (R-HiPIMS). The scope of this tutorial is focused on plasma processes and mechanisms of operation and only briefly touches upon film properties. It introduces R-HiPIMS in a systematic, step-by-step approach by covering sputtering, magnetron sputtering, reactive magnetron sputtering, pulsed reactive magnetron sputtering, HiPIMS, and finally R-HiPIMS. The tutorial is concluded by considering variations of R-HiPIMS known as modulated pulsed power magnetron sputtering and deep-oscillation magnetron sputtering and combinations of R-HiPIMS with superimposed dc magnetron sputtering.« less

Tutorial: Reactive high power impulse magnetron sputtering (R-HiPIMS)

DOE PAGES

Anders, André

2017-03-21

High Power Impulse Magnetron Sputtering (HiPIMS) is a coating technology that combines magnetron sputtering with pulsed power concepts. Furthermore, by applying power in pulses of high amplitude and a relatively low duty cycle, large fractions of sputtered atoms and near-target gases are ionized. In contrast to conventional magnetron sputtering, HiPIMS is characterized by self-sputtering or repeated gas recycling for high and low sputter yield materials, respectively, and both for most intermediate materials. The dense plasma in front of the target has the dual function of sustaining the discharge and providing plasma-assistance to film growth, affecting the microstructure of growing films.more » Many technologically interesting thin films are compound films, which are composed of one or more metals and a reactive gas, most often oxygen or nitrogen. When reactive gas is added, non-trivial consequences arise for the system because the target may become “poisoned,” i.e., a compound layer forms on the target surface affecting the sputtering yield and the yield of secondary electron emission and thereby all other parameters. It is emphasized that the target state depends not only on the reactive gas' partial pressure (balanced via gas flow and pumping) but also on the ion flux to the target, which can be controlled by pulse parameters. This is a critical technological opportunity for reactive HiPIMS (R-HiPIMS). The scope of this tutorial is focused on plasma processes and mechanisms of operation and only briefly touches upon film properties. It introduces R-HiPIMS in a systematic, step-by-step approach by covering sputtering, magnetron sputtering, reactive magnetron sputtering, pulsed reactive magnetron sputtering, HiPIMS, and finally R-HiPIMS. The tutorial is concluded by considering variations of R-HiPIMS known as modulated pulsed power magnetron sputtering and deep-oscillation magnetron sputtering and combinations of R-HiPIMS with superimposed dc magnetron sputtering.« less

Tutorial: Reactive high power impulse magnetron sputtering (R-HiPIMS)

NASA Astrophysics Data System (ADS)

Anders, André

2017-05-01

High Power Impulse Magnetron Sputtering (HiPIMS) is a coating technology that combines magnetron sputtering with pulsed power concepts. By applying power in pulses of high amplitude and a relatively low duty cycle, large fractions of sputtered atoms and near-target gases are ionized. In contrast to conventional magnetron sputtering, HiPIMS is characterized by self-sputtering or repeated gas recycling for high and low sputter yield materials, respectively, and both for most intermediate materials. The dense plasma in front of the target has the dual function of sustaining the discharge and providing plasma-assistance to film growth, affecting the microstructure of growing films. Many technologically interesting thin films are compound films, which are composed of one or more metals and a reactive gas, most often oxygen or nitrogen. When reactive gas is added, non-trivial consequences arise for the system because the target may become "poisoned," i.e., a compound layer forms on the target surface affecting the sputtering yield and the yield of secondary electron emission and thereby all other parameters. It is emphasized that the target state depends not only on the reactive gas' partial pressure (balanced via gas flow and pumping) but also on the ion flux to the target, which can be controlled by pulse parameters. This is a critical technological opportunity for reactive HiPIMS (R-HiPIMS). The scope of this tutorial is focused on plasma processes and mechanisms of operation and only briefly touches upon film properties. It introduces R-HiPIMS in a systematic, step-by-step approach by covering sputtering, magnetron sputtering, reactive magnetron sputtering, pulsed reactive magnetron sputtering, HiPIMS, and finally R-HiPIMS. The tutorial is concluded by considering variations of R-HiPIMS known as modulated pulsed power magnetron sputtering and deep-oscillation magnetron sputtering and combinations of R-HiPIMS with superimposed dc magnetron sputtering.

The Repression-Sensitization Dimension in Relation to Impending Painful Stimulation

ERIC Educational Resources Information Center

Scarpetti, William L.

1973-01-01

The study attempted to replicate previous findings of differences between self-report and physiological indices of disturbance in repressors and sensitizers placed in threatening situations. Results indicate that repressors admit to less anxiety on the self-report measure while producing more physiological reactivity to threat of shock. No such…

MITOCHONDRIAL OXIDANT PRODUCTION BY POLLUTANT DUST AND NO-MEDIATED APOPTOSIS IN HUMAN ALVEOLAR MACHROPHAGE

EPA Science Inventory

Residual oil fly ash (ROFA) is a pollutant dust that stimulates production of reactive oxygen species (ROS) from mitochondria and apoptosis in alveolar macrophages (AM), but the relationship between these two processes is unclear. In this study, human AM were incubated with RO...

Effects of Nitrogen Deposition on Greenhouse-Gas Fluxes for Forests and Grasslands of North America

EPA Science Inventory

Human activities have substantially elevated the atmospheric deposition of reactive nitrogen (N) onto terrestrial ecosystems of North America. Some of this N can stimulate carbon (C) storage in terrestrial ecosystems, but the fertilization effect of added N can be diminished by e...

Gene expression profiles of Aspergillus flavus isolates responding to oxidative stress in different culture media

USDA-ARS?s Scientific Manuscript database

Aflatoxin contamination of peanut by Aspergillus flavus is exacerbated by drought stress. Drought also stimulates the production of reactive oxygen species (ROS) in plant tissues implying a correlation between ROS and aflatoxin production. Here, we performed gene expression analysis by RNAseq of tox...

The Complexity Trap

DTIC Science & Technology

2012-01-01

proactively and effectively to today’s international environment, prioritization is the key first step —and precisely the opposite reaction to the complacency...formidable than just endless grains of sand.”32 This is not to deny the possibility of nonlinear phenomena, butterfly effects, self-organizing systems...The first step is replac- ing the current reactive worship of complexity with proactive prioritization. To escape the complexity trap, let us dare

Ultrahigh vacuum process for the deposition of nanotubes and nanowires

DOEpatents

Das, Biswajit; Lee, Myung B

2015-02-03

A system and method A method of growing an elongate nanoelement from a growth surface includes: a) cleaning a growth surface on a base element; b) providing an ultrahigh vacuum reaction environment over the cleaned growth surface; c) generating a reactive gas of an atomic material to be used in forming the nanoelement; d) projecting a stream of the reactive gas at the growth surface within the reactive environment while maintaining a vacuum of at most 1.times.10.sup.-4 Pascal; e) growing the elongate nanoelement from the growth surface within the environment while maintaining the pressure of step c); f) after a desired length of nanoelement is attained within the environment, stopping direction of reactive gas into the environment; and g) returning the environment to an ultrahigh vacuum condition.

Different dynamin blockers interfere with distinct phases of synaptic endocytosis during stimulation in motoneurones

PubMed Central

Linares-Clemente, Pedro; Rozas, José L; Mircheski, Josif; García-Junco-Clemente, Pablo; Martínez-López, José A; Nieto-González, José L; Vázquez, M Eugenio; Pintado, C Oscar; Fernández-Chacón, Rafael

2015-01-01

Key points Neurotransmitter release requires a tight coupling between synaptic vesicle exocytosis and endocytosis with dynamin being a key protein in that process. We used imaging techniques to examine the time course of endocytosis at mouse motor nerve terminals expressing synaptopHluorin, a genetically encoded reporter of the synaptic vesicle cycle. We separated two sequential phases of endocytosis taking place during the stimulation train: early and late endocytosis. Freshly released synaptic vesicle proteins are preferentially retrieved during the early phase, which is very sensitive to dynasore, an inhibitor of dynamin GTPase activity. Synaptic vesicle proteins pre-existing at the plasma membrane before the stimulation are preferentially retrieved during the late phase, which is very sensitive to myristyl trimethyl ammonium bromide (MitMAB), an inhibitor of the dynamin–phospholipid interaction. Abstract Synaptic endocytosis is essential at nerve terminals to maintain neurotransmitter release by exocytosis. Here, at the neuromuscular junction of synaptopHluorin (spH) transgenic mice, we have used imaging to study exo- and endocytosis occurring simultaneously during nerve stimulation. We observed two endocytosis components, which occur sequentially during stimulation. The early component of endocytosis apparently internalizes spH molecules freshly exocytosed. This component was sensitive to dynasore, a blocker of dynamin 1 GTPase activity. In contrast, this early component was resistant to myristyl trimethyl ammonium bromide (MiTMAB), a competitive agent that blocks dynamin binding to phospholipid membranes. The late component of endocytosis is likely to internalize spH molecules that pre-exist at the plasma membrane before stimulation starts. This component was blocked by MiTMAB, perhaps by impairing the binding of dynamin or other key endocytic proteins to phospholipid membranes. Our study suggests the co-existence of two sequential synaptic endocytosis steps taking place during stimulation that are susceptible to pharmacological dissection: an initial step, preferentially sensitive to dynasore, that internalizes vesicular components immediately after they are released, and a MiTMAB-sensitive step that internalizes vesicular components pre-existing at the plasma membrane surface. In addition, we report that post-stimulus endocytosis also has several components with different sensitivities to dynasore and MiTMAB. PMID:25981717

Different dynamin blockers interfere with distinct phases of synaptic endocytosis during stimulation in motoneurones.

PubMed

Linares-Clemente, Pedro; Rozas, José L; Mircheski, Josif; García-Junco-Clemente, Pablo; Martínez-López, José A; Nieto-González, José L; Vázquez, M Eugenio; Pintado, C Oscar; Fernández-Chacón, Rafael

2015-07-01

Neurotransmitter release requires a tight coupling between synaptic vesicle exocytosis and endocytosis with dynamin being a key protein in that process. We used imaging techniques to examine the time course of endocytosis at mouse motor nerve terminals expressing synaptopHluorin, a genetically encoded reporter of the synaptic vesicle cycle. We separated two sequential phases of endocytosis taking place during the stimulation train: early and late endocytosis. Freshly released synaptic vesicle proteins are preferentially retrieved during the early phase, which is very sensitive to dynasore, an inhibitor of dynamin GTPase activity. Synaptic vesicle proteins pre-existing at the plasma membrane before the stimulation are preferentially retrieved during the late phase, which is very sensitive to myristyl trimethyl ammonium bromide (MitMAB), an inhibitor of the dynamin-phospholipid interaction. Synaptic endocytosis is essential at nerve terminals to maintain neurotransmitter release by exocytosis. Here, at the neuromuscular junction of synaptopHluorin (spH) transgenic mice, we have used imaging to study exo- and endocytosis occurring simultaneously during nerve stimulation. We observed two endocytosis components, which occur sequentially during stimulation. The early component of endocytosis apparently internalizes spH molecules freshly exocytosed. This component was sensitive to dynasore, a blocker of dynamin 1 GTPase activity. In contrast, this early component was resistant to myristyl trimethyl ammonium bromide (MiTMAB), a competitive agent that blocks dynamin binding to phospholipid membranes. The late component of endocytosis is likely to internalize spH molecules that pre-exist at the plasma membrane before stimulation starts. This component was blocked by MiTMAB, perhaps by impairing the binding of dynamin or other key endocytic proteins to phospholipid membranes. Our study suggests the co-existence of two sequential synaptic endocytosis steps taking place during stimulation that are susceptible to pharmacological dissection: an initial step, preferentially sensitive to dynasore, that internalizes vesicular components immediately after they are released, and a MiTMAB-sensitive step that internalizes vesicular components pre-existing at the plasma membrane surface. In addition, we report that post-stimulus endocytosis also has several components with different sensitivities to dynasore and MiTMAB. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

Updates of operative techniques for upper airway stimulation.

PubMed

Heiser, Clemens; Thaler, Erica; Boon, Maurits; Soose, Ryan J; Woodson, B Tucker

2016-09-01

Selective upper airway stimulation has been established as an additional treatment for obstructive sleep apnea (OSA). Essential for the treatment is the precise placement of the cuff electrode for select branches of the hypoglossal nerve, which innervate the protrusors and stiffeners of the tongue. A direct approach to the distal hypoglossal nerve has been established to achieve this goal. For surgeons, detailed knowledge of this anatomy is vital. Another decisive step is the placement of the sensing lead between the intercostal muscles. Also, the complexity of follow-up care postoperatively should be kept in mind. The aim of this article is to provide the latest knowledge on the neuroanatomy of the hypoglossal nerve and to give surgeons a step-by-step guide on the current operative technique. Laryngoscope, 126:S12-S16, 2016. © 2016 The American Laryngological, Rhinological and Otological Society, Inc.

Fetal acoustic stimulation test for early intrapartum fetal monitoring.

PubMed

Goonewardene, M; Hanwellage, K

2011-03-01

The fetal acoustic stimulation test (FAST) is a simple cost effective screening test for antenatal fetal monitoring. The aim of the study was to evaluate the FAST as a screening test for early intrapartum fetal well being. An initial non stress test (NST) followed by a FAST using corometric model 146 was carried out in 486 participants in early labour with uncomplicated singleton pregnancies and > 32 weeks gestation. A repeat NST was recorded in the participants who had an initial non reactive NST. The results of the NST and FAST were compared with fetal outcome. Maternal perception of fetal movements after FAST, results of NST before and after FAST, and the babies' 5 minute APGAR scores were measured. Of the 486 participants 413 (85%) noticed fetal movements after FAST. Initial NST was non reactive in 203 (42%) but 149 (31%) became reactive after FAST. Compared to the NST, FAST had a better sensitivity (97% vs 62%, p < 0.001), specificity (100% vs 87%, p = 0.017), positive predictive value (100% vs 98%, p = 0.024), negative predictive value (79% vs 17%, p < 0.001) and accuracy (99%vs 64%, p < 0.001) in predicting 5 minute APGAR < 7 in the baby. FAST is a reliable screening test for assessing fetal well being in early labour. It complements the NST and is better than the NST alone.

AMPK Re-Activation Suppresses Hepatic Steatosis but its Downregulation Does Not Promote Fatty Liver Development.

PubMed

Boudaba, Nadia; Marion, Allison; Huet, Camille; Pierre, Rémi; Viollet, Benoit; Foretz, Marc

2018-02-01

Nonalcoholic fatty liver disease is a highly prevalent component of disorders associated with disrupted energy homeostasis. Although dysregulation of the energy sensor AMP-activated protein kinase (AMPK) is viewed as a pathogenic factor in the development of fatty liver its role has not been directly demonstrated. Unexpectedly, we show here that liver-specific AMPK KO mice display normal hepatic lipid homeostasis and are not prone to fatty liver development, indicating that the decreases in AMPK activity associated with hepatic steatosis may be a consequence, rather than a cause, of changes in hepatic metabolism. In contrast, we found that pharmacological re-activation of downregulated AMPK in fatty liver is sufficient to normalize hepatic lipid content. Mechanistically, AMPK activation reduces hepatic triglyceride content both by inhibiting lipid synthesis and by stimulating fatty acid oxidation in an LKB1-dependent manner, through a transcription-independent mechanism. Furthermore, the effect of the antidiabetic drug metformin on lipogenesis inhibition and fatty acid oxidation stimulation was enhanced by combination treatment with small-molecule AMPK activators in primary hepatocytes from mice and humans. Overall, these results demonstrate that AMPK downregulation is not a triggering factor in fatty liver development but in contrast, establish the therapeutic impact of pharmacological AMPK re-activation in the treatment of fatty liver disease. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

A novel rabbit anti-hepatocyte growth factor monoclonal neutralizing antibody inhibits tumor growth in prostate cancer cells and mouse xenografts

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

Yu, Yanlan; Chen, Yicheng; Ding, Guoqing

The hepatocyte growth factor and its receptor c-Met are correlated with castration-resistance in prostate cancer. Although HGF has been considered as an attractive target for therapeutic antibodies, the lack of cross-reactivity of monoclonal antibodies with human/mouse HGFs is a major obstacle in preclinical developments. We generated a panel of anti-HGF RabMAbs either blocking HGF/c-Met interaction or inhibiting c-Met phosphorylation. We selected one RabMAb with mouse cross-reactivity and demonstrated that it blocked HGF-stimulated downstream activation in PC-3 and DU145 cells. Anti-HGF RabMAb inhibited not only the growth of PC-3 cells but also HGF-dependent proliferation in HUVECs. We further demonstrated the efficacymore » and potency of the anti-HGF RabMAb in tumor xenograft mice models. Through these in vitro and in vivo experiments, we explored a novel therapeutic antibody for advanced prostate cancer. - Highlights: • HGF is an attractive target for castration-refractory prostate cancer. • We generated and characterized a panel of anti-HGF rabbit monoclonal antibodies. • More than half of these anti-HGF RabMAbs was cross-reactive with mouse HGF. • Anti-HGF RabMAb blocks HGF-stimulated phosphorylation and cell growth in vitro. • Anti-HGF RabMAb inhibits tumor growth and angiogenesis in xenograft mice.« less

Identification of a B cell-dependent subpopulation of multiple sclerosis by measurements of brain-reactive B cells in the blood.

PubMed

Kuerten, Stefanie; Pommerschein, Giovanna; Barth, Stefanie K; Hohmann, Christopher; Milles, Bianca; Sammer, Fabian W; Duffy, Cathrina E; Wunsch, Marie; Rovituso, Damiano M; Schroeter, Michael; Addicks, Klaus; Kaiser, Claudia C; Lehmann, Paul V

2014-01-01

B cells are increasingly coming into play in the pathogenesis of multiple sclerosis (MS). Here, we screened peripheral blood mononuclear cells (PBMC) from patients with clinically isolated syndrome (CIS), MS, other non-inflammatory neurological, inflammatory neurological or autoimmune diseases, and healthy donors for their B cell reactivity to CNS antigen using the enzyme-linked immunospot technique (ELISPOT) after 96 h of polyclonal stimulation. Our data show that nine of 15 patients with CIS (60.0%) and 53 of 67 patients with definite MS (79.1%) displayed CNS-reactive B cells, compared to none of the control donors. The presence of CNS-reactive B cells in the blood of the majority of patients with MS or at risk to develop MS along with their absence in control subjects suggests that they might be indicative of a B cell-dependent subpopulation of the disease. Copyright © 2014. Published by Elsevier Inc.

Culture and the Immune System: Cultural Consonance in Social Support and C-reactive Protein in Urban Brazil.

PubMed

Dressler, William W; Balieiro, Mauro C; Ribeiro, Rosane P; Dos Santos, José Ernesto

2016-06-01

In this article, we examine the distribution of a marker of immune system stimulation-C-reactive protein-in urban Brazil. Social relationships are associated with immunostimulation, and we argue that cultural dimensions of social support, assessed by cultural consonance, are important in this process. Cultural consonance is the degree to which individuals, in their own beliefs and behaviors, approximate shared cultural models. A measure of cultural consonance in social support, based on a cultural consensus analysis regarding sources and patterns of social support in Brazil, was developed. In a survey of 258 persons, the association of cultural consonance in social support and C-reactive protein was examined, controlling for age, sex, body mass index, low-density lipoprotein cholesterol, depressive symptoms, and a social network index. Lower cultural consonance in social support was associated with higher C-reactive protein. Implications of these results for future research are discussed. © 2016 by the American Anthropological Association.

Melatonin promotes diabetic wound healing in vitro by regulating keratinocyte activity

PubMed Central

Song, Ruipeng; Ren, Lijun; Ma, Haoli; Hu, Ruijing; Gao, Honghong; Wang, Li; Chen, Xuehui; Zhao, Zhigang; Liu, Jialin

2016-01-01

Diabetic patients are at high risk of developing delayed cutaneous wound healing. Proper keratinocyte proliferation and migration are crucial steps during re-epithelialization. Melatonin (Mel) accelerates wound repair in full-thickness incisional wounds; however, its role in diabetic wound healing is unknown. This study explored the role of Mel in diabetic wound healing in vitro by using high glucose (HG)-cultured keratinocytes. Mel reduced the HG-induced mRNA expression and release of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and IL-8, in keratinocytes. Mel inhibited oxidative stress, as evidenced by reduced production of reactive oxygen species and malondialdehyde and increased activity of superoxide dismutase in HG-stimulated keratinocytes. Mel also inhibited HG-induced nucleotide binding oligomerization domain-like receptor family pyrin domain-containing 3 inflammasome activation in keratinocytes. HG-induced reduced migration and proliferation and increased apoptosis of keratinocytes were counteracted by Mel treatment. The pro-proliferative, pro-migratory, and anti-apoptotic effects of Mel on HG-treated keratinocytes were mediated by extracellular signal-regulated kinase signaling pathway. Results collectively suggested that Mel is an alternative therapeutic strategy to ameliorate poor condition for diabetic wound healing by regulating keratinocyte activity. PMID:27904671

Atomistic insight into the adsorption site selectivity of stepped Au(111) surfaces

NASA Astrophysics Data System (ADS)

Gaspari, Roberto; Pignedoli, Carlo A.; Fasel, Roman; Treier, Matthias; Passerone, Daniele

2010-07-01

Using classical and ab initio simulations, we study the interplay between the Au(111) surface reconstruction and monoatomic steps on a vicinal face. The experimentally observed discommensuration line patterns on a specific vicinal are reproduced and explained, and a complete description of the structure is given. An unusual atomic arrangement is shown to be responsible for the lower reactivity of hcp segments of step edges compared to the one of fcc segments. Our results provide an unprecedented understanding of the electronic and geometric properties of the complex Au(111) surface.

Modulation of inherent dynamical tendencies of the bisabolyl cation via preorganization in epi-isozizaene synthase.

PubMed

Pemberton, Ryan P; Ho, Krystina C; Tantillo, Dean J

2015-04-01

The relative importance of preorganization, selective transition state stabilization and inherent reactivity are assessed through quantum chemical and docking calculations for a sesquiterpene synthase ( epi -isozizaene synthase, EIZS). Inherent reactivity of the bisabolyl cation, both static and dynamic, appears to determine the pathway to product, although preorganization and selective binding of the final transition state structure in the multi-step carbocation cascade that forms epi -isozizaene appear to play important roles.

Predictor - Predictive Reaction Design via Informatics, Computation and Theories of Reactivity

DTIC Science & Technology

2017-10-10

into more complex and valuable molecules, but are limited by: 1. The extensive time it takes to design and optimize a synthesis 2. Multi-step...system. As it is fully compatible to the industry standard SQL, designing a server- based system at a later time will be trivial. Producing a JAVA front...Report: PREDICTOR - Predictive REaction Design via Informatics, Computation and Theories of Reactivity The goal of this program was to create a cyber

Structure reactivity relationships during N2O hydrogenation over Au-Ag alloys: A study by field emission techniques

NASA Astrophysics Data System (ADS)

Jacobs, Luc; Barroo, Cédric; Gilis, Natalia; Lambeets, Sten V.; Genty, Eric; Visart de Bocarmé, Thierry

2018-03-01

To make available atomic oxygen at the surface of a catalyst is the key step for oxidation reactions on Au-based catalysts. In this context, Au-Ag alloys catalysts exhibit promising properties for selective oxidation reactions of alcohols: low temperature activity and high selectivity. The presence of O(ads) and its effects on the catalytic reactivity is studied via the N2O dissociative adsorption and subsequent hydrogenation. Field emission techniques are particularly suited to study this reaction: Field Ion Microscopy (FIM) and Field Emission Microscopy (FEM) enable to image the extremity of sharp metallic tips, the size and morphology of which are close to those of one single catalytic particle. The reaction dynamics is studied in the 300-320 K temperature range and at a pressure of 3.5 × 10-3 Pa. The main results are a strong structure/reactivity relationship during N2O + H2 reaction over Au-8.8 at.%Ag model catalysts. Comparison of high-resolution FIM images of the clean sample and FEM images during reaction shows a sensitivity of the reaction to the local structure of the facets, independently of the used partial pressures of both N2O and H2. This suggests a localised dissociative adsorption step for N2O and H2 with the formation of a reactive interface around the {210} facets.

Bovine Herpes Virus 1 (BHV-1) and Herpes Simplex Virus Type 1 (HSV-1) Promote Survival of Latently Infected Sensory Neurons, in Part by Inhibiting Apoptosis

PubMed Central

Jones, Clinton

2013-01-01

α-Herpesvirinae subfamily members, including herpes simplex virus type 1 (HSV-1) and bovine herpes virus 1 (BHV-1), initiate infection in mucosal surfaces. BHV-1 and HSV-1 enter sensory neurons by cell-cell spread where a burst of viral gene expression occurs. When compared to non-neuronal cells, viral gene expression is quickly extinguished in sensory neurons resulting in neuronal survival and latency. The HSV-1 latency associated transcript (LAT), which is abundantly expressed in latently infected neurons, inhibits apoptosis, viral transcription, and productive infection, and directly or indirectly enhances reactivation from latency in small animal models. Three anti-apoptosis genes can be substituted for LAT, which will restore wild type levels of reactivation from latency to a LAT null mutant virus. Two small non-coding RNAs encoded by LAT possess anti-apoptosis functions in transfected cells. The BHV-1 latency related RNA (LR-RNA), like LAT, is abundantly expressed during latency. The LR-RNA encodes a protein (ORF2) and two microRNAs that are expressed in certain latently infected neurons. Wild-type expression of LR gene products is required for stress-induced reactivation from latency in cattle. ORF2 has anti-apoptosis functions and interacts with certain cellular transcription factors that stimulate viral transcription and productive infection. ORF2 is predicted to promote survival of infected neurons by inhibiting apoptosis and sequestering cellular transcription factors which stimulate productive infection. In addition, the LR encoded microRNAs inhibit viral transcription and apoptosis. In summary, the ability of BHV-1 and HSV-1 to interfere with apoptosis and productive infection in sensory neurons is crucial for the life-long latency-reactivation cycle in their respective hosts. PMID:25278776

Uterine flushing proteome of the tammar wallaby after reactivation from diapause.

PubMed

Martin, Florine C; Ang, Ching-Seng; Gardner, David K; Renfree, Marilyn B; Shaw, Geoff

2016-11-01

The marsupial tammar wallaby has the longest period of embryonic diapause of any mammal, up to 11 months, during which there is no cell division or blastocyst growth. Since the blastocyst in diapause is surrounded by acellular coats, the signals that maintain or terminate diapause involve factors that reside in uterine secretions. The nature of such factors remains to be resolved. In this study, uterine flushings (UFs) were used to assess changes in uterine secretions of tammars using liquid chromatography-mass spectrometry (LC-MS/MS) during diapause (day 0 and 3) and reactivation days (d) 4, 5, 6, 8, 9, 11 and 24 after removal of pouch young (RPY), which initiates embryonic development. This study supports earlier suggestions that the presence of specific factors stimulate reactivation, early embryonic growth and cell proliferation. A mitogen, hepatoma-derived growth factor and soluble epidermal growth factor receptors were observed from d3 until at least d11 RPY when these secreted proteins constituted 21% of the UF proteome. Binding of these factors to specific cellular receptors or growth factors may directly stimulate DNA synthesis and division in endometrial gland cells. Proteins involved in the p53/CDKN1A (p21) cell cycle inhibition pathway were also observed in the diapause samples. Progesterone and most of the oestrogen-regulated proteins were present in the UF after d3, which is concomitant with the start of blastocyst mitoses at d4. We propose that once the p21 inhibition of the cell cycle is lost, growth factors including HDGF and EGFR are responsible for reactivation of the diapausing blastocyst via the uterine secretions. © 2016 Society for Reproduction and Fertility.

Ten Steps to a Learning Organization.

ERIC Educational Resources Information Center

Kline, Peter; Saunders, Bernard

This guide provides a 10-step process for building a learning organization. It shows any organization how to develop and sustain an environment favorable to learning at every level, to reawaken and stimulate the power of learning in all members of the organization, and to harness the new learning that was generated to produce the maximum benefit…

Carnivalesque Enactment at the Children's Medical Centre of Rabin Hospital.

ERIC Educational Resources Information Center

Lev-Aladgem, Shulamith

2000-01-01

Describes the basic characteristics of the "carnivalesque enactment" and its therapeutic potential. Explains a case study of the drama project at the Rabin Children's Medical Centre, how the carnivalesque enactment was developed step by step, and the kind of effect it stimulated among the children. Suggests new theatrical experiments with…

Enhance, delete, incept: Manipulating hippocampus-dependent memories☆

PubMed Central

Spiers, Hugo J.; Bendor, Daniel

2014-01-01

Here we provide a brief overview of recent research on memory manipulation. We focus primarily on memories for which the hippocampus is thought to be required due to its central importance in the study of memory. The repertoire of methods employed is expanding and includes optogenetics, transcranial stimulation, deep brain stimulation, cued reactivation during sleep and the use of pharmacological agents. In addition, the possible mechanisms underlying these memory changes have been investigated using techniques such as single unit recording and functional magnetic resonance imaging (fMRI). This article is part of a Special Issue entitled ‘Memory enhancement’. PMID:24397964

The Vagal Nerve Stimulates Activation of the Hepatic Progenitor Cell Compartment via Muscarinic Acetylcholine Receptor Type 3

PubMed Central

Cassiman, David; Libbrecht, Louis; Sinelli, Nicoletta; Desmet, Valeer; Denef, Carl; Roskams, Tania

2002-01-01

In the rat the hepatic branch of the nervus vagus stimulates proliferation of hepatocytes after partial hepatectomy and growth of bile duct epithelial cells after bile duct ligation. We studied the effect of hepatic vagotomy on the activation of the hepatic progenitor cell compartment in human and rat liver. The number of hepatic progenitor cells and atypical reactive ductular cells in transplanted (denervated) human livers with hepatitis was significantly lower than in innervated matched control livers and the number of oval cells in vagotomized rat livers with galactosamine hepatitis was significantly lower than in livers of sham-operated rats with galactosamine hepatitis. The expression of muscarinic acetylcholine receptors (M1-M5 receptor) was studied by immunohistochemistry and reverse transcriptase-polymerase chain reaction. In human liver, immunoreactivity for M3 receptor was observed in hepatic progenitor cells, atypical reactive ductules, intermediate hepatocyte-like cells, and bile duct epithelial cells. mRNA for the M1-M3 and the M5 receptor, but not the M4 receptor, was detected in human liver homogenates. In conclusion, the hepatic vagus branch stimulates activation of the hepatic progenitor cell compartment in diseased liver, most likely through binding of acetylcholine to the M3 receptor expressed on these cells. These findings may be of clinical importance for patients with a transplant liver. PMID:12163377

Rapid and transient stimulation of intracellular reactive oxygen species by melatonin in normal and tumor leukocytes

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

Radogna, Flavia; Paternoster, Laura; Istitututo di Chimica Biologica, Universita di Urbino Carlo Bo

Melatonin is a modified tryptophan with potent biological activity, exerted by stimulation of specific plasma membrane (MT1/MT2) receptors, by lower affinity intracellular enzymatic targets (quinone reductase, calmodulin), or through its strong anti-oxidant ability. Scattered studies also report a perplexing pro-oxidant activity, showing that melatonin is able to stimulate production of intracellular reactive oxygen species (ROS). Here we show that on U937 human monocytes melatonin promotes intracellular ROS in a fast (< 1 min) and transient (up to 5-6 h) way. Melatonin equally elicits its pro-radical effect on a set of normal or tumor leukocytes; intriguingly, ROS production does not leadmore » to oxidative stress, as shown by absence of protein carbonylation, maintenance of free thiols, preservation of viability and regular proliferation rate. ROS production is independent from MT1/MT2 receptor interaction, since a) requires micromolar (as opposed to nanomolar) doses of melatonin; b) is not contrasted by the specific MT1/MT2 antagonist luzindole; c) is not mimicked by a set of MT1/MT2 high affinity melatonin analogues. Instead, chlorpromazine, the calmodulin inhibitor shown to prevent melatonin-calmodulin interaction, also prevents melatonin pro-radical effect, suggesting that the low affinity binding to calmodulin (in the micromolar range) may promote ROS production.« less

Heat shock protein 70 surface-positive tumor exosomes stimulate migratory and cytolytic activity of natural killer cells.

