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Sample records for activation modulates permeability

  1. Acute Modulations in Permeability Barrier Function Regulate Epidermal Cornification : Role of Caspase-14 and the Protease-Activated Receptor Type 2

    Demerjian, Marianne; Hachem, Jean-Pierre; Tschachler, Erwin; Denecker, Geertrui; Declercq, Wim; Vandenabeele, Peter; Mauro, Theodora; Hupe, Melanie; Crumrine, Debra; Roelandt, Truus; Houben, Evi; Elias, Peter M.; Feingold, Kenneth R.

    2008-01-01

    Stratum corneum comprises corneocytes, derived from outer stratum granulosum during terminal differentiation, embedded in a lipid-enriched extracellular matrix, secreted from epidermal lamellar bodies. Permeability barrier insults stimulate rapid secretion of preformed lamellar bodies from the outer stratum granulosum, regulated through modulations in ionic gradients and serine protease (SP)/protease-activated receptor type 2 (PAR2) signaling. Because corneocytes are also required for barrier...

  2. Composite Crew Module (CCM) Permeability Characterization

    Kirsch, Michael T.

    2013-01-01

    In January 2007, the NASA Administrator chartered the NASA Engineering and Safety Center (NESC) to form an Agency team to design and build a composite crew module in 18 months in order to gain hands-on experience in anticipation that future exploration systems may be made of composite materials. One of the conclusions from this Composite Crew Module Primary Structure assessment was that there was a lack of understanding regarding the ability for composite pressure shells to contain consumable gases, which posed a technical risk relative to the use of a metallic design. After the completion of the Composite Crew Module test program, the test article was used in a new program to assess the overall leakage/permeability and identify specific features associated with high leak rates. This document contains the outcome of the leakage assessment.

  3. Vesicles as tools for the modulation of skin permeability.

    Dubey, Vaibhav; Mishra, Dinesh; Nahar, Manoj; Jain, Narendra K

    2007-11-01

    Human skin is a remarkably efficient barrier designed to keep our insides in and the outside out. The modulation of this efficient barrier's properties, including its permeability to chemicals, drugs and biologically active agents is the prime target for various dermal, transdermal, drug, antigen and gene delivery approaches. Therefore, several methods have been attempted to enhance the permeation rate of biologically active agents, temporarily and locally. One of the approaches is the application of drug-laden vesicular formulations. This review presents various mechanisms involved in increasing drug transport across the skin via different vesicular approaches, such as liposomes, elastic vesicles and ethosomes, along with compiling the research work conducted in this field. PMID:17970662

  4. Endocannabinoids modulate human blood–brain barrier permeability in vitro

    Hind, William H.; Tufarelli, Cristina; Neophytou, Maria; Anderson, Susan I; England, Timothy J.; O'Sullivan, Saoirse E

    2015-01-01

    Background and Purpose Endocannabinoids alter permeability at various epithelial barriers, and cannabinoid receptors and endocannabinoid levels are elevated by stroke, with potential neuroprotective effects. We therefore explored the role of endocannabinoids in modulating blood–brain barrier (BBB) permeability in normal conditions and in an ischaemia/reperfusion model. Experimental Approach Human brain microvascular endothelial cell and astrocyte co-cultures modelled the BBB. Ischaemia was mo...

  5. Endocannabinoids modulate human blood–brain barrier permeability in vitro

    Hind, William H; Tufarelli, Cristina; Neophytou, Maria; Anderson, Susan I; England, Timothy J; O'Sullivan, Saoirse E

    2015-01-01

    Background and Purpose Endocannabinoids alter permeability at various epithelial barriers, and cannabinoid receptors and endocannabinoid levels are elevated by stroke, with potential neuroprotective effects. We therefore explored the role of endocannabinoids in modulating blood–brain barrier (BBB) permeability in normal conditions and in an ischaemia/reperfusion model. Experimental Approach Human brain microvascular endothelial cell and astrocyte co-cultures modelled the BBB. Ischaemia was modelled by oxygen-glucose deprivation (OGD) and permeability was measured by transepithelial electrical resistance. Endocannabinoids or endocannabinoid-like compounds were assessed for their ability to modulate baseline permeability or OGD-induced hyperpermeability. Target sites of action were investigated using receptor antagonists and subsequently identified with real-time PCR. Key Results Anandamide (10 μM) and oleoylethanolamide (OEA, 10 μM) decreased BBB permeability (i.e. increased resistance). This was mediated by cannabinoid CB2 receptors, transient receptor potential vanilloid 1 (TRPV1) channels, calcitonin gene-regulated peptide (CGRP) receptor (anandamide only) and PPARα (OEA only). Application of OEA, palmitoylethanolamide (both PPARα mediated) or virodhamine (all 10 μM) decreased the OGD-induced increase in permeability during reperfusion. 2-Arachidonoyl glycerol, noladin ether and oleamide did not affect BBB permeability in normal or OGD conditions. N-arachidonoyl-dopamine increased permeability through a cytotoxic mechanism. PPARα and γ, CB1 receptors, TRPV1 channels and CGRP receptors were expressed in both cell types, but mRNA for CB2 receptors was only present in astrocytes. Conclusion and Implication The endocannabinoids may play an important modulatory role in normal BBB physiology, and also afford protection to the BBB during ischaemic stroke, through a number of target sites. PMID:25651941

  6. Temporal photonic crystals with modulations of both permittivity and permeability

    Martínez-Romero, Juan Sabino; Becerra-Fuentes, O. M.; Halevi, P.

    2016-06-01

    We present an in-depth study of electromagnetic wave propagation in a temporal photonic crystal, namely, a nonconducting medium whose permittivity ɛ (t ) and/or permeability μ (t ) are modulated periodically by unspecified agents (these modulations not necessarily being in phase). Maxwell's equations lead to an eigenvalue problem whose solution provides the dispersion relation ω (k ) for the waves that can propagate in such a dynamic medium. This is a generalization of previous work [J. R. Zurita-Sánchez and P. Halevi, Phys. Rev. A 81, 053834 (2010)], 10.1103/PhysRevA.81.053834 that was restricted to the electric modulation ɛ (t ) . For our numerical work (only) we assumed the harmonic modulations ɛ (t ) =ɛ ¯[1 +mɛsin(Ω t ) ] and μ (t ) =μ ¯[1 +mμsin(Ω t +θ ) ] , where Ω is the circular modulation frequency; mɛ and mμ are, respectively, the strengths of the electric and magnetic modulations; and θ is the phase difference between these modulations. An analytic calculation for weak modulations (mɛ≪1 ,mμ≪1 ) leads to two k bands, k1(ω ) and k2(ω ) , that are separated by a k gap. If the modulations are in phase (θ =0 ) , this gap is proportional to | mɛ-mμ| , while the gap is proportional to (mɛ+mμ) if the modulations are out of phase (θ =π ) . The gap thus disappears for equal, in-phase, modulations (mɛ=mμ) . An exact solution of the eigenvalue equation confirms that these approximations hold reasonably well even for moderate modulations. In fact, there are no k gaps for equal modulations even if these are very strong (mɛ ,μ≲1 ) . The photonic band structure k (ω ) is periodic in ω , with period Ω , and there is an infinite number of bands k1(ω ) , k2(ω ) ,... Further, by allowing ɛ (t ) and μ (t ) to have imaginary parts, we examined the effects of damping [Im k (ω )] on the k bands. We also determined the optical response of a temporal photonic crystal slab, applying the above harmonic model for ɛ (t ) and μ (t

  7. Non-invasive optical modulation of local vascular permeability

    Choi, Myunghwan; Choi, Chulhee

    2011-03-01

    For a systemically administered drug to act, it first needs to cross the vascular wall. This step represents a bottleneck for drug development, especially in the brain or retina, where tight junctions between endothelial cells form physiological barriers. Here, we demonstrate that femtosecond pulsed laser irradiation focused on the blood vessel wall induces transient permeabilization of plasma. Nonlinear absorption of the pulsed laser enabled the noninvasive modulation of vascular permeability with high spatial selectivity in three dimensions. By combining this method with systemic injection, we could locally deliver molecular probes in various tissues, such as brain cortex, meninges, ear, striated muscle, and bone. We suggest this method as a novel delivery tool for molecular probes or drugs.

  8. Intracellular calcium modulates basolateral K(+)-permeability in frog skin epithelium

    Brodin, Birger; Rytved, K A; Nielsen, R

    1994-01-01

    Cytosolic calcium ([Ca2+]i) has been suggested as a key modulator in the regulation of active sodium transport across electrically "tight" (high resistance) epithelia. In this study we investigated the effects of calcium on cellular electrophysiological parameters in a classical model tissue, the...... frog skin. [Ca2+]i was measured with fura-2 in an epifluorescence microscope setup. An inhibition of basolateral potassium permeability was observed when cytosolic calcium was increased. This inhibition was reversible upon removal of calcium from the serosal solution....

  9. In vitro blood-brain barrier permeability predictions for GABAA receptor modulating piperine analogs.

    Eigenmann, Daniela Elisabeth; Dürig, Carmen; Jähne, Evelyn Andrea; Smieško, Martin; Culot, Maxime; Gosselet, Fabien; Cecchelli, Romeo; Helms, Hans Christian Cederberg; Brodin, Birger; Wimmer, Laurin; Mihovilovic, Marko D; Hamburger, Matthias; Oufir, Mouhssin

    2016-06-01

    The alkaloid piperine from black pepper (Piper nigrum L.) and several synthetic piperine analogs were recently identified as positive allosteric modulators of γ-aminobutyric acid type A (GABAA) receptors. In order to reach their target sites of action, these compounds need to enter the brain by crossing the blood-brain barrier (BBB). We here evaluated piperine and five selected analogs (SCT-66, SCT-64, SCT-29, LAU397, and LAU399) regarding their BBB permeability. Data were obtained in three in vitro BBB models, namely a recently established human model with immortalized hBMEC cells, a human brain-like endothelial cells (BLEC) model, and a primary animal (bovine endothelial/rat astrocytes co-culture) model. For each compound, quantitative UHPLC-MS/MS methods in the range of 5.00-500ng/mL in the corresponding matrix were developed, and permeability coefficients in the three BBB models were determined. In vitro predictions from the two human BBB models were in good agreement, while permeability data from the animal model differed to some extent, possibly due to protein binding of the screened compounds. In all three BBB models, piperine and SCT-64 displayed the highest BBB permeation potential. This was corroborated by data from in silico prediction. For the other piperine analogs (SCT-66, SCT-29, LAU397, and LAU399), BBB permeability was low to moderate in the two human BBB models, and moderate to high in the animal BBB model. Efflux ratios (ER) calculated from bidirectional permeability experiments indicated that the compounds were likely not substrates of active efflux transporters. PMID:27018328

  10. Thyroid hormone modulates rabbit proximal straight tubule paracellular permeability

    Baum, Michel; Quigley, Raymond

    2003-01-01

    Proximal straight tubules (PST) from both neonatal and hypothyroid adult rabbits have a lower rate of passive volume absorption when perfused with a high-chloride solution simulating late proximal tubular fluid than adult rabbit PST. We hypothesized that the maturational increase in serum thyroid hormone levels mediates the developmental changes in PST paracellular permeability. Neonatal tubules had lower chloride permeability, higher transepithelial resistance, but comparable mannitol permea...

  11. Zinc modulation of water permeability reveals that aquaporin 0 functions as a cooperative tetramer.

    Németh-Cahalan, Karin L; Kalman, Katalin; Froger, Alexandrine; Hall, James E

    2007-11-01

    We previously showed that the water permeability of AQP0, the water channel of the lens, increases with acid pH and that His40 is required (Németh-Cahalan, K.L., and J.E. Hall. 2000. J. Biol. Chem. 275:6777-6782; Németh-Cahalan, K.L., K. Kalman, and J.E. Hall. 2004. J. Gen. Physiol. 123:573-580). We have now investigated the effect of zinc (and other transition metals) on the water permeability of AQP0 expressed in Xenopus oocytes and determined the amino acid residues that facilitate zinc modulation. Zinc (1 mM) increased AQP0 water permeability by a factor of two and prevented any additional increase induced by acid pH. Zinc had no effect on water permeability of AQP1, AQP4 or MIPfun (AQP0 from killifish), or on mutants of AQP1 and MIPfun with added external histidines. Nickel, but not copper, had the same effect on AQP0 water permeability as zinc. A fit of the concentration dependence of the zinc effect to the Hill equation gives a coefficient greater than three, suggesting that binding of more than one zinc ion is necessary to enhance water permeability. His40 and His122 are necessary for zinc modulation of AQP0 water permeability, implying structural constraints for zinc binding and functional modulation. The change in water permeability was highly sensitive to a coinjected zinc-insensitive mutant and a single insensitive monomer completely abolished zinc modulation. Our results suggest a model in which positive cooperativity among subunits of the AQP0 tetramer is required for zinc modulation, implying that the tetramer is the functional unit. The results also offer the possibility of a pharmacological approach to manipulate the water permeability and transparency of the lens. PMID:17938229

  12. Permeability and modulation of the intestinal epithelial barrier in vitro

    Duizer, E.

    1999-01-01

    The bioavailability of all ingested compounds is to a great extend determined by the ability of these compounds to pass the intestinal epithelium. A high bioavailability is guaranteed for most nutrients and electrolytes since they are actively absorbed by the epithelium. The same epithelium, however

  13. Permeability and modulation of the intestinal epithelial barrier in vitro

    Duizer, E.

    1999-01-01

    The bioavailability of all ingested compounds is to a great extend determined by the ability of these compounds to pass the intestinal epithelium. A high bioavailability is guaranteed for most nutrients and electrolytes since they are actively absorbed by the epithelium. The same epithelium, however, renders the entrance of non-nutrient (potentially harmful) hydrophilic (macro-) molecules, viruses and bacteria into the systemic circulation very low by presenting an almost impermeable barrier ...

  14. Tuning PAK Activity to Rescue Abnormal Myelin Permeability in HNPP.

    Hu, Bo; Arpag, Sezgi; Zhang, Xuebao; Möbius, Wiebke; Werner, Hauke; Sosinsky, Gina; Ellisman, Mark; Zhang, Yang; Hamilton, Audra; Chernoff, Jonathan; Li, Jun

    2016-09-01

    Schwann cells in the peripheral nervous systems extend their membranes to wrap axons concentrically and form the insulating sheath, called myelin. The spaces between layers of myelin are sealed by myelin junctions. This tight insulation enables rapid conduction of electric impulses (action potentials) through axons. Demyelination (stripping off the insulating sheath) has been widely regarded as one of the most important mechanisms altering the action potential propagation in many neurological diseases. However, the effective nerve conduction is also thought to require a proper myelin seal through myelin junctions such as tight junctions and adherens junctions. In the present study, we have demonstrated the disruption of myelin junctions in a mouse model (Pmp22+/-) of hereditary neuropathy with liability to pressure palsies (HNPP) with heterozygous deletion of Pmp22 gene. We observed a robust increase of F-actin in Pmp22+/- nerve regions where myelin junctions were disrupted, leading to increased myelin permeability. These abnormalities were present long before segmental demyelination at the late phase of Pmp22+/- mice. Moreover, the increase of F-actin levels correlated with an enhanced activity of p21-activated kinase (PAK1), a molecule known to regulate actin polymerization. Pharmacological inhibition of PAK normalized levels of F-actin, and completely prevented the progression of the myelin junction disruption and nerve conduction failure in Pmp22+/- mice. Our findings explain how abnormal myelin permeability is caused in HNPP, leading to impaired action potential propagation in the absence of demyelination. We call it "functional demyelination", a novel mechanism upstream to the actual stripping of myelin that is relevant to many demyelinating diseases. This observation also provides a potential therapeutic approach for HNPP. PMID:27583434

  15. Permeability-controlled optical modulator with Tri-gate metamaterial: control of permeability on InP-based photonic integration platform.

    Amemiya, Tomohiro; Ishikawa, Atsushi; Kanazawa, Toru; Kang, JoonHyung; Nishiyama, Nobuhiko; Miyamoto, Yasuyuki; Tanaka, Takuo; Arai, Shigehisa

    2015-01-01

    Metamaterials are artificially structured materials that can produce innovative optical functionalities such as negative refractive index, invisibility cloaking, and super-resolution imaging. Combining metamaterials with semiconductors enables us to develop novel optoelectronic devices based on the new concept of operation. Here we report the first experimental demonstration of a permeability-controlled waveguide optical modulator consisting of an InGaAsP/InP Mach-Zehnder interferometer with 'tri-gate' metamaterial attached on its arms. The tri-gate metamaterial consists of metal resonator arrays and triple-gate field effect elements. It changes its permeability with a change in the controlling gate voltage, thereby changing the refractive index of the interferometer arm to switch the modulator with an extinction ratio of 6.9 dB at a wavelength of 1.55 μm. The result shows the feasibility of InP-based photonic integrated devices that can produce new functions by controlling their permeability as well as their permittivity. PMID:25797041

  16. Redox-active media for permeable reactive barriers

    In this paper, three classes of redox-active media are described and evaluated in terms of their long-term effectiveness in treating TCE-contaminated groundwater in permeable reactive zones. Zero-valent iron, in the form of recycled cast iron filings, the first class, has received considerable attention as a reactive media and has been used in about a dozen pilot- and full-scale subsurface wall installations. Criteria used in selecting commercial sources of granular iron, will be discussed. Two other classes of redox-active media that have not yet seen wide use in pilot- or full-scale installations will also be described: Fe(II) minerals and bimetallic systems. Fe(II) minerals, including magnetite (Fe3O4), and ferrous sulfide (troilite, FeS), are redox-active and afford TCE reduction rates and product distributions that suggest that they react via a reductive mechanism similar to that which operates in the FeO system. Fe(II) species within the passive oxide layer coating the iron metal may act as electron transfer mediators, with FeO serving as the bulk reductant. Bimetallic systems, the third class of redox-active media, are commonly prepared by plating a second metal onto zero-valent iron (e.g., Ni/Fe and Pd/Fe) and have been shown to accelerate solvent degradation rates relative to untreated iron metal. The long-term effectiveness of this approach, however, has not yet been determined in groundwater treatability tests. The results of a Ni-plated iron column study using site groundwater indicate that a change in reduction mechanism (to catalytic dehydrohalogenation/hydrogenation) accounts for the observed rate enhancement. A significant loss in media reactivity was observed over time, attributable to Ni catalyst deactivation or poisoning. Zero-valent iron systems have not shown similar losses in reactivity in long-term laboratory, pilot or field investigations

  17. Myeloid tissue factor does not modulate lung inflammation or permeability during experimental acute lung injury.

    Shaver, Ciara M; Grove, Brandon S; Clune, Jennifer K; Mackman, Nigel; Ware, Lorraine B; Bastarache, Julie A

    2016-01-01

    Tissue factor (TF) is a critical mediator of direct acute lung injury (ALI) with global TF deficiency resulting in increased airspace inflammation, alveolar-capillary permeability, and alveolar hemorrhage after intra-tracheal lipopolysaccharide (LPS). In the lung, TF is expressed diffusely on the lung epithelium and intensely on cells of the myeloid lineage. We recently reported that TF on the lung epithelium, but not on myeloid cells, was the major source of TF during intra-tracheal LPS-induced ALI. Because of a growing body of literature demonstrating important pathophysiologic differences between ALI caused by different etiologies, we hypothesized that TF on myeloid cells may have distinct contributions to airspace inflammation and permeability between direct and indirect causes of ALI. To test this, we compared mice lacking TF on myeloid cells (TF(∆mye), LysM.Cre(+/-)TF(flox/flox)) to littermate controls during direct (bacterial pneumonia, ventilator-induced ALI, bleomycin-induced ALI) and indirect ALI (systemic LPS, cecal ligation and puncture). ALI was quantified by weight loss, bronchoalveolar lavage (BAL) inflammatory cell number, cytokine concentration, protein concentration, and BAL procoagulant activity. There was no significant contribution of TF on myeloid cells in multiple models of experimental ALI, leading to the conclusion that TF in myeloid cells is not a major contributor to experimental ALI. PMID:26924425

  18. Glucocorticoids Regulate Tight Junction Permeability of Lung Epithelia by Modulating Claudin 8.

    Kielgast, Felix; Schmidt, Hanna; Braubach, Peter; Winkelmann, Veronika E; Thompson, Kristin E; Frick, Manfred; Dietl, Paul; Wittekindt, Oliver H

    2016-05-01

    The lung epithelium constitutes a selective barrier that separates the airways from the aqueous interstitial compartment. Regulated barrier function controls water and ion transport across the epithelium and is essential for maintaining lung function. Tight junctions (TJs) seal the epithelial barrier and determine the paracellular transport. The properties of TJs depend especially on their claudin composition. Steroids are potent drugs used to treat a variety of airway diseases. Therefore, we addressed whether steroid hormones directly act on TJ properties in lung epithelia. Primary human tracheal epithelial cells and NCI-H441 cells, both cultivated under air-liquid interface conditions, were used as epithelial cell models. Our results demonstrate that glucocorticoids, but not mineralocorticoids, decreased paracellular permeability and shifted the ion permselectivity of TJs toward Cl(-). Glucocorticoids up-regulated claudin 8 (cldn8) expression via glucocorticoid receptors. Silencing experiments revealed that cldn8 is necessary to recruit occludin at the TJs. Immunohistochemistry on human lung tissue showed that cldn8 is specifically expressed in resorptive epithelia of the conducting and respiratory airways but not in the alveolar epithelium. We conclude that glucocorticoids enhance lung epithelia barrier function and increase paracellular Cl(-) selectivity via modulation of cldn8-dependent recruitment of occludin at the TJs. This mode of glucocorticoid action on lung epithelia might be beneficial to patients who suffer from impaired lung barrier function in various diseased conditions. PMID:26473470

  19. Dopamine modulated ionic permeability in mesoporous silica sphere based biomimetic compartment.

    Liu, Wei; Yang, Xiaohai; He, Dinggeng; He, Leiliang; Li, Li; Liu, Yu; Liu, Jianbo; Wang, Kemin

    2016-06-01

    The building of artificial systems with similar structure and function as cellular compartments will expand our understanding of compartmentalization related biological process and facilitate the construction of biomimetic highly functional structures. Herein, surface phenylboronic acid functionalized mesoporous silica sphere was developed as a biomimetic dopamine gated compartment, in which the ionic permeability can be well modulated through the dopamine-binding induced charge reversal. As the phenylboronic acid is negatively charged, the negatively charged 1, 3, 6, 8-pyrenetetrasulfonic acid (TPSA) was hindered from permeation into the biomimetic compartment. However, the presence of dopamine and its binding with phenylboronic acid reversed the gatekeeper shell from negative to positive charged and gated the permeation of TPSA into the interior. The dopamine gated permeation phenomenon resembles that in biological system, and thus the phenylboronic acid functionalized mesoporous silica sphere was taken as a simple model for dopamine gated ion channel decorated biological compartment. It will also contribute to the development of artificial cell and responsive nanoreactor. PMID:26962763

  20. Phosphatidylcholine Reverses Ethanol-Induced Increase in Transepithelial Endotoxin Permeability and Abolishes Transepithelial Leukocyte Activation

    Mitzscherling, Katja; Volynets, Valentina; Parlesak, Alexandr

    2009-01-01

    Chronic alcohol abuse increases both intestinal bacterial overgrowth and intestinal permeability to macromolecules. Intestinal permeability of endotoxin, a component of the outer cell membrane of Gram-negative bacteria, plays a crucial role in the development of alcohol-induced liver disease (ALD......). As impaired bile flow leads to endotoxemia and the bile component phosphatidylcholine (PC) is therapeutically active in ALD, we tested the hypothesis that conjugated primary bile salts (CPBS) and PC inhibit ethanol-enhanced transepithelial permeability of endotoxin and the subsequent transepithelial...

  1. Effects of GSM modulated radio-frequency electromagnetic radiation on permeability of blood-brain barrier in male & female rats.

    Sırav, Bahriye; Seyhan, Nesrin

    2016-09-01

    With the increased use of mobile phones, their biological and health effects have become more important. Usage of mobile phones near the head increases the possibility of effects on brain tissue. This study was designed to investigate the possible effects of pulse modulated 900MHz and 1800MHz radio-frequency radiation on the permeability of blood-brain barrier of rats. Study was performed with 6 groups of young adult male and female wistar albino rats. The permeability of blood-brain barrier to intravenously injected evans blue dye was quantitatively examined for both control and radio-frequency radiarion exposed groups. For male groups; Evans blue content in the whole brain was found to be 0.08±0.01mg% in the control, 0.13±0.03mg% in 900MHz exposed and 0.26±0.05mg% in 1800MHz exposed animals. In both male radio-frequency radiation exposed groups, the permeability of blood-brain barrier found to be increased with respect to the controls (pmale animals (pfemale groups; dye contents in the whole brains were 0.14±0.01mg% in the control, 0.24±0.03mg% in 900MHz exposed and 0.14±0.02mg% in 1800MHz exposed animals. No statistical variance found between the control and 1800MHz exposed animals (p>0.01). However 900MHz pulse modulated radio-frequency exposure was found effective on the permeability of blood-brain barrier of female animals. Results have shown that 20min pulse modulated radio-frequency radiation exposure of 900MHz and 1800MHz induces an effect and increases the permeability of blood-brain barrier of male rats. For females, 900MHz was found effective and it could be concluded that this result may due to the physiological differences between female and male animals. The results of this study suggest that mobile phone radation could lead to increase the permeability of blood-brain barrier under non-thermal exposure levels. More studies are needed to demonstrate the mechanisms of that breakdown. PMID:26723545

  2. Quantitative Retention-Activity Relationship Studies by Liposome Electrokinetic Chromatography to Predict Skin Permeability

    XIAN De-Ling; HUANG Ke-Long; LIU Su-Qin; XIAO Jing-Yi

    2008-01-01

    Liposome electrokinetic chromatography (LEKC) provides a simple and facile approach for drug membrane interactions using liposome as a pseudostationary phase. This study evaluated the potential of LEKC for high-throughput skin permeability profiled as an in vitro technique. A quantitative retention-activity relationship(QRAR) model for the estimation of skin permeability was proposed. For the 16 structurally diverse chemicals, lg k correlated well with permeability values (R2=0.886). The predictive ability of the model was evaluated by cross-validation. The result was compared to traditional quantitative structure-activity relationship, QSAR, models using some molecular descriptors and physicochemical parameters. Interestingly, a single LEKC retention parameter was capable of describing the skin permeability, while three variables in QSAR were needed to achieve a similar correlation (R2=0.704). The QRAR models developed in this paper may be a useful method to screening new chemicals and in the early stage of development and selection of chemicals.

  3. A calcium-permeable cGMP-activated cation conductance in hippocampal neurons

    Leinders-Zufall, T.; Rosenboom, H.; Barnstable, C. J.; Shepherd, G. M.; Zufall, F.

    1995-01-01

    Whole-cell patch clamp recordings detected a previously unidentified cGMP-activated membrane conductance in cultured rat hippocampal neurons. This conductance is nonselectively permeable for cations and is completely but reversibly blocked by external Cd2+. The Ca2+ permeability of the hippocampal cGMP-activated conductance was examined in detail, indicating that the underlying ion channels display a high relative permeability for Ca2+. The results indicate that hippocampal neurons contain a cGMP-activated membrane conductance that has some properties similar to the cyclic nucleotide-gated channels previously shown in sensory receptor cells and retinal neurons. In hippocampal neurons this conductance similarly could mediate membrane depolarization and Ca2+ fluxes in response to intracellular cGMP elevation.

  4. Activation of TRPA1 by membrane permeable local anesthetics

    Kronewald Sergej

    2011-08-01

    Full Text Available Abstract Background Low concentrations of local anesthetics (LAs suppress cellular excitability by inhibiting voltage-gated Na+ channels. In contrast, LAs at high concentrations can be excitatory and neurotoxic. We recently demonstrated that LA-evoked activation of sensory neurons is mediated by the capsaicin receptor TRPV1, and, to a lesser extent by the irritant receptor TRPA1. LA-induced activation and sensitization of TRPV1 involves a domain that is similar, but not identical to the vanilloid-binding domain. Additionally, activation of TRPV1 by LAs involves PLC and PI(4,5P2-signalling. In the present study we aimed to characterize essential structural determinants for LA-evoked activation of TRPA1. Results Recombinant rodent and human TRPA1 were expressed in HEK293t cells and investigated by means of whole-cell patch clamp recordings. The LA lidocaine activates TRPA1 in a concentration-dependent manner. The membrane impermeable lidocaine-derivative QX-314 is inactive when applied extracellularly. Lidocaine-activated TRPA1-currents are blocked by the TRPA1-antagonist HC-030031. Lidocaine is also an inhibitor of TRPA1, an effect that is more obvious in rodent than in human TRPA1. This species-specific difference is linked to the pore region (transmembrane domain 5 and 6 as described for activation of TRPA1 by menthol. Unlike menthol-sensitivity however, lidocaine-sensitivity is not similarly determined by serine- and threonine-residues within TM5. Instead, intracellular cysteine residues known to be covalently bound by reactive TRPA1-agonists seem to mediate activation of TRPA1 by LAs. Conclusions The structural determinants involved in activation of TRPA1 by LAs are disparate from those involved in activation by menthol or those involved in activation of TRPV1 by LAs.

  5. Myeloid tissue factor does not modulate lung inflammation or permeability during experimental acute lung injury

    Shaver, Ciara M.; Grove, Brandon S.; Clune, Jennifer K.; Nigel Mackman; Lorraine B. Ware; Bastarache, Julie A

    2016-01-01

    Tissue factor (TF) is a critical mediator of direct acute lung injury (ALI) with global TF deficiency resulting in increased airspace inflammation, alveolar-capillary permeability, and alveolar hemorrhage after intra-tracheal lipopolysaccharide (LPS). In the lung, TF is expressed diffusely on the lung epithelium and intensely on cells of the myeloid lineage. We recently reported that TF on the lung epithelium, but not on myeloid cells, was the major source of TF during intra-tracheal LPS-indu...

  6. Erythropoietin modulation of astrocyte water permeability as a component of neuroprotection

    Gunnarson, Eli; Song, Yutong; Kowalewski, Jacob M.; Brismar, Hjalmar; Brines, Michael; Cerami, Anthony; Andersson, Ulf; Zelenina, Marina; Aperia, Anita

    2009-01-01

    Disturbed brain water homeostasis with swelling of astroglial cells is a common complication in stroke, trauma, and meningitis and is considered to be a major cause of permanent brain damage. Astroglial cells possess the water channel aquaporin 4 (AQP4). Recent studies from our laboratory have shown that glutamate, acting on group I metabotropic glutamate receptors (mGluRs), increases the permeability of astrocyte AQP4, which, in situations of hypoxia-ischemia, will increase astrocyte water u...

  7. C-type natriuretic peptide modulates permeability of the blood–brain barrier

    BOHARA, Manoj; Kambe, Yuki; Nagayama, Tetsuya; TOKIMURA, Hiroshi; Arita, Kazunori; Miyata, Atsuro

    2014-01-01

    C-type natriuretic peptide (CNP) is abundant in brain and is reported to exert autocrine function in vascular cells, but its effect on blood–brain barrier (BBB) permeability has not been clarified yet. Here, we examined this effect. Transendothelial electrical resistance (TEER) of in vitro BBB model, composed of bovine brain microvascular endothelial cells and astrocytes, was significantly dose dependently decreased by CNP (1, 10, and 100 nmol/L). C-type natriuretic peptide treatment reduced ...

  8. Membrane Permeable Esterase–Activated Fluorescent Imaging Probe

    Kim, Youngmi; Choi, Yongdoo; Weissleder, Ralph; Tung, Ching-Hsuan

    2007-01-01

    An esterase-triggered probe 2 derived from a cyanine-based pH sensitive dye was developed for cell labeling. Permeation of probe 2 into cells and subsequent hydrolytic activation by cellular esterases result in a bright fluorescent intracellular signal.

  9. A PERMEABLE ACTIVE AMENDMENT CONCRETE (PAAC) FOR CONTAMINANT REMEDIATION AND EROSION CONTROL

    Knox, A.; Paller, M.; Dixon, K.

    2012-06-29

    The final project report for SEED SERDP ER - 2134 describes the development of permeable active amendment concrete (PAAC), which was evaluated through four tasks: 1) development of PAAC; 2) assessment of PAAC for contaminant removal; 3) evaluation of promising PAAC formulations for potential environmental impacts; and 4) assessment of the hydraulic, physical, and structural properties of PAAC. Conventional permeable concrete (often referred to as pervious concrete) is concrete with high porosity as a result of an extensive and interconnected void content. It is made from carefully controlled amounts of water and cementitious materials used to create a paste that forms a coating around aggregate particles. The mixture has a substantial void content (e.g., 15% - 25%) that results in a highly permeable structure that drains quickly. In PAAC, the aggregate material is partly replaced by chemically-active amendments that precipitate or adsorb contaminants in water that flows through the concrete interstices. PAAC combines the relatively high structural strength, ample void space, and water permeability of pervious concrete with the contaminant sequestration ability of chemically-active amendments to produce a new material with superior durability and ability to control contaminant mobility. The high surface area provided by the concrete interstices in PAAC provides significant opportunity for contaminants to react with the amendments incorporated into the concrete matrix. PAAC has the potential to immobilize a large variety of organic and inorganic contaminants by incorporating different active sequestering agents including phosphate materials (rock phosphate), organoclays, zeolite, and lime individually or in combinations.

  10. Global spatial sensitivity of runoff to subsurface permeability using the active subspace method

    Gilbert, James M.; Jefferson, Jennifer L.; Constantine, Paul G.; Maxwell, Reed M.

    2016-06-01

    Hillslope scale runoff is generated as a result of interacting factors that include water influx rate, surface and subsurface properties, and antecedent saturation. Heterogeneity of these factors affects the existence and characteristics of runoff. This heterogeneity becomes an increasingly relevant consideration as hydrologic models are extended and employed to capture greater detail in runoff generating processes. We investigate the impact of one type of heterogeneity - subsurface permeability - on runoff using the integrated hydrologic model ParFlow. Specifically, we examine the sensitivity of runoff to variation in three-dimensional subsurface permeability fields for scenarios dominated by either Hortonian or Dunnian runoff mechanisms. Ten thousand statistically consistent subsurface permeability fields are parameterized using a truncated Karhunen-Loéve (KL) series and used as inputs to 48-h simulations of integrated surface-subsurface flow in an idealized 'tilted-v' domain. Coefficients of the spatial modes of the KL permeability fields provide the parameter space for analysis using the active subspace method. The analysis shows that for Dunnian-dominated runoff conditions the cumulative runoff volume is sensitive primarily to the first spatial mode, corresponding to permeability values in the center of the three-dimensional model domain. In the Hortonian case, runoff volume is sensitive to multiple smaller-scale spatial modes and the locus of that sensitivity is in the near-surface zone upslope from the domain outlet. Variation in runoff volume resulting from random heterogeneity configurations can be expressed as an approximately univariate function of the active variable, a weighted combination of spatial parameterization coefficients computed through the active subspace method. However, this relationship between the active variable and runoff volume is more well-defined for Dunnian runoff than for the Hortonian scenario.

  11. Acylation of salmon calcitonin modulates in vitro intestinal peptide flux through membrane permeability enhancement

    Trier, Sofie; Linderoth, Lars; Bjerregaard, Simon;

    2015-01-01

    Acylation of peptide drugs with fatty acid chains has proven beneficial for prolonging systemic circulation, as well as increasing enzymatic stability and interactions with lipid cell membranes. Thus, acylation offers several potential benefits for oral delivery of therapeutic peptides, and we...... its influence on intestinal cell translocation and membrane interaction. We find that acylation drastically increases in vitro intestinal peptide flux and confers a transient permeability enhancing effect on the cell layer. The analogues permeabilize model lipid membranes, indicating that the effect...... is due to a solubilization of the cell membrane, similar to transcellular oral permeation enhancers. The effect is dependent on pH, with larger effect at lower pH, and is impacted by acylation chain length and position. Compared to the unacylated peptide backbone, N-terminal acylation with a short...

  12. Nanomechanics and sodium permeability of endothelial surface layer modulated by hawthorn extract WS 1442.

    Wladimir Peters

    Full Text Available The endothelial glycocalyx (eGC plays a pivotal role in the physiology of the vasculature. By binding plasma proteins, the eGC forms the endothelial surface layer (ESL which acts as an interface between bloodstream and endothelial cell surface. The functions of the eGC include mechanosensing of blood flow induced shear stress and thus flow dependent vasodilation. There are indications that levels of plasma sodium concentrations in the upper range of normal and beyond impair flow dependent regulation of blood pressure and may therefore increase the risk for hypertension. Substances, therefore, that prevent sodium induced endothelial dysfunction may be attractive for the treatment of cardiovascular disease. By means of combined atomic force-epifluorescence microscopy we studied the impact of the hawthorn (Crataegus spp. extract WS 1442, a herbal therapeutic with unknown mechanism of action, on the mechanics of the ESL of ex vivo murine aortae. Furthermore, we measured the impact of WS 1442 on the sodium permeability of endothelial EA.hy 926 cell monolayer. The data show that (i the ESL contributes by about 11% to the total endothelial barrier resistance for sodium and (ii WS 1442 strengthens the ESL resistance for sodium up to about 45%. This mechanism may explain some of the vasoprotective actions of this herbal therapeutic.

  13. Antibacterial activity of Syzygium aromaticum seed: Studies on oxidative stress biomarkers and membrane permeability.

    Ajiboye, T O; Mohammed, A O; Bello, S A; Yusuf, I I; Ibitoye, O B; Muritala, H F; Onajobi, I B

    2016-06-01

    Oxidative stress and membrane permeability as mode of antibacterial activity of aqueous extract of Syzygium aromaticum seeds against Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus was investigated. The concentration of phytochemical constituents of Syzygium aromaticum was determined using gas chromatography. Syzygium aromaticum seeds contain eugenol acetate > β-carophyllene > eugenin > eugenol > methyl salicylate > β-humulene > rhamnatin > fernesol > α-copeane > β-ylangene > kaempferol > cinnamic acid > oleanolic acid > benzaldehyde > α-humulene > vanillin > α-cubebene > carvicol > benzoic acid. Syzygium aromaticum showed antimicrobial activity with minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values as 0.06 and 0.10 mg/mL respectively. Time kill susceptibility by Syzygium aromaticum at MBC values showed significant decrease in the optical density and colony-forming unit (CFU) of Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus. Superoxide anion radical content of the bacterial cells increased significantly following exposure to the extract. In a similar vein, superoxide dismutase and catalase activities increased significantly, while the level of reduced glutathione reduced, malondialdehyde increased significantly in bacterial cells exposed to the extract. The extract at MBC also enhanced the leakage of 260 nm absorbing materials and outer membrane permeability. It is evident from the data generated from this study that aqueous extract of Syzygium aromaticum seeds enhanced membrane permeability and oxidative stress in Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus. PMID:27038843

  14. Modulation of Emotion by Cognitive Activity

    Saea Iida

    2013-09-01

    Full Text Available While emotions themselves are beneficial for our survival, they are also the targets to be regulated appropriately to adapt to social environments. Previous studies have demonstrated that cognitive strategies such as cognitive reappraisal and expressive suppression can effectively enhance and attenuate emotions. Such cognitive strategies of emotion regulation are based on cortical modulation of sub-cortical emotion-related brain regions. Though in the prior studies emotion regulation was conducted in parallel with or after the emotion elicitation, a series of our studies showed that prior cognitive activities can automatically and unintentionally attenuate subsequent emotional responses. In this article, after reviewing the previous findings about emotion regulation, we introduce our empirical findings showing that cognitive activities where the neural system of emotion regulation would be recruited can unintentionally and automatically dampen psychological and physiological emotional responses. Finally, we propose possible neural mechanisms underlying modulation of emotion by cognitive activity.

  15. Effects of Neodymium on Growth, Pectinase Activity and Mycelium Permeability of Fusarium oxysporum

    2007-01-01

    The diameter of the colony of Fusarium oxysporum in solid medium, and the mycelium growth, pectinase activity, and mycelium permeability of Fusarium oxysporum in liquid medium under varying concentrations of Nd3+ (0, 2, 4, 10, 20, 40, 60, 80, 100, 120, 140, 160, 180, 200, 300, and 400 mg·L-1) were measured. The results indicated that the growth of Fusarium oxysporum was stimulated in solid medium when the concentration of Nd3+ ranges from 2 to 180 mg·L-1, whereas it was inhibited when Nd3+ concentration was greater than 200 mg·L-1. The colonies were fewer and smaller when Nd3+ was used in the solid medium. The growth of Fusarium oxysporum was inhibited in liquid medium when Nd3+ was used. The inhibition rate showed by the dry weight of mycelium ranged from 4.83% to 52.18% and increased with Nd3+ concentration. The pectinase activity decreased compared with that of controls. When the concentration of Nd3+ was 10 and 400 mg·L-1, the pectinase activity decreased by 95% at both concentrations. Mycelium cell membrane permeability increased when Nd3+ concentrations ranged from 10 to 400 mg·L-1 but decreased when Nd3+ concentration was 2 mg·L-1.

  16. An active cooling system for photovoltaic modules

    The electrical efficiency of photovoltaic (PV) cell is adversely affected by the significant increase of cell operating temperature during absorption of solar radiation. A hybrid photovoltaic/thermal (PV/T) solar system was designed, fabricated and experimentally investigated in this work. To actively cool the PV cells, a parallel array of ducts with inlet/outlet manifold designed for uniform airflow distribution was attached to the back of the PV panel. Experiments were performed with and without active cooling. A linear trend between the efficiency and temperature was found. Without active cooling, the temperature of the module was high and solar cells can only achieve an efficiency of 8–9%. However, when the module was operated under active cooling condition, the temperature dropped significantly leading to an increase in efficiency of solar cells to between 12% and 14%. A heat transfer simulation model was developed to compare to the actual temperature profile of PV module and good agreement between the simulation and experimental results is obtained.

  17. Preparation and Visible Light Photocatalytic Activity for Photocatalyst of Permeable Glass Membrane/TiO2 Doped with Co

    HU Ke-Yan; CUI Ping; CHEN Xiao-Ming; ZHANG Min; LI Yong

    2007-01-01

    @@ The photocatalyst of permeable glass membrane/TiO2 doped with Co (permeable glass membrane/TiO2 doped with Co) is prepared by the sol-gel method. The morphology and phase of the samples are determined by the field emission scanning electron microscopy (FESEM) and x-ray diffraction experiment, respectively. The photocatalytic results show that the photocatalyst is sensitive to the visible light and exhibits excellent photocatalytic activity of photodegradation methylene blue. The photocatalytic mechanism is also discussed.

  18. Specific binding of a mutated fragment of Clostridium perfringens enterotoxin to endothelial claudin-5 and its modulation of cerebral vascular permeability.

    Liao, Zhuangbin; Yang, Zhenguo; Piontek, Anna; Eichner, Miriam; Krause, Gerd; Li, Longxuan; Piontek, Joerg; Zhang, Jingjing

    2016-07-01

    The vertebrate blood-brain barrier (BBB) creates an obstacle for central nervous system-related drug delivery. Claudin-5 (Cldn5), expressed in large quantities in BBB, plays a vital role in restricting BBB permeability. The C-terminal domain of Clostridium perfringens enterotoxin (cCPE) has been verified as binding to a subset of claudins (Cldns). The Cldn5-binding cCPE194-319 variant cCPEY306W/S313H was applied in this study to investigate its ability to modulate the permeability of zebrafish larval BBB. In vitro results showed that cCPEY306W/S313H is able to bind specifically to Cldn5 in murine brain vascular endothelial (bEnd.3) cells, and is transported along with Cldn5 from the cell membrane to the cytoplasm, which in turn results in a reduction in transendothelial electrical resistance (TEER). Conversely, this effect can be reversed by removal of cCPEY306W/S313H. In an in vivo experiment, this study estimates the capability of cCPEY306W/S313H to modulate Cldn5 using a rhodamine B-Dextran dye diffusion assay in zebrafish larval BBB. The results show that cCPEY306W/S313H co-localized with Cldn5 in zebrafish cerebral vascular cells and modulated BBB permeability, resulting in dye leakage. Taken together, this study suggests that cCPEY306W/S313H has the capability - both in vitro and in vivo - to modulate BBB permeability temporarily by specific binding to Cldn5. PMID:27095710

  19. Gaia Payload Module Testing and Analysis Activities

    Soula, Laurent

    2012-07-01

    The Gaia objective is to produce a very accurate catalogue of 1 billion of sky objects in our galaxy and beyond. ASTRIUM’s extensive experience on silicon carbide (SiC) instruments has helped developing the latest-generation payload module. It integrates the most sensitive and stable telescopes ever made, mounted on a SiC torus structure supported by three bipods. This payload module has been tested in June 2011 by ASTRIUM at INTESPACE facilities in Toulouse. To conduct the sine qualification tests and support the data analyses in real-time, advanced tools have been used. Most of them have been developed in a previous ESA R&D project [1] “DYNamics: AssessMent and Improvement of TEst Data (DYNAMITED)” and implemented in a DynaWorks® environment. Mass Operator calculation, to evaluate the payload module interface loads from measured accelerations, or automatic correlation through a criterion based on FRF from tests or predictions, are part of these tools. Testing such a structure also revealed some piloting difficulties due to a quite low and varying damping of the structure and a strong coupling with the shaker. To take into account such phenomena in the correlation work, enhanced simulations have also been performed considering multi-points phased excitations. These analyses demonstrate the payload module qualification status and allow derivate a more representative model to be used in further coupled system activities.

  20. Caco-2 cells permeability evaluation of nifuroxazide derivatives with potential activity against methicillin-resistant Staphylococcus aureus (MRSA).

    B Fernandes, Mariane; Gonçalves, José E; C Tavares, Leoberto; Storpirtis, Sílvia

    2015-01-01

    Throughout the period of evaluation and selection in drug development, the assessment of the permeability potential of a compound to achieve an efficient refinement of the molecular structure has been widely appraised by the transport of substances across cell monolayers. This study aims to develop in vitro assays through Caco-2 cells in order to analyze the permeability of 5-nitro-heterocyclic compounds analogues to nifuroxazide with antimicrobial activity, especially showing promising activity against multidrug-resistant Staphylococcus aureus (MRSA). Caco-2 cell monolayers cultivated for 21 days in Transwell® plates were used for the in vitro permeability assays. The quantification of the nifuroxazide derivatives in the basolateral chambers was performed by a validated high performance liquid chromatography with UV (HPLC-UV) method. Apparent permeability values (Papp) show that these compounds can be considered as new drug candidates with the potential to present high absorption in vivo, according to the classifications of Yee and Biganzoli. The thiophenic derivatives showed permeability values higher than the furanic ones, being AminoTIO the compound with the greatest potential for the development of a new drug against MRSA, since it showed the best cytotoxicity, permeability and solubility ratio among all the derivatives. PMID:24918173

  1. IgE receptor-activated calcium permeability pathway in rat basophilic leukemia cells

    When antigen-stimulated 45Ca uptake is measured in RBL cells loaded with > 3 mM quin2, re-extrusion of 45Ca is minimized and the initial rate of 45Ca uptake reflects the true unidirectional influx of Ca. This influx correlates more closely with secretion than with the number of IgE receptors aggregated by antigen. The antigen-induced permeability pathway is saturable, having a Km of about 0.7 mM and a Vmax of 0.9 nmol Ca/106 cells/min and it persists for at least an hour provided that receptor aggregation is maintained. The negatively charged fluorescent probe bis-oxonol is insensitive to changes in the mitochondrial membrane potential and is, therefore, a useful plasma membrane potential indicator. Antigen-stimulation of RBL cells equilibrated with bis-oxonol causes a rapid depolarization that peaks within 2-3 minutes and persists until receptor aggregates are disrupted. Antigen-induced depolarization is seen in the absence of extracellular calcium, but is almost completely abolished when both sodium and calcium are replaced by glucose. Addition of calcium restores this response even when sodium is absent. This suggests that the IgE receptor-activated permeability pathway has a similar conductance for sodium and calcium ions

  2. The effect of microneedles on the skin permeability and antitumor activity of topical 5-fluorouracil

    Youssef W. Naguib

    2014-02-01

    Full Text Available Topical 5-fluorouracil (5-FU is approved for the treatment of superficial basal cell carcinoma and actinic keratosis. However, 5-FU suffers from poor skin permeation. Microneedles have been successfully applied to improve the skin permeability of small and large molecules, and even nanoparticles, by creating micron-sized pores in the stratum corneum layer of the skin. In this report, the feasibility of using microneedles to increase the skin permeability of 5-FU was tested. Using full thickness mouse skin mounted on Franz diffusion apparatus, it was shown that the flux of 5-FU through the skin was increased by up to 4.5-fold when the skin was pretreated with microneedles (500 μm in length, 50 μm in base diameter. In a mouse model with B16-F10 mouse melanoma cells implanted in the subcutaneous space, the antitumor activity of a commercially available 5-FU topical cream (5% was significantly enhanced when the cream was applied on a skin area that was pretreated with microneedles, as compared to when the cream was simply applied on a skin area, underneath which the tumor cells were implanted, and without pretreatment of the skin with microneedles. Fluorouracil is not approved for melanoma therapy, but the clinical efficacy of topical 5-FU against tumors such as basal cell carcinoma may be improved by integrating microneedle technology into the therapy.

  3. Propofol and magnesium attenuate isoflurane-induced caspase-3 activation via inhibiting mitochondrial permeability transition pore

    Zhang Yiying

    2012-08-01

    Full Text Available Abstract Background The inhalation anesthetic isoflurane has been shown to open the mitochondrial permeability transition pore (mPTP and induce caspase activation and apoptosis, which may lead to learning and memory impairment. Cyclosporine A, a blocker of mPTP opening might attenuate the isoflurane-induced mPTP opening, lessening its ripple effects. Magnesium and anesthetic propofol are also mPTP blockers. We therefore set out to determine whether propofol and magnesium can attenuate the isoflurane-induced caspase activation and mPTP opening. Methods We investigated the effects of magnesium sulfate (Mg2+, propofol, and isoflurane on the opening of mPTP and caspase activation in H4 human neuroglioma cells stably transfected to express full-length human amyloid precursor protein (APP (H4 APP cells and in six day-old wild-type mice, employing Western blot analysis and flowcytometry. Results Here we show that Mg2+ and propofol attenuated the isoflurane-induced caspase-3 activation in H4-APP cells and mouse brain tissue. Moreover, Mg2+ and propofol, the blockers of mPTP opening, mitigated the isoflurane-induced mPTP opening in the H4-APP cells. Conclusion These data illustrate that Mg2+ and propofol may ameliorate the isoflurane-induced neurotoxicity by inhibiting its mitochondrial dysfunction. Pending further studies, these findings may suggest the use of Mg2+ and propofol in preventing and treating anesthesia neurotoxicity.

  4. Effects of light activated in-office bleaching on permeability, microhardness, and mineral content of enamel.

    Parreiras, S O; Vianna, P; Kossatz, S; Loguercio, A D; Reis, A

    2014-01-01

    The aim of this study was to evaluate the permeability (PE), microhardness (KHN), and mineral change in enamel after LED/laser activated in-office bleaching. For PE, the coronal portion of premolars (n=51) was subjected to bleaching with 35% hydrogen peroxide (Whiteness HP Maxx, FGM Dental Products, Joinville, SC, Brazil). The samples were stained via the histochemical method, which involves a copper sulphate solution and rubeanic acid. The penetration of dye into the enamel was measured. The KHN of enamel was assessed before treatment, immediately after the bleaching treatment, and again after one week. The calcium and phosphorus content were analyzed with a scanning electron microscope with energy-dispersive X-ray (JSM 6360LV, Jeol Ltd, Tokyo, Japan). The data set from each test was subjected to appropriate parametric statistical analysis (α=0.05). No significant differences were observed for PE in NLA and LA compared to the control group (p=0.98), as well as for calcium (p=0.16) and phosphorus (p=0.80) content. Significant reduction of KHN after bleaching occurred for both groups (p<0.001). After immersion in artificial saliva, the KHN of the enamel for all groups was similar to that seen before bleaching. Light activation during in-office bleaching does not produce significant changes in the enamel compared to a non-light-activated technique. PMID:24815914

  5. Solar active envelope module with an adjustable transmittance/absorptance

    C. Villasante Villasante; I. del Hoyo; Pagola, I. (I.); Sanchez, M.; E. Aranzabe

    2015-01-01

    A solar active envelope module with a high flexibility degree is proposed in this paper. The transparent module controls the day-lighting of the room, improving the indoor environment, while absorbing the superfluous solar energy inside. That energy is used to increase the efficiency of heating, ventilation, and the air-conditioning (HVAC) system of the building. This is carried out through a fine control of the absorptance of the envelope module. The active envelope module consists of three ...

  6. Helium gas permeability of low activation SiC/SiC composite

    Permeability of helium gas in SiC fiber reinforced SiC composite (SiC/SiC composite) was measured by using a vacuum apparatus consisting two chambers. The SiC/SiC samples were prepared by different methods; polymer infiltration and pyrolysis (PIP), PIP and melt impregnation (MI), hot pressing (HP) and liquid phase sintering (LPS). The measurement of permeability was carried out with pressure of helium ranging from 102 to 105 Pa at room temperature. The permeability of the sample made by LPS method was several orders of magnitude lower than those of the other SiC/SiC composites. The lowest permeability, 4 x 10-11 m2s-1, was observed for the SiC/SiC composite made by LPS using SiC fibers and nano powder of β-SiC. The largest permeability, 5 x 10-5 m2s-1, was observed for the SiC/SiC composite made by PIP. The permeability of the SiC/SiC composite depended on the structures of fiber bundle and matrix, and roughly corresponded to the microscopic structures, i.e. pores and cracks. (author)

  7. Revision of the DELFIC Particle Activity Module

    Hooper, David A [ORNL; Jodoin, Vincent J [ORNL

    2010-09-01

    The Defense Land Fallout Interpretive Code (DELFIC) was originally released in 1968 as a tool for modeling fallout patterns and for predicting exposure rates. Despite the continual advancement of knowledge of fission yields, decay behavior of fission products, and biological dosimetry, the decay data and logic of DELFIC have remained mostly unchanged since inception. Additionally, previous code revisions caused a loss of conservation of radioactive nuclides. In this report, a new revision of the decay database and the Particle Activity Module is introduced and explained. The database upgrades discussed are replacement of the fission yields with ENDF/B-VII data as formatted in the Oak Ridge Isotope Generation (ORIGEN) code, revised decay constants, revised exposure rate multipliers, revised decay modes and branching ratios, and revised boiling point data. Included decay logic upgrades represent a correction of a flaw in the treatment of the fission yields, extension of the logic to include more complex decay modes, conservation of nuclides (including stable nuclides) at all times, and conversion of key variables to double precision for nuclide conservation. Finally, recommended future work is discussed with an emphasis on completion of the overall radiation physics upgrade, particularly for dosimetry, induced activity, decay of the actinides, and fractionation.

  8. Tempol modulates changes in xenobiotic permeability and occludin oligomeric assemblies at the blood-brain barrier during inflammatory pain

    Lochhead, Jeffrey J; McCaffrey, Gwen; Sanchez-Covarrubias, Lucy; Finch, Jessica D.; DeMarco, Kristin M; Quigley, Colleen E.; Davis, Thomas P.; Ronaldson, Patrick T

    2011-01-01

    Our laboratory has shown that λ-carrageenan-induced peripheral inflammatory pain (CIP) can alter tight junction (TJ) protein expression and/or assembly leading to changes in blood-brain barrier xenobiotic permeability. However, the role of reactive oxygen species (ROS) and subsequent oxidative stress during CIP is unknown. ROS (i.e., superoxide) are known to cause cellular damage in response to pain/inflammation. Therefore, we examined oxidative stress-associated effects at the blood-brain ba...

  9. Effects of ionizing radiation on the blood brain barrier permeability to pharmacologically active substances

    Trnovec, T.; Kallay, Z.; Bezek, S. (Institute of Experimental Pharmacology, Bratislava (Yugoslavia))

    1990-12-01

    Ionizing radiation can impair the integrity of the blood brain barrier (BBB). Data on early and late damage after brain irradiation are usually reported separately, yet a gradual transition between these two types has become evident. Signs appearing within 3 weeks after irradiation are considered to be early manifestations. The mechanism of radiation-effected integrity impairment of the BBB is discussed in relation to changes in morphological structures forming the BBB, the endothelium of intracerebral vessels, and in the surrounding astrocytes. Alterations in the function of the BBB are manifested in the endothelium by changes in the ultrastructural location of the activity of phosphatases and by the activation of pinocytotic vesicular transport, and in astrocyte cytoplasm by glycogen deposition. The changes in ultrastructure were critically surveyed with regard to increasing doses of radiation to the brain in the range of 5 Gy to 960 Gy. The qualitative as well as the semiquantitative and quantitative observations on the passage of substances across the damaged BBB were treated separately. Qualitative changes are based mainly on findings of extravasation of vital stains and of labelled proteins. The quantitative studies established differences in radiation-induced changes in the permeability of the BBB depending on the structure and physico-chemical properties of the barrier penetrating tracers. Indirect evaluation of radiation-induced BBB changes is based on studies of pharmacological effects of substances acting on the CNS. In conclusion, radiation impairs significantly the integrity of the BBB following single irradiation of the brain with a dose exceeding 10-15 Gy. The response of the BBB to ionizing radiation is dependent both on the dose to which the brain is exposed and on specific properties of the tracer. 68 references.

  10. Sensitivity of predicted scaling and permeability in Enhanced Geothermal Systems to Thermodynamic Data and Activity Models

    Hingerl, Ferdinand F.; Wagner, Thomas; Kulik, Dmitrii A.; Kosakowski, Georg; Driesner, Thomas; Thomsen, Kaj

    2010-05-01

    A consortium of research groups from ETH Zurich, EPF Lausanne, the Paul Scherrer Institut and the University of Bonn collaborates in a comprehensive program of basic research on key aspects of the Enhanced Geothermal Systems (EGSs). As part of this GEOTHERM project (www.geotherm.ethz.ch), we concentrate on the fundamental investigation of thermodynamic models suitable for describing fluid-rock interactions at geothermal conditions. Predictions of the fluid-rock interaction in EGS still face several major challenges. Slight variations in the input thermodynamic and kinetic parameters may result in significant differences in the predicted mineral solubilities and stable assemblage. Realistic modeling of mineral precipitation in turn has implications onto our understanding of the permeability evolution of the geothermal reservoir, as well as the scaling in technical installations. In order to reasonably model an EGS, thermodynamic databases and activity models must be tailored to geothermal conditions. We therefore implemented in GEMS code the Pitzer formalism, which is the standard model used for computing thermodynamic excess properties of brines at elevated temperatures and pressures. This model, however, depends on a vast amount of interaction parameters, which are to a substantial extend unknown. Furthermore, a high order polynomial temperature interpolation makes extrapolation unreliable if not impossible. As an alternative we additionally implemented the EUNIQUAC activity model. EUNIQUAC requires fewer empirical fit parameters (only binary interaction parameters needed) and uses simpler and more stable temperature and pressure extrapolations. This results in an increase in computation speed, which is of crucial importance when performing coupled long term simulations of geothermal reservoirs. To achieve better performance under geothermal conditions, we are currently partly reformulating EUNIQUAC and refitting the existing parameter set. First results of the

  11. FECAL CALPROTECTIN AND GASTROINTESTINAL (GI) PERMEABILITY CORRELATE WITH DISEASE ACTIVITY INDEX, AND HISTOLOGIC, ENDOSCOPIC, AND RADIOLOGIC FINDINGS IN CHILDREN WITH CROHN DISEASE (CD)

    Fecal calprotectin and permeability are noninvasive measures of GI inflammation and damage, respectively. However, there are scant data as to the possible association between the tests and CD disease activity in children. We hypothesized that levels of fecal calprotectin and permeability would corre...

  12. Heavy metal removal from MSWI fly ash by electrokinetic remediation coupled with a permeable activated charcoal reactive barrier

    Tao Huang; Dongwei Li; Liu Kexiang; Yuewei Zhang

    2015-01-01

    This paper presents the investigations into the feasibility of the application of a remediation system that couples electrokinetic remediation (EKR) with the permeable reactive barrier (PRB) concept for municipal solid waste incineration (MSWI) fly ash with activated charcoal as the PRB material. The experimental results of this study showed that the proposed combined method can effectively improve the remediation efficiency and that the addition of the oxalic acid to the PRB media before the...

  13. Blockage of protease-activated receptor 1 ameliorates heat-stress induced intestinal high permeability and bacterial translocation.

    Xu, Qiu-lin; Guo, Xiao-hua; Liu, Jing-xian; Chen, Bin; Liu, Zhi-feng; Su, Lei

    2015-04-01

    Accumulated evidences indicate intestinal lesions play an important role in the pathogenesis of heatstroke. However, the underlying mechanisms by which heat stress causes intestinal barrier dysfunction and bacterial translocation remain unclear. In this study, we investigated the role of protease-activated receptor 1 (PAR1) in heat stress-induced intestinal hyper-permeability and bacterial translocation. Intestinal permeability in heat stressed mouse was evaluated by determining plasma endotoxin concentration and urinal lactulose/mannitol (L/M) ratio with gastric administration of L/M solution. Venous blood, liver, spleen and mesenteric lymph node tissues were collected for bacterial load test. Real time PCR was used to determine ileum PAR1 mRNA expression. In vitro study, permeability was assessed by determining trans-epithelial electrical resistance (TEER) in human intestinal Caco-2 cell line. RWJ-58259, a selective antagonist of PAR1, was used both in vivo and in vitro studies. The results showed that heat stress could increase ileum PAR1 mRNA level, urinal L/M ratio, plasma endotoxin concentration and bacterial load in the blood, spleen and mesenteric lymph nodes. Blocking PAR1 with RWJ-58259 (10 mg/kg) pretreatment could significantly reduce heat stress-induced above changes, but have no role to PAR1 mRNA level. In Caco-2 cells, heat stress-induced high permeability could also be reduced by RWJ-58259 (5-20 µmol/L). In summary, our results demonstrated that PAR1 signaling pathway may play an important role in the heat stress-induced elevation of intestinal permeability, bacterial translocation and the occurrence of endotoxemia. PMID:25492552

  14. Lipid modulation of neuronal cholinergic activity

    Phospholipids are the major lipids in the plasma membrane, and it is now evident that the function of phospholipids exceeds that of the role of barrier between different aqueous compartments. Several lines of evidence suggest that a major plasma membrane lipids, phosphatidylcholine, may be a useful compound for modulating presynaptic cholinergic transmission. In order to investigate the effects of PC on cholinergic terminals, rat cortical synaptosomes were preloaded with [3H]-ACh and then treated with small unilamellar vesicles (SUV) composed of dipalmitoylphosphatidylcholine (DPPC) at concentrations (0.8-1.5 mg/ml) similar to those found circulating in plasma. The effects of DPPC on levels, hydrolysis, release, and synthesis of [3H]-ACh were then examined. Dipalmitoylphosphatidylcholine decreased the levels of [3H]-ACh. This decrease does not result from a dilution of the radioactive [3H]-choline by nonradioactive choline derived from PC. Specifically, it is the S3 (cytoplasmic) level of [3H]-ACh that is decreased by DPPC treatment. This decrease appears to be partially due to lipid activation of an intraterminal cholinesterase which results in hydrolysis of nonvesicular [3H]-ACh. The ability of the lipid to interfere with exocytosis may account for the blockade of the K+ induced [3H]-ACh release from the P3 (vesicular) fraction. The high affinity choline transporter was competitively inhibited by DPPC treatment when synaptosomes were treated with DPPC prior to [3H]-choline loading; the ubiquitous low affinity transport was not affected. These effects were specific for cholinergic neurons since the uptake and release of dopamine and norepinephrine from the substantia nigra and the cortex, respectively, were not affected

  15. An In-tether Chiral Center Modulates the Helicity, Cell Permeability, and Target Binding Affinity of a Peptide.

    Hu, Kuan; Geng, Hao; Zhang, Qingzhou; Liu, Qisong; Xie, Mingsheng; Sun, Chengjie; Li, Wenjun; Lin, Huacan; Jiang, Fan; Wang, Tao; Wu, Yun-Dong; Li, Zigang

    2016-07-01

    The addition of a precisely positioned chiral center in the tether of a constrained peptide is reported, yielding two separable peptide diastereomers with significantly different helicity, as supported by circular dichroism (CD) and NMR spectroscopy. Single crystal X-ray diffraction analysis suggests that the absolute configuration of the in-tether chiral center in helical form is R, which is in agreement with theoretical simulations. The relationship between the secondary structure of the short peptides and their biochemical/biophysical properties remains elusive, largely because of the lack of proper controls. The present strategy provides the only method for investigating the influence of solely conformational differences upon the biochemical/biophysical properties of peptides. The significant differences in permeability and target binding affinity between the peptide diastereomers demonstrate the importance of helical conformation. PMID:27167181

  16. Bile enhances glucose uptake, reduces permeability, and modulates effects of lectins, trypsin inhibitors and saponins on intestinal tissue.

    Bakke, Anne Marie; Chikwati, Elvis M; Venold, Fredrik F; Sahlmann, Christian; Holm, Halvor; Penn, Michael H; Oropeza-Moe, Marianne; Krogdahl, Åshild

    2014-02-01

    Antinutritional factors (ANFs) can disrupt digestive and other intestinal functions. ANFs in soybean meal (SBM) are implicated in proliferative and inflammatory responses in the intestine of various (functionally) monogastric animals, including Atlantic salmon (Salmo salar L.). The goal of the current study was to investigate the effect of ex vivo exposure of mid and distal intestinal tissue of salmon to soybean saponins (SAP), lectin (LEC) and Kunitz' trypsin inhibitor (KTI), singly and in combination, on epithelial function, as assessed by measuring in vitro glucose uptake pathways along a glucose concentration gradient. As solubilization of SAP in the calcium-containing Ringer's solution was problematic but resolved with the addition of a physiological concentration of bile collected from the gall bladder of salmon, an evaluation of bile effects became an added element. Results indicated that bile increased baseline glucose absorption and possibly transport, and also had a protective effect on the epithelial barrier, at least partially due to taurocholate. Compared to controls, tissues exposed to LEC+bile, KTI+bile and LEC+KTI+bile exhibited increased glucose uptake at the higher glucose concentrations, apparently due to markedly increased tissue permeability. Addition of SAP, however, attenuated the response, possibly by binding bile components. SAP+bile, also in combination with LEC and/or KTI, as well as LEC, KTI and LEC+KTI without bile often reduced transcellular glucose uptake pathways, while maintaining low tissue permeability. SAP+LEC+KTI+bile, LEC and KTI caused the most marked reductions. The distal intestine was more affected, reflecting the restriction of in vivo SBM-induced inflammatory changes to this region. PMID:24291392

  17. Activated protein C modulates the proinflammatory activity of dendritic cells

    Matsumoto T

    2015-05-01

    Full Text Available Takahiro Matsumoto,1,2* Yuki Matsushima,1* Masaaki Toda,1 Ziaurahman Roeen,1 Corina N D'Alessandro-Gabazza,1,5 Josephine A Hinneh,1 Etsuko Harada,1,3 Taro Yasuma,4 Yutaka Yano,4 Masahito Urawa,1,5 Tetsu Kobayashi,5 Osamu Taguchi,5 Esteban C Gabazza1 1Department of Immunology, Mie University Graduate School of Medicine, Tsu, Mie Prefecture, 2BONAC Corporation, BIO Factory 4F, Fukuoka, 3Iwade Research Institute of Mycology, 4Department of Endocrinology, Diabetes and Metabolism, 5Department of Pulmonary and Critical Care Medicine, Mie University Graduate School of Medicine, Tsu, Mie Prefecture, Japan *These authors contributed equally to this work Background: Previous studies have demonstrated the beneficial activity of activated protein C in allergic diseases including bronchial asthma and rhinitis. However, the exact mechanism of action of activated protein C in allergies is unclear. In this study, we hypothesized that pharmacological doses of activated protein C can modulate allergic inflammation by inhibiting dendritic cells. Materials and methods: Dendritic cells were prepared using murine bone marrow progenitor cells and human peripheral monocytes. Bronchial asthma was induced in mice that received intratracheal instillation of ovalbumin-pulsed dendritic cells. Results: Activated protein C significantly increased the differentiation of tolerogenic plasmacytoid dendritic cells and the secretion of type I interferons, but it significantly reduced lipopolysaccharide-mediated maturation and the secretion of inflammatory cytokines in myeloid dendritic cells. Activated protein C also inhibited maturation and the secretion of inflammatory cytokines in monocyte-derived dendritic cells. Activated protein C-treated dendritic cells were less effective when differentiating naïve CD4 T-cells from Th1 or Th2 cells, and the cellular effect of activated protein C was mediated by its receptors. Mice that received adoptive transfer of activated protein C

  18. Endothelial cell permeability during hantavirus infection involves factor XII-dependent increased activation of the kallikrein-kinin system.

    Shannon L Taylor

    Full Text Available Hemorrhagic fever with renal syndrome (HFRS and hantavirus pulmonary syndrome (HPS are diseases caused by hantavirus infections and are characterized by vascular leakage due to alterations of the endothelial barrier. Hantavirus-infected endothelial cells (EC display no overt cytopathology; consequently, pathogenesis models have focused either on the influx of immune cells and release of cytokines or on increased degradation of the adherens junction protein, vascular endothelial (VE-cadherin, due to hantavirus-mediated hypersensitization of EC to vascular endothelial growth factor (VEGF. To examine endothelial leakage in a relevant in vitro system, we co-cultured endothelial and vascular smooth muscle cells (vSMC to generate capillary blood vessel-like structures. In contrast to results obtained in monolayers of cultured EC, we found that despite viral replication in both cell types as well as the presence of VEGF, infected in vitro vessels neither lost integrity nor displayed evidence of VE-cadherin degradation. Here, we present evidence for a novel mechanism of hantavirus-induced vascular leakage involving activation of the plasma kallikrein-kinin system (KKS. We show that incubation of factor XII (FXII, prekallikrein (PK, and high molecular weight kininogen (HK plasma proteins with hantavirus-infected EC results in increased cleavage of HK, higher enzymatic activities of FXIIa/kallikrein (KAL and increased liberation of bradykinin (BK. Measuring cell permeability in real-time using electric cell-substrate impedance sensing (ECIS, we identified dramatic increases in endothelial cell permeability after KKS activation and liberation of BK. Furthermore, the alterations in permeability could be prevented using inhibitors that directly block BK binding, the activity of FXIIa, or the activity of KAL. Lastly, FXII binding and autoactivation is increased on the surface of hantavirus-infected EC. These data are the first to demonstrate KKS activation

  19. Active and Repressive Chromatin-Associated Proteome after MPA Treatment and the Role of Midkine in Epithelial Monolayer Permeability

    Khan, Niamat; Lenz, Christof; Binder, Lutz; Pantakani, Dasaradha Venkata Krishna; Asif, Abdul R.

    2016-01-01

    Mycophenolic acid (MPA) is prescribed to maintain allografts in organ-transplanted patients. However, gastrointestinal (GI) complications, particularly diarrhea, are frequently observed as a side effect following MPA therapy. We recently reported that MPA altered the tight junction (TJ)-mediated barrier function in a Caco-2 cell monolayer model system. This study investigates whether MPA induces epigenetic changes which lead to GI complications, especially diarrhea. Methods: We employed a Chromatin Immunoprecipitation-O-Proteomics (ChIP-O-Proteomics) approach to identify proteins associated with active (H3K4me3) as well as repressive (H3K27me3) chromatin histone modifications in MPA-treated cells, and further characterized the role of midkine, a H3K4me3-associated protein, in the context of epithelial monolayer permeability. Results: We identified a total of 333 and 306 proteins associated with active and repressive histone modification marks, respectively. Among them, 241 proteins were common both in active and repressive chromatin, 92 proteins were associated exclusively with the active histone modification mark, while 65 proteins remained specific to repressive chromatin. Our results show that 45 proteins which bind to the active and seven proteins which bind to the repressive chromatin region exhibited significantly altered abundance in MPA-treated cells as compared to DMSO control cells. A number of novel proteins whose function is not known in bowel barrier regulation were among the identified proteins, including midkine. Our functional integrity assays on the Caco-2 cell monolayer showed that the inhibition of midkine expression prior to MPA treatment could completely block the MPA-mediated increase in barrier permeability. Conclusions: The ChIP-O-Proteomics approach delivered a number of novel proteins with potential implications in MPA toxicity. Consequently, it can be proposed that midkine inhibition could be a potent therapeutic approach to prevent the

  20. Regulation of alveolar procoagulant activity and permeability in direct acute lung injury by lung epithelial tissue factor.

    Shaver, Ciara M; Grove, Brandon S; Putz, Nathan D; Clune, Jennifer K; Lawson, William E; Carnahan, Robert H; Mackman, Nigel; Ware, Lorraine B; Bastarache, Julie A

    2015-11-01

    Tissue factor (TF) initiates the extrinsic coagulation cascade in response to tissue injury, leading to local fibrin deposition. Low levels of TF in mice are associated with increased severity of acute lung injury (ALI) after intratracheal LPS administration. However, the cellular sources of the TF required for protection from LPS-induced ALI remain unknown. In the current study, transgenic mice with cell-specific deletions of TF in the lung epithelium or myeloid cells were treated with intratracheal LPS to determine the cellular sources of TF important in direct ALI. Cell-specific deletion of TF in the lung epithelium reduced total lung TF expression to 39% of wild-type (WT) levels at baseline and to 29% of WT levels after intratracheal LPS. In contrast, there was no reduction of TF with myeloid cell TF deletion. Mice lacking myeloid cell TF did not differ from WT mice in coagulation, inflammation, permeability, or hemorrhage. However, mice lacking lung epithelial TF had increased tissue injury, impaired activation of coagulation in the airspace, disrupted alveolar permeability, and increased alveolar hemorrhage after intratracheal LPS. Deletion of epithelial TF did not affect alveolar permeability in an indirect model of ALI caused by systemic LPS infusion. These studies demonstrate that the lung epithelium is the primary source of TF in the lung, contributing 60-70% of total lung TF, and that lung epithelial, but not myeloid, TF may be protective in direct ALI. PMID:25884207

  1. Exploring the biophysical evidence that mammalian two-pore channels are NAADP-activated calcium-permeable channels.

    Pitt, Samantha J; Reilly-O'Donnell, Benedict; Sitsapesan, Rebecca

    2016-08-01

    Nicotinic acid adenine dinucleotide phosphate (NAADP) potently releases Ca(2+) from acidic intracellular endolysosomal Ca(2+) stores. It is widely accepted that two types of two-pore channels, termed TPC1 and TPC2, are responsible for the NAADP-mediated Ca(2+) release but the underlying mechanisms regulating their gating appear to be different. For example, although both TPC1 and TPC2 are activated by NAADP, TPC1 appears to be additionally regulated by cytosolic Ca(2+) . Ion conduction and permeability also differ markedly. TPC1 and TPC2 are permeable to a range of cations although biophysical experiments suggest that TPC2 is slightly more selective for Ca(2+) over K(+) than TPC1 and hence capable of releasing greater quantities of Ca(2+) from acidic stores. TPC1 is also permeable to H(+) and therefore may play a role in regulating lysosomal and cytosolic pH, possibly creating localised acidic domains. The significantly different gating and ion conducting properties of TPC1 and TPC2 suggest that these two ion channels may play complementary physiological roles as Ca(2+) -release channels of the endolysosomal system. PMID:26872338

  2. Thermal anomalies in fumaroles at Vulcano island (Italy) and their relationship with seismic activity and stress-induced permeability changes

    Madonia, Paolo; Cusano, Paola; Diliberto, Iole Serena; Cangemi, Marianna

    2016-04-01

    Fumarole thermal monitoring is a useful tool in the evaluation of volcanic activity, since temperatures strongly relate to the upward flux of magmatic volatiles. Once depurated from meteorological noise, their variations can reflect permeability changes due to crustal stress dynamics eventually associated to seismic activity. In this work, we discuss a fumarole temperature record acquired in the period September 2009 - May 2012 at Vulcano island (Italy), during which changes of volcanic state, local seismic activity and teleseisms occurred. Apart from positive thermal anomalies driven by increments in volcanic activity, we observed 3 episodes at least of concurrence between tectonic earthquakes and fumarole temperature increments, with particular reference to the local August 16th, 2010 Lipari earthquake, the March 11th, 2011 Sendai-Honshu (Japan) earthquake and a seismic swarm occurred along the Tindari-Letojanni fault in July-August 2011. We interpreted the seismic-related anomalies as "crustal fluid transients", i.e. signals of volcanogenic vapour flow variations induced by stress-induced permeability changes. From this perspective fumarolic activity can be considered as a tracer of geodynamic instability but, since seismic and volcanic phenomena are in mutual cause-effect relationships, a multidisciplinary observation system is mandatory for correctly addressing thermal data interpretation.

  3. Modulation of Emotion by Cognitive Activity

    Saea Iida; Hiroki C. Tanabe; Takashi Nakao; Hideki Ohira

    2013-01-01

    While emotions themselves are beneficial for our survival, they are also the targets to be regulated appropriately to adapt to social environments. Previous studies have demonstrated that cognitive strategies such as cognitive reappraisal and expressive suppression can effectively enhance and attenuate emotions. Such cognitive strategies of emotion regulation are based on cortical modulation of sub-cortical emotion-related brain regions. Though in the prior studies emotion regulation was cond...

  4. Tuning Liposome Membrane Permeability by Competitive Peptide Dimerization and Partitioning-Folding Interactions Regulated by Proteolytic Activity

    Lim, Seng Koon; Sandén, Camilla; Selegård, Robert; Liedberg, Bo; Aili, Daniel

    2016-02-01

    Membrane active peptides are of large interest for development of drug delivery vehicles and therapeutics for treatment of multiple drug resistant infections. Lack of specificity can be detrimental and finding routes to tune specificity and activity of membrane active peptides is vital for improving their therapeutic efficacy and minimize harmful side effects. We describe a de novo designed membrane active peptide that partition into lipid membranes only when specifically and covalently anchored to the membrane, resulting in pore-formation. Dimerization with a complementary peptide efficiently inhibits formation of pores. The effect can be regulated by proteolytic digestion of the inhibitory peptide by the matrix metalloproteinase MMP-7, an enzyme upregulated in many malignant tumors. This system thus provides a precise and specific route for tuning the permeability of lipid membranes and a novel strategy for development of recognition based membrane active peptides and indirect enzymatically controlled release of liposomal cargo.

  5. Photothermal configuration applied to the study of water vapor permeability in biodegradable films under several water activities

    Lopez-Bueno, G.; Martín-Martínez, E. San; Cruz-Orea, A.; Tomas, S. A.; Tufiño, M.; Sanchez, F.

    2003-01-01

    A photothermal configuration was used to determine the water vapor permeability of biodegradable films (nixtamalized corn pericarps). The films were obtained from corn grains boiled in an alkaline solution containing water and Ca(OH)2. Samples were exposed to saturated salt solutions with relative humidity in the range 7%-97%. The water vapor diffusion coefficient was determined as a function of relative humidity. The obtained coefficients agreed with data available in the literature. It was also found that the photoacoustic amplitude shows a linear dependence on the water activity, in agreement with our theoretical model.

  6. Recombinant Bactericidal/Permeability-Increasing Protein (rBPI21) in Combination with Sulfadiazine Is Active against Toxoplasma gondii

    Khan, Anis A.; Lambert, Lewis H.; Remington, Jack S.; Araujo, Fausto G.

    1999-01-01

    The activity of recombinant bactericidal/permeability-increasing protein (rBPI21), alone or in combination with sulfadiazine, on the intracellular replication of Toxoplasma gondii was assessed in vitro and in mice with acute toxoplasmosis. rBPI21 markedly inhibited the intracellular growth of T. gondii in human foreskin fibroblasts (HFFs). Following 72 h of exposure, the 50% inhibitory concentration of rBPI21 for T. gondii was 2.6 μg/ml, whereas only slight cytotoxicity for HFF cells was obse...

  7. Wireless multi-level terahertz amplitude modulator using active metamaterial-based spatial light modulation.

    Rout, Saroj; Sonkusale, Sameer

    2016-06-27

    The ever increasing demand for bandwidth in wireless communication systems will inevitably lead to the extension of operating frequencies toward the terahertz (THz) band known as the 'THz gap'. Towards closing this gap, we present a multi-level amplitude shift keying (ASK) terahertz wireless communication system using terahertz spatial light modulators (SLM) instead of traditional voltage mode modulation, achieving higher spectral efficiency for high speed communication. The fundamental principle behind this higher efficiency is the conversion of a noisy voltage domain signal to a noise-free binary spatial pattern for effective amplitude modulation of a free-space THz carrier wave. Spatial modulation is achieved using an an active metamaterial array embedded with pseudomorphic high-electron mobility (pHEMT) designed in a consumer-grade galium-arsenide (GaAs) integrated circuit process which enables electronic control of its THz transmissivity. Each array is assembled as individually controllable tiles for transmissive terahertz spatial modulation. Using the experimental data from our metamaterial based modulator, we show that a four-level ASK digital communication system has two orders of magnitude improvement in symbol error rate (SER) for a degradation of 20 dB in transmit signal-to-noise ratio (SNR) using spatial light modulation compared to voltage controlled modulation. PMID:27410614

  8. Flos Lonicera ameliorates obesity and associated endotoxemia in rats through modulation of gut permeability and intestinal microbiota.

    Jing-Hua Wang

    ameliorates obesity and related metabolic endotoxemia via regulating distribution of gut flora and gut permeability.

  9. Optimal Coding Predicts Attentional Modulation of Activity in Neural Systems

    Jaramillo, Santiago; Pearlmutter, Barak A.

    2007-01-01

    Neuronal activity in response to a fixed stimulus has been shown to change as a function of attentional state, implying that the neural code also changes with attention. We propose an information-theoretic account of such modulation: that the nervous system adapts to optimally encode sensory stimuli while taking into account the changing relevance of different features. We show using computer simulation that such modulation emerges in a coding system informed about the uneven relevance of ...

  10. Network-dependent modulation of brain activity during sleep

    Watanabe, T.; Kan, S.; Koike, T.; Misaki, M; Konishi, S.; Miyauchi, S; Miyahsita, Y.; Masuda, N.

    2014-01-01

    Brain activity dynamically changes even during sleep. A line of neuroimaging studies has reported changes in functional connectivity and regional activity across different sleep stages such as slow-wave sleep (SWS) and rapid-eye-movement (REM) sleep. However, it remains unclear whether and how the large-scale network activity of human brains changes within a given sleep stage. Here, we investigated modulation of network activity within sleep stages by applying the pairwise maximum entropy mod...

  11. Modulation of brain activity during phonological familiarization

    Majerus, Steve; Van der Linden, Martial; Collette, Fabienne; Laureys, Steven; Poncelet, Martine; Degueldre, Christian; Delfiore, Guy; Luxen, André; Salmon, Eric

    2005-01-01

    We measured brain activity in 12 adults for the repetition of auditorily presented words and nonwords, before and after repeated exposure to their phonological form. The nonword phoneme combinations were either of high (HF) or low (LF) phonotactic frequency. After familiarization, we observed, for both word and nonword conditions, decreased activation in the left posterior superior temporal gyrus, in the bilateral temporal pole and middle temporal gyri. At the same time, interaction analysis ...

  12. Nonlinear active wave modulation approach for microdamage detection

    Wu, Hwai-Chung; Warnemuende, Kraig

    2001-07-01

    Several nondestructive testing methods can be used to estimate the extents of damage in a concrete structure. Pulse-velocity and amplitude attenuation, are very common in nondestructive ultrasonic evaluation. Velocity of propagation is not very sensitive to the degrees of damage unless a great deal of micro-damage having evolving into localized macro-damage. Amplitude attenuation is potentially more sensitive than pulse-velocity. However, this method depends strongly on the coupling conditions between transducers and concrete, hence unreliable. A new active modulation approach, Nonlinear Active Wave Modulation Spectroscopy, is adopted in our study. In this procedure, a probe wave will be passed through the system in a similar fashion to regular acoustics. Simultaneously, a second, low frequency modulating wave will be applied to the system to effectively change the size and stiffness of flaws microscopically and cyclically, thereby causing the frequency modulation to change cyclically as well. The resulting amplified modulations will be correlated to the extents of damage with the effect that even slight damage should become quantifiable. This study unveils the potential of nonlinear frequency analysis methods for micro-damage detection and evaluation using actively modulated acoustic signals. This method can interrogate materials exaggerating the nonlinearly that exists due to microcracking and deterioration.

  13. Intracellular protease activation in apoptosis and cell-mediated cytotoxicity characterized by cell-permeable fluorogenic protease substrates

    Beverly Z Packard; Akira Komoriya

    2008-01-01

    Over the past decade the importance of signaling from reporter molecules inside live cells and tissues has been clearly established. Biochemical events related to inflammation, tumor metastasis and proliferation, and viral infectivity and replication are examples of processes being further defined as more molecular tools for live cell measurements become available. Moreover, in addition to quantitating parameters related to physiologic processes, real-time imaging of molecular interactions that compose basic cellular activities are providing insights into understanding disease mechanisms as well as extending clinical efficacy of therapeutic regimens. In this review the use of highly cell-permeable fluorogenic substrates that report protease activities inside live cells is described; applications to defining the molecular events of two cellular processes, i.e., apoptosis and cell-mediated cytotoxicity, are then illustrated.

  14. Modulation of Brain Activity during Phonological Familiarization

    Majerus, S.; Van der Linden, M.; Collette, F.; Laureys, S.; Poncelet, M.; Degueldre, C.; Delfiore, G.; Luxen, A.; Salmon, E.

    2005-01-01

    We measured brain activity in 12 adults for the repetition of auditorily presented words and nonwords, before and after repeated exposure to their phonological form. The nonword phoneme combinations were either of high (HF) or low (LF) phonotactic frequency. After familiarization, we observed, for both word and nonword conditions, decreased…

  15. Nitroprusside modulates pulmonary vein arrhythmogenic activity

    Chen Yao-Chang

    2010-03-01

    Full Text Available Abstract Background Pulmonary veins (PVs are the most important sources of ectopic beats with the initiation of paroxysmal atrial fibrillation, or the foci of ectopic atrial tachycardia and focal atrial fibrillation. Elimination of nitric oxide (NO enhances cardiac triggered activity, and NO can decrease PV arrhythmogensis through mechano-electrical feedback. However, it is not clear whether NO may have direct electrophysiological effects on PV cardiomyocytes. This study is aimed to study the effects of nitroprusside (NO donor, on the ionic currents and arrhythmogenic activity of single cardiomyocytes from the PVs. Methods Single PV cardiomyocytes were isolated from the canine PVs. The action potential and ionic currents were investigated in isolated single canine PV cardiomyocytes before and after sodium nitroprusside (80 μM, using the whole-cell patch clamp technique. Results Nitroprusside decreased PV cardiomyocytes spontaneous beating rates from 1.7 ± 0.3 Hz to 0.5 ± 0.4 Hz in 9 cells (P Conclusion Nitroprusside regulates the electrical activity of PV cardiomyocytes, which suggests that NO may play a role in PV arrhythmogenesis.

  16. Up-Regulation of Pressure-activated Ca2+-permeable Cation Channel in Intact Vascular Endothelium of Hypertensive Rats

    Hoyer, J.; Kohler, R.; Haase, W.; Distler, A.

    1996-10-01

    In endothelial cells, stretch-activated cation channels have been proposed to act as mechanosensors for changes in hemodynamic forces. We have identified a novel mechanosensitive pressure-activated channel in intact endothelium from rat aorta and mesenteric artery. The 18-pS cation channel responded with a multifold increase in channel activity when positive pressure was applied to the luminal cell surface with the patch pipette and inactivated at negative pipette pressure. Channel permeability ratio for K+, Na+, and Ca2+ ions was 1:0.98:0.23. Ca2+ influx through the channel was sufficient to activate a neighboring Ca2+-dependent K+ channel. Hemodynamic forces are chronically disturbed in arterial hypertension. Endothelial cell dysfunction has been implicated in the pathogenesis of arterial hypertension. In two comparative studies, density of the pressure-activated channel was found to be significantly higher in spontaneously hypertensive rats and renovascular hypertensive rats compared with their respective normotensive controls. Channel activity presumably leads to mechanosensitive Ca2+ influx and induces cell hyperpolarization by K+ channel activity. Both Ca2+ influx and hyperpolarization are known to induce a vasodilatory endothelial response by stimulating endothelial nitric oxide (NO) production. Up-regulation of channel density in hypertension could, therefore, represent a counterregulatory mechanism of vascular endothelium.

  17. Intestinal permeability and malabsorption of rifampin and isoniazid in active pulmonary tuberculosis

    Valéria G. F. Pinheiro

    2006-12-01

    Full Text Available Low antimycobacterial drug concentrations have been observed in tuberculosis (TB patients under treatment. The lactulose/mannitol urinary excretion test (L/M, normally used to measure intestinal permeability, may be useful to assess drug absorption. The objective of this research was to study intestinal absorptive function and bioavailability of rifampin and isoniazid in TB patients. A cross sectional study was done with 41 patients and 28 healthy controls, using the L/M test. The bioavailabilities of rifampin (R and isoniazid (H were evaluated in 18 patients receiving full doses. Urinary excretion of mannitol and lactulose, measured by HPLC, was significantly lower in TB patients. The serum concentrations of the drugs were below the expected range for R (8-24 mcg/mL or H (3-6 mcg/mL in 16/18 patients. Analyzing the drugs individually, 12/18 patients had low serum concentrations of R, 13/18 for H and 8/18 for both drugs. We suggest that there is a decrease in the functional absorptive area of the intestine in TB patients, which would explain the reduced serum concentrations of antituberculosis drugs. There is a need for new approaches to improve drug bioavailability in TB patients.

  18. Hydrophobic core flexibility modulates enzyme activity in HIV-1 protease

    Mittal, Seema; Cai, Yufeng; Nalam, Madhavi N.; Bolon, Daniel N. A.; Schiffer, Celia A.

    2012-01-01

    Human immunodeficiency virus Type-1 (HIV-1) protease is crucial for viral maturation and infectivity. Studies of protease dynamics suggest that the rearrangement of the hydrophobic core is essential for enzyme activity. Many mutations in the hydrophobic core are also associated with drug resistance and may modulate the core flexibility. To test the role of flexibility in protease activity, pairs of cysteines were introduced at the interfaces of flexible regions remote from the active site. Di...

  19. [Peptidergic modulation of the hippocampus synaptic activity].

    Skrebitskiĭ, V G; Kondratenko, R V; Povarov, I S; Dereviagin, V I

    2011-11-01

    Effects of two newly synthesized nootropic and anxiolytic dipeptides: Noopept and Selank on inhibitory synaptic transmission in hippocampal CA1 pyramidal cells were investigated using patch-clamp technique in whole-cell configuration. Bath application of Noopept (1 microM) or Selank (2 microM) significantly increased the frequency of spike-dependent spontaneous m1PSCs, whereas spike-independent mlPSCs remained unchanged. It was suggested that both peptides mediated their effect sue to activation of inhibitory interneurons terminating on CA1 pyramidal cells. Results of current clamp recording of inhibitory interneurons residing in stratum radiatum confirmed this suggestion, at least for Noonent. PMID:22390072

  20. Muscle metaboreceptor modulation of cutaneous active vasodilation

    Crandall, C. G.; Stephens, D. P.; Johnson, J. M.

    1998-01-01

    PURPOSE: Isometric handgrip exercise in hyperthermia has been shown to reduce cutaneous vascular conductance (CVC) by inhibiting the cutaneous active vasodilator system. METHODS: To identify whether this response was initiated by muscle metaboreceptors, in seven subjects two 3-min bouts of isometric handgrip exercise in hyperthermia were performed, followed by 2 min of postexercise ischemia (PEI). An index of forearm skin blood flow (laser-Doppler flowmetry) was measured on the contralateral arm at an unblocked site and at a site at which adrenergic vasoconstrictor function was blocked via bretylium iontophoresis to reveal active cutaneous vasodilator function unambiguously. Sweat rate was measured via capacitance hygrometry, CVC was indexed from the ratio of skin blood flow to mean arterial pressure and was expressed as a percentage of maximal CVC at that site. In normothermia, neither isometric exercise nor PEI affected CVC (P > 0.05). RESULTS: The first bout of isometric handgrip exercise in hyperthermia reduced CVC at control sites and this reduction persisted through PEI (pre-exercise: 59.8 +/- 5.4, exercise: 49.8 +/- 4.9, PEI: 49.7 +/- 5.3% of maximum; both P < 0.05), whereas there were no significant changes in CVC at the bretylium treated sites. The succeeding bout of isometric exercise in hyperthermia significantly reduced CVC at both untreated (pre-exercise: 59.0 +/- 4.8, exercise: 47.3 +/- 4.0, PEI: 50.1 +/- 4.1% of maximum; both P < 0.05) and bretylium treated sites (pre-exercise: 61.4 +/- 7.3, exercise: 50.6 +/- 5.1, PEI: 53.9 +/- 6.0% of maximum, both P < 0.05). At both sites, CVC during PEI was lower than during the pre-exercise period (P < 0.05). Sweat rate rose significantly during both bouts of isometric exercise and remained elevated during PEI. CONCLUSIONS: These data suggest that the reduction in CVC during isometric exercise in hyperthermia, including the inhibition of the active vasodilator system, is primarily mediated by muscle

  1. Total Cellular RNA Modulates Protein Activity.

    Majumder, Subhabrata; DeMott, Christopher M; Reverdatto, Sergey; Burz, David S; Shekhtman, Alexander

    2016-08-16

    RNA constitutes up to 20% of a cell's dry weight, corresponding to ∼20 mg/mL. This high concentration of RNA facilitates low-affinity protein-RNA quinary interactions, which may play an important role in facilitating and regulating biological processes. In the yeast Pichia pastoris, the level of ubiquitin-RNA colocalization increases when cells are grown in the presence of dextrose and methanol instead of methanol as the sole carbon source. Total RNA isolated from cells grown in methanol increases β-galactosidase activity relative to that seen with RNA isolated from cells grown in the presence of dextrose and methanol. Because the total cellular RNA content changes with growth medium, protein-RNA quinary interactions can alter in-cell protein biochemistry and may play an important role in cell adaptation, critical to many physiological and pathological states. PMID:27456029

  2. Introduction of an active enzyme into permeable cells of Escherichia coli

    Plasmolysed cells of Escherichia coli N212 (uvrA recA) acquired ultraviolet resistance when the cells were exposed to high concentrations of T4 endonuclease V. With increasing concentrations of T4 enzyme, survivals of plasmolysed cells after ultraviolet irradiation increased while colony-forming ability of unirradiated plasmolysed cells was not significantly affected by the enzyme treatment. Under appropriate conditions more than 200 fold increase in survivals was observed. When plasmolysed cells were treated with a pre-heated enzyme preparation or enzyme fractions derived from T4v1 (endonuclease V-deficient mutant)-infected cells, only little or no reactivation took place. Permeabilization of cells prior to the enzyme treatment was essential for the effective reactivation. Treatment of intact cells with the T4 enzyme did not cause any reactivation. Cells treated with 20mMEGTA or 50mM CaCl2 in cold were reactivated to certain extents by the enzyme, but the extents of the reactivation were far less compared to those of plasmolysed cells. Plasmolysed cells of strains carrying a mutation in one of uvrA, uvrB and uvrC genes were reactivated by introduction of T4 endonuclease V, as was the uvrA recA double mutant. UvrD mutants were also reactivated, but rather slightly. However, wild type strain as well as strains having a mutation in recA or polA gene were not reactivated. From these results it was suggested that T4 endonuclease V, taken up into permeable cells, can function in vivo to replace defective functions, which are controlled by the uvr genes. The conditions established in the present study may be used for introduction of other proteins into viable bacterial cells. (orig.)

  3. Chemoprotective activity of boldine: modulation of drug-metabolizing enzymes.

    Kubínová, R; Machala, M; Minksová, K; Neca, J; Suchý, V

    2001-03-01

    Possible chemoprotective effects of the naturally occurring alkaloid boldine, a major alkaloid of boldo (Peumus boldus Mol.) leaves and bark, including in vitro modulations of drug-metabolizing enzymes in mouse hepatoma Hepa-1 cell line and mouse hepatic microsomes, were investigated. Boldine manifested inhibition activity on hepatic microsomal CYP1A-dependent 7-ethoxyresorufin O-deethylase and CYP3A-dependent testosterone 6 beta-hydroxylase activities and stimulated glutathione S-transferase activity in Hepa-1 cells. In addition to the known antioxidant activity, boldine could decrease the metabolic activation of other xenobiotics including chemical mutagens. PMID:11265593

  4. Application of Discontinuous PWM Modulation in Active Power Filters

    Blaabjerg, Frede; Asiminoaei, Lucian; Rodriguez, Pedro

    2008-01-01

    Classical discontinuous pulsewidth modulations (DPWMs) may not be efficiently applied in active power filters (APFs), because it is hard to predict the peak values of the inverter current, and consequently it is difficult to calculate the position of the clamped interval, that minimizes the switc...

  5. Hydrophobic Core Flexibility Modulates Enzyme Activity in HIV-1 Protease

    Mittal, Seema; Cai, Yufeng; Nalam, Madhavi N.L.; Bolon, Daniel N.A.; Schiffer, Celia A. (UMASS, MED)

    2012-09-11

    Human immunodeficiency virus Type-1 (HIV-1) protease is crucial for viral maturation and infectivity. Studies of protease dynamics suggest that the rearrangement of the hydrophobic core is essential for enzyme activity. Many mutations in the hydrophobic core are also associated with drug resistance and may modulate the core flexibility. To test the role of flexibility in protease activity, pairs of cysteines were introduced at the interfaces of flexible regions remote from the active site. Disulfide bond formation was confirmed by crystal structures and by alkylation of free cysteines and mass spectrometry. Oxidized and reduced crystal structures of these variants show the overall structure of the protease is retained. However, cross-linking the cysteines led to drastic loss in enzyme activity, which was regained upon reducing the disulfide cross-links. Molecular dynamics simulations showed that altered dynamics propagated throughout the enzyme from the engineered disulfide. Thus, altered flexibility within the hydrophobic core can modulate HIV-1 protease activity, supporting the hypothesis that drug resistant mutations distal from the active site can alter the balance between substrate turnover and inhibitor binding by modulating enzyme activity.