PubMed

Gastpar, Robert; Gehrmann, Mathias; Bausero, Maria A; Asea, Alexzander; Gross, Catharina; Schroeder, Josef A; Multhoff, Gabriele

2005-06-15

Detergent-soluble membrane vesicles are actively released by human pancreas (Colo-/Colo+) and colon (CX-/CX+) carcinoma sublines, differing in their capacity to present heat shock protein 70 (Hsp70)/Bag-4 on their plasma membranes. Floating properties, acetylcholine esterase activity, and protein composition characterized them as exosomes. An enrichment of Rab-4 documented their intracellular transport route from early endosomes to the plasma membrane. After solubilization, comparable amounts of cytosolic proteins, including tubulin, Hsp70, Hsc70, and Bag-4, but not ER-residing Grp94 and calnexin, were detectable in tumor-derived exosomes. However, with respect to the exosomal surface, only Colo+/CX+ but not Colo-/CX- derived exosomes were Hsp70 membrane positive. Therefore, concomitant with an up-regulated cell surface density of activation markers, migration and Hsp70 reactivity of natural killer (NK) cells was stimulated selectively by Hsp70/Bag-4 surface-positive exosomes, but not by their negative counterparts and tumor cell lysates. Moreover, the exosome-mediated lytic activity of NK cells was blockable by Hsp70-specific antibody. As already shown for TKD stimulation, NK cells preincubated with Hsp70 surface-positive exosomes initiated apoptosis in tumors through granzyme B release. In summary, our data provide an explanation how Hsp70 reactivity in NK cells is induced by tumor-derived exosomes.

Heat Shock Protein 70 Surface-Positive Tumor Exosomes Stimulate Migratory and Cytolytic Activity of Natural Killer Cells

PubMed Central

Gastpar, Robert; Gehrmann, Mathias; Bausero, Maria A.; Asea, Alexzander; Gross, Catharina; Schroeder, Josef A.

2006-01-01

Detergent-soluble membrane vesicles are actively released by human pancreas (Colo−/Colo+) and colon (CX−/CX+) carcinoma sublines, differing in their capacity to present heat shock protein 70 (Hsp70)/Bag-4 on their plasma membranes. Floating properties, acetylcholine esterase activity, and protein composition characterized them as exosomes. An enrichment of Rab-4 documented their intracellular transport route from early endosomes to the plasma membrane. After solubilization, comparable amounts of cytosolic proteins, including tubulin, Hsp70, Hsc70, and Bag-4, but not ER-residing Grp94 and calnexin, were detectable in tumor-derived exosomes. However, with respect to the exosomal surface, only Colo+/CX+ but not Colo−/CX exosomes were Hsp70 membrane derived positive. Therefore, concomitant with an up-regulated cell surface density of activation markers, migration and Hsp70 reactivity of natural killer (NK) cells was stimulated selectively by Hsp70/Bag-4 surface-positive exosomes, but not by their negative counterparts and tumor cell lysates. Moreover, the exosome-mediated lytic activity of NK cells was blockable by Hsp70-specific antibody. As already shown for TKD stimulation, NK cells preincubated with Hsp70 surface-positive exosomes initiated apoptosis in tumors through granzyme B release. In summary, our data provide an explanation how Hsp70 reactivity in NK cells is induced by tumor-derived exosomes. PMID:15958569

Mechanistic Details and Reactivity Descriptors in Oxidation and Acid Catalysis of Methanol

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

Deshlahra, Prashant; Carr, Robert T.; Chai, Song-Hai

2015-02-06

Acid and redox reaction rates of CH₃OH-O₂ mixtures on polyoxometalate (POM) clusters, together with isotopic, spectroscopic, and theoretical assessments of catalyst properties and reaction pathways, were used to define rigorous descriptors of reactivity and to probe the compositional effects for oxidative dehydrogenation (ODH) and dehydration reactions. ³¹P-MAS NMR, transmission electron microscopy and titrations of protons with di-tert-butylpyridine during catalysis showed that POM clusters retained their Keggin structure upon dispersion on SiO₂ and after use in CH₃OH reactions. The effects of CH₃OH and O₂ pressures and of D-substitution on ODH rates show that C-H activation in molecularly adsorbed CH₃OH is themore » sole kinetically relevant step and leads to reduced centers as intermediates present at low coverages; their concentrations, measured from UV-vis spectra obtained during catalysis, are consistent with the effects of CH₃OH/O₂ ratios predicted from the elementary steps proposed. First-order ODH rate constants depend strongly on the addenda atoms (Mo vs W) but weakly on the central atom (P vs Si) in POM clusters, because C-H activation steps inject electrons into the lowest unoccupied molecular orbitals (LUMO) of the clusters, which are the d-orbitals at Mo⁶⁺ and W⁶⁺ centers. H-atom addition energies (HAE) at O-atoms in POM clusters represent the relevant theoretical probe of the LUMO energies and of ODH reactivity. The calculated energies of ODH transition states at each O-atom depend linearly on their HAE values with slopes near unity, as predicted for late transition states in which electron transfer and C-H cleavage are essentially complete. HAE values averaged over all accessible O-atoms in POM clusters provide the appropriate reactivity descriptor for oxides whose known structures allow accurate HAE calculations. CH₃OH dehydration proceeds via parallel pathways mediated by late carbenium-ion transition states; effects of composition on dehydration reactivity reflect changes in charge reorganizations and electrostatic forces that stabilize protons at Brønsted acid sites.« less

Leap Frog and Time Step Sub-Cycle Scheme for Coupled Neutronics and Thermal-Hydraulic Codes

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

Lu, S.

2002-07-01

As the result of the advancing TCP/IP based inter-process communication technology, more and more legacy thermal-hydraulic codes have been coupled with neutronics codes to provide best-estimate capabilities for reactivity related reactor transient analysis. Most of the coupling schemes are based on closely coupled serial or parallel approaches. Therefore, the execution of the coupled codes usually requires significant CPU time, when a complicated system is analyzed. Leap Frog scheme has been used to reduce the run time. The extent of the decoupling is usually determined based on a trial and error process for a specific analysis. It is the intent ofmore » this paper to develop a set of general criteria, which can be used to invoke the automatic Leap Frog algorithm. The algorithm will not only provide the run time reduction but also preserve the accuracy. The criteria will also serve as the base of an automatic time step sub-cycle scheme when a sudden reactivity change is introduced and the thermal-hydraulic code is marching with a relatively large time step. (authors)« less

Supramolecular "Step Polymerization" of Preassembled Micelles: A Study of "Polymerization" Kinetics.

PubMed

Yang, Chaoying; Ma, Xiaodong; Lin, Jiaping; Wang, Liquan; Lu, Yingqing; Zhang, Liangshun; Cai, Chunhua; Gao, Liang

2018-03-01

In nature, sophisticated functional materials are created through hierarchical self-assembly of nanoscale motifs, which has inspired the fabrication of man-made materials with complex architectures for a variety of applications. Herein, a kinetic study on the self-assembly of spindle-like micelles preassembled from polypeptide graft copolymers is reported. The addition of dimethylformamide and, subsequently, a selective solvent (water) can generate a "reactive point" at both ends of the spindles as a result of the existence of structural defects, which induces the "polymerization" of the spindles into nanowires. Experimental results combined with dissipative particle dynamics simulations show that the polymerization of the micellar subunits follows a step-growth polymerization mechanism with a second-order reaction characteristic. The assembly rate of the micelles is dependent on the subunit concentration and on the activity of the reactive points. The present work reveals a law governing the self-assembly kinetics of micelles with structural defects and opens the door for the construction of hierarchical structures with a controllable size through supramolecular step polymerization. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Microtrenching-free two-step reactive ion etching of 4H-SiC using NF{sub 3}/HBr/O{sub 2} and Cl{sub 2}/O{sub 2}

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

Tseng, Yuan-Hung, E-mail: yhtseng.ee99g@nctu.edu.tw; Tsui, Bing-Yue

2014-05-15

In this paper, the authors performed a reactive ion etch of a 4H-SiC substrate with a gas mixture of NF{sub 3}, HBr, and O{sub 2}, resulting in a microtrenching-free etch. The etch rate was 107.8 nm/min, and the selectivity over the oxide hard mask was ∼3.85. Cross-sectional scanning electron microscopy showed no microtrenching compared with etches using plasmas of NF{sub 3}, NF{sub 3}/HBr, and NF{sub 3}/O{sub 2}. Analyzing a variety of HBr/O{sub 2} mixing ratios, the authors discuss the additive effect of each gas and their respective potential mechanisms for alleviating microtrenching. To increase the radius of gyration of the bottommore » corners, they introduced a second etch step with Cl{sub 2}/O{sub 2} plasma. Fabricating simple metal-oxide-semiconductor capacitors on the two-step etched surface, the authors found that the electrical characteristics of the etched sample were nearly the same as the nonetched sample.« less

Gas-Phase Formation Rates of Nitric Acid and Its Isomers Under Urban Conditions

NASA Technical Reports Server (NTRS)

Okumura, M.; Mollner, A. K.; Fry, J. L.; Feng, L.

2005-01-01

Ozone formation in urban smog is controlled by a complex set of reactions which includes radical production from photochemical processes, catalytic cycles which convert NO to NO2, and termination steps that tie up reactive intermediates in long-lived reservoirs. The reaction OH + NO2 + M -4 HONO2 + M (la) is a key termination step because it transforms two short-lived reactive intermediates, OH and NO2, into relatively long-lived nitric acid. Under certain conditions (low VOC/NOx), ozone production in polluted urban airsheds can be highly sensitive to this reaction, but the rate parameters are not well constrained. This report summarizes the results of new laboratory studies of the OH + NO2 + M reaction including direct determination of the overall rate constant and branching ratio for the two reaction channels under atmospherically relevant conditions.

Boron-carbide-aluminum and boron-carbide-reactive metal cermets

DOEpatents

Halverson, Danny C.; Pyzik, Aleksander J.; Aksay, Ilhan A.

1986-01-01

Hard, tough, lightweight boron-carbide-reactive metal composites, particularly boron-carbide-aluminum composites, are produced. These composites have compositions with a plurality of phases. A method is provided, including the steps of wetting and reacting the starting materials, by which the microstructures in the resulting composites can be controllably selected. Starting compositions, reaction temperatures, reaction times, and reaction atmospheres are parameters for controlling the process and resulting compositions. The ceramic phases are homogeneously distributed in the metal phases and adhesive forces at ceramic-metal interfaces are maximized. An initial consolidation step is used to achieve fully dense composites. Microstructures of boron-carbide-aluminum cermets have been produced with modulus of rupture exceeding 110 ksi and fracture toughness exceeding 12 ksi.sqroot.in. These composites and methods can be used to form a variety of structural elements.

Boron-carbide-aluminum and boron-carbide-reactive metal cermets. [B/sub 4/C-Al

DOEpatents

Halverson, D.C.; Pyzik, A.J.; Aksay, I.A.

1985-05-06

Hard, tough, lighweight boron-carbide-reactive metal composites, particularly boron-carbide-aluminum composites, are produced. These composites have compositions with a plurality of phases. A method is provided, including the steps of wetting and reacting the starting materials, by which the microstructures in the resulting composites can be controllably selected. Starting compositions, reaction temperatures, reaction times, and reaction atmospheres are parameters for controlling the process and resulting compositions. The ceramic phases are homogeneously distributed in the metal phases and adhesive forces at ceramic-metal interfaces are maximized. An initial consolidated step is used to achieve fully dense composites. Microstructures of boron-carbide-aluminum cermets have been produced with modules of rupture exceeding 110 ksi and fracture toughness exceeding 12 ksi..sqrt..in. These composites and methods can be used to form a variety of structural elements.

A simple, enaminone-based approach to some bicyclic pyridazinium tetrafluoroborates

PubMed Central

Josefík, František; Svobodová, Markéta; Bertolasi, Valerio

2013-01-01

Summary Easily obtainable cyclic enaminones (piperidin-2-ylidenealkanones) can be transformed into substituted bicyclic pyridazinium tetrafluoroborates upon treatment with corresponding diazonium salts. The transformation can be performed either in a one-pot way or in a two-step process with the isolation of single azo-coupled enaminone as the intermediate. The former method is superior. Under the optimized conditions, a number of pyridazinium salts substituted with both electron-donating and electron-withdrawing substituents was easily synthesized. A mechanism of the formation of the pyridazinium salts is suggested. A partial drawback is the possibility of the formation of a mixture of products when using a different diazonium salt in each step due to a reversibility of the azo coupling. This can be suppressed by using a more reactive diazonium salt before a less reactive one. PMID:23946844

Adaptive control reduces trip-induced forward gait instability among young adults.

PubMed

Wang, Ting-Yun; Bhatt, Tanvi; Yang, Feng; Pai, Yi-Chung

2012-04-30

A vital functional plasticity of humans is their ability to adapt to threats to posture stability. The purpose of this study was to investigate adaptation to repeated trips in walking. Sixteen young adults were recruited and exposed to the sudden (electronic-mechanical) release of an obstacle, 11-cm in height, in the path of over ground walking during the mid-to-late left swing phase. Although none of the subjects fell on the first of eight unannounced, consecutive trips, all of them had to rely on compensatory step with a step length significantly longer than their regular to reduce their instability. In the subsequent trials, they were able to rapidly make adaptive adjustments in the control of their center-of-mass (COM) stability both proactively and reactively (i.e., before and after hitting or crossing the obstacle), such that the need for taking compensatory step was substantially diminished. The proactive adaptations included a reduced forward COM velocity that lessened forward instability in mid-to-late stance and an elevated toe clearance that reduced the likelihood of obstacle contact. The reactive adjustments were characterized by improved trunk control (by reducing its forward rotation) and limb support (by increasing hip height), and reduced forward instability (by both the posterior COM shift and the reduction in its forward velocity). These findings suggest that young adults can adapt appropriately to repeated trip perturbations and to reduce trip-induced excessive instability in both proactive and reactive manners. Copyright © 2012 Elsevier Ltd. All rights reserved.

Dicarbonyls stimulate cellular protection systems in primary rat hepatocytes and show anti-inflammatory properties.

PubMed

Buetler, Timo M; Latado, Hélia; Baumeyer, Alexandra; Delatour, Thierry

2008-04-01

Advanced glycation endproducts (AGEs) and their precursor dicarbonyls are generally perceived as having adverse health effects. They are also considered to be initiators and promoters of disease and aging. However, proof for a causal relationship is lacking. On the other hand, it is known that AGEs and melanoidins possess beneficial properties, such as antioxidant and metal-chelating activities. Furthermore, some AGEs may stimulate the cellular detoxification system, generally known as the phase II drug metabolizing system. We show here that several reactive dicarbonyl intermediates have the capability to stimulate the cellular phase II detoxification systems in both a reporter cell line and primary rat hepatocytes. In addition, we demonstrate that dicarbonyls can attenuate the inflammatory signaling induced by tumor necrosis factor-alpha in a reporter cell system.

A Reactive Balance Rating Method that Correlates with Kinematics after Trip-Like Perturbations on a Treadmill and Fall Risk Among Residents of Older Adult Congregate Housing.

PubMed

Madigan, Michael L; Aviles, Jessica; Allin, Leigh J; Nussbaum, Maury A; Alexander, Neil B

2018-04-16

A growing number of studies are using modified treadmills to train reactive balance after trip-like perturbations that require multiple steps to recover balance. The goal of this study was thus to develop and validate a low-tech reactive balance rating method in the context of trip-like treadmill perturbations to facilitate the implementation of this training outside the research setting. Thirty-five residents of five senior congregate housing facilities participated in the study. Subjects completed a series of reactive balance tests on a modified treadmill from which the reactive balance rating was determined, along with a battery of standard clinical balance and mobility tests that predict fall risk. We investigated the strength of correlation between the reactive balance rating and reactive balance kinematics. We compared the strength of correlation between the reactive balance rating and clinical tests predictive of fall risk, with the strength of correlation between reactive balance kinematics and the same clinical tests. We also compared the reactive balance rating between subjects predicted to be at a high or low risk of falling. The reactive balance rating was correlated with reactive balance kinematics (Spearman's rho squared = .04 - .30), exhibited stronger correlations with clinical tests than most kinematic measures (Spearman's rho squared = .00 - .23), and was 42-60% lower among subjects predicted to be at a high risk for falling. The reactive balance rating method may provide a low-tech, valid measure of reactive balance kinematics, and an indicator of fall risk, after trip-like postural perturbations.

UPF1 Governs Synaptic Plasticity through Association with a STAU2 RNA Granule.

PubMed

Graber, Tyson E; Freemantle, Erika; Anadolu, Mina N; Hébert-Seropian, Sarah; MacAdam, Robyn L; Shin, Unkyung; Hoang, Huy-Dung; Alain, Tommy; Lacaille, Jean-Claude; Sossin, Wayne S

2017-09-20

Neuronal mRNAs can be packaged in reversibly stalled polysome granules before their transport to distant synaptic locales. Stimulation of synaptic metabotropic glutamate receptors (mGluRs) reactivates translation of these particular mRNAs to produce plasticity-related protein; a phenomenon exhibited during mGluR-mediated LTD. This form of plasticity is deregulated in Fragile X Syndrome, a monogenic form of autism in humans, and understanding the stalling and reactivation mechanism could reveal new approaches to therapies. Here, we demonstrate that UPF1, known to stall peptide release during nonsense-mediated RNA decay, is critical for assembly of stalled polysomes in rat hippocampal neurons derived from embryos of either sex. Moreover, UPF1 and its interaction with the RNA binding protein STAU2 are necessary for proper transport and local translation from a prototypical RNA granule substrate and for mGluR-LTD in hippocampal neurons. These data highlight a new, neuronal role for UPF1, distinct from its RNA decay functions, in regulating transport and/or translation of mRNAs that are critical for synaptic plasticity. SIGNIFICANCE STATEMENT The elongation and/or termination steps of mRNA translation are emerging as important control points in mGluR-LTD, a form of synaptic plasticity that is compromised in a severe monogenic form of autism, Fragile X Syndrome. Deciphering the molecular mechanisms controlling this type of plasticity may thus open new therapeutic opportunities. Here, we describe a new role for the ATP-dependent helicase UPF1 and its interaction with the RNA localization protein STAU2 in mediating mGluR-LTD through the regulation of mRNA translation complexes stalled at the level of elongation and/or termination. Copyright © 2017 the authors 0270-6474/17/379116-16$15.00/0.

Medroxyprogesterone acetate inhibits CD8+ T cell viral specific effector function and induces herpes simplex virus type 1 reactivation

PubMed Central

Cherpes, Thomas L.; Busch, James L.; Sheridan, Brian S.; Harvey, Stephen A. K.; Hendricks, Robert L.

2008-01-01

Clinical research suggests hormonal contraceptive use is associated with increased frequencies of herpes simplex virus (HSV) reactivation and shedding. We examined the effects of medroxyprogesterone acetate (MPA), the compound most commonly used for injectable hormonal contraception, on HSV-1 reactivation and CD8+ T cell function in murine trigeminal ganglia (TG). In ex vivo TG cultures, MPA dramatically inhibited canonical CD8+ T cell effector functions, including IFN-γ production and lytic granule release, and increased HSV-1 reactivation from latency. In vivo, MPA treatment of latently infected ovariectomized mice inhibited IFN-γ production and lytic granule release by TG resident CD8+ T cells stimulated directly ex vivo. RNA specific for the essential immediate early viral gene ICP4 as well as viral genome DNA copy number were increased in mice that received MPA during latency, suggesting that treatment increased in vivo reactivation. The increase in HSV-1 copy number appeared to be the result of a two-tine effect, as MPA induced higher reactivation frequencies from latently infected explanted TG neurons in the presence or absence of CD45+ cells. Our data suggest hormonal contraceptives that contain MPA may promote increased frequency of HSV reactivation from latency through the combinatory effects of inhibiting protective CD8+ T cell responses and by a leukocyte-independent effect on infected neurons. PMID:18606648

Paf receptor expression in the marsupial embryo and endometrium during embryonic diapause.

PubMed

Fenelon, Jane C; Shaw, Geoff; O'Neill, Chris; Frankenberg, Stephen; Renfree, Marilyn B

2014-01-01

The control of reactivation from embryonic diapause in the tammar wallaby (Macropus eugenii) involves sequential activation of the corpus luteum, secretion of progesterone that stimulates endometrial secretion and subsequent changes in the uterine environment that activate the embryo. However, the precise signals between the endometrium and the blastocyst are currently unknown. In eutherians, both the phospholipid Paf and its receptor, platelet-activating factor receptor (PTAFR), are present in the embryo and the endometrium. In the tammar, endometrial Paf release in vitro increases around the time of the early progesterone pulse that occurs around the time of reactivation, but whether Paf can reactivate the blastocyst is unknown. We cloned and characterised the expression of PTAFR in the tammar embryo and endometrium at entry into embryonic diapause, during its maintenance and after reactivation. Tammar PTAFR sequence and protein were highly conserved with mammalian orthologues. In the endometrium, PTAFR was expressed at a constant level in the glandular epithelium across all stages and in the luminal epithelium during both diapause and reactivation. Thus, the presence of the receptor appears not to be a limiting factor for Paf actions in the endometrium. However, the low levels of PTAFR in the embryo during diapause, together with its up-regulation and subsequent internalisation at reactivation, supports earlier results suggesting that endometrial Paf could be involved in reactivation of the tammar blastocyst from embryonic diapause.

Do kinematic metrics of walking balance adapt to perturbed optical flow?

PubMed

Thompson, Jessica D; Franz, Jason R

2017-08-01

Visual (i.e., optical flow) perturbations can be used to study balance control and balance deficits. However, it remains unclear whether walking balance control adapts to such perturbations over time. Our purpose was to investigate the propensity for visuomotor adaptation in walking balance control using prolonged exposure to optical flow perturbations. Ten subjects (age: 25.4±3.8years) walked on a treadmill while watching a speed-matched virtual hallway with and without continuous mediolateral optical flow perturbations of three different amplitudes. Each of three perturbation trials consisted of 8min of prolonged exposure followed by 1min of unperturbed walking. Using 3D motion capture, we analyzed changes in foot placement kinematics and mediolateral sacrum motion. At their onset, perturbations elicited wider and shorter steps, alluding to a more cautious, general anticipatory balance control strategy. As perturbations continued, foot placement tended toward values seen during unperturbed walking while step width variability and mediolateral sacrum motion concurrently increased. Our findings suggest that subjects progressively shifted from a general anticipatory balance control strategy to a reactive, task-specific strategy using step-to-step adjustments. Prolonged exposure to optical flow perturbations may have clinical utility to reinforce reactive, task-specific balance control through training. Copyright © 2017 Elsevier B.V. All rights reserved.

Stimulation-Based Control of Dynamic Brain Networks

PubMed Central

Pasqualetti, Fabio; Gu, Shi; Cieslak, Matthew

2016-01-01

The ability to modulate brain states using targeted stimulation is increasingly being employed to treat neurological disorders and to enhance human performance. Despite the growing interest in brain stimulation as a form of neuromodulation, much remains unknown about the network-level impact of these focal perturbations. To study the system wide impact of regional stimulation, we employ a data-driven computational model of nonlinear brain dynamics to systematically explore the effects of targeted stimulation. Validating predictions from network control theory, we uncover the relationship between regional controllability and the focal versus global impact of stimulation, and we relate these findings to differences in the underlying network architecture. Finally, by mapping brain regions to cognitive systems, we observe that the default mode system imparts large global change despite being highly constrained by structural connectivity. This work forms an important step towards the development of personalized stimulation protocols for medical treatment or performance enhancement. PMID:27611328

First Tracer Test After Circulation in Desert Peak 27-15

DOE Data Explorer

Rose, Peter

2013-11-16

Following the successful stimulation of Desert Peak target EGS well 27-15, a circulation test was initiated by injecting a conservative tracer (1,5-nds) in combination with a reactive tracer (7-amino-1,3-naphthalene disulfonate). The closest production well 74-21 was monitored over the subsequent several months.

RNAseq analysis reveals oxidative stress responses of Aspergillus flavus related to stress tolerance and aflatoxin production

USDA-ARS?s Scientific Manuscript database

Aflatoxin contamination by Aspergillus flavus is exacerbated by drought stress in the field. Given that reactive oxygen species (ROS) both accumulate in plant tissues during drought and can stimulate aflatoxin production in vitro, we examined the responses of toxigenic isolates of A. flavus to oxida...

Simplified Large-Scale Refolding, Purification, and Characterization of Recombinant Human Granulocyte-Colony Stimulating Factor in Escherichia coli

PubMed Central

Kim, Chang Kyu; Lee, Chi Ho; Lee, Seung-Bae; Oh, Jae-Wook

2013-01-01

Granulocyte-colony stimulating factor (G-CSF) is a pleiotropic cytokine that stimulates the development of committed hematopoietic progenitor cells and enhances the functional activity of mature cells. Here, we report a simplified method for fed-batch culture as well as the purification of recombinant human (rh) G-CSF. The new system for rhG-CSF purification was performed using not only temperature shift strategy without isopropyl-l-thio-β-d-galactoside (IPTG) induction but also the purification method by a single step of prep-HPLC after the pH precipitation of the refolded samples. Through these processes, the final cell density and overall yield of homogenous rhG-CSF were obtained 42.8 g as dry cell weights, 1.75 g as purified active proteins, from 1 L culture broth, respectively. The purity of rhG-CSF was finally 99% since the isoforms of rhG-CSF could be separated through the prep-HPLC step. The result of biological activity indicated that purified rhG-CSF has a similar profile to the World Health Organization (WHO) 2nd International Standard for G-CSF. Taken together, our results demonstrate that the simple purification through a single step of prep-HPLC may be valuable for the industrial-scale production of biologically active proteins. PMID:24224041

Real-time control of hind limb functional electrical stimulation using feedback from dorsal root ganglia recordings

NASA Astrophysics Data System (ADS)

Bruns, Tim M.; Wagenaar, Joost B.; Bauman, Matthew J.; Gaunt, Robert A.; Weber, Douglas J.

2013-04-01

Objective. Functional electrical stimulation (FES) approaches often utilize an open-loop controller to drive state transitions. The addition of sensory feedback may allow for closed-loop control that can respond effectively to perturbations and muscle fatigue. Approach. We evaluated the use of natural sensory nerve signals obtained with penetrating microelectrode arrays in lumbar dorsal root ganglia (DRG) as real-time feedback for closed-loop control of FES-generated hind limb stepping in anesthetized cats. Main results. Leg position feedback was obtained in near real-time at 50 ms intervals by decoding the firing rates of more than 120 DRG neurons recorded simultaneously. Over 5 m of effective linear distance was traversed during closed-loop stepping trials in each of two cats. The controller compensated effectively for perturbations in the stepping path when DRG sensory feedback was provided. The presence of stimulation artifacts and the quality of DRG unit sorting did not significantly affect the accuracy of leg position feedback obtained from the linear decoding model as long as at least 20 DRG units were included in the model. Significance. This work demonstrates the feasibility and utility of closed-loop FES control based on natural neural sensors. Further work is needed to improve the controller and electrode technologies and to evaluate long-term viability.

Real-time control of hind limb functional electrical stimulation using feedback from dorsal root ganglia recordings

PubMed Central

Bruns, Tim M; Wagenaar, Joost B; Bauman, Matthew J; Gaunt, Robert A; Weber, Douglas J

2013-01-01

Objective Functional electrical stimulation (FES) approaches often utilize an open-loop controller to drive state transitions. The addition of sensory feedback may allow for closed-loop control that can respond effectively to perturbations and muscle fatigue. Approach We evaluated the use of natural sensory nerve signals obtained with penetrating microelectrode arrays in lumbar dorsal root ganglia (DRG) as real-time feedback for closed-loop control of FES-generated hind limb stepping in anesthetized cats. Main results Leg position feedback was obtained in near real-time at 50 ms intervals by decoding the firing rates of more than 120 DRG neurons recorded simultaneously. Over 5 m of effective linear distance was traversed during closed-loop stepping trials in each of two cats. The controller compensated effectively for perturbations in the stepping path when DRG sensory feedback was provided. The presence of stimulation artifacts and the quality of DRG unit sorting did not significantly affect the accuracy of leg position feedback obtained from the linear decoding model as long as at least 20 DRG units were included in the model. Significance This work demonstrates the feasibility and utility of closed-loop FES control based on natural neural sensors. Further work is needed to improve the controller and electrode technologies and to evaluate long-term viability. PMID:23503062

The Effect of Reactive Oxygen Species on Embryo Quality in IVF.