  6. Solar active envelope module with an adjustable transmittance/absorptance

    C. Villasante Villasante

    2015-06-01

    Full Text Available A solar active envelope module with a high flexibility degree is proposed in this paper. The transparent module controls the day-lighting of the room, improving the indoor environment, while absorbing the superfluous solar energy inside. That energy is used to increase the efficiency of heating, ventilation, and the air-conditioning (HVAC system of the building. This is carried out through a fine control of the absorptance of the envelope module. The active envelope module consists of three glazed chambers with advanced coatings and frames to assure a minimum thermal transmittance while allowing transparency. A fluid containing heat-absorbing nanoparticles flows inside the central chamber and is heated up due to the impinging solar energy. Unlike other systems proposed in the past, which included transparency control systems based on complex filters and chemical processes, the absorption of the module is controlled by the variation of the thickness of the central chamber with a mechanical device. That is, varying the thickness of the central chamber, it allows controlling the absorptance of the whole system and, as a result, indoor day-lighting and thermal loads. Therefore, a new system is proposed that enables to:  

  7. Neuronal modulation of calcium channel activity in cultured rat astrocytes.

    Corvalan, V; Cole, R; de Vellis, J.; Hagiwara, S.

    1990-01-01

    The patch-clamp technique was used to study whether cocultivation of neurons and astrocytes modulates the expression of calcium channel activity in astrocytes. Whole-cell patch-clamp recordings from rat brain astrocytes cocultured with rat embryonic neurons revealed two types of voltage-dependent inward currents carried by Ca2+ and blocked by either Cd2+ or Co2+ that otherwise were not detected in purified astrocytes. This expression of calcium channel activity in astrocytes was neuron depend...

  8. Synergistic inhibition of T-cell activation by a cell-permeable ZAP-70 mutant and ctCTLA-4

    Kim, Kyun-Do [Department of Biotechnology, Yonsei University, Seodaemun-Gu, Shinchon-Dong 134, Seoul 120-749 (Korea, Republic of); Choi, Je-Min; Chae, Wook-Jin [Department of Immunobiology, Yale University School of Medicine, New Haven CT 06520 (United States); Lee, Sang-Kyou, E-mail: sjrlee@yonsei.ac.kr [Department of Biotechnology, Yonsei University, Seodaemun-Gu, Shinchon-Dong 134, Seoul 120-749 (Korea, Republic of); ForHumanTech Co., Ltd., Kowoon Institute of Technology Innovation, Bldg. 706, Suwon (Korea, Republic of)

    2009-04-10

    T-cell activation requires TcR-mediated and co-stimulatory signals. ZAP-70 participates in the initial step of TcR signal transduction, while a co-receptor, CTLA-4, inhibits T-cell activation. In previous studies, the overexpression of a ZAP-70 mutant (ZAP-70-Y319F) inhibited the TcR-induced activation of NFAT and IL-2 production, while Hph-1-ctCTLA-4 prevented allergic inflammation. To develop an effective immunosuppressive protein drug that blocks both TcR-mediated and co-stimulatory signaling pathways, a fusion protein of ZAP-70-Y319F and the Hph-1 protein transduction domain was generated. Hph-1-ZAP-70-Y319F inhibited the phosphorylation of ZAP-70-Tyr{sup 319}, LAT-Tyr{sup 191}, and p44/42 MAPK induced by TcR stimulation, NFAT- and AP-1-mediated gene transcription, and the induction of CD69 expression and IL-2 secretion. Hph-1-ZAP-70-Y319F and Hph-1-ctCTLA-4 synergistically inhibited signaling events during T-cell activation. This is the first report to demonstrate the synergistic inhibition of signals transmitted via TcR and its co-stimulatory receptor by cell-permeable forms of intracellular signal mediators.

  9. Optimized Pulse Width Modulation for transformerless active-NPC inverters

    Achilladelis, Nikolaos; Koutroulis, Eftichios; Blaabjerg, Frede

    2014-01-01

    The transformerless DC/AC inverter topologies are employed in Photovoltaic systems in order to improve the power conversion efficiency, power density and cost. The Active-Neutral Point Clamped (Active-NPC) transformerless inverters have the advantage of achieving better thermal balance among their...... power semiconductors. In this paper, a new modulation technique is proposed for optimally controlling the power switches employed in transformerless Active-NPC inverters. The design results demonstrate that compared to the existing PWM strategies, using the proposed method results in lower total power...... losses and significantly better distribution of the power losses among the semiconductors of the Active-NPC inverter....

  10. Enhancement of vascular permeability by specific activation of protease-activated receptor-1 in rat hindpaw: a protective role of endogenous and exogenous nitric oxide

    Kawabata, Atsufumi; Kuroda, Ryotaro; Nishikawa, Hiroyuki; Asai, Toshiharu; Kataoka, Kazuo; Taneda, Mamoru

    1999-01-01

    To clarify the role of the first thrombin receptor/protease-activated receptor (PAR)-1 in an inflammatory process, we tested and characterized the effect of intraplantar (i.pl.) administration of the highly specific PAR-1 agonist TFLLR-NH2 in rat hindpaw.TFLLR-NH2 administered i.pl. at 0.01–0.03 μmol per paw enhanced vascular permeability in the hindpaw and produced paw oedema in a dose-dependent manner. This effect was almost completely abolished by repeated pretreatment with compound 48/80 ...

  11. Sodium Permeability of a Cloned Small-Conductance Calcium-Activated Potassium Channel

    Shin, Narae; Soh, Heun; Chang, Sunghoe; Kim, Do Han; Park, Chul-Seung

    2005-01-01

    Small-conductance Ca2+-activated potassium channels (SKCa channels) are heteromeric complexes of pore-forming main subunits and constitutively bound calmodulin. SKCa channels in neuronal cells are activated by intracellular Ca2+ that increases during action potentials, and their ionic currents have been considered to underlie neuronal afterhyperpolarization. However, the ion selectivity of neuronal SKCa channels has not been rigorously investigated. In this study, we determined the monovalent...

  12. Contextual modulation of hippocampal activity during picture naming.

    Llorens, A; Dubarry, A-S; Trébuchon, A; Chauvel, P; Alario, F-X; Liégeois-Chauvel, C

    2016-08-01

    Picture naming is a standard task used to probe language processes in healthy and impaired speakers. It recruits a broad neural network of language related areas, among which the hippocampus is rarely included. However, the hippocampus could play a role during picture naming, subtending, for example, implicit learning of the links between pictured objects and their names. To test this hypothesis, we recorded hippocampal activity during plain picture naming, without memorization requirement; we further assessed whether this activity was modulated by contextual factors such as repetition priming and semantic interference. Local field potentials recorded from intracerebral electrodes implanted in the healthy hippocampi of epileptic patients revealed a specific and reliable pattern of activity, markedly modulated by repetition priming and semantic context. These results indicate that the hippocampus is recruited during picture naming, presumably in relation to implicit learning, with contextual factors promoting differential hippocampal processes, possibly subtended by different sub-circuitries. PMID:27380274

  13. Effects of ε-viniferin, a dehydrodimer of resveratrol, on transepithelial active ion transport and ion permeability in the rat small and large intestinal mucosa.

    Karaki, Shin-Ichiro; Ishikawa, Junji; Tomizawa, Yuka; Kuwahara, Atsukazu

    2016-05-01

    ε-Viniferin is a dehydrodimer of resveratrol, a polyphenol synthesized in many plants, including grapevine. The present study investigated the effects of ε-viniferin and resveratrol on epithelial secretory and barrier functions in isolated rat small and large intestinal mucosa. Mucosa-submucosa tissue preparations of various segments of the rat large and small intestines were mounted on Ussing chambers, and short-circuit current (Isc) and tissue conductance (Gt) were continuously measured. The mucosal addition of ε-viniferin (>10(-5) mol/L) and resveratrol (>10(-4) mol/L) to the cecal mucosa, which was the most sensitive region, induced an increase in Isc and a rapid phase decrease (P-1) followed by rapid (P-2) and broad (P-3) peak increases in Gt in concentration-dependent manners. Mucosal ε-viniferin (10(-4) mol/L), but not resveratrol (10(-4) mol/L), increased the permeability of FITC-conjugated dextran (4 kDa). The mucosal ε-viniferin-evoked changes in Isc (Cl(-) secretion), but not in Gt, were attenuated by a selective cyclooxygenase (COX)-1 inhibitor and a selective EP4 prostaglandin receptor. The mucosal ε-viniferin-evoked increase in Isc was partially attenuated, and P-2, but not P-1 or P-3, change in Gt was abolished by a transient receptor potential cation channel, subfamily A, member 1 (TRPA1) inhibitor. Moreover, the mucosal ε-viniferin concentration-dependently attenuated the mucosal propionate (1 mmol/L)-evoked increases in Isc and Gt Immunohistochemical studies revealed COX-1-immunoreactive epithelial cells in the cecal crypt. The present study showed that mucosal ε-viniferin modulated transepithelial ion transport and permeability, possibly by activating sensory epithelial cells expressing COX-1 and TRPA1. Moreover, mucosal ε-viniferin decreased mucosal sensitivity to other luminal molecules such as short-chain fatty acids. In conclusion, these results suggest that ε-viniferin modifies intestinal mucosal transport and barrier

  14. Vascular endothelial growth factor regulates angiogenesis and vascular permeability in Kaposi's sarcoma.

    Cornali, E.; Zietz, C; Benelli, R; Weninger, W.; Masiello, L.; Breier, G; Tschachler, E; Albini, A; Stürzl, M

    1996-01-01

    Abundant vasculature with increased permeability is a prominent histological feature of Kaposi's sarcoma (KS), a multifocal, cytokine-regulated tumor. Here we report on the role of vascular endothelial growth factor (VEGF) in AIDS-KS angiogenesis and vascular permeability. We demonstrate that different cytokines, which were previously shown to be active in KS development, modulate VEGF expression in KS spindle cells and cooperate with VEGF on the functional level. Northern blot analysis as we...

  15. Impact of the Enhanced Permeability and Retention (EPR Effect and Cathepsins Levels on the Activity of Polymer-Drug Conjugates

    Amit K. Rajora

    2014-08-01

    Full Text Available Polymer-drug conjugates have demonstrated clinical potential in the context of anticancer therapy. However, such promising results have, to date, failed to translate into a marketed product. Polymer-drug conjugates rely on two factors for activity: (i the presence of a defective vasculature, for passive accumulation of this technology into the tumour tissue (enhanced permeability and retention (EPR effect and (ii the presence of a specific trigger at the tumour site, for selective drug release (e.g., the enzyme cathepsin B. Here, we retrospectively analyse literature data to investigate which tumour types have proved more responsive to polymer-drug conjugates and to determine correlations between the magnitude of the EPR effect and/or expression of cathepsin B. Lung, breast and ovarian cancers showed the highest response rate (30%, 47% and 41%, respectively for cathepsin-activated conjugates and 31%, 43%, 40%, across all conjugates. An analysis of literature data on cathepsin content in various tumour types showed that these tumour types had high cathepsin content (up to 3835 ng/mg for lung cancer, although marked heterogeneity was observed across different studies. In addition, these tumour types were also reported as having a high EPR effect. Our results suggest that a pre-screening of patient population could bring a more marked clinical benefit.

  16. Capsaicin modulates proliferation, migration, and activation of hepatic stellate cells.

    Bitencourt, Shanna; Mesquita, Fernanda; Basso, Bruno; Schmid, Júlia; Ferreira, Gabriela; Rizzo, Lucas; Bauer, Moises; Bartrons, Ramon; Ventura, Francesc; Rosa, Jose Luis; Mannaerts, Inge; van Grunsven, Leo Adrianus; Oliveira, Jarbas

    2014-03-01

    Capsaicin, the active component of chili pepper, has been reported to have antiproliferative and anti-inflammatory effects on a variety of cell lines. In the current study, we aimed to investigate the effects of capsaicin during HSC activation and maintenance. Activated and freshly isolated HSCs were treated with capsaicin. Proliferation was measured by incorporation of EdU. Cell cycle arrest and apoptosis were investigated using flow cytometry. The migratory response to chemotactic stimuli was evaluated by a modified Boyden chamber assay. Activation markers and inflammatory cytokines were determined by qPCR, immunocytochemistry, and flow cytometry. Our results show that capsaicin reduces HSC proliferation, migration, and expression of profibrogenic markers of activated and primary mouse HSCs. In conclusion, the present study shows that capsaicin modulates proliferation, migration, and activation of HSC in vitro. PMID:23955514

  17. Permeable reactive barrier of surface hydrophobic granular activated carbon coupled with elemental iron for the removal of 2,4-dichlorophenol in water

    Granular activated carbon was modified with dimethyl dichlorosilane to improve its surface hydrophobicity, and therefore to improve the performance of permeable reactive barrier constructed with the modified granular activated carbon and elemental iron. X-ray photoelectron spectroscopy shows that the surface silicon concentration of the modified granular activated carbon is higher than that of the original one, leading to the increased surface hydrophobicity. Although the specific surface area decreased from 895 to 835 m2 g-1, the modified granular activated carbon could adsorb 20% more 2,4-dichlorophenol than the original one did in water. It is also proven that the permeable reactive barrier with the modified granular activated carbon is more efficient at 2,4-dichlorophenol dechlorination, in which process 2,4-dichlorophenol is transformed to 2-chlorophenol or 4-chlorophenol then to phenol, or to phenol directly.

  18. Surface plasmon polariton modulator with optimized active layer

    Babicheva, Viktoriia; Lavrinenko, Andrei

    2012-01-01

    A multilayered waveguide, which supports surface plasmon polaritons, is considered as an absorption modulator. The waveguide core consists of a silicon nitride layer and ultrathin layer with the varied carrier density embedded between two silver plates, which also serve as electrodes. Under apply...... from the pattern size and filling factor of the active material are analyzed for tuned permittivity of the ITO layer. Direct simulation of the device functionality validates optimization design....

  19. Active removal of large massive objects by hybrid propulsion module

    Luigi T. De Luca; Lavagna, Mich?le; Maggi, Filippo; Tadini, Pietro; Pardini, Carmen; Anselmo, Luciano; Grassi, Michele; Tancredi, Urbano; Francesconi, Alessandro; Chiesa, Sergio; Viola, Nicole; Bonnal, Christophe

    2013-01-01

    This paper deals with the feasibility study of a mission for the active removal of a large massive object, such as the second stage of the Zenit launcher or the Envisat spacecraft, abandoned in the most populated orbit region in low Earth orbit. Critical mission aspects and related technologies are investigated at a preliminary level. In particular, an innovative electro-adhesive system for target capture, mechanical systems for chaser-debris hard docking and a hybrid propulsion module for re...

  20. Target cell-specific modulation of neuronal activity by astrocytes

    Kozlov, A. S.; Angulo, M. C.; Audinat, E.; Charpak, S

    2006-01-01

    Interaction between astrocytes and neurons enriches the behavior of brain circuits. By releasing glutamate and ATP, astrocytes can directly excite neurons and modulate synaptic transmission. In the rat olfactory bulb, we demonstrate that the release of GABA by astrocytes causes long-lasting and synchronous inhibition of mitral and granule cells. In addition, astrocytes release glutamate, leading to a selective activation of granule-cell NMDA receptors. Thus, by releasing excitatory and inhibi...

  1. Activation of SIRT3 attenuates triptolide-induced toxicity through closing mitochondrial permeability transition pore in cardiomyocytes.

    Yang, Yanqin; Wang, Wenwen; Xiong, Zhewen; Kong, Jiamin; Qiu, Yuwen; Shen, Feihai; Huang, Zhiying

    2016-08-01

    Triptolide (TP), an active component of the traditional Chinese herb Tripterygium wilfordii Hook f. (TWHF), has multiple pharmacological effects. However, the severe toxicity of TP greatly restricts its clinical applications. Although TP exposure causes serious heart injury, the mechanism underlying TP-induced cardiotoxicity has rarely been investigated. In previous studies, we found that TP-induced oxidative stress was involved in the mitochondria-dependent apoptosis of cardiomyocytes. Opening of the mitochondrial permeability transition pore (mPTP) is the key to the mitochondrial dysfunction in cardiac toxicity. The aim of this study was to investigate the potential cardioprotective effects of sirtuin 3 (SIRT3) on the mPTP. In the present study, the cytotoxicity of TP was accompanied by the up-regulation of the SIRT3 protein level and its rapid aggregation in nuclei and mitochondria. The SIRT3-FOXO3 signaling pathway was activated simultaneously, resulting in increased transcription of manganese superoxide dismutase (MnSOD) and catalase (CAT) for the elimination of reactive oxygen species (ROS). In addition, augmentation of the SIRT3 level via the overexpression plasmid SIRT3-Flag provided resistance to TP-induced cellular damage, whereas knocking down the SIRT3 level via siRNA accelerated the damage. Because it is an activator of SIRT3, the protective effect of resveratrol was also evaluated in H9c2 cells. In conclusion, the current results suggest that activation of SIRT3 substantially ameliorates the detrimental effects of TP by closing the mPTP. PMID:27064125

  2. Maternal antibiotic-induced early changes in microbial colonization selectively modulate colonic permeability and inducible heat shock proteins, and digesta concentrations of alkaline phosphatase and TLR-stimulants in swine offspring.

    Marie-Edith Arnal

    Full Text Available Elevated intake of high energy diets is a risk factor for the development of metabolic diseases and obesity. High fat diets cause alterations in colonic microbiota composition and increase gut permeability to bacterial lipopolysaccharide, and subsequent low-grade chronic inflammation in mice. Chronic inflammatory bowel diseases are increasing worldwide and may involve alterations in microbiota-host dialog. Metabolic disorders appearing in later life are also suspected to reflect changes in early programming. However, how the latter affects the colon remains poorly studied. Here, we hypothesized that various components of colonic physiology, including permeability, ion exchange and protective inducible heat shock proteins (HSP are influenced in the short- and long-terms by early disturbances in microbial colonization. The hypothesis was tested in a swine model. Offspring were born to control mothers (n = 12 or mothers treated with the antibiotic (ATB amoxicillin around parturition (n = 11. Offspring were slaughtered between 14 and 42 days of age to study short-term effects. For long-term effects, young adult offspring from the same litters consumed a normal or a palm oil-enriched diet for 4 weeks between 140 and 169 days of age. ATB treatment transiently modified maternal fecal microbiota although the minor differences observed for offspring colonic microbiota were nonsignificant. In the short-term, consistently higher HSP27 and HSP70 levels and transiently increased horseradish peroxidase permeability in ATB offspring colon were observed. Importantly, long-term consequences included reduced colonic horseradish peroxidase permeability, and increased colonic digesta alkaline phosphatase (AP and TLR2- and TLR4-stimulant concentrations in rectal digesta in adult ATB offspring. Inducible HSP27 and HSP70 did not change. Interactions between early ATB treatment and later diet were noted for paracellular permeability and concentrations of colonic

  3. Heavy metal removal from MSWI fly ash by electrokinetic remediation coupled with a permeable activated charcoal reactive barrier

    Huang, Tao; Li, Dongwei; Kexiang, Liu; Zhang, Yuewei

    2015-10-01

    This paper presents the investigations into the feasibility of the application of a remediation system that couples electrokinetic remediation (EKR) with the permeable reactive barrier (PRB) concept for municipal solid waste incineration (MSWI) fly ash with activated charcoal as the PRB material. The experimental results of this study showed that the proposed combined method can effectively improve the remediation efficiency and that the addition of the oxalic acid to the PRB media before the coupled system can further enhance the remediation process. In the optimization tests, the maximum removals of Zn, Pb, Cu and Cd were achieved under different experimental conditions. The voltage gradient and processing time were shown to have significant effects on the removal of Cu and Cd, whereas the addition of the oxalic acid had a more significant influence on the removal of Pb. Generally, the processing time is the most significant factor in changing the removal rates of HMs in the enhanced coupled system. In terms of the leaching toxicity, the specimen remediated by ENEKR + PRB showed the lowest leaching value for each HM in the S2 and S3 regions.

  4. Cardioprotective effects of luteolin on ischemia/reperfusion injury in diabetic rats are modulated by eNOS and the mitochondrial permeability transition pathway.

    Yang, Jin-Ting; Qian, Ling-Bo; Zhang, Feng-Jiang; Wang, Jue; Ai, Heng; Tang, Li-Hui; Wang, Hui-Ping

    2015-04-01

    Myocardial ischemia/reperfusion (I/R) injury in diabetes is associated with oxidative stress, endothelial nitric oxide synthase (eNOS) dysfunction, and mitochondrial collapse, whereas luteolin is known to protect the cardiovascular system against diabetes and I/R injury. Here, we investigated whether luteolin pretreatment diminishes myocardial I/R injury in diabetic rats by affecting eNOS and the mitochondrial permeability transition pore (mPTP). After diabetic rats were produced by streptozotocin treatment (65 mg/kg) for 3 weeks, luteolin (100 mg·kg·d) or L-NAME (25 mg·kg·d) was administered intragastrically for 2 weeks. Hearts were then isolated and subjected to 30 minutes of global ischemia followed by 120 minutes of reperfusion. Pretreatment with luteolin significantly improved left ventricular function and coronary flow throughout reperfusion, increased cardiac tissue viability and manganese superoxide dismutase (MnSOD) activity, and reduced coronary lactate dehydrogenase release, and the myocardial malonaldehyde level in diabetic I/R rat hearts. All these improving effects of luteolin were significantly attenuated by L-NAME. Luteolin also significantly upregulated eNOS expression in diabetic rat hearts after I/R. Ca-induced mPTP opening and mitochondrial inner membrane potential reduction were significantly inhibited in ventricular myocytes isolated from luteolin-treated diabetic rats, and this effect was attenuated by L-NAME. These findings indicate that luteolin protects the diabetic heart against I/R injury by upregulating the myocardial eNOS pathway, and downstream effects include the enhancement of MnSOD and inhibition of mPTP. PMID:25502309

  5. Cost Effective System Modeling of Active Micro- Module Solar Tracker

    Md. Faisal Shuvo

    2014-01-01

    Full Text Available The increasing interests in using renewable energies are coming from solar thermal energy and solar photovoltaic systems to the micro production of electricity. Usually we already have considered the solar tracking topology in large scale applications like power plants and satellite but most of small scale applications don’t have any solar tracker system, mainly because of its high cost and complex circuit design. From that aspect, this paper confab microcontroller based one dimensional active micro-module solar tracking system, in which inexpensive LDR is used to generate reference voltage to operate microcontroller for functioning the tracking system. This system provides a fast response of tracking system to the parameters like change of light intensity as well as temperature variations. This micro-module model of tracking system can be used for small scale applications like portable electronic devices and running vehicles.

  6. Abnormal Task Modulation of Oscillatory Neural Activity in Schizophrenia

    Elisa C Dias

    2013-08-01

    Full Text Available Schizophrenia patients have deficits in cognitive function that are a core feature of the disorder. AX-CPT is commonly used to study cognition in schizophrenia, and patients have characteristic pattern of behavioral and ERP response. In AX-CPT subjects respond when a flashed cue A is followed by a target X, ignoring other letter combinations. Patients show reduced hit rate to go trials, and increased false alarms to sequences that require inhibition of a prepotent response. EEG recordings show reduced sensory (P1/N1, as well as later cognitive components (N2, P3, CNV. Behavioral deficits correlate most strongly with sensory dysfunction. Oscillatory analyses provide critical information regarding sensory/cognitive processing over and above standard ERP analyses. Recent analyses of induced oscillatory activity in single trials during AX-CPT in healthy volunteers showed characteristic response patterns in theta, alpha and beta frequencies tied to specific sensory and cognitive processes. Alpha and beta modulated during the trials and beta modulation over the frontal cortex correlated with reaction time. In this study, EEG data was obtained from 18 schizophrenia patients and 13 controls during AX-CPT performance, and single trial decomposition of the signal yielded power in the target wavelengths.Significant task-related event-related desynchronization (ERD was observed in both alpha and beta frequency bands over parieto-occipital cortex related to sensory encoding of the cue. This modulation was reduced in patients for beta, but not for alpha. In addition, significant beta ERD was observed over motor cortex, related to motor preparation for the response, and was also reduced in patients. These findings demonstrate impaired dynamic modulation of beta frequency rhythms in schizophrenia, and suggest that failures of oscillatory activity may underlie impaired sensory information processing in schizophrenia that in turn contributes to cognitive deficits.

  7. Antioxidant, antimicrobial and neutrophil-modulating activities of herb extracts.

    Denev, Petko; Kratchanova, Maria; Ciz, Milan; Lojek, Antonin; Vasicek, Ondrej; Blazheva, Denitsa; Nedelcheva, Plamena; Vojtek, Libor; Hyrsl, Pavel

    2014-01-01

    The present study provides a comprehensive data on the antioxidant, antimicrobial and neutrophil-modulating activities of extracts from six medicinal plants--blackberry (Rubus fruticosus) leaves, chokeberry (Aronia melanocarpa) leaves, hawthorn (Crataegus monogyna) leaves, lady's mantle (Alchemilla glabra) aerial parts, meadowsweet (Filipendula ulmaria) aerial parts and raspberry (Rubus idaeus) leaves. In order to analyze the antioxidant activity of the herbs, several methods (ORAC, TRAP, HORAC and inhibition of lipid peroxidation) were used. Blackberry leaves and meadowsweet extracts revealed the highest antioxidant activities via all methods. All extracts studied blocked almost completely the opsonized zymosan particle-activated ROS production by neutrophils from human whole blood. On the other hand, the effect of extracts on phorbol myristate acetate-activated ROS production was much milder and even nonsignificant in the case of chokeberry leaves. This latter result suggests that extracts (apart from their antioxidative activity) interfere with the signaling cascade of phagocyte activation upstream of the protein kinase C activation. The antimicrobial activity of the investigated extracts against 11 human pathogens was investigated using three different methods. Meadowsweet and blackberry leaves extracts had the highest antimicrobial effect and the lowest minimal inhibiting concentrations (MICs) against the microorganisms tested. PMID:24945135

  8. Quantification of active mitochondrial permeability transition pores using GNX-4975 inhibitor titrations provides insights into molecular identity.

    Richardson, Andrew P; Halestrap, Andrew P

    2016-05-01

    Inhibition of the mitochondrial permeability transition pore (MPTP) by the novel inhibitor GNX-4975 was characterized. Titration of MPTP activity in de-energized rat liver mitochondria allowed determination of the number of GNX-4975-binding sites and their dissociation constant (Ki). Binding sites increased in number when MPTP opening was activated by increasing [Ca(2+)], phenylarsine oxide (PAO) or KSCN, and decreased when MPTP opening was inhibited with bongkrekic acid (BKA) or ADP. Values ranged between 9 and 50 pmol/mg of mitochondrial protein, but the Ki remained unchanged at ∼1.8 nM when the inhibitor was added before Ca(2+) However, when GNX-4975 was added after Ca(2+) it was much less potent with a Ki of ∼140 nM. These data imply that a protein conformational change is required to form the MPTP complex and generate the GNX-4975-binding site. Occupation of the latter with GNX-4975 prevents the Ca(2+) binding that triggers pore opening. We also demonstrated that GNX-4975 stabilizes an interaction between the adenine nucleotide translocase (ANT), held in its 'c' conformation with carboxyatractyloside (CAT), and the phosphate carrier (PiC) bound to immobilized PAO. No components of the F1Fo-ATP synthase bound significantly to immobilized PAO. Our data are consistent with our previous proposal that the MPTP may form at an interface between the PiC and ANT (or other similar mitochondrial carrier proteins) when they adopt novel conformations induced by factors that sensitize the MPTP to [Ca(2+)]. We propose that GNX-4975 binds to this interface preventing a calcium-triggered event that opens the interface into a pore. PMID:26920024

  9. Regulating the regulators: modulators of transcription factor activity.

    Everett, Logan; Hansen, Matthew; Hannenhalli, Sridhar

    2010-01-01

    Gene transcription is largely regulated by DNA-binding transcription factors (TFs). However, the TF activity itself is modulated via, among other things, post-translational modifications (PTMs) by specific modification enzymes in response to cellular stimuli. TF-PTMs thus serve as "molecular switchboards" that map upstream signaling events to the downstream transcriptional events. An important long-term goal is to obtain a genome-wide map of "regulatory triplets" consisting of a TF, target gene, and a modulator gene that specifically modulates the regulation of the target gene by the TF. A variety of genome-wide data sets can be exploited by computational methods to obtain a rough map of regulatory triplets, which can guide directed experiments. However, a prerequisite to developing such computational tools is a systematic catalog of known instances of regulatory triplets. We first describe PTM-Switchboard, a recent database that stores triplets of genes such that the ability of one gene (the TF) to regulate a target gene is dependent on one or more PTMs catalyzed by a third gene, the modifying enzyme. We also review current computational approaches to infer regulatory triplets from genome-wide data sets and conclude with a discussion of potential future research. PTM-Switchboard is accessible at http://cagr.pcbi.upenn.edu/PTMswitchboard / PMID:20827600

  10. Modulating enzyme activity using ionic liquids or surfactants.

    Goldfeder, Mor; Fishman, Ayelet

    2014-01-01

    One of the important strategies for modulating enzyme activity is the use of additives to affect their microenvironment and subsequently make them suitable for use in different industrial processes. Ionic liquids (ILs) have been investigated extensively in recent years as such additives. They are a class of solvents with peculiar properties and a "green" reputation in comparison to classical organic solvents. ILs as co-solvents in aqueous systems have an effect on substrate solubility, enzyme structure and on enzyme-water interactions. These effects can lead to higher reaction yields, improved selectivity, and changes in substrate specificity, and thus there is great potential for IL incorporation in biocatalysis. The use of surfactants, which are usually denaturating agents, as additives in enzymatic reactions is less reviewed in recent years. However, interesting modulations in enzyme activity in their presence have been reported. In the case of surfactants there is a more pronounced effect on the enzyme structure, as can be observed in a number of crystal structures obtained in their presence. For each additive and enzymatic process, a specific optimization process is needed and there is no one-fits-all solution. Combining ILs and surfactants in either mixed micelles or water-in-IL microemulsions for use in enzymatic reaction systems is a promising direction which may further expand the range of enzyme applications in industrial processes. While many reviews exist on the use of ILs in biocatalysis, the present review centers on systems in which ILs or surfactants were able to modulate and improve the natural activity of enzymes in aqueous systems. PMID:24281758

  11. Antifungal Activity of Salvia miltiorrhiza Against Candida albicans Is Associated with the Alteration of Membrane Permeability and (1,3)-β-D-Glucan Synthase Activity.

    Lee, Heung-Shick; Kim, Younhee

    2016-03-28

    Candidiasis has posed a serious health risk to immunocompromised patients owing to the increase in resistant yeasts, and Candida albicans is the prominent pathogen of fungal infections. Therefore, there is a critical need for the discovery and characterization of novel antifungals to treat infections caused by C. albicans. In the present study, we report on the antifungal activity of the ethanol extract from Salvia miltiorrhiza against C. albicans and the possible mode of action against C. albicans. The increase in the membrane permeability was evidenced by changes in diphenylhexatriene binding and release of both 260-nm-absorbing intracellular materials and protein. In addition, inhibition of cell wall synthesis was demonstrated by the enhanced minimal inhibitory concentration in the presence of sorbitol and reduced (1,3)-β-D-glucan synthase activity. The above evidence supports the notion that S. miltiorrhiza has antifungal activity against C. albicans by the synergistic activity of targeting the cell membrane and cell wall. These findings indicate that S. miltiorrhiza displays effective activity against C. albicans in vitro and merits further investigation to treat C. albicansassociated infections. PMID:26699747

  12. Visual experience modulates spatio-temporal dynamics of circuit activation

    Arianna Maffei

    2011-06-01

    Full Text Available Persistent reduction in sensory drive in early development results in multiple plastic changes of different cortical synapses. How these experience-dependent modifications affect the spatio-temporal dynamics of signal propagation in neocortical circuits is poorly understood. Here we demonstrate that brief visual deprivation significantly affects the propagation of electrical signals in the primary visual cortex. The spatio-temporal spread of circuit activation upon direct stimulation of its input layer (Layer 4 is reduced, as is the activation of Layer 2/3 – the main recipient of the output from Layer 4. Our data suggest that the decrease in spatio-temporal activation of L2/3 depends on reduced L4 output, and is not intrinsically generated within L2/3. The data shown here suggest that changes in the synaptic components of the visual cortical circuit result not only in alteration of local integration of excitatory and inhibitory inputs, but also in a significant decrease in overall circuit activation. Furthermore, our data indicate a differential effect of visual deprivation on L4 and L2/3, suggesting that while feedforward activation of L2/3 is reduced, its activation by long range, within layer inputs is unaltered. Thus, brief visual deprivation induces experience-dependent circuit re-organization by modulating not only circuit excitability, but also the spatio-temporal patterns of cortical activation within and between layers.

  13. Integrated Brain Circuits: Astrocytic Networks Modulate Neuronal Activity and Behavior

    Halassa, Michael M.; Haydon, Philip G.

    2011-01-01

    The past decade has seen an explosion of research on roles of neuron-astrocyte interactions in the control of brain function. We highlight recent studies performed on the tripartite synapse, the structure consisting of pre- and postsynaptic elements of the synapse and an associated astrocytic process. Astrocytes respond to neuronal activity and neuro-transmitters, through the activation of metabotropic receptors, and can release the gliotransmitters ATP, D-serine, and glutamate, which act on neurons. Astrocyte-derived ATP modulates synaptic transmission, either directly or through its metabolic product adenosine. D-serine modulates NMDA receptor function, whereas glia-derived glutamate can play important roles in relapse following withdrawal from drugs of abuse. Cell type–specific molecular genetics has allowed a new level of examination of the function of astrocytes in brain function and has revealed an important role of these glial cells that is mediated by adenosine accumulation in the control of sleep and in cognitive impairments that follow sleep deprivation. PMID:20148679

  14. Selective modulation of promoter recruitment and transcriptional activity of PPARγ

    Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor regulated by the insulin-sensitizing thiazolidinediones (TZDs). We studied selective modulation of endogenous genes by PPARγ ligands using microarray, RNA expression kinetics, and chromatin immunoprecipitation (ChIP) in 3T3-L1 adipocytes. We found over 300 genes that were significantly regulated the TZDs pioglitazone, rosiglitazone, and troglitazone. TZD-mediated expression profiles were unique but overlapping. Ninety-one genes were commonly regulated by all three ligands. TZD time course and dose-response studies revealed gene- and TZD-specific expression kinetics. PEPCK expression was induced rapidly but PDK4 expression was induced gradually. Troglitazone EC50 values for PEPCK, PDK4, and RGS2 regulation were greater than those for pioglitazone and rosiglitazone. TZDs differentially induced histone acetylation of and PPARγ recruitment to target gene promoters. Selective modulation of PPARγ by TZDs resulted in distinct expression profiles and transcription kinetics which may be due to differential promoter activation and chromatin remodeling of target genes

  15. Regular exercise modulates cardiac mast cell activation in ovariectomized rats.

    Phungphong, Sukanya; Kijtawornrat, Anusak; Wattanapermpool, Jonggonnee; Bupha-Intr, Tepmanas

    2016-03-01

    It is well accepted that regular exercise is a significant factor in the prevention of cardiac dysfunction; however, the cardioprotective mechanism is as yet not well defined. We have examined whether regular exercise can modulate the activity of cardiac mast cells (CMC) after deprivation of female sex hormones, as well as the density and percentage degranulation of mast cells, in ventricular tissue of ovariectomized (OVX) rats after an 11-week running program. A significant increase in CMC density with a greater percentage degranulation was induced after ovarian sex hormone deprivation. Increased CMC density was prevented by estrogen supplements, but not by regular training. To the contrary, increased CMC degranulation in the OVX rat heart was attenuated by exercise training, but not by estrogen supplement. These findings indicate a significant correlation between the degree of CMC degranulation and myocyte cross-section area. However, no change in the expression of inflammatory mediators, including chymase, interleukin-6, and interleukin-10, was detected. Taken together, these results clearly indicate one of the cardioprotective mechanisms of regular aerobic exercise is the modulation of CMC activation. PMID:26467449

  16. The mechanical environment modulates intracellular calcium oscillation activities of myofibroblasts.

    Charles Godbout

    Full Text Available Myofibroblast contraction is fundamental in the excessive tissue remodeling that is characteristic of fibrotic tissue contractures. Tissue remodeling during development of fibrosis leads to gradually increasing stiffness of the extracellular matrix. We propose that this increased stiffness positively feeds back on the contractile activities of myofibroblasts. We have previously shown that cycles of contraction directly correlate with periodic intracellular calcium oscillations in cultured myofibroblasts. We analyze cytosolic calcium dynamics using fluorescent calcium indicators to evaluate the possible impact of mechanical stress on myofibroblast contractile activity. To modulate extracellular mechanics, we seeded primary rat subcutaneous myofibroblasts on silicone substrates and into collagen gels of different elastic modulus. We modulated cell stress by cell growth on differently adhesive culture substrates, by restricting cell spreading area on micro-printed adhesive islands, and depolymerizing actin with Cytochalasin D. In general, calcium oscillation frequencies in myofibroblasts increased with increasing mechanical challenge. These results provide new insight on how changing mechanical conditions for myofibroblasts are encoded in calcium oscillations and possibly explain how reparative cells adapt their contractile behavior to the stresses occurring in normal and pathological tissue repair.

  17. A method to predict different mechanisms for blood-brain barrier permeability of CNS activity compounds in Chinese herbs using support vector machine.

    Jiang, Ludi; Chen, Jiahua; He, Yusu; Zhang, Yanling; Li, Gongyu

    2016-02-01

    The blood-brain barrier (BBB), a highly selective barrier between central nervous system (CNS) and the blood stream, restricts and regulates the penetration of compounds from the blood into the brain. Drugs that affect the CNS interact with the BBB prior to their target site, so the prediction research on BBB permeability is a fundamental and significant research direction in neuropharmacology. In this study, we combed through the available data and then with the help of support vector machine (SVM), we established an experiment process for discovering potential CNS compounds and investigating the mechanisms of BBB permeability of them to advance the research in this field four types of prediction models, referring to CNS activity, BBB permeability, passive diffusion and efflux transport, were obtained in the experiment process. The first two models were used to discover compounds which may have CNS activity and also cross the BBB at the same time; the latter two were used to elucidate the mechanism of BBB permeability of those compounds. Three optimization parameter methods, Grid Search, Genetic Algorithm (GA), and Particle Swarm Optimization (PSO), were used to optimize the SVM models. Then, four optimal models were selected with excellent evaluation indexes (the accuracy, sensitivity and specificity of each model were all above 85%). Furthermore, discrimination models were utilized to study the BBB properties of the known CNS activity compounds in Chinese herbs and this may guide the CNS drug development. With the relatively systematic and quick approach, the application rationality of traditional Chinese medicines for treating nervous system disease in the clinical practice will be improved. PMID:26632324

  18. Modulation of cortical oscillatory activity during transcranial magnetic stimulation.

    Brignani, Debora; Manganotti, Paolo; Rossini, Paolo M; Miniussi, Carlo

    2008-05-01

    Transcranial magnetic stimulation (TMS) can transiently modulate cortical excitability, with a net effect depending on the stimulation frequency ( or =5 Hz facilitation, at least for the motor cortex). This possibility has generated interest in experiments aiming to improve deficits in clinical settings, as well as deficits in the cognitive domain. The aim of the present study was to investigate the on-line effects of low frequency (1 Hz) TMS on the EEG oscillatory activity in the healthy human brain, focusing particularly on the outcome of these modulatory effects in relation to the duration of the TMS stimulation. To this end, we used the event-related desynchronization/synchronization (ERD/ERS) approach to determine the patterns of oscillatory activity during two consecutive trains of sham and real TMS. Each train of stimulation was delivered to the left primary motor cortex (MI) of healthy subjects over a period of 10 min, while EEG rhythms were simultaneously recorded. Results indicated that TMS induced an increase in the power of brain rhythms that was related to the period of the stimulation, i.e. the synchronization of the alpha band increased with the duration of the stimulation, and this increase was inversely correlated with motor-evoked potentials (MEPs) amplitude. In conclusion, low frequency TMS over primary motor cortex induces a synchronization of the background oscillatory activity on the stimulated region. This induced modulation in brain oscillations seems to increase coherently with the duration of stimulation, suggesting that TMS effects may involve short-term modification of the neural circuitry sustaining MEPs characteristics. PMID:17557296

  19. Cinobufagin Modulates Human Innate Immune Responses and Triggers Antibacterial Activity.

    Xie, Shanshan; Spelmink, Laura; Codemo, Mario; Subramanian, Karthik; Pütsep, Katrin; Henriques-Normark, Birgitta; Olliver, Marie

    2016-01-01

    The traditional Chinese medicine Chan-Su is widely used for treatment of cancer and cardiovascular diseases, but also as a remedy for infections such as furunculosis, tonsillitis and acute pharyngitis. The clinical use of Chan-Su suggests that it has anti-infective effects, however, the mechanism of action is incompletely understood. In particular, the effect on the human immune system is poorly defined. Here, we describe previously unrecognized immunomodulatory activities of cinobufagin (CBG), a major bioactive component of Chan-Su. Using human monocyte-derived dendritic cells (DCs), we show that LPS-induced maturation and production of a number of cytokines was potently inhibited by CBG, which also had a pro-apoptotic effect, associated with activation of caspase-3. Interestingly, CBG triggered caspase-1 activation and significantly enhanced IL-1β production in LPS-stimulated cells. Finally, we demonstrate that CBG upregulates gene expression of the antimicrobial peptides (AMPs) hBD-2 and hBD-3 in DCs, and induces secretion of HNP1-3 and hCAP-18/LL-37 from neutrophils, potentiating neutrophil antibacterial activity. Taken together, our data indicate that CBG modulates the inflammatory phenotype of DCs in response to LPS, and triggers an antibacterial innate immune response, thus proposing possible mechanisms for the clinical effects of Chan-Su in anti-infective therapy. PMID:27529866

  20. Superoxide radical and iron modulate aconitase activity in mammalian cells.

    Gardner, P R; Raineri, I; Epstein, L B; White, C W

    1995-06-01

    Aconitase is a member of a family of iron-sulfur-containing (de)hydratases whose activities are modulated in bacteria by superoxide radical (O2-.)-mediated inactivation and iron-dependent reactivation. The inactivation-reactivation of aconitase(s) in cultured mammalian cells was explored since these reactions may impact important and diverse aconitase functions in the cytoplasm and mitochondria. Conditions which increase O2-. production including exposure to the redox-cycling agent phenazine methosulfate (PMS), inhibitors of mitochondrial ubiquinol-cytochrome c oxidoreductase, or hyperoxia inactivated aconitase in mammalian cells. Overproduction of mitochondrial Mn-superoxide dismutase protected aconitase from inactivation by PMS or inhibitors of ubiquinol-cytochrome c oxidoreductase, but not from normobaric hyperoxia. Aconitase activity was reactivated (t1/2 of 12 +/- 3 min) upon removal of PMS. The iron chelator deferoxamine impaired reactivation and increased net inactivation of aconitase by O2-.. The ability of ubiquinol-cytochrome c oxidoreductase-generated O2-. to inactivate aconitase in several cell types correlated with the fraction of the aconitase activity localized in mitochondria. Extracellular O2-. generated with xanthine oxidase did not affect aconitase activity nor did exogenous superoxide dismutase decrease aconitase inactivation by PMS. The results demonstrate a dynamic and cyclical O2-.-mediated inactivation and iron-dependent reactivation of the mammalian [4Fe-4S] aconitases under normal and stress conditions and provide further evidence for the membrane compartmentalization of O2-.. PMID:7768942

  1. Functional Expression of a Ca(2+)-activated Cl(-) Channel Modulator Involved in Ion Transport and Epithelial Cell Differentiation.

    Yamazaki, Jun

    2016-01-01

      Cl(-)-permeable channels and transporters expressed on the cell membranes of various mammalian cell types play pivotal roles in the transport of electrolytes and water, pH regulation, cell volume and membrane excitability, and are therefore expected to be useful molecular targets for drug discovery. Both TMEM16A (a possible candidate for Ca(2+)-regulated Cl(-) channels recently identified) and cystic fibrosis transmembrane conductance regulator (CFTR) (or cAMP-regulated Cl(-) channels) have been known to be involved in Cl(-) secretion and reabsorption in the rat salivary gland. Crosstalk between two types of regulatory pathways through these two types of channels has also been described. Previously, we demonstrated that CLCA, a Ca(2+)-activated Cl(-) channel modulator, was involved in Cl(-) absorption in rat salivary ducts. In addition to Ca(2+), basal NF-κB activity in a mouse keratinocyte line was shown to be involved in the transcriptional regulation of CLCA. Conversely, a truncated isoform of CLCA was found in undifferentiated epithelial cells present in the rat epidermal basal layers. Under regulation by Ca(2+) and PKC, the surface expression of β1-integrin and cell adhesion were decreased in the CLCA-overexpressing cells. Knockdown of this isoform elevated the expression of β1-integrin in rat epidermis in vivo. These results indicate that the specific differentiation-dependent localization of CLCA, and transcriptional regulation through Ca(2+), are likely to affect ion permeability and the adhesive potential of epithelial cells. In summary, these types of Cl(-) channels and their modulators may function in a coordinated manner in regulating the functions of epithelial cells under different physiological conditions. PMID:26935091

  2. Workshop Physics Activity Guide, Module 4: Electricity and Magnetism

    Laws, Priscilla W.

    2004-05-01

    The Workshop Physics Activity Guide is a set of student workbooks designed to serve as the foundation for a two-semester calculus-based introductory physics course. It consists of 28 units that interweave text materials with activities that include prediction, qualitative observation, explanation, equation derivation, mathematical modeling, quantitative experiments, and problem solving. Students use a powerful set of computer tools to record, display, and analyze data, as well as to develop mathematical models of physical phenomena. The design of many of the activities is based on the outcomes of physics education research. The Workshop Physics Activity Guide is supported by an Instructor's Website that: (1) describes the history and philosophy of the Workshop Physics Project; (2) provides advice on how to integrate the Guide into a variety of educational settings; (3) provides information on computer tools (hardware and software) and apparatus; and (4) includes suggested homework assignments for each unit. Log on to the Workshop Physics Project website at http://physics.dickinson.edu/ Workshop Physics is a component of the Physics Suite--a collection of materials created by a group of educational reformers known as the Activity Based Physics Group. The Physics Suite contains a broad array of curricular materials that are based on physics education research, including: Understanding Physics, by Cummings, Laws, Redish and Cooney (an introductory textbook based on the best-selling text by Halliday/Resnick/Walker) RealTime Physics Laboratory Modules Physics by Inquiry (intended for use in a workshop setting) Interactive Lecture Demonstration Tutorials in Introductory Physics Activity Based Tutorials (designed primarily for use in recitations)

  3. MCT SWIR modules for passive and active imaging applications

    Breiter, R.; Benecke, M.; Eich, D.; Figgemeier, H.; Weber, A.; Wendler, J.; Sieck, A.

    2016-05-01

    Based on AIM's state-of-the-art MCT IR technology, detector modules for the SWIR spectral range have been developed, fabricated and characterized. While LPE grown MCT FPAs with extended 2.5μm cut-off have been fabricated and integrated also MBE grown MCT on GaAs is considered for future production. Two imaging applications have been in focus operating either in passive mode by making use of e.g. the night glow, or in active mode by laser illumination for gated viewing. Dedicated readout integrated circuits (ROIC), realized in 0.18μm Si-CMOS technology providing the required functionality for passive imaging and gated imaging, have been designed and implemented. For both designs a 640x512 15μm pitch format was chosen. The FPAs are integrated in compact dewar cooler configurations using AIM's split linear coolers. A command and control electronics (CCE) provides supply voltages, biasing, clocks, control and video digitization for easy system interfacing. For imaging under low-light conditions a low-noise 640x512 15μm pitch ROIC with CTIA input stages and correlated double sampling was designed. The ROIC provides rolling shutter and snapshot integration. To reduce size, weight, power and cost (SWaP-C) a 640x512 format detector in a 10μm pitch is under development. The module makes use of the extended SWIR spectral cut-off up to 2.5μm. To be used for active gated-viewing operation SWIR MCT avalanche photodiodes have been implemented and characterized on FPA level in a 640x512 15μm pitch format. The specific ROIC provides also the necessary functions for range gate control and triggering by the laser illumination. First lab and field tests of a gated viewing demonstrator have been carried out. The paper will present the development status and performance results of AIM's MCT based SWIR Modules for imaging applications.

  4. The Influence of Gasotransmitters on Membrane Permeability and Activity of Tonoplast H+-ATPase Under Oxidative Stress

    E.V. Spiridonova; Ozolina, N. V.; I.S. Nesterkina; V.N. Nurminsky

    2016-01-01

    The investigation of the influence of gasotransmitters – a new class of signaling molecules – on the root tissues of red beet (Beta vulgaris L.) was conducted. It was found, that hydrogen sulfide (H2S) had some stabilizing effect on cellular membranes, reducing their permeability detected with the aid of conductometric technique. The reliable influence of carbon monoxide (CO) and nitrogen oxide (NO) in our experiments was not observed. A significant increase in efflux of electrolytes from bee...

  5. Caenorhabditis elegans glia modulate neuronal activity and behavior

    Randy F Stout

    2014-03-01

    Full Text Available Glial cells of C. elegans can modulate neuronal activity and behavior, which is the focus of this review. Initially, we provide an overview of neuroglial evolution, making a comparison between C. elegans glia and their genealogical counterparts. What follows is a brief discussion on C. elegans glia characteristics in terms of their exact numbers, germ layers origin, their necessity for proper development of sensory organs, and lack of their need for neuronal survival. The more specific roles that various glial cells have on neuron-based activity/behavior are succinctly presented. The cephalic sheath glia are important for development, maintenance and activity of central synapses, whereas the amphid glia seem to set the tone of sensory synapses; these glial cell types are ectoderm-derived. Mesoderm-derived GLR glia appear to be a part of the circuit for production of motor movement of the worm anterior. Finally, we discuss tools and approaches utilized in studying C. elegans glia, which are an extension of those experimental assets available for this animal, making it an appealing model, not only in neurosciences, but in biology in general.

  6. Fine-grained clay fraction (,0.2 {mu}m): An interesting tool to approach the present thermal and permeability state in active geothermal systems

    Patrier, P.; Papapanagiotou, P.; Beaufort, D.; Traineau, H.; Bril, H.

    1992-01-01

    We have investigated by X-ray diffraction the very fine grained secondary minerals (< 0.2 {micro}m) developed in geothermal systems, in relation with their present thermal and permeability state. Because the smallest particles are the most reactive part of a rock, they are the youngest mineral phases of the geothermal fields. This study has been performed on two active geothermal fields: Milos field, Greece (130 < T < 320 C) and Chipilapa field, Salvador (90 < T < 215 C). In the Milos field, the mineralogical composition of the < 0.2 {micro}m clay fraction observed in the reservoir strongly differs from the overlying altered metamorphic schists in the presence of abundant quantities of saponite and talc/saponite interstratified minerals at unusually high temperature. These phases are considered to be kinetically control-led ''metastable'' minerals which rapidly evolve towards actinolite and talc for present temperatures higher than 300 C. Their occurrence is a good indicator of discharge in highly permeable zones. In the geothermal field of Chipilapa, the mineralogical composition of the < 0.2 {micro}m clay fractions fairly agrees with the temperatures presently measured in the wells, whereas several discrepancies may be pointed out from the compositions of coarser clay fractions (< 5 {micro}m) which contain minerals inherited from higher temperature stages. Permeable zones may be evidenced from an increase of expandable components in the interstratified minerals and a decrease of the coherent domain of the unexpandable clay particles (chlorite).

  7. Ca2+ permeability of unedited and edited versions of the kainate selective glutamate receptor GluR6.

    Egebjerg, J; Heinemann, S F

    1993-01-01

    The Ca2+ permeability of the kainate selective glutamate receptor GluR6 depends on the editing of the RNA (or DNA). The unedited version of GluR6, GluR6Q, encodes a glutamine at position 621 (Q/R site) and exhibits a Ca2+/monovalent ion permeability ratio of 1.2, while the edited version of GluR6, GluR6R, encodes an arginine at position 621 and exhibits a permeability ratio of 0.47. Kainate activation of the GluR6 receptor results in currents that are modulated by extracellular calcium ions. ...

  8. Tiazofurin modulates lipopolysaccharide-activated microglia in vitro

    Savić Danijela

    2014-01-01

    Full Text Available Tiazofurin is a purine nucleoside analogue, with a broad spectrum of antitumoral and anti-inflammatory properties. In the present study, we have investigated the effect of tiazofurin on microglial inflammatory response to lipopolysaccharide in vitro. The cytotoxic effect of the drug was examined by sulforhodamine B assay. The Griess method was used to quantify nitrite production. Microglial morphology was assessed by measuring cell body size. Release of the pro-inflammatory cytokines, tumor necrosis factor-α, interleukin-1β, interleukin-6, and the anti-inflammatory cytokine interleukin- 10, were evaluated by enzyme-linked immunosorbent assay. Our data showed that tiazofurin decreased the number of activated microglia, lowered nitric oxide production and reduced the average cell surface of these cells. Tiazofurin reduced tumor necrosis factor-α, interleukin-6 and increased interleukin-10 secretion. Conversely, this drug promoted the release of interleukin-1β. Results obtained in this study indicate that TR displayed both anti- and pro-inflammatory modulation of activated microglia that could be relevant for its antitumor action within the central nervous system. [Projekat Ministarstva nauke Republike Srbije, br. III41014

  9. Modulation of Group I Ribozyme Activity by Cationic Porphyrins

    Shigeyoshi Matsumura

    2015-03-01

    Full Text Available The effects of cationic porphyrins on the catalytic activities of four group I ribozymes were investigated. A cationic porphyrin possessing four pyridinium moieties (pPyP inhibited two group IC3 ribozymes (Syn Rz and Azo Rz and a group IC1 ribozyme (Tet Rz. In the case of a group IA2 ribozyme (Td Rz, however, pPyP served not only as an inhibitor but also as an activator, and the effects of pPyP were dependent on its concentration. To analyze the structural and electronic factors determining the effects of pPyP on group I ribozymes, three cationic porphyrins (pPyNCP, pPyF4P, and TMPyP were also examined. As interactions between small organic molecules and nucleic acids are attractive and important issues in biochemistry and biotechnology, this study contributes to the development of porphyrin-based molecules that can modulate functions of structured RNA molecules.

  10. Discovery and Characterization of a Cell-Permeable, Small-Molecule c-Abl Kinase Activator that Binds to the Myristoyl Binding Site

    Yang, Jingsong; Campobasso, Nino; Biju, Mangatt P.; Fisher, Kelly; Pan, Xiao-Qing; Cottom, Josh; Galbraith, Sarah; Ho, Thau; Zhang, Hong; Hong, Xuan; Ward, Paris; Hofmann, Glenn; Siegfried, Brett; Zappacosta, Francesca; Washio, Yoshiaki; Cao, Ping; Qu, Junya; Bertrand, Sophie; Wang, Da-Yuan; Head, Martha S.; Li, Hu; Moores, Sheri; Lai, Zhihong; Johanson, Kyung; Burton, George; Erickson-Miller, Connie; Simpson, Graham; Tummino, Peter; Copeland, Robert A.; Oliff, Allen (GSKPA)

    2014-10-02

    c-Abl kinase activity is regulated by a unique mechanism involving the formation of an autoinhibited conformation in which the N-terminal myristoyl group binds intramolecularly to the myristoyl binding site on the kinase domain and induces the bending of the {alpha}I helix that creates a docking surface for the SH2 domain. Here, we report a small-molecule c-Abl activator, DPH, that displays potent enzymatic and cellular activity in stimulating c-Abl activation. Structural analyses indicate that DPH binds to the myristoyl binding site and prevents the formation of the bent conformation of the {alpha}I helix through steric hindrance, a mode of action distinct from the previously identified allosteric c-Abl inhibitor, GNF-2, that also binds to the myristoyl binding site. DPH represents the first cell-permeable, small-molecule tool compound for c-Abl activation.

  11. Multiplicative and Additive Modulation of Neuronal Tuning with Population Activity Affects Encoded Information.

    Arandia-Romero, Iñigo; Tanabe, Seiji; Drugowitsch, Jan; Kohn, Adam; Moreno-Bote, Rubén

    2016-03-16

    Numerous studies have shown that neuronal responses are modulated by stimulus properties and also by the state of the local network. However, little is known about how activity fluctuations of neuronal populations modulate the sensory tuning of cells and affect their encoded information. We found that fluctuations in ongoing and stimulus-evoked population activity in primate visual cortex modulate the tuning of neurons in a multiplicative and additive manner. While distributed on a continuum, neurons with stronger multiplicative effects tended to have less additive modulation and vice versa. The information encoded by multiplicatively modulated neurons increased with greater population activity, while that of additively modulated neurons decreased. These effects offset each other so that population activity had little effect on total information. Our results thus suggest that intrinsic activity fluctuations may act as a "traffic light" that determines which subset of neurons is most informative. PMID:26924437

  12. Developments in permeable and low permeability barriers

    The concept of the reactive treatment zone whereby pollutants are attenuated as they move along a pathway in the ground has enabled a re-thinking of many of the concepts of containment. In particular it offers the potential for the control of the flux from a contaminated area by controlling the contaminant concentration in the pathway(s) as well as or instead of using a low permeability barrier. The paper outlines the basic concepts of the reactive treatment zone and the use of permeable and low permeability reactive systems. The paper then gives a case history of the installation of a permeable barrier using an in-situ reaction chamber

  13. Coincident helminth infection modulates systemic inflammation and immune activation in active pulmonary tuberculosis.

    Parakkal Jovvian George

    Full Text Available Helminth infections are known to modulate innate and adaptive immune responses in active and latent tuberculosis (TB. However, the role of helminth infections in modulating responses associated with inflammation and immune activation (reflecting disease activity and/or severity in TB is not known.We measured markers of inflammation and immune activation in active pulmonary TB individuals (ATB with co-incidental Strongyloides stercoralis (Ss infection. These included systemic levels of acute phase proteins, matrix metalloproteinases and their endogenous inhibitors and immune activation markers. As a control, we measured the systemic levels of the same molecules in TB-uninfected individuals (NTB with or without Ss infection.Our data confirm that ATB is associated with elevated levels of the various measured molecules when compared to those seen in NTB. Our data also reveal that co-incident Ss infection in ATB individuals is associated with significantly decreased circulating levels of acute phase proteins, matrix metalloproteinases, tissue inhibitors of matrix metalloproteinases as well as the systemic immune activation markers, sCD14 and sCD163. These changes are specific to ATB since they are absent in NTB individuals with Ss infection.Our data therefore reveal a profound effect of Ss infection on the markers associated with TB disease activity and severity and indicate that co-incidental helminth infections might dampen the severity of TB disease.

  14. Antileishmanial activity of the estrogen receptor modulator raloxifene.

    Juliana Q Reimão

    2014-05-01

    Full Text Available BACKGROUND: The treatment of leishmaniasis relies mostly on parenteral drugs with potentially serious adverse effects. Additionally, parasite resistance in the treatment of leishmaniasis has been demonstrated for the majority of drugs available, making the search for more effective and less toxic drugs and treatment regimens a priority for the control of leishmaniasis. The aims of this study were to evaluate the antileishmanial activity of raloxifene in vitro and in vivo and to investigate its mechanism of action against Leishmania amazonensis. METHODOLOGY/PRINCIPAL FINDINGS: Raloxifene was shown to possess antileishmanial activity in vitro against several species with EC50 values ranging from 30.2 to 38.0 µM against promastigotes and from 8.8 to 16.2 µM against intracellular amastigotes. Raloxifene's mechanism of action was investigated through transmission electron microscopy and labeling with propidium iodide, DiSBAC2(3, rhodamine 123 and monodansylcadaverine. Microscopic examinations showed that raloxifene treated parasites displayed autophagosomes and mitochondrial damage while the plasma membrane remained continuous. Nonetheless, plasma membrane potential was rapidly altered upon raloxifene treatment with initial hyperpolarization followed by depolarization. Loss of mitochondrial membrane potential was also verified. Treatment of L. amazonensis-infected BALB/c mice with raloxifene led to significant decrease in lesion size and parasite burden. CONCLUSIONS/SIGNIFICANCE: The results of this work extend the investigation of selective estrogen receptor modulators as potential candidates for leishmaniasis treatment. The antileishmanial activity of raloxifene was demonstrated in vitro and in vivo. Raloxifene produces functional disorder on the plasma membrane of L. amazonensis promastigotes and leads to functional and morphological disruption of mitochondria, which culminate in cell death.

  15. Active space debris removal by a hybrid propulsion module

    DeLuca, L. T.; Bernelli, F.; Maggi, F.; Tadini, P.; Pardini, C.; Anselmo, L.; Grassi, M.; Pavarin, D.; Francesconi, A.; Branz, F.; Chiesa, S.; Viola, N.; Bonnal, C.; Trushlyakov, V.; Belokonov, I.

    2013-10-01

    During the last 40 years, the mass of the artificial objects in orbit increased quite steadily at the rate of about 145 metric tons annually, leading to a total tally of approximately 7000 metric tons. Now, most of the cross-sectional area and mass (97% in LEO) is concentrated in about 4600 intact objects, i.e. abandoned spacecraft and rocket bodies, plus a further 1000 operational spacecraft. Simulations and parametric analyses have shown that the most efficient and effective way to prevent the outbreak of a long-term exponential growth of the catalogued debris population would be to remove enough cross-sectional area and mass from densely populated orbits. In practice, according to the most recent NASA results, the active yearly removal of approximately 0.1% of the abandoned intact objects would be sufficient to stabilize the catalogued debris in low Earth orbit, together with the worldwide adoption of mitigation measures. The candidate targets for removal would have typical masses between 500 and 1000 kg, in the case of spacecraft, and of more than 1000 kg, in the case of rocket upper stages. Current data suggest that optimal active debris removal missions should be carried out in a few critical altitude-inclination bands. This paper deals with the feasibility study of a mission in which the debris is removed by using a hybrid propulsion module as propulsion unit. Specifically, the engine is transferred from a servicing platform to the debris target by a robotic arm so to perform a controlled disposal. Hybrid rocket technology for de-orbiting applications is considered a valuable option due to high specific impulse, intrinsic safety, thrust throttle ability, low environmental impact and reduced operating costs. Typically, in hybrid rockets a gaseous or liquid oxidizer is injected into the combustion chamber along the axial direction to burn a solid fuel. However, the use of tangential injection on a solid grain Pancake Geometry allows for more compact design of

  16. Extracellular magnesium and calcium blockers modulate macrophage activity.

    Libako, Patrycja; Nowacki, Wojciech; Castiglioni, Sara; Mazur, Andrzej; Maier, Jeanette A M

    2016-03-01

    Magnesium (Mg) possesses anti-inflammatory properties, partly because it antagonizes calcium (Ca) and inhibits L-type Ca channels. Our aim was to determine the effects of different concentrations of extracellular Mg, with or without Ca-channel blockers, in macrophages. A macrophage-like cell line J774.E was cultured in different concentrations of extracellular Mg and exposed to i) the phorbol ester PMA to induce the production of reactive oxygen species ii) lipopolysaccharide to induce the production of pro-inflammatory cytokines, or iii) ovalbumin to study endocytosis. The Ca antagonists verapamil and/or TMB-8 were used to interfere with Ca homeostasis. Different concentrations of extracellular Mg did not impact on endocytosis, while Ca antagonists markedly decreased it. Low extracellular Mg exacerbated, whereas Ca antagonists inhibited, PMA-induced production of free radicals. Ca blockers prevented lipopolysaccharide-induced transcription and release of IL-1β, IL-6 and TNF-α, while extracellular Mg had only a marginal effect. Ca channel inhibitors markedly reduced the activity of J774.E cells, thus underscoring the critical role of Ca in the non-specific immune response, a role which was, in some instances, also modulated by extracellular Mg. PMID:27160489

  17. CD83 Modulates B Cell Activation and Germinal Center Responses.

    Krzyzak, Lena; Seitz, Christine; Urbat, Anne; Hutzler, Stefan; Ostalecki, Christian; Gläsner, Joachim; Hiergeist, Andreas; Gessner, André; Winkler, Thomas H; Steinkasserer, Alexander; Nitschke, Lars

    2016-05-01

    CD83 is a maturation marker for dendritic cells. In the B cell lineage, CD83 is expressed especially on activated B cells and on light zone B cells during the germinal center (GC) reaction. The function of CD83 during GC responses is unclear. CD83(-/-) mice have a strong reduction of CD4(+) T cells, which makes it difficult to analyze a functional role of CD83 on B cells during GC responses. Therefore, in the present study we generated a B cell-specific CD83 conditional knockout (CD83 B-cKO) model. CD83 B-cKO B cells show defective upregulation of MHC class II and CD86 expression and impaired proliferation after different stimuli. Analyses of GC responses after immunization with various Ags revealed a characteristic shift in dark zone and light zone B cell numbers, with an increase of B cells in the dark zone of CD83 B-cKO mice. This effect was not accompanied by alterations in the level of IgG immune responses or by major differences in affinity maturation. However, an enhanced IgE response was observed in CD83 B-cKO mice. Additionally, we observed a strong competitive disadvantage of CD83-cKO B cells in GC responses in mixed bone marrow chimeras. Furthermore, infection of mice with Borrelia burgdorferi revealed a defect in bacterial clearance of CD83 B-cKO mice with a shift toward a Th2 response, indicated by a strong increase in IgE titers. Taken together, our results show that CD83 is important for B cell activation and modulates GC composition and IgE Ab responses in vivo. PMID:26983787

  18. Allergy Enhances Neurogenesis and Modulates Microglial Activation in the Hippocampus

    Klein, Barbara; Mrowetz, Heike; Thalhamer, Josef; Scheiblhofer, Sandra; Weiss, Richard; Aigner, Ludwig

    2016-01-01

    Allergies and their characteristic TH2-polarized inflammatory reactions affect a substantial part of the population. Since there is increasing evidence that the immune system modulates plasticity and function of the central nervous system (CNS), we investigated the effects of allergic lung inflammation on the hippocampus—a region of cellular plasticity in the adult brain. The focus of the present study was on microglia, the resident immune cells of the CNS, and on hippocampal neurogenesis, i.e., the generation of new neurons. C57BL/6 mice were sensitized with a clinically relevant allergen derived from timothy grass pollen (Phl p 5). As expected, allergic sensitization induced high serum levels of allergen-specific immunoglobulins (IgG1 and IgE) and of TH2 cytokines (IL-5 and IL-13). Surprisingly, fewer Iba1+ microglia were found in the granular layer (GL) and subgranular zone (SGZ) of the hippocampal dentate gyrus and also the number of Iba1+MHCII+ cells was lower, indicating a reduced microglial surveillance and activation in the hippocampus of allergic mice. Neurogenesis was analyzed by labeling of proliferating cells with bromodeoxyuridine (BrdU) and determining their fate 4 weeks later, and by quantitative analysis of young immature neurons, i.e., cells expressing doublecortin (DCX). The number of DCX+ cells was clearly increased in the allergy animals. Moreover, there were more BrdU+ cells present in the hippocampus of allergic mice, and these newly born cells had differentiated into neurons as indicated by a higher number of BrdU+NeuN+ cells. In summary, allergy led to a reduced microglia presence and activity and to an elevated level of neurogenesis in the hippocampus. This effect was apparently specific to the hippocampus, as we did not observe these alterations in the subventricular zone (SVZ)/olfactory bulb (OB) system, also a region of high cellular plasticity and adult neurogenesis.

  19. Telmisartan Modulates Glial Activation: In Vitro and In Vivo Studies

    Torika, Nofar; Asraf, Keren; Danon, Abraham; Apte, Ron N.; Fleisher-Berkovich, Sigal

    2016-01-01

    The circulating renin-angiotensin system (RAS), including the biologically active angiotensin II, is a fundamental regulatory mechanism of blood pressure conserved through evolution. Angiotensin II components of the RAS have also been identified in the brain. In addition to pro-inflammatory cytokines, neuromodulators, such as angiotensin II can induce (through angiotensin type 1 receptor (AT1R)) some of the inflammatory actions of brain glial cells and influence brain inflammation. Moreover, in Alzheimer’s disease (AD) models, where neuroinflammation occurs, increased levels of cortical AT1Rs have been shown. Still, the precise role of RAS in neuroinflammation is not completely clear. The overall aim of the present study was to elucidate the role of RAS in the modulation of glial functions and AD pathology. To reach this goal, the specific aims of the present study were a. to investigate the long term effect of telmisartan (AT1R blocker) on tumor necrosis factor-α (TNF-α), interleukin 1-β (IL1-β) and nitric oxide (NO) release from glial cells. b. to examine the effect of intranasally administered telmisartan on amyloid burden and microglial activation in 5X familial AD (5XFAD) mice. Telmisartan effects in vivo were compared to those of perindopril (angiotensin converting enzyme inhibitor). Long-term-exposure of BV2 microglia to telmisartan significantly decreased lipopolysaccharide (LPS) -induced NO, inducible NO synthase, TNF-α and IL1-β synthesis. The effect of Telmisartan on NO production in BV2 cells was confirmed also in primary neonatal rat glial cells. Intranasal administration of telmisartan (1 mg/kg/day) for up to two months significantly reduced amyloid burden and CD11b expression (a marker for microglia) both in the cortex and hipoccampus of 5XFAD. Based on the current view of RAS and our data, showing reduced amyloid burden and glial activation in the brains of 5XFAD transgenic mice, one may envision potential intervention with the progression

  20. Telmisartan Modulates Glial Activation: In Vitro and In Vivo Studies.

    Nofar Torika

    Full Text Available The circulating renin-angiotensin system (RAS, including the biologically active angiotensin II, is a fundamental regulatory mechanism of blood pressure conserved through evolution. Angiotensin II components of the RAS have also been identified in the brain. In addition to pro-inflammatory cytokines, neuromodulators, such as angiotensin II can induce (through angiotensin type 1 receptor (AT1R some of the inflammatory actions of brain glial cells and influence brain inflammation. Moreover, in Alzheimer's disease (AD models, where neuroinflammation occurs, increased levels of cortical AT1Rs have been shown. Still, the precise role of RAS in neuroinflammation is not completely clear. The overall aim of the present study was to elucidate the role of RAS in the modulation of glial functions and AD pathology. To reach this goal, the specific aims of the present study were a. to investigate the long term effect of telmisartan (AT1R blocker on tumor necrosis factor-α (TNF-α, interleukin 1-β (IL1-β and nitric oxide (NO release from glial cells. b. to examine the effect of intranasally administered telmisartan on amyloid burden and microglial activation in 5X familial AD (5XFAD mice. Telmisartan effects in vivo were compared to those of perindopril (angiotensin converting enzyme inhibitor. Long-term-exposure of BV2 microglia to telmisartan significantly decreased lipopolysaccharide (LPS -induced NO, inducible NO synthase, TNF-α and IL1-β synthesis. The effect of Telmisartan on NO production in BV2 cells was confirmed also in primary neonatal rat glial cells. Intranasal administration of telmisartan (1 mg/kg/day for up to two months significantly reduced amyloid burden and CD11b expression (a marker for microglia both in the cortex and hipoccampus of 5XFAD. Based on the current view of RAS and our data, showing reduced amyloid burden and glial activation in the brains of 5XFAD transgenic mice, one may envision potential intervention with the

  1. Telmisartan Modulates Glial Activation: In Vitro and In Vivo Studies.

    Torika, Nofar; Asraf, Keren; Danon, Abraham; Apte, Ron N; Fleisher-Berkovich, Sigal

    2016-01-01

    The circulating renin-angiotensin system (RAS), including the biologically active angiotensin II, is a fundamental regulatory mechanism of blood pressure conserved through evolution. Angiotensin II components of the RAS have also been identified in the brain. In addition to pro-inflammatory cytokines, neuromodulators, such as angiotensin II can induce (through angiotensin type 1 receptor (AT1R)) some of the inflammatory actions of brain glial cells and influence brain inflammation. Moreover, in Alzheimer's disease (AD) models, where neuroinflammation occurs, increased levels of cortical AT1Rs have been shown. Still, the precise role of RAS in neuroinflammation is not completely clear. The overall aim of the present study was to elucidate the role of RAS in the modulation of glial functions and AD pathology. To reach this goal, the specific aims of the present study were a. to investigate the long term effect of telmisartan (AT1R blocker) on tumor necrosis factor-α (TNF-α), interleukin 1-β (IL1-β) and nitric oxide (NO) release from glial cells. b. to examine the effect of intranasally administered telmisartan on amyloid burden and microglial activation in 5X familial AD (5XFAD) mice. Telmisartan effects in vivo were compared to those of perindopril (angiotensin converting enzyme inhibitor). Long-term-exposure of BV2 microglia to telmisartan significantly decreased lipopolysaccharide (LPS) -induced NO, inducible NO synthase, TNF-α and IL1-β synthesis. The effect of Telmisartan on NO production in BV2 cells was confirmed also in primary neonatal rat glial cells. Intranasal administration of telmisartan (1 mg/kg/day) for up to two months significantly reduced amyloid burden and CD11b expression (a marker for microglia) both in the cortex and hipoccampus of 5XFAD. Based on the current view of RAS and our data, showing reduced amyloid burden and glial activation in the brains of 5XFAD transgenic mice, one may envision potential intervention with the progression of

  2. Indicaxanthin inhibits NADPH oxidase (NOX)-1 activation and NF-κB-dependent release of inflammatory mediators and prevents the increase of epithelial permeability in IL-1β-exposed Caco-2 cells.

    Tesoriere, L; Attanzio, A; Allegra, M; Gentile, C; Livrea, M A

    2014-02-01

    Dietary redox-active/antioxidant phytochemicals may help control or mitigate the inflammatory response in chronic inflammatory bowel disease (IBD). In the present study, the anti-inflammatory activity of indicaxanthin (Ind), a pigment from the edible fruit of cactus pear (Opuntia ficus-indica, L.), was shown in an IBD model consisting of a human intestinal epithelial cell line (Caco-2 cells) stimulated by IL-1β, a cytokine known to play a major role in the initiation and amplification of inflammatory activity in IBD. The exposure of Caco-2 cells to IL-1β brought about the activation of NADPH oxidase (NOX-1) and the generation of reactive oxygen species (ROS) to activate intracellular signalling leading to the activation of NF-κB, with the over-expression of inflammatory enzymes and release of pro-inflammatory mediators. The co-incubation of the cells with Ind, at a nutritionally relevant concentration (5-25 μM), and IL-1β prevented the release of the pro-inflammatory cytokines IL-6 and IL-8, PGE2 and NO, the formation of ROS and the loss of thiols in a dose-dependent manner. The co-incubation of the cells with Ind and IL-1β also prevented the IL-1β-induced increase of epithelial permeability. It was also shown that the activation of NOX-1 and NF-κB was prevented by Ind and the expression of COX-2 and inducible NO synthase was reduced. The uptake of Ind in Caco-2 cell monolayers appeared to be unaffected by the inflamed state of the cells. In conclusion, our findings suggest that the dietary pigment Ind may have the potential to modulate inflammatory processes at the intestinal level. PMID:23931157

  3. Role of the endogenous kallikrein-kinin system in modulating vasopressin-stimulated water flow and urea permeability in the toad urinary bladder.

    Carvounis, C P; Carvounis, G; Arbeit, L A

    1981-01-01

    This study investigates the endogenous kallikrein-kinin system's role as a modulator of vasopressin action in the toad urinary bladder. Kalli-krein inhibition by aprotinin, which results in decreased kinin production, significantly increased both vasopressin and 8-Br-cyclic (c) AMP-stimulated water flow. Kinin potentiation by the kininase II inhibitor captopril (SQ 14225) significantly decreased vasopressin and 8-Br-cAMP-stimulated water flow. In contrast to water flow, vasopressin-stimulated...

  4. Escherichia coli strain Nissle 1917 ameliorates experimental colitis by modulating intestinal permeability, the inflammatory response and clinical signs in a faecal transplantation model.

    Souza, Éricka L; Elian, Samir D; Paula, Laís M; Garcia, Cristiana C; Vieira, Angélica T; Teixeira, Mauro M; Arantes, Rosa M; Nicoli, Jacques R; Martins, Flaviano S

    2016-03-01

    Inflammatory bowel diseases (IBDs) are a group of inflammatory conditions of the gut that include ulcerative colitis and Crohn's disease. Probiotics are live micro-organisms that may be used as adjuvant therapy for patients with IBD. The aim of this study was to evaluate the effect of prophylactic ingestion of Escherichia coli strain Nissle 1917 (EcN) in a murine model of colitis. For induction of colitis, mice were given a 3.5 % dextran sodium sulfate (DSS) solution for 7 days in drinking water. EcN administration to mice subjected to DSS-induced colitis resulted in significant reduction in clinical and histopathological signs of disease and preservation of intestinal permeability. We observed reduced inflammation, as assessed by reduced levels of neutrophils, eosinophils, chemokines and cytokines. We observed an increase in the number of regulatory T-cells in Peyer's patches. Germ-free mice received faecal content from control or EcN-treated mice and were then subjected to DSS-induced colitis. We observed protection from colitis in animals that were colonized with faecal content from EcN-treated mice. These results suggest that preventative oral administration of EcN or faecal microbiota transplantation with EcN-containing microbiota ameliorates DSS-induced colitis by modifying inflammatory responsiveness to DSS. PMID:26758971

  5. Ion pairing with bile salts modulates intestinal permeability and contributes to food-drug interaction of BCS class III compound trospium chloride.

    Heinen, Christian A; Reuss, Stefan; Amidon, Gordon L; Langguth, Peter

    2013-11-01

    In the current study the involvement of ion pair formation between bile salts and trospium chloride (TC), a positively charged Biopharmaceutical Classification System (BCS) class III substance, showing a decrease in bioavailability upon coadministration with food (negative food effect) was investigated. Isothermal titration calorimetry provided evidence of a reaction between TC and bile acids. An effect of ion pair formation on the apparent partition coefficient (APC) was examined using (3)H-trospium. The addition of bovine bile and bile extract porcine led to a significant increase of the APC. In vitro permeability studies of trospium were performed across Caco-2-monolayers and excised segments of rat jejunum in a modified Ussing chamber. The addition of bile acids led to an increase of trospium permeation across Caco-2-monolayers and rat excised segments by approximately a factor of 1.5. The addition of glycochenodeoxycholate (GCDC) was less effective than taurodeoxycholate (TDOC). In the presence of an olive oil emulsion, a complete extinction of the permeation increasing effects of bile salts was observed. Thus, although there are more bile acids in the intestine in the fed state compared to the fasted state, these are not able to form ion pairs with trospium in fed state, because they are involved in the emulsification of dietary fats. In conclusion, the formation of ion pairs between trospium and bile acids can partially explain its negative food effect. Our results are presumably transferable to other organic cations showing a negative food effect. PMID:23750707

  6. A Teleost Bactericidal Permeability-Increasing Protein Kills Gram-Negative Bacteria, Modulates Innate Immune Response, and Enhances Resistance against Bacterial and Viral Infection.

    Sun, Yuan-Yuan; Sun, Li

    2016-01-01

    Bactericidal/permeability-increasing protein (BPI) is an important factor of innate immunity that in mammals is known to take part in the clearance of invading Gram-negative bacteria. In teleost, the function of BPI is unknown. In the present work, we studied the function of tongue sole (Cynoglossus semilaevis) BPI, CsBPI. We found that CsBPI was produced extracellularly by peripheral blood leukocytes (PBL). Recombinant CsBPI (rCsBPI) was able to bind to a number of Gram-negative bacteria but not Gram-positive bacteria. Binding to bacteria led to bacterial death through membrane permeabilization and structural destruction, and the bound bacteria were more readily taken up by PBL. In vivo, rCsBPI augmented the expression of a wide arrange of genes involved in antibacterial and antiviral immunity. Furthermore, rCsBPI enhanced the resistance of tongue sole against bacterial as well as viral infection. These results indicate for the first time that a teleost BPI possesses immunoregulatory effect and plays a significant role in antibacterial and antiviral defense. PMID:27105425

  7. Cytotoxic Effect and Permeability Activities of Curcumin Analogue; 2, 6-Bis (2, 5-dimethoxybenzy-lidene cyclohexanone (BDMC33 in Caco-2 Cell Model

    N. Yakubu

    2015-11-01

    Full Text Available Previously, curcumin analogue, 2, 6-bis (2, 5-dimethoxybenzylidene cyclohexanone (BDMC33 with high anti-inflammatory activity was chemically synthesized in our laboratory to enhance the biological activity of curcumin. In this study, the toxicity and permeability activities of 2,6-bis(2,5-dimethoxybenzy-lidenecyclohexanone (BDMC33 in Caco-2 cells was investigated. Toxicity effects using MTT assay and apparent permeability coefficient (Papp, uptake (UR and efflux (ER ratios, and mass balance of BDMC33 after permeation in Caco-2 cells for 180 min were evaluated in apical (A to basolateral (B and basolateral (B to apical (A directions. The similar analyses on 3-(2-fluoro-benzylidene-5-(2-fluorocyclohexylmethylene-piperidin-4-one; (EF-24 (check control were also conducted. The 24 hr LC50 value for BDMC33 and EF-24 on Caco-2 cells were both 50 µM. The Papp value in A→B direction was 3.37 ± 0.47 cm/s (BDMC33 and 2.47 ± 0.15 cm/s (EF-24. Whereas in B→A direction, it was 1.9 ± 0.36 cm/s (BDMC33 and 1.8 ± 0.15 cm/s (EF-24 upon 120 min incubation. The UR and ER ratios calculated were 1.77% and 0.56%, respectively, and the mass balance calculated were 41-44% (BDMC33 and 31-34% (EF-24 in A→B and B→A direction. This study has suggested BDMC33 to be more absorbable than EF-24 in Caco-2 cells. Therefore, BDMC33 could be a leading feature, the anti-inflammatory agent, as it biological activities would be expected outside the intestine.

  8. Recombinant Treponema pallidum protein Tp0965 activates endothelial cells and increases the permeability of endothelial cell monolayer.

    Zhang, Rui-Li; Zhang, Jing-Ping; Wang, Qian-Qiu

    2014-01-01

    The recombinant Treponema pallidum protein Tp0965 (rTp0965), one of the many proteins derived from the genome of T. pallidum subsp. pallidum, shows strong immunogenicity and immunoreactivity. In this study, we investigated the effects of rTp0965 on the endothelial barrier. Treatment of human umbilical vein endothelial cells (HUVECs) with rTp0965 resulted in increased levels of ICAM-1, E-selectin, and MCP-1 mRNA and protein expression. These increases contributed to the adhesion and chemataxis of monocytes (THP-1 cells) to HUVECs preincubated with rTp0965. In addition, rTp0965 induced reorganization of F-actin and decreased expression of claudin-1 in HUVECs. Interestingly, inhibition of the RhoA/ROCK signal pathway protected against rTp0965-induced higher endothelial permeability as well as transendothelial migration of monocytes. These data indicate that Tp0965 protein may play an important role in the immunopathogenesis of syphilis. PMID:25514584

  9. Recombinant Treponema pallidum protein Tp0965 activates endothelial cells and increases the permeability of endothelial cell monolayer.

    Rui-Li Zhang

    Full Text Available The recombinant Treponema pallidum protein Tp0965 (rTp0965, one of the many proteins derived from the genome of T. pallidum subsp. pallidum, shows strong immunogenicity and immunoreactivity. In this study, we investigated the effects of rTp0965 on the endothelial barrier. Treatment of human umbilical vein endothelial cells (HUVECs with rTp0965 resulted in increased levels of ICAM-1, E-selectin, and MCP-1 mRNA and protein expression. These increases contributed to the adhesion and chemataxis of monocytes (THP-1 cells to HUVECs preincubated with rTp0965. In addition, rTp0965 induced reorganization of F-actin and decreased expression of claudin-1 in HUVECs. Interestingly, inhibition of the RhoA/ROCK signal pathway protected against rTp0965-induced higher endothelial permeability as well as transendothelial migration of monocytes. These data indicate that Tp0965 protein may play an important role in the immunopathogenesis of syphilis.

  10. Surfactant Protein A integrates activation signal strength to differentially modulate T cell proliferation

    Mukherjee, Sambuddho; Giamberardino, Charles; Thomas, Joseph; Evans, Kathy; GOTO, HISATSUGU; Ledford, Julie G.; Hsia, Bethany; Pastva, Amy M.; Wright, Jo Rae

    2012-01-01

    Pulmonary surfactant lipoproteins lower the surface tension at the alveolar:airway interface of the lung and participate in host defense. Previous studies reported that surfactant protein A (SP-A) inhibits lymphocyte proliferation. We hypothesized that SP-A mediated modulation of T cell activation depends upon the strength, duration and type of lymphocyte activating signals. Modulation of T cell signal strength imparted by different activating agents ex and in vivo in different mouse models, ...

  11. Active cancellation of residual amplitude modulation in a frequency-modulation based Fabry-Perot interferometer

    Yu, Yinan; Wang, Yicheng; Pratt, Jon R.

    2016-03-01

    Residual amplitude modulation (RAM) is one of the most common noise sources known to degrade the sensitivity of frequency modulation spectroscopy. RAM can arise as a result of the temperature dependent birefringence of the modulator crystal, which causes the orientation of the crystal's optical axis to shift with respect to the polarization of the incident light with temperature. In the fiber-based optical interferometer used on the National Institute of Standards and Technology calculable capacitor, RAM degrades the measured laser frequency stability and correlates with the environmental temperature fluctuations. We have demonstrated a simple approach that cancels out excessive RAM due to polarization mismatch between the light and the optical axis of the crystal. The approach allows us to measure the frequency noise of a heterodyne beat between two lasers individually locked to different resonant modes of a cavity with an accuracy better than 0.5 ppm, which meets the requirement to further determine the longitudinal mode number of the cavity length. Also, this approach has substantially mitigated the temperature dependency of the measurements of the cavity length and consequently the capacitance.

  12. Energy-Storage Modules for Active Solar Heating and Cooling

    Parker, J. C.

    1982-01-01

    34 page report describes a melting salt hydrate that stores 12 times as much heat as rocks and other heavy materials. Energy is stored mostly as latent heat; that is, heat that can be stored and recovered without any significant change in temperature. Report also describes development, evaluation and testing of permanently sealed modules containing salt hydrate mixture.

  13. Task-dependent modulation of oscillatory neural activity during movements

    Herz, D. M.; Christensen, M. S.; Reck, C.;

    2011-01-01

    -dependent modulation of frequency coupling within this network. To this end we recorded 122-multichannel EEG in 13 healthy subjects while they performed three simple motor tasks. EEG data source modeling using individual MR images was carried out with a multiple source beamformer approach. A bilateral motor network...

  14. Noninvasive transcranial focused ultrasonic-magnetic stimulation for modulating brain oscillatory activity

    Yuan, Yi; Chen, Yudong; Li, Xiaoli

    2016-02-01

    A novel technique, transcranial focused ultrasonic-magnetic stimulation (tFUMS), has been developed for noninvasive brain modulation in vivo. tFUMS has a higher spatial resolution (stimulation on the neuromodulation. The results demonstrate that tFUMS can modulate brain oscillatory activities by stimulating brain tissues.

  15. Radiation Effects on the Cytoskeleton of Endothelial Cells and Endothelial Monolayer Permeability

    Purpose: To investigate the effects of radiation on the endothelial cytoskeleton and endothelial monolayer permeability and to evaluate associated signaling pathways, which could reveal potential mechanisms of known vascular effects of radiation. Methods and Materials: Cultured endothelial cells were X-ray irradiated, and actin filaments, microtubules, intermediate filaments, and vascular endothelial (VE)-cadherin junctions were examined by immunofluorescence. Permeability was determined by the passage of fluorescent dextran through cell monolayers. Signal transduction pathways were analyzed using RhoA, Rho kinase, and stress-activated protein kinase-p38 (SAPK2/p38) inhibitors by guanosine triphosphate-RhoA activation assay and transfection with RhoAT19N. The levels of junction protein expression and phosphorylation of myosin light chain and SAPK2/p38 were assessed by Western blotting. The radiation effects on cell death were verified by clonogenic assays. Results: Radiation induced rapid and persistent actin stress fiber formation and redistribution of VE-cadherin junctions in microvascular, but not umbilical vein endothelial cells, and microtubules and intermediate filaments remained unaffected. Radiation also caused a rapid and persistent increase in microvascular permeability. RhoA-guanosine triphosphatase and Rho kinase were activated by radiation and caused phosphorylation of downstream myosin light chain and the observed cytoskeletal and permeability changes. SAPK2/p38 was activated by radiation but did not influence either the cytoskeleton or permeability. Conclusion: This study is the first to show rapid activation of the RhoA/Rho kinase by radiation in endothelial cells and has demonstrated a link between this pathway and cytoskeletal remodeling and permeability. The results also suggest that the RhoA pathway might be a useful target for modulating the permeability and other effects of radiation for therapeutic gain

  16. Modulation of pulmonary macrophage superoxide release and tumoricidal activity following activation by biological response modifiers.

    Drath, D B

    1986-10-01

    Following immunologic activation, pulmonary macrophages may prevent or cause regression of lung metastases by mechanisms which remain largely unknown. The studies described here were designed to determine if enhanced oxygen metabolite release was related to postactivation tumoricidal activity. We have shown that in vitro activation of Fischer 344 rat pulmonary macrophages by either free or liposome-encapsulated muramyl dipeptide leads to both enhanced release of superoxide anions and marked tumoricidal activity against syngenic (Fischer 13762), allogeneic (Schmidt-Ruppin RR 1022) and xenogeneic (Fibrosarcoma MCA-F) 125I-deoxyuridine-labeled target cells. This immune modulator did not, however, metabolically activate pulmonary macrophages as effectively as liposome-encapsulated lipopolysaccharide. A 24-h in vitro incubation with either 150 U or 300 U of interferon-gamma (3 X 10(6) U/mg) or 30 U, 150 U or 300 U of interferon-alpha (6 X 10(5) U/mg) caused a significant elevation in superoxide release above controls, whereas short-term exposure (2 or 4 h) had little or no effect. Free or encapsulated 6-O-stearoyl muramyl dipeptide, on the other hand, did increase superoxide levels at all 3 time periods. When either interferon-gamma or free or encapsulated muramyl dipeptide derivative were administered to intact rats by either i.v. injection, intratracheal instillation or osmotic minipump infusion, pulmonary macrophage tumoricidal activity was observed 96 h after cell harvesting. Zymosan-stimulated superoxide release, however, was not consistently elevated above control or empty liposome treatment following this course of in vivo activation. The data collectively suggest that in vivo pulmonary macrophage activation to a tumoricidal state and metabolic activation resulting in enhanced superoxide may be separable events. PMID:3021650

  17. M19 modulates skeletal muscle differentiation and insulin secretion in pancreatic β-cells through modulation of respiratory chain activity.

    Linda Cambier

    Full Text Available Mitochondrial dysfunction due to nuclear or mitochondrial DNA alterations contributes to multiple diseases such as metabolic myopathies, neurodegenerative disorders, diabetes and cancer. Nevertheless, to date, only half of the estimated 1,500 mitochondrial proteins has been identified, and the function of most of these proteins remains to be determined. Here, we characterize the function of M19, a novel mitochondrial nucleoid protein, in muscle and pancreatic β-cells. We have identified a 13-long amino acid sequence located at the N-terminus of M19 that targets the protein to mitochondria. Furthermore, using RNA interference and over-expression strategies, we demonstrate that M19 modulates mitochondrial oxygen consumption and ATP production, and could therefore regulate the respiratory chain activity. In an effort to determine whether M19 could play a role in the regulation of various cell activities, we show that this nucleoid protein, probably through its modulation of mitochondrial ATP production, acts on late muscle differentiation in myogenic C2C12 cells, and plays a permissive role on insulin secretion under basal glucose conditions in INS-1 pancreatic β-cells. Our results are therefore establishing a functional link between a mitochondrial nucleoid protein and the modulation of respiratory chain activities leading to the regulation of major cellular processes such as myogenesis and insulin secretion.

  18. Direct Modulation of Small GTPase Activity and Function.

    Cromm, Philipp M; Spiegel, Jochen; Grossmann, Tom N; Waldmann, Herbert

    2015-11-01

    Small GTPases are a family of GDP-/GTP-binding proteins that serve as biomolecular switches inside cells to control a variety of essential cellular processes. Aberrant function and regulation of small GTPases is associated with a variety of human diseases, thus rendering these proteins highly interesting targets in drug discovery. However, this class of proteins has been considered "undruggable", as intensive decade-long efforts did not yield clinically relevant direct modulators of small GTPases. Recently, the targeting of small GTPases has gained fresh impetus through the discovery of novel transient cavities on the protein surfaces and the application of new targeting strategies. Besides Ras proteins, other small GTPases have attracted increased attention since improved biological insight in combination with novel targeting strategies identified them as promising targets in drug discovery. This Review gives an overview of relevant aspects of the superfamily of small GTPases and summarizes recent progress and perspectives for the direct modulation of these challenging targets. PMID:26470842

  19. Variable Glutamine-Rich Repeats Modulate Transcription Factor Activity

    Gemayel, Rita; Chavali, Sreenivas; Pougach, Ksenia; Legendre, Matthieu; Zhu, Bo; Boeynaems, Steven; van der Zande, Elisa; Gevaert, Kris; Rousseau, Frederic; Schymkowitz, Joost; Babu, M Madan; Verstrepen, Kevin J.

    2015-01-01

    Summary Excessive expansions of glutamine (Q)-rich repeats in various human proteins are known to result in severe neurodegenerative disorders such as Huntington’s disease and several ataxias. However, the physiological role of these repeats and the consequences of more moderate repeat variation remain unknown. Here, we demonstrate that Q-rich domains are highly enriched in eukaryotic transcription factors where they act as functional modulators. Incremental changes in the number of repeats i...

  20. Finite Element Learning Modules as Active Learning Tools

    Brown, Ashland O.; Jensen, Daniel; Rencis, Joseph; Wood, Kristin; Wood, John; White, Christina; Raaberg, Kristen Kaufman; Coffman, Josh

    2012-01-01

    The purpose of active learning is to solicit participation by students beyond the passive mode of traditional classroom lectures. Reading, writing, participating in discussions, hands-on activities, engaging in active problem solving, and collaborative learning can all be involved. The skills acquired during active learning tend to go above and…

  1. Modulation of PPAR Expression and Activity in Response to Polyphenolic Compounds in High Fat Diets

    J. Abraham Domínguez-Avila; Gustavo A. González-Aguilar; Emilio Alvarez-Parrilla; de la Rosa, Laura A.

    2016-01-01

    Peroxisome proliferator-activated receptors (PPAR) are transcription factors that modulate energy metabolism in liver, adipose tissue and muscle. High fat diets (HFD) can negatively impact PPAR expression or activity, favoring obesity, dyslipidemia, insulin resistance and other conditions. However, polyphenols (PP) found in vegetable foodstuffs are capable of positively modulating this pathway. We therefore focused this review on the possible effects that PP can have on PPAR when administered...

  2. Modulation of Neuronal Voltage-Activated Calcium and Sodium Channels by Polyamines and pH

    Chen, Wenyan; Harnett, Mark T.; Smith, Stephen M.

    2007-01-01

    The endogenous polyamines spermine, spermidine and putrescine are present at high concentrations inside neurons and can be released into the extracellular space where they have been shown to modulate ion channels. Here, we have examined polyamine modulation of voltage-activated Ca2+ channels (VACCs) and voltage-activated Na+ channels (VANCs) in rat superior cervical ganglion neurons using whole-cell voltage-clamp at physiological divalent concentrations. Polyamines inhibited VACCs in a concen...

  3. Curcumin Pretreatment Prevents Potassium Dichromate-Induced Hepatotoxicity, Oxidative Stress, Decreased Respiratory Complex I Activity, and Membrane Permeability Transition Pore Opening

    Wylly Ramsés García-Niño

    2013-01-01

    Full Text Available Curcumin is a polyphenol derived from turmeric with recognized antioxidant properties. Hexavalent chromium is an environmental toxic and carcinogen compound that induces oxidative stress. The objective of this study was to evaluate the potential protective effect of curcumin on the hepatic damage generated by potassium dichromate (K2Cr2O7 in rats. Animals were pretreated daily by 9-10 days with curcumin (400 mg/kg b.w. before the injection of a single intraperitoneal of K2Cr2O7 (15 mg/kg b.w.. Groups of animals were sacrificed 24 and 48 h later. K2Cr2O7-induced damage to the liver was evident by histological alterations and increase in the liver weight and in the activity of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and alkaline phosphatase in plasma. In addition, K2Cr2O7 induced oxidative damage in liver and isolated mitochondria, which was evident by the increase in the content of malondialdehyde and protein carbonyl and decrease in the glutathione content and in the activity of several antioxidant enzymes. Moreover, K2Cr2O7 induced decrease in mitochondrial oxygen consumption, in the activity of respiratory complex I, and permeability transition pore opening. All the above-mentioned alterations were prevented by curcumin pretreatment. The beneficial effects of curcumin against K2Cr2O7-induced liver oxidative damage were associated with prevention of mitochondrial dysfunction.

  4. AUTOCRINE/PARACRINE MODULATION OF BARORECEPTOR ACTIVITY AFTER ANTIDROMIC STIMULATION OF AORTIC DEPRESSOR NERVE IN VIVO

    Valter J. Santana-Filho; Davis, Greg J.; Castania, Jaci A.; Ma, Xiuying; Salgado, Helio C; Abboud, Francois M.; Fazan, Rubens; Chapleau, Mark W.