PubMed

Siristatidis, Charalampos; Vogiatzi, Paraskevi; Varounis, Christos; Askoxylaki, Marily; Chrelias, Charalampos; Papantoniou, Nikolaos

2016-01-01

BACKROUND/AIM: Reactive oxygen species (ROS) are involved in critical biological processes in human reproduction. The aim of this study was to evaluate the association of embryo quality following in vitro fertilization (IVF), with ROS levels in the serum and follicular fluid (FF). Eighty-five participants underwent ovarian stimulation and IVF; ROS levels were measured in blood samples on the day of oocyte retrieval and in the FF from follicular aspirates using enzyme-linked immunosorbent assay. These values were associated with the quality of embryos generated. Univariable zero-inflated Poisson model revealed that ROS levels at both oocyte retrieval and in FF were not associated with the number of grade I, II, III and IV embryos (p>0.05). Age, body mass index, stimulation protocol and smoking status were not associated with the number of embryos of any grade (p>0.05). Neither ROS levels in serum nor in FF are associated with the quality of embryos produced following IVF. Copyright © 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Sensory modality, temperament, and the development of sustained attention: a vigilance study in children and adults.

PubMed

Curtindale, Lori; Laurie-Rose, Cynthia; Bennett-Murphy, Laura; Hull, Sarah

2007-05-01

Applying optimal stimulation theory, the present study explored the development of sustained attention as a dynamic process. It examined the interaction of modality and temperament over time in children and adults. Second-grade children and college-aged adults performed auditory and visual vigilance tasks. Using the Carey temperament questionnaires (S. C. McDevitt & W. B. Carey, 1995), the authors classified participants according to temperament composites of reactivity and task orientation. In a preliminary study, tasks were equated across age and modality using d' matching procedures. In the main experiment, 48 children and 48 adults performed these calibrated tasks. The auditory task proved more difficult for both children and adults. Intermodal relations changed with age: Performance across modality was significantly correlated for children but not for adults. Although temperament did not significantly predict performance in adults, it did for children. The temperament effects observed in children--specifically in those with the composite of reactivity--occurred in connection with the auditory task and in a manner consistent with theoretical predictions derived from optimal stimulation theory. Copyright (c) 2007 APA, all rights reserved.

Sex differences in sensorimotor mu rhythms during selective attentional processing.

PubMed

Popovich, C; Dockstader, C; Cheyne, D; Tannock, R

2010-12-01

We used magnetoencephalography to investigate the effect of directed attention on sensorimotor mu (8-12 Hz) response (mu reactivity) to non-painful electrical stimulation of the median nerve in healthy adults. Mu desynchronization in the 10-12 Hz bandwidth is typically observed during higher-order cognitive functions including selective attentional processing of sensorimotor information (Pfurtscheller, Neuper, & Krauz, 2000). We found attention-related sex differences in mu reactivity, with females showing (i) prolonged mu desynchrony when attending to somatosensory stimuli, (ii) attentional modulation of the mu response based on whether attention was directed towards or away from somatosensory stimuli, which was absent in males, and (iii) a trend for greater neuronal excitability of the primary somatosensory region suggesting greater physiological responsiveness to sensory stimulation overall. Our findings suggest sex differences in attentional control strategies when processing somatosensory stimuli, whose salience may be greater for females. These sex differences in attention to somatosensory stimuli may help elucidate the well-documented sex biases in pain processing wherein females typically report greater sensitivity to experimental and clinical pain. Copyright © 2010 Elsevier Ltd. All rights reserved.

Streptococcus sanguinis induces foam cell formation and cell death of macrophages in association with production of reactive oxygen species.

PubMed

Okahashi, Nobuo; Okinaga, Toshinori; Sakurai, Atsuo; Terao, Yutaka; Nakata, Masanobu; Nakashima, Keisuke; Shintani, Seikou; Kawabata, Shigetada; Ooshima, Takashi; Nishihara, Tatsuji

2011-10-01

Streptococcus sanguinis, a normal inhabitant of the human oral cavity, is a common streptococcal species implicated in infective endocarditis. Herein, we investigated the effects of infection with S. sanguinis on foam cell formation and cell death of macrophages. Infection with S. sanguinis stimulated foam cell formation of THP-1, a human macrophage cell line. At a multiplicity of infection >100, S. sanguinis-induced cell death of the macrophages. Viable bacterial infection was required to trigger cell death because heat-inactivated S. sanguinis did not induce cell death. The production of cytokines interleukin-1β and tumor necrosis factor-α from macrophages was also stimulated during bacterial infection. Inhibition of the production of reactive oxygen species (ROS) resulted in reduced cell death, suggesting an association of ROS with cell death. Furthermore, S. sanguinis-induced cell death appeared to be independent of activation of inflammasomes, because cleavage of procaspase-1 was not evident in infected macrophages. © 2011 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.

Assessing the impact of nano- and micro-scale zerovalent iron particles on soil microbial activities: particle reactivity interferes with assay conditions and interpretation of genuine microbial effects.

PubMed

Cullen, Laurence G; Tilston, Emma L; Mitchell, Geoff R; Collins, Chris D; Shaw, Liz J

2011-03-01

The effects of nano-scale and micro-scale zerovalent iron (nZVI and mZVI) particles on general (dehydrogenase and hydrolase) and specific (ammonia oxidation potential, AOP) activities mediated by the microbial community in an uncontaminated soil were examined. nZVI (diameter 12.5 nm; 10 mg g⁻¹ soil) apparently inhibited AOP and nZVI and mZVI apparently stimulated dehydrogenase activity but had minimal influence on hydrolase activity. Sterile experiments revealed that the apparent inhibition of AOP could not be interpreted as such due to the confounding action of the particles, whereas, the nZVI-enhanced dehydrogenase activity could represent the genuine response of a stimulated microbial population or an artifact of ZVI reactivity. Overall, there was no evidence for negative effects of nZVI or mZVI on the processes studied. When examining the impact of redox active particles such as ZVI on microbial oxidation-reduction reactions, potential confounding effects of the test particles on assay conditions should be considered. Copyright © 2010 Elsevier Ltd. All rights reserved.

Boron nitride encapsulated copper nanoparticles: a facile one-step synthesis and their effect on thermal decomposition of ammonium perchlorate.

PubMed

Huang, Caijin; Liu, Qiuwen; Fan, Wenjie; Qiu, Xiaoqing

2015-11-16

Reactivity is of great importance for metal nanoparticles used as catalysts, biomaterials and advanced sensors, but seeking for high reactivity seems to be conflict with high chemical stability required for metal nanoparticles. There is a subtle balance between reactivity and stability. This could be reached for colloidal metal nanoparticles using organic capping reagents, whereas it is challenging for powder metal nanoparticles. Here, we developed an alternative approach to encapsulate copper nanoparticles with a chemical inertness material--hexagonal boron nitride. The wrapped copper nanoparticles not only exhibit high oxidation resistance under air atmosphere, but also keep excellent promoting effect on thermal decomposition of ammonium perchlorate. This approach opens the way to design metal nanoparticles with both high stability and reactivity for nanocatalysts and their technological application.

Boron nitride encapsulated copper nanoparticles: a facile one-step synthesis and their effect on thermal decomposition of ammonium perchlorate

PubMed Central

Huang, Caijin; liu, Qiuwen; Fan, Wenjie; Qiu, Xiaoqing

2015-01-01

Reactivity is of great importance for metal nanoparticles used as catalysts, biomaterials and advanced sensors, but seeking for high reactivity seems to be conflict with high chemical stability required for metal nanoparticles. There is a subtle balance between reactivity and stability. This could be reached for colloidal metal nanoparticles using organic capping reagents, whereas it is challenging for powder metal nanoparticles. Here, we developed an alternative approach to encapsulate copper nanoparticles with a chemical inertness material—hexagonal boron nitride. The wrapped copper nanoparticles not only exhibit high oxidation resistance under air atmosphere, but also keep excellent promoting effect on thermal decomposition of ammonium perchlorate. This approach opens the way to design metal nanoparticles with both high stability and reactivity for nanocatalysts and their technological application. PMID:26567862

Ab initio molecular dynamics of the reactivity of vitamin C toward hydroxyl and HO₂/O⁻₂ radicals.

PubMed

Lespade, Laure

2017-11-21

Vitamin C is one of the most abundant exogenous antioxidants in the cell, and it is of the utmost importance to elucidate its mechanism of action against radicals. In this study, the reactivity of vitamin C toward OH and [Formula: see text] radicals in aqueous medium was analyzed by ab initio molecular dynamics using CPMD code. The simulations led to results similar to those of static studies or experiments for the pair of [Formula: see text] radicals but bring new insights for the reactivity with hydroxyl radical: the reaction takes place before the formation of an adduct and consists of two steps: first an electron is transferred to hydroxyl radical and then the ascorbyl radical loses a proton. Graphical Abstract Reactivity of vitamin C toward hydroxyl and [Formula: see text] radicals.

Electron Gyro-Harmonic Effects on Ionospheric Stimulated Brillouin Scatter

DTIC Science & Technology

2014-08-21

27709-2211 Brillouin, SBS, emission lines, pump frequency stepping, cyclotron , EIC, airglow, upper hybrid REPORT DOCUMENTATION PAGE 11. SPONSOR...direction and the background magnetic field vector, the excited electrostatic wave could be either ion acoustic (IA) or electrostatic ion cyclotron (EIC...A. Hedberg, B. Lundborg, P. Stubbe, H. Kopka, and M. T. Rietveld (1989), Stimulated electromagnetic emission near electron cyclotron harmonics in

Effect of Rhythmic Auditory Stimulation on Controlling Stepping Cadence of Individuals with Mental Retardation and Cerebral Palsy

ERIC Educational Resources Information Center

Varsamis, Panagiotis; Staikopoulos, Konstantinos; Kartasidou, Lefkothea

2012-01-01

One of the purposes of Rhythmic Auditory Stimulation (RAS) is to improve the control of dysfunctional movement patterns. This study aimed to extend the line of research by focussing on secondary students with mental retardation and cerebral palsy. According to the study's assumption, cadence can be controlled through a stable and low signal…

Multiprofessional education to stimulate collaboration: a circular argument and its consequences.

PubMed

Roodbol, Petrie F

2010-01-01

The current developments in healthcare are unprecedented. The organization of health care is complex. Collaboration is essential to meet all the healthcare needs of patients and to achieve coordinated and unambiguous information. Multiprofessional education (MPE) or multidisciplinary training (MDT) seems a logical step to stimulate teamwork. However, collaboration and MPE are wrestling with the same problems: social identity and acceptance.

Assessing gait adaptability in people with a unilateral amputation on an instrumented treadmill with a projected visual context.

PubMed

Houdijk, Han; van Ooijen, Mariëlle W; Kraal, Jos J; Wiggerts, Henri O; Polomski, Wojtek; Janssen, Thomas W J; Roerdink, Melvyn

2012-11-01

Gait adaptability, including the ability to avoid obstacles and to take visually guided steps, is essential for safe movement through a cluttered world. This aspect of walking ability is important for regaining independent mobility but is difficult to assess in clinical practice. The objective of this study was to investigate the validity of an instrumented treadmill with obstacles and stepping targets projected on the belt's surface for assessing prosthetic gait adaptability. This was an observational study. A control group of people who were able bodied (n=12) and groups of people with transtibial (n=12) and transfemoral (n=12) amputations participated. Participants walked at a self-selected speed on an instrumented treadmill with projected visual obstacles and stepping targets. Gait adaptability was evaluated in terms of anticipatory and reactive obstacle avoidance performance (for obstacles presented 4 steps and 1 step ahead, respectively) and accuracy of stepping on regular and irregular patterns of stepping targets. In addition, several clinical tests were administered, including timed walking tests and reports of incidence of falls and fear of falling. Obstacle avoidance performance and stepping accuracy were significantly lower in the groups with amputations than in the control group. Anticipatory obstacle avoidance performance was moderately correlated with timed walking test scores. Reactive obstacle avoidance performance and stepping accuracy performance were not related to timed walking tests. Gait adaptability scores did not differ in groups stratified by incidence of falls or fear of falling. Because gait adaptability was affected by walking speed, differences in self-selected walking speed may have diminished differences in gait adaptability between groups. Gait adaptability can be validly assessed by use of an instrumented treadmill with a projected visual context. When walking speed is taken into account, this assessment provides unique, quantitative information about walking ability in people with a lower-limb amputation.

Method for generating a highly reactive plasma for exhaust gas aftertreatment and enhanced catalyst reactivity

DOEpatents

Whealton, John H.; Hanson, Gregory R.; Storey, John M.; Raridon, Richard J.; Armfield, Jeffrey S.; Bigelow, Timothy S.; Graves, Ronald L.

2002-01-01

A method for non-thermal plasma aftertreatment of exhaust gases the method comprising the steps of providing short risetime, high frequency, high power bursts of low-duty factor microwaves sufficient to generate a plasma discharge and passing a gas to be treated through the discharge so as to cause dissociative reduction of the exhaust gases and enhanced catalyst reactivity through application of the pulsed microwave fields directly to the catalyst material sufficient to cause a polarizability catastrophe and enhanced heating of the metal crystallite particles of the catalyst, and in the presence or absence of the plasma. The invention also includes a reactor for aftertreatment of exhaust gases.

Multidentate oligomeric ligands to enhance the biocompatibility of iron oxide and other metal nanoparticles

NASA Astrophysics Data System (ADS)

Wang, Wentao; Palui, Goutam; Ji, Xin; Aldeek, Fadi; Mattoussi, Hedi

2014-03-01

We prepared a set of multi-coordinating and reactive amphiphilic polymer ligands and used them for surface-functionalizing magnetic iron oxide nanoparticles. The amphiphilic oligomers were prepared by coupling (via one step nucleophilic addition) several dopamine anchoring groups, polyethylene glycol moieties and reactive groups onto a poly(isobutylene-alt-maleic anhydride) chain. The availability of several anchoring groups in the same ligand greatly enhances the ligand affinity to the nanoparticle surfaces, via multiplecoordination, while the hydrophilic and reactive groups promote colloidal stability in buffer media and allow subsequent conjugation to target biomolecules. The hydrophilic nanoparticles capped with these polymers maintain compact size and exhibit great long term colloidal stability.

Photoredox Catalysis Unlocks Single-Electron Elementary Steps in Transition Metal Catalyzed Cross-Coupling

PubMed Central

2016-01-01

Since initial reports, cross-coupling technologies employing photoredox catalysts to access novel reactivity have developed with increasing pace. In this Outlook, prominent examples from the recent literature are organized on the basis of the elementary transformation enabled by photoredox catalysis and are discussed in the context of relevant historical precedent in stoichiometric organometallic chemistry. This treatment allows mechanistic similarities inherent to odd-electron transition metal reactivity to be generalized to a set of lessons for future reaction development. PMID:27280163

Method for generating a highly reactive plasma for exhaust gas aftertreatment and enhanced catalyst reactivity

DOEpatents

Whealton, John H.; Hanson, Gregory R.; Storey, John M.; Raridon, Richard J.; Armfield, Jeffrey S.; Bigelow, Timothy S.; Graves, Ronald L.

2001-01-01

A method for non-thermal plasma aftertreatment of exhaust gases the method comprising the steps of providing short risetime (about 40 ps), high frequency (about 5G hz), high power bursts of low-duty factor microwaves sufficient to generate a dielectric barrier discharge and passing a gas to treated through the discharge so as to cause dissociative reduction of the exhaust gases. The invention also includes a reactor for generating the non-thermal plasma.

Development and characterization of Histoplasma capsulatum-reactive murine T-cell lines and clones

NASA Technical Reports Server (NTRS)

Deepe, George S., Jr.; Smith, James G.; Denman, David; Bullock, Ward E.; Sonnenfeld, Gerald

1986-01-01

Several Histoplasma capsulatum-reactive murine cloned T-cell lines (TCLs) were isolated from spleens of C57BL/6 mice immunized with viable H. capsulatum yeast cells, using the methodology of Kimoto and Fathman (1980). These T-cells were characterized phenotypically as Thy-1.2(+) Lyt-1(+) L3T4(+) Lyt-2(-), that is, as the helper/inducer phenotype. The cloned T cells proliferate in response to histoplasmin and, in some cases, to heterologous fungal anigens. Upon injection of mice with the antigen, the T-cells mediate local delayed-type hypersensitivity responses and, after stimulation, release regulatory lymphokines.

[Comparative study of effects of cortical nucleus of amygdala and pyriform cortex on activity of bulbar respiratory neurons in cats].

PubMed

Nersesian, L B; Eganova, V S; Pogosian, N L; Avetisian, I N

2011-01-01

Comparative microelectrophysiological study of character and peculiarities of effects of the cortical nucleus of amygdala and of the periamygdalar area of pyriform cortex on impulse activity was performed on the same single functionally identified respiratory medullar neurons. A high reactivity of bulbar respiratory neurons on stimulation is established in both studied limbic structures. There is established the qualitatively different character of their response reactions at stimulation of the cortical amygdala nucleus and the periamygdalar cortex. The cortical amygdala nucleus has been shown to produce on the activity of medullar respiratory neurons both facilitating and inhibitory action with predominance of the activating one (without topographical orderliness). The effect of periamygdalar cortex at stimulation of various parts was characterized by topographic differentiation. The suppressing reactions of neurons in the majority of cases were recorded at stimulation of the rostral area of periamygdalar cortex, whereas the excitatory reactions--at stimulation of its caudal part. Functional organization of respiratory control of the studied limbic system structures is discussed.

Ultradian hormone stimulation induces glucocorticoid receptor-mediated pulses of gene transcription.

PubMed

Stavreva, Diana A; Wiench, Malgorzata; John, Sam; Conway-Campbell, Becky L; McKenna, Mervyn A; Pooley, John R; Johnson, Thomas A; Voss, Ty C; Lightman, Stafford L; Hager, Gordon L

2009-09-01

Studies on glucocorticoid receptor (GR) action typically assess gene responses by long-term stimulation with synthetic hormones. As corticosteroids are released from adrenal glands in a circadian and high-frequency (ultradian) mode, such treatments may not provide an accurate assessment of physiological hormone action. Here we demonstrate that ultradian hormone stimulation induces cyclic GR-mediated transcriptional regulation, or gene pulsing, both in cultured cells and in animal models. Equilibrium receptor-occupancy of regulatory elements precisely tracks the ligand pulses. Nascent RNA transcripts from GR-regulated genes are released in distinct quanta, demonstrating a profound difference between the transcriptional programs induced by ultradian and constant stimulation. Gene pulsing is driven by rapid GR exchange with response elements and by GR recycling through the chaperone machinery, which promotes GR activation and reactivation in response to the ultradian hormone release, thus coupling promoter activity to the naturally occurring fluctuations in hormone levels. The GR signalling pathway has been optimized for a prompt and timely response to fluctuations in hormone levels, indicating that biologically accurate regulation of gene targets by GR requires an ultradian mode of hormone stimulation.

Novel 2-step synthetic indole compound 1,1,3-tri(3-indolyl)cyclohexane inhibits cancer cell growth in lung cancer cells and xenograft models.

PubMed

Lee, Ching-Hsiao; Yao, Ching-Fa; Huang, Sin-Ming; Ko, Shengkai; Tan, Yi-Hung; Lee-Chen, Guey-Jen; Wang, Yi-Ching

2008-08-15

The clinical responses to chemotherapy in lung cancer patients are unsatisfactory. Thus, the development of more effective anticancer drugs for lung cancer is urgently needed. A 2-step novel synthetic compound, referred to as 1,1,3-tri(3-indolyl)cyclohexane (3-indole), was generated in high purity and yield. 3-Indole was tested for its biologic activity in A549, H1299, H1435, CL1-1, and H1437 lung cancer cells. Animal studies were also performed. The data indicate that 3-indole induced apoptosis in various lung cancer cells. Increased cytochrome-c release from mitochondria to cytosol, decreased expression of antiapoptotic Bcl-2, and increased expression of proapoptotic Bax were observed. In addition, 3-indole stimulated caspases-3, -9, and to a lesser extent caspase-8 activities in cancer cells, suggesting that the intrinsic mitochondria pathway was the potential mechanism involved in 3-indole-induced apoptosis. 3-Indole-induced a concentration-dependent mitochondrial membrane potential dissipation and an increase in reactive oxygen species (ROS) production. Activation of c-Jun N-terminal kinase (JNK) and triggering of DNA damage were also apparent. Note that 3-indole-induced JNK activation and DNA damage can be partially suppressed by an ROS inhibitor. Apoptosis induced by 3-indole could be abrogated by ROS or JNK inhibitors, suggesting the importance of ROS and JNK stress-related pathways in 3-indole-induced apoptosis. Moreover, 3-indole showed in vivo antitumor activities against human xenografts in murine models. On the basis of its potent anticancer activity in cell and animal models, the data suggest that this 2-step synthetic 3-indole compound of high purity and yield is a potential candidate to be tested as a lead pharmaceutical compound for cancer treatment. 2008 American Cancer Society

Cell-mediated T lymphocyte responses against syngeneic cells modified with amino-reactive hapten (AED-NH2): H-2Dk serves as an element for cell-mediated lympholysis to amino-reactive hapten (AED-NH2)-modified self.

PubMed

Mizuochi, T; Fujiwara, H; Takai, Y; Hamaoka, T

1985-02-01

Spleen cells from C3H/He mice immunized to the newly synthesized amino-reactive hapten, 5-sulfo-1-naphthoxy acetic acid N-hydroxysuccinimide (AED-NH2), were stimulated in vitro with AED-NH2 modified syngeneic cells. After 5 days of culture, effector cells were assayed for their cytotoxic activity against AED-NH2-modified target blast cells. In contrast to other amino-reactive haptens reported so far, a strong cytotoxic activity against AED-NH2-modified syngeneic cells was found in H-2b mice as well as in H-2k mice. Furthermore, Dk-restricted anti-AED-NH2 CTL recognition was observed in H-2k mice as shown by cold target inhibition. Previous studies have demonstrated the predominant influence of K over D region self determinants, and of the chemical reactivity of the haptenic reagent in Ir gene control of CTL response to hapten-self. The present report illustrates the importance of the hapten itself in genetic regulation of these CTL responses.

Redox regulation of electrophilic signaling by reactive persulfides in cardiac cells.

PubMed

Nishida, Motohiro; Nishimura, Akiyuki; Matsunaga, Tetsuro; Motohashi, Hozumi; Kasamatsu, Shingo; Akaike, Takaaki

2017-08-01

Maintaining a redox balance by means of precisely controlled systems that regulate production, and elimination, and metabolism of electrophilic substances (electrophiles) is essential for normal cardiovascular function. Electrophilic signaling is mainly regulated by endogenous electrophiles that are generated from reactive oxygen species, nitric oxide, and the derivative reactive species of nitric oxide during stress responses, as well as by exogenous electrophiles including compounds in foods and environmental pollutants. Among electrophiles formed endogenously, 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP) has unique cell signaling functions, and pathways for its biosynthesis, signaling mechanism, and metabolism in cells have been clarified. Reactive persulfide species such as cysteine persulfides and polysulfides that are endogenously produced in cells are likely to be involved in 8-nitro-cGMP metabolism. These new aspects of redox biology may stimulate innovative and multidisciplinary research in cardiovascular physiology and pathophysiology. In our review, we focus on the redox-dependent regulation of electrophilic signaling via reduction and metabolism of electrophiles by reactive persulfides in cardiac cells, and we include suggestions for a new therapeutic strategy for cardiovascular disease. Copyright © 2017 Elsevier Inc. All rights reserved.

Trypsin impaired epithelial barrier function and induced IL-8 secretion through basolateral PAR-2: a lesson from a stratified squamous epithelial model.

PubMed

Shan, Jing; Oshima, Tadayuki; Chen, Xin; Fukui, Hirokazu; Watari, Jiro; Miwa, Hiroto

2012-11-15

Immune-mediated injury by the protease-activated receptor-2-interleukin-8 (PAR-2-IL8) pathway may underlie the development of gastroesophageal reflux disease (GERD). However, the localization of PAR-2 and the mechanism of PAR-2 activation remain unclear. This study aimed to address these questions on an esophageal stratified squamous epithelial model and in the human esophageal mucosa of GERD patients. Normal human esophageal epithelial cells were cultured with the air-liquid interface system to establish the model. SLIGKV-NH2 (PAR-2 synthetic agonist), trypsin (PAR-2 natural activator), and weak acid (pH 4, 5, and 6) were added to either the apical or basolateral compartment to evaluate their effects on transepithelial electrical resistance (TEER) and IL-8 production. PAR-2 localization was examined both in the cell model and biopsies from GERD patients by immunohistochemistry. Apical trypsin stimulation induced IL-8 accompanied by decreased TEER in vitro, whereas the effective concentration from the basolateral side was 10 times lower. SLIGKV-NH2 from basolateral but not apical stimulation induced IL-8 production. Apical weak acid stimulation did not influence TEER or IL-8 production. Immunohistochemistry showed intense reactivity of PAR-2 in the basal and suprabasal layers after stimulation with trypsin. A similar PAR-2 reactivity that was mainly located at the basal and suprabasal layers was detected in GERD patients. In conclusion, the activation of the PAR-2-IL-8 pathway probably occurred at the basal and suprabasal layers, while the esophageal epithelial barrier may influence the activation of PAR-2. Under proton pump inhibitor therapy, refluxed trypsin may remain active and be a potential agent in the pathogenesis of refractory GERD.

Ultraviolet B preconditioning enhances the hair growth-promoting effects of adipose-derived stem cells via generation of reactive oxygen species.

PubMed

Jeong, Yun-Mi; Sung, Young Kwan; Kim, Wang-Kyun; Kim, Ji Hye; Kwack, Mi Hee; Yoon, Insoo; Kim, Dae-Duk; Sung, Jong-Hyuk

2013-01-01

Hypoxia induces the survival and regenerative potential of adipose-derived stem cells (ASCs), but there are tremendous needs to find alternative methods for ASC preconditioning. Therefore, this work investigated: (1) the ability of low-dose ultraviolet B (UVB) radiation to stimulate the survival, migration, and tube-forming activity of ASCs in vitro; (2) the ability of UVB preconditioning to enhance the hair growth-promoting capacity of ASCs in vivo; and (3) the mechanism of action for ASC stimulation by UVB. Although high-dose UVB decreased the proliferation of ASCs, low-dose (10 or 20 mJ/cm(2)) treatment increased their survival, migration, and tube-forming activity. In addition, low-dose UVB upregulated the expression of ASC-derived growth factors, and a culture medium conditioned by UVB-irradiated ASCs increased the proliferation of dermal papilla and outer root sheet cells. Notably, injection of UVB-preconditioned ASCs into C(3)H/HeN mice significantly induced the telogen-to-anagen transition and increased new hair weight in vivo. UVB treatment significantly increased the generation of reactive oxygen species (ROS) in cultured ASCs, and inhibition of ROS generation by diphenyleneiodonium chloride (DPI) significantly attenuated UVB-induced ASC stimulation. Furthermore, NADPH oxidase 4 (Nox4) expression was induced in ASCs by UVB irradiation, and Nox4 silencing by small interfering RNA, like DPI, significantly reduced UVB-induced ROS generation. These results suggest that the primary involvement of ROS generation in UVB-mediated ASC stimulation occurs via the Nox4 enzyme. This is the first indication that a low dose of UVB radiation and/or the control of ROS generation could potentially be incorporated into a novel ASC preconditioning method for hair regeneration.

Herba Cistanches stimulates cellular glutathione redox cycling by reactive oxygen species generated from mitochondrial respiration in H9c2 cardiomyocytes.

PubMed

Wong, Hoi Shan; Ko, Kam Ming

2013-01-01

Earlier findings demonstrated that pretreatment of Herba Cistanches [the dried whole plant of Cistanche deserticola Y.C. Ma (Orobanchaceae)], a "Yang-invigorating" Chinese tonic herb, stimulated the ATP-generation capacity (ATP-GC) in mitochondria isolated from rat heart ex vivo. The enhancement of mitochondrial ATP-GC by Herba Cistanches was associated with induction of glutathione antioxidant status and protection against ischemia/reperfusion (I/R) injury in rat hearts. This study investigated the relationship between enhancements in mitochondrial ATP-GC and glutathione antioxidant status in H9c2 cardiomyocytes using a semipurified fraction of Herba Cistanches (HCF1). HCF1 (10-300 ng/mL) was tested for its effects on mitochondrial ATP generation, glutathione antioxidant status and protection against oxidant injury in H9c2 cardiomyocytes and rat hearts. HCF1 at 30 ng/mL increased mitochondrial ATP-GC and ADP-stimulated state 3 respiration (by 50 and 100%, respectively) in H9c2 cardiomyocytes. The stimulation of mitochondrial respiration was associated with the induction of mitochondrial uncoupling (27%) and enhancement of cellular glutathione redox cycling as well as protection against hypoxia/reoxygenation (hypox/reoxy)-induced apoptosis (by 60%). While HCF1 treatment increased reactive oxygen species generation from mitochondrial respiration in H9c2 cardiomyocytes, pretreatment with antioxidants (DMTU) abrogated the HCF1-induced cellular responses and the associated cytoprotective effect. HCF1 pretreatment (1.14 and 3.41 mg/kg × 14) also protected against myocardial I/R injury in rats (by 13 and 32%), presumably mediated by the induction of glutathione antioxidant response. The long-term intake of HCF1 may offer a prospect for the prevention of ischemic heart disease.

The Impact of Accelerated Right Prefrontal High-Frequency Repetitive Transcranial Magnetic Stimulation (rTMS) on Cue-Reactivity: An fMRI Study on Craving in Recently Detoxified Alcohol-Dependent Patients

PubMed Central

Herremans, Sarah C.; Van Schuerbeek, Peter; De Raedt, Rudi; Matthys, Frieda; Buyl, Ronald; De Mey, Johan; Baeken, Chris

2015-01-01

In alcohol-dependent patients craving is a difficult-to-treat phenomenon. It has been suggested that high-frequency (HF) repetitive transcranial magnetic stimulation (rTMS) may have beneficial effects. However, exactly how this application exerts its effect on the underlying craving neurocircuit is currently unclear. In an effort to induce alcohol craving and to maximize detection of HF-rTMS effects to cue-induced alcohol craving, patients were exposed to a block and event-related alcohol cue-reactivity paradigm while being scanned with fMRI. Hence, we assessed the effect of right dorsolateral prefrontal cortex (DLPFC) stimulation on cue-induced and general alcohol craving, and the related craving neurocircuit. Twenty-six recently detoxified alcohol-dependent patients were included. First, we evaluated the impact of one sham-controlled stimulation session. Second, we examined the effect of accelerated right DLPFC HF-rTMS treatment: here patients received 15 sessions in an open label accelerated design, spread over 4 consecutive days. General craving significantly decreased after 15 active HF-rTMS sessions. However, cue-induced alcohol craving was not altered. Our brain imaging results did not show that the cue-exposure affected the underlying craving neurocircuit after both one and fifteen active HF-rTMS sessions. Yet, brain activation changes after one and 15 HF-rTMS sessions, respectively, were observed in regions associated with the extended reward system and the default mode network, but only during the presentation of the event-related paradigm. Our findings indicate that accelerated HF-rTMS applied to the right DLPFC does not manifestly affect the craving neurocircuit during an alcohol-related cue-exposure, but instead it may influence the attentional network. PMID:26295336

Molecular crowding favors reactivity of a human ribozyme under physiological ionic conditions.

PubMed

Strulson, Christopher A; Yennawar, Neela H; Rambo, Robert P; Bevilacqua, Philip C

2013-11-19

In an effort to relate RNA folding to function under cellular-like conditions, we monitored the self-cleavage reaction of the human hepatitis delta virus-like CPEB3 ribozyme in the background of physiological ionic concentrations and various crowding and cosolute agents. We found that at physiological free Mg(2+) concentrations (∼0.1-0.5 mM), both crowders and cosolutes stimulate the rate of self-cleavage, up to ∼6-fold, but that in 10 mM Mg(2+) (conditions widely used for in vitro ribozyme studies) these same additives have virtually no effect on the self-cleavage rate. We further observe a dependence of the self-cleavage rate on crowder size, wherein the level of rate stimulation is diminished for crowders larger than the size of the unfolded RNA. Monitoring effects of crowding and cosolute agents on rates in biological amounts of urea revealed additive-promoted increases at both low and high Mg(2+) concentrations, with a maximal stimulation of more than 10-fold and a rescue of the rate to its urea-free values. Small-angle X-ray scattering experiments reveal a structural basis for this stimulation in that higher-molecular weight crowding agents favor a more compact form of the ribozyme in 0.5 mM Mg(2+) that is essentially equivalent to the form under standard ribozyme conditions of 10 mM Mg(2+) without a crowder. This finding suggests that at least a portion of the rate enhancement arises from favoring the native RNA tertiary structure. We conclude that cellular-like crowding supports ribozyme reactivity by favoring a compact form of the ribozyme, but only under physiological ionic and cosolute conditions.

Potent NLRP3 Inflammasome Activation by the HIV Reverse Transcriptase Inhibitor Abacavir.

PubMed

Toksoy, Atiye; Sennefelder, Helga; Adam, Christian; Hofmann, Sonja; Trautmann, Axel; Goebeler, Matthias; Schmidt, Marc

2017-02-17

There is experimental and clinical evidence that some exanthematous allergic drug hypersensitivity reactions are mediated by drug-specific T cells. We hypothesized that the capacity of certain drugs to directly stimulate the innate immune system may contribute to generate drug-specific T cells. Here we analyzed whether abacavir, an HIV-1 reverse transcriptase inhibitor often inducing severe delayed-type drug hypersensitivity, can trigger innate immune activation that may contribute to its allergic potential. We show that abacavir fails to generate direct innate immune activation in human monocytes but potently triggers IL-1β release upon pro-inflammatory priming with phorbol ester or Toll-like receptor stimulation. IL-1β processing and secretion were sensitive to Caspase-1 inhibition, NLRP3 knockdown, and K + efflux inhibition and were not observed with other non-allergenic nucleoside reverse transcriptase inhibitors, identifying abacavir as a specific inflammasome activator. It further correlated with dose-dependent mitochondrial reactive oxygen species production and cytotoxicity, indicating that inflammasome activation resulted from mitochondrial damage. However, both NLRP3 depletion and inhibition of K + efflux mitigated abacavir-induced mitochondrial reactive oxygen species production and cytotoxicity, suggesting that these processes were secondary to NLRP3 activation. Instead, depletion of cardiolipin synthase 1 abolished abacavir-induced IL-1β secretion, suggesting that mitochondrial cardiolipin release may trigger abacavir-induced inflammasome activation. Our data identify abacavir as a novel inflammasome-stimulating drug allergen. They implicate a potential contribution of innate immune activation to medication-induced delayed-type hypersensitivity, which may stimulate new concepts for treatment and prevention of drug allergies. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Attenuated Listeria monocytogenes vectors overcome suppressive plasma factors during HIV infection to stimulate myeloid dendritic cells to promote adaptive immunity and reactivation of latent virus.

PubMed

Miller, Elizabeth A; Spadaccia, Meredith R; Norton, Thomas; Demmler, Morgan; Gopal, Ramya; O'Brien, Meagan; Landau, Nathaniel; Dubensky, Thomas W; Lauer, Peter; Brockstedt, Dirk G; Bhardwaj, Nina

2015-01-01

HIV-1 infection is characterized by myeloid dendritic cell (DC) dysfunction, which blunts the responsiveness to vaccine adjuvants. We previously showed that nonviral factors in HIV-seropositive plasma are partially responsible for mediating this immune suppression. In this study we investigated recombinant Listeria monocytogenes (Lm) vectors, which naturally infect and potently activate DCs from seronegative donors, as a means to overcome DC dysfunction associated with HIV infection. Monocyte-derived DCs were cocultured with plasma from HIV-infected donors (HIV-moDCs) to induce a dysregulated state and infected with an attenuated, nonreplicative vaccine strain of Lm expressing full length clade B consensus gag (KBMA Lm-gag). Lm infection stimulated cytokine secretion [interleukin (IL)-12p70, tumor necrosis factor (TNF)-α, and IL-6] and Th-1 skewing of allogeneic naive CD4 T cells by HIV-moDCs, in contrast to the suppressive effects observed by HIV plasma on moDCs on toll-like receptor ligand stimulation. Upon coculture of "killed" but metabolically active (KBMA) Lm-gag-infected moDCs from HIV-infected donors with autologous cells, expansion of polyfunctional, gag-specific CD8(+) T cells was observed. Reactivation of latent proviruses by moDCs following Lm infection was also observed in models of HIV latency in a TNF-α-dependent manner. These findings reveal the unique ability of Lm vectors to contend with dysregulation of HIV-moDCs, while simultaneously possessing the capacity to activate latent virus. Concurrent stimulation of innate and adaptive immunity and disruption of latency may be an approach to reduce the pool of latently infected cells during HIV infection. Further study of Lm vectors as part of therapeutic vaccination and eradication strategies may advance this evolving field.

Unexpected function of the phagocyte NADPH oxidase in supporting hyperglycolysis in stimulated neutrophils: key role of 6-phosphofructo-2-kinase.

PubMed

Baillet, Athan; Hograindleur, Marc-André; El Benna, Jamel; Grichine, Alexei; Berthier, Sylvie; Morel, Françoise; Paclet, Marie-Hélène

2017-02-01

The phagocyte NADPH oxidase 2 (Nox2) is an enzymatic complex that is involved in innate immunity, notably via its capacity to produce toxic reactive oxygen species. Recently, a proteomic analysis of the constitutively active Nox2 complex, isolated from neutrophil fractions, highlighted the presence of 6-phosphofructo-2-kinase (PFK-2). The purpose of this work was to study the relationship between PFK-2 and NADPH oxidase in neutrophils. Data have underlined a specific association of the active phosphorylated form of PFK-2 with Nox2 complex in stimulated neutrophils. In its active form, PFK-2 catalyzes the production of fructose-2,6-bisphosphate, which is the main allosteric activator of phosphofructo-1-kinase, the limiting enzyme in glycolysis. Pharmacologic inhibition of PFK-2 phosphorylation and cell depletion in PFK-2 by a small interfering RNA strategy led to a decrease in the glycolysis rate and a reduction in NADPH oxidase activity in stimulated cells. Surprisingly, alteration of Nox2 activity impacted the glycolysis rate, which indicated that Nox2 in neutrophils was not only required for reactive oxygen species production but was also involved in supporting the energetic metabolism increase that was induced by inflammatory conditions. PFK-2 seems to be a strategic element that links NADPH oxidase activation and glycolysis modulation, and, as such, is proposed as a potential therapeutic target in inflammatory diseases.-Baillet, A., Hograindleur, M.-A., El Benna, J., Grichine, A., Berthier, S., Morel, F., Paclet, M.-H. Unexpected function of the phagocyte NADPH oxidase in supporting hyperglycolysis in stimulated neutrophils: key role of 6-phosphofructo-2-kinase. © FASEB.

Nitration of naphthalene and remarks on the mechanism of electrophilic aromatic nitration.

PubMed

Olah, G A; Narang, S C; Olah, J A

1981-06-01

Naphthalene was nitrated with a variety of nitrating agents. Comparison of data with Perrin's electrochemical nitration [Perrin, C. L. (1977) J. Am. Chem. Soc. 99, 5516-5518] shows that nitration of naphthalene gives an alpha-nitronaphthalene to beta-nitronaphthalene ratio that varies between 9 and 29 and is thus not constant. Perrin's data, therefore, are considered to be inconclusive evidence for the proposed one-electron transfer mechanism for the nitration of naphthalene and other reactive aromatics. Moodie and Schoefield [Hoggett, J. G., Moodie, R. B., Penton, J. R. & Schoefield, K. (1971) Nitration and Aromatic Reactivity (Cambridge Univ. Press, London)], as well as Perrin, independently concluded that, in the general scheme of nitration of reactive aromatics, there is the necessity to introduce into the classical Ingold mechanism an additional step involving a distinct intermediate preceding the formation of the Wheland intermediate (sigma complexes). This view coincides with our two-step mechanistic picture [Kuhn, S. J. & Olah, G. A. (1961) J. Am. Chem. Soc. 83, 4564-4571] of the nitronium salt nitration of aromatic hydrocarbons (including benzene and toluene), in which low substrate selectivity but high positional selectivity was found, indicating the independence of substrate from positional selectivity.

Nitration of naphthalene and remarks on the mechanism of electrophilic aromatic nitration*

PubMed Central

Olah, George A.; Narang, Subhash C.; Olah, Judith A.

1981-01-01

Naphthalene was nitrated with a variety of nitrating agents. Comparison of data with Perrin's electrochemical nitration [Perrin, C. L. (1977) J. Am. Chem. Soc. 99, 5516-5518] shows that nitration of naphthalene gives an α-nitronaphthalene to β-nitronaphthalene ratio that varies between 9 and 29 and is thus not constant. Perrin's data, therefore, are considered to be inconclusive evidence for the proposed one-electron transfer mechanism for the nitration of naphthalene and other reactive aromatics. Moodie and Schoefield [Hoggett, J. G., Moodie, R. B., Penton, J. R. & Schoefield, K. (1971) Nitration and Aromatic Reactivity (Cambridge Univ. Press, London)], as well as Perrin, independently concluded that, in the general scheme of nitration of reactive aromatics, there is the necessity to introduce into the classical Ingold mechanism an additional step involving a distinct intermediate preceding the formation of the Wheland intermediate (σ complexes). This view coincides with our two-step mechanistic picture [Kuhn, S. J. & Olah, G. A. (1961) J. Am. Chem. Soc. 83, 4564-4571] of the nitronium salt nitration of aromatic hydrocarbons (including benzene and toluene), in which low substrate selectivity but high positional selectivity was found, indicating the independence of substrate from positional selectivity. PMID:16593026

Principles for identification of High Potency Category Chemicals for which the Dermal Sensitisation Threshold (DST) approach should not be applied.

PubMed

Roberts, David W; Api, Anne Marie; Safford, Robert J; Lalko, Jon F

2015-08-01

An essential step in ensuring the toxicological safety of chemicals used in consumer products is the evaluation of their skin sensitising potential. The sensitising potency, coupled with information on exposure levels, can be used in a Quantitative Risk Assessment (QRA) to determine an acceptable level of a given chemical in a given product. Where consumer skin exposure is low, a risk assessment can be conducted using the Dermal Sensitisation Threshold (DST) approach, avoiding the need to determine potency experimentally. Since skin sensitisation involves chemical reaction with skin proteins, the first step in the DST approach is to assess, on the basis of the chemical structure, whether the chemical is expected to be reactive or not. Our accompanying publication describes the probabilistic derivation of a DST of 64 μg/cm(2) for chemicals assessed as reactive. This would protect against 95% of chemicals assessed as reactive, but the remaining 5% would include chemicals with very high potency. Here we discuss the chemical properties and structural features of high potency sensitisers, and derive an approach whereby they can be identified and consequently excluded from application of the DST. Copyright © 2015 Elsevier Inc. All rights reserved.

T-cell receptor signaling enhances transcriptional elongation from latent HIV proviruses by activating P-TEFb through an ERK-dependent pathway.

PubMed

Kim, Young Kyeung; Mbonye, Uri; Hokello, Joseph; Karn, Jonathan

2011-07-29

Latent human immunodeficiency virus (HIV) proviruses are thought to be primarily reactivated in vivo through stimulation of the T-cell receptor (TCR). Activation of the TCR induces multiple signal transduction pathways, leading to the ordered nuclear migration of the HIV transcription initiation factors NF-κB (nuclear factor κB) and NFAT (nuclear factor of activated T-cells), as well as potential effects on HIV transcriptional elongation. We have monitored the kinetics of proviral reactivation using chromatin immunoprecipitation assays to measure changes in the distribution of RNA polymerase II in the HIV provirus. Surprisingly, in contrast to TNF-α (tumor necrosis factor α) activation, where early transcription elongation is highly restricted due to rate-limiting concentrations of Tat, efficient and sustained HIV elongation and positive transcription elongation factor b (P-TEFb) recruitment are detected immediately after the activation of latent proviruses through the TCR. Inhibition of NFAT activation by cyclosporine had no effect on either HIV transcription initiation or elongation. However, examination of P-TEFb complexes by gel-filtration chromatography showed that TCR signaling led to the rapid dissociation of the large inactive P-TEFb:7SK RNP (small nuclear RNA 7SK ribonucleoprotein) complex and the release of active low-molecular-weight P-TEFb complexes. Both P-TEFb recruitment to the HIV long terminal repeat and enhanced HIV processivity were blocked by the ERK (extracellular-signal-regulated kinase) inhibitor U0126, but not by AKT (serine/threonine protein kinase Akt) and PI3K (phosphatidylinositol 3-kinase) inhibitors. In contrast to treatment with HMBA (hexamethylene bisacetamide) and DRB (5,6-dichlorobenzimidazole 1-β-ribofuranoside), which disrupt the large 7SK RNP complex but do not stimulate early HIV elongation, TCR signaling provides the first example of a physiological pathway that can shift the balance between the inactive P-TEFb pool and the active P-TEFb pool and thereby stimulate proviral reactivation. Copyright © 2011 Elsevier Ltd. All rights reserved.

A synopsis of short-term response to alternative restoration treatments in Sagebrush-Steppe: The SageSTEP Project

Treesearch

James McIver; Mark Brunson; Steve Bunting; Jeanne Chambers; Paul Doescher; James Grace; April Hulet; Dale Johnson; Steve Knick; Richard Miller; Mike Pellant; Fred Pierson; David Pyke; Benjamin Rau; Kim Rollins; Bruce Roundy; Eugene Schupp; Robin Tausch; Jason Williams

2014-01-01

The Sagebrush Steppe Treatment Evaluation Project (SageSTEP) is an integrated long-term study that evaluates ecological effects of alternative treatments designed to reduce woody fuels and to stimulate the herbaceous understory of sagebrush steppe communities of the Intermountain West. This synopsis summarizes results through 3 yr posttreatment. Woody vegetation...

Reactive multi-particle collision dynamics with reactive boundary conditions

NASA Astrophysics Data System (ADS)

Sayyidmousavi, Alireza; Rohlf, Katrin

2018-07-01

In the present study, an off-lattice particle-based method called the reactive multi-particle collision (RMPC) dynamics is extended to model reaction-diffusion systems with reactive boundary conditions in which the a priori diffusion coefficient of the particles needs to be maintained throughout the simulation. To this end, the authors have made use of the so-called bath particles whose purpose is only to ensure proper diffusion of the main particles in the system. In order to model partial adsorption by a reactive boundary in the RMPC, the probability of a particle being adsorbed, once it hits the boundary, is calculated by drawing an analogy between the RMPC and Brownian Dynamics. The main advantages of the RMPC compared to other molecular based methods are less computational cost as well as conservation of mass, energy and momentum in the collision and free streaming steps. The proposed approach is tested on three reaction-diffusion systems and very good agreement with the solutions to their corresponding partial differential equations is observed.

Nonenzymatic Wearable Sensor for Electrochemical Analysis of Perspiration Glucose.

PubMed

Zhu, Xiaofei; Ju, Yinhui; Chen, Jian; Liu, Deye; Liu, Hong

2018-05-25

We report a nonenzymatic wearable sensor for electrochemical analysis of perspiration glucose. Multipotential steps are applied on a Au electrode, including a high negative pretreatment potential step for proton reduction which produces a localized alkaline condition, a moderate potential step for electrocatalytic oxidation of glucose under the alkaline condition, and a positive potential step to clean and reactivate the electrode surface for the next detection. Fluorocarbon-based materials were coated on the Au electrode for improving the selectivity and robustness of the sensor. A fully integrated wristband is developed for continuous real-time monitoring of perspiration glucose during physical activities, and uploading the test result to a smartphone app via Bluetooth.

ATP-dependent Conformational Changes Trigger Substrate Capture and Release by an ECF-type Biotin Transporter.

PubMed

Finkenwirth, Friedrich; Sippach, Michael; Landmesser, Heidi; Kirsch, Franziska; Ogienko, Anastasia; Grunzel, Miriam; Kiesler, Cornelia; Steinhoff, Heinz-Jürgen; Schneider, Erwin; Eitinger, Thomas

2015-07-03

Energy-coupling factor (ECF) transporters for vitamins and metal ions in prokaryotes consist of two ATP-binding cassette-type ATPases, a substrate-specific transmembrane protein (S component) and a transmembrane protein (T component) that physically interacts with the ATPases and the S component. The mechanism of ECF transporters was analyzed upon reconstitution of a bacterial biotin transporter into phospholipid bilayer nanodiscs. ATPase activity was not stimulated by biotin and was only moderately reduced by vanadate. A non-hydrolyzable ATP analog was a competitive inhibitor. As evidenced by cross-linking of monocysteine variants and by site-specific spin labeling of the Q-helix followed by EPR-based interspin distance analyses, closure and reopening of the ATPase dimer (BioM2) was a consequence of ATP binding and hydrolysis, respectively. A previously suggested role of a stretch of small hydrophobic amino acid residues within the first transmembrane segment of the S units for S unit/T unit interactions was structurally and functionally confirmed for the biotin transporter. Cross-linking of this segment in BioY (S) using homobifunctional thiol-reactive reagents to a coupling helix of BioN (T) indicated a reorientation rather than a disruption of the BioY/BioN interface during catalysis. Fluorescence emission of BioY labeled with an environmentally sensitive fluorophore was compatible with an ATP-induced reorientation and consistent with a hypothesized toppling mechanism. As demonstrated by [(3)H]biotin capture assays, ATP binding stimulated substrate capture by the transporter, and subsequent ATP hydrolysis led to substrate release. Our study represents the first experimental insight into the individual steps during the catalytic cycle of an ECF transporter in a lipid environment. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

ATP-dependent Conformational Changes Trigger Substrate Capture and Release by an ECF-type Biotin Transporter*

PubMed Central

Finkenwirth, Friedrich; Sippach, Michael; Landmesser, Heidi; Kirsch, Franziska; Ogienko, Anastasia; Grunzel, Miriam; Kiesler, Cornelia; Steinhoff, Heinz-Jürgen; Schneider, Erwin; Eitinger, Thomas

2015-01-01

Energy-coupling factor (ECF) transporters for vitamins and metal ions in prokaryotes consist of two ATP-binding cassette-type ATPases, a substrate-specific transmembrane protein (S component) and a transmembrane protein (T component) that physically interacts with the ATPases and the S component. The mechanism of ECF transporters was analyzed upon reconstitution of a bacterial biotin transporter into phospholipid bilayer nanodiscs. ATPase activity was not stimulated by biotin and was only moderately reduced by vanadate. A non-hydrolyzable ATP analog was a competitive inhibitor. As evidenced by cross-linking of monocysteine variants and by site-specific spin labeling of the Q-helix followed by EPR-based interspin distance analyses, closure and reopening of the ATPase dimer (BioM2) was a consequence of ATP binding and hydrolysis, respectively. A previously suggested role of a stretch of small hydrophobic amino acid residues within the first transmembrane segment of the S units for S unit/T unit interactions was structurally and functionally confirmed for the biotin transporter. Cross-linking of this segment in BioY (S) using homobifunctional thiol-reactive reagents to a coupling helix of BioN (T) indicated a reorientation rather than a disruption of the BioY/BioN interface during catalysis. Fluorescence emission of BioY labeled with an environmentally sensitive fluorophore was compatible with an ATP-induced reorientation and consistent with a hypothesized toppling mechanism. As demonstrated by [3H]biotin capture assays, ATP binding stimulated substrate capture by the transporter, and subsequent ATP hydrolysis led to substrate release. Our study represents the first experimental insight into the individual steps during the catalytic cycle of an ECF transporter in a lipid environment. PMID:25991724

Mobile Phone Radiation Induces Reactive Oxygen Species Production and DNA Damage in Human Spermatozoa In Vitro

PubMed Central

De Iuliis, Geoffry N.; Newey, Rhiannon J.; King, Bruce V.; Aitken, R. John

2009-01-01

Background In recent times there has been some controversy over the impact of electromagnetic radiation on human health. The significance of mobile phone radiation on male reproduction is a key element of this debate since several studies have suggested a relationship between mobile phone use and semen quality. The potential mechanisms involved have not been established, however, human spermatozoa are known to be particularly vulnerable to oxidative stress by virtue of the abundant availability of substrates for free radical attack and the lack of cytoplasmic space to accommodate antioxidant enzymes. Moreover, the induction of oxidative stress in these cells not only perturbs their capacity for fertilization but also contributes to sperm DNA damage. The latter has, in turn, been linked with poor fertility, an increased incidence of miscarriage and morbidity in the offspring, including childhood cancer. In light of these associations, we have analyzed the influence of RF-EMR on the cell biology of human spermatozoa in vitro. Principal Findings Purified human spermatozoa were exposed to radio-frequency electromagnetic radiation (RF-EMR) tuned to 1.8 GHz and covering a range of specific absorption rates (SAR) from 0.4 W/kg to 27.5 W/kg. In step with increasing SAR, motility and vitality were significantly reduced after RF-EMR exposure, while the mitochondrial generation of reactive oxygen species and DNA fragmentation were significantly elevated (P<0.001). Furthermore, we also observed highly significant relationships between SAR, the oxidative DNA damage bio-marker, 8-OH-dG, and DNA fragmentation after RF-EMR exposure. Conclusions RF-EMR in both the power density and frequency range of mobile phones enhances mitochondrial reactive oxygen species generation by human spermatozoa, decreasing the motility and vitality of these cells while stimulating DNA base adduct formation and, ultimately DNA fragmentation. These findings have clear implications for the safety of extensive mobile phone use by males of reproductive age, potentially affecting both their fertility and the health and wellbeing of their offspring. PMID:19649291

Do measures of reactive balance control predict falls in people with stroke returning to the community?

PubMed

Mansfield, A; Wong, J S; McIlroy, W E; Biasin, L; Brunton, K; Bayley, M; Inness, E L

2015-12-01

To determine if reactive balance control measures predict falls after discharge from stroke rehabilitation. Prospective cohort study. Rehabilitation hospital and community. Independently ambulatory individuals with stroke who were discharged home after inpatient rehabilitation (n=95). Balance and gait measures were obtained from a clinical assessment at discharge from inpatient stroke rehabilitation. Measures of reactive balance control were obtained: (1) during quiet standing; (2) when walking; and (3) in response to large postural perturbations. Participants reported falls and activity levels up to 6 months post-discharge. Logistic and Poisson regressions were used to identify measures of reactive balance control that were related to falls post-discharge. Decreased paretic limb contribution to standing balance control [rate ratio 0.8, 95% confidence interval (CI) 0.7 to 1.0; P=0.011], reduced between-limb synchronisation of quiet standing balance control (rate ratio 0.9, 95% CI 0.8 to 0.9; P<0.0001), increased step length variability (rate ratio 1.4, 95% CI 1.2 to 1.7; P=0.0011) and inability to step with the blocked limb (rate ratio 1.2, 95% CI 1.0 to 1.3; P=0.013) were significantly associated with increased fall rates when controlling for age, stroke severity, functional balance and daily walking activity. Impaired reactive balance control in standing and walking predicted increased risk of falls post-discharge from stroke rehabilitation. Specifically, measures that revealed the capacity of both limbs to respond to instability were related to increased risk of falls. These results suggest that post-stroke rehabilitation strategies for falls prevention should train responses to instability, and focus on remediating dyscontrol in the more-affected limb. Copyright © 2015 Chartered Society of Physiotherapy. Published by Elsevier Ltd. All rights reserved.

Effects of estrogen on cerebrovascular function: age-dependent shifts from beneficial to detrimental in small cerebral arteries of the rat

PubMed Central

Deer, Rachel R.

2016-01-01

In the present study, interactions of age and estrogen in the modulation of cerebrovascular function were examined in small arteries <150 μM. The hypothesis tested was that age enhances deleterious effects of exogenous estrogen by augmenting constrictor prostanoid (CP)-potentiated reactivity of the female (F) cerebrovasculature. F Sprague-Dawley rats approximating key stages of “hormonal aging” in humans were studied: perimenopausal (mature multi-gravid, MA, cyclic, 5–6 mo of age) and postmenopausal (reproductively senescent, RS, acyclic 10–12 mo of age). Rats underwent bilateral ovariectomy and were given estrogen replacement therapy (E) or placebo (O) for 14–21 days. Vasopressin reactivity (VP, 10−12–10−7 M) was measured in pressurized middle cerebral artery segments, alone or in the presence of COX-1- (SC560, 1 μM) or COX-2- (NS398, 10 μM) selective inhibitors. VP-stimulated release of prostacyclin (PGI2) and thromboxane (TXA2) were assessed by radioimmunoassay of 6-keto-PGF1α and TXB2 (stable metabolites). VP-induced vasoconstriction was attenuated in ovariectomized + estrogen-replaced, multigravid adult rats (5–6 mo; MAE) but potentiated in older ovariectomized + estrogen-replaced, reproductively senescent rats (12–14 mo; RSE). SC560 and NS398 reduced reactivity similarly in ovariectomized multigravid adult rats (5–6 mo; MAO) and ovariectomized reproductively senescent rat (12–14 mo; RSO). In MAE, reactivity to VP was reduced to a greater extent by SC560 than by NS398; however, in RSE, this effect was reversed. VP-stimulated PGI2 was increased by estrogen, yet reduced by age. VP-stimulated TXA2 was increased by estrogen and age in RSE but did not differ in MAO and RSO. Taken together, these data reveal that the vascular effects of estrogen are distinctly age-dependent in F rats. In younger MA, beneficial and protective effects of estrogen are evident (decreased vasoconstriction, increased dilator prostanoid function). Conversely, in older RS, detrimental effects of estrogen begin to be manifested (enhanced vasoconstriction and CP function). These findings may lead to age-specific estrogen replacement therapies that maximize beneficial and minimize detrimental effects of this hormone on small cerebral arteries that regulate blood flow. PMID:26993224

An In-Depth Comparison of Latency-Reversing Agent Combinations in Various In Vitro and Ex Vivo HIV-1 Latency Models Identified Bryostatin-1+JQ1 and Ingenol-B+JQ1 to Potently Reactivate Viral Gene Expression.

PubMed

Darcis, Gilles; Kula, Anna; Bouchat, Sophie; Fujinaga, Koh; Corazza, Francis; Ait-Ammar, Amina; Delacourt, Nadège; Melard, Adeline; Kabeya, Kabamba; Vanhulle, Caroline; Van Driessche, Benoit; Gatot, Jean-Stéphane; Cherrier, Thomas; Pianowski, Luiz F; Gama, Lucio; Schwartz, Christian; Vila, Jorge; Burny, Arsène; Clumeck, Nathan; Moutschen, Michel; De Wit, Stéphane; Peterlin, B Matija; Rouzioux, Christine; Rohr, Olivier; Van Lint, Carine

2015-07-01

The persistence of latently infected cells in patients under combinatory antiretroviral therapy (cART) is a major hurdle to HIV-1 eradication. Strategies to purge these reservoirs are needed and activation of viral gene expression in latently infected cells is one promising strategy. Bromodomain and Extraterminal (BET) bromodomain inhibitors (BETi) are compounds able to reactivate latent proviruses in a positive transcription elongation factor b (P-TEFb)-dependent manner. In this study, we tested the reactivation potential of protein kinase C (PKC) agonists (prostratin, bryostatin-1 and ingenol-B), which are known to activate NF-κB signaling pathway as well as P-TEFb, used alone or in combination with P-TEFb-releasing agents (HMBA and BETi (JQ1, I-BET, I-BET151)). Using in vitro HIV-1 post-integration latency model cell lines of T-lymphoid and myeloid lineages, we demonstrated that PKC agonists and P-TEFb-releasing agents alone acted as potent latency-reversing agents (LRAs) and that their combinations led to synergistic activation of HIV-1 expression at the viral mRNA and protein levels. Mechanistically, combined treatments led to higher activations of P-TEFb and NF-κB than the corresponding individual drug treatments. Importantly, we observed in ex vivo cultures of CD8+-depleted PBMCs from 35 cART-treated HIV-1+ aviremic patients that the percentage of reactivated cultures following combinatory bryostatin-1+JQ1 treatment was identical to the percentage observed with anti-CD3+anti-CD28 antibodies positive control stimulation. Remarkably, in ex vivo cultures of resting CD4+ T cells isolated from 15 HIV-1+ cART-treated aviremic patients, the combinations bryostatin-1+JQ1 and ingenol-B+JQ1 released infectious viruses to levels similar to that obtained with the positive control stimulation. The potent effects of these two combination treatments were already detected 24 hours post-stimulation. These results constitute the first demonstration of LRA combinations exhibiting such a potent effect and represent a proof-of-concept for the co-administration of two different types of LRAs as a potential strategy to reduce the size of the latent HIV-1 reservoirs.