    2014-01-01

    Activation of the sensory nerve endings of nonmyelinated C-fiber afferents evokes release of autocrine/paracrine factors that cause localized vasodilation, neurogenic inflammation, and modulation of sensory nerve activity. The aims of this study were to determine the effect of antidromic electrical stimulation on afferent baroreceptor activity in vivo, and investigate the role of endogenous prostanoids and hydrogen peroxide (H2O2) in mediating changes in nerve activity. Baroreceptor activity ...

  5. Structure-Activity Relations In Enzymes: An Application Of IR-ATR Modulation Spectroscopy

    Fringeli, Urs P.; Ahlstrom, Peter; Vincenz, Claudius; Fringeli, Marianna

    1985-12-01

    Relations between structure and specific activity in immobilized acetylcholinesterase (ACNE) have been studied by means of pH- and Ca++-modulation technique combined with attenuated total reflection (ATR) infrared (IR) spectroscopy and enzyme activity measurement. Periodic modulation of pH and Ca++-concentration enabled a periodic on-off switching of about 40% of the total enzyme activity. It was found that about 0.5 to 1% of the amino acids were involved in this process. These 15 to 30 amino acids assumed antiparallel pleated sheet structure in the inhibited state and random and/or helical structure in the activated state.

  6. Permeability of Dentine

    Ghazali, Farid Bin Che

    2003-01-01

    This is an update on the present integrated knowledge regarding dentine permeability that assumed a role in dentine sensitivity and contribute clinically to the effective bonding properties of restorative dental materials. This paper will attempt to refer to in vivo and in vitro studies of dentine permeability and the various interrelated factors governing it.

  7. Permeable Pavements at Purdue

    Knapp, Jim

    2013-01-01

    Two case studies will be presented describing sustainable drainage alternatives. The processes used for the 2nd Street project in Seymour will provide a comparison of the design processes for conventional and green infrastructure solutions. Purdue University will discuss a number of permeable pavement installations on campus and provide a map for viewing. Asphalt, concrete, and permeable paver options will be discussed.

  8. Permeability prediction in chalks

    Alam, Mohammad Monzurul; Fabricius, Ida Lykke; Prasad, Manika

    2011-01-01

    The velocity of elastic waves is the primary datum available for acquiring information about subsurface characteristics such as lithology and porosity. Cheap and quick (spatial coverage, ease of measurement) information of permeability can be achieved, if sonic velocity is used for permeability...... prediction, so we have investigated the use of velocity data to predict permeability. The compressional velocity fromwireline logs and core plugs of the chalk reservoir in the South Arne field, North Sea, has been used for this study. We compared various methods of permeability prediction from velocities....... The relationships between permeability and porosity from core data were first examined using Kozeny’s equation. The data were analyzed for any correlations to the specific surface of the grain, Sg, and to the hydraulic property defined as the flow zone indicator (FZI). These two methods use two...

  9. ATPase activity of erythrocyte membranes and their permeability for the K-ions as influenced by irradiation and serotonin

    Na, K-ATPase activity of membranes of erytrocytes after 1 hour of X-ray irradiation of citrate blood of rats (25.8 Kl/kg)-increased, and after irradiation of isolated erytrocytes, placed in the isotonic solution of NaCl did not change. The exflux of K-ions out of irradiated erytrocytes increased equally in both cases. Serotonin (2x10-4 M), added to the probes 10 minutes before irradiation, decreased the exflux of K+ by irradiated erytrocytes, but Na, K-ATPase activity under the influence of amine was without changes

  10. Glucose Enhances Leptin Signaling through Modulation of AMPK Activity

    Haoran Su; Lin Jiang; Christin Carter-Su; Liangyou Rui

    2012-01-01

    Leptin exerts its action by binding to and activating the long form of leptin receptors (LEPRb). LEPRb activates JAK2 that subsequently phosphorylates and activates STAT3. The JAK2/STAT3 pathway is required for leptin control of energy balance and body weight. Defects in leptin signaling lead to leptin resistance, a primary risk factor for obesity. Body weight is also regulated by nutrients, including glucose. Defects in glucose sensing also contribute to obesity. Here we report crosstalk bet...

  11. Staphylococcal Enterotoxin O Exhibits Cell Cycle Modulating Activity

    Hodille, Elisabeth; Alekseeva, Ludmila; Berkova, Nadia; Serrier, Asma; Badiou, Cedric; Gilquin, Benoit; Brun, Virginie; Vandenesch, François; Terman, David S.; Lina, Gerard

    2016-01-01

    Maintenance of an intact epithelial barrier constitutes a pivotal defense mechanism against infections. Staphylococcus aureus is a versatile pathogen that produces multiple factors including exotoxins that promote tissue alterations. The aim of the present study is to investigate the cytopathic effect of staphylococcal exotoxins SEA, SEG, SEI, SElM, SElN and SElO on the cell cycle of various human cell lines. Among all tested exotoxins only SEIO inhibited the proliferation of a broad panel of human tumor cell lines in vitro. Evaluation of a LDH release and a DNA fragmentation of host cells exposed to SEIO revealed that the toxin does not induce necrosis or apoptosis. Analysis of the DNA content of tumor cells synchronized by serum starvation after exposure to SEIO showed G0/G1 cell cycle delay. The cell cycle modulating feature of SEIO was confirmed by the flow cytometry analysis of synchronized cells exposed to supernatants of isogenic S. aureus strains wherein only supernatant of the SElO producing strain induced G0/G1 phase delay. The results of yeast-two-hybrid analysis indicated that SEIO’s potential partner is cullin-3, involved in the transition from G1 to S phase. In conclusion, we provide evidence that SEIO inhibits cell proliferation without inducing cell death, by delaying host cell entry into the G0/G1 phase of the cell cycle. We speculate that this unique cell cycle modulating feature allows SEIO producing bacteria to gain advantage by arresting the cell cycle of target cells as part of a broader invasive strategy. PMID:27148168

  12. Pentameric ligand-gated ion channel ELIC is activated by GABA and modulated by benzodiazepines

    Spurny, R.; Ramerstorfer, J.; Price, K; Brams, M.; M. Ernst; Nury, H.; Verheij, M.; Legrand, P.; Bertrand, D.; Bertrand, S.; Dougherty, D A; de Esch, I. J. P.; Corringer, P.-J.; Sieghart, W.; Lummis, S. C. R.

    2012-01-01

    GABA_A receptors are pentameric ligand-gated ion channels involved in fast inhibitory neurotransmission and are allosterically modulated by the anxiolytic, anticonvulsant, and sedative-hypnotic benzodiazepines. Here we show that the prokaryotic homolog ELIC also is activated by GABA and is modulated by benzodiazepines with effects comparable to those at GABA_A receptors. Crystal structures reveal important features of GABA recognition and indicate that benzodiazepines, depending on their conc...

  13. Program-Controlled High Voltage Module in Active Voltage Dividers(AVD) for MPGD

    Ginting, Muhammad Fadhil

    2016-01-01

    Micro Pattern Gas Detectors (MPGD) applications are rapidly developing and became an important part of upgrades for the LHC detectors. RD51/CERN have worked on Active Voltage Divider (AVD) technology for multistage MPGDs, One of the next developments for the AVD is to design and integrate high voltage module in a single box. The Program-Controlled High Voltage Module, part of one AIDA2020 project, has been successfully designed and developed, and can be integrated in AVD design.

  14. Modulation of bulbospinal RVLM neurons by hypoxia/hypercapnia but not medullary respiratory activity

    Boychuk, Carie R.; Woerman, Amanda L.; Mendelowitz, David

    2012-01-01

    Although sympathetic vasomotor discharge has respiratory modulation, the site(s) responsible for this cardiorespiratory interaction are unknown. One likely source for this coupling is the RVLM where pre-sympathetic neurons originate in close apposition to respiratory neurons. The current study tested the hypothesis that RVLM bulbospinal neurons are modulated by medullary respiratory network activity using whole-cell patch-clamp electrophysiological recordings of RVLM neurons while simultaneou...

  15. Modulation of Banana Polyphenol Oxidase (Ppo) Activity by Naturally Occurring Bioactive Compounds From Plant Extracts

    Alamelumangai. M; Dhanalakshmi, J; M. Mathumitha; R. Saranya Renganayaki; P. Muthukumaran; N.Rajalakshmi

    2015-01-01

    Polyphenol Oxidase (PPO) (E.C number 1.14.18.1) was extracted from banana (Musa paradisiaca) and partially purified by acetone precipitation. The enzyme was found to have high affinity towards its substrate, catechol. In this study, various plant extracts like Glycyrrhiza glabra, Rubia cordifolia, Hesperethusa crenulata and oil from the seeds of Hydnocarpus laurifolia were observed to modulate the activity of banana PPO. Method In this study, various plant extracts were observed to modulate t...

  16. Antioxidant, antimicrobial and neutrophil-modulating activities of herb extracts

    Denev, P.; Kratchanova, M.; Číž, Milan; Lojek, Antonín; Vašíček, Ondřej; Blazheva, D.; Nedelcheva, P.; Vojtek, L.; Hyršl, P.

    2014-01-01

    Roč. 61, č. 2 (2014), s. 359-367. ISSN 0001-527X Institutional support: RVO:68081707 Keywords : herbs * polyphenols * antioxidant activity Subject RIV: BO - Biophysics Impact factor: 1.153, year: 2014

  17. Development and construction of a thermoelectric active facade module

    Marıa Ibanez-Puy; Jose Antonio Fernandez Sacristan; Cesar Martın-Gomez; Marina Vidaurre-Arbizu

    2015-01-01

    In order to fulfil the current challenges for the European building sector, building design has diverged into two alternative directions: active technologies and passive design strategies. In the last few years, advanced and responsive building envelope components have represented a promising answer to these challenges. This paper presents the design and construction process of a project that aims to design, build and control the energy performance of an industrial-scale modular active ventil...

  18. Activity-dependent modulation of neural circuit synaptic connectivity

    Tessier, Charles R.; Kendal Broadie

    2009-01-01

    In many nervous systems, the establishment of neural circuits is known to proceed via a two-stage process; 1) early, activity-independent wiring to produce a rough map characterized by excessive synaptic connections, and 2) subsequent, use-dependent pruning to eliminate inappropriate connections and reinforce maintained synapses. In invertebrates, however, evidence of the activity-dependent phase of synaptic refinement has been elusive, and the dogma has long been that invertebrate circ...

  19. Fuzzy Behavior Modulation with Threshold Activation for Autonomous Vehicle Navigation

    Tunstel, Edward

    2000-01-01

    This paper describes fuzzy logic techniques used in a hierarchical behavior-based architecture for robot navigation. An architectural feature for threshold activation of fuzzy-behaviors is emphasized, which is potentially useful for tuning navigation performance in real world applications. The target application is autonomous local navigation of a small planetary rover. Threshold activation of low-level navigation behaviors is the primary focus. A preliminary assessment of its impact on local navigation performance is provided based on computer simulations.

  20. Cloning and characterization of two lipopolysaccharide-binding protein/bactericidal permeability-increasing protein (LBP/BPI) genes from the sea cucumber Apostichopus japonicus with diversified function in modulating ROS production.

    Shao, Yina; Li, Chenghua; Che, Zhongjie; Zhang, Pengjuan; Zhang, Weiwei; Duan, Xuemei; Li, Ye

    2015-09-01

    Lipopolysaccharide-binding protein and bactericidal permeability-increasing protein (LBP/BPI) play crucial role in modulating cellular signals in response to Gram-negative bacteria infection. In the present study, two isoforms of LBP/BPI genes (designated as AjLBP/BPI1 and AjLBP/BPI2, respectively) were cloned from the sea cucumber Apostichopus japonicus by RACE approach. The full-length cDNAs of AjLBP/BPI1 and AjLBP/BPI2 were of 1479 and 1455 bp and encoded two secreted proteins of 492 and 484 amino acid residues, respectively. Signal peptide, two BPI/LBP/CETP and one central domain were totally conserved in the deduced amino acid of AjLBP/BPI1 and AjLBP/BPI2. Phylogentic analysis further supported that AjLBP/BPI1 and AjLBP/BPI2 belonged to new members of invertebrates LBP/BPI family. Spatial expression analysis revealed that both AjLBP/BPI1 and AjLBP/BPI2 were ubiquitously expressed in all examined tissues with the larger magnitude in AjLBP/BPI1. The Vibrio splenfidus challenge and LPS stimulation could significantly up-regulate the mRNA expression of both AjLBP/BPI1 and AjLBP/BPI2, with the increase of AjLBP/BPI2 expression occurred earlier than that of AjLBP/BPI1. More importantly, we found that LPS induced ROS production was markedly depressed after AjLBP/BPI1 knock-down, but there was no significant change by AjLBP/BPI2 silencing. Consistently, the expression level of unclassified AjToll, not AjTLR3, was tightly correlated with that of AjLBP/BPI1. Silencing the AjToll also depressed the ROS production in the cultured coelomocytes. All these results indicated that AjLBP/BPI1 and AjLBP/BPI2 probably played distinct roles in bacterial mediating immune response in sea cucumber, and AjLBP/BPI1 depressed coelomocytes ROS production via modulating AjToll cascade. PMID:25956196

  1. Modulation of the protein kinase activity of mTOR.

    Lawrence, J C; Lin, T A; McMahon, L P; Choi, K M

    2004-01-01

    mTOR is a founding member of a family of protein kinases having catalytic domains homologous to those in phosphatidylinositol 3-OH kinase. mTOR participates in the control by insulin of the phosphorylation of lipin, which is required for adipocyte differentiation, and the two translational regulators, p70S6K and PHAS-I. The phosphorylation of mTOR, itself, is stimulated by insulin in Ser2448, a site that is also phosphorylated by protein kinase B (PKB) in vitro and in response to activation of PKB activity in vivo. Ser2448 is located in a short stretch of amino acids not found in the two TOR proteins in yeast. A mutant mTOR lacking this stretch exhibited increased activity, and binding of the antibody, mTAb-1, to this region markedly increased mTOR activity. In contrast, rapamycin-FKBP12 inhibited mTOR activity towards both PHAS-I and p70S6K, although this complex inhibited the phosphorylation of some sites more than that of others. Mutating Ser2035 to Ile in the FKBP12-rapamycin binding domain rendered mTOR resistant to inhibition by rapamycin. Unexpectedly, this mutation markedly decreased the ability of mTOR to phosphorylate certain sites in both PHAS-I and p70S6K. The results support the hypotheses that rapamycin disrupts substrate recognition instead of directly inhibiting phosphotransferase activity and that mTOR activity in cells is controlled by the phosphorylation of an inhibitory regulatory domain containing the mTAb-1 epitope. PMID:14560959

  2. Modulation of β-catenin signaling by glucagon receptor activation.

    Jiyuan Ke

    Full Text Available The glucagon receptor (GCGR is a member of the class B G protein-coupled receptor family. Activation of GCGR by glucagon leads to increased glucose production by the liver. Thus, glucagon is a key component of glucose homeostasis by counteracting the effect of insulin. In this report, we found that in addition to activation of the classic cAMP/protein kinase A (PKA pathway, activation of GCGR also induced β-catenin stabilization and activated β-catenin-mediated transcription. Activation of β-catenin signaling was PKA-dependent, consistent with previous reports on the parathyroid hormone receptor type 1 (PTH1R and glucagon-like peptide 1 (GLP-1R receptors. Since low-density-lipoprotein receptor-related protein 5 (Lrp5 is an essential co-receptor required for Wnt protein mediated β-catenin signaling, we examined the role of Lrp5 in glucagon-induced β-catenin signaling. Cotransfection with Lrp5 enhanced the glucagon-induced β-catenin stabilization and TCF promoter-mediated transcription. Inhibiting Lrp5/6 function using Dickkopf-1(DKK1 or by expression of the Lrp5 extracellular domain blocked glucagon-induced β-catenin signaling. Furthermore, we showed that Lrp5 physically interacted with GCGR by immunoprecipitation and bioluminescence resonance energy transfer assays. Together, these results reveal an unexpected crosstalk between glucagon and β-catenin signaling, and may help to explain the metabolic phenotypes of Lrp5/6 mutations.

  3. Cell proliferation in vitro modulates fibroblast collagenase activity

    Collagenase enzyme activity is regulated by numerous control mechanisms which prevent excessive release and activation of this protease. A primary mechanism for regulating enzyme extracellular activity may be linked to cell division, therefore they have examined the release of collagenase by fibroblasts in vitro in response to cellular proliferation. Studies were performed using fibroblasts derived from adult rat dermis maintained in DMEM containing 10% newborn calf serum, 25 mM tricine buffer, and antibiotics. Cells between subculture 10 and 19 were used with enzyme activity determined with a 14C-labelled soluble Type I collagen substrate with and without trypsin activation. Fibroblasts, trypsinized and plated at low density secreted 8.5 fold more enzyme than those cells at confluence (975 vs. 115 dpm/μg DNA). This diminution occurred gradually as the cells went from logrithmic growth towards confluence. Confluent fibroblast monolayers were scraped in a grid arrangement, stimulating the remaining cells to divide, without exposure to trypsin. Within 24-48 hr postscraping enzyme levels had increased 260-400%, accompanied by enhanced incorporation of 3H-thymidine and 3H-uridine into cell macromolecules. The burst of enzyme release began to subside 12 hr later. These results support a close relationship between fibroblast proliferation and collagenase secretion

  4. Interleukin 6 modulates acetylcholinesterase activity of brain neurons

    Classically, radiation injuries results in a peripheral inflammatory process, and we have previously observed an early systemic interleukin 6 (IL-6) release following whole-body irradiation. Besides, we have demonstrated an early decrease of rat or primate brain acetylcholinesterase (AChE) activity a gamma exposure. The object of the present study is to find possible IL-6 systemic effects on the brain AChE activity. We show that, though intravenous (i.v.) or intra-cerebro-ventricular (ICV) injection of IL-6 can induce a drop in rat brain AChE activity, this cytokine induces only a slight decrease of the AChE release in cultured brain cells. (author)

  5. Regular exercise improves cardiac contractile activation by modulating MHC isoforms and SERCA activity in orchidectomized rats.

    Vutthasathien, Pavarana; Wattanapermpool, Jonggonnee

    2015-10-01

    Data from the trial known as Testosterone in Older Men with Mobility Limitations (TOM) has indicated an association between testosterone administration and a greater risk for adverse cardiovascular events. We therefore propose that regular exercise is a cardioprotective alternative that prevents detrimental changes in contractile activation when a deficiency in male sex hormones exists. Ten-week-old orchidectomized (ORX) rats were subjected to a 9-wk treadmill running program at moderate intensity starting 1 wk after surgery. Although exercise-induced cardiac hypertrophy was observed both in rats that underwent ORX and sham surgery, regular exercise enhanced cardiac myofilament Ca(2+) sensitivity and myosin light-chain 2 phosphorylation only in rats that underwent a sham operation. Although the rats that had sham surgery and and given exercise exhibited no change in maximum developed tension, regular running prevented the suppression of maximum active tension in the hearts of ORX rats. Regular exercise also prevented a shift in myosin heavy chain (MHC) isoforms toward β-MHC, a reduction in sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) activity, and an increase in SERCA sensitivity in the hearts of ORX rats. Neither SERCA content nor its modulating component, phospholamban (PLB), was altered by exercise in either sham-operated or ORX rats. However, decreases in the phosphorylated Thr(17) form of PLB and the phosphorylated Thr(287) form of Ca(2+)/calmodulin-dependent kinase II in the hearts of ORX rats were abolished after regular exercise. These results thus support the use of regular running as a cardioprotective alternative to testosterone replacement in hypogonadal conditions. PMID:26272317

  6. Activity-dependent modulation of neural circuit synaptic connectivity

    Charles R Tessier

    2009-07-01

    Full Text Available In many nervous systems, the establishment of neural circuits is known to proceed via a two-stage process; 1 early, activity-independent wiring to produce a rough map characterized by excessive synaptic connections, and 2 subsequent, use-dependent pruning to eliminate inappropriate connections and reinforce maintained synapses. In invertebrates, however, evidence of the activity-dependent phase of synaptic refinement has been elusive, and the dogma has long been that invertebrate circuits are “hard-wired” in a purely activity-independent manner. This conclusion has been challenged recently through the use of new transgenic tools employed in the powerful Drosophila system, which have allowed unprecedented temporal control and single neuron imaging resolution. These recent studies reveal that activity-dependent mechanisms are indeed required to refine circuit maps in Drosophila during precise, restricted windows of late-phase development. Such mechanisms of circuit refinement may be key to understanding a number of human neurological diseases, including developmental disorders such as Fragile X syndrome (FXS and autism, which are hypothesized to result from defects in synaptic connectivity and activity-dependent circuit function. This review focuses on our current understanding of activity-dependent synaptic connectivity in Drosophila, primarily through analyzing the role of the fragile X mental retardation protein (FMRP in the Drosophila FXS disease model. The particular emphasis of this review is on the expanding array of new genetically-encoded tools that are allowing cellular events and molecular players to be dissected with ever greater precision and detail.

  7. How Orthography Modulates Morphological Priming: Subliminal Kanji Activation in Japanese

    Nakano, Yoko; Ikemoto, Yu; Jacob, Gunnar; Clahsen, Harald

    2016-01-01

    The current study investigates to what extent masked morphological priming is modulated by language-particular properties, specifically by its writing system. We present results from two masked priming experiments investigating the processing of complex Japanese words written in less common (moraic) scripts. In Experiment 1, participants performed lexical decisions on target verbs; these were preceded by primes which were either (i) a past-tense form of the same verb, (ii) a stem-related form with the epenthetic vowel -i, (iii) a semantically-related form, and (iv) a phonologically-related form. Significant priming effects were obtained for prime types (i), (ii), and (iii), but not for (iv). This pattern of results differs from previous findings on languages with alphabetic scripts, which found reliable masked priming effects for morphologically related prime/target pairs of type (i), but not for non-affixal and semantically-related primes of types (ii), and (iii). In Experiment 2, we measured priming effects for prime/target pairs which are neither morphologically, semantically, phonologically nor - as presented in their moraic scripts—orthographically related, but which—in their commonly written form—share the same kanji, which are logograms adopted from Chinese. The results showed a significant priming effect, with faster lexical-decision times for kanji-related prime/target pairs relative to unrelated ones. We conclude that affix-stripping is insufficient to account for masked morphological priming effects across languages, but that language-particular properties (in the case of Japanese, the writing system) affect the processing of (morphologically) complex words. PMID:27065895

  8. How Orthography Modulates Morphological Priming: Subliminal Kanji Activation in Japanese

    Yoko eNakano

    2016-03-01

    Full Text Available The current study investigates to what extent masked morphological priming is modulated by language-particular properties, specifically by its writing system. We present results from two masked priming experiments investigating the processing of complex Japanese words written in less common (moraic scripts. In Experiment 1, participants performed lexical decisions on target verbs; these were preceded by primes which were either (i a past-tense form of the same verb, (ii a stem-related form with the epenthetic vowel -i, (iii a semantically-related form, and (iv a phonologically-related form. Significant priming effects were obtained for prime types (i, (ii and (iii, but not for (iv. This pattern of results differs from previous findings on languages with alphabetic scripts, which found reliable masked priming effects for morphologically related prime/target pairs of type (i, but not for non-affixal and semantically-related primes of types (ii and (iii. In Experiment 2, we measured priming effects for prime/target pairs which are neither morphologically, semantically, phonologically nor - as presented in their moraic scripts – orthographically related, but which - in their commonly written form - share the same kanji, which are logograms adopted from Chinese. The results showed a significant priming effect, with faster lexical-decision times for kanji-related prime/target pairs relative to unrelated ones. We conclude that affix-stripping is insufficient to account for masked morphological priming effects across languages, but that language-particular properties (in the case of Japanese, the writing system affect the processing of (morphologically complex words.

  9. How Orthography Modulates Morphological Priming: Subliminal Kanji Activation in Japanese.

    Nakano, Yoko; Ikemoto, Yu; Jacob, Gunnar; Clahsen, Harald

    2016-01-01

    The current study investigates to what extent masked morphological priming is modulated by language-particular properties, specifically by its writing system. We present results from two masked priming experiments investigating the processing of complex Japanese words written in less common (moraic) scripts. In Experiment 1, participants performed lexical decisions on target verbs; these were preceded by primes which were either (i) a past-tense form of the same verb, (ii) a stem-related form with the epenthetic vowel -i, (iii) a semantically-related form, and (iv) a phonologically-related form. Significant priming effects were obtained for prime types (i), (ii), and (iii), but not for (iv). This pattern of results differs from previous findings on languages with alphabetic scripts, which found reliable masked priming effects for morphologically related prime/target pairs of type (i), but not for non-affixal and semantically-related primes of types (ii), and (iii). In Experiment 2, we measured priming effects for prime/target pairs which are neither morphologically, semantically, phonologically nor - as presented in their moraic scripts-orthographically related, but which-in their commonly written form-share the same kanji, which are logograms adopted from Chinese. The results showed a significant priming effect, with faster lexical-decision times for kanji-related prime/target pairs relative to unrelated ones. We conclude that affix-stripping is insufficient to account for masked morphological priming effects across languages, but that language-particular properties (in the case of Japanese, the writing system) affect the processing of (morphologically) complex words. PMID:27065895

  10. Complex modulation of peptidolytic activity of cathepsin D by sphingolipids

    Žebrakovská, Iva; Máša, Martin; Srp, Jaroslav; Horn, Martin; Vávrová, K.; Mareš, Michael

    2011-01-01

    Roč. 1811, č. 12 (2011), s. 1097-1104. ISSN 1388-1981 R&D Projects: GA AV ČR IAA400550705 Institutional research plan: CEZ:AV0Z40550506 Keywords : sphingolipid * phospholipid * inhibition * activation * cathepsin D * enzyme regulation Subject RIV: CE - Biochemistry Impact factor: 5.269, year: 2011

  11. Modulation of Erythrocyte Plasma Membrane Redox System Activity by Curcumin

    Prabhakar Singh

    2016-01-01

    Full Text Available Plasma membrane redox system (PMRS is an electron transport chain system ubiquitously present throughout all cell types. It transfers electron from intracellular substrates to extracellular acceptors for regulation of redox status. Curcumin, isolated from Curcuma longa, has modulatory effects on cellular physiology due to its membrane interaction ability and antioxidant potential. The present study investigates the effect of curcumin on PMRS activity of erythrocytes isolated from Wistar rats in vitro and in vivo and validated through an in silico docking simulation study using Molegro Virtual Docker (MVD. Effects of curcumin were also evaluated on level of glutathione (GSH and the oxidant potential of plasma measured in terms of plasma ferric equivalent oxidative potentials (PFEOP. Results show that curcumin significantly (p<0.01 downregulated the PMRS activity in a dose-dependent manner. Molecular docking results suggest that curcumin interacts with amino acids at the active site cavity of cytochrome b5 reductase, a key constituent of PMRS. Curcumin also increased the GSH level in erythrocytes and plasma while simultaneously decreasing the oxidant potential (PFEOP of plasma. Altered PMRS activity and redox status are associated with the pathophysiology of several health complications including aging and diabetes; hence, the above finding may explain part of the role of curcumin in health beneficial effects.

  12. Interrelations between blood-brain barrier permeability and matrix metalloproteinases are differently affected by tissue plasminogen activator and hyperoxia in a rat model of embolic stroke

    Michalski Dominik

    2012-01-01

    Full Text Available Abstract Background In ischemic stroke, blood-brain barrier (BBB regulations, typically involving matrix metalloproteinases (MMPs and inhibitors (TIMPs as mediators, became interesting since tissue plasminogen activator (tPA-related BBB breakdown with risk of secondary hemorrhage was considered to involve these mediators too. Despite high clinical relevance, detailed interactions are purely understood. After a pilot study addressing hyperoxia as potential neuroprotective co-treatment to tPA, we analyzed interrelations between BBB permeability (BBB-P, MMPs and TIMPs. Findings Rats underwent embolic middle cerebral artery occlusion (eMCAO and treatment with normobaric (NBO or hyperbaric oxygen (HBO, tPA, tPA+HBO, or no treatment. BBB-P was assessed by intravenously applied FITC-albumin at 4 or 24 hours. MMP-2/-9 and TIMP-1/-2 serum levels were determined at 5 or 25 hours. Time point-corrected partial correlations were used to explore interrelations of BBB-P in ischemic regions (extra-/intravasal FITC-albumin ratio and related serum markers. BBB-P correlated positively with MMP-2 and MMP-9 in controls, whereas hyperoxia led to an inverse association, most pronounced for HBO/MMP-9 (r = -0.606; P Conclusions HBO was found to reverse the positively directed interrelation of BBB-P and MMPs after eMCAO, but this effect failed to sustain in the expected amount when HBO and tPA were given simultaneously.

  13. MDMA (ecstasy) modulates locomotor and prefrontal cortex sensory evoked activity.

    Atkins, Kristal; Burks, Tilithia; Swann, Alan C; Dafny, Nachum

    2009-12-11

    Ingestion of 3, 4-methylenedioxymethamphetamine (MDMA) leads to heightened response to sensory stimulation; thus, MDMA is referred to as "ecstasy" because it produces pleasurable enhancement of such sensation. There have been no electrophysiological studies that report the consequences of MDMA on sensory input. The present study was initiated to study the effects of acute and chronic MDMA on locomotor activity and sensory evoked field potential from freely behaving rats previously implanted with permanent electrodes in the prefrontal cortex (PFC). The main findings of this study are that: (1) acute MDMA augments locomotor behavior and attenuates the incoming sensory input, (2) chronic treatment of MDMA elicits behavioral sensitization, (3) chronic administration of MDMA results in attenuation of the baseline activity of the sensory evoked field potential, and (4) administration of rechallenge MDMA result in enhancement of the PFC sensory evoked field potential. PMID:19769950

  14. Sendai Virus Fusion Activity as Modulated by Target Membrane Components

    Nunes-Correia, Isabel; Ramalho-Santos, João; Maria C Pedroso de Lima

    1998-01-01

    We have studied the differences between erythrocytes and erythrocyte ghosts as target membranes for the study of Sendai virus fusion activity. Fusion was monitored continuously by fluorescence dequenching of R18-labeled virus. Experiments were carried out either with or without virus/target membrane prebinding. When Sendai virus was added directly to a erythrocyte/erythrocyte ghost suspension, fusion was always lower than that obtained when experiments were carried out with virus already boun...

  15. Visual Experience Modulates Spatio-Temporal Dynamics of Circuit Activation

    Wang, Lang; Fontanini, Alfredo; Maffei, Arianna

    2011-01-01

    Persistent reduction in sensory drive in early development results in multiple plastic changes of different cortical synapses. How these experience-dependent modifications affect the spatio-temporal dynamics of signal propagation in neocortical circuits is poorly understood. Here we demonstrate that brief visual deprivation significantly affects the propagation of electrical signals in the primary visual cortex. The spatio-temporal spread of circuit activation upon direct stimulation of its i...

  16. Visual experience modulates spatio-temporal dynamics of circuit activation

    Arianna Maffei

    2011-01-01

    Persistent reduction in sensory drive in early development results in multiple plastic changes of different cortical synapses. How these experience-dependent modifications affect the spatio-temporal dynamics of signal propagation in neocortical circuits is poorly understood. Here we demonstrate that brief visual deprivation significantly affects the propagation of electrical signals in the primary visual cortex. The spatio-temporal spread of circuit activation upon direct stimulation of its i...

  17. Substrate modulation of enzyme activity in the herpesvirus protease family

    Lazic, Ana; Goetz, David H.; Nomura, Anson M.; Marnett, Alan B.; Craik, Charles S.

    2007-01-01

    The herpesvirus proteases are an example in which allosteric regulation of an enzyme activity is achieved through the formation of quaternary structure. Here, we report a 1.7 Å resolution structure of Kaposi’s Sarcoma herpesvirus protease in complex with a hexapeptide transition state analogue that stabilizes the dimeric state of the enzyme. Extended substrate binding sites are induced upon peptide binding. In particular, 104 Å2 of surface are buried in the newly formed S4 pocket when tyrosin...

  18. Modulation of insulin degrading enzyme activity and liver cell proliferation

    Pivovarova, Olga; von Loeffelholz, Christian; Ilkavets, Iryna; Sticht, Carsten; Zhuk, Sergei; Murahovschi, Veronica; Lukowski, Sonja; Döcke, Stephanie; Kriebel, Jennifer; de las Heras Gala, Tonia; Malashicheva, Anna; Kostareva, Anna; Lock, Johan F; Stockmann, Martin; Grallert, Harald

    2015-01-01

    Diabetes mellitus type 2 (T2DM), insulin therapy, and hyperinsulinemia are independent risk factors of liver cancer. Recently, the use of a novel inhibitor of insulin degrading enzyme (IDE) was proposed as a new therapeutic strategy in T2DM. However, IDE inhibition might stimulate liver cell proliferation via increased intracellular insulin concentration. The aim of this study was to characterize effects of inhibition of IDE activity in HepG2 hepatoma cells and to analyze liver specific expre...

  19. Insect Repellents: Modulators of Mosquito Odorant Receptor Activity

    Bohbot, Jonathan D.; Joseph C. Dickens

    2010-01-01

    Background DEET, 2-undecanone (2-U), IR3535 and Picaridin are widely used as insect repellents to prevent interactions between humans and many arthropods including mosquitoes. Their molecular action has only recently been studied, yielding seemingly contradictory theories including odorant-dependent inhibitory and odorant-independent excitatory activities on insect olfactory sensory neurons (OSNs) and odorant receptor proteins (ORs). Methodology/Principal Findings Here we characterize the act...

  20. Modulating basal ganglia and cerebellar activity to suppress parkinsonian tremor

    Heida, T.; Zhao, Yan; Wezel, van, H.B.

    2013-01-01

    Despite extensive research, the detailed pathophysiology of the parkinsonian tremor is still unknown. It has been hypothesized that the generation of parkinsonian tremor is related to abnormal activity within the basal ganglia. The cerebello-thalamic-cortical loop has been suggested to indirectly contribute to the expression of parkinsonian tremor. However, the observed tremor-related hyperactivity in the cerebellar loop may have a compensatory rather than a causal role in Parkinson's disease...

  1. Implicitly perceived vocal attractiveness modulates prefrontal cortex activity.

    Bestelmeyer, Patricia E G; Latinus, Marianne; Bruckert, Laetitia; Rouger, Julien; Crabbe, Frances; Belin, Pascal

    2012-06-01

    Social interactions involve more than "just" language. As important is a more primitive nonlinguistic mode of communication acting in parallel with linguistic processes and driving our decisions to a much higher degree than is generally suspected. Amongst the "honest signals" that influence our behavior is perceived vocal attractiveness. Not only does vocal attractiveness reflect important biological characteristics of the speaker, it also influences our social perceptions according to the "what sounds beautiful is good" phenomenon. Despite the widespread influence of vocal attractiveness on social interactions revealed by behavioral studies, its neural underpinnings are yet unknown. We measured brain activity while participants listened to a series of vocal sounds ("ah") and performed an unrelated task. We found that voice-sensitive auditory and inferior frontal regions were strongly correlated with implicitly perceived vocal attractiveness. While the involvement of auditory areas reflected the processing of acoustic contributors to vocal attractiveness ("distance to mean" and spectrotemporal regularity), activity in inferior prefrontal regions (traditionally involved in speech processes) reflected the overall perceived attractiveness of the voices despite their lack of linguistic content. These results suggest the strong influence of hidden nonlinguistic aspects of communication signals on cerebral activity and provide an objective measure of this influence. PMID:21828348

  2. Lipid metabolizing enzyme activities modulated by phospholipid substrate lateral distribution.

    Salinas, Dino G; Reyes, Juan G; De la Fuente, Milton

    2011-09-01

    Biological membranes contain many domains enriched in phospholipid lipids and there is not yet clear explanation about how these domains can control the activity of phospholipid metabolizing enzymes. Here we used the surface dilution kinetic theory to derive general equations describing how complex substrate distributions affect the activity of enzymes following either the phospholipid binding kinetic model (which assumes that the enzyme molecules directly bind the phospholipid substrate molecules), or the surface-binding kinetic model (which assumes that the enzyme molecules bind to the membrane before binding the phospholipid substrate). Our results strongly suggest that, if the enzyme follows the phospholipid binding kinetic model, any substrate redistribution would increase the enzyme activity over than observed for a homogeneous distribution of substrate. Besides, enzymes following the surface-binding model would be independent of the substrate distribution. Given that the distribution of substrate in a population of micelles (each of them a lipid domain) should follow a Poisson law, we demonstrate that the general equations give an excellent fit to experimental data of lipases acting on micelles, providing reasonable values for kinetic parameters--without invoking special effects such as cooperative phenomena. Our theory will allow a better understanding of the cellular-metabolism control in membranes, as well as a more simple analysis of the mechanisms of membrane acting enzymes. PMID:21108012

  3. Hybrid Modulation of Bidirectional Three-Phase Dual-Active-Bridge DC Converters for Electric Vehicles

    Yen-Ching Wang

    2016-06-01

    Full Text Available Bidirectional power converters for electric vehicles (EVs have received much attention recently, due to either grid-supporting requirements or emergent power supplies. This paper proposes a hybrid modulation of the three-phase dual-active bridge (3ΦDAB converter for EV charging systems. The designed hybrid modulation allows the converter to switch its modulation between phase-shifted and trapezoidal modes to increase the conversion efficiency, even under light-load conditions. The mode transition is realized in a real-time manner according to the charging or discharging current. The operation principle of the converter is analyzed in different modes and thus design considerations of the modulation are derived. A lab-scaled prototype circuit with a 48V/20Ah LiFePO4 battery is established to validate the feasibility and effectiveness.

  4. Respiratory modulation of sympathetic nerve activity is enhanced in male rat offspring following uteroplacental insufficiency.

    Menuet, C; Wlodek, M E; Fong, A Y; Allen, A M

    2016-06-01

    Sympathetic nerve activity to the cardiovascular system displays prominent respiratory-related modulation which leads to the generation of rhythmic oscillations in blood pressure called Traube-Hering waves. An amplification of this respiratory modulation of sympathetic activity is observed in hypertension of both genetic, the spontaneously hypertensive rat, and induced, chronic intermittent hypoxia or maternal protein restriction during gestation, origin. Male offspring of mothers with uteroplacental insufficiency, induced by bilateral uterine vessel ligation at 18 days of gestation, are also hypertensive in adulthood. In this study we examined whether these male offspring display altered respiratory modulation of sympathetic activity at pre-hypertensive ages compared to controls. Respiratory, cardiovascular and sympathetic parameters were examined using the working heart-brainstem preparation in 35 day old male rats that had reduced birth weight due to uteroplacental insufficiency. Whilst all respiratory parameters were not different between groups, we observed an enhanced respiratory-related burst of thoracic sympathetic nerve activity and amplified Traube-Hering waves in the growth-restricted group. This group also showed an increased sympathetic and bradycardic response to activation of peripheral chemoreceptors. The observations add support to the view that altered respiratory modulation of sympathetic activity represents a common mechanism involved in the development of several forms of hypertension. PMID:26593642

  5. Electrostatically gated membrane permeability in inorganic protocells

    Li, Mei; Harbron, Rachel; Weaver, Jonathan; Binks, Bernard; Mann, Stephen.

    2013-01-01

    Although several strategies are now available to produce functional microcompartments analogous to primitive cell-like structures, little progress has been made in generating protocell constructs with self-controlled membrane permeability. Here we describe the preparation of water-dispersible colloidosomes based on silica nanoparticles and delineated by a continuous semipermeable inorganic membrane capable of self-activated, electrostatically gated permeability. We use crosslinking and covale...

  6. Noradrenergic modulation of basolateral amygdala neuronal activity: opposing influences of alpha-2 and beta receptor activation.

    Buffalari, Deanne M; Grace, Anthony A

    2007-11-01

    Substantial data exists demonstrating the importance of the amygdala and the locus ceruleus (LC) in responding to stress, aversive memory formation, and the development of stress-related disorders; however, little is known about the effects of norepinephrine (NE) on amygdala neuronal activity in vivo. The basolateral nucleus of the amygdala (BLA) receives dense NE projections from the LC, NE increases in the BLA in response to stress, and the BLA can also modulate the LC via reciprocal projections. These experiments examined the effects of noradrenergic agents on spontaneous and evoked responses of BLA neurons. NE iontophoresis inhibited spontaneous firing and decreased the responsiveness of BLA neurons to electrical stimulation of entorhinal cortex and sensory association cortex (Te3). Confirmed BLA projection neurons exhibited exclusively inhibitory responses to NE. Systemic administration of propranolol, a beta-receptor antagonist, decreased the spontaneous firing rate and potentiated the NE-evoked inhibition of BLA neurons. In addition, iontophoresis of the alpha-2 agonist clonidine, footshock administration, and LC stimulation mimicked the effects of NE iontophoresis on spontaneous activity. Furthermore, the effects of LC stimulation were partially blocked by systemic administration of alpha 2 and beta receptor antagonists. This is the first study to demonstrate the actions of directly applied and stimulus-evoked NE in the BLA in vivo, and provides a mechanism by which beta receptors can mediate the important behavioral consequences of NE within the BLA. The interaction between these two structures is particularly relevant with regard to their known involvement in stress responses and stress-related disorders. PMID:17989300

  7. Tissue plasminogen activator modulates the cellular and behavioral response to cocaine

    Maiya, Rajani; Zhou, Yan; Norris, Erin H.; Kreek, Mary Jeanne; Strickland, Sidney

    2009-01-01

    Cocaine exposure induces long-lasting molecular and structural adaptations in the brain. In this study, we show that tissue plasminogen activator (tPA), an extracellular protease involved in neuronal plasticity, modulates the biochemical and behavioral response to cocaine. When injected in the acute binge paradigm, cocaine enhanced tPA activity in the amygdala, which required activation of corticotropin-releasing factor type-1 (CRF-R1) receptors. Compared with WT mice, tPA−/− mice injected wi...

  8. Activation of the Endoperoxide Ascaridole Modulates Its Sensitizing Capacity.

    Krutz, Nora L; Hennen, Jennifer; Korb, Corinna; Schellenberger, Mario T; Gerberick, G Frank; Blömeke, Brunhilde

    2015-10-01

    The monoterpene ascaridole, a fairly stable endoperoxide found in essential oils such as tea tree oil can provoke allergic contact dermatitis which has been evidenced under patch test conditions. However, concomitantly we observed irritative skin reactions that demand further data underlining the sensitization potential of ascaridole. Here, we studied the effects of ascaridole on dendritic cell (DC) activation and protein reactivity, 2 key steps of chemical-induced skin sensitization. Treatment of human monocyte-derived DC with ascaridole found support for full DC maturation, a capability of sensitizers but not irritants. It induced significant upregulation of the expression of the costimulatory molecules CD86, CD80, CD40, and the adhesion molecule CD54 in a time-dependent manner. Maturation was accompanied by release of proinflammatory cytokines interleukin (IL)-1ß, tumor necrosis factor-α, IL-6, and IL-8. Similar to other chemical skin sensitizers including hydroperoxides, we observed a certain reactivity of ascaridole toward cysteine- but not lysine-containing peptides. During recent years, evidence accumulated for a radical mechanism as trigger for protein reactivity of peroxides. Treatment of the fairly stable endoperoxide ascaridole with iron as radical inducer ("activated ascaridole") resulted in cysteine peptide reactivity exceeding by far that of ascaridole itself. Furthermore, activated ascaridole showed increased potential for induction of the Nrf2 target gene heme oxygenase 1 and upregulation of CD86 and CD54 on THP-1 cells, an established DC surrogate. These results indicate that radical formation could be involved in the steps leading to skin sensitization induced by the endoperoxide ascaridole. PMID:26185204

  9. Acetylcholinesterase Modulates Presenilin-1 Levels and γ-Secretase Activity

    Campanari, María-Letizia; García Ayllón, María Salud; Belbin, Olivia; Galcerán, Joan; Lleó, Alberto; Sáez-Valero, Javier

    2014-01-01

    The cholinergic enzyme acetylcholinesterase (AChE) and the catalytic component of the ¿-secretase complex, presenilin-1 (PS1), are known to interact. In this study, we investigate the consequences of AChE-PS1 interactions, particularly the influence of AChE in PS1 levels and ¿-secretase activity. PS1 is able to co-immunoprecipitate all AChE variants (AChE-R and AChE-T) and molecular forms (tetramers and light subunits) present in the human brain. Overexpression of AChE-R or AChE-T, or their r...

  10. Development and construction of a thermoelectric active facade module

    Marıa Ibanez-Puy

    2015-06-01

    Full Text Available In order to fulfil the current challenges for the European building sector, building design has diverged into two alternative directions: active technologies and passive design strategies. In the last few years, advanced and responsive building envelope components have represented a promising answer to these challenges. This paper presents the design and construction process of a project that aims to design, build and control the energy performance of an industrial-scale modular active ventilated facade prototype with a new Themoelectric Peltier System (TPS. The TPS is a thermoelectric HVAC heat pump system designed to be located in the building envelope and providing a high comfort level. Trying to optimize the energy performance of the traditional ventilated opaque facade, and make more efficient the energy performance of the TPS, the concept of adaptability has been applied to ventilated opaque facades. The essential research theme is to control the natural phenomena that take place inside the ventilated air cavity of the facade: taking advantage when heat dissipation is needed, and avoiding it when heat losses are not welcome. In order to quantify the previous statements, some facade prototypes are being built in Pamplona (Spain and their energy performance is going to be analyzed during a year.  

  11. Control of Foxp3 stability through modulation of TET activity.

    Yue, Xiaojing; Trifari, Sara; Äijö, Tarmo; Tsagaratou, Ageliki; Pastor, William A; Zepeda-Martínez, Jorge A; Lio, Chan-Wang J; Li, Xiang; Huang, Yun; Vijayanand, Pandurangan; Lähdesmäki, Harri; Rao, Anjana

    2016-03-01

    Ten-eleven translocation (TET) enzymes oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine and other oxidized methylcytosines, intermediates in DNA demethylation. In this study, we examine the role of TET proteins in regulating Foxp3, a transcription factor essential for the development and function of regulatory T cells (T reg cells), a distinct lineage of CD4(+) T cells that prevent autoimmunity and maintain immune homeostasis. We show that during T reg cell development in the thymus, TET proteins mediate the loss of 5mC in T reg cell-specific hypomethylated regions, including CNS1 and CNS2, intronic cis-regulatory elements in the Foxp3 locus. Similar to CNS2-deficient T reg cells, the stability of Foxp3 expression is markedly compromised in T reg cells from Tet2/Tet3 double-deficient mice. Vitamin C potentiates TET activity and acts through Tet2/Tet3 to increase the stability of Foxp3 expression in TGF-β-induced T reg cells. Our data suggest that targeting TET enzymes with small molecule activators such as vitamin C might increase induced T reg cell efficacy. PMID:26903244

  12. Modulation of P-glycoprotein ATPase activity by some phytoconstituents.

    Najar, I A; Sachin, B S; Sharma, S C; Satti, N K; Suri, K A; Johri, R K

    2010-03-01

    In the present investigation 16 phytoconstituents, which are active moieties found in several medicinal herbs, have been evaluated for their P-glycoprotein (P-gp) stimulation/inhibition profiles using a P-gp-dependent ATPase assay in rat jejunal membrane (in vitro). Acteoside, agnuside, catechin, chlorogenic acid, picroside -II and santonin showed an inhibitory effect. Negundoside, picroside -I and oleanolic acid caused a stimulatory effect. Andrographolide, apocyanin, berberine, glycyrrhizin, magniferin and piperine produced a biphasic response (stimulation at low concentration and inhibition at high concentration). The results suggested that a possible interaction of these phytoconstituents at the level of P-gp, could be an important parameter in determining their role in several key pharmacodynamic events. PMID:19653312

  13. Seismic waves increase permeability.

    Elkhoury, Jean E; Brodsky, Emily E; Agnew, Duncan C

    2006-06-29

    Earthquakes have been observed to affect hydrological systems in a variety of ways--water well levels can change dramatically, streams can become fuller and spring discharges can increase at the time of earthquakes. Distant earthquakes may even increase the permeability in faults. Most of these hydrological observations can be explained by some form of permeability increase. Here we use the response of water well levels to solid Earth tides to measure permeability over a 20-year period. At the time of each of seven earthquakes in Southern California, we observe transient changes of up to 24 degrees in the phase of the water level response to the dilatational volumetric strain of the semidiurnal tidal components of wells at the Piñon Flat Observatory in Southern California. After the earthquakes, the phase gradually returns to the background value at a rate of less than 0.1 degrees per day. We use a model of axisymmetric flow driven by an imposed head oscillation through a single, laterally extensive, confined, homogeneous and isotropic aquifer to relate the phase response to aquifer properties. We interpret the changes in phase response as due to changes in permeability. At the time of the earthquakes, the permeability at the site increases by a factor as high as three. The permeability increase depends roughly linearly on the amplitude of seismic-wave peak ground velocity in the range of 0.21-2.1 cm s(-1). Such permeability increases are of interest to hydrologists and oil reservoir engineers as they affect fluid flow and might determine long-term evolution of hydrological and oil-bearing systems. They may also be interesting to seismologists, as the resulting pore pressure changes can affect earthquakes by changing normal stresses on faults. PMID:16810253

  14. Urokinase and type I plasminogen activator inhibitor production by normal human hepatocytes: modulation by inflammatory agents.