An In-Depth Comparison of Latency-Reversing Agent Combinations in Various In Vitro and Ex Vivo HIV-1 Latency Models Identified Bryostatin-1+JQ1 and Ingenol-B+JQ1 to Potently Reactivate Viral Gene Expression

PubMed Central

Bouchat, Sophie; Fujinaga, Koh; Corazza, Francis; Ait-Ammar, Amina; Delacourt, Nadège; Melard, Adeline; Kabeya, Kabamba; Vanhulle, Caroline; Van Driessche, Benoit; Gatot, Jean-Stéphane; Cherrier, Thomas; Pianowski, Luiz F.; Gama, Lucio; Schwartz, Christian; Vila, Jorge; Burny, Arsène; Clumeck, Nathan; Moutschen, Michel; De Wit, Stéphane; Peterlin, B. Matija; Rouzioux, Christine; Rohr, Olivier; Van Lint, Carine

2015-01-01

The persistence of latently infected cells in patients under combinatory antiretroviral therapy (cART) is a major hurdle to HIV-1 eradication. Strategies to purge these reservoirs are needed and activation of viral gene expression in latently infected cells is one promising strategy. Bromodomain and Extraterminal (BET) bromodomain inhibitors (BETi) are compounds able to reactivate latent proviruses in a positive transcription elongation factor b (P-TEFb)-dependent manner. In this study, we tested the reactivation potential of protein kinase C (PKC) agonists (prostratin, bryostatin-1 and ingenol-B), which are known to activate NF-κB signaling pathway as well as P-TEFb, used alone or in combination with P-TEFb-releasing agents (HMBA and BETi (JQ1, I-BET, I-BET151)). Using in vitro HIV-1 post-integration latency model cell lines of T-lymphoid and myeloid lineages, we demonstrated that PKC agonists and P-TEFb-releasing agents alone acted as potent latency-reversing agents (LRAs) and that their combinations led to synergistic activation of HIV-1 expression at the viral mRNA and protein levels. Mechanistically, combined treatments led to higher activations of P-TEFb and NF-κB than the corresponding individual drug treatments. Importantly, we observed in ex vivo cultures of CD8+-depleted PBMCs from 35 cART-treated HIV-1+ aviremic patients that the percentage of reactivated cultures following combinatory bryostatin-1+JQ1 treatment was identical to the percentage observed with anti-CD3+anti-CD28 antibodies positive control stimulation. Remarkably, in ex vivo cultures of resting CD4+ T cells isolated from 15 HIV-1+ cART-treated aviremic patients, the combinations bryostatin-1+JQ1 and ingenol-B+JQ1 released infectious viruses to levels similar to that obtained with the positive control stimulation. The potent effects of these two combination treatments were already detected 24 hours post-stimulation. These results constitute the first demonstration of LRA combinations exhibiting such a potent effect and represent a proof-of-concept for the co-administration of two different types of LRAs as a potential strategy to reduce the size of the latent HIV-1 reservoirs. PMID:26225566

U-937 Toxicity Testing of Lunar Dust Stimulant (JSC-1A-vf)

NASA Technical Reports Server (NTRS)

Bales, Kristyn; Hammond, Dianne; Wallace, William; Jeevarajan, Antony

2007-01-01

With NASA planning to extend the human presence to the moon by 2020, the dangers of the lunar environment must be assessed and appropriate countermeasures must be developed. Possible toxic effects of the lunar dust are of particular importance to human health because of the dust's chemical composition, reactivity, and small size. This project focuses on the toxicity of lunar dust stimulant (JSC-1A-vf), in both its active and passive forms, using U-937 human monocyte cells. Simulant was mechanically activated from its passive form by grinding, and its ability to produce hydroxyl radicals was determined. To test for toxicity, active and passivated simulant was diluted in media and applied to the cells for various time periods. Toxicity was then estimated using flow cytometry on the Guava Personal Cell Analysis system. Preliminary results suggest that passivated stimulant is slightly toxic, with an increase in toxicity for activated stimulant. Toxicity results may be affected by cell lysing behavior and quenching of hydroxyl radical production by the cell media.

Antioxidative characteristics and inhibition of alpha-melanocyte-stimulating hormone-stimulated melanogenesis of vanillin and vanillic acid from Origanum vulgare.

PubMed

Chou, Tzung-Han; Ding, Hsiou-Yu; Hung, Wei Jing; Liang, Chia-Hua

2010-08-01

The antioxidant activities of vanillin and vanillic acid isolated from Origanum vulgare are investigated. These compounds may serve as agents for antimelanogenesis. Vanillic acid is a stronger antioxidant than vanillin, in terms of free radical scavenging activity, reducing power and inhibition of lipid peroxidation. The inhibition of cellular reactive oxygen species (ROS) in H(2)O(2)-treated BNLCL2 cells by vanillic acid exceeds that of ascorbic acid (AA) or trolox. In B16F0 cells stimulated with alpha-melanocyte-stimulating hormone (alpha-MSH), vanillic acid reduced cellular tyrosinase activity, DOPA oxidase and melanin contents, as well as down-regulated expressions of melanocortin-1 receptor (MC1R), microphthalmia-associated transcription factor (MITF), tyrosinase, tyrosinase-related proteins 2 (TRP-2) and TRP-1. Vanillin did not express inhibition of tyrosinase activity. These results supported that vanillic acid is a significantly stronger antioxidant than vanillin and exhibited stronger antimelanogenesis performance because of the structural presence of the carboxyl group.

A computer vision-based system for monitoring Vojta therapy.

PubMed

Khan, Muhammad Hassan; Helsper, Julien; Farid, Muhammad Shahid; Grzegorzek, Marcin

2018-05-01

A neurological illness is t he disorder in human nervous system that can result in various diseases including the motor disabilities. Neurological disorders may affect the motor neurons, which are associated with skeletal muscles and control the body movement. Consequently, they introduce some diseases in the human e.g. cerebral palsy, spinal scoliosis, peripheral paralysis of arms/legs, hip joint dysplasia and various myopathies. Vojta therapy is considered a useful technique to treat the motor disabilities. In Vojta therapy, a specific stimulation is given to the patient's body to perform certain reflexive pattern movements which the patient is unable to perform in a normal manner. The repetition of stimulation ultimately brings forth the previously blocked connections between the spinal cord and the brain. After few therapy sessions, the patient can perform these movements without external stimulation. In this paper, we propose a computer vision-based system to monitor the correct movements of the patient during the therapy treatment using the RGBD data. The proposed framework works in three steps. In the first step, patient's body is automatically detected and segmented and two novel techniques are proposed for this purpose. In the second step, a multi-dimensional feature vector is computed to define various movements of patient's body during the therapy. In the final step, a multi-class support vector machine is used to classify these movements. The experimental evaluation carried out on the large captured dataset shows that the proposed system is highly useful in monitoring the patient's body movements during Vojta therapy. Copyright © 2018 Elsevier B.V. All rights reserved.

Novel, one-step synthesis of zwitterionic polymer nanoparticles via distillation-precipitation polymerization and its application for dye removal membrane.

PubMed

Ibrahim, G P Syed; Isloor, Arun M; Inamuddin; Asiri, Abdullah M; Ismail, Norafiqah; Ismail, Ahmed Fauzi; Ashraf, Ghulam Md

2017-11-21

In this work, poly(MBAAm-co-SBMA) zwitterionic polymer nanoparticles were synthesized in one-step via distillation-precipitation polymerization (DPP) and were characterized. [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide (SBMA) as monomer and N, N'-methylene bis(acrylamide) (MBAAm) as cross-linker are used for the synthesis of nanoparticles. As  far as our knowledge, this is the first such report on the synthesis of poly(MBAAm-co-SBMA) nanoparticles via DPP. The newly synthesized nanoparticles were further employed for the surface modification of polysulfone (PSF) hollow fiber membranes for dye removal. The modified hollow fiber membrane exhibited the improved permeability (56 L/ m 2 h bar) and dye removal (>98% of Reactive Black 5 and >80.7% of Reactive orange 16) with the high permeation of salts. Therefore, the as-prepared membrane can have potential application in textile and industrial wastewater treatment.

Sleep for cognitive enhancement.

PubMed

Diekelmann, Susanne

2014-01-01

Sleep is essential for effective cognitive functioning. Loosing even a few hours of sleep can have detrimental effects on a wide variety of cognitive processes such as attention, language, reasoning, decision making, learning and memory. While sleep is necessary to ensure normal healthy cognitive functioning, it can also enhance performance beyond the boundaries of the normal condition. This article discusses the enhancing potential of sleep, mainly focusing on the domain of learning and memory. Sleep is known to facilitate the consolidation of memories learned before sleep as well as the acquisition of new memories to be learned after sleep. According to a widely held model this beneficial effect of sleep relies on the neuronal reactivation of memories during sleep that is associated with sleep-specific brain oscillations (slow oscillations, spindles, ripples) as well as a characteristic neurotransmitter milieu. Recent research indicates that memory processing during sleep can be boosted by (i) cueing memory reactivation during sleep; (ii) stimulating sleep-specific brain oscillations; and (iii) targeting specific neurotransmitter systems pharmacologically. Olfactory and auditory cues can be used, for example, to increase reactivation of associated memories during post-learning sleep. Intensifying neocortical slow oscillations (the hallmark of slow wave sleep (SWS)) by electrical or auditory stimulation and modulating specific neurotransmitters such as noradrenaline and glutamate likewise facilitates memory processing during sleep. With this evidence in mind, this article concludes by discussing different methodological caveats and ethical issues that should be considered when thinking about using sleep for cognitive enhancement in everyday applications.

Sleep for cognitive enhancement

PubMed Central

Diekelmann, Susanne

2014-01-01

Sleep is essential for effective cognitive functioning. Loosing even a few hours of sleep can have detrimental effects on a wide variety of cognitive processes such as attention, language, reasoning, decision making, learning and memory. While sleep is necessary to ensure normal healthy cognitive functioning, it can also enhance performance beyond the boundaries of the normal condition. This article discusses the enhancing potential of sleep, mainly focusing on the domain of learning and memory. Sleep is known to facilitate the consolidation of memories learned before sleep as well as the acquisition of new memories to be learned after sleep. According to a widely held model this beneficial effect of sleep relies on the neuronal reactivation of memories during sleep that is associated with sleep-specific brain oscillations (slow oscillations, spindles, ripples) as well as a characteristic neurotransmitter milieu. Recent research indicates that memory processing during sleep can be boosted by (i) cueing memory reactivation during sleep; (ii) stimulating sleep-specific brain oscillations; and (iii) targeting specific neurotransmitter systems pharmacologically. Olfactory and auditory cues can be used, for example, to increase reactivation of associated memories during post-learning sleep. Intensifying neocortical slow oscillations (the hallmark of slow wave sleep (SWS)) by electrical or auditory stimulation and modulating specific neurotransmitters such as noradrenaline and glutamate likewise facilitates memory processing during sleep. With this evidence in mind, this article concludes by discussing different methodological caveats and ethical issues that should be considered when thinking about using sleep for cognitive enhancement in everyday applications. PMID:24765066

Thyrotropin Receptor Antibody (TRAb)-IgM Levels Are Markedly Higher Than TRAb-IgG Levels in Graves' Disease Patients and Controls, and TRAb-IgM Production Is Related to Epstein-Barr Virus Reactivation.

PubMed

Kumata, Keisuke; Nagata, Keiko; Matsushita, Michiko; Kuwamoto, Satoshi; Kato, Masako; Murakami, Ichiro; Fukata, Shuji; Hayashi, Kazuhiko

2016-10-01

Graves' disease is an autoimmune thyroid disorder that mainly presents as hyperthyroidism and is caused by thyrotropin receptor antibodies (TRAbs) that stimulate thyroid-stimulating hormone receptors. We previously reported that Graves' disease patients and healthy controls both had Epstein-Barr virus (EBV)-infected TRAb-positive B cells and the EBV-reactivated induction of these B cells in cultures may induce the production of TRAbs. In the present study, we quantified serum TRAb-IgG and TRAb-IgM levels in 34 Graves' disease patients and 15 controls using ELISA to elucidate the mechanisms underlying EBV-related antibody production. As expected, TRAb-IgG and TRAb-IgM levels were higher in Graves' disease patients than in controls; however, TRAb-IgM levels were significantly higher than those of TRAb-IgG levels, whereas total IgM levels were lower than total IgG levels. On the other hand, the enhanced production of TRAb-IgM was frequently observed in patients with EBV reactivation. These results are consistent with the fact that the percentage of autoreactive IgM B cells are higher than that of autoreactive IgG B cells, and support the EBV-related polyclonal B cell activation. It is necessary to clarify the biological characteristics of TRAb-IgM and the relationship between TRAb isotypes and the biology of Graves' disease.

Tiled Microarray Identification of Novel Viral Transcript Structures and Distinct Transcriptional Profiles during Two Modes of Productive Murine Gammaherpesvirus 68 Infection

PubMed Central

Cheng, Benson Yee Hin; Zhi, Jizu; Santana, Alexis; Khan, Sohail; Salinas, Eduardo; Forrest, J. Craig; Zheng, Yueting; Jaggi, Shirin; Leatherwood, Janet

2012-01-01

We applied a custom tiled microarray to examine murine gammaherpesvirus 68 (MHV68) polyadenylated transcript expression in a time course of de novo infection of fibroblast cells and following phorbol ester-mediated reactivation from a latently infected B cell line. During de novo infection, all open reading frames (ORFs) were transcribed and clustered into four major temporal groups that were overlapping yet distinct from clusters based on the phorbol ester-stimulated B cell reactivation time course. High-density transcript analysis at 2-h intervals during de novo infection mapped gene boundaries with a 20-nucleotide resolution, including a previously undefined ORF73 transcript and the MHV68 ORF63 homolog of Kaposi's sarcoma-associated herpesvirus vNLRP1. ORF6 transcript initiation was mapped by tiled array and confirmed by 5′ rapid amplification of cDNA ends. The ∼1.3-kb region upstream of ORF6 was responsive to lytic infection and MHV68 RTA, identifying a novel RTA-responsive promoter. Transcription in intergenic regions consistent with the previously defined expressed genomic regions was detected during both types of productive infection. We conclude that the MHV68 transcriptome is dynamic and distinct during de novo fibroblast infection and upon phorbol ester-stimulated B cell reactivation, highlighting the need to evaluate further transcript structure and the context-dependent molecular events that govern viral gene expression during chronic infection. PMID:22318145

Reactivity of rolandic spikes.

PubMed

Fonseca, L C; Tedrus, G M; Bastos, A; Bosco, A; Laloni, D T

1996-07-01

Factors influencing the frequency of rolandic spikes are rarely reported. We examined the influence of movement, tactile stimulation and cognitive test on the discharge rate of rolandic spikes. We studied 35 children with EEG rolandic spikes. Eighteen children had nonfebrile convulsions. Benign childhood epilepsy with centrotemporal spikes was diagnosed in 12 cases. Testing during the EEG included hand and tongue movements, cognitive tasks and tactile stimulation of face and hands. Rolandic spikes were counted by visual analysis in each phase of the test and the frequency expressed as mean number per min. During tongue movements there was a significantly lower discharge rate when compared to previous and subsequent rest phases. For the left hemisphere there was reduction in discharge rate during right hand movements and looking at colored spots but only when compared with the previous rest phase. The reduction in mean number of spikes/min by tongue movements occurred in patients with and without epilepsy. For patients with cerebral lesion the decrease in discharge rate during tongue movements was not significant whereas for those without cerebral lesion a significant reduction was evident. A decrease in the mean number of spikes/min of 50% or more was significantly more frequent among 29 patients without than among 6 patients with cerebral lesion. Our study showed the inhibition of rolandic spikes by tongue movements confirming the hypothesis that the localization of discharges is an important factor in determining its reactivity. The presence or not of cerebral lesion may be an important factor in the degree of reactivity.

MicroRNA-211/BDNF axis regulates LPS-induced proliferation of normal human astrocyte through PI3K/AKT pathway

PubMed Central

Zhang, Kexiang; Wu, Song; Li, Zhiyue

2017-01-01

Spinal cord injury (SCI) makes a major contribution to disability and deaths worldwide. Reactive astrogliosis, a typical feature after SCI, which undergoes varying molecular and morphological changes, is ubiquitous but poorly understood. Reactive astrogliosis contributes to glial scar formation that impedes axonal regeneration. Brain-derived neurotrophic factor (BDNF), a well-established neurotrophic factor, exerts neuroprotective and growth-promoting effects on a variety of neuronal populations after injury. In the present study, by using LPS-induced in vitro injury model of astroglial cultures, we observed a high expression of interleukin (IL)-6, IL-1β, and BDNF in LPS-stimulated normal human astrocytes (NHAs). BDNF significantly promoted NHA proliferation. Further, online tools were employed to screen the candidate miRNAs which might directly target BDNF to inhibit its expression. Amongst the candidate miRNAs, miR-211 expression was down-regulated by LPS stimulation in a dose-dependent manner. Through direct targetting, miR-211 inhibited BDNF expression. Ectopic miR-211 expression significantly suppressed NHA proliferation, as well as LPS-induced activation of PI3K/Akt pathway. In contrast, inhibition of miR-211 expression significantly promoted NHA proliferation and LPS-induced activation of PI3K/Akt pathway. Taken together, miR-211/BDNF axis regulates LPS-induced NHA proliferation through PI3K/AKT pathway; miR-211/BDNF might serve as a promising target in the strategy against reactive astrocyte proliferation after SCI. PMID:28790168

Multiprofessional education to stimulate collaboration: a circular argument and its consequences

PubMed Central

Roodbol, Petrie F.

2010-01-01

The current developments in healthcare are unprecedented. The organization of health care is complex. Collaboration is essential to meet all the healthcare needs of patients and to achieve coordinated and unambiguous information. Multiprofessional education (MPE) or multidisciplinary training (MDT) seems a logical step to stimulate teamwork. However, collaboration and MPE are wrestling with the same problems: social identity and acceptance. PMID:21818197

Computationally optimized ECoG stimulation with local safety constraints.

PubMed

Guler, Seyhmus; Dannhauer, Moritz; Roig-Solvas, Biel; Gkogkidis, Alexis; Macleod, Rob; Ball, Tonio; Ojemann, Jeffrey G; Brooks, Dana H

2018-06-01

Direct stimulation of the cortical surface is used clinically for cortical mapping and modulation of local activity. Future applications of cortical modulation and brain-computer interfaces may also use cortical stimulation methods. One common method to deliver current is through electrocorticography (ECoG) stimulation in which a dense array of electrodes are placed subdurally or epidurally to stimulate the cortex. However, proximity to cortical tissue limits the amount of current that can be delivered safely. It may be desirable to deliver higher current to a specific local region of interest (ROI) while limiting current to other local areas more stringently than is guaranteed by global safety limits. Two commonly used global safety constraints bound the total injected current and individual electrode currents. However, these two sets of constraints may not be sufficient to prevent high current density locally (hot-spots). In this work, we propose an efficient approach that prevents current density hot-spots in the entire brain while optimizing ECoG stimulus patterns for targeted stimulation. Specifically, we maximize the current along a particular desired directional field in the ROI while respecting three safety constraints: one on the total injected current, one on individual electrode currents, and the third on the local current density magnitude in the brain. This third set of constraints creates a computational barrier due to the huge number of constraints needed to bound the current density at every point in the entire brain. We overcome this barrier by adopting an efficient two-step approach. In the first step, the proposed method identifies the safe brain region, which cannot contain any hot-spots solely based on the global bounds on total injected current and individual electrode currents. In the second step, the proposed algorithm iteratively adjusts the stimulus pattern to arrive at a solution that exhibits no hot-spots in the remaining brain. We report on simulations on a realistic finite element (FE) head model with five anatomical ROIs and two desired directional fields. We also report on the effect of ROI depth and desired directional field on the focality of the stimulation. Finally, we provide an analysis of optimization runtime as a function of different safety and modeling parameters. Our results suggest that optimized stimulus patterns tend to differ from those used in clinical practice. Copyright © 2018 Elsevier Inc. All rights reserved.

Reservoir response to thermal and high-pressure well stimulation efforts at Raft River, Idaho

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

Plummer, Mitchell; Bradford, Jacob; Moore, Joseph

An injection stimulation test begun at the Raft River geothermal reservoir in June, 2013 has produced a wealth of data describing well and reservoir response via high-resolution temperature logging and distributed temperature sensing, seismic monitoring, periodic borehole televiewer logging, periodic stepped flow rate tests and tracer injections before and after stimulation efforts. One of the primary measures of response to the stimulation is the relationship between fluid pressure and flow rate, short-term during forced flow rate changes and the long-term change in injectivity. In this paper we examine that hydraulic response using standard pumping test analysis methods, largely because pressuremore » response to the stimulation was not detected, or measurable, in other wells. Analysis of stepped rate flow tests supports the inference from other data that a large fracture, with a radial extent of one to several meters, intersects the well in the target reservoir, suggests that the flow regime is radial to a distance of only several meters and demonstrates that the pressure build-up cone reaches an effective constant head at that distance. The well’s longer term hydraulic response demonstrated continually increasing injectivity but at a dramatically faster rate later from ~2 years out and continuing to the present. The net change in injectivity is significantly greater than observed in other longterm injectivity monitoring studies, with an approximately 150–fold increase occurring over ~2.5 years. While gradually increasing injectivity is a likely consequence of slow migration of a cooling front, and consequent dilation of fractures, the steady, ongoing, rate of increase is contrary to what would be expected in a radial or linear flow regime, where the cooling front would slow with time. As a result, occasional step-like changes in injectivity, immediately following high-flow rate tests suggest that hydro shearing during high-pressure testing altered the near-well permeability structure.« less

NASA Glenn's Engine Components Research Lab, Cell 2B, Reactivated to Support the U.S. Army Research Laboratory T700 Engine Test

NASA Technical Reports Server (NTRS)

Beltran, Luis R.; Griffin, Thomas A.

2004-01-01

The U.S. Army Vehicle Technology Directorate at the NASA Glenn Research Center has been directed by their parent command, the U.S. Army Research Laboratory (ARL), to demonstrate active stall technology in a turboshaft engine as the next step in transitioning this technology to the Army and aerospace industry. Therefore, the Vehicle Technology Directorate requested the reactivation of Glenn's Engine Components Research Lab, Cell 2B, (ECRL 2B). They wanted to test a T700 engine that had been used previously for turboshaft engine research as a partnership between the Army and NASA on small turbine engine research. ECRL 2B had been placed in standby mode in 1997. Glenn's Testing Division initiated reactivation in May 2002 to support the new research effort, and they completed reactivation and improvements in September 2003.

Transcriptome Wide Annotation of Eukaryotic RNase III Reactivity and Degradation Signals

PubMed Central

Gagnon, Jules; Lavoie, Mathieu; Catala, Mathieu; Malenfant, Francis; Elela, Sherif Abou

2015-01-01

Detection and validation of the RNA degradation signals controlling transcriptome stability are essential steps for understanding how cells regulate gene expression. Here we present complete genomic and biochemical annotations of the signals required for RNA degradation by the dsRNA specific ribonuclease III (Rnt1p) and examine its impact on transcriptome expression. Rnt1p cleavage signals are randomly distributed in the yeast genome, and encompass a wide variety of sequences, indicating that transcriptome stability is not determined by the recurrence of a fixed cleavage motif. Instead, RNA reactivity is defined by the sequence and structural context in which the cleavage sites are located. Reactive signals are often associated with transiently expressed genes, and their impact on RNA expression is linked to growth conditions. Together, the data suggest that Rnt1p reactivity is triggered by malleable RNA degradation signals that permit dynamic response to changes in growth conditions. PMID:25680180

Carbohydrates as allergens.

PubMed

Commins, Scott P

2015-01-01

Complex carbohydrates are effective inducers of Th2 responses, and carbohydrate antigens can stimulate the production of glycan-specific antibodies. In instances where the antigen exposure occurs through the skin, the resulting antibody production can contain IgE class antibody. The glycan-stimulated IgE may be non-specific but may also be antigen specific. This review focuses on the production of cross-reactive carbohydrate determinants, the recently identified IgE antibody response to a mammalian oligosaccharide epitope, galactose-alpha-1,3-galactose (alpha-gal), as well as discusses practical implications of carbohydrates in allergy. In addition, the biological effects of carbohydrate antigens are reviewed in setting of receptors and host recognition.

Transcriptome analysis of Aspergillus flavus reveals isolate specific gene profiles in the response to oxidative stresses and carbon sources in vitro

USDA-ARS?s Scientific Manuscript database

Aflatoxin contamination of peanut and maize is exacerbated by drought stress. Reactive oxygen species (ROS) are produced in host plants during drought/heat stress, and are hypothesized to stimulate aflatoxin production. In order to better understand why Aspergillus flavus produces aflatoxin and the ...

Development and characterization of mouse monoclonal antibodies reactive with chicken CD80

USDA-ARS?s Scientific Manuscript database

CD80 is one of the ligands for CD28 and is an important co-stimulator molecule on antigen presenting cells necessary for T-cell activation. Although CD80 is well characterized in human, swine, ovine, feline, and canine species, there is no information on its chicken counterpart. This study was car...

In vitro characterization of cutaneous immunotoxicity of immortalized human keratinocytes (HaCaT) exposed to reactive and disperse textile dyes.

PubMed

Leme, Daniela Morais; Sehr, Andrea; Grummt, Tamara; Gonçalves, Jenifer Pendiuk; Jacomasso, Thiago; Winnischofer, Sheila Maria Brochado; Potrich, Francine Bittencourt; Oliveira, Carolina Camargo de; Trindade, Edvaldo da Silva; de Oliveira, Danielle Palma

2018-05-01

Several synthetic dyes are used by textile industry for supplying the market of colored clothes. However, these chemicals have been associated with a variety of adverse human health effects, including textile dermatitis. Thus, there is a growing concern to identify textile dyes potentially as skin immunotoxicants. The aim of this in vitro study was to characterize the immunotoxic potential of reactive (Reactive Green 19 [RG19], Reactive Blue 2 [RB2], Reactive Black 5 [RB5]) and disperse (Disperse Red 1 [DR1]) textile dyes using a dermal cell line. For this purpose, a cell-based approach was conducted with immortalized human keratinocytes (KC) (HaCaT) using selected biomarkers of cutaneous inflammation including modulation of matrix metalloproteinases (MMP), oxidative stress such as reactive oxygen species (ROS) generation, and inflammatory cytokine profile. DR1 was the only dye able to trigger an immune response such as release of IL-12 cytokine, a potent co-stimulator of T helper 1 cell, which may be considered as a skin immunotoxicant. The reactive dyes including RB5 that were previously reported as skin sensitizers failed to induce inflammatory reactions under the conditions tested. The reactive dyes studied may pose a risk to human KC by induction of effects related to modulation of MMP-2 (RB5) and -9 (RB5 and RB2) and generation of ROS (RG19 and RB2). Thus, all these dyes need to be used with caution to avoid undesirable effects to consumers who may be exposed dermally.

Randomized controlled trial comparing impact on platelet reactivity of twice-daily with once-daily aspirin in people with Type 2 diabetes.

PubMed

Bethel, M A; Harrison, P; Sourij, H; Sun, Y; Tucker, L; Kennedy, I; White, S; Hill, L; Oulhaj, A; Coleman, R L; Holman, R R

2016-02-01

Reduced aspirin efficacy has been demonstrated in people with Type 2 diabetes. Because increased platelet reactivity and/or turnover are postulated mechanisms, we examined whether higher and/or more frequent aspirin dosing might reduce platelet reactivity more effectively. Participants with Type 2 diabetes (n = 24) but without known cardiovascular disease were randomized in a three-way crossover design to 2-week treatment periods with aspirin 100 mg once daily, 200 mg once daily or 100 mg twice daily. The primary outcome was platelet reactivity, assessed using the VerifyNow(™) ASA method. Relationships between platelet reactivity and aspirin dosing were examined using generalized linear mixed models with random subject effects. Platelet reactivity decreased from baseline with all doses of aspirin. Modelled platelet reactivity was more effectively reduced with aspirin 100 mg twice daily vs. 100 mg once daily, but not vs. 200 mg once daily. Aspirin 200 mg once daily did not differ from 100 mg once daily. Aspirin 100 mg twice daily was also more effective than once daily as measured by collagen/epinephrine-stimulated platelet aggregation and urinary thromboxane levels, with a similar trend measured by serum thromboxane levels. No episodes of bleeding occurred. In Type 2 diabetes, aspirin 100 mg twice daily reduced platelet reactivity more effectively than 100 mg once daily, and numerically more than 200 mg once daily. Clinical outcome trials evaluating primary cardiovascular disease prevention with aspirin in Type 2 diabetes may need to consider using a more frequent dosing schedule. © 2015 The Authors. Diabetic Medicine © 2015 Diabetes UK.

Does aging with a cortical lesion increase fall-risk: Examining effect of age versus stroke on intensity modulation of reactive balance responses from slip-like perturbations.

PubMed

Patel, Prakruti J; Bhatt, Tanvi

2016-10-01

We examined whether aging with and without a cerebral lesion such as stroke affects modulation of reactive balance response for recovery from increasing intensity of sudden slip-like stance perturbations. Ten young adults, older age-match adults and older chronic stroke survivors were exposed to three different levels of slip-like perturbations, level 1 (7.75m/s(2)), Level II (12.00m/s(2)) and level III (16.75m/s(2)) in stance. The center of mass (COM) state stability was computed as the shortest distance of the instantaneous COM position and velocity relative to base of support (BOS) from a theoretical threshold for backward loss of balance (BLOB). The COM position (XCOM/BOS) and velocity (ẊCOM/BOS) relative to BOS at compensatory step touchdown, compensatory step length and trunk angle at touchdown were also recorded. At liftoff, stability reduced with increasing perturbation intensity across all groups (main effect of intensity p<0.05). At touchdown, while the young group showed a linear improvement in stability with increasing perturbation intensity, such a trend was absent in other groups (intensity×group interaction, p<0.05). Between-group differences in stability at touchdown were thus observed at levels II and III. Further, greater stability at touchdown positively correlated with anterior XCOM/BOS however not with ẊCOM/BOS. Young adults maintained anterior XCOM/BOS by increasing compensatory step length and preventing greater trunk extension at higher perturbation intensities. The age-match group attempted to increase step length from intensity I to II to maintain stability however could not further increase step length at intensity III, resulting in lower stability on this level compared with the young group. Stroke group on the other hand was unable to modulate compensatory step length or control trunk extension at higher perturbation intensities resulting in reduced stability on levels II and III compared with the other groups. The findings reflect impaired modulation of recovery response with increasing intensity of sudden perturbations among stroke survivors compared with their healthy counter parts. Thus, aging superimposed with a cortical lesion could further impair reactive balance control, potentially contributing toward a higher fall risk in older stroke survivors. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Specificity of EIA immunoassay for complement factor Bb testing.