    Busso, N; Nicodeme, E; Chesne, C; Guillouzo, A; Belin, D; Hyafil, F

    1994-07-01

    We examined the effects of inflammatory cytokines (interleukin-1 beta, tumor necrosis factor-alpha and transforming growth factor-beta) on the plasminogen activator system (urokinase, tissue-type plasminogen activator, type 1 plasminogen activator inhibitor) in primary cultures of human hepatocytes. We show that interleukin-1 beta and tumor necrosis factor-alpha increase urokinase-type plasminogen activator production, reinforcing the concept that increased urokinase production is associated with inflammatory processes. By contrast, the same agents (i.e., interleukin-1 beta and tumor necrosis factor-alpha) do not stimulate plasminogen activator inhibitor type 1 production. This latter observation rules out hepatocytes as a major cellular source of plasmatic plasminogen activator inhibitor type 1 during acute-phase-related responses. Among the inflammatory agents used, transforming growth factor-beta was found to be the most effective modulator of both urokinase-type plasminogen activator and plasminogen activator inhibitor type 1, inducing severalfold increases of activity of urokinase-type plasminogen activator, antigen and the corresponding mRNA and increasing plasminogen activator inhibitor type 1 antigen and mRNA levels. Urokinase-type plasminogen activator and plasminogen activator inhibitor type 1 modulation by transforming growth factor-beta may play a critical role in hepatic pathophysiology. PMID:8020888

  15. CK2 activity is modulated by growth rate in Saccharomyces cerevisiae

    Research highlights: → CK2 subunits are nuclear both in glucose and in ethanol growing yeast cells. → CK2 activity is modulated in S. cerevisiae. → CK2 activity is higher in conditions supporting higher growth rates. → Vmax is higher in faster growing cells, while Km is not affected. -- Abstract: CK2 is a highly conserved protein kinase controlling different cellular processes. It shows a higher activity in proliferating mammalian cells, in various types of cancer cell lines and tumors. The findings presented herein provide the first evidence of an in vivo modulation of CK2 activity, dependent on growth rate, in Saccharomyces cerevisiae. In fact, CK2 activity, assayed on nuclear extracts, is shown to increase in exponential growing batch cultures at faster growth rate, while localization of catalytic and regulatory subunits is not nutritionally modulated. Differences in intracellular CK2 activity of glucose- and ethanol-grown cells appear to depend on both increase in molecule number and kcat. Also in chemostat cultures nuclear CK2 activity is higher in faster growing cells providing the first unequivocal demonstration that growth rate itself can affect CK2 activity in a eukaryotic organism.

  16. CCL2/MCP-1 modulation of microglial activation and proliferation

    Garcia-Bueno Borja

    2011-07-01

    Full Text Available Abstract Background Monocyte chemoattractant protein (CCL2/MCP-1 is a chemokine that attracts cells involved in the immune/inflammatory response. As microglia are one of the main cell types sustaining inflammation in brain, we proposed here to analyze the direct effects of MCP-1 on cultured primary microglia. Methods Primary microglia and neuronal cultures were obtained from neonatal and embryonic Wistar rats, respectively. Microglia were incubated with different concentrations of recombinant MCP-1 and LPS. Cell proliferation was quantified by measuring incorporation of bromodeoxyuridine (BrdU. Nitrite accumulation was measured using the Griess assay. The expression and synthesis of different proteins was measured by RT-PCR and ELISA. Cell death was quantified by measuring release of LDH into the culture medium. Results MCP-1 treatment (50 ng/ml, 24 h did not induce morphological changes in microglial cultures. Protein and mRNA levels of different cytokines were measured, showing that MCP-1 was not able to induce proinflammatory cytokines (IL-1β, IL6, MIP-1α, either by itself or in combination with LPS. A similar lack of effect was observed when measuring inducible nitric oxide synthase (NOS2 expression or accumulation of nitrites in the culture media as a different indicator of microglial activation. MCP-1 was also unable to alter the expression of different trophic factors that were reduced by LPS treatment. In order to explore the possible release of other products by microglia and their potential neurotoxicity, neurons were co-cultured with microglia: no death of neurons could be detected when treated with MCP-1. However, the presence of MCP-1 induced proliferation of microglia, an effect opposite to that observed with LPS. Conclusion These data indicate that, while causing migration and proliferation of microglia, MCP-1 does not appear to directly activate an inflammatory response in this cell type, and therefore, other factors may be

  17. Isolated PWM DC-AC SICAM with an active capacitive voltage clamp[Pulse Density Modulated; Pulse Width Modulation

    Ljusev, P.

    2004-03-15

    In this report an isolated PWM DC-AC SICAM with an active capacitive voltage clamp is presented. AC-DC power supply is implemented in its simplest form: diode rectifier followed by a medium-size charge-storage capacitors and possibly with an EMC filter on the mains entrance. Isolation from the AC mains is achieved using a high frequency (HF) transformer, whose voltages are not audio-modulated. The latter simplifies the design and is expected to have many advantages over the approach where the transformer voltages are modulated in regards to the audio signal reference. Input stage is built as a DC-AC inverter (push-pull, half-bridge or a full-bridge) and operated with 50% duty cycle, with all the challenges to avoid transformer saturation and obtain symmetrical operation. On the secondary side the output section is implemented as rectifier+inverter AC-AC stage, i.e. a true bidirectional bridge, which operation is aimed towards amplification of the audio signal. In order to solve the problem with the commutation of the load current, a dead time between the incoming and outgoing bidirectional switch is implemented, while a capacitive voltage clamp is used to keep the induced overvoltage to reasonable levels. The energy stored in the clamping capacitor is not wasted as in the dissipative clamps, but is rather transferred back to the primary side for further processing using an auxiliary isolated single-switch converter, i.e. an active clamping technique is used. (au)

  18. Varying modulation of HIV-1 LTR activity by Baf complexes.

    Van Duyne, Rachel; Guendel, Irene; Narayanan, Aarthi; Gregg, Edward; Shafagati, Nazly; Tyagi, Mudit; Easley, Rebecca; Klase, Zachary; Nekhai, Sergei; Kehn-Hall, Kylene; Kashanchi, Fatah

    2011-08-19

    The human immunodeficiency virus type 1 (HIV-1) long terminal repeat is present on both ends of the integrated viral genome and contains regulatory elements needed for transcriptional initiation and elongation. Post-integration, a highly ordered chromatin structure consisting of at least five nucleosomes, is found at the 5' long terminal repeat, the location and modification state of which control the state of active viral replication as well as silencing of the latent HIV-1 provirus. In this context, the chromatin remodeling field rapidly emerges as having a critical role in the control of viral gene expression. In the current study, we focused on unique Baf subunits that are common to the most highly recognized of chromatin remodeling proteins, the SWI/SNF (switching-defective-sucrose non-fermenting) complexes. We find that at least two Baf proteins, Baf53 and Baf170, are highly regulated in HIV-1-infected cells. Previously, studies have shown that the depletion of Baf53 in uninfected cells leads to the expansion of chromosomal territories and the decompaction of the chromatin. Baf53, in the presence of HIV-1 infection, co-elutes off of a chromatographic column as a different-sized complex when compared to uninfected cells and appears to be predominantly phosphorylated. The innate function of Baf53-containing complexes appears to be transcriptionally suppressive, in that knocking down Baf53 increases viral gene expression from cells both transiently and chronically infected with HIV-1. Additionally, cdk9/cyclin T in the presence of Tat is able to phosphorylate Baf53 in vitro, implying that this posttranslationally modified form relieves the suppressive effect and allows for viral transcription to proceed. PMID:21699904

  19. Gyroid Nanoporous Membranes with Tunable Permeability

    Li, Li; Schulte, Lars; Clausen, Lydia D.;

    2011-01-01

    Understanding the relevant permeability properties of ultrafiltration membranes is facilitated by using materials and procedures that allow a high degree of control on morphology and chemical composition. Here we present the first study on diffusion permeability through gyroid nanoporous cross...... chemistry of 1,2-PB nanoporous membranes can be controlled, for example, by hydrophilic patterning of the originally hydrophobic membranes, which allows for different active porosity toward aqueous solutions and, therefore, different permeability. The membrane selectivity is evaluated by comparing the...... effective diffusion coefficients of a series of antibiotics, proteins, and other biomolecules; solute permeation is discussed in terms of hindered diffusion. The combination of uniform bulk morphology, isotropically percolating porosity, controlled surface chemistry, and tunable permeability is distinctive...

  20. MODULATION BREATHING OF THE ELECTRICAL ACTIVITY IN THE PHRENIC NERVE DURING STARTLES REFLEXES

    Emanov, Sergey

    2006-01-01

    In the paper the reflex activity in the phrenic nerve is studied in chloralose anesthetized cats during development of somatic startle reflexes. Modulation of responses during the respiratory cycle is described. Organization of possible neurophysiologic mechanisms of phrenic responses during startle reflexes is discussed

  1. Real-time MEG neurofeedback training of posterior alpha activity modulates subsequent visual detection performance

    Okazaki, Y.O.; Horschig, J.; Luther, L.M.; Oostenveld, R.; Murakami, I.; Jensen, O.

    2015-01-01

    It has been demonstrated that alpha activity is lateralized when attention is directed to the left or right visual hemifield. We investigated whether real-time neurofeedback training of the alpha lateralization enhances participants' ability to modulate posterior alpha lateralization and causes subs

  2. Modulators of membrane drug transporters potentiate the activity of the DMI fungicide oxpoconazole against Botrytis cinerea

    Hayashi, K.; Schoonbeek, H.; Waard, de M.A.

    2003-01-01

    Modulators known to reduce multidrug resistance in tumour cells were tested for their potency to synergize the fungitoxic activity of the fungicide oxpoconazole, a sterol demethylation inhibitor (DMI), against Botrytis cinerea Pers. Chlorpromazine, a phenothiazine compound known as a calmodulin anta

  3. MODULATION OF EASTERN OYSTER HEMOCYTE ACTIVITIES BY PERKINSUS MARINUS EXTRACELLULAR PROTEINS

    The oyster pathogen Perkinsus marinusproduces many extracellular proteins (ECP) in vitro. Analysis of this ECP revealed a battery of hydrolytic enzymes. Some of these enzymes are known to modulate the activity of host defense cells. Although information on the effects of P. marin...

  4. Vestibular Activation Differentially Modulates Human Early Visual Cortex and V5/MT Excitability and Response Entropy

    Guzman-Lopez, Jessica; Arshad, Qadeer; Schultz, Simon R; Walsh, Vincent; Yousif, Nada

    2013-01-01

    Head movement imposes the additional burdens on the visual system of maintaining visual acuity and determining the origin of retinal image motion (i.e., self-motion vs. object-motion). Although maintaining visual acuity during self-motion is effected by minimizing retinal slip via the brainstem vestibular-ocular reflex, higher order visuovestibular mechanisms also contribute. Disambiguating self-motion versus object-motion also invokes higher order mechanisms, and a cortical visuovestibular reciprocal antagonism is propounded. Hence, one prediction is of a vestibular modulation of visual cortical excitability and indirect measures have variously suggested none, focal or global effects of activation or suppression in human visual cortex. Using transcranial magnetic stimulation-induced phosphenes to probe cortical excitability, we observed decreased V5/MT excitability versus increased early visual cortex (EVC) excitability, during vestibular activation. In order to exclude nonspecific effects (e.g., arousal) on cortical excitability, response specificity was assessed using information theory, specifically response entropy. Vestibular activation significantly modulated phosphene response entropy for V5/MT but not EVC, implying a specific vestibular effect on V5/MT responses. This is the first demonstration that vestibular activation modulates human visual cortex excitability. Furthermore, using information theory, not previously used in phosphene response analysis, we could distinguish between a specific vestibular modulation of V5/MT excitability from a nonspecific effect at EVC. PMID:22291031

  5. Efficacy Coefficients Determined Using Nail Permeability and Antifungal Activity in Keratin-Containing Media Are Useful for Predicting Clinical Efficacies of Topical Drugs for Onychomycosis.

    Yoshiki Matsuda

    Full Text Available Onychomycosis is difficult to treat topically due to the deep location of the infection under the densely keratinized nail plate. In order to obtain an in vitro index that is relevant to the clinical efficacy of topical anti-onychomycosis drugs, we profiled five topical drugs: amorolfine, ciclopirox, efinaconazole, luliconazole, and terbinafine, for their nail permeabilities, keratin affinities, and anti-dermatophytic activities in the presence of keratin. Efinaconazole and ciclopirox permeated full-thickness human nails more deeply than luliconazole. Amorolfine and terbinafine did not show any detectable permeation. The free-drug concentration of efinaconazole in a 5% human nail keratin suspension was 24.9%, which was significantly higher than those of the other drugs (1.1-3.9%. Additionally, efinaconazole was released from human nail keratin at a greater proportion than the other drugs. The MICs of the five drugs for Trichophyton rubrum were determined at various concentrations of keratin (0-20% in RPMI 1640 medium. The MICs of ciclopirox were not affected by keratin, whereas those of efinaconazole were slightly increased and those of luliconazole and terbinafine were markedly increased in the presence of 20% keratin. Efficacy coefficients were calculated using the nail permeation flux and MIC in media without or with keratin. Efinaconazole showed the highest efficacy coefficient, which was determined using MIC in media with keratin. The order of efficacy coefficients determined using MIC in keratin-containing media rather than keratin-free media was consistent with that of complete cure rates in previously reported clinical trials. The present study revealed that efficacy coefficients determined using MIC in keratin-containing media are useful for predicting the clinical efficacies of topical drugs. In order to be more effective, topical drugs have to possess higher efficacy coefficients.

  6. Efficacy Coefficients Determined Using Nail Permeability and Antifungal Activity in Keratin-Containing Media Are Useful for Predicting Clinical Efficacies of Topical Drugs for Onychomycosis.

    Matsuda, Yoshiki; Sugiura, Keita; Hashimoto, Takashi; Ueda, Akane; Konno, Yoshihiro; Tatsumi, Yoshiyuki

    2016-01-01

    Onychomycosis is difficult to treat topically due to the deep location of the infection under the densely keratinized nail plate. In order to obtain an in vitro index that is relevant to the clinical efficacy of topical anti-onychomycosis drugs, we profiled five topical drugs: amorolfine, ciclopirox, efinaconazole, luliconazole, and terbinafine, for their nail permeabilities, keratin affinities, and anti-dermatophytic activities in the presence of keratin. Efinaconazole and ciclopirox permeated full-thickness human nails more deeply than luliconazole. Amorolfine and terbinafine did not show any detectable permeation. The free-drug concentration of efinaconazole in a 5% human nail keratin suspension was 24.9%, which was significantly higher than those of the other drugs (1.1-3.9%). Additionally, efinaconazole was released from human nail keratin at a greater proportion than the other drugs. The MICs of the five drugs for Trichophyton rubrum were determined at various concentrations of keratin (0-20%) in RPMI 1640 medium. The MICs of ciclopirox were not affected by keratin, whereas those of efinaconazole were slightly increased and those of luliconazole and terbinafine were markedly increased in the presence of 20% keratin. Efficacy coefficients were calculated using the nail permeation flux and MIC in media without or with keratin. Efinaconazole showed the highest efficacy coefficient, which was determined using MIC in media with keratin. The order of efficacy coefficients determined using MIC in keratin-containing media rather than keratin-free media was consistent with that of complete cure rates in previously reported clinical trials. The present study revealed that efficacy coefficients determined using MIC in keratin-containing media are useful for predicting the clinical efficacies of topical drugs. In order to be more effective, topical drugs have to possess higher efficacy coefficients. PMID:27441843

  7. Engineering a hyper-catalytic enzyme by photo-activated conformation modulation

    Agarwal, Pratul K [ORNL

    2012-01-01

    Enzyme engineering for improved catalysis has wide implications. We describe a novel chemical modification of Candida antarctica lipase B that allows modulation of the enzyme conformation to promote catalysis. Computational modeling was used to identify dynamical enzyme regions that impact the catalytic mechanism. Surface loop regions located distal to active site but showing dynamical coupling to the reaction were connected by a chemical bridge between Lys136 and Pro192, containing a derivative of azobenzene. The conformational modulation of the enzyme was achieved using two sources of light that alternated the azobenzene moiety in cis and trans conformations. Computational model predicted that mechanical energy from the conformational fluctuations facilitate the reaction in the active-site. The results were consistent with predictions as the activity of the engineered enzyme was found to be enhanced with photoactivation. Preliminary estimations indicate that the engineered enzyme achieved 8-52 fold better catalytic activity than the unmodulated enzyme.

  8. Novel Active Bouncer Topology for Klystron Modulators based on Pulsed Transformers

    AUTHOR|(CDS)2079689; Aguglia, Davide; Viarouge, Philippe; Cros, Jérôme

    2015-01-01

    Active droop compensation systems, so called active bouncers, for klystron modulators based on monolithic pulse transformers perform the regulation of the output pulse voltage while simultaneously withstand all the primary current of the modulator. This imposes the utilization of high power semiconductors which can produce high switching losses and degrade the overall system efficiency. In order to overcome this issue, this paper proposes a new active bouncer topology based on the parallel connection of two different power converters: the first one is in charge of handling the majority of the primary current at high efficiency, and the second one is used to fine tune the bouncer voltage via a high bandwidth converter rated at a fraction of the first parallel connected converter. Detailed comparison between a classical active bouncer and two variants of the proposed topology are presented and based on numerical simulations.

  9. Dopamine Modulates Reward System Activity During Subconscious Processing of Sexual Stimuli

    Oei, Nicole Y. L.; Rombouts, Serge ARB; Soeter, Roelof P.; van Gerven, Joop M; Both, Stephanie

    2012-01-01

    Dopaminergic medication influences conscious processing of rewarding stimuli, and is associated with impulsive–compulsive behaviors, such as hypersexuality. Previous studies have shown that subconscious subliminal presentation of sexual stimuli activates brain areas known to be part of the ‘reward system'. In this study, it was hypothesized that dopamine modulates activation in key areas of the reward system, such as the nucleus accumbens, during subconscious processing of sexual stimuli. You...

  10. Human immunodeficiency virus-1 gp120 and gp160 envelope proteins modulate mesangial cell gelatinolytic activity.

    Singhal, P. C.; Sagar, S.; D. Chandra; Garg, P

    1995-01-01

    Patients with human immunodeficiency virus (HIV) infection often develop glomerular lesions (mesangial expansion and sclerosis). Modulation of matrix degradation may be important in the expansion of the mesangium. We studied the effect of HIV sera and HIV-1 envelope glycoproteins on gelatinolytic activity of human mesangial cells. HIV serum-treated cells showed lower (P < 0.01) gelatinolytic activity when compared with cells treated with control serum (control serum, 4.3 +/- 0.1 versus HIV se...

  11. Identification of Functionally Relevant Lysine Residues That Modulate Human Farnesoid X Receptor Activation

    Sun, An-Qiang; Luo, Yuhuan; Backos, Donald S.; Xu, Shuhua; Balasubramaniyan, Natarajan; Reigan, Philip; Suchy, Frederick J.

    2013-01-01

    Base amino acid lysine residues play an important role in regulation of nuclear receptors [e.g., farnesyl X receptor (FXR)], leading to enhanced or suppressed biologic activity. To understand the molecular mechanisms and the subsequent effects in modulating FXR functions in diverse biologic processes, we individually replaced eight highly conserved lysine residues of human FXR (hFXR) with arginine. The effects of each mutated FXR on target gene activation, subcellular localization, protein-pr...

  12. Noradrenergic Activation of the Basolateral Amygdala Modulates Consolidation of Object Recognition Memory

    Roozendaal, Benno; Castello, Nicholas A.; Vedana, Gustavo; Barsegyan, Areg; McGaugh, James L.

    2008-01-01

    Noradrenergic activation of the basolateral complex of the amygdala (BLA) modulates the consolidation of memory for many kinds of highly emotionally arousing training tasks. The present experiments investigated whether posttraining noradrenergic activation of the BLA is sufficient to enable memory consolidation of a low-arousing training experience. Sprague-Dawley rats received intra-BLA infusions of norepinephrine, the β-adrenoceptor antagonist propranolol or saline immediately after either ...

  13. Copper modulates the phenotypic response of activated BV2 microglia through the release of nitric oxide

    Rossi-George, Alba; GUO, CHANG-JIANG; Oakes, Benjamin L.; Gow, Andrew J.

    2012-01-01

    Microglia are resident immune cells of the central nervous system. Their persistent activation in neurodegenerative diseases, traditionally attributed to neuronal dysfunction, may be due to a microglial failure to modulate the release of cytotoxic mediators such as nitric oxide (NO). The persistent activation of microglia with the subsequent release of NO vis-á-vis the accumulation of redox transition metals such as copper (Cu) in neurodegenerative diseases, prompted the hypothesis that coppe...

  14. Cardiotoxicity of acetogenins from Persea americana occurs through the mitochondrial permeability transition pore and caspase-dependent apoptosis pathways.

    Silva-Platas, Christian; García, Noemí; Fernández-Sada, Evaristo; Dávila, Daniel; Hernández-Brenes, Carmen; Rodríguez, Dariana; García-Rivas, Gerardo

    2012-08-01

    Acetogenins are cell-membrane permeable, naturally occurring secondary metabolites of plants such as Annonaceae, Lauraceae and other related phylogenic families. They belong to the chemical derivatives of polyketides, which are synthesized from fatty acid precursors. Although acetogenins have displayed diverse biological activities, the anti-proliferative effect on human cancer cells has been widely reported. Acetogenins are inhibitors of complex I in the electron transport chain therefore they interrupt ATP synthesis in mitochondria. We tested a new acetogenins-enriched extract from the seed of Persea americana in order to investigate if any toxicity was induced on cardiac tissue and determine the involved mechanism. In isolated perfused heart we found that contractility was completely inhibited at an accumulative dose of 77 μg/ml. In isolated cardiomyocytes, the acetogenins-enriched extract induced apoptosis through the activation of the intrinsic pathway at 43 μg/ml. In isolated mitochondria, it inhibited complex I activity on NADH-linked respiration, as would be expected, but also induced permeability transition on succinate-linked respiration. Cyclosporine A, a known blocker of permeability transition, significantly prevented the permeability transition triggered by the acetogenins-enriched extract. In addition, our acetogenins-enriched extract inhibited ADP/ATP exchange, suggesting that an important element in phosphate or adenylate transport was affected. In this manner we suggest that acetogenins-enriched extract from Persea americana could directly modulate permeability transition, an entity not yet associated with the acetogenins' direct effects, resulting in cardiotoxicity. PMID:22733015

  15. Plasmonic modulator optimized by patterning of active layer and tuning permittivity

    Babicheva, Viktoriia; Lavrinenko, Andrei

    2012-01-01

    -dimension periodic stripes increases transmittance through the device and keeps the modulator's performance at the same level. The dependence on the pattern size and filling factor of the active material is analyzed and optimum parameters are found. Patterned ITO layers allow us to design a Bragg grating inside the...... waveguide. The grating can be turned on and off, thus modulating reflection from the structure. The considered structure with electrical control possesses a high performance and can efficiently work as a plasmonic component in nanophotonic architectures....

  16. Projective Synchronization in Modulated Time-Delayed Chaotic Systems Using an Active Control Approach

    Projective synchronization in modulated time-delayed systems is studied by applying an active control method. Based on the Lyapunov asymptotical stability theorem, the controller and sufficient condition for projective synchronization are calculated analytically. We give a general method with which we can achieve projective synchronization in modulated time-delayed chaotic systems. This method allows us to adjust the desired scaling factor arbitrarily. The effectiveness of our method is confirmed by using the famous delay-differential equations related to optical bistable or hybrid optical bistable devices. Numerical simulations fully support the analytical approach. (general)

  17. Bicarbonate and Ca(2+) Sensing Modulators Activate Photoreceptor ROS-GC1 Synergistically.

    Duda, Teresa; Pertzev, Alexandre; Makino, Clint L; Sharma, Rameshwar K

    2016-01-01

    Photoreceptor ROS-GC1, a prototype subfamily member of the membrane guanylate cyclase family, is a central component of phototransduction. It is a single transmembrane-spanning protein, composed of modular blocks. In rods, guanylate cyclase activating proteins (GCAPs) 1 and 2 bind to its juxtamembrane domain (JMD) and the C-terminal extension, respectively, to accelerate cyclic GMP synthesis when Ca(2+) levels are low. In cones, the additional expression of the Ca(2+)-dependent guanylate cyclase activating protein (CD-GCAP) S100B which binds to its C-terminal extension, supports acceleration of cyclic GMP synthesis at high Ca(2+) levels. Independent of Ca(2+), ROS-GC1 activity is also stimulated directly by bicarbonate binding to the core catalytic domain (CCD). Several enticing molecular features of this transduction system are revealed in the present study. In combination, bicarbonate and Ca(2+)-dependent modulators raised maximal ROS-GC activity to levels that exceeded the sum of their individual effects. The F(514)S mutation in ROS-GC1 that causes blindness in type 1 Leber's congenital amaurosis (LCA) severely reduced basal ROS-GC1 activity. GCAP2 and S100B Ca(2+) signaling modes remained functional, while the GCAP1-modulated mode was diminished. Bicarbonate nearly restored basal activity as well as GCAP2- and S100B-stimulated activities of the F(514)S mutant to normal levels but could not resurrect GCAP1 stimulation. We conclude that GCAP1 and GCAP2 forge distinct pathways through domain-specific modules of ROS-GC1 whereas the S100B and GCAP2 pathways may overlap. The synergistic interlinking of bicarbonate to GCAPs- and S100B-modulated pathways intensifies and tunes the dependence of cyclic GMP synthesis on intracellular Ca(2+). Our study challenges the recently proposed GCAP1 and GCAP2 "overlapping" phototransduction model (Peshenko et al., 2015b). PMID:26858600

  18. Performance Evaluation of a High Bandwidth Liquid Fuel Modulation Valve for Active Combustion Control

    Saus, Joseph R.; DeLaat, John C.; Chang, Clarence T.; Vrnak, Daniel R.

    2012-01-01

    At the NASA Glenn Research Center, a characterization rig was designed and constructed for the purpose of evaluating high bandwidth liquid fuel modulation devices to determine their suitability for active combustion control research. Incorporated into the rig s design are features that approximate conditions similar to those that would be encountered by a candidate device if it were installed on an actual combustion research rig. The characterized dynamic performance measures obtained through testing in the rig are planned to be accurate indicators of expected performance in an actual combustion testing environment. To evaluate how well the characterization rig predicts fuel modulator dynamic performance, characterization rig data was compared with performance data for a fuel modulator candidate when the candidate was in operation during combustion testing. Specifically, the nominal and off-nominal performance data for a magnetostrictive-actuated proportional fuel modulation valve is described. Valve performance data were collected with the characterization rig configured to emulate two different combustion rig fuel feed systems. Fuel mass flows and pressures, fuel feed line lengths, and fuel injector orifice size was approximated in the characterization rig. Valve performance data were also collected with the valve modulating the fuel into the two combustor rigs. Comparison of the predicted and actual valve performance data show that when the valve is operated near its design condition the characterization rig can appropriately predict the installed performance of the valve. Improvements to the characterization rig and accompanying modeling activities are underway to more accurately predict performance, especially for the devices under development to modulate fuel into the much smaller fuel injectors anticipated in future lean-burning low-emissions aircraft engine combustors.

  19. Leishmania amazonensis: PKC-like protein kinase modulates the (Na++K+)ATPase activity.

    Almeida-Amaral, Elmo Eduardo de; Caruso-Neves, Celso; Lara, Lucienne Silva; Pinheiro, Carla Mônica; Meyer-Fernandes, José Roberto

    2007-08-01

    The present study aimed to identify the presence of protein kinase C-like (PKC-like) in Leishmania amazonensis and to elucidate its possible role in the modulation of the (Na(+)+K(+))ATPase activity. Immunoblotting experiments using antibody against a consensus sequence (Ac 543-549) of rabbit protein kinase C (PKC) revealed the presence of a protein kinase of 80 kDa in L. amazonensis. Measurements of protein kinase activity showed the presence of both (Ca(2+)-dependent) and (Ca(2+)-independent) protein kinase activity in plasma membrane and cytosol. Phorbol ester (PMA) activation of the Ca(2+)-dependent protein kinase stimulated the (Na(+)+K(+))ATPase activity, while activation of the Ca(2+)-independent protein kinase was inhibitory. Both effects of protein kinase on the (Na(+)+K(+))ATPase of the plasma membrane were lower than that observed in intact cells. PMA induced the translocation of protein kinase from cytosol to plasma membrane, indicating that the maximal effect of protein kinase on the (Na(+)+K(+))ATPase activity depends on the synergistic action of protein kinases from both plasma membrane and cytosol. This is the first demonstration of a protein kinase activated by PMA in L. amazonensis and the first evidence for a possible role in the regulation of the (Na(+)+K(+))ATPase activity in this trypanosomatid. Modulation of the (Na(+)+K(+))ATPase by protein kinase in a trypanosomatid opens up new possibilities to understand the regulation of ion homeostasis in this parasite. PMID:17475255

  20. Vascular permeability modulation and isolated perfused microvessel approach%血管通透性的调节和游离微血管技术在其研究中的应用

    王述昀; 赵克森

    2005-01-01

    Vascular hyperpermeability is a cardinal feature of inflammation or bum in which an array of inflammatory mediators can cause such changes in the microvessels. The fimctional measures of microvascular exchange that represent the properties of microvascular wails are the permeability coefficients which have been reported from measurements on intact whole organisms (including human subjects}, on perfused tissues and organs, on single perfused microvessels, and on monolayers of cultured microvascular endothelial cells. In this review, we summarize some experiments of vascular permeability in individually isolated perfused microvessels.

  1. Improved prognostic classification of breast cancer defined by antagonistic activation patterns of immune response pathway modules

    Elucidating the activation pattern of molecular pathways across a given tumour type is a key challenge necessary for understanding the heterogeneity in clinical response and for developing novel more effective therapies. Gene expression signatures of molecular pathway activation derived from perturbation experiments in model systems as well as structural models of molecular interactions ('model signatures') constitute an important resource for estimating corresponding activation levels in tumours. However, relatively few strategies for estimating pathway activity from such model signatures exist and only few studies have used activation patterns of pathways to refine molecular classifications of cancer. Here we propose a novel network-based method for estimating pathway activation in tumours from model signatures. We find that although the pathway networks inferred from cancer expression data are highly consistent with the prior information contained in the model signatures, that they also exhibit a highly modular structure and that estimation of pathway activity is dependent on this modular structure. We apply our methodology to a panel of 438 estrogen receptor negative (ER-) and 785 estrogen receptor positive (ER+) breast cancers to infer activation patterns of important cancer related molecular pathways. We show that in ER negative basal and HER2+ breast cancer, gene expression modules reflecting T-cell helper-1 (Th1) and T-cell helper-2 (Th2) mediated immune responses play antagonistic roles as major risk factors for distant metastasis. Using Boolean interaction Cox-regression models to identify non-linear pathway combinations associated with clinical outcome, we show that simultaneous high activation of Th1 and low activation of a TGF-beta pathway module defines a subtype of particularly good prognosis and that this classification provides a better prognostic model than those based on the individual pathways. In ER+ breast cancer, we find that

  2. Is Brain Activity during Action Observation Modulated by the Perceived Fairness of the Actor?

    Joset A Etzel

    Full Text Available Perceiving other people's actions triggers activity in premotor and parietal areas, brain areas also involved in executing and sensing our own actions. Paralleling this phenomenon, observing emotional states (including pain in others is associated with activity in the same brain areas as activated when experiencing similar emotions directly. This emotion perception associated activity has been shown to be affected by the perceived fairness of the actor, and in-group membership more generally. Here, we examine whether action observation associated brain activity is also affected by the perceived social fairness of the actors. Perceived fairness was manipulated using an alternating iterated Prisoner's Dilemma game between the participant and two confederates, one of whom played fairly and the other unfairly. During fMRI scanning the participants watched movies of the confederates performing object-directed hand actions, and then performed hand actions themselves. Mass-univariate analysis showed that observing the actions triggered robust activation in regions associated with action execution, but failed to identify a strong modulation of this activation based on perceived fairness. Multivariate pattern analysis, however, identified clusters potentially carrying information about the perceived fairness of the actor in the middle temporal gyrus, left postcentral gyrus, right inferior parietal lobule, right middle cingulate cortex, right angular gyrus, and right superioroccipital gyrus. Despite being identified by a whole-brain searchlight analysis (and so without anatomical restriction, these clusters fall into areas frequently associated with action observation. We conclude that brain activity during action observation may be modulated by perceived fairness, but such modulation is subtle; robust activity is associated with observing the actions of both fair and unfair individuals.

  3. Is Brain Activity during Action Observation Modulated by the Perceived Fairness of the Actor?

    Etzel, Joset A; Valchev, Nikola; Gazzola, Valeria; Keysers, Christian

    2016-01-01

    Perceiving other people's actions triggers activity in premotor and parietal areas, brain areas also involved in executing and sensing our own actions. Paralleling this phenomenon, observing emotional states (including pain) in others is associated with activity in the same brain areas as activated when experiencing similar emotions directly. This emotion perception associated activity has been shown to be affected by the perceived fairness of the actor, and in-group membership more generally. Here, we examine whether action observation associated brain activity is also affected by the perceived social fairness of the actors. Perceived fairness was manipulated using an alternating iterated Prisoner's Dilemma game between the participant and two confederates, one of whom played fairly and the other unfairly. During fMRI scanning the participants watched movies of the confederates performing object-directed hand actions, and then performed hand actions themselves. Mass-univariate analysis showed that observing the actions triggered robust activation in regions associated with action execution, but failed to identify a strong modulation of this activation based on perceived fairness. Multivariate pattern analysis, however, identified clusters potentially carrying information about the perceived fairness of the actor in the middle temporal gyrus, left postcentral gyrus, right inferior parietal lobule, right middle cingulate cortex, right angular gyrus, and right superioroccipital gyrus. Despite being identified by a whole-brain searchlight analysis (and so without anatomical restriction), these clusters fall into areas frequently associated with action observation. We conclude that brain activity during action observation may be modulated by perceived fairness, but such modulation is subtle; robust activity is associated with observing the actions of both fair and unfair individuals. PMID:26820995

  4. Hand modulation of visual, preparatory, and saccadic activity in the monkey frontal eye field.

    Thura, David; Hadj-Bouziane, Fadila; Meunier, Martine; Boussaoud, Driss

    2011-04-01

    Behavioral studies have shown that hand position influences saccade characteristics. This study examined the neuronal changes that could underlie this behavioral observation. Single neurons were recorded in the frontal eye field (FEF) of 2 monkeys as they executed a visually guided saccade task, while holding their hand at given locations on a touch screen. The task was performed with the hand either visible or invisible, in order to assess the relative contribution of visual and proprioceptive information on hand position. Among the 224 neurons tested, the visual, saccadic and/or preparatory activity of more than half of them was modulated by hand position, whether the hand was visible or invisible. Comparison of lower (hand's workspace) and upper (out of reach) visual targets showed that hand modulation was predominant in the hand's workspace. Finally, some cells preferred congruency of hand and target in space, others preferred incongruency. Interestingly, hand modulation of saccadic activity correlated with hand position effects on saccade reaction times. We conclude that visual and proprioceptive signals derived from the hand are integrated by FEF neurons. These signals can modulate target selection through attention and allow the oculomotor system to use hand-related somatosensory signals for the initiation of visually guided saccades. PMID:20713503

  5. Projective Synchronization in Modulated Time-Delayed Chaotic Systems Using an Active Control Approach

    冯存芳; 汪映海

    2011-01-01

    Projective synchronization in modulated time-delayed systems is studied by applying an active control method. Based on the Lyapunov asymptotical stability theorem, the controller and sufficient condition for projective synchronization are calculated analytically. We give a genera./ method with which we can achieve projective synchronization in modulated time-delayed chaotic systems. This method allows us to adjust the desired scaling factor arbitrarily. The effectiveness of our method is confirmed by using the famous delay-differential equations related to optical bistable or hybrid optical bistable devices. Numerical simulations fully support the analytical approach.%Projective synchronization in modulated time-delayed systems is studied by applying an active control method.Based on the Lyapunov asymptotical stability theorem,the controller and sufficient condition for projective synchronization are calculated analytically.We give a general method with which we can achieve projective synchronization in modulated time-delayed chaotic systems.This method allows us to adjust the desired scaling factor arbitrarily.The effectiveness of our method is confirmed by using the famous delay-differential equations related to optical bistable or hybrid optical bistable devices.Numerical simulations fully support the analytical approach.

  6. Activation Characteristics of Fuel Breeding Blanket Module in Fusion Driven Subcritical System

    HUANG Qun-Ying; LI Jian-Gang; CHEN Yi-Xue

    2004-01-01

    @@ Shortage of energy resources and production of long-lived radioactivity wastes from fission reactors are among the main problems which will be faced in the world in the near future. The conceptual design of a fusion driven subcritical system (FDS) is underway in Institute of Plasma Physics, Chinese Academy of Sciences. There are alternative designs for multi-functional blanket modules of the FDS, such as fuel breeding blanket module (FBB)to produce fuels for fission reactors, tritium breeding blanket module to produce the fuel, i.e. tritium, for fusion reactor and waste transmutation blanket module to try to permanently dispose of long-lived radioactivity wastes from fission reactors, etc. Activation of the fuel breeding blanket of the fusion driven subcritical system (FDS-FBB) by D-T fusion neutrons from the plasma and fission neutrons from the hybrid blanket are calculated and analysed under the neutron wall loading 0.5 MW/m2 and neutron fluence 15 MW. yr/m2. The neutron spectrum is calculated with the worldwide-used transport code MCNP/4C and activation calculations are carried out with the well known European inventory code FISPACT/99 with the latest released IAEA Fusion Evaluated Nuclear Data Library FENDL-2.0 and the ENDF/B-V uranium evaluated data. Induced radioactivities, dose rates and afterheats, etc, for different components of the FDS-FBB are compared and analysed.

  7. The skin migratory stage of the schistosomulum of Schistosoma mansoni has a surface showing greater permeability and activity in membrane internalisation than other forms of skin or mechanical schistosomula.

    DE Jesus Jeremias, Wander; DA Cunha Melo, Jose Renan; Baba, Elio Hideo; Coelho, Paulo Marcos Zech; Kusel, John Robert

    2015-08-01

    Skin schistosomula can be prepared by collecting them after isolated mouse skin have been penetrated by cercariae in vitro. The schistosomula can also migrate out of isolated mouse skin penetrated by cercariae in vitro and from mouse skin penetrated by cercariae in vivo. Schistosomula can also be produced from cercariae applied through a syringe or in a vortex. When certain surface properties of the different forms of schistosomula were compared, those migrating from mouse skin penetrated by cercariae in vivo or in vitro had greatly increased permeability to membrane impermeant molecules such as Lucifer yellow and high molecular weight dextrans. These migrating forms also possessed surfaces which showed greatly enhanced uptake into internal membrane vesicles of the dye FM 143, a marker for endocytosis. This greatly enhanced activity and permeability of the surfaces of tissue migrating schistosomula is likely to be of great importance in the adaptation to the new host. PMID:26028506

  8. Screening and characterization of molecules that modulate the biological activity of IFNs-I.

    Bürgi, Milagros; Zapol'skii, Viktor A; Hinkelmann, Bettina; Köster, Mario; Kaufmann, Dieter E; Sasse, Florenz; Hauser, Hansjörg; Etcheverrigaray, Marina; Kratje, Ricardo; Bollati-Fogolín, Mariela; Oggero, Marcos

    2016-09-10

    Type I Interferons (IFNs-I) are species-specific glycoproteins which play an important role as primary defence against viral infections and that can also modulate the adaptive immune system. In some autoimmune diseases, interferons (IFNs) are over-produced. IFNs are widely used as biopharmaceuticals for a variety of cancer indications, chronic viral diseases, and for their immuno-modulatory action in patients with multiple sclerosis; therefore, increasing their therapeutic efficiency and decreasing their side effects is of high clinical value. In this sense, it is interesting to find molecules that can modulate the activity of IFNs. In order to achieve that, it was necessary to establish a simple, fast and robust assay to analyze numerous compounds simultaneously. We developed four reporter gene assays (RGAs) to identify IFN activity modulator compounds by using WISH-Mx2/EGFP, HeLa-Mx2/EGFP, A549-Mx2/EGFP, and HEp2-Mx2/EGFP reporter cell lines (RCLs). All of them present a Z' factor higher than 0.7. By using these RGAs, natural and synthetic compounds were analyzed simultaneously. A total of 442 compounds were studied by the Low Throughput Screening (LTS) assay using the four RCLs to discriminate between their inhibitory or enhancing effects on IFN activity. Some of them were characterized and 15 leads were identified. Finally, one promising candidate with enhancing effect on IFN-α/-β activity and five compounds with inhibitory effect were described. PMID:27346232

  9. Insights into structure-activity relationship of GABAA receptor modulating coumarins and furanocoumarins.

    Singhuber, Judith; Baburin, Igor; Ecker, Gerhard F; Kopp, Brigitte; Hering, Steffen

    2011-10-01

    The coumarins imperatorin and osthole are known to exert anticonvulsant activity. We have therefore analyzed the modulation of GABA-induced chloride currents (I(GABA)) by a selection of 18 coumarin derivatives on recombinant α(1)β(2)γ(2S) GABA(A) receptors expressed in Xenopus laevis oocytes by means of the two-microelectrode voltage clamp technique. Osthole (EC(50)=14 ± 1 μM) and oxypeucedanin (EC(50)=25 ± 8 μM) displayed the highest efficiency with I(GABA) potentiation of 116 ± 4 % and 547 ± 56 %, respectively. I(GABA) enhancement by osthole and oxypeucedanin was not inhibited by flumazenil (1 μM) indicating an interaction with a binding site distinct from the benzodiazepine binding site. In general, prenyl residues are essential for the positive modulatory activity, while longer side chains or bulkier residues (e.g. geranyl residues) diminish I(GABA) modulation. Generation of a binary classification tree revealed the importance of polarisability, which is sufficient to distinguish actives from inactives. A 4-point pharmacophore model based on oxypeucedanin - comprising three hydrophobic and one aromatic feature - identified 6 out of 7 actives as hits. In summary, (oxy-)prenylated coumarin derivatives from natural origin represent new GABA(A) receptor modulators. PMID:21749864

  10. Functional insights into modulation of BKCa channel activity to alter myometrial contractility

    RamónALorca

    2014-07-01

    Full Text Available The large-conductance voltage- and Ca2+-activated K+ channel (BKCa is an important regulator of membrane excitability in a wide variety of cells and tissues. In myometrial smooth muscle, activation of BKCa plays essential roles in buffering contractility to maintain uterine quiescence during pregnancy and in the transition to a more contractile state at the onset of labor. Multiple mechanisms of modulation have been described to alter BKCa channel activity, expression, and cellular localization. In the myometrium, BKCa is regulated by alternative splicing, protein targeting to the plasma membrane, compartmentation in membrane microdomains, and posttranslational modifications. In addition, interaction with auxiliary proteins (i.e., β1- and β2-subunits, association with G-protein coupled receptor signaling pathways, such as those activated by adrenergic and oxytocin receptors, and hormonal regulation provide further mechanisms of variable modulation of BKCa channel function in myometrial smooth muscle. Here, we provide an overview of these mechanisms of BKCa channel modulation and provide a context for them in relation to myometrial function.

  11. Ablation of MMP9 gene ameliorates paracellular permeability and fibrinogen-amyloid beta complex formation during hyperhomocysteinemia.

    Muradashvili, Nino; Tyagi, Reeta; Metreveli, Naira; Tyagi, Suresh C; Lominadze, David

    2014-09-01

    Increased blood level of homocysteine (Hcy), called hyperhomocysteinemia (HHcy) accompanies many cognitive disorders including Alzheimer's disease. We hypothesized that HHcy-enhanced cerebrovascular permeability occurs via activation of matrix metalloproteinase-9 (MMP9) and leads to an increased formation of fibrinogen-β-amyloid (Fg-Aβ) complex. Cerebrovascular permeability changes were assessed in C57BL/6J (wild type, WT), cystathionine-β-synthase heterozygote (Cbs+/-, a genetic model of HHcy), MMP9 gene knockout (Mmp9-/-), and Cbs and Mmp9 double knockout (Cbs+/-/Mmp9-/-) mice using a dual-tracer probing method. Expression of vascular endothelial cadherin (VE-cadherin) and Fg-Aβ complex formation was assessed in mouse brain cryosections by immunohistochemistry. Short-term memory of mice was assessed with a novel object recognition test. The cerebrovascular permeability in Cbs+/- mice was increased via mainly the paracellular transport pathway. VE-cadherin expression was the lowest and Fg-Aβ complex formation was the highest along with the diminished short-term memory in Cbs+/- mice. These effects of HHcy were ameliorated in Cbs+/-/Mmp9-/- mice. Thus, HHcy causes activation of MMP9 increasing cerebrovascular permeability by downregulation of VE-cadherin resulting in an enhanced formation of Fg-Aβ complex that can be associated with loss of memory. These data may lead to the identification of new targets for therapeutic intervention that can modulate HHcy-induced cerebrovascular permeability and resultant pathologies. PMID:24865997

  12. Erythropoietin Modulates Cerebral and Serum Degradation Products from Excess Calpain Activation following Prenatal Hypoxia-Ischemia.

    Jantzie, Lauren L; Winer, Jesse L; Corbett, Christopher J; Robinson, Shenandoah

    2016-01-01

    Preterm infants suffer central nervous system (CNS) injury from hypoxia-ischemia and inflammation - termed encephalopathy of prematurity. Mature CNS injury activates caspase and calpain proteases. Erythropoietin (EPO) limits apoptosis mediated by activated caspases, but its role in modulating calpain activation has not yet been investigated extensively following injury to the developing CNS. We hypothesized that excess calpain activation degrades developmentally regulated molecules essential for CNS circuit formation, myelination and axon integrity, including neuronal potassium-chloride co-transporter (KCC2), myelin basic protein (MBP) and phosphorylated neurofilament (pNF), respectively. Further, we predicted that post-injury EPO treatment could mitigate CNS calpain-mediated degradation. Using prenatal transient systemic hypoxia-ischemia (TSHI) in rats to mimic CNS injury from extreme preterm birth, and postnatal EPO treatment with a clinically relevant dosing regimen, we found sustained postnatal excess cortical calpain activation following prenatal TSHI, as shown by the cleavage of alpha II-spectrin (αII-spectrin) into 145-kDa αII-spectrin degradation products (αII-SDPs) and p35 into p25. Postnatal expression of the endogenous calpain inhibitor calpastatin was also reduced following prenatal TSHI. Calpain substrate expression following TSHI, including cortical KCC2, MBP and NF, was modulated by postnatal EPO treatment. Calpain activation was reflected in serum levels of αII-SDPs and KCC2 fragments, and notably, EPO treatment also modulated KCC2 fragment levels. Together, these data indicate that excess calpain activity contributes to the pathogenesis of encephalopathy of prematurity. Serum biomarkers of calpain activation may detect ongoing cerebral injury and responsiveness to EPO or similar neuroprotective strategies. PMID:26551007

  13. Positive affect modulates activity in the visual cortex to images of high calorie foods.

    Killgore, William D S; Yurgelun-Todd, Deborah A

    2007-05-01

    Activity within the visual cortex can be influenced by the emotional salience of a stimulus, but it is not clear whether such cortical activity is modulated by the affective status of the individual. This study used functional magnetic resonance imaging (fMRI) to examine the relationship between affect ratings on the Positive and Negative Affect Schedule and activity within the occipital cortex of 13 normal-weight women while viewing images of high calorie and low calorie foods. Regression analyses revealed that when participants viewed high calorie foods, Positive Affect correlated significantly with activity within the lingual gyrus and calcarine cortex, whereas Negative Affect was unrelated to visual cortex activity. In contrast, during presentations of low calorie foods, affect ratings, regardless of valence, were unrelated to occipital cortex activity. These findings suggest a mechanism whereby positive affective state may affect the early stages of sensory processing, possibly influencing subsequent perceptual experience of a stimulus. PMID:17464782

  14. Development of active edge pixel sensors and four-side buttable modules using vertical integration technologies

    Macchiolo, A; Moser, H-G; Nisius, R; Richter, R H; Terzo, S; Weigell, P

    2014-01-01

    We present an R&D activity focused on the development of novel modules for the upgrade of the ATLAS pixel system at the High Luminosity LHC (HL-LHC). The modules consist of n-in-p pixel sensors, 100 or 200 $\\mu$m thick, produced at VTT (Finland) with an active edge technology, which considerably reduces the dead area at the periphery of the device. The sensors are interconnected with solder bump-bonding to the ATLAS FE-I3 and FE-I4 read-out chips, and characterized with radioactive sources and beam tests at the CERN-SPS and DESY. The results of these measurements will be discussed for devices before and after irradiation up to a fluence of $5\\times 10^{15}$ \

  15. Aloe vera: Potential candidate in health management via modulation of biological activities.

    Rahmani, Arshad H; Aldebasi, Yousef H; Srikar, Sauda; Khan, Amjad A; Aly, Salah M

    2015-01-01

    Treatment based on natural products is rapidly increasing worldwide due to the affordability and fewer side effects of such treatment. Various plants and the products derived from them are commonly used in primary health treatment, and they play a pivotal role in the treatment of diseases via modulation of biochemical and molecular pathways. Aloe vera, a succulent species, produces gel and latex, plays a therapeutic role in health management through antioxidant, antitumor, and anti-inflammatory activities, and also offers a suitable alternative approach for the treatment of various types of diseases. In this review, we summarize the possible mechanism of action and the therapeutic implications of Aloe vera in health maintenance based on its modulation of various biological activities. PMID:26392709

  16. Permeability measuremens of brazilian Eucalyptus

    Marcio Rogério da Silva; Gilmara de Oliveira Machado; Jay Deiner; Carlito Calil Junior

    2010-01-01

    The permeability of Brazilian Eucalyptus grandis and Eucalyptus citriodora wood was measured in a custom build gas analysis chamber in order to determine which species could be successfully treated with preservatives. Liquid permeability was tested using an emulsion of Neen oil and a control of distillated water. Air was used to test the gas phase permeability. For both Eucalyptus grandis and Eucalyptus citriodora, the longitudinal permeability of gas was shown to be about twice as great as t...

  17. Modulation of the chaperone-like activity of bovine α-crystallin

    Clark, John I.; Huang, Qing-ling

    1996-01-01

    The effects of pantethine, glutathione, and selected chemical reagents on the anti-aggregation activity of α-crystallin was evaluated. Protein aggregation was monitored by light scattering of solutions of denatured βL-crystallin or alcohol dehydrogenase (ADH). The ratios of βL-crystallin/α-crystallin and ADH/α-crystallin were adjusted so that partial inhibition of protein aggregation at 60°C or 37°C, respectively, was observed and modulation of the chaperone ac...

  18. Evaluation of Antibacterial Activity of Aminoglycosides and Modulating the Essential Oil of Cymbopogon citratus (DC.) Stapf

    Tintino, Saulo R.; Lucena, Bruno F. F.; Fernando G. Figueredo; Cícera Datiane de M. OLIVEIRA; José J. DOS S. AGUIAR; Edmilson DO N. CARDOSO; Pedro E. A. DE AQUINO; Jacqueline C. ANDRADE; Coutinho, Henrique D. M.; Ednardo F. F. MATIAS

    2014-01-01

     Several works demonstrated the importance of the study of natural products as an alternative source for new antimicrobial drugs or for modulators for these ones. In this point, the aim of this was to investigate the antibacterial activity and the possible interactions between the essential oil of Cymbopogon citratus alone and in association with aminoglycosides against standard and clinically isolated strains of multidrug-resistant bacteria such as S. aureus, E. coli and P. aeruginosa by mic...

  19. A biased activation theory of the cognitive and attentional modulation of emotion

    Edmund eRolls

    2013-01-01

    Cognition can influence emotion by biasing neural activity in the first cortical region in which the reward value and subjective pleasantness of stimuli is made explicit in the representation, the orbitofrontal cortex. The same effect occurs in a second cortical tier for emotion, the anterior cingulate cortex. Similar effects are found for selective attention, to for example the pleasantness vs the intensity of stimuli, which modulates representations of reward value and affect in the orbitof...

  20. A biased activation theory of the cognitive and attentional modulation of emotion

    Rolls, Edmund T.

    2013-01-01

    Cognition can influence emotion by biasing neural activity in the first cortical region in which the reward value and subjective pleasantness of stimuli is made explicit in the representation, the orbitofrontal cortex (OFC). The same effect occurs in a second cortical tier for emotion, the anterior cingulate cortex (ACC). Similar effects are found for selective attention, to for example the pleasantness vs. the intensity of stimuli, which modulates representations of reward value and affect i...

  1. Respiratory activity in medulla oblongata and its modulation by adenosine and opioids

    Herlenius, Eric

    1998-01-01

    From the moment of birth the complex neuronal networks generating breathing has to function continuously and adapt to the new postnatal environmental demands. This thesis aims at studying the perinatal development of respiratory control and its modulation by adenosine and opioids. Respiratory activity was studied in vitro using brainstem spinal cord preparations and in vivo with a barometric plethysmograph. In vitro whole-cell patch clamp recordings of respiratory related ne...

  2. Multi-Senses Explication Activities Module for Dyslexic Children in Malaysia

    Vijayaletchumy Subramaniam; Vijay Kumar Mallan; Noor Hayati Che Mat

    2013-01-01

    Dyslexic children are having abnormal difficulties in reading, spelling and writing. The awareness on these problems leads researcher to conduct a case study in the psycholinguistic field about the multi-senses explication activities in the words mastery among the dyslexic children in Sekolah Kebangsaan Padang Temu Melaka. Starting from the Information Processing Theory by Robert M. Gagne (1975) as the theoretical framework, this research aims to produce a module on the multi-senses explicati...

  3. Parallel Processing System for Sensory Information Controlled by Mathematical Activation-Input-Modulation Model

    Mikawa, Masahiko; Tsujimura, Takeshi; Tanaka, Kazuyo

    2008-01-01

    We proposed a new architecture for an intelligent perceptual information processing system that has sleep and wake functions, and applied it to an audition and vision system. Plural perceptual information processes and storing processes run in parallel and these processes are controlled by the mathematical Activation-Input-Modulation (AIM) model. The memory architecture consists of a working memory (WM), a short-term memory (STM) and a longterm memory (LTM), that can store environment informa...

  4. Modulation of matrix metalloproteinase activity by EDTA prevents posterior capsular opacification

    Hazra, Sarbani; Guha, Rajdeep; Jongkey, Geram; Palui, Himangshu; Mishra, Akhilesh; Vemuganti, Geeta K; Basak, Samar K; Mandal, Tapan Kumar; Konar, Aditya

    2012-01-01

    Purpose To evaluate the effect of ethylenediaminetetraacetic acid (EDTA) on posterior capsular opacification (PCO) of rabbits and to assess its effect on intraocular tissues. Methods Modulation of matrix metalloproteinase (MMP) activity in the aqueous following cataract surgery in rabbits and its prevention by different doses of EDTA was determined by zymography. For evaluation of PCO, lensectomized rabbits were intracamerally injected with single dose of either 5 mg EDTA or normal saline. Af...

  5. Face gender modulates women’s brain activity during face encoding

    Lovén, Johanna; Svärd, Joakim; Natalie C Ebner; Herlitz, Agneta; Fischer, Håkan

    2013-01-01

    Women typically remember more female than male faces, whereas men do not show a reliable own-gender bias. However, little is known about the neural correlates of this own-gender bias in face recognition memory. Using functional magnetic resonance imaging (fMRI), we investigated whether face gender modulated brain activity in fusiform and inferior occipital gyri during incidental encoding of faces. Fifteen women and 14 men underwent fMRI while passively viewing female and male faces, followed ...

  6. Amperometric NOx-sensor for Combustion Exhaust Gas Control. Studies on transport properties and catalytic activity of oxygen permeable ceramic membranes

    The aim of the research described in this thesis is the development of a mixed conducting oxide layer, which can be used as an oxygen permselective membrane in an amperometric NOx sensor. The sensor will be used in exhaust gas systems. The exhaust gas-producing engine will run in the lean mix mode. The preparation of this sensor is carried out using screen-printing technology, in which the different layers of the sensor are applied successively. Hereafter, a co-firing step is applied in which all layers are sintered together. This co-firing step imposes several demands on the selection of materials. The design specifications of the sensor further include requirements concerning the operating temperature, measurement range and overall stability. The operating temperature of the sensor varies between 700 and 850C, enabling measurement of NOx concentrations between 50 and 1200 ppm with a measurement accuracy of 10 ppm. Concerning the stability of the sensor, it must withstand the exhaust gas atmosphere containing, amongst others, smoke, acids, abrasive particles and sulphur. Because of the chosen lean-mix engine concept, in which the fuel/air mixture switches continuously between lean (excess oxygen) and fat (excess fuel) mixtures, the sensor must withstand alternately oxidising and reducing atmospheres. Besides, it should be resistant to thermal shock and show no cross-sensitivity of NOx with other exhaust gas constituents like oxygen and hydrocarbons. The response time should be short, typically less than 500 ms. Because of the application in combustion engines of cars, the operational lifetime should be longer than 10 years. Demands on the mixed conducting oxide layer include the following ones. The layer should show minimal catalytic activity towards NOx-reduction. The oxygen permeability must be larger than 6.22 10-8 mol/cm2s at a layer thickness between 3-50 μm. Since the mixed conducting oxide layer is coated on the YSZ electrolyte embodiment, the two

  7. Transcranial Direct Current Stimulation Modulates Neuronal Activity and Learning in Pilot Training.

    Choe, Jaehoon; Coffman, Brian A; Bergstedt, Dylan T; Ziegler, Matthias D; Phillips, Matthew E

    2016-01-01

    Skill acquisition requires distributed learning both within (online) and across (offline) days to consolidate experiences into newly learned abilities. In particular, piloting an aircraft requires skills developed from extensive training and practice. Here, we tested the hypothesis that transcranial direct current stimulation (tDCS) can modulate neuronal function to improve skill learning and performance during flight simulator training of aircraft landing procedures. Thirty-two right-handed participants consented to participate in four consecutive daily sessions of flight simulation training and received sham or anodal high-definition-tDCS to the right dorsolateral prefrontal cortex (DLPFC) or left motor cortex (M1) in a randomized, double-blind experiment. Continuous electroencephalography (EEG) and functional near infrared spectroscopy (fNIRS) were collected during flight simulation, n-back working memory, and resting-state assessments. tDCS of the right DLPFC increased midline-frontal theta-band activity in flight and n-back working memory training, confirming tDCS-related modulation of brain processes involved in executive function. This modulation corresponded to a significantly different online and offline learning rates for working memory accuracy and decreased inter-subject behavioral variability in flight and n-back tasks in the DLPFC stimulation group. Additionally, tDCS of left M1 increased parietal alpha power during flight tasks and tDCS to the right DLPFC increased midline frontal theta-band power during n-back and flight tasks. These results demonstrate a modulation of group variance in skill acquisition through an increasing in learned skill consistency in cognitive and real-world tasks with tDCS. Further, tDCS performance improvements corresponded to changes in electrophysiological and blood-oxygenation activity of the DLPFC and motor cortices, providing a stronger link between modulated neuronal function and behavior. PMID:26903841

  8. Indomethacin induces increase in gastric epithelial tight junction permeability via redistribution of occludin and activation of p38 MAPK in MKN-28 Cells.

    Thakre-Nighot, Meghali; Blikslager, Anthony T

    2016-01-01

    Tight Junctions (TJ) create a paracellular barrier that is compromised when nonsteriodal anti-inflammatory drugs (NSAIDs) injure the gastric epithelium, leading to increased permeability. However, the mechanism of NSAID-induced gastric injury is unclear. Here, we examined the effect of indomethacin on barrier function and TJ in gastric MKN-28 cells. In concentration response studies, 500 µm indomethacin induced a significant decrease in transepithelial resistance (TER; 380 vs. 220 Ω·cm(2) for control and indomethacin-treated cells respectively, p permeability by 0.2 vs 1.2 g/l (p permeability. Pretreatment with the p38 MAPK inhibitor significantly attenuated the disruption of barrier function, but JNK and MEK/ERK inhibition had no effect. Western blot analysis on gastric mucosa reveled loss of TJ protein occludin by indomethacin, which was prevented by inhibition of p38 MAPK. This data suggests that indomethacin compromises the gastric epithelial barrier via p38 MAPK inducing occludin alterations in the TJs. PMID:27583191

  9. Biodiesel permeability in polyethylene

    RICHAUD, Emmanuel; FLACONNÈCHE, Bruno; Verdu, Jacques

    2012-01-01

    This paper reports solubility and diffusivity data for soy and rapeseed methyl esters in polyethylene together with comparisons with methyl oleate and linoleate. These data showed that there is no significant difference in diffusivity and solubility between all these penetrants. Data were used to discuss the reliability of predictive models for diffusion and solubility of additive type molecules into semi-crystalline thermoplastic polymers. Permeability data were monitored by a new device, th...

  10. Exploring the scale-dependent permeability of fractured andesite

    Heap, Michael J.; Kennedy, Ben M.

    2016-08-01

    rock (10-12 to 10-11 m2) is essentially unaffected by the presence of numerous tensile fractures. By contrast, a single tensile fracture increases the equivalent permeability of low-permeability rock (volcanic systems. While our laboratory measurements show that, regardless of the initial porosity, the equivalent permeability of fractured rock on the laboratory scale is 2- 6 ×10-11 m2, the equivalent permeability of low-permeability rock is significantly reduced as the scale of interest is increased. Therefore, due to the scale-dependence of permeability, laboratory measurements on pristine, low-permeability rocks significantly underestimate the equivalent permeability of fractured volcanic rock. Further, measurements on fractured rock samples can significantly overestimate the equivalent permeability. As a result, care must be taken when selecting samples in the field and when using laboratory data in volcano outgassing models. The data and modelling presented herein provide insight into the scale-dependence of the permeability of fractured volcanic rock, a prerequisite for understanding outgassing at active volcanoes.

  11. Fast oscillatory activity in the anterior cingulate cortex: dopaminergic modulation and efect of perineuronal net loss

    Pascal eSteullet

    2014-08-01

    Full Text Available Dopamine release in the prefrontal cortex plays a critical role in cognitive function such as working memory, attention and planning. Dopamine exerts complex modulation on excitability of pyramidal neurons and interneurons, and regulates excitatory and inhibitory synaptic transmission. Because of the complexity of this modulation, it is difficult to fully comprehend the effect of dopamine on neuronal network activity. In this study, we investigated the effect of dopamine on local high-frequency oscillatory neuronal activity (in  band in slices of the mouse anterior cingulate cortex (ACC. We found that dopamine enhanced the power of these oscillations induced by kainate and carbachol, but did not affect their peak frequency. Activation of D2R and in a lesser degree D1R increased the oscillation power, while activation of D4R had no effect. These high-frequency oscillations in the ACC relied on both phasic inhibitory and excitatory transmission and functional gap junctions. Thus, dopamine released in the ACC promotes high-frequency synchronized local cortical activity which is known to favor information transfer, fast selection and binding of distributed neuronal responses. Finally, the power of these oscillations was significantly enhanced after degradation of the perineuronal nets enwrapping most parvalbumin interneurons. This study provides new insights for a better understanding of the abnormal prefrontal gamma activity in schizophrenia patients who display prefrontal anomalies of both the dopaminergic system and the perineuronal nets.

  12. Impaired Peroxisome Proliferator-activated Receptor-γ Contributes to Phenotypic Modulation of Vascular Smooth Muscle Cells during Hypertension*

    Zhang, Lili; Xie, Peng; Wang, Jingzhou; Yang, Qingwu; Fang, Chuanqin; Zhou, Shuang; Li, Jingcheng

    2010-01-01

    The phenotypic modulation of vascular smooth muscle cells (VSMCs) plays a pivotal role in hypertension-induced vascular changes including vascular remodeling. The precise mechanisms underlying VSMC phenotypic modulation remain elusive. Here we test the role of peroxisome proliferator-activated receptor (PPAR)-γ in the VSMC phenotypic modulation during hypertension. Both spontaneously hypertensive rat (SHR) aortas and SHR-derived VSMCs exhibited reduced PPAR-γ expression and excessive VSMC phe...

  13. Cells in the monkey ponto-medullary reticular formation modulate their activity with slow finger movements.

    Soteropoulos, Demetris S; Williams, Elizabeth R; Baker, Stuart N

    2012-08-15

    Recent work has shown that the primate reticulospinal tract can influence spinal interneurons and motoneurons involved in control of the hand. However, demonstrating connectivity does not reveal whether reticular outputs are modulated during the control of different types of hand movement. Here, we investigated how single unit discharge in the pontomedullary reticular formation (PMRF) modulated during performance of a slow finger movement task in macaque monkeys. Two animals performed an index finger flexion–extension task to track a target presented on a computer screen; single units were recorded both from ipsilateral PMRF (115 cells) and contralateral primary motor cortex (M1, 210 cells). Cells in both areas modulated their activity with the task (M1: 87%, PMRF: 86%). Some cells (18/115 in PMRF; 96/210 in M1) received sensory input from the hand, showing a short-latency modulation in their discharge following a rapid passive extension movement of the index finger. Effects in ipsilateral electromyogram to trains of stimuli were recorded at 45 sites in the PMRF. These responses involved muscles controlling the digits in 13/45 sites (including intrinsic hand muscles, 5/45 sites). We conclude that PMRF may contribute to the control of fine finger movements, in addition to its established role in control of more proximal limb and trunk movements. This finding may be especially important in understanding functional recovery after brain lesions such as stroke. PMID:22641776

  14. Stainless Steel Permeability

    Buchenauer, Dean A. [Sandia National Laboratories (SNL-CA), Livermore, CA (United States); Karnesky, Richard A. [Sandia National Laboratories (SNL-CA), Livermore, CA (United States)

    2015-09-01

    An understanding of the behavior of hydrogen isotopes in materials is critical to predicting tritium transport in structural metals (at high pressure), estimating tritium losses during production (fission environment), and predicting in-vessel inventory for future fusion devices (plasma driven permeation). Current models often assume equilibrium diffusivity and solubility for a class of materials (e.g. stainless steels or aluminum alloys), neglecting trapping effects or, at best, considering a single population of trapping sites. Permeation and trapping studies of the particular castings and forgings enable greater confidence and reduced margins in the models. For FY15, we have continued our investigation of the role of ferrite in permeation for steels of interest to GTS, through measurements of the duplex steel 2507. We also initiated an investigation of the permeability in work hardened materials, to follow up on earlier observations of unusual permeability in a particular region of 304L forgings. Samples were prepared and characterized for ferrite content and coated with palladium to prevent oxidation. Issues with the poor reproducibility of measurements at low permeability were overcome, although the techniques in use are tedious. Funding through TPBAR and GTS were secured for a research grade quadrupole mass spectrometer (QMS) and replacement turbo pumps, which should improve the fidelity and throughput of measurements in FY16.

  15. Synthesis and antiprotozoal activity of N-alkoxy analogues of the trypanocidal lead compound 4,4'-bis(imidazolinylamino)diphenylamine with improved human blood-brain barrier permeability.

    Nieto, Lidia; Mascaraque, Ainhoa; Miller, Florence; Glacial, Fabienne; Ríos Martínez, Carlos; Kaiser, Marcel; Brun, Reto; Dardonville, Christophe

    2011-01-27

    To improve the blood-brain barrier permeability of the trypanocidal lead compound 4,4'-bis(imidazolinylamino)diphenylamine (1), five N-alkoxy analogues were synthesized from bis(4-isothiocyanatophenyl)amine and N-alkoxy-N-(2-aminoethyl)-2-nitrobenzenesulfonamides following successive chemical reactions in just one reactor ("one-pot procedure"). This involved: (a) formation of a thiourea intermediate, (b) removal of the amine protecting groups, and (c) intramolecular cyclization. The blood-brain barrier permeability of the compounds determined in vitro by transport assays through the hCMEC/D3 human cell line, a well-known and characterized human cellular blood-brain barrier model, showed that the N-hydroxy analogue 16 had enhanced blood-brain barrier permeability compared with the unsubstituted lead compound. Moreover, this compound displayed low micromolar IC(50) against Trypanosoma brucei rhodesiense and Plasmodium falciparum and moderate activity by intraperitoneal administration in the STIB900 murine model of acute sleeping sickness. PMID:21175162

  16. Inhibition of the host proteasome facilitates papaya ringspot virus accumulation and proteosomal catalytic activity is modulated by viral factor HcPro.

    Nandita Sahana

    Full Text Available The ubiquitin/26S proteasome system plays an essential role not only in maintaining protein turnover, but also in regulating many other plant responses, including plant-pathogen interactions. Previous studies highlighted different roles of the 20S proteasome in plant defense during virus infection, either indirectly through viral suppressor-mediated degradation of Argonaute proteins, affecting the RNA interference pathway, or directly through modulation of the proteolytic and RNase activity of the 20S proteasome, a component of the 20S proteasome, by viral proteins, affecting the levels of viral proteins and RNAs. Here we show that MG132, a cell permeable proteasomal inhibitor, caused an increase in papaya ringspot virus (PRSV accumulation in its natural host papaya (Carica papaya. We also show that the PRSV HcPro interacts with the papaya homologue of the Arabidopsis PAA (α1 subunit of the 20S proteasome, but not with the papaya homologue of Arabidopsis PAE (α5 subunit of the 20S proteasome, associated with the RNase activity, although the two 20S proteasome subunits interacted with each other. Mutated forms of PRSV HcPro showed that the conserved KITC54 motif in the N-terminal domain of HcPro was necessary for its binding to PAA. Co-agroinfiltration assays demonstrated that HcPro expression mimicked the action of MG132, and facilitated the accumulation of bothtotal ubiquitinated proteins and viral/non-viral exogenous RNA in Nicotiana benthamiana leaves. These effects were not observed by using an HcPro mutant (KITS54, which impaired the HcPro - PAA interaction. Thus, the PRSV HcPro interacts with a proteasomal subunit, inhibiting the action of the 20S proteasome, suggesting that HcPro might be crucial for modulating its catalytic activities in support of virus accumulation.

  17. KATP channels modulate intrinsic firing activity of immature entorhinal cortex layer III neurons

    Maria S. Lemak

    2014-08-01

    Full Text Available Medial temporal lobe structures are essential for memory formation which is associated with coherent network oscillations. During ontogenesis, these highly organized patterns develop from distinct, less synchronized forms of network activity. This maturation process goes along with marked changes in intrinsic firing patterns of individual neurons. One critical factor determining neuronal excitability is activity of ATP-sensitive K+ channels (KATP channels which coupled electrical activity to metabolic state. Here, we examined the role of KATP channels for intrinsic firing patterns and emerging network activity in the immature medial entorhinal cortex (mEC of rats. Western blot analysis of Kir6.2 (a subunit of the KATP channel confirmed expression of this protein in the immature entorhinal cortex. Neuronal activity was monitored by field potential (fp and whole-cell recordings from layer III of the mEC in horizontal brain slices obtained at postnatal day (P 6-13. Spontaneous fp-bursts were suppressed by the KATP channel opener diazoxide and prolonged after blockade of KATP channels by glibenclamide. Immature mEC LIII principal neurons displayed two dominant intrinsic firing patterns, prolonged bursts or regular firing activity, respectively. Burst discharges were suppressed by the KATP channel openers diazoxide and NN414, and enhanced by the KATP channel blockers tolbutamide and glibenclamide. Activity of regularly firing neurons was modulated in a frequency-dependent manner: the diazoxide-mediated reduction of firing correlated negatively with basal frequency, while the tolbutamide-mediated increase of firing showed a positive correlation. These data are in line with an activity-dependent regulation of KATP channel activity. Together, KATP channels exert powerful modulation of intrinsic firing patterns and network activity in the immature mEC.

  18. Bovine colostrum modulates immune activation cascades in human peripheral blood mononuclear cells in vitro

    Jenny, Marcel; Pedersen, Ninfa R; Hidayat, Budi J; Schennach, Harald; Fuchs, Dietmar

    2010-01-01

    factors and has a long history of use in traditional medicine. In an approach to evaluate the effects of bovine colostrum (BC) on the T-cell/macrophage interplay, we investigated and compared the capacity of BC containing low and high amounts of lactose and lactoferrin to modulate tryptophan degradation...... amount of lactose present in BC seems to diminish the activity of BC in our test system, since BC with higher amounts of lactose attenuated the stimulatory as well as the suppressive activity of BC....

  19. Amplification of Frequency-Modulated Similariton Pulses in Length-Inhomogeneous Active Fibers

    I. O. Zolotovskii

    2012-01-01

    Full Text Available The possibility of an effective gain of the self-similar frequency-modulated (FM wave packets is studied in the length-inhomogeneous active fibers. The dynamics of parabolic pulses with the constant chirp has been considered. The optimal profile for the change of the group-velocity dispersion corresponding to the optimal similariton pulse amplification has been obtained. It is shown that the use of FM pulses in the active (gain and length-inhomogeneous optical fibers with the normal group-velocity dispersion can provide subpicosecond optical pulse amplification up to the energies higher than 1 nJ.

  20. Preferential binding of allosteric modulators to active and inactive conformational states of metabotropic glutamate receptors

    Klein-Seetharaman Judith

    2008-02-01

    Full Text Available Abstract Metabotropic glutamate receptors (mGluRs are G protein coupled receptors that play important roles in synaptic plasticity and other neuro-physiological and pathological processes. Allosteric mGluR ligands are particularly promising drug targets because of their modulatory effects – enhancing or suppressing the response of mGluRs to glutamate. The mechanism by which this modulation occurs is not known. Here, we propose the hypothesis that positive and negative modulators will differentially stabilize the active and inactive conformations of the receptors, respectively. To test this hypothesis, we have generated computational models of the transmembrane regions of different mGluR subtypes in two different conformations. The inactive conformation was modeled using the crystal structure of the inactive, dark state of rhodopsin as template and the active conformation was created based on a recent model of the light-activated state of rhodopsin. Ligands for which the nature of their allosteric effects on mGluRs is experimentally known were docked to the modeled mGluR structures using ArgusLab and Autodock softwares. We find that the allosteric ligand binding pockets of mGluRs are overlapping with the retinal binding pocket of rhodopsin, and that ligands have strong preferences for the active and inactive states depending on their modulatory nature. In 8 out of 14 cases (57%, the negative modulators bound the inactive conformations with significant preference using both docking programs, and 6 out of 9 cases (67%, the positive modulators bound the active conformations. Considering results by the individual programs only, even higher correlations were observed: 12/14 (86% and 8/9 (89% for ArgusLab and 10/14 (71% and 7/9 (78% for AutoDock. These findings strongly support the hypothesis that mGluR allosteric modulation occurs via stabilization of different conformations analogous to those identified in rhodopsin where they are induced by

  1. Dark/light transition and vigilance states modulate jaw-closing muscle activity level in mice.

    Katayama, Keisuke; Mochizuki, Ayako; Kato, Takafumi; Ikeda, Minako; Ikawa, Yasuha; Nakamura, Shiro; Nakayama, Kiyomi; Wakabayashi, Noriyuki; Baba, Kazuyoshi; Inoue, Tomio

    2015-12-01

    Bruxism is associated with an increase in the activity of the jaw-closing muscles during sleep and wakefulness. However, the changes in jaw-closing muscle activity across states of vigilance over a 24-h period are unclear. In this study, we investigated the effects of dark/light transition and sleep/wake state on EMG activity of the masseter (jaw-closing) muscle in comparison with the activity of the upper trapezius muscle (a neck muscle) over a 24-h period in mice. The activities of the masseter and neck muscles during wakefulness were much greater than during non-REM and REM sleep. In contrast, the activities of both muscles slightly, but significantly, decreased during the transition period from dark to light. Histograms of masseter activity during wakefulness and non-REM sleep showed bimodal distributions, whereas the neck muscle showed unimodal activation in all states. These results suggest that the activities of jaw-closing and neck muscles are modulated by both sleep/wake state and dark/light transition, with the latter being to a lesser degree. Furthermore, even during non-REM sleep, jaw-closing muscles display bimodal activation, which may contribute to the occurrence of exaggerated aberrant muscle activity, such as sleep bruxism. PMID:26188127

  2. Enhanced BBB permeability of osmotically active poly(mannitol-co-PEI) modified with rabies virus glycoprotein via selective stimulation of caveolar endocytosis for RNAi therapeutics in Alzheimer's disease.

    Park, Tae-Eun; Singh, Bijay; Li, Huishan; Lee, Jun-Yeong; Kang, Sang-Kee; Choi, Yun-Jaie; Cho, Chong-Su

    2015-01-01

    RNA interference (RNAi) holds one of the promising tools for Alzheimer's disease (AD) treatment by directly arresting the causative genes. For successful RNAi therapeutics for AD, limited access of therapeutic genes to the brain needs to be overcome by developing siRNA delivery system that could cross the blood-brain barrier (BBB). Here, we report a non-viral vector, rabies virus glycoprotein (RVG)-modified poly(mannitol-co-PEI) gene transporter (PMT), R-PEG-PMT. The RVG ligand directed the PMT/siRNA complexes toward the brain through binding to nicotinic acetylcholine receptors expressed on BBB. In mechanistic study using in vitro BBB model, we observed that osmotically-active PMT enhanced the receptor-mediated transcytosis by stimulating the caveolar endocytosis. The potential of RNAi therapeutics for AD using R-PEG-PMT/siBACE1 complexes was demonstrated in vitro and in vivo. Our results suggest that R-PEG-PMT is a powerful gene carrier system for brain targeted RNAi therapeutics with synergistic effect of RVG ligand and PMT on well-modulated receptor-mediated transcytosis through BBB. PMID:25457984

  3. Plant carbohydrate binding module enhances activity of hybrid microbial cellulase enzyme

    Caitlin Siobhan Byrt

    2012-11-01

    Full Text Available A synthetic, highly active cellulase enzyme suitable for in planta production may be a valuable tool for biotechnological approaches to develop transgenic biofuel crops with improved digestibility. Here, we demonstrate that the addition of a plant derived carbohydrate binding module (CBM to a synthetic glycosyl hydrolase (GH improved the activity of the hydrolase in releasing sugar from plant biomass. A CEL-HYB1-CBM enzyme was generated by fusing a hybrid microbial cellulase, CEL-HYB1, with the carbohydrate-binding module (CBM of the tomato (Solanum lycopersicum SlCel9C1 cellulase. CEL-HYB1 and CEL-HYB1-CBM enzymes were produced in vitro using Pichia pastoris and the activity of these enzymes was tested using CMC, MUC and native crystalline cellulose assays. The presence of the CBM substantially improved the endo-glucanase activity of CEL-HYB1, especially against the native crystalline cellulose encountered in Sorghum plant cell walls. These results indicate that addition of an endogenous plant derived CBM to cellulase enzymes may enhance hydrolytic activity.

  4. Modulation of Banana Polyphenol Oxidase (Ppo Activity by Naturally Occurring Bioactive Compounds From Plant Extracts

    Alamelumangai. M

    2015-01-01

    Full Text Available Polyphenol Oxidase (PPO (E.C number 1.14.18.1 was extracted from banana (Musa paradisiaca and partially purified by acetone precipitation. The enzyme was found to have high affinity towards its substrate, catechol. In this study, various plant extracts like Glycyrrhiza glabra, Rubia cordifolia, Hesperethusa crenulata and oil from the seeds of Hydnocarpus laurifolia were observed to modulate the activity of banana PPO. Method In this study, various plant extracts were observed to modulate the activity of banana PPO at two different concentrations (0.4 and 40 μg/ml concentrations Result Among these 4 plant extracts, Glycyrrhiza glabra and Rubia cordifolia were found to increase the activity of PPO up to 1.35- 2.7 fold at two different concentrations (4 and 40 μg/ml. Few other two samples like Chaulmogra oil (2 and 4 μl/ml and the Hesperethusa crenulata plant extract (0.4 and 40 μg/ml concentrations, when used at low concentrations decreased the enzyme activity (38 %. Conclusion The novelty of this study is to screen their naturally occurring bioactive compounds from the plant extracts and their inhibitory activity against PPO.

  5. Different Brain Network Activations Induced by Modulation and Nonmodulation Laser Acupuncture

    Chang-Wei Hsieh

    2011-01-01

    Full Text Available The aim of this study is to compare the distinct cerebral activation with continued wave (CW and 10 Hz-modulated wave (MW stimulation during low-level laser acupuncture. Functional magnetic resonance imaging (fMRI studies were performed to investigate the possible mechanism during laser acupuncture stimulation at the left foot's yongquan (K1 acupoint. There are 12 healthy right-handed volunteers for each type of laser stimulation (10-Hz-Modulated wave: 8 males and 4 females; continued wave: 9 males and 3 females. The analysis of multisubjects in this experiment was applied by random-effect (RFX analysis. In CW groups, significant activations were found within the inferior parietal lobule, the primary somatosensory cortex, and the precuneus of left parietal lobe. Medial and superior frontal gyrus of left frontal lobe were also aroused. In MW groups, significant activations were found within the primary motor cortex and middle temporal gyrus of left hemisphere and bilateral cuneus. Placebo stimulation did not show any activation. Most activation areas were involved in the functions of memory, attention, and self-consciousness. The results showed the cerebral hemodynamic responses of two laser acupuncture stimulation modes and implied that its mechanism was not only based upon afferent sensory information processing, but that it also had the hemodynamic property altered during external stimulation.

  6. TRAF-mediated modulation of NF-kB AND JNK activation by TNFR2.

    Cabal-Hierro, Lucía; Rodríguez, Montserrat; Artime, Noelia; Iglesias, Julián; Ugarte, Lorea; Prado, Miguel A; Lazo, Pedro S

    2014-12-01

    Tumor Necrosis Factor Receptor 2 (TNFR2) activates transcription factor κB (NF-κB) and c-Jun N-terminal kinase (JNK). Most of the biological activities triggered by TNFR2 depend on the recruitment of TNF Receptor-Associated Factor 2 (TRAF2) to the intracellular region of the receptor. The intracellular region of TNFR2 contains five highly conserved amino acid sequences, three of which appear implicated in receptor signaling. In this work we have studied the interaction of TNFR2 with TRAF proteins as well as the functional consequences of this interaction. We show that TRAF1, TRAF2 and TRAF3 bind to the receptor through two different binding sites located at conserved modules IV and V of its intracellular region, respectively. We also show that TRAF1 and TRAF3 have opposite effects to TRAF2 on NF-κB and JNK activation by TNFR2. Moreover, we show that TNFR2 is able to induce JNK activation in a TRAF2-independent fashion. This new receptor activity relies on a sequence located in the conserved module III. This region is also responsible for the ability of TNFR2 to induce TRAF2 degradation, thus emphasizing the role of conserved module III (amino acids 338-379) on receptor signaling and regulation. We show that only TNFR2 can induce TRAF2 degradation while TRAF1 or TRAF3 is not subjected to this regulatory mechanism and that TRAF1, but not TRAF3, is able to inhibit TRAF2 degradation. PMID:25152365

  7. Cucurbitacin IIb exhibits anti-inflammatory activity through modulating multiple cellular behaviors of mouse lymphocytes.

    Yao Wang

    Full Text Available Cucurbitacin IIb (CuIIb is one of the major active compounds in Hemsleyadine tablets which have been used for clinical treatment of bacillary dysentery, enteritis and acute tonsilitis. However, its action mechanism has not been completely understood. This study aimed to explore the anti-inflammatory activity of CuIIb and its underlying mechanism in mitogen-activated lymphocytes isolated from mouse mesenteric lymph nodes. The results showed that CuIIb inhibited the proliferation of concanavalin A (Con A-activated lymphocytes in a time- and dose-dependent manner. CuIIb treatment arrested their cell cycle in S and G2/M phases probably due to the disruption of the actin cytoskeleton and the modulation of p27(Kip1 and cyclin levels. Moreover, the surface expression of activation markers CD69 and CD25 on Con A-activated CD3(+ T lymphocytes was suppressed by CuIIb treatment. Both Con A- and phorbol ester plus ionomycin-induced expression of TNF-α, IFN-γ and IL-6 proteins was attenuated upon exposure to CuIIb. Mechanistically, CuIIb treatment suppressed the phosphorylation of JNK and Erk1/2 but not p38 in Con A-activated lymphocytes. Although CuIIb unexpectedly enhanced the phosphorylation of IκB and NF-κB (p65, it blocked the nuclear translocation of NF-κB (p65. In support of this, CuIIb significantly decreased the mRNA levels of IκBα and TNF-α, two target genes of NF-κB, in Con A-activated lymphocytes. In addition, CuIIb downregulated Con A-induced STAT3 phosphorylation and increased cell apoptosis. Collectively, these results suggest that CuIIb exhibits its anti-inflammatory activity through modulating multiple cellular behaviors and signaling pathways, leading to the suppression of the adaptive immune response.

  8. Activation of murine invariant NKT cells promotes susceptibility to candidiasis by IL-10 induced modulation of phagocyte antifungal activity.

    Haraguchi, Norihiro; Kikuchi, Norihiro; Morishima, Yuko; Matsuyama, Masashi; Sakurai, Hirofumi; Shibuya, Akira; Shibuya, Kazuko; Taniguchi, Masaru; Ishii, Yukio

    2016-07-01

    Invariant NKT (iNKT) cells play an important role in a variety of antimicrobial immune responses due to their ability to produce high levels of immune-modulating cytokines. Here, we investigated the role of iNKT cells in host defense against candidiasis using Jα18-deficient mice (Jα18(-/-) ), which lack iNKT cells. Jα18(-/-) mice were more resistant to the development of lethal candidiasis than wild-type (WT) mice. In contrast, treatment of WT mice with the iNKT cell activating ligand α-galactosylceramide markedly enhanced their mortality after infection with Candida albicans. Serum IL-10 levels were significantly elevated in WT mice in response to infection with C. albicans. Futhermore, IL-10 production increased after in vitro coculture of peritoneal macrophages with iNKT cells and C. albicans. The numbers of peritoneal macrophages, the production of IL-1β and IL-18, and caspase-1 activity were also significantly elevated in Jα18(-/-) mice after infection with C. albicans. The adoptive transfer of iNKT cells or exogenous administration of IL-10 into Jα18(-/-) reversed susceptibility to candidiasis to the level of WT mice. These results suggest that activation of iNKT cells increases the initial severity of C. albicans infection, most likely mediated by IL-10 induced modulation of macrophage antifungal activity. PMID:27151377

  9. Bicarbonate and Ca2+ sensing modulators activate photoreceptor ROS-GC1 synergistically

    Teresa eDuda

    2016-01-01

    Full Text Available Photoreceptor ROS-GC1, a prototype subfamily member of the membrane guanylate cyclase family, is a central component of phototransduction. It is a single transmembrane-spanning protein, composed of modular blocks. In rods, guanylate cyclase activating proteins (GCAPs 1 and 2 bind to its juxtamembrane domain and the C-terminal extension, respectively, to accelerate cyclic GMP synthesis when Ca2+ levels are low. In cones, the additional expression of the Ca2+-dependent guanylate cyclase activating protein (CD-GCAP S100B which binds to its C-terminal extension, supports acceleration of cyclic GMP synthesis at high Ca2+ levels. Independent of Ca2+, ROS-GC1 activity is also stimulated directly by bicarbonate binding to the core catalytic domain. Several enticing molecular features of this transduction system are revealed in the present study. In combination, bicarbonate and Ca2+-dependent modulators raised maximal ROS-GC activity to levels that exceeded the sum of their individual effects. The F514S mutation in ROS-GC1 that causes blindness in type 1 Leber’s congenital amaurosis severely reduced basal ROS-GC1 activity. GCAP2 and S100B Ca2+ signaling modes remained functional, while the GCAP1-modulated mode was diminished. Bicarbonate nearly restored basal activity as well as GCAP2- and S100B-stimulated activities of the F514S mutant to normal levels but could not resurrect GCAP1 stimulation. We conclude that GCAP1 and GCAP2 forge distinct pathways through domain-specific modules of ROS-GC1 whereas the S100B and GCAP2 pathways may overlap. The synergistic interlinking of bicarbonate to GCAPs- and S100B-modulated pathways intensifies and tunes the dependence of cyclic GMP synthesis on intracellular Ca2+. Our study challenges the recently proposed GCAP1 and GCAP2 overlapping phototransduction model (Peshenko, I.V., Olshevskaya, and Dizhoor, A. M. (2015 J Biol. Chem 290, 6913-6924.

  10. Determination Permeability Coefficient from Piezocone

    Qiang Wang

    2014-01-01

    Full Text Available The permeability coefficient of soil profile is one of the problems concerned by engineers, and the determination of permeability coefficient method mainly relies on the laboratory permeability test and field pumping test, but these tests are time-consuming and inefficient, and especially the permeability coefficient of soil under the condition of partial drainage was difficult to determine; in this paper, the modern digital CPTU technology was used. Dimensional permeability KT was defined by using the dimensionless normalized cone tip resistance Qt, friction factor Fr, and pore pressure ratio Bq, these parameters enable plots of Bq-Qt, Fr-Qt, Bq-Fr to be contoured KT and hence for permeability coefficient. The relationship has been applied to Nanjing 4th Yangtze river bridge, and compared with laboratory penetration test. The results indicate that the method can accurately determine the permeability coefficient of soil under partial drainage condition and provide the theoretical basis for engineering application.

  11. Mangroves Build Land. "Mangroves are a Valuable Resource." Grades 7 and 8. A Two Lesson Unit. Student Learning Activity Module.

    Frank, James

    This module is an activity and film-oriented unit focusing on the importance of mangroves in the South Florida ecosystem. The module is part of a series designed to be used by teachers, students, and community members to help them utilize community resources in developing and teaching environmental concepts and responsibility, and in seeking ways…

  12. Pre-irradiation testing of actively cooled Be-Cu divertor modules

    Linke, J.; Duwe, R.; Kuehnlein, W. [Forschungszentrum Juelich GmbH (Germany)] [and others

    1995-09-01

    A set of neutron irradiation tests is prepared on different plasma facing materials (PFM) candidates and miniaturized components for ITER. Beside beryllium the irradiation program which will be performed in the High Flux Reactor (HFR) in Petten, includes different carbon fiber composites (CFQ) and tungsten alloys. The target values for the neutron irradiation will be 0.5 dpa at temperatures of 350{degrees}C and 700{degrees}C, resp.. The post irradiation examination (PIE) will cover a wide range of mechanical tests; in addition the degradation of thermal conductivity will be investigated. To determine the high heat flux (HHF) performance of actively cooled divertor modules, electron beam tests which simulate the expected heat loads during the operation of ITER, are scheduled in the hot cell electron beam facility JUDITH. These tests on a selection of different actively cooled beryllium-copper and CFC-copper divertor modules are performed before and after neutron irradiation; the pre-irradiation testing is an essential part of the program to quantify the zero-fluence high heat flux performance and to detect defects in the modules, in particular in the brazed joints.

  13. Vascular permeability in cerebral cavernous malformations

    Mikati, Abdul G; Khanna, Omaditya; Zhang, Lingjiao;

    2015-01-01

    Patients with the familial form of cerebral cavernous malformations (CCMs) are haploinsufficient for the CCM1, CCM2, or CCM3 gene. Loss of corresponding CCM proteins increases RhoA kinase-mediated endothelial permeability in vitro, and in mouse brains in vivo. A prospective case-controlled observ......Patients with the familial form of cerebral cavernous malformations (CCMs) are haploinsufficient for the CCM1, CCM2, or CCM3 gene. Loss of corresponding CCM proteins increases RhoA kinase-mediated endothelial permeability in vitro, and in mouse brains in vivo. A prospective case......-controlled observational study investigated whether the brains of human subjects with familial CCM show vascular hyperpermeability by dynamic contrast-enhanced quantitative perfusion magnetic resonance imaging, in comparison with CCM cases without familial disease, and whether lesional or brain vascular permeability...... correlates with CCM disease activity. Permeability in white matter far (WMF) from lesions was significantly greater in familial than in sporadic cases, but was similar in CCM lesions. Permeability in WMF increased with age in sporadic patients, but not in familial cases. Patients with more aggressive...

  14. Model documentation report: Macroeconomic Activity Module (MAM) of the National Energy Modeling System

    1994-02-07

    This report documents the objectives, analytical approach, and development of the National Energy Modeling System (NEMS) Macroeconomic Activity Module (MAM) used to develop the Annual Energy Outlook for 1994 (AEO94). The report catalogues and describes the module assumptions, computations, methodology, parameter estimation techniques, and mainframe source code. This document serves three purposes. First, it is a reference document providing a detailed description of the NEMS MAM used for the AEO 1994 production runs for model analysts, users, and the public. Second, this report meets the legal requirement of the Energy Information Administration (EIA) to provide adequate documentation in support of its models (Public Law 94-385, section 57.b.2). Third, it facilitates continuity in model development by providing documentation from which energy analysts can undertake model enhancements, data updates, and parameter refinements as future projects.

  15. Different pulse pattern generation by frequency detuning in pulse modulated actively mode-locked ytterbium doped fiber laser

    Chen, He; Chen, Sheng-Ping; Si, Lei; Zhang, Bin; Jiang, Zong-Fu

    2015-10-01

    We report the results of our recent experimental investigation of the modulation frequency detuning effect on the output pulse dynamics in a pulse modulated actively mode-locked ytterbium doped fiber laser. The experimental study shows the existence of five different mode-locking states that mainly depend on the modulation frequency detuning, which are: (a) amplitude-even harmonic/fundamental mode-locking, (b) Q-switched harmonic/fundamental mode-locking, (c) sinusoidal wave modulation mode, (d) pulses bundle state, and (e) noise-like state. A detailed experimental characterization of the output pulses dynamics in each operating mode is presented.

  16. Modulation of HMG-CoA reductase activity by pantetheine/pantethine.

    Cighetti, G; Del Puppo, M; Paroni, R; Galli Kienle, M

    1988-11-25

    The ability of pantetheine/pantethine to modulate the activity of HMG-CoA reductase (EC 1.1.1.34) was determined in vitro with rat liver microsomes. The decay of the activity was obtained with pantethine in the 10(-5)-10(-4) M range, whereas stimulation by pantetheine occurred at 10(-3)-10(-2) M, as previously reported for GSSG and GSH, respectively. Inhibition of HMG-CoA by pantethine in isolated liver cells was also investigated by measuring the enzyme activity in microsomes isolated from hepatocytes incubated without or with 1 mM pantethine under conditions previously shown by us to induce inhibition of cholesterol synthesis from acetate. The enzyme amount was not modified by pantethine, but in cells treated with the disulphide, the relative amounts of the thiolic active forms of the enzyme, both phosphorylated and dephosphorylated, were decreased to about half compared to controls. PMID:3196742

  17. Somatostatin modulates insulin-degrading-enzyme metabolism: implications for the regulation of microglia activity in AD.

    Grazia Tundo

    Full Text Available The deposition of β-amyloid (Aβ into senile plaques and the impairment of somatostatin-mediated neurotransmission are key pathological events in the onset of Alzheimer's disease (AD. Insulin-degrading-enzyme (IDE is one of the main extracellular protease targeting Aβ, and thus it represents an interesting pharmacological target for AD therapy. We show that the active form of somatostatin-14 regulates IDE activity by affecting its expression and secretion in microglia cells. A similar effect can also be observed when adding octreotide. Following a previous observation where somatostatin directly interacts with IDE, here we demonstrate that somatostatin regulates Aβ catabolism by modulating IDE proteolytic activity in IDE gene-silencing experiments. As a whole, these data indicate the relevant role played by somatostatin and, potentially, by analogue octreotide, in preventing Aβ accumulation by partially restoring IDE activity.

  18. Leukotriene B4-loaded microspheres: a new therapeutic strategy to modulate cell activation

    Sanz Maria J

    2008-07-01

    Full Text Available Abstract Background Leukotriene B4 (LTB4 is a potent inflammatory mediator that also stimulates the immune response. In addition, it promotes polymorphonuclear leukocyte phagocytosis, chemotaxis, chemokinesis and modulates cytokines release. Regarding chemical instability of the leukotriene molecule, in the present study we assessed the immunomodulatory activities conferred by LTB4 released from microspheres (MS. A previous oil-in-water emulsion solvent extraction-evaporation method was chosen to prepare LTB4-loaded MS. Results In the mice cremasteric microcirculation, intraescrotal injection of 0.1 ml of LTB4-loaded MS provoked significant increases in leukocyte rolling flux, adhesion and emigration besides significant decreases in the leukocyte rolling velocity. LTB4-loaded MS also increase peroxisome proliferator-activated receptor-α (PPARα expression by murine peritoneal macrophages and stimulate them to generate nitrite levels. Monocyte chemoattractant protein-1 (MCP-1 and nitric oxide (NO productions were also increased when human umbilical vein and artery endothelial cells (HUVECs and HUAECs, respectively were stimulated with LTB4-loaded MS. Conclusion LTB4-loaded MS preserve the biological activity of the encapsulated mediator indicating their use as a new strategy to modulate cell activation, especially in the innate immune response.

  19. Modulation of the Activity of Secretory Phospholipase A2 by Antimicrobial Peptides

    Zhao, Hongxia; Kinnunen, Paavo K. J.