PubMed

Pavlov, Igor Y; De Forest, Nikol; Delgado, Julio C

2011-01-01

During the alternative complement pathway activation, factor B is cleaved in two fragments, Ba and Bb. Concentration of those fragments is about 2 logs lower than of factor B present in the blood, which makes fragment detection challenging because of potential cross-reactivity. Lack of information on Bb assay cross-reactivity stimulated the authors to investigate this issue. We ran 109 healthy donor EDTA plasmas and 80 sera samples with both factor B immunodiffusion (The Binding Site) and Quidel Bb EIA assays. During the study it was shown that physiological concentrations of gently purified factor B demonstrated approximately 0.15% cross-reactivity in the Quidel Bb EIA assay. We also observed that Bb concentration in serum is higher than in plasma due to complement activation during clot formation which let us use sera as samples representing complement activated state. Our study demonstrated that despite the potential 0.15% cross-reactivity between endogenous factor B and cleaved Bb molecule, measuring plasma concentrations of factor Bb is adequate to evaluate the activation of the alternative complement pathway.

Synthesis, chemical reactivity as Michael acceptors, and biological potency of monocyclic cyanoenones, novel and highly potent anti-inflammatory and cytoprotective agents.

PubMed

Zheng, Suqing; Santosh Laxmi, Y R; David, Emilie; Dinkova-Kostova, Albena T; Shiavoni, Katherine H; Ren, Yanqing; Zheng, Ying; Trevino, Isaac; Bumeister, Ronald; Ojima, Iwao; Wigley, W Christian; Bliska, James B; Mierke, Dale F; Honda, Tadashi

2012-05-24

Novel monocyclic cyanoenones examined to date display unique features regarding chemical reactivity as Michael acceptors and biological potency. Remarkably, in some biological assays, the simple structure is more potent than pentacyclic triterpenoids (e.g., CDDO and bardoxolone methyl) and tricycles (e.g., TBE-31). Among monocyclic cyanoenones, 1 is a highly reactive Michael acceptor with thiol nucleophiles. Furthermore, an important feature of 1 is that its Michael addition is reversible. For the inhibition of NO production, 1 shows the highest potency. Notably, its potency is about three times higher than CDDO, whose methyl ester (bardoxolone methyl) is presently in phase III clinical trials. For the induction of NQO1, 1 also demonstrated the highest potency. These results suggest that the reactivity of these Michael acceptors is closely related to their biological potency. Interestingly, in LPS-stimulated macrophages, 1 causes apoptosis and inhibits secretion of TNF-α and IL-1β with potencies that are higher than those of bardoxolone methyl and TBE-31.

A patient with cerebral Whipple disease with gastric involvement but no gastrointestinal symptoms: a consequence of local protective immunity?

PubMed Central

Prüss, Harald; Katchanov, Juri; Zschenderlein, Rolf; Loddenkemper, Christoph; Schneider, Thomas; Moos, Verena

2007-01-01

Whipple disease is a granulomatous infectious disease caused by Tropheryma whipplei. The bacteria accumulate within macrophages, preferentially in the intestinal mucosa. Disease manifestation seems to be linked to immunological abnormalities of macrophages. We describe a patient with cerebral Whipple disease who presented with changes in mental status, confusion, inverse sleep–wake cycle, bilateral ptosis and vertical gaze palsy. Endoscopic biopsy sampling revealed Whipple disease in the gastric antrum but not in the duodenum. Whole blood stimulation displayed reactivity to T whipplei that was at the lower end of healthy controls while reactivity of duodenal lymphocytes was not diminished. We propose that in cases of neurological symptoms suspicious of Whipple disease with normal duodenal and jenunal findings, biopsy sampling should be extended to the gastric mucosa. The robust reactivity of duodenal lymphocytes may have prevented our patient from developing small bowel disease, whereas the impaired reactivity in peripheral blood lymphocytes might yet explain the bacterial spreading to the central nervous system leading to the rare case of predominant neurological symptoms without relevant systemic involvement. PMID:17371903

[Hypertension, cardiovascular reactivity to stress and sensibility to pain].

PubMed

Conde-Guzón, P A; Bartolomé-Albistegui, M T; Quirós-Expósito, P; Grzib-Schlosky, G

To provide a review of empirical evidence of decreased pain perception in hypertensive persons or exaggerated cardiovascular reactivity to stress. To following article will briefly review the existing literature on the association between hypoalgesia and high blood pressure. In particular, evidence of hypoalgesia in normotensive individuals at increased risk for hypertension (exaggerated cardiovascular reactivity to stress) will be offered in support of the notion that high cardiovascular reactivity to stress and decreased pain perception may result from a common physiological dysfunction. Cardiovascular reactivity refers to changes in cardiovascular activity associated primarily with exposure to psychological stress. Different individuals show different amounts of reactivity under the same conditions. The greater cardiovascular reactivity to behavioral stressors may play some role in the development of sustained arterial hypertension. Central opioid hyposensitivity is hypothesized as a mechanism of both hypoalgesia and exaggerated autonomic and neuroendocrine responses to stress in individuals at risk for hypertension. The paraventricular nucleus of the hypothalamus (PVN) serves the crucial function of integrating cardiovascular and painful responses. The central opioid hyposensitivity model of hypoalgesia asserts that attenuation of inhibitory opioid input to the PVN may have important consequences for pain modulation. These consequences includes: 1) greater activation of baroreceptor reflex arcs, 2) enhanced release of endogenous opioids during stress, and 3) increased stimulation of descending pain modulation pathways. High elevated thresholds to painful thermal stressors might serve as a behavioral marker of risk for hypertension before the onset of high blood pressure levels.

Stimulant Use and HIV Risk Behavior: The Influence of Peer Support Group Participation

ERIC Educational Resources Information Center

Lyons, Thomas; Chandra, Gopika; Goldstein, Jerome

2006-01-01

This study examines 12-step groups for recovery from methamphetamine and cocaine use that are attended by men having sex with men and the impact of attendance on HIV risk behavior. Participants in Crystal Meth Anonymous and other 12-step groups were interviewed up to 3 months since their last substance use. Sixty-two initial interviews, and…

Evaluation of a Problem Based Learning Curriculum Using Content Analysis

ERIC Educational Resources Information Center

Prihatiningsih, Titi Savitri; Qomariyah, Nurul

2016-01-01

Faculty of Medicine UGM has implemented Problem Based Learning (PBL) since 1985. Seven jump tutorial discussions are applied. A scenario is used as a trigger to stimulate students to identify learning objectives (LOs) in step five which are used as the basis for self study in step six. For each scenario, the Block Team formulates the LOs which are…

In vivo and T cell cross-reactivity between walnut, cashew and peanut.

PubMed

Kulis, Michael; Pons, Laurent; Burks, A Wesley

2009-01-01

Examination of IgE cross-reactivity among nuts has been limited to in vitro experiments. Cross-reactivity studies of nuts at the T cell level are difficult to interpret because of the inability to determine which cellular responses are from a true sensitization and which are due to cross-reactivity. Using a mouse model in which the sensitizing nuts are controlled may provide novel methods to investigate in vivo and T cell cross-reactivity. C3H/HeJ mice were sensitized by intraperitoneal injection of cashew alone (monosensitized mice), or cashew plus walnut, utilizing alum as an adjuvant. Both groups underwent challenges to cashew, walnut and peanut, with subsequent monitoring of anaphylactic reactions. Anaphylactic antibodies were quantified by ELISA, and protein allergens were identified by Western blotting. Cellular responses were studied via splenocyte proliferation assay and measurement of secreted cytokines. The monosensitized mice reacted to cashew and walnut during challenges, with significantly weaker reactions induced on challenge with peanut. Cross-reactive IgE to walnut and peanut were detected by ELISA, and the cross-reactive allergens were identified as vicilin proteins. In cellular assays, splenocytes from the monosensitized mice proliferated and produced IL-4 and IL-5 in response to cashew, walnut and peanut. The cashew- plus walnut-sensitized mice experienced stronger clinical reactions to walnut, recognized additional walnut allergens and secreted significantly more IL-4 and IL-5 in walnut-stimulated splenocyte assays compared to the monosensitized mice. Cross-reactivity in vivo was found between cashew and walnut, while cross-reactivity among cashew, walnut and peanut was demonstrated at the T cell level. Copyright 2008 S. Karger AG, Basel.

Effects of obesity on lung function and airway reactivity in healthy dogs.

PubMed

Manens, J; Bolognin, M; Bernaerts, F; Diez, M; Kirschvink, N; Clercx, C

2012-07-01

The present study investigated the effects of bodyweight (BW) gain on respiratory function and airway responsiveness in healthy Beagles using barometric whole body plethysmography (BWBP). Six adult dogs were examined before and after a fattening diet. The high-energy diet induced a mean increase in BW of 41±6%. BWBP basal parameters were recorded prior to airway reactivity testing (using increasing concentrations of histamine nebulisations). An airway responsiveness index (H-Penh300) was calculated as the histamine concentration necessary to reach 300% of basal enhanced pause (Penh, bronchoconstriction index). The same dogs underwent a doxapram hydrochloride (Dxp) stimulation testing 2 weeks later. Basal measurements showed that obese dogs had tidal volume per kg (TV/BW) that was significantly decreased whilst respiratory rate (RR) increased significantly. H-Penh300 decreased significantly in obese Beagles, indicating increased bronchoreactivity. Dxp administration induced a significant increase in TV/BW, minute volume per kg (MV/BW), peak inspiratory and expiratory flows per kg (PIF/BW and PEF/BW) in both normal and obese dogs although the TV/BW increase was significantly less marked in the obese group. In conclusion, obesity induced changes in basal respiratory parameters, increased bronchoreactivity and a blunted response to Dxp-induced respiratory stimulation. This combination of basal respiratory parameters, bronchoreactivity testing and pharmacological stimulation testing using non-invasive BWBP can help characterize pulmonary function and airway responsiveness in obese dogs. Copyright © 2011 Elsevier Ltd. All rights reserved.

Reactive oxygen species as a signal in glucose-stimulated insulin secretion.

PubMed

Pi, Jingbo; Bai, Yushi; Zhang, Qiang; Wong, Victoria; Floering, Lisa M; Daniel, Kiefer; Reece, Jeffrey M; Deeney, Jude T; Andersen, Melvin E; Corkey, Barbara E; Collins, Sheila

2007-07-01

One of the unique features of beta-cells is their relatively low expression of many antioxidant enzymes. This could render beta-cells susceptible to oxidative damage but may also provide a system that is sensitive to reactive oxygen species as signals. In isolated mouse islets and INS-1(832/13) cells, glucose increases intracellular accumulation of H2O2. In both models, insulin secretion could be stimulated by provision of either exogenous H2O2 or diethyl maleate, which raises intracellular H2O2 levels. Provision of exogenous H2O2 scavengers, including cell permeable catalase and N-acetyl-L-cysteine, inhibited glucose-stimulated H2O2 accumulation and insulin secretion (GSIS). In contrast, cell permeable superoxide dismutase, which metabolizes superoxide into H2O2, had no effect on GSIS. Because oxidative stress is an important risk factor for beta-cell dysfunction in diabetes, the relationship between glucose-induced H2O2 generation and GSIS was investigated under various oxidative stress conditions. Acute exposure of isolated mouse islets or INS-1(832/13) cells to oxidative stressors, including arsenite, 4-hydroxynonenal, and methylglyoxal, led to decreased GSIS. This impaired GSIS was associated with increases in a battery of endogenous antioxidant enzymes. Taken together, these findings suggest that H2O2 derived from glucose metabolism is one of the metabolic signals for insulin secretion, whereas oxidative stress may disturb its signaling function.

Understanding the mechanisms of solid-water reactions through analysis of surface topography.

PubMed

Bandstra, Joel Z; Brantley, Susan L

2015-12-01

The topography of a reactive surface contains information about the reactions that form or modify the surface and, therefore, it should be possible to characterize reactivity using topography parameters such as surface area, roughness, or fractal dimension. As a test of this idea, we consider a two-dimensional (2D) lattice model for crystal dissolution and examine a suite of topography parameters to determine which may be useful for predicting rates and mechanisms of dissolution. The model is based on the assumption that the reactivity of a surface site decreases with the number of nearest neighbors. We show that the steady-state surface topography in our model system is a function of, at most, two variables: the ratio of the rate of loss of sites with two neighbors versus three neighbors (d(2)/d(3)) and the ratio of the rate of loss of sites with one neighbor versus three neighbors (d(1)/d(3)). This means that relative rates can be determined from two parameters characterizing the topography of a surface provided that the two parameters are independent of one another. It also means that absolute rates cannot be determined from measurements of surface topography alone. To identify independent sets of topography parameters, we simulated surfaces from a broad range of d(1)/d(3) and d(2)/d(3) and computed a suite of common topography parameters for each surface. Our results indicate that the fractal dimension D and the average spacing between steps, E[s], can serve to uniquely determine d(1)/d(3) and d(2)/d(3) provided that sufficiently strong correlations exist between the steps. Sufficiently strong correlations exist in our model system when D>1.5 (which corresponds to D>2.5 for real 3D reactive surfaces). When steps are uncorrelated, surface topography becomes independent of step retreat rate and D is equal to 1.5. Under these conditions, measures of surface topography are not independent and any single topography parameter contains all of the available mechanistic information about the surface. Our results also indicate that root-mean-square roughness cannot be used to reliably characterize the surface topography of fractal surfaces because it is an inherently noisy parameter for such surfaces with the scale of the noise being independent of length scale.

Kinetics of dissolution of UO2 in nitric acid solutions: A multiparametric study of the non-catalysed reaction

NASA Astrophysics Data System (ADS)

Cordara, T.; Szenknect, S.; Claparede, L.; Podor, R.; Mesbah, A.; Lavalette, C.; Dacheux, N.

2017-12-01

UO2 pellets were prepared by densification of oxides obtained from the conversion of the oxalate precursor. Then characterized in order to perform a multiparametric study of the dissolution in nitric acid medium. In this frame, for each sample, the densification rate, the grain size and the specific surface area of the prepared pellets were determined prior to the final dissolution experiments. By varying the concentration of the nitric acid solution and temperature, three different and successive steps were identified during the dissolution. Under the less aggressive conditions considered, a first transient step corresponding to the dissolution of the most reactive phases was observed at the solid/solution interface. Then, for all the tested conditions, a steady state step was established during which the normalised dissolution rate was found to be constant. It was followed by a third step characterized by a strong and continuous increase of the normalised dissolution rate. The duration of the steady state, also called "induction period", was found to vary drastically as a function of the HNO3 concentration and temperature. However, independently of the conditions, this steady state step stopped at almost similar dissolved material weight loss and dissolved uranium concentration. During the induction period, no important evolution of the topology of the solid/liquid interface was evidenced authorizing the use of the starting reactive specific surface area to evaluate the normalised dissolution rates thus the chemical durability of the sintered pellets. From the multiparametric study of UO2 dissolution proposed, oxidation of U(IV) to U(VI) by nitrate ions at the solid/liquid interface constitutes the limiting step in the overall dissolution mechanism associated to this induction period.

Volcanic Ash Activates the NLRP3 Inflammasome in Murine and Human Macrophages.

PubMed

Damby, David E; Horwell, Claire J; Baxter, Peter J; Kueppers, Ulrich; Schnurr, Max; Dingwell, Donald B; Duewell, Peter

2017-01-01

Volcanic ash is a heterogeneous mineral dust that is typically composed of a mixture of amorphous (glass) and crystalline (mineral) fragments. It commonly contains an abundance of the crystalline silica (SiO 2 ) polymorph cristobalite. Inhalation of crystalline silica can induce inflammation by stimulating the NLRP3 inflammasome, a cytosolic receptor complex that plays a critical role in driving inflammatory immune responses. Ingested material results in the assembly of NLRP3, ASC, and caspase-1 with subsequent secretion of the interleukin-1 family cytokine IL-1β. Previous toxicology work suggests that cristobalite-bearing volcanic ash is minimally reactive, calling into question the reactivity of volcanically derived crystalline silica, in general. In this study, we target the NLRP3 inflammasome as a crystalline silica responsive element to clarify volcanic cristobalite reactivity. We expose immortalized bone marrow-derived macrophages of genetically engineered mice and primary human peripheral blood mononuclear cells (PBMCs) to ash from the Soufrière Hills volcano as well as representative, pure-phase samples of its primary componentry (volcanic glass, feldspar, cristobalite) and measure NLRP3 inflammasome activation. We demonstrate that respirable Soufrière Hills volcanic ash induces the activation of caspase-1 with subsequent release of mature IL-1β in a NLRP3 inflammasome-dependent manner. Macrophages deficient in NLRP3 inflammasome components are incapable of secreting IL-1β in response to volcanic ash ingestion. Cellular uptake induces lysosomal destabilization involving cysteine proteases. Furthermore, the response involves activation of mitochondrial stress pathways leading to the generation of reactive oxygen species. Considering ash componentry, cristobalite is the most reactive pure-phase with other components inducing only low-level IL-1β secretion. Inflammasome activation mediated by inhaled ash and its potential relevance in chronic pulmonary disease was further evidenced in PBMC using the NLRP3 small-molecule inhibitor CP-456,773 (CRID3, MCC950). Our data indicate the functional activation of the NLRP3 inflammasome by volcanic ash in murine and human macrophages in vitro . Cristobalite is identified as the apparent driver, thereby contesting previous assertions that chemical and structural imperfections may be sufficient to abrogate the reactivity of volcanically derived cristobalite. This is a novel mechanism for the stimulation of a pro-inflammatory response by volcanic particulate and provides new insight regarding chronic exposure to environmentally occurring particles.

Volcanic ash activates the NLRP3 inflammasome in murine and human macrophages

USGS Publications Warehouse

Damby, David; Horwell, Claire J.; Baxter, Peter J.; Kueppers, Ulrich; Schnurr, Max; Dingwell, Donald B.; Duewell, Peter

2018-01-01

Volcanic ash is a heterogeneous mineral dust that is typically composed of a mixture of amorphous (glass) and crystalline (mineral) fragments. It commonly contains an abundance of the crystalline silica (SiO2) polymorph cristobalite. Inhalation of crystalline silica can induce inflammation by stimulating the NLRP3 inflammasome, a cytosolic receptor complex that plays a critical role in driving inflammatory immune responses. Ingested material results in the assembly of NLRP3, ASC, and caspase-1 with subsequent secretion of the interleukin-1 family cytokine IL-1β. Previous toxicology work suggests that cristobalite-bearing volcanic ash is minimally reactive, calling into question the reactivity of volcanically derived crystalline silica, in general. In this study, we target the NLRP3 inflammasome as a crystalline silica responsive element to clarify volcanic cristobalite reactivity. We expose immortalized bone marrow-derived macrophages of genetically engineered mice and primary human peripheral blood mononuclear cells (PBMCs) to ash from the Soufrière Hills volcano as well as representative, pure-phase samples of its primary componentry (volcanic glass, feldspar, cristobalite) and measure NLRP3 inflammasome activation. We demonstrate that respirable Soufrière Hills volcanic ash induces the activation of caspase-1 with subsequent release of mature IL-1β in a NLRP3 inflammasome-dependent manner. Macrophages deficient in NLRP3 inflammasome components are incapable of secreting IL-1β in response to volcanic ash ingestion. Cellular uptake induces lysosomal destabilization involving cysteine proteases. Furthermore, the response involves activation of mitochondrial stress pathways leading to the generation of reactive oxygen species. Considering ash componentry, cristobalite is the most reactive pure-phase with other components inducing only low-level IL-1β secretion. Inflammasome activation mediated by inhaled ash and its potential relevance in chronic pulmonary disease was further evidenced in PBMC using the NLRP3 small-molecule inhibitor CP-456,773 (CRID3, MCC950). Our data indicate the functional activation of the NLRP3 inflammasome by volcanic ash in murine and human macrophages in vitro. Cristobalite is identified as the apparent driver, thereby contesting previous assertions that chemical and structural imperfections may be sufficient to abrogate the reactivity of volcanically derived cristobalite. This is a novel mechanism for the stimulation of a pro-inflammatory response by volcanic particulate and provides new insight regarding chronic exposure to environmentally occurring particles.

Volcanic Ash Activates the NLRP3 Inflammasome in Murine and Human Macrophages

PubMed Central

Damby, David E.; Horwell, Claire J.; Baxter, Peter J.; Kueppers, Ulrich; Schnurr, Max; Dingwell, Donald B.; Duewell, Peter

2018-01-01

Volcanic ash is a heterogeneous mineral dust that is typically composed of a mixture of amorphous (glass) and crystalline (mineral) fragments. It commonly contains an abundance of the crystalline silica (SiO2) polymorph cristobalite. Inhalation of crystalline silica can induce inflammation by stimulating the NLRP3 inflammasome, a cytosolic receptor complex that plays a critical role in driving inflammatory immune responses. Ingested material results in the assembly of NLRP3, ASC, and caspase-1 with subsequent secretion of the interleukin-1 family cytokine IL-1β. Previous toxicology work suggests that cristobalite-bearing volcanic ash is minimally reactive, calling into question the reactivity of volcanically derived crystalline silica, in general. In this study, we target the NLRP3 inflammasome as a crystalline silica responsive element to clarify volcanic cristobalite reactivity. We expose immortalized bone marrow-derived macrophages of genetically engineered mice and primary human peripheral blood mononuclear cells (PBMCs) to ash from the Soufrière Hills volcano as well as representative, pure-phase samples of its primary componentry (volcanic glass, feldspar, cristobalite) and measure NLRP3 inflammasome activation. We demonstrate that respirable Soufrière Hills volcanic ash induces the activation of caspase-1 with subsequent release of mature IL-1β in a NLRP3 inflammasome-dependent manner. Macrophages deficient in NLRP3 inflammasome components are incapable of secreting IL-1β in response to volcanic ash ingestion. Cellular uptake induces lysosomal destabilization involving cysteine proteases. Furthermore, the response involves activation of mitochondrial stress pathways leading to the generation of reactive oxygen species. Considering ash componentry, cristobalite is the most reactive pure-phase with other components inducing only low-level IL-1β secretion. Inflammasome activation mediated by inhaled ash and its potential relevance in chronic pulmonary disease was further evidenced in PBMC using the NLRP3 small-molecule inhibitor CP-456,773 (CRID3, MCC950). Our data indicate the functional activation of the NLRP3 inflammasome by volcanic ash in murine and human macrophages in vitro. Cristobalite is identified as the apparent driver, thereby contesting previous assertions that chemical and structural imperfections may be sufficient to abrogate the reactivity of volcanically derived cristobalite. This is a novel mechanism for the stimulation of a pro-inflammatory response by volcanic particulate and provides new insight regarding chronic exposure to environmentally occurring particles. PMID:29403480

Boosting heterosubtypic neutralization antibodies in recipients of 2009 pandemic H1N1 influenza vaccine.

PubMed

Qiu, Chao; Huang, Yang; Wang, Qian; Tian, Di; Zhang, Wanju; Hu, Yunwen; Yuan, Zhenghong; Zhang, Xiaoyan; Xu, Jianqing

2012-01-01

A mass vaccination has been implemented to prevent the spread of 2009 pandemic influenza virus in China. Highly limited information is available on whether this vaccine induces cross-reactive neutralization antibodies against other subtypes of influenza viruses. We employed pseudovirus-based assays to analyze heterosubtypic neutralization responses in serum samples of 23 recipients of 2009 pandemic influenza vaccine. One dose of pandemic vaccine not only stimulated good neutralization antibodies against cognate influenza virus 2009 influenza A (H1N1), but also raised broad cross-reactive neutralization activities against seasonal H3N2 and highly pathogenic avian influenza virus H5N1 and lesser to H2N2. The cross-reactive neutralization activities were completely abolished after the removal of immunoglobin G (IgG). In contrast, H1N1 vaccination alone in influenza-naive mice elicited only vigorous homologous neutralizing activities but not cross-reactive neutralization activities. Our data suggest that the cross-reactive neutralization epitopes do exist in this vaccine and could elicit significant cross-reactive neutralizing IgG antibodies in the presence of preexisting responses. The exposure to H1N1 vaccine is likely to modify the hierarchical order of preexisting immune responses to influenza viruses. These findings provide insights into the evolution of human immunity to influenza viruses after experiencing multiple influenza virus infections and vaccinations.

Autoantigen cross-reactive environmental antigen can trigger multiple sclerosis-like disease.

PubMed

Reynolds, Catherine J; Sim, Malcolm J W; Quigley, Kathryn J; Altmann, Daniel M; Boyton, Rosemary J

2015-05-13

Multiple sclerosis is generally considered an autoimmune disease resulting from interaction between predisposing genes and environmental factors, together allowing immunological self-tolerance to be compromised. The precise nature of the environmental inputs has been elusive, infectious agents having received considerable attention. A recent study generated an algorithm predicting naturally occurring T cell receptor (TCR) ligands from the proteome database. Taking the example of a multiple sclerosis patient-derived anti-myelin TCR, the study identified a number of stimulatory, cross-reactive peptide sequences from environmental and human antigens. Having previously generated a spontaneous multiple sclerosis (MS) model through expression of this TCR, we asked whether any of these could indeed function in vivo to trigger CNS disease by cross-reactive activation. A number of myelin epitope cross-reactive epitopes could stimulate T cell immunity in this MS anti-myelin TCR transgenic model. Two of the most stimulatory of these 'environmental' epitopes, from Dictyostyelium slime mold and from Emiliania huxleyi, were tested for the ability to induce MS-like disease in the transgenics. We found that immunization with cross-reactive peptide from Dictyostyelium slime mold (but not from E. huxleyi) induces severe disease. These specific environmental epitopes are unlikely to be common triggers of MS, but this study suggests that our search for the cross-reactivity triggers of autoimmune activation leading to MS should encompass epitopes not just from the 'infectome' but also from the full environmental 'exposome.'

Balance confidence is related to features of balance and gait in individuals with chronic stroke

PubMed Central

Schinkel-Ivy, Alison; Wong, Jennifer S.; Mansfield, Avril

2016-01-01

Reduced balance confidence is associated with impairments in features of balance and gait in individuals with sub-acute stroke. However, an understanding of these relationships in individuals at the chronic stage of stroke recovery is lacking. This study aimed to quantify relationships between balance confidence and specific features of balance and gait in individuals with chronic stroke. Participants completed a balance confidence questionnaire and clinical balance assessment (quiet standing, walking, and reactive stepping) at 6 months post-discharge from inpatient stroke rehabilitation. Regression analyses were performed using balance confidence as a predictor variable and quiet standing, walking, and reactive stepping outcome measures as the dependent variables. Walking velocity was positively correlated with balance confidence, while medio-lateral centre of pressure excursion (quiet standing) and double support time, step width variability, and step time variability (walking) were negatively correlated with balance confidence. This study provides insight into the relationships between balance confidence and balance and gait measures in individuals with chronic stroke, suggesting that individuals with low balance confidence exhibited impaired control of quiet standing as well as walking characteristics associated with cautious gait strategies. Future work should identify the direction of these relationships to inform community-based stroke rehabilitation programs for individuals with chronic stroke, and determine the potential utility of incorporating interventions to improve balance confidence into these programs. PMID:27955809

Rapid one-step whole blood C-reactive protein magnetic permeability immunoassay with monoclonal antibody conjugated nanoparticles as superparamagnetic labels and enhanced sedimentation.

PubMed

Ibraimi, Filiz; Kriz, Dario; Lu, Min; Hansson, Lars-Olof; Kriz, Kirstin

2006-02-01

A rapid (5.5 min) one-step whole blood C-reactive protein (CRP) magnetic permeability immunoassay utilizing monoclonal antibody conjugated dextran iron oxide nanoparticles (70 nm) as superparamagnetic labels and mixed fractions (1:1 ratio of 15-40 and 60 microm) of polyclonal anti-CRP conjugated silica microparticles for enhanced sedimentation is described. In this one-step assay procedure, a whole blood sample (4 microl) is applied to an assay glass vial, containing both antibody conjugates, and mixed for 30 s. The target analyte, CRP, forms a sandwich complex between the conjugated nanoparticles and microparticles, and, subsequently, the complex sediments under normal gravitation within 5 min to the bottom of the vial. The magnetic permeability increase of the sediment due to the presence of the complexed superparamagnetic nanoparticles is determined using an inductance-based transducer. Assayed patient whole blood samples were compared with the Abbott Diagnostics Architect reference method. A strong linear correlation was observed for the CRP concentration range 0-260 mg/l in whole blood (y=1.001x+0.42, R2=0.982, n=50). The CRP assay presented showed a limit of detection of 3 mg/l and a total imprecision (coefficient of variation) of 10.5%. On the basis of our observations, we propose a rapid, one-step, CRP assay for near-patient testing.

Formation, Migration, and Reactivity of Au CO Complexes on Gold Surfaces

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

Wang, Jun; McEntee, Monica; Tang, Wenjie

2016-01-12

Here, we report experimental as well as theoretical evidence that suggests Au CO complex formation upon the exposure of CO to active sites (step edges and threading dislocations) on a Au(111) surface. Room-temperature scanning tunneling microscopy (STM), X-ray photoelectron spectroscopy, transmission infrared spectroscopy, and density functional theory calculations point to Au CO complex formation and migration. Room-temperature STM of the Au(111) surface at CO pressures in the range from 10^ 8 to 10^ 4 Torr (dosage up to 10^6 langmuir) indicates Au atom extraction from dislocation sites of the herringbone reconstruction, mobile Au CO complex formation and diffusion, and Aumore » adatom cluster formation on both elbows and step edges on the Au surface. The formation and mobility of the Au CO complex result from the reduced Au Au bonding at elbows and step edges leading to stronger Au CO bonding and to the formation of a more positively charged CO (CO +) on Au. These studies indicate that the mobile Au CO complex is involved in the Au nanoparticle formation and reactivity, and that the positive charge on CO increases due to the stronger adsorption of CO at Au sites with lower coordination numbers.« less

United States-Vietnam Relations 1945-1967 (Book 11 of 12)

DTIC Science & Technology

1971-01-01

Encourage again the movement of refugees into the South by stimulating the desire to do so among the people in the North, by establishing...person of immense moral courage and of demonstrated physical courage. He is intensely honest. And, despite seeing hundreds of people daily and...109 15; The presence of United Nations observers would stimulate the Indian and Canadian members of the ICC to step up their surveillances

Oleic acid stimulates glucagon-like peptide-1 release from enteroendocrine cells by modulating cell respiration and glycolysis.

PubMed

Clara, Rosmarie; Langhans, Wolfgang; Mansouri, Abdelhak

2016-03-01

Glucagon-like peptide-1 (GLP-1) is a potent satiating and incretin hormone released by enteroendocrine L-cells in response to eating. Dietary fat, in particular monounsaturated fatty acids, such as oleic acid (OA), potently stimulates GLP-1 secretion from L-cells. It is, however, unclear whether the intracellular metabolic handling of OA is involved in this effect. First we determined the optimal medium for the bioenergetics measurements. Then we examined the effect of OA on the metabolism of the immortalized enteroendocrine GLUTag cell model and assessed GLP-1 release in parallel. We measured oxygen consumption rate and extracellular acidification rate in response to OA and to different metabolic inhibitors with the Seahorse extracellular flux analyzer. OA increased cellular respiration and potently stimulated GLP-1 release. The fatty acid oxidation inhibitor etomoxir did neither reduce OA-induced respiration nor affect the OA-induced GLP-1 release. In contrast, inhibition of the respiratory chain or of downstream steps of aerobic glycolysis reduced the OA-induced GLP-1 release, and an inhibition of the first step of glycolysis by addition of 2-deoxy-d-glucose even abolished it. These findings indicate that an indirect stimulation of glycolysis is crucial for the OA-induced release of GLP-1. Copyright © 2015 Elsevier Inc. All rights reserved.

Experimental parameter identification of a multi-scale musculoskeletal model controlled by electrical stimulation: application to patients with spinal cord injury.

PubMed

Benoussaad, Mourad; Poignet, Philippe; Hayashibe, Mitsuhiro; Azevedo-Coste, Christine; Fattal, Charles; Guiraud, David

2013-06-01

We investigated the parameter identification of a multi-scale physiological model of skeletal muscle, based on Huxley's formulation. We focused particularly on the knee joint controlled by quadriceps muscles under electrical stimulation (ES) in subjects with a complete spinal cord injury. A noninvasive and in vivo identification protocol was thus applied through surface stimulation in nine subjects and through neural stimulation in one ES-implanted subject. The identification protocol included initial identification steps, which are adaptations of existing identification techniques to estimate most of the parameters of our model. Then we applied an original and safer identification protocol in dynamic conditions, which required resolution of a nonlinear programming (NLP) problem to identify the serial element stiffness of quadriceps. Each identification step and cross validation of the estimated model in dynamic condition were evaluated through a quadratic error criterion. The results highlighted good accuracy, the efficiency of the identification protocol and the ability of the estimated model to predict the subject-specific behavior of the musculoskeletal system. From the comparison of parameter values between subjects, we discussed and explored the inter-subject variability of parameters in order to select parameters that have to be identified in each patient.

Association of SNPs on Chromosome 9p21.3 with Platelet Reactivity: A Potential Mechanism for Increased Vascular Disease

PubMed Central

Musunuru, Kiran; Post, Wendy S.; Herzog, William; Shen, Haiqing; O’Connell, Jeffrey R.; McArdle, Patrick F.; Ryan, Kathleen A.; Gibson, Quince; Cheng, Yu-Ching; Clearfield, Elizabeth; Johnson, Andrew D.; Tofler, Geoffrey; Yang, Qiong; O’Donnell, Christopher J.; Becker, Diane M.; Yanek, Lisa R.; Becker, Lewis C.; Faraday, Nauder; Bielak, Lawrence F.; Peyser, Patricia A.; Shuldiner, Alan R.; Mitchell, Braxton D.

2010-01-01

Background Genome-wide association studies have identified a locus on chromosome 9p21.3 to be strongly associated with myocardial infarction/coronary artery disease (MI/CAD) and ischemic stroke. To gain insights into the mechanisms underlying these associations, we hypothesized that single nucleotide polymorphisms (SNPs) in this region would be associated with platelet reactivity across multiple populations. Methods and Results Subjects in the initial population included 1,402 asymptomatic Amish adults in whom we measured platelet reactivity (n=788) and/or coronary artery calcification (CAC) (n=939). Platelet reactivity on agonist stimulation was measured by impedence aggregometry, and CAC by electron beam computed tomography. Twenty-nine SNPs at the 9p21.3 locus were genotyped using the Affymetrix 500K array. Twelve correlated SNPs in the locus were significantly associated with platelet reactivity (all p ≤ 0.001). The SNP most strongly associated with platelet reactivity, rs10965219 (p = 0.0002) was also associated with CAC (p = 0.002), along with 9 other SNPs (all p < 0.004). Association of rs10965219 with platelet reactivity persisted after adjustment for CAC, a measure of underlying atherosclerotic burden known to affect platelet reactivity. We then tested rs10965219 for association with platelet function in 2,364 subjects from the Framingham Heart Study (FHS) and 1,169 subjects from the GeneSTAR Study. The rs10965219 G allele (frequency ~ 51% across all three populations) was significantly associated with higher platelet reactivity in FHS (p = 0.001) and trended toward higher reactivity in GeneSTAR (p = 0.087); the combined p-value for meta-analysis was 0.0002. Conclusions These results suggest that risk alleles at 9p21.3 locus may have pleiotropic effects on MI/CAD and stroke risk, possibly through their influence on platelet reactivity. PMID:20858905

Effects of prenatal and postnatal depression, and maternal stroking, at the glucocorticoid receptor gene.

PubMed

Murgatroyd, C; Quinn, J P; Sharp, H M; Pickles, A; Hill, J

2015-05-05

In animal models, prenatal and postnatal stress is associated with elevated hypothalamic-pituitary axis (HPA) reactivity mediated via altered glucocorticoid receptor (GR) gene expression. Postnatal tactile stimulation is associated with reduced HPA reactivity mediated via increased GR gene expression. In this first study in humans to examine the joint effects of prenatal and postnatal environmental exposures, we report that GR gene (NR3C1) 1-F promoter methylation in infants is elevated in the presence of increased maternal postnatal depression following low prenatal depression, and that this effect is reversed by self-reported stroking of the infants by their mothers over the first weeks of life.

Organic Arsenicals as Functional Motifs in Polymer and Biomaterials Science.

PubMed

Tanaka, Joji; Davis, Thomas P; Wilson, Paul

2018-05-28

Arsenic (As) exhibits diverse (bio)chemical reactivity and biological activity depending upon its oxidation state. However, this distinctive reactivity has been largely overlooked across many fields owing to concerns regarding the toxicity of arsenic. Recently, a clinical renaissance in the use of arsenicals, including organic arsenicals that are known to be less toxic than inorganic arsenicals, alludes to the possibility of broader acceptance and application in the field of polymer and biomaterials science. Here, current examples of polymeric/macromolecular arsenicals are reported to stimulate interest and highlight their potential as a novel platform for functional, responsive, and bioactive materials. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Cathode for aluminum producing electrolytic cell

DOEpatents

Brown, Craig W.

2004-04-13

A method of producing aluminum in an electrolytic cell comprising the steps of providing an anode in a cell, preferably a non-reactive anode, and also providing a cathode in the cell, the cathode comprised of a base material having low electrical conductivity reactive with molten aluminum to provide a highly electrically conductive layer on the base material. Electric current is passed from the anode to the cathode and alumina is reduced and aluminum is deposited at the cathode. The cathode base material is selected from boron carbide, and zirconium oxide.

Parkinsonian gait improves with bilateral subthalamic nucleus deep brain stimulation during cognitive multi-tasking.

PubMed

Chenji, Gaurav; Wright, Melissa L; Chou, Kelvin L; Seidler, Rachael D; Patil, Parag G

2017-05-01

Gait impairment in Parkinson's disease reduces mobility and increases fall risk, particularly during cognitive multi-tasking. Studies suggest that bilateral subthalamic deep brain stimulation, a common surgical therapy, degrades motor performance under cognitive dual-task conditions, compared to unilateral stimulation. To measure the impact of bilateral versus unilateral subthalamic deep brain stimulation on walking kinematics with and without cognitive dual-tasking. Gait kinematics of seventeen patients with advanced Parkinson's disease who had undergone bilateral subthalamic deep brain stimulation were examined off medication under three stimulation states (bilateral, unilateral left, unilateral right) with and without a cognitive challenge, using an instrumented walkway system. Consistent with earlier studies, gait performance declined for all six measured parameters under cognitive dual-task conditions, independent of stimulation state. However, bilateral stimulation produced greater improvements in step length and double-limb support time than unilateral stimulation, and achieved similar performance for other gait parameters. Contrary to expectations from earlier studies of dual-task motor performance, bilateral subthalamic deep brain stimulation may assist in maintaining temporal and spatial gait performance under cognitive dual-task conditions. Copyright © 2017 Elsevier Ltd. All rights reserved.

TRANC - a novel fast-response converter to measure total reactive atmospheric nitrogen

NASA Astrophysics Data System (ADS)

Marx, O.; Brümmer, C.; Ammann, C.; Wolff, V.; Freibauer, A.

2012-05-01

The input and loss of plant available nitrogen (reactive nitrogen: Nr) from/to the atmosphere can be an important factor for the productivity of ecosystems and thus for its carbon and greenhouse gas exchange. We present a novel converter for reactive nitrogen (TRANC: Total Reactive Atmospheric Nitrogen Converter), which offers the opportunity to quantify the sum of all airborne reactive nitrogen compounds (∑Nr) in high time resolution. The basic concept of the TRANC is the full conversion of all Nr to nitrogen monoxide (NO) within two reaction steps. Initially, reduced Nr compounds are being oxidised, and oxidised Nr compounds are thermally converted to lower oxidation states. Particulate Nr is being sublimated and oxidised or reduced afterwards. In a second step, remaining higher nitrogen oxides or those generated in the first step are catalytically converted to NO with carbon monoxide used as reduction gas. The converter is combined with a fast response chemiluminescence detector (CLD) for NO analysis and its performance was tested for the most relevant gaseous and particulate Nr species under both laboratory and field conditions. Recovery rates during laboratory tests for NH3 and NO2 were found to be 95 and 99%, respectively, and 97% when the two gases were combined. In-field longterm stability over an 11-month period was approved by a value of 91% for NO2. Effective conversion was also found for ammonium and nitrate containing particles. The recovery rate of total ambient Nr was tested against the sum of individual measurements of NH3, HNO3, HONO, NH4+, NO3-, and NOx using a combination of different well-established devices. The results show that the TRANC-CLD system precisely captures fluctuations in ∑Nr concentrations and also matches the sum of all individual Nr compounds measured by the different single techniques. The TRANC features a specific design with very short distance between the sample air inlet and the place where the thermal and catalytic conversions to NO occur. This assures a short residence time of the sample air inside the instrument, and minimises wall sorption problems of water soluble compounds. The fast response time (e-folding times of 0.30 to 0.35 s were found during concentration step changes) and high accuracy in capturing the dominant Nr species enables the converter to be used in an eddy covariance setup. Although a source attribution of specific Nr compounds is not possible, the TRANC is a new reliable tool for permanent measurements of the net ∑Nr flux between ecosystem and atmosphere at a relatively low maintenance and reasonable cost level allowing for diurnal, seasonal and annual investigations.

Cluster analysis and subgrouping to investigate inter-individual variability to non-invasive brain stimulation: a systematic review.

PubMed

Pellegrini, Michael; Zoghi, Maryam; Jaberzadeh, Shapour

2018-01-12

Cluster analysis and other subgrouping techniques have risen in popularity in recent years in non-invasive brain stimulation research in the attempt to investigate the issue of inter-individual variability - the issue of why some individuals respond, as traditionally expected, to non-invasive brain stimulation protocols and others do not. Cluster analysis and subgrouping techniques have been used to categorise individuals, based on their response patterns, as responder or non-responders. There is, however, a lack of consensus and consistency on the most appropriate technique to use. This systematic review aimed to provide a systematic summary of the cluster analysis and subgrouping techniques used to date and suggest recommendations moving forward. Twenty studies were included that utilised subgrouping techniques, while seven of these additionally utilised cluster analysis techniques. The results of this systematic review appear to indicate that statistical cluster analysis techniques are effective in identifying subgroups of individuals based on response patterns to non-invasive brain stimulation. This systematic review also reports a lack of consensus amongst researchers on the most effective subgrouping technique and the criteria used to determine whether an individual is categorised as a responder or a non-responder. This systematic review provides a step-by-step guide to carrying out statistical cluster analyses and subgrouping techniques to provide a framework for analysis when developing further insights into the contributing factors of inter-individual variability in response to non-invasive brain stimulation.

Vestibulo-ocular reflex and motion sickness in figure skaters.

PubMed

Tanguy, Sébastien; Quarck, Gaëlle; Etard, Olivier; Gauthier, Antoine; Denise, Pierre

2008-12-01

In order to determine the effect of figure skating on the functional plasticity of the vestibular system, we quantified vestibulo-ocular reflex (VOR) and motion sickness (MS) intensity in 11 female figure skaters and 11 matched control subjects. Vestibular stimulation consisted of three cycles of sinusoidal rotation (0.025 Hz, +/-60 degrees /s) and two velocity steps of 60 degrees /s (acceleration 60 degrees /s(2)). Nauseogenic stimulation consisted of a constant velocity (60 degrees /s) off vertical axis rotation (OVAR) using a 15 degrees tilt angle. Subjective sickness symptoms were rated immediately after OVAR with the Pensacola diagnostic index. During sinusoidal stimulations, the skaters' VOR, as compared with that of the controls, demonstrates a gain that is 27% lower (0.44 +/- 0.12 vs. 0.58 +/- 0.10; P < 0.01) and a phase advance (10 +/- 12 degrees vs. -0.3 +/- 6.4 degrees ; P < 0.05). During velocity steps, the VOR gain is 32% lower among the skaters (0.52 +/- 0.14 vs. 0.71 +/- 0.12; P < 0.01), but there is no difference in time constant (10.8 +/- 1.8 s vs. 10.5 +/- 2.7 s; P = 0.78). Nauseogenic stimulation evokes significantly less MS in figure skaters than in control subjects (2.8 +/- 2.8 vs. 16.2 +/- 13.7; P < 0.01). Quantitative alterations in VOR parameters observed in figure skaters probably result from vestibular habituation induced by repeated unusual stimulations when practicing figure skating.

A novel biochemical platform for fuels and chemicals production from cellulosic biomass

USDA-ARS?s Scientific Manuscript database

The conventional biochemical platform for biofuels production featuring enzymatic hydrolysis involves five key steps: pretreatment, cellulase production, enzymatic hydrolysis, fermentation, and product recovery. Sugars are produced as reactive intermediates for subsequent fermentation to fuels and c...

Impact of Behavioral Control on the Processing of Nociceptive Stimulation

PubMed Central

Grau, James W.; Huie, J. Russell; Garraway, Sandra M.; Hook, Michelle A.; Crown, Eric D.; Baumbauer, Kyle M.; Lee, Kuan H.; Hoy, Kevin C.; Ferguson, Adam R.

2012-01-01

How nociceptive signals are processed within the spinal cord, and whether these signals lead to behavioral signs of neuropathic pain, depends upon their relation to other events and behavior. Our work shows that these relations can have a lasting effect on spinal plasticity, inducing a form of learning that alters the effect of subsequent nociceptive stimuli. The capacity of lower spinal systems to adapt, in the absence of brain input, is examined in spinally transected rats that receive a nociceptive shock to the tibialis anterior muscle of one hind leg. If shock is delivered whenever the leg is extended (controllable stimulation), it induces an increase in flexion duration that minimizes net shock exposure. This learning is not observed in subjects that receive the same amount of shock independent of leg position (uncontrollable stimulation). These two forms of stimulation have a lasting, and divergent, effect on subsequent learning: controllable stimulation enables learning whereas uncontrollable stimulation disables it (learning deficit). Uncontrollable stimulation also enhances mechanical reactivity. We review evidence that training with controllable stimulation engages a brain-derived neurotrophic factor (BDNF)-dependent process that can both prevent and reverse the consequences of uncontrollable shock. We relate these effects to changes in BDNF protein and TrkB signaling. Controllable stimulation is also shown to counter the effects of peripheral inflammation (from intradermal capsaicin). A model is proposed that assumes nociceptive input is gated at an early sensory stage. This gate is sensitive to current environmental relations (between proprioceptive and nociceptive input), allowing stimulation to be classified as controllable or uncontrollable. We further propose that the status of this gate is affected by past experience and that a history of uncontrollable stimulation will promote the development of neuropathic pain. PMID:22934018

Acetylsalicylic acid is compounding to antiplatelet effect of C-reactive protein.

PubMed

Boncler, Magdalena; Luzak, Boguslawa; Rozalski, Marcin; Golanski, Jacek; Rychlik, Blazej; Watala, Cezary

2007-01-01

The contribution of inflammatory process to the modulation of platelet response to acetylsalicylic acid (ASA) remains obscure. In our study, we examined the in vitro effect of C-reactive protein (CRP) on the ASA-mediated inhibition of collagen-stimulated platelet reactivity. Influence of CRP on platelet responsiveness to ASA was analysed using classical turbidimetric aggregation and flow cytometry. When acting alone, both C-reactive protein and ASA inhibited collagen-dependent platelet aggregation and reduced the expressions of two platelet surface membrane activation markers: P-selectin and activated GPIIbIIIa complex. Compared to the effects observed for ASA alone, the simultaneous action of both agents lead to further reductions in platelet aggregation (by 56.7+/-1.0% vs. 14.9+/-0.6%, p<0.0001) and lowered the expressions of platelet surface membrane P-selectin (by 72.1+/-5.3% vs. 65.0+/-6.0%, p<0.01) and activated GPIIbIIIa (by 67.0+/-5.6% vs. 47.7+/-8.3%, p<0.01). In general, our findings showed for the first time the augmenting effect of native C-reactive protein in the antiplatelet action of acetylsalicylic acid. Thus, we conclude that the effectiveness of aspirin therapy may strongly depend upon the presence of native CRP in circulation.

Regulating NETosis: Increasing pH Promotes NADPH Oxidase-Dependent NETosis

PubMed Central

Khan, Meraj A.; Philip, Lijy M.; Cheung, Guillaume; Vadakepeedika, Shawn; Grasemann, Hartmut; Sweezey, Neil; Palaniyar, Nades

2018-01-01

Neutrophils migrating from the blood (pH 7.35–7.45) into the surrounding tissues encounter changes in extracellular pH (pHe) conditions. Upon activation of NADPH oxidase 2 (Nox), neutrophils generate large amounts of H+ ions reducing the intracellular pH (pHi). Nevertheless, how extracellular pH regulates neutrophil extracellular trap (NET) formation (NETosis) is not clearly established. We hypothesized that increasing pH increases Nox-mediated production of reactive oxygen species (ROS) and neutrophil protease activity, stimulating NETosis. Here, we found that raising pHe (ranging from 6.6 to 7.8; every 0.2 units) increased pHi of both activated and resting neutrophils within 10–20 min (Seminaphtharhodafluor dual fluorescence measurements). Since Nox activity generates H+ ions, pHi is lower in neutrophils that are activated compared to resting. We also found that higher pH stimulated Nox-dependent ROS production (R123 generation; flow cytometry, plate reader assay, and imaging) during spontaneous and phorbol myristate acetate-induced NETosis (Sytox Green assays, immunoconfocal microscopy, and quantifying NETs). In neutrophils that are activated and not resting, higher pH stimulated histone H4 cleavage (Western blots) and NETosis. Raising pH increased Escherichia coli lipopolysaccharide-, Pseudomonas aeruginosa (Gram-negative)-, and Staphylococcus aureus (Gram-positive)-induced NETosis. Thus, higher pHe promoted Nox-dependent ROS production, protease activity, and NETosis; lower pH has the opposite effect. These studies provided mechanistic steps of pHe-mediated regulation of Nox-dependent NETosis. Raising pH either by sodium bicarbonate or Tris base (clinically known as Tris hydroxymethyl aminomethane, tromethamine, or THAM) increases NETosis. Each Tris molecule can bind 3H+ ions, whereas each bicarbonate HCO3− ion binds 1H+ ion. Therefore, the amount of Tris solution required to cause the same increase in pH level is less than that of equimolar bicarbonate solution. For that reason, regulating NETosis by pH with specific buffers such as THAM could be more effective than bicarbonate in managing NET-related diseases. PMID:29487850

Regulating NETosis: Increasing pH Promotes NADPH Oxidase-Dependent NETosis.

PubMed

Khan, Meraj A; Philip, Lijy M; Cheung, Guillaume; Vadakepeedika, Shawn; Grasemann, Hartmut; Sweezey, Neil; Palaniyar, Nades

2018-01-01

Neutrophils migrating from the blood (pH 7.35-7.45) into the surrounding tissues encounter changes in extracellular pH (pH e ) conditions. Upon activation of NADPH oxidase 2 (Nox), neutrophils generate large amounts of H + ions reducing the intracellular pH (pH i ). Nevertheless, how extracellular pH regulates neutrophil extracellular trap (NET) formation (NETosis) is not clearly established. We hypothesized that increasing pH increases Nox-mediated production of reactive oxygen species (ROS) and neutrophil protease activity, stimulating NETosis. Here, we found that raising pH e (ranging from 6.6 to 7.8; every 0.2 units) increased pH i of both activated and resting neutrophils within 10-20 min (Seminaphtharhodafluor dual fluorescence measurements). Since Nox activity generates H + ions, pH i is lower in neutrophils that are activated compared to resting. We also found that higher pH stimulated Nox-dependent ROS production (R123 generation; flow cytometry, plate reader assay, and imaging) during spontaneous and phorbol myristate acetate-induced NETosis (Sytox Green assays, immunoconfocal microscopy, and quantifying NETs). In neutrophils that are activated and not resting, higher pH stimulated histone H4 cleavage (Western blots) and NETosis. Raising pH increased Escherichia coli lipopolysaccharide-, Pseudomonas aeruginosa (Gram-negative)-, and Staphylococcus aureus (Gram-positive)-induced NETosis. Thus, higher pH e promoted Nox-dependent ROS production, protease activity, and NETosis; lower pH has the opposite effect. These studies provided mechanistic steps of pH e -mediated regulation of Nox-dependent NETosis. Raising pH either by sodium bicarbonate or Tris base (clinically known as Tris hydroxymethyl aminomethane, tromethamine, or THAM) increases NETosis. Each Tris molecule can bind 3H + ions, whereas each bicarbonate HCO3 - ion binds 1H + ion. Therefore, the amount of Tris solution required to cause the same increase in pH level is less than that of equimolar bicarbonate solution. For that reason, regulating NETosis by pH with specific buffers such as THAM could be more effective than bicarbonate in managing NET-related diseases.

Controlling the Local Electronic Properties of Si(553)-Au through Hydrogen Doping

NASA Astrophysics Data System (ADS)

Hogan, C.; Speiser, E.; Chandola, S.; Suchkova, S.; Aulbach, J.; Schäfer, J.; Meyer, S.; Claessen, R.; Esser, N.

2018-04-01

We propose a quantitative and reversible method for tuning the charge localization of Au-stabilized stepped Si surfaces by site-specific hydrogenation. This is demonstrated for Si(553)-Au as a model system by combining density functional theory simulations and reflectance anisotropy spectroscopy experiments. We find that controlled H passivation is a two-step process: step-edge adsorption drives excess charge into the conducting metal chain "reservoir" and renders it insulating, while surplus H recovers metallic behavior. Our approach illustrates a route towards microscopic manipulation of the local surface charge distribution and establishes a reversible switch of site-specific chemical reactivity and magnetic properties on vicinal surfaces.

The serum and glucocorticoid-regulated protein kinases (SGK) stimulate bovine herpesvirus 1 and herpes simplex virus 1 productive infection.

PubMed

Kook, Insun; Jones, Clinton

2016-08-15

Serum and glucocorticoid-regulated protein kinases (SGK) are serine/threonine protein kinases that contain a catalytic domain resembling other protein kinases: AKT/protein kinase B, protein kinase A, and protein kinase C-Zeta for example. Unlike these constitutively expressed protein kinases, SGK1 RNA and protein levels are increased by growth factors and corticosteroids. Stress can directly stimulate SGK1 levels as well as stimulate bovine herpesvirus 1 (BoHV-1) and herpes simplex virus 1 (HSV-1) productive infection and reactivation from latency suggesting SGK1 can stimulate productive infection. For the first time, we provide evidence that a specific SGK inhibitor (GSK650394) significantly reduced BoHV-1 and HSV-1 replication in cultured cells. Proteins encoded by the three BoHV-1 immediate early genes (bICP0, bICP4, and bICP22) and two late proteins (VP16 and gE) were consistently reduced by GSK650394 during early stages of productive infection. In summary, these studies suggest SGK may stimulate viral replication following stressful stimuli. Copyright © 2016 Elsevier B.V. All rights reserved.

Transcranial Direct Current Stimulation of the Left Dorsolateral Prefrontal Cortex Shifts Preference of Moral Judgments

PubMed Central

Kuehne, Maria; Heimrath, Kai; Heinze, Hans-Jochen; Zaehle, Tino

2015-01-01

Attitude to morality, reflecting cultural norms and values, is considered unique to human social behavior. Resulting moral behavior in a social environment is controlled by a widespread neural network including the dorsolateral prefrontal cortex (DLPFC), which plays an important role in decision making. In the present study we investigate the influence of neurophysiological modulation of DLPFC reactivity by means of transcranial direct current stimulation (tDCS) on moral reasoning. For that purpose we administered anodal, cathodal, and sham stimulation of the left DLPFC while subjects judged the appropriateness of hard moral personal dilemmas. In contrast to sham and cathodal stimulation, anodal stimulation induced a shift in judgment of personal moral dilemmas towards more non-utilitarian actions. Our results demonstrate that alterations of left DLPFC activity can change moral judgments and, in consequence, provide a causal link between left DLPFC activity and moral reasoning. Most important, the observed shift towards non-utilitarian actions suggests that moral decision making is not a permanent individual trait but can be manipulated; consequently individuals with boundless, uncontrollable, and maladaptive moral behavior, such as found in psychopathy, might benefit from neuromodulation-based approaches. PMID:25985442

Effect of bacterial stimulants on release of reactive oxygen metabolites from peripheral blood neutrophils in periodontitis.

PubMed

Zekonis, Gediminas; Zekonis, Jonas

2004-01-01

The aim of the present investigation was to explore the oxidative activity of peripheral blood polymorphonuclear neutrophils of periodontitis patients and of healthy subjects stimulated with non-opsonized E. coli and lipopolysaccharide of E. coli. The leukocytes for this study were obtained from peripheral venous blood of 22 parodontitis patients and 16 healthy subjects. Oxidative activity of peripheral blood polymorphonuclear neutrophils was measured by method of the luminol-dependent chemiluminescence. The luminol-dependent chemiluminescence of stimulated neutrophils of periodontitis patients with non-opsonized E. coli increased less significantly (p<0.001) as compared to analogous chemiluminescence of control subjects (147126+/-8386 cpm and 189247+/-9134 cpm, respectively). However, the luminol-dependent chemiluminescence of stimulated neutrophils of periodontitis patients with lipopolysaccharide was five times higher than that of the subjects with intact periodontal tissues and comprised 13261+/-1251 cpm and 2627+/-638 cpm, respectively. Our study results show a complex dependence of oxidative function of peripheral polymorphonuclear neutrophils of periodontitis patients upon the nature of stimulants. Therefore further attempts should be made to evaluate its significance in the etiopathogenesis of periodontal tissue diseases of inflammatory origin.

The Stimulated Glycolytic Pathway Is Able to Maintain ATP Levels and Kinetic Patterns of Bovine Epididymal Sperm Subjected to Mitochondrial Uncoupling.

PubMed

Losano, João D A; Padín, Juan Fernando; Méndez-López, Iago; Angrimani, Daniel S R; García, Antonio G; Barnabe, Valquiria H; Nichi, Marcilio

2017-01-01

Studies have reported the importance of mitochondria in sperm functionality. However, for some species, the glycolytic pathway appears to be as important as oxidative phosphorylation in ATP synthesis and sperm kinetics. These mechanisms have not been fully elucidated for bovine spermatozoa. Therefore, the aim of this study was to evaluate the role of mitochondria and the glycolytic pathway in ATP synthesis, sperm movement patterns, and oxidative homeostasis of epididymal spermatozoa in bovine specimens. We observed that mitochondrial uncoupling with protonophores significantly reduced ATP levels. However, these levels were reestablished after stimulation of the glycolytic pathway. We verified the same pattern of results for sperm kinetic variables and the production of reactive oxygen species (ROS). Thus, we suggest that, after its appropriate stimulation, the glycolytic pathway is capable of maintaining ATP levels, sperm kinetic patterns, and oxidative balance of bovine epididymal spermatozoa submitted to mitochondrial uncoupling.

Endothelial cell stimulating angiogenesis factor.

PubMed

Weiss, J B; McLaughlin, B

1998-04-01

Endothelial cell stimulating angiogenesis factor (ESAF) is a small (> 1000 Da) dialysable non-peptide molecule with potent angiogenic activity. ESAF activates the major pro-matrix metalloproteinases and also uniquely reactivates the complex of these active enzymes with their tissue inhibitors resulting in both active enzyme and inhibitor. These actions may be pivotal in its role as an angiogenic factor. ESAF is primarily involved in angiogenic conditions where inflammatory cells are not evident such as foetal bone growth and electrically stimulated skeletal muscles and proliferative retinopathy. However, high levels also occur in actively growing human intracranial tumours but it is not noticeably elevated in rheumatoid arthritic synovial fluid. Its extreme potency and low molecular mass make its structural determination difficult. Possible therapeutic applications would be in the treatment of ischaemic ulcers, acceleration of fracture repair, infertility and more modestly in the correction of baldness. Analogues of ESAF could be of value in treating angiogenic diseases such as psoriasis and proliferative retinopathy.

Choline and dimethylglycine produce superoxide/hydrogen peroxide from the electron transport chain in liver mitochondria.

PubMed

Mailloux, Ryan J; Young, Adrian; Chalker, Julia; Gardiner, Danielle; O'Brien, Marisa; Slade, Liam; Brosnan, John T

2016-12-01

Here, we report that choline and dimethylglycine can stimulate reactive oxygen species (ROS) production in liver mitochondria. Choline stimulated O 2 ˙ - /H 2 O 2 formation at a concentration of 5 μm. We also observed that Complex II and III inhibitors, atpenin A5 and myxothiazol, collectively induced a 95% decrease in O 2 ˙ - /H 2 O 2 production indicating both sites serve as the main sources of ROS during choline oxidation. Dimethylglycine, an intermediate of choline oxidation, was a more effective ROS generator. Rates of production were ~ 43% higher than choline-mediated O 2 ˙ - /H 2 O 2 production. The main site for dimethylglycine-mediated ROS production was via reverse electron transfer to Complex I. Our results demonstrate that metabolism of essential metabolites involved in methionine and folic acid biosynthesis can stimulate mitochondrial ROS production. © 2016 Federation of European Biochemical Societies.

Enhanced stimulated emission in ZnO thin films using microdisk top-down structuring

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

Nomenyo, K.; Kostcheev, S.; Lérondel, G.

2014-05-05

Microdisks were fabricated in zinc oxide (ZnO) thin films using a top-down approach combining electron beam lithography and reactive ion etching. These microdisk structured thin films exhibit a stimulated surface emission between 3 and 7 times higher than that from a reference film depending on the excitation power density. Emission peak narrowing, reduction in lasing threshold and blue-shifting of the emission wavelength were observed along with enhancement in the emitted intensity. Results indicate that this enhancement is due to an increase in the internal quantum efficiency combined with an amplification of the stimulated emission. An analysis in terms of waveguidingmore » is presented in order to explain these effects. These results demonstrate that very significant gains in emission can be obtained through conventional microstructuration without the need for more onerous top-down nanostructuration techniques.« less

Integrated transcriptome and proteome analyses reveal a close association between secondary metabolite production capabilities and Aspergillus flavus isolate oxidative stress tolerance

USDA-ARS?s Scientific Manuscript database

The contamination of crops with aflatoxins during Aspergillus flavus infection is exacerbated by drought stress. Reactive oxygen species have been shown to be produced in plant tissues in response to drought and to stimulate the production of aflatoxin by A. flavus in vitro. To better understand the...

Dye-ligand affinity systems.

PubMed

Denizli, A; Pişkin, E

2001-10-30

Dye-ligands have been considered as one of the important alternatives to natural counterparts for specific affinity chromatography. Dye-ligands are able to bind most types of proteins, in some cases in a remarkably specific manner. They are commercially available, inexpensive, and can easily be immobilized, especially on matrices bearing hydroxyl groups. Although dyes are all synthetic in nature, they are still classified as affinity ligands because they interact with the active sites of many proteins mimicking the structure of the substrates, cofactors, or binding agents for those proteins. A number of textile dyes, known as reactive dyes, have been used for protein purification. Most of these reactive dyes consist of a chromophore (either azo dyes, anthraquinone, or phathalocyanine), linked to a reactive group (often a mono- or dichlorotriazine ring). The interaction between the dye ligand and proteins can be by complex combination of electrostatic, hydrophobic, hydrogen bonding. Selection of the supporting matrix is the first important consideration in dye-affinity systems. There are several methods for immobilization of dye molecules onto the support matrix, in which usually several intermediate steps are followed. Both the adsorption and elution steps should carefully be optimized/designed for a successful separation. Dye-affinity systems in the form of spherical sorbents or as affinity membranes have been used in protein separation.

Thermal formation of hydroxynitriles, precursors of hydroxyacids in astrophysical ice analogs: Acetone ((CH3)2Cdbnd O) and hydrogen cyanide (HCN) reactivity

NASA Astrophysics Data System (ADS)

Fresneau, Aurélien; Danger, Grégoire; Rimola, Albert; Duvernay, Fabrice; Theulé, Patrice; Chiavassa, Thierry

2015-11-01

Reactivity in astrophysical environments is still poorly understood. In this contribution, we investigate the thermal reactivity of interstellar ice analogs containing acetone ((CH3)2CO), ammonia (NH3), hydrogen cyanide (HCN) and water (H2O) by means of infrared spectroscopy and mass spectrometry techniques, complemented by quantum chemical calculations. We show that no reaction occurs in H2O:HCN:(CH3)2CO ices. Nevertheless, HCN does indeed react with acetone once activated by NH3 into CN- to form 2-hydroxy-2-methylpropanenitrile (HOsbnd C(CH3)2sbnd CN), with a calculated activation energy associated with the rate determining step of about 51 kJ mol-1. This reaction inhibits the formation of 2-aminopropan-2-ol (HOsbnd C(CH3)2sbnd NH2) from acetone and NH3, even in the presence of water, which is the first step of the Strecker synthesis to form 2-aminoisobutyric acid (NH2C(CH3)2COOH). However, HOsbnd C(CH3)2sbnd CN formation could be part of an alternative chemical pathway leading to 2-hydroxy-2-methyl-propanoic acid (HOC(CH3)2COOH), which could explain the presence of hydroxy acids in some meteorites.

TCR signaling by conventional CD4+ T cells is required for optimal maintenance of peripheral regulatory T cell numbers.

PubMed

Leichner, Theresa M; Satake, Atsushi; Kambayashi, Taku

2016-06-01

To maintain immune tolerance, regulatory T cell (Treg) numbers must be closely indexed to the number of conventional T cells (Tconvs) so that an adequate Treg:Tconv ratio can be maintained. Two factors important in this process are the cytokine interleukin-2 (IL-2) and T cell receptor (TCR) stimulation by major histocompatibility complex class II (MHC-II). Here, we report that in addition to TCR stimulation of Tregs themselves, the maintenance of Tregs also requires TCR signaling by Tconvs. We found that Tconvs produce IL-2 in response to self-peptide-MHC-II complexes and that Tconvs possessing more highly self-reactive TCRs express more IL-2 at baseline. Furthermore, selective disruption of TCR signaling in Tconvs led to a trend toward decreased expression of IL-2 and attenuated their ability to maintain Treg numbers. These data suggest that in order to maintain an adequate Treg:Tconv ratio, Tregs are continuously indexed to self-peptide-MHC-II-induced TCR signaling of Tconvs. These results have implications in attempts to modulate immune tolerance, as Treg numbers adjust to the self-reactivity, and ultimately IL-2 production by the T cells around them.

Crataegus special extract WS 1442 causes endothelium-dependent relaxation via a redox-sensitive Src- and Akt-dependent activation of endothelial NO synthase but not via activation of estrogen receptors.

PubMed

Anselm, Eric; Socorro, Vanesca Frota Madeira; Dal-Ros, Stéphanie; Schott, Christa; Bronner, Christian; Schini-Kerth, Valérie B

2009-03-01

This study determined whether the Crataegus (Hawthorn species) special extract WS 1442 stimulates the endothelial formation of nitric oxide (NO), a vasoprotective factor, and characterized the underlying mechanism. Vascular reactivity was assessed in porcine coronary artery rings, reactive oxygen species (ROS) formation in artery sections by microscopy, and phosphorylation of Akt and endothelial NO synthase (eNOS) in endothelial cells by Western blot analysis. WS 1442 caused endothelium-dependent relaxations in coronary artery rings, which were reduced by N-nitro-L-arginine (a competitive inhibitor of NO synthase) and by charybdotoxin plus apamin (two inhibitors of endothelium-derived hyperpolarizing factor-mediated responses). Relaxations to WS 1442 were inhibited by intracellular ROS scavengers and inhibitors of Src and PI3-kinase, but not by an estrogen receptor antagonist. WS 1442 stimulated the endothelial formation of ROS in artery sections, and a redox-sensitive phosphorylation of Akt and eNOS in endothelial cells. WS 1442 induced endothelium-dependent NO-mediated relaxations of coronary artery rings through the redox-sensitive Src/PI3-kinase/Akt-dependent phosphorylation of eNOS.

A canine distemper model of virus-induced anergy.

PubMed

Mangi, R J; Munyer, T P; Krakowka, S; Jacoby, R O; Kantor, F S

1976-05-01

For development of an animal model of virus-induced anergy, the effect of canine distemper virus (CDV) upon cell-mediated immunity in dogs was investigated. First, canine cutaneous reactions and in vitro lymphocyte responses to soluble protein antigens were characterized. Dogs immunized with picryl guinea pig albumin and with keyhole limpet hemocyanin (both in complete Freund's adjuvant) responded reproducibly to intracutaneous challenge with these antigens. Reactivity peaked in 20-40 days (maximal induration, 6-50 mm). Lymphocytes from these animals responded in vitro to stimulation with keyhole limpet hemocyanin or purified protein derivative. This stimulation was antigen-specific and was maximal on day 6 of culture. Infection with CDV depressed cutaneous reactivity and lymphocyte response in vitro to antigens and mitogens. This effect was transient in animals previously vaccinated with attenuated CDV; however, gnotobiotic puppies (susceptible to CDV) had prolonged depression of cell-mediated immunity and lymphopenia. Some of these animals developed neurologic symptoms and died. The findings indicate that CDV infection is a potentially useful model for study of virus-induced depression of T (thymus)-cell responses and support the hypothesis that there is more than one mechanism responsible for this phenomenon.

Antioxidants change platelet responses to various stimulating events

PubMed Central

Sobotková, Alžběta; Mášová-Chrastinová, Leona; Suttnar, Jiří; Štikarová, Jana; Májek, Pavel; Reicheltová, Zuzana; Kotlín, Roman; Weisel, John W.; Malý, Martin; Dyr, Jan E.

2010-01-01

The role of platelets in hemostasis may be influenced by alteration of the platelet redox state—the presence of antioxidants and the formation of reactive oxygen and nitrogen species. We investigated the effects of two antioxidants, resveratrol and trolox, on platelet activation. Trolox and resveratrol inhibited aggregation of washed platelets and platelet-rich plasma activated by ADP, collagen, and thrombin receptor-activating peptide. Resveratrol was a more effective agent in reducing platelet static and dynamic adhesion in comparison with trolox. The antioxidant capacity of resveratrol was, however, the same as that of trolox. After incubation of platelets with antioxidants, the resveratrol intraplatelet concentration was about five times lower than the intracellular concentration of trolox. Although both antioxidants comparably lowered hydroxyl radical and malondialdehyde production in platelets stimulated with collagen, TxB2 levels were decreased by resveratrol much more effectively than by trolox. Cyclooxygenase 1 was inhibited by resveratrol and not by trolox. Our data indicate that antioxidants, apart from nonspecific redox or radical-quenching mechanisms, inhibit platelet activation also by specific interaction with target proteins. The results also show the importance of studying platelet activation under conditions of real blood flow in contact with reactive surfaces, e.g., using dynamic adhesion experiments. PMID:19766712

Antioxidants change platelet responses to various stimulating events.

PubMed

Sobotková, Alzbeta; Másová-Chrastinová, Leona; Suttnar, Jirí; Stikarová, Jana; Májek, Pavel; Reicheltová, Zuzana; Kotlín, Roman; Weisel, John W; Malý, Martin; Dyr, Jan E

2009-12-15

The role of platelets in hemostasis may be influenced by alteration of the platelet redox state-the presence of antioxidants and the formation of reactive oxygen and nitrogen species. We investigated the effects of two antioxidants, resveratrol and trolox, on platelet activation. Trolox and resveratrol inhibited aggregation of washed platelets and platelet-rich plasma activated by ADP, collagen, and thrombin receptor-activating peptide. Resveratrol was a more effective agent in reducing platelet static and dynamic adhesion in comparison with trolox. The antioxidant capacity of resveratrol was, however, the same as that of trolox. After incubation of platelets with antioxidants, the resveratrol intraplatelet concentration was about five times lower than the intracellular concentration of trolox. Although both antioxidants comparably lowered hydroxyl radical and malondialdehyde production in platelets stimulated with collagen, TxB(2) levels were decreased by resveratrol much more effectively than by trolox. Cyclooxygenase 1 was inhibited by resveratrol and not by trolox. Our data indicate that antioxidants, apart from nonspecific redox or radical-quenching mechanisms, inhibit platelet activation also by specific interaction with target proteins. The results also show the importance of studying platelet activation under conditions of real blood flow in contact with reactive surfaces, e.g., using dynamic adhesion experiments.

Rifampin-stimulated uv resistance of phage lambda on Escherichia coli K12

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

Bronner, C.E.; Fluke, D.J.; Pollard, E.C.

1983-01-01

The plaque survival of uv-irradiated phage lambda on excision-proficient E.coli strain AB1157 is greater if the host cells are exposed to rifampin for 10 minutes prior to infection. This repair is accompanied by little or no clear-plaque mutagenesis. Host cells uv-irradiated and incubated for 30 minutes in growth medium prior to treatment with rifampin show some Weigle-reactivation in addition to the repair stimulated by rifampin. Some clear-plaque Weigle-mutagenesis is also observed in the presence of rifampin: however, the amount is less than that seen in the absence of rifampin treatment. In contrast, the uv sensitivity of lambda on strain AB1886,more » an excision-repair deficient mutant, is unchanged by pre-treating the cells with rifampin, and no Weigle-reactivation is observed. These results suggest that repair of lambda on unirradiated cells in the presence of rifampin is an excision-dependent, error-free phenomenon. Since initiation of replication of lambda DNA requires RNA polymerase, and since rifampin blocks transcription by that polymerase, the effect of rifampin on the survival of lambda may be to delay phage replication, thereby allowing more time for excision repair to operate. 6 figures.« less

Estimating the reactivation potential of existing fractures in subsurface granitoids from outcrop analogues and in-situ stress modeling: implications for EGS reservoir stimulation with an example from Meiningen (Thuringia, Central Germany)

NASA Astrophysics Data System (ADS)

Ustaszewski, Kamil; Kasch, Norbert; Siegburg, Melanie; Navabpour, Payman; Thieme, Manuel

2014-05-01

The southwestern part of Thuringia (central Germany) hosts large subsurface extents of Lower Carboniferous granitoids of the Mid-German Crystalline Rise, overlain by an up to several kilometer thick succession of Lower Permian to Mid-Triassic volcanic and sedimentary rocks. The granitic basement represents a conductivity-controlled ('hot dry rock') reservoir of high potential that could be targeted for economic exploitation as an enhanced geothermal system (EGS) in the future. As a preparatory measure, the federal states of Thuringia and Saxony have jointly funded a collaborative research and development project ('Optiriss') aimed at mitigating non-productivity risks during the exploration of such reservoirs. In order to provide structural constraints on the fracture network design during reservoir stimulation, we have carried out a geometric and kinematic analysis of pre-existing fracture patterns in exposures of the Carboniferous basement and Mesozoic cover rocks within an area of c. 500 km2 around the towns of Meiningen and Suhl, where granitic basement and sedimentary cover are juxtaposed along the southern border fault of the Thuringian Forest basement high. The frequency distribution of fractures was assessed by combining outcrop-scale fracture measurements in 31 exposures and photogrammetric analysis of fractures using a LIDAR DEM with 5 m horizontal resolution and rectified aerial images at 4 localities. This analysis revealed a prevalence of NW-SE-trending fractures of mainly joints, extension veins, Permian magmatic dikes and subordinately brittle faults in the Carboniferous granitic basement, which probably resulted from Permian tectonics. In order to assess the reactivation potential of fractures in the reservoir during a stimulation phase, constraints on the current strain regime and in-situ stress magnitudes, including borehole data and earthquake focal mechanisms in a larger area, were needed. These data reveal a presently NW-SE-trending maximum horizontal stress SHmax and a strike-slip regime (Heidbach et al. 2008). In-situ stress magnitudes at a reservoir depth of 4.5 km were calculated assuming hydrostatic pore pressures and frictional equilibrium along pre-existing fractures. Our estimates allow predicting that NW-SE-trending fractures in the reservoir would probably be reactivated as dilational veins during stimulation. In order to ensure that the stimulated rock volume is as large as possible and injected fluids circulate along newly-formed fractures rather than other pre-existing fractures, hydraulic fracturing at reservoir depth should follow a well trajectory parallel to the minimum horizontal stress Shmin, i.e. subhorizontal and NE-SW-oriented. References: Heidbach, O., et al., 2008, World Stress Map database release 2008, doi:10.1594/GFZ.WSM.Rel2008.

Multi-Step Deep Reactive Ion Etching Fabrication Process for Silicon-Based Terahertz Components

NASA Technical Reports Server (NTRS)

Reck, Theodore (Inventor); Perez, Jose Vicente Siles (Inventor); Lee, Choonsup (Inventor); Cooper, Ken B. (Inventor); Jung-Kubiak, Cecile (Inventor); Mehdi, Imran (Inventor); Chattopadhyay, Goutam (Inventor); Lin, Robert H. (Inventor); Peralta, Alejandro (Inventor)

2016-01-01

A multi-step silicon etching process has been developed to fabricate silicon-based terahertz (THz) waveguide components. This technique provides precise dimensional control across multiple etch depths with batch processing capabilities. Nonlinear and passive components such as mixers and multipliers waveguides, hybrids, OMTs and twists have been fabricated and integrated into a small silicon package. This fabrication technique enables a wafer-stacking architecture to provide ultra-compact multi-pixel receiver front-ends in the THz range.

Rhythmic motor activity and interlimb co-ordination in the developing pouch young of a wallaby (Macropus eugenii).

PubMed Central

Ho, S M

1997-01-01

1. The forelimb motor behaviour of developing wallaby was studied. A clock-like alternating movement was reactivated whenever the animal was removed from the pouch. 2. Forelimb stepping frequency increased during the first 3 weeks of development, while the phase relationship remained constant. Forelimb activity could be affected by altering the afferent feedback from the contralateral limb, or an increase in ambient temperature. 3. In vitro experiments were performed using an isolated brainstem-spinal cord preparation from animals up to 6 weeks postnatal. Fictive locomotor activity could be evoked by electrical stimulation or bath-applied NMDA (< 10 microM). 4. Bath-applied strychnine (10-25 microM) and bicuculline (10-50 microM) disrupted the phase relationship between motor pools, while rhythmic motor discharge remained in the absence of these inhibitory pathways. 5. The present findings indicate that the pattern generator that underlies the robust forelimb movement during the first journey to the pouch is retained for different motor functions during in-pouch development. The neural network that underlies such behaviour can be divided into two major components, a rhythm generator within each hemicord, and a pattern co-ordinating pathway which involve both glycinergic and GABAergic interneurones. PMID:9218221

Role of redox signaling in the autonomous proliferative response of endothelial cells to hypoxia.

PubMed

Schäfer, M; Schäfer, C; Ewald, N; Piper, H M; Noll, Th

2003-05-16

Endothelial cells exhibit an autonomous proliferative response to hypoxia, independent of paracrine effectors. In cultured endothelial cells of porcine aorta, we analyzed the signaling of this response, with a focus on the roles of redox signaling and the MEK/ERK pathway. Transient hypoxia (1 hour) stimulated proliferation by 61+/-4% (n=16; P<0.05 versus control), quantified after 24 hours normoxic postincubation. Hypoxia induced an activation of ERK2 and of NAD(P)H oxidase and a burst of reactive oxygen species (ROS), determined by DCF fluorescence. To inhibit the MEK/ERK pathway, we used PD 98059 (PD, 20 micromol/L); to downregulate NAD(P)H oxidase, we applied p22phox antisense oligonucleotides; and to inhibit mitochondrial ROS generation, we used the ubiquinone derivate mitoQ (MQ, 10 micromol/L). All three inhibitions suppressed the proliferative response: PD inhibited NAD(P)H oxidase activation; p22phox antisense transfection did not inhibit ERK2 activation, but suppressed ROS production; and MQ inhibited ERK2 activation and ROS production. The autonomous proliferative response depends on the MEK/ERK pathway and redox signaling steps upstream and downstream of ERK. Located upstream is ROS generation by mitochondria, downstream is NAD(P)H oxidase.

Inhibition of glycogen-synthase kinase 3 stimulates glycogen synthase and glucose transport by distinct mechanisms in 3T3-L1 adipocytes.

PubMed

Oreña, S J; Torchia, A J; Garofalo, R S

2000-05-26

The role of glycogen-synthase kinase 3 (GSK3) in insulin-stimulated glucose transport and glycogen synthase activation was investigated in 3T3-L1 adipocytes. GSK3 protein was clearly present in adipocytes and was found to be more abundant than in muscle and liver cell lines. The selective GSK3 inhibitor, LiCl, stimulated glucose transport and glycogen synthase activity (20 and 65%, respectively, of the maximal (1 microm) insulin response) and potentiated the responses to a submaximal concentration (1 nm) of insulin. LiCl- and insulin-stimulated glucose transport were abolished by the phosphatidylinositol 3-kinase (PI3-kinase) inhibitor, wortmannin; however, LiCl stimulation of glycogen synthase was not. In contrast to the rapid stimulation of glucose transport by insulin, transport stimulated by LiCl increased gradually over 3-5 h reaching 40% of the maximal insulin-stimulated level. Both LiCl- and insulin-stimulated glycogen synthase activity were maximal at 25 min. However, insulin-stimulated glycogen synthase activity returned to basal after 2 h, coincident with reactivation of GSK3. After a 2-h exposure to insulin, glycogen synthase was refractory to restimulation with insulin, indicating selective desensitization of this pathway. However, LiCl could partially stimulate glycogen synthase in desensitized cells. Furthermore, coincubation with LiCl during the 2 h exposure to insulin completely blocked desensitization of glycogen synthase activity. In summary, inhibition of GSK3 by LiCl: 1) stimulated glycogen synthase activity directly and independently of PI3-kinase, 2) stimulated glucose transport at a point upstream of PI3-kinase, 3) stimulated glycogen synthase activity in desensitized cells, and 4) prevented desensitization of glycogen synthase due to chronic insulin treatment. These data are consistent with GSK3 playing a central role in the regulation of glycogen synthase activity and a contributing factor in the regulation of glucose transport in 3T3-L1 adipocytes.

Agonist-induced platelet reactivity correlates with bleeding in haemato-oncological patients.

PubMed

Batman, B; van Bladel, E R; van Hamersveld, M; Pasker-de Jong, P C M; Korporaal, S J A; Urbanus, R T; Roest, M; Boven, L A; Fijnheer, R

2017-11-01

Prophylactic platelet transfusions are administered to prevent bleeding in haemato-oncological patients. However, bleeding still occurs, despite these transfusions. This practice is costly and not without risk. Better predictors of bleeding are needed, and flow cytometric evaluation of platelet function might aid the clinician in identifying patients at risk of bleeding. This evaluation can be performed within the hour and is not hampered by low platelet count. Our objective was to assess a possible correlation between bleeding and platelet function in thrombocytopenic haemato-oncological patients. Inclusion was possible for admitted haemato-oncology patients aged 18 years and above. Furthermore, an expected need for platelet transfusions was necessary. Bleeding was graded according to the WHO bleeding scale. Platelet reactivity to stimulation by either adenosine diphosphate (ADP), cross-linked collagen-related peptide (CRP-xL), PAR1- or PAR4-activating peptide (AP) was measured using flow cytometry. A total of 114 evaluations were available from 21 consecutive patients. Platelet reactivity in response to stimulation by all four studied agonists was inversely correlated with significant bleeding. Odds ratios (OR) for bleeding were 0·28 for every unit increase in median fluorescence intensity (MFI) [95% confidence interval (CI) 0·11-0·73] for ADP; 0·59 [0·40-0·87] for CRP-xL; 0·59 [0·37-0·94] for PAR1-AP; and 0·43 [0·23-0·79] for PAR4-AP. The platelet count was not correlated with bleeding (OR 0·99 [0·96-1·02]). Agonist-induced platelet reactivity was significantly correlated to bleeding. Platelet function testing could provide a basis for a personalized transfusion regimen, in which platelet transfusions are limited to those at risk of bleeding. © 2017 International Society of Blood Transfusion.

Definition of a pool of epitopes that recapitulates the T cell reactivity against major house dust mite allergens.

PubMed

Hinz, D; Oseroff, C; Pham, J; Sidney, J; Peters, B; Sette, A

2015-10-01

Allergens from house dust mites (HDM) are a common cause of asthma. Der p and Der f from Dermatophagoides sp. are strong immunogens in humans. Allergen extracts are used to study T helper (Th2) cell responses to HDM, which are implicated in the development and regulation of allergic disease. To define an epitope mixture that recapitulates, and might substitute for, HDM extract in terms of detecting and characterizing Th2 cell responses. Peripheral blood mononuclear cells (PBMC) from 52 HDM allergic and 10 non-allergic individuals were stimulated with HDM extracts and assayed with a set of 178 peptides spanning mite allergens group Der p 1, 2, 23 and Der f group 1 and 2 allergens. A pool of the most dominant T cell epitopes identified in the present study and from published literature was assembled and tested for ex vivo T cell responses. Correlation with HDM-specific IgE titres was examined. Patterns of T cell reactivity to Der p and Der f - derived peptides revealed a large number of epitopes. Clear patterns of immunodominance were apparent, with HDM allergen group 1 and 2 dominant over group 23. Furthermore, within a given antigen, 6-11 epitopes accounted for the vast majority of responses. Based on these results and published data, a comprehensive dust mite pool (DMP) of epitopes was designed and found to allow detection of ex vivo T cell responses. DMP ex vivo reactivity correlated with HDM-specific IgE titres and was similar to that detected with commonly used HDM extracts. Ex vivo DMP stimulation was associated with a predominant Th2 response in allergic donors, and minor reactivity of T cells producing IFNγ, IL17 and IL10. A detailed map of Der p and Der f antigens defined a pool of epitopes that can be used to detect ex vivo HDM responses. © 2015 John Wiley & Sons Ltd.

Photochemistry of Aqueous C60 Clusters: Wavelength Dependency and Product Characterization

EPA Science Inventory

To construct accurate risk assessment models for engineered nanomaterials, there is urgent need for information on the reactivity (or conversely, persistence) and transformation pathways of these materials in the natural environment. As an important step toward addressing this is...

Attentional Retraining Administered to Cigarette Smokers in the Field: Effects on Attentional Bias, Craving, and Smoking

DTIC Science & Technology

2013-08-30

in cognitive bias modification was originally stimulated by the work of MacLeod, Mathews, and colleagues in their studies of the cognitive processes...probe would always replace the neutral stimulus which may not necessarily have occurred without these instructions). This may have stimulated the...retrain auditory or even olfactory attention. An important first step in this process would be the exploration of possible attentional biases for

Effects of intensive glucose control on platelet reactivity in patients with acute coronary syndromes. Results of the CHIPS Study ("Control de Hiperglucemia y Actividad Plaquetaria en Pacientes con Sindrome Coronario Agudo").

PubMed

Vivas, David; García-Rubira, Juan C; Bernardo, Esther; Angiolillo, Dominick J; Martín, Patricia; Calle-Pascual, Alfonso; Núñez-Gil, Iván; Macaya, Carlos; Fernández-Ortiz, Antonio

2011-05-01

Hyperglycaemia has been associated with increased platelet reactivity and impaired prognosis in patients with acute coronary syndrome (ACS). Whether platelet reactivity can be reduced by lowering glucose in this setting is unknown. The aim of this study was to assess the functional impact of intensive glucose control with insulin on platelet reactivity in patients admitted with ACS and hyperglycaemia. This is a prospective, randomised trial evaluating the effects of either intensive glucose control (target glucose 80-120 mg/dl) or conventional control (target glucose 180 mg/dl or less) with insulin on platelet reactivity in patients with ACS and hyperglycaemia. The primary endpoint was platelet aggregation following stimuli with 20 μM ADP at 24 h and at hospital discharge. Aggregation following collagen, epinephrine and thrombin receptor-activated peptide, as well as P2Y₁₂ reactivity index and surface expression of glycoprotein IIb/IIIa and P-selectin were also measured. Of the 115 patients who underwent random assignment, 59 were assigned to intensive and 56 to conventional glucose control. Baseline platelet functions and inhospital management were similar in both groups. Maximal aggregation after ADP stimulation at hospital discharge was lower in the intensive group (47.9 ± 13.2% vs 59.1 ± 17.3%; p=0.002), whereas no differences were found at 24 h. Similarly all other parameters of platelet reactivity measured at hospital discharge were significantly reduced in the intensive glucose control group. In this randomised trial, early intensive glucose control with insulin in patients with ACS presenting with hyperglycaemia was found to decrease platelet reactivity. Clinical Trial Registration Number http://www.controlledtrials.com/ISRCTN35708451/ISRCTN35708451.

Establishment of an in silico phototoxicity prediction method by combining descriptors related to photo-absorption and photo-reaction.

PubMed

Haranosono, Yu; Kurata, Masaaki; Sakaki, Hideyuki

2014-08-01

One of the mechanisms of phototoxicity is photo-reaction, such as reactive oxygen species (ROS) generation following photo-absorption. We focused on ROS generation and photo-absorption as key-steps, because these key-steps are able to be described by photochemical properties, and these properties are dependent on chemical structure. Photo-reactivity of a compound is described by HOMO-LUMO Gap (HLG), generally. Herein, we showed that HLG can be used as a descriptor of the generation of reactive oxygen species. Moreover, the maximum-conjugated π electron number (PENMC), which we found as a descriptor of photo-absorption, could also predict in vitro phototoxicity. Each descriptor could predict in vitro phototoxicity with 70.0% concordance, but there was un-predicted area found (gray zone). Interestingly, some compounds in each gray zone were not common, indicating that the combination of two descriptors could improve prediction potential. We reset the cut-off lines to define positive zone, negative zone and gray zone for each descriptor. Thereby we overlapped HLG and PENMC in a graph, and divided the total area to nine zones with cut-off lines of each descriptor. The rules to prediction were decided to achieve the best concordance, and the concordances were improved up to 82.8% for self-validation, 81.6% for cross-validation. We found common properties among false positive or negative compounds, photo-reactive structure and photo-allergenic, respectively. In addition, our method could be adapted to compounds rich in structural diversity using only chemical structure without any statistical analysis and complicated calculation.