    2003-01-01

    The antimicrobial peptides magainin 2, indolicidin, and temporins B and L were found to modulate the hydrolytic activity of secretory phospholipase A2 (sPLA2) from bee venom and in human lacrimal fluid. More specifically, hydrolysis of phosphatidylcholine (PC) liposomes by bee venom sPLA2 at 10 μM Ca2+ was attenuated by these peptides while augmented product formation was observed in the presence of 5 mM Ca2+. The activity of sPLA2 towards anionic liposomes was significantly enhanced by the antimicrobial peptides at low [Ca2+] and was further enhanced in the presence of 5 mM Ca2+. Similarly, with 5 mM Ca2+ the hydrolysis of anionic liposomes was enhanced significantly by human lacrimal fluid sPLA2, while that of PC liposomes was attenuated. These results indicate that concerted action of antimicrobial peptides and sPLA2 could improve the efficiency of the innate response to infections. Interestingly, inclusion of a cationic gemini surfactant in the vesicles showed an essentially similar pattern on sPLA2 activity, suggesting that the modulation of the enzyme activity by the antimicrobial peptides may involve also charge properties of the substrate surface. PMID:12604528

  20. Activated H-Ras regulates hematopoietic cell survival by modulating Survivin

    Survivin expression and Ras activation are regulated by hematopoietic growth factors. We investigated whether activated Ras could circumvent growth factor-regulated Survivin expression and if a Ras/Survivin axis mediates growth factor independent survival and proliferation in hematopoietic cells. Survivin expression is up-regulated by IL-3 in Ba/F3 and CD34+ cells and inhibited by the Ras inhibitor, farnesylthiosalicylic acid. Over-expression of constitutively activated H-Ras (CA-Ras) in Ba/F3 cells blocked down-modulation of Survivin expression, G0/G1 arrest, and apoptosis induced by IL-3 withdrawal, while dominant-negative (DN) H-Ras down-regulated Survivin. Survivin disruption by DN T34A Survivin blocked CA-Ras-induced IL-3-independent cell survival and proliferation; however, it did not affect CA-Ras-mediated enhancement of S-phase, indicating that the anti-apoptotic activity of CA-Ras is Survivin dependent while its S-phase enhancing effect is not. These results indicate that CA-Ras modulates Survivin expression independent of hematopoietic growth factors and that a CA-Ras/Survivin axis regulates survival and proliferation of transformed hematopoietic cells

  1. Oscillatory phase modulates the timing of neuronal activations and resulting behavior.

    Coon, W G; Gunduz, A; Brunner, P; Ritaccio, A L; Pesaran, B; Schalk, G

    2016-06-01

    Human behavioral response timing is highly variable from trial to trial. While it is generally understood that behavioral variability must be due to trial-by-trial variations in brain function, it is still largely unknown which physiological mechanisms govern the timing of neural activity as it travels through networks of neuronal populations, and how variations in the timing of neural activity relate to variations in the timing of behavior. In our study, we submitted recordings from the cortical surface to novel analytic techniques to chart the trajectory of neuronal population activity across the human cortex in single trials, and found joint modulation of the timing of this activity and of consequent behavior by neuronal oscillations in the alpha band (8-12Hz). Specifically, we established that the onset of population activity tends to occur during the trough of oscillatory activity, and that deviations from this preferred relationship are related to changes in the timing of population activity and the speed of the resulting behavioral response. These results indicate that neuronal activity incurs variable delays as it propagates across neuronal populations, and that the duration of each delay is a function of the instantaneous phase of oscillatory activity. We conclude that the results presented in this paper are supportive of a general model for variability in the effective speed of information transmission in the human brain and for variability in the timing of human behavior. PMID:26975551

  2. Relative permeability through fractures

    Diomampo, Gracel, P.

    2001-08-01

    The mechanism of two-phase flow through fractures is of importance in understanding many geologic processes. Currently, two-phase flow through fractures is still poorly understood. In this study, nitrogen-water experiments were done on both smooth and rough parallel plates to determine the governing flow mechanism for fractures and the appropriate methodology for data analysis. The experiments were done using a glass plate to allow visualization of flow. Digital video recording allowed instantaneous measurement of pressure, flow rate and saturation. Saturation was computed using image analysis techniques. The experiments showed that gas and liquid phases flow through fractures in nonuniform separate channels. The localized channels change with time as each phase path undergoes continues breaking and reforming due to invasion of the other phase. The stability of the phase paths is dependent on liquid and gas flow rate ratio. This mechanism holds true for over a range of saturation for both smooth and rough fractures. In imbibition for rough-walled fractures, another mechanism similar to wave-like flow in pipes was also observed. The data from the experiments were analyzed using Darcy's law and using the concept of friction factor and equivalent Reynold's number for two-phase flow. For both smooth- and rough-walled fractures a clear relationship between relative permeability and saturation was seen. The calculated relative permeability curves follow Corey-type behavior and can be modeled using Honarpour expressions. The sum of the relative permeabilities is not equal one, indicating phase interference. The equivalent homogeneous single-phase approach did not give satisfactory representation of flow through fractures. The graphs of experimentally derived friction factor with the modified Reynolds number do not reveal a distinctive linear relationship.

  3. Permeability measuremens of brazilian Eucalyptus

    Marcio Rogério da Silva

    2010-09-01

    Full Text Available The permeability of Brazilian Eucalyptus grandis and Eucalyptus citriodora wood was measured in a custom build gas analysis chamber in order to determine which species could be successfully treated with preservatives. Liquid permeability was tested using an emulsion of Neen oil and a control of distillated water. Air was used to test the gas phase permeability. For both Eucalyptus grandis and Eucalyptus citriodora, the longitudinal permeability of gas was shown to be about twice as great as the liquid phase permeability. No radial permeability was observed for either wood. The permeability of air and water through the sapwood of Eucalyptus grandis was greater than that through the sapwood of Eucalyptus citriodora. The permeability of neen oil preservative through the sapwood of Eucalyptus grandis was also greater than through the sapwood of E. Citradora, but the difference was not statistically significant. Scanning Electron Microscopy images showed that the distribution and obstruction in the vessels could be correlated with observed permeability properties. Irrespective of the causes of differences in permeability between the species, the fluid phase flux through the sapwood of both species was significant, indicating that both Eucalyptus grandis and Eucalyptus citriodora could be successfully treated with wood preservative.

  4. Modulation of cocaine-induced activity by intracerebral administration of CXCL12.

    Trecki, J; Unterwald, E M

    2009-06-16

    The role of chemokines in immune function is clearly established. Recent evidence suggests that these molecules also play an important role in the central nervous system as modulators of neuronal activity. The chemokine CXCL12 has been identified in several regions of the adult rat brain including the substantia nigra, ventral tegmental area and caudate putamen. CXCR4, a receptor activated by CXCL12, is expressed by dopaminergic neurons in the substantia nigra. The present study tested the effects of intracranial injections of CXCL12 on cocaine-induced locomotion and stereotypic activity in adult male Sprague-Dawley rats. Results demonstrate that intracerebral ventricular administration of CXCL12 (25 ng/4 microl) 15 min prior to cocaine (20 mg/kg intraperitoneal (i.p.)) produced a significant potentiation of both ambulatory and stereotypic activity as compared to cocaine alone. The effects of CXCL12 were blocked by administration of the selective CXCR4 antagonist, AMD 3100. Administration of CXCL12 into specific brain regions was performed to further understand the site of action of CXCL12. Bilateral administration of CXCL12 (25 ng/0.5 microl) into the ventral tegmental area 15 min prior to cocaine (20 mg/kg i.p.) significantly potentiated cocaine-induced ambulatory activity, whereas microinjections of CXCL12 into the caudate putamen selectively increased stereotypy. Conversely, administration of CXCL12 into the lateral shell of the nucleus accumbens resulted in an inhibition of cocaine-stimulated ambulatory activity. No alterations in ambulatory or stereotypic activity were observed following CXCL12 administration into the core of the nucleus accumbens. These results demonstrate that CXCL12 can modulate the behavioral effects produced by cocaine in a brain region-specific manner. PMID:19303923

  5. Histamine modulates multiple functional activities of monocyte-derived dendritic cell subsets via histamine receptor 2.

    Simon, Tünde; Gogolák, Péter; Kis-Tóth, Katalin; Jelinek, Ivett; László, Valéria; Rajnavölgyi, Eva

    2012-02-01

    Expression of CD1a proteins in human monocyte-derived dendritic cells (DCs) specifies functionally distinct subsets with different inflammatory properties. Histamine is recognized as an inflammatory mediator released by various cell types including DCs. The diverse biological effects of histamine are mediated by G-protein-coupled histamine receptors (HRs), which are able to modulate the functional activities of DC subsets. The goal of the present study was to compare the expression and activity of HRs in the CD1a(-) and CD1a(+) monocyte-derived DC subsets and to test the effects of histamine on the differentiation, activation and functional activities of these subsets. We show that H2R is present at high levels in both DC subsets, whereas H1R and H4R are expressed in a subset-specific manner. Histamine shifts DC differentiation to the development of CD1a(-) DCs and modulates DC activation through its inhibitory effect on CD1a(+) DC differentiation. Histamine-induced reduction of CD1a(+) DCs is associated with increased secretion of IL-6 and IL-10, up-regulation of a typical combination of chemokines, expression C5aR1 by the CD1a(-) DC subset and enhanced migration of both activated DC subsets supported by the production of MMP-9 and MMP-12 enzymes. All these effects were shown to be mediated in a H2R-specific manner as revealed by the specific antagonist of the receptor. As H2R is expressed at high levels in both DC subsets, we propose that it may dominate the regulation of multiple DC functions. In contrast, H1R and H4R with opposing subset-related expression may have a regulatory or fine-tuning role in histamine-induced functional activities. PMID:22232416

  6. Effect of low-level laser therapy on the modulation of the mitochondrial activity of macrophages

    Nadhia H. C. Souza

    2014-08-01

    Full Text Available BACKGROUND: Macrophages play a major role among the inflammatory cells that invade muscle tissue following an injury. Low-level laser therapy (LLLT has long been used in clinical practice to accelerate the muscle repair process. However, little is known regarding its effect on macrophages. OBJECTIVE: This study evaluated the effect of LLLT on the mitochondrial activity (MA of macrophages. METHOD: J774 macrophages were treated with lipopolysaccharide (LPS and interferon - gamma (IFN-γ (activation for 24 h to simulate an inflammatory process, then irradiated with LLLT using two sets of parameters (780 nm; 70 mW; 3 J/cm2 and 660 nm; 15 mW; 7.5 J/cm2. Non-activated/non-irradiated cells composed the control group. MA was evaluated by the cell mitochondrial activity (MTT assay (after 1, 3 and 5 days in three independent experiments. The data were analyzed statistically. RESULTS: After 1 day of culture, activated and 780 nm irradiated macrophages showed lower MA than activated macrophages, but activated and 660 nm irradiated macrophages showed MA similar to activated cells. After 3 days, activated and irradiated (660 nm and 780 nm macrophages showed greater MA than activated macrophages, and after 5 days, the activated and irradiated (660 nm and 780 nm macrophages showed similar MA to the activated macrophages. CONCLUSIONS: These results show that 660 nm and 780 nm LLLT can modulate the cellular activation status of macrophages in inflammation, highlighting the importance of this resource and of the correct determination of its parameters in the repair process of skeletal muscle.

  7. Liver Fatty acid binding protein (L-Fabp) modulates murine stellate cell activation and diet induced nonalcoholic fatty liver disease

    Chen, Anping; Tang, Youcai; Davis, Victoria; Hsu, Fong-Fu; Kennedy, Susan M; Song, Haowei; Turk, John; Brunt, Elizabeth M.; Newberry, Elizabeth P.; Davidson, Nicholas O.

    2013-01-01

    Activation of hepatic stellate cells (HSCs) is crucial to the development of fibrosis in nonalcoholic fatty liver disease. Quiescent HSCs contain lipid droplets (LDs), whose depletion upon activation induces a fibrogenic gene program. Here we show that liver fatty acid-binding protein (L-Fabp), an abundant cytosolic protein that modulates fatty acid (FA) metabolism in enterocytes and hepatocytes also modulates HSC FA utilization and in turn regulates the fibrogenic program. L-Fabp expression ...

  8. Large sample activation analysis. Monitoring of photovoltaic module recycling using radioanalytical methods

    Photovoltaic modules are the most promising sources of renewable energy. According to respective EU Directives both the glass carrier material and the photo-active layer (CdTe in this study) shall be re-used. Analyses for process surveillance and control have to be carried out, primarily for monitoring of the separation efficiency and the enrichment level of CdTe. For on-site measurement and process control energy-dispersive X-ray fluorescence spectrometry was used. Instrumental photon activation analysis using an electron linear accelerator as activating bremsstrahlung source is intended to be used later for iterative intermediate analysis of random samples for quality control. In this work, the feasibility of both methods for this task was studied. (author)

  9. Modulation of Backbone Flexibility for Effective Dissociation of Antibacterial and Hemolytic Activity in Cyclic Peptides.

    Oddo, Alberto; Thomsen, Thomas T; Britt, Hannah M; Løbner-Olesen, Anders; Thulstrup, Peter W; Sanderson, John M; Hansen, Paul R

    2016-08-11

    Bacterial resistance to antibiotic therapy is on the rise and threatens to evolve into a worldwide emergency: alternative solutions to current therapies are urgently needed. Cationic amphipathic peptides are potent membrane-active agents that hold promise as the next-generation therapy for multidrug-resistant infections. The peptides' behavior upon encountering the bacterial cell wall is crucial, and much effort has been dedicated to the investigation and optimization of this amphipathicity-driven interaction. In this study we examined the interaction of a novel series of nine-membered flexible cyclic AMPs with liposomes mimicking the characteristics of bacterial membranes. Employed techniques included circular dichroism and marker release assays, as well as microbiological experiments. Our analysis was aimed at correlating ring flexibility with their antimicrobial, hemolytic, and membrane activity. By doing so, we obtained useful insights to guide the optimization of cyclic antimicrobial peptides via modulation of their backbone flexibility without loss of activity. PMID:27563396

  10. Modulation of expression and activity of intestinal multidrug resistance-associated protein 2 by xenobiotics.

    Tocchetti, Guillermo Nicolás; Rigalli, Juan Pablo; Arana, Maite Rocío; Villanueva, Silvina Stella Maris; Mottino, Aldo Domingo

    2016-07-15

    The multidrug resistance-associated protein 2 (MRP2/ABCC2) is a transporter that belongs to the ATP-binding cassette (ABC) superfamily. In the intestine, it is localized to the apical membrane of the enterocyte and plays a key role in limiting the absorption of xenobiotics incorporated orally. MRP2 may also play a role in systemic clearance of xenobiotics available from the serosal side of the intestine. MRP2 transports a wide range of substrates, mainly organic anions conjugated with glucuronic acid, glutathione and sulfate and its expression can be modulated by xenobiotics at transcriptional- and post-transcriptional levels. Transcriptional regulation is usually mediated by a group of nuclear receptors. The pregnane X receptor (PXR) is a major member of this group. Relevant drugs described to up-regulate intestinal MRP2 via PXR are rifampicin, spironolactone and carbamazepine, among others. The constitutive androstane receptor (CAR, NR1I3) was also reported to modulate MRP2 expression, phenobarbital being a typical activator. Dietary compounds, including micronutrients and other natural products, are also capable of regulating intestinal MRP2 expression transcriptionally. We have given them particular attention since the composition of the food ingested daily is not necessarily supervised and may result in interactions with therapeutic drugs. Post-transcriptional regulation of MRP2 activity by xenobiotics, e.g. as a consequence of inhibitory actions, is also described in this review. Unfortunately, only few studies report on drug-drug or nutrient-drug interactions as a consequence of modulation of intestinal MRP2 activity by xenobiotics. Future clinical studies are expected to identify additional interactions resulting in changes in efficacy or safety of therapeutic drugs. PMID:27155371

  11. Advanced glycation end products induce fibrogenic activity in NASH by modulating the TNFα converting enzyme activity

    Joy, Jiang X; Chen, Xiangling; Fukada, Hiroo; Serizawa, Nobuko; Devaraj, Sridevi; Török, Natalie J.

    2013-01-01

    Advanced glycation end products (AGEs) accumulate in patients with diabetes, yet the link between AGEs and the inflammatory and fibrogenic activity in non-alcoholic steatohepatitis (NASH) has not been explored. TNFα converting enzyme (TACE) is at the center of inflammatory processes. As the main natural regulator of TACE activity is the tissue inhibitor of metalloproteinase 3 (Timp3), we hypothesized that AGEs induce TACE through NADPH oxidase 2 (NOX2); and the downregulation of Sirtuin 1 (Si...

  12. Modulation of the chaperone-like activity of bovine alpha-crystallin.

    Clark, J I; Huang, Q L

    1996-12-24

    The effects of pantethine, glutathione, and selected chemical reagents on the anti-aggregation activity of alpha-crystallin was evaluated. Protein aggregation was monitored by light scattering of solutions of denatured beta L-crystallin or alcohol dehydrogenase (ADH). The ratios of beta L-crystallin/alpha-crystallin and ADH/alpha-crystallin were adjusted so that partial inhibition of protein aggregation at 60 degrees C or 37 degrees C, respectively, was observed and modulation of the chaperone action of alpha-crystallin could be evaluated easily with selected endogenous metabolites. Enhancement of the anti-aggregation activity in the beta L-crystallin assay was strongest with pantethine, which appeared to interact with alpha-crystallin. Enhancement of the anti-aggregation activity in the ADH assay was strongest with glutathione which appeared to interact with ADH. The results indicated that the products of common metabolic pathways can modulate the chaperone-like effects of alpha-crystallin on protein aggregation. PMID:8986785

  13. Development of active edge pixel sensors and four-side buttable modules using vertical integration technologies

    Macchiolo, A.; Andricek, L.; Moser, H.-G.; Nisius, R.; Richter, R. H.; Terzo, S.; Weigell, P.

    2014-11-01

    We present an R&D activity focused on the development of novel modules for the upgrade of the ATLAS pixel system at the High Luminosity LHC (HL-LHC). The modules consist of n-in-p pixel sensors, 100 or 200 μm thick, produced at VTT (Finland) with an active edge technology, which considerably reduces the dead area at the periphery of the device. The sensors are interconnected with solder bump-bonding to the ATLAS FE-I3 and FE-I4 read-out chips, and characterised with radioactive sources and beam tests at the CERN-SPS and DESY. The results of these measurements will be discussed for devices before and after irradiation up to a fluence of 5 ×1015neq /cm2. We will also report on the R&D activity to obtain Inter Chip Vias (ICVs) on the ATLAS read-out chip in collaboration with the Fraunhofer Institute EMFT. This step is meant to prove the feasibility of the signal transport to the newly created readout pads on the backside of the chips allowing for four side buttable devices without the presently used cantilever for wire bonding. The read-out chips with ICVs will be interconnected to thin pixel sensors, 75 μm and 150 μm thick, with the Solid Liquid Interdiffusion (SLID) technology, which is an alternative to the standard solder bump-bonding.

  14. Development of active edge pixel sensors and four-side buttable modules using vertical integration technologies

    Macchiolo, A., E-mail: Anna.Macchiolo@mpp.mpg.de [Max-Planck-Institut for Physics, Föhringer Ring 6, D-80805 Munich (Germany); Andricek, L. [Semiconductor Laboratory of the Max-Planck-Society, Otto Hahn Ring 6, D-81739 Munich (Germany); Moser, H.-G.; Nisius, R. [Max-Planck-Institut for Physics, Föhringer Ring 6, D-80805 Munich (Germany); Richter, R.H. [Semiconductor Laboratory of the Max-Planck-Society, Otto Hahn Ring 6, D-81739 Munich (Germany); Terzo, S.; Weigell, P. [Max-Planck-Institut for Physics, Föhringer Ring 6, D-80805 Munich (Germany)

    2014-11-21

    We present an R and D activity focused on the development of novel modules for the upgrade of the ATLAS pixel system at the High Luminosity LHC (HL-LHC). The modules consist of n-in-p pixel sensors, 100 or 200 μm thick, produced at VTT (Finland) with an active edge technology, which considerably reduces the dead area at the periphery of the device. The sensors are interconnected with solder bump-bonding to the ATLAS FE-I3 and FE-I4 read-out chips, and characterised with radioactive sources and beam tests at the CERN-SPS and DESY. The results of these measurements will be discussed for devices before and after irradiation up to a fluence of 5×10{sub 15}n{sub eq}/cm{sup 2}. We will also report on the R and D activity to obtain Inter Chip Vias (ICVs) on the ATLAS read-out chip in collaboration with the Fraunhofer Institute EMFT. This step is meant to prove the feasibility of the signal transport to the newly created readout pads on the backside of the chips allowing for four side buttable devices without the presently used cantilever for wire bonding. The read-out chips with ICVs will be interconnected to thin pixel sensors, 75 μm and 150 μm thick, with the Solid Liquid Interdiffusion (SLID) technology, which is an alternative to the standard solder bump-bonding.

  15. Modulation of PPAR Expression and Activity in Response to Polyphenolic Compounds in High Fat Diets

    J. Abraham Domínguez-Avila

    2016-06-01

    Full Text Available Peroxisome proliferator-activated receptors (PPAR are transcription factors that modulate energy metabolism in liver, adipose tissue and muscle. High fat diets (HFD can negatively impact PPAR expression or activity, favoring obesity, dyslipidemia, insulin resistance and other conditions. However, polyphenols (PP found in vegetable foodstuffs are capable of positively modulating this pathway. We therefore focused this review on the possible effects that PP can have on PPAR when administered together with HFD. We found that PP from diverse sources, such as coffee, olives, rice, berries and others, are capable of inducing the expression of genes involved in a decrease of adipose mass, liver and serum lipids and lipid biosynthesis in animal and cell models of HFD. Since cells or gut bacteria can transform PP into different metabolites, it is possible that a synergistic or antagonistic effect ultimately occurs. PP molecules from vegetable sources are an interesting option to maintain or return to a state of energy homeostasis, possibly due to an adequate PPAR expression and activity.

  16. Modulation of PPAR Expression and Activity in Response to Polyphenolic Compounds in High Fat Diets.

    Domínguez-Avila, J Abraham; González-Aguilar, Gustavo A; Alvarez-Parrilla, Emilio; de la Rosa, Laura A

    2016-01-01

    Peroxisome proliferator-activated receptors (PPAR) are transcription factors that modulate energy metabolism in liver, adipose tissue and muscle. High fat diets (HFD) can negatively impact PPAR expression or activity, favoring obesity, dyslipidemia, insulin resistance and other conditions. However, polyphenols (PP) found in vegetable foodstuffs are capable of positively modulating this pathway. We therefore focused this review on the possible effects that PP can have on PPAR when administered together with HFD. We found that PP from diverse sources, such as coffee, olives, rice, berries and others, are capable of inducing the expression of genes involved in a decrease of adipose mass, liver and serum lipids and lipid biosynthesis in animal and cell models of HFD. Since cells or gut bacteria can transform PP into different metabolites, it is possible that a synergistic or antagonistic effect ultimately occurs. PP molecules from vegetable sources are an interesting option to maintain or return to a state of energy homeostasis, possibly due to an adequate PPAR expression and activity. PMID:27367676

  17. Modulation of PPAR Expression and Activity in Response to Polyphenolic Compounds in High Fat Diets

    Domínguez-Avila, J. Abraham; González-Aguilar, Gustavo A.; Alvarez-Parrilla, Emilio; de la Rosa, Laura A.

    2016-01-01

    Peroxisome proliferator-activated receptors (PPAR) are transcription factors that modulate energy metabolism in liver, adipose tissue and muscle. High fat diets (HFD) can negatively impact PPAR expression or activity, favoring obesity, dyslipidemia, insulin resistance and other conditions. However, polyphenols (PP) found in vegetable foodstuffs are capable of positively modulating this pathway. We therefore focused this review on the possible effects that PP can have on PPAR when administered together with HFD. We found that PP from diverse sources, such as coffee, olives, rice, berries and others, are capable of inducing the expression of genes involved in a decrease of adipose mass, liver and serum lipids and lipid biosynthesis in animal and cell models of HFD. Since cells or gut bacteria can transform PP into different metabolites, it is possible that a synergistic or antagonistic effect ultimately occurs. PP molecules from vegetable sources are an interesting option to maintain or return to a state of energy homeostasis, possibly due to an adequate PPAR expression and activity. PMID:27367676

  18. Modulation of electroencephalograph activity by manual acupuncture stimulation in healthy subjects: An autoregressive spectral analysis

    To investigate whether and how manual acupuncture (MA) modulates brain activities, we design an experiment where acupuncture at acupoint ST36 of the right leg is used to obtain electroencephalograph (EEG) signals in healthy subjects. We adopt the autoregressive (AR) Burg method to estimate the power spectrum of EEG signals and analyze the relative powers in delta (0 Hz–4 Hz), theta (4 Hz–8 Hz), alpha (8 Hz–13 Hz), and beta (13 Hz–30 Hz) bands. Our results show that MA at ST36 can significantly increase the EEG slow wave relative power (delta band) and reduce the fast wave relative powers (alpha and beta bands), while there are no statistical differences in theta band relative power between different acupuncture states. In order to quantify the ratio of slow to fast wave EEG activity, we compute the power ratio index. It is found that the MA can significantly increase the power ratio index, especially in frontal and central lobes. All the results highlight the modulation of brain activities with MA and may provide potential help for the clinical use of acupuncture. The proposed quantitative method of acupuncture signals may be further used to make MA more standardized. (interdisciplinary physics and related areas of science and technology)

  19. Modulation of electroencephalograph activity by manual acupuncture stimulation in healthy subjects: An autoregressive spectral analysis

    Yi Guo-Sheng; Wang Jiang; Deng Bin; Wei Xi-Le; Han Chun-Xiao

    2013-01-01

    To investigate whether and how manual acupuncture (MA) modulates brain activities,we design an experiment where acupuncture at acupoint ST36 of the right leg is used to obtain electroencephalograph (EEG) signals in healthy subjects.We adopt the autoregressive (AR) Burg method to estimate the power spectrum of EEG signals and analyze the relative powers in delta (0 Hz-4 Hz),theta (4 Hz-8 Hz),alpha (8 Hz-13 Hz),and beta (13 Hz-30 Hz) bands.Our results show that MA at ST36 can significantly increase the EEG slow wave relative power (delta band) and reduce the fast wave relative powers (alpha and beta bands),while there are no statistical differences in theta band relative power between different acupuncture states.In order to quantify the ratio of slow to fast wave EEG activity,we compute the power ratio index.It is found that the MA can significantly increase the power ratio index,especially in frontal and central lobes.All the results highlight the modulation of brain activities with MA and may provide potential help for the clinical use of acupuncture.The proposed quantitative method of acupuncture signals may be further used to make MA more standardized.

  20. Significant Modules and Biological Processes between Active Components of Salvia miltiorrhiza Depside Salt and Aspirin

    Yuan Li

    2016-01-01

    Full Text Available The aim of this study is to examine and compare the similarities and differences between active components of S. miltiorrhiza depside salt and aspirin using perspective of pharmacological molecular networks. Active components of S. miltiorrhiza depside salt and aspirin’s related genes were identified via the STITCH4.0 and GeneCards Database. A text search engine (Agilent Literature Search 2.71 and MCODE software were applied to construct network and divide modules, respectively. Finally, 32, 2, and 28 overlapping genes, modules, and pathways were identified between active components of S. miltiorrhiza depside salt and aspirin. A multidimensional framework of drug network showed that two networks reflected commonly in human aortic endothelial cells and atherosclerosis process. Aspirin plays a more important role in metabolism, such as the well-known AA metabolism pathway and other lipid or carbohydrate metabolism pathways. S. miltiorrhiza depside salt still plays a regulatory role in type II diabetes mellitus, insulin resistance, and adipocytokine signaling pathway. Therefore, this study suggests that aspirin combined with S. miltiorrhiza depside salt may be more efficient in treatment of CHD patients, especially those with diabetes mellitus or hyperlipidemia. Further clinical trials to confirm this hypothesis are still needed.

  1. Development of active edge pixel sensors and four-side buttable modules using vertical integration technologies

    We present an R and D activity focused on the development of novel modules for the upgrade of the ATLAS pixel system at the High Luminosity LHC (HL-LHC). The modules consist of n-in-p pixel sensors, 100 or 200 μm thick, produced at VTT (Finland) with an active edge technology, which considerably reduces the dead area at the periphery of the device. The sensors are interconnected with solder bump-bonding to the ATLAS FE-I3 and FE-I4 read-out chips, and characterised with radioactive sources and beam tests at the CERN-SPS and DESY. The results of these measurements will be discussed for devices before and after irradiation up to a fluence of 5×1015neq/cm2. We will also report on the R and D activity to obtain Inter Chip Vias (ICVs) on the ATLAS read-out chip in collaboration with the Fraunhofer Institute EMFT. This step is meant to prove the feasibility of the signal transport to the newly created readout pads on the backside of the chips allowing for four side buttable devices without the presently used cantilever for wire bonding. The read-out chips with ICVs will be interconnected to thin pixel sensors, 75 μm and 150 μm thick, with the Solid Liquid Interdiffusion (SLID) technology, which is an alternative to the standard solder bump-bonding

  2. Modulation of statin-activated shedding of Alzheimer APP ectodomain by ROCK.

    Steve Pedrini

    2005-01-01

    Full Text Available BACKGROUND: Statins are widely used cholesterol-lowering drugs that act by inhibiting HMGCoA reductase, the rate-limiting enzyme in cholesterol biosynthesis. Recent evidence suggests that statin use may be associated with a decreased risk for Alzheimer disease, although the mechanisms underlying this apparent risk reduction are poorly understood. One popular hypothesis for statin action is related to the drugs' ability to activate alpha-secretase-type shedding of the alpha-secretase-cleaved soluble Alzheimer amyloid precursor protein ectodomain (sAPP(alpha. Statins also inhibit the isoprenoid pathway, thereby modulating the activities of the Rho family of small GTPases-Rho A, B, and C-as well as the activities of Rac and cdc42. Rho proteins, in turn, exert many of their effects via Rho-associated protein kinases (ROCKs. Several cell-surface molecules are substrates for activated alpha-secretase-type ectodomain shedding, and regulation of shedding typically occurs via activation of protein kinase C or extracellular-signal-regulated protein kinases, or via inactivation of protein phosphatase 1 or 2A. However, the possibility that these enzymes play a role in statin-stimulated shedding has been excluded, leading us to investigate whether the Rho/ROCK1 protein phosphorylation pathway might be involved. METHODS AND FINDINGS: We found that both atorvastatin and simvastatin stimulated sAPP(alpha shedding from a neuroblastoma cell line via a subcellular mechanism apparently located upstream of endocytosis. A farnesyl transferase inhibitor also increased sAPP(alpha shedding, as did a dominant negative form of ROCK1. Most conclusively, a constitutively active ROCK1 molecule inhibited statin-stimulated sAPP(alpha shedding. CONCLUSION: Together, these data suggest that statins exert their effects on shedding of sAPP(alpha from cultured cells, at least in part, by modulation of the isoprenoid pathway and ROCK1.

  3. Modulation of Statin-Activated Shedding of Alzheimer APP Ectodomain by ROCK

    Pedrini Steve

    2005-01-01

    Full Text Available Background Statins are widely used cholesterol-lowering drugs that act by inhibiting HMGCoA reductase, the rate-limiting enzyme in cholesterol biosynthesis. Recent evidence suggests that statin use may be associated with a decreased risk for Alzheimer disease, although the mechanisms underlying this apparent risk reduction are poorly understood. One popular hypothesis for statin action is related to the drugs' ability to activate alpha-secretase-type shedding of the alpha-secretase-cleaved soluble Alzheimer amyloid precursor protein ectodomain (sAPPalpha. Statins also inhibit the isoprenoid pathway, thereby modulating the activities of the Rho family of small GTPases-Rho A, B, and C-as well as the activities of Rac and cdc42. Rho proteins, in turn, exert many of their effects via Rho-associated protein kinases (ROCKs. Several cell-surface molecules are substrates for activated alpha-secretase-type ectodomain shedding, and regulation of shedding typically occurs via activation of protein kinase C or extracellular-signal-regulated protein kinases, or via inactivation of protein phosphatase 1 or 2A. However, the possibility that these enzymes play a role in statin-stimulated shedding has been excluded, leading us to investigate whether the Rho/ROCK1 protein phosphorylation pathway might be involved. Methods and Findings We found that both atorvastatin and simvastatin stimulated sAPPalpha shedding from a neuroblastoma cell line via a subcellular mechanism apparently located upstream of endocytosis. A farnesyl transferase inhibitor also increased sAPPalpha shedding, as did a dominant negative form of ROCK1. Most conclusively, a constitutively active ROCK1 molecule inhibited statin-stimulated sAPPalpha shedding. Conclusion Together, these data suggest that statins exert their effects on shedding of sAPPalpha from cultured cells, at least in part, by modulation of the isoprenoid pathway and ROCK1.

  4. Role of local prostaglandin synthesis in the modulation of proliferative activity of rat colonic epithelium.

    Craven, P A; R. Saito; DeRubertis, F R

    1983-01-01

    The role of local prostaglandin (PG) synthesis in the modulation of the proliferative activity of colonic epithelium was examined in rat colon. Experimental rats were given either indomethacin (5 mg/kg s.c. every 8 h for three doses) or aspirin (0.5 g/100 g diet for 3 d). In rats treated with indomethacin or aspirin, the incorporation of [3H]thymidine (dThd) into DNA in vivo was increased approximately twofold over control in mucosal scrapings from distal colon, and approximately threefold ov...

  5. Integration of Optical Manipulation and Electrophysiological Tools to Modulate and Record Activity in Neural Networks

    Difato, F.; Schibalsky, L.; Benfenati, F.; Blau, A.

    2011-07-01

    We present an optical system that combines IR (1064 nm) holographic optical tweezers with a sub-nanosecond-pulsed UV (355 nm) laser microdissector for the optical manipulation of single neurons and entire networks both on transparent and non-transparent substrates in vitro. The phase-modulated laser beam can illuminate the sample concurrently or independently from above or below assuring compatibility with different types of microelectrode array and patch-clamp electrophysiology. By combining electrophysiological and optical tools, neural activity in response to localized stimuli or injury can be studied and quantified at sub-cellular, cellular, and network level.

  6. Modulation of Subgenual Anterior Cingulate Cortex Activity With Real-Time Neurofeedback

    Hamilton, J. Paul; Glover, Gary H.; Hsu, Jung-Jiin; Johnson, Rebecca F.; Gotlib, Ian H.

    2011-01-01

    The advent of real-time neurofeedback techniques has allowed us to begin to map the controllability of sensory and cognitive and, more recently, affective centers in the brain. The subgenual anterior cingulate cortex (sACC) is thought to be involved in generation of affective states and has been implicated in psychopathology. In this study, we examined whether individuals could use realtime fMRI neurofeedback to modulate sACC activity. Following a localizer task used to identify an sACC regio...

  7. 2 MW Active Bouncer Converter Design for Long Pulse Klystron Modulators

    Aguglia, D

    2012-01-01

    This paper presents some design issues of a 2 MW interleaved buck converter which is used as an active bouncer droop compensator for a 5.5MW long pulse klystron modulator. This novel design concept presents many challenges in terms of voltage ripple versus pulse rise-time. Issues related to the voltage ripple specification versus output filter design are discussed in detail. The design study is analyzed analytically, simulated numerically and is validated by experimental results obtained from a full power prototype.

  8. Modulation of hurricane activity in the gulf of mexico by the madden-julian oscillation

    Maloney; Hartmann

    2000-03-17

    The Madden-Julian oscillation (MJO) is a large-scale episodic modulation of tropical winds and precipitation that travels eastward from Asia to America, with a characteristic repeat time of 30 to 60 days. Here it is shown that when MJO wind anomalies in the lower troposphere of the eastern Pacific are westerly, Gulf of Mexico and western Caribbean hurricane genesis is four times more likely than when the MJO winds are easterly. Accurate predictions of the MJO may lead to improved long-range forecasts of tropical cyclone activity. PMID:10720323

  9. Dopaminergic modulation of the spectral characteristics in the rat brain oscillatory activity

    Highlights: ► The oscillatory activity recorded at different locations of the rat brain present a power law characteristic (PLC). ► Dopaminergic drugs are able to modify the power law spectral characteristic of the oscillatory activity. ► Drugs with opposite effects over the dopaminergic system (agonists/antagonists), induce opposite changes in the PLC. ► There is a fulcrum point for the modulation of the PLC around 20 Hz. ► The brain operates in a state of self-organized criticality (SOC) sensitive to dopaminergic modulation. - Abstract: Oscillatory activity can be widely recorded in the brain. It has been demonstrated to play an important role not only in the physiology of movement, perception and cognition, but also in the pathophysiology of a variety of diseases. In frequency domain, neurophysiological recordings show a power spectrum (PSD) following a log (PSD) ∝ log (f)−β, that reveals an intrinsic feature of many complex systems in nature: the presence of a scale-free dynamics characterized by a power-law component (PLC). Here we analyzed the influence of dopaminergic drugs over the PLC of the oscillatory activity recorded from different locations of the rat brain. Dopamine (DA) is a neurotransmitter that is required for a number of physiological functions like normal feeding, locomotion, posturing, grooming and reaction time. Alterations in the dopaminergic system cause vast effects in the dynamics of the brain activity, that may be crucial in the pathophysiology of neurological (like Parkinson’s disease) or psychiatric (like schizophrenia) diseases. Our results show that drugs with opposite effects over the dopaminergic system, induce opposite changes in the characteristics of the PLC: DA agonists/antagonists cause the PLC to swing around a fulcrum point in the range of 20 Hz. Changes in the harmonic component of the spectrum were also detected. However, differences between recordings are better explained by the modulation of the PLC than

  10. Modulation of hepatocarcinoma cell morphology and activity by parylene-C coating on PDMS.

    Nazaré Pereira-Rodrigues

    Full Text Available BACKGROUND: The ability to understand and locally control the morphogenesis of mammalian cells is a fundamental objective of cell and developmental biology as well as tissue engineering research. We present parylene-C (ParC deposited on polydimethylsiloxane (PDMS as a new substratum for in vitro advanced cell culture in the case of Human Hepatocarcinoma (HepG2 cells. PRINCIPAL FINDINGS: Our findings establish that the intrinsic properties of ParC-coated PDMS (ParC/PDMS influence and modulate initial extracellular matrix (ECM; here, type-I collagen surface architecture, as compared to non-coated PDMS substratum. Morphological changes induced by the presence of ParC on PDMS were shown to directly affect liver cell metabolic activity and the expression of transmembrane receptors implicated in cell adhesion and cell-cell interaction. These changes were characterized by atomic force microscopy (AFM, which elucidated differences in HepG2 cell adhesion, spreading, and reorganization into two- or three-dimensional structures by neosynthesis of ECM components. Local modulation of cell aggregation was successfully performed using ParC/PDMS micropatterns constructed by simple microfabrication. CONCLUSION/SIGNIFICANCE: We demonstrated for the first time the modulation of HepG2 cells' behavior in relation to the intrinsic physical properties of PDMS and ParC, enabling the local modulation of cell spreading in a 2D or 3D manner by simple microfabrication techniques. This work will provide promising insights into the development of cell-based platforms that have many applications in the field of in vitro liver tissue engineering, pharmacology and therapeutics.

  11. Apparent permeability of electrical steel under PWM magnetisation

    In recent years much attention has been paid to material performance under pulse width modulation (PWM) excitation conditions, which is of increasing importance to motor applications particularly in energy efficient variable speed drive systems. It is well known that in general, losses increase significantly with reducing modulation index, the increase depending on parameters such as silicon contents, thickness and grain size. The effect of the PWM waveform on permeability has attracted little attention until now. So in this paper its influence on the permeability of electrical steel is analysed and characterised. A prediction approach based on the permeability under sine wave excitation and total harmonic distortion is introduced which results in errors below 10% for non-electrical steel at 1.5 T

  12. Low Permeability Polyimide Insulation Project

    National Aeronautics and Space Administration — Resodyn Technologies proposes a new technology that enables the application of polyimide based cryogenic insulation with low hydrogen permeability. This effort...

  13. Surfactant protein A integrates activation signal strength to differentially modulate T cell proliferation.

    Mukherjee, Sambuddho; Giamberardino, Charles; Thomas, Joseph; Evans, Kathy; Goto, Hisatsugu; Ledford, Julie G; Hsia, Bethany; Pastva, Amy M; Wright, Jo Rae

    2012-02-01

    Pulmonary surfactant lipoproteins lower the surface tension at the alveolar-airway interface of the lung and participate in host defense. Previous studies reported that surfactant protein A (SP-A) inhibits lymphocyte proliferation. We hypothesized that SP-A-mediated modulation of T cell activation depends upon the strength, duration, and type of lymphocyte activating signals. Modulation of T cell signal strength imparted by different activating agents ex vivo and in vivo in different mouse models and in vitro with human T cells shows a strong correlation between strength of signal (SoS) and functional effects of SP-A interactions. T cell proliferation is enhanced in the presence of SP-A at low SoS imparted by exogenous mitogens, specific Abs, APCs, or in homeostatic proliferation. Proliferation is inhibited at higher SoS imparted by different doses of the same T cell mitogens or indirect stimuli such as LPS. Importantly, reconstitution with exogenous SP-A into the lungs of SP-A(-/-) mice stimulated with a strong signal also resulted in suppression of T cell proliferation while elevating baseline proliferation in unstimulated T cells. These signal strength and SP-A-dependent effects are mediated by changes in intracellular Ca(2+) levels over time, involving extrinsic Ca(2+)-activated channels late during activation. These effects are intrinsic to the global T cell population and are manifested in vivo in naive as well as memory phenotype T cells. Thus, SP-A appears to integrate signal thresholds to control T cell proliferation. PMID:22219327

  14. TOUCHING MOMENTS: DESIRE MODULATES THE NEURAL ANTICIPATION OF ACTIVE ROMANTIC CARESS

    Sjoerd J.H. Ebisch

    2014-02-01

    Full Text Available A romantic caress is a basic expression of affiliative behavior and a primary reinforcer. Given its inherent affective valence, its performance also would imply the prediction of reward values. For example, touching a person for whom one has strong passionate feelings likely is motivated by a strong desire for physical contact and associated with the anticipation of hedonic experiences. The present study aims at investigating how the anticipatory neural processes of active romantic caress are modulated by the intensity of the desire for affective contact as reflected by passionate feelings for the other. Functional magnetic resonance imaging scanning was performed in romantically involved partners using a paradigm that allowed to isolate the specific anticipatory representations of active romantic caress, compared with control caress, while testing for the relationship between neural activity and measures of feelings of passionate love for the other. The results demonstrated that right posterior insula activity in anticipation of romantic caress significantly co-varied with the intensity of desire for union with the other. This effect was independent of the sensory-affective properties of the performed touch, like its pleasantness. Furthermore, functional connectivity analysis showed that the same posterior insula cluster interacted with brain regions related to sensory-motor functions as well as to the processing and anticipation of reward. The findings provide insight on the neural substrate mediating between the desire for and the performance of romantic caress. In particular, we propose that anticipatory activity patterns in posterior insula may modulate subsequent sensory-affective processing of skin-to-skin contact.

  15. Regulation of endothelial permeability and transendothelial migration of cancer cells by tropomyosin-1 phosphorylation

    Simoneau Bryan

    2012-11-01

    Full Text Available Abstract Background Loss of endothelial cell integrity and selective permeability barrier is an early event in the sequence of oxidant-mediated injury and may result in atherosclerosis, hypertension and facilitation of transendothelial migration of cancer cells during metastasis. We already reported that endothelial cell integrity is tightly regulated by the balanced co-activation of p38 and ERK pathways. In particular, we showed that phosphorylation of tropomyosin-1 (tropomyosin alpha-1 chain = Tm1 at Ser283 by DAP kinase, downstream of the ERK pathway might be a key event required to maintain the integrity and normal functions of the endothelium in response to oxidative stress. Methods Endothelial permeability was assayed by monitoring the passage of Dextran-FITC through a tight monolayer of HUVECs grown to confluence in Boyden chambers. Actin and Tm1 dynamics and distribution were evaluated by immunofluorescence. We modulated the expression of Tm1 by siRNA and lentiviral-mediated expression of wild type and mutated forms of Tm1 insensitive to the siRNA. Transendothelial migration of HT-29 colon cancer cells was monitored in Boyden chambers similarly as for permeability. Results We provide evidence indicating that Tm1 phosphorylation at Ser283 is essential to regulate endothelial permeability under oxidative stress by modulating actin dynamics. Moreover, the transendothelial migration of colon cancer cells is also regulated by the phosphorylation of Tm1 at Ser283. Conclusion Our finding strongly support the role for the phosphorylation of endothelial Tm1 at Ser283 to prevent endothelial barrier dysfunction associated with oxidative stress injury.

  16. Activity in ventral premotor cortex is modulated by vision of own hand in action

    Luciano Fadiga

    2013-07-01

    Full Text Available Parietal and premotor cortices of the macaque monkey contain distinct populations of neurons which, in addition to their motor discharge, are also activated by visual stimulation. Among these visuomotor neurons, a population of grasping neurons located in the anterior intraparietal area (AIP shows discharge modulation when the own hand is visible during object grasping. Given the dense connections between AIP and inferior frontal regions, we aimed at investigating whether two hand-related frontal areas, ventral premotor area F5 and primary motor cortex (area F1, contain neurons with similar properties. Two macaques were involved in a grasping task executed in various light/dark conditions in which the to-be-grasped object was kept visible by a dim retro-illumination. Approximately 62% of F5 and 55% of F1 motor neurons showed light/dark modulations. To better isolate the effect of hand-related visual input, we introduced two further conditions characterized by kinematic features similar to the dark condition. The scene was briefly illuminated (i during hand preshaping (pre-touch flash, PT-flash and (ii at hand-object contact (touch flash, T-flash. Approximately 48% of F5 and 44% of F1 motor neurons showed a flash-related modulation. Considering flash-modulated neurons in the two flash conditions, ∼40% from F5 and ∼52% from F1 showed stronger activity in PT- than T-flash (PT-flash-dominant, whereas ∼60% from F5 and ∼48% from F1 showed stronger activity in T- than PT-flash (T-flash-dominant. Furthermore, F5, but not F1, flash-dominant neurons were characterized by a higher peak and mean discharge in the preferred flash condition as compared to light and dark conditions. Still considering F5, the distribution of the time of peak discharge was similar in light and preferred flash conditions. This study shows that the frontal cortex contains neurons, previously classified as motor neurons, which are sensitive to the observation of meaningful

  17. An Oligodeoxynucleotide with Promising Modulation Activity for the Proliferation and Activation of Osteoblast

    Xinhua Sun

    2011-04-01

    Full Text Available The paper explored the regulatory role of oligodeoxynucleotides (ODNs with specific sequences in the proliferation and activation of osteoblast, using human osteoblast-like cell line MG 63 as the model. Through the administration of ODNs to MG 63 cells at a concentration of 1.0 µg/mL, ODN MT01 with positive effects on proliferation and activation of osteoblast was selected from 11 different ODNs by methyl thiazolyl tetrazolium (MTT assay and alkaline phosphatase (ALP activity measurement. To get a deeper insight into the molecular mechanism, effects of ODN MT01 treatment on the expression level of Sp7, runx-2, collagen-I, osteoprotegerin (OPG and RANK ligand (RANKL were determined using quantitative real time PCR and Western blotting. Remarkably, the mRNA and protein expression levels of Sp7, runx-2, collagen-I and OPG were improved after ODN MT01 treatment. Meanwhile, the protein expression level of RANKL was dramatically decreased. These results suggested that ODN MT01 had a significant impact in facilitating osteogenic proliferation and activation, and provided a direct evidence for the notion that single strand ODN could regulate the balance of bone formation and resorption, and thus was of great potential in the rebuilding of alveolar bone.

  18. Activation of glycine receptors modulates spontaneous epileptiform activity in the immature rat hippocampus

    Chen, Rongqing; Okabe, Akihito; Sun, Haiyan; Sharopov, Salim; Hanganu-Opatz, Ileana L; Kolbaev, Sergei N; Fukuda, Atsuo; Luhmann, Heiko J; Kilb, Werner

    2014-01-01

    While the expression of glycine receptors in the immature hippocampus has been shown, no information about the role of glycine receptors in controlling the excitability in the immature CNS is available. Therefore, we examined the effect of glycinergic agonists and antagonists in the CA3 region of an intact corticohippocampal preparation of the immature (postnatal days 4–7) rat using field potential recordings. Bath application of 100 μm taurine or 10 μm glycine enhanced the occurrence of recurrent epileptiform activity induced by 20 μm 4-aminopyridine in low Mg2+ solution. This proconvulsive effect was prevented by 3 μm strychnine or after incubation with the loop diuretic bumetanide (10 μm), suggesting that it required glycine receptors and an active NKCC1-dependent Cl− accumulation. Application of higher doses of taurine (≥1 mm) or glycine (100 μm) attenuated recurrent epileptiform discharges. The anticonvulsive effect of taurine was also observed in the presence of the GABAA receptor antagonist gabazine and was attenuated by strychnine, suggesting that it was partially mediated by glycine receptors. Bath application of the glycinergic antagonist strychnine (0.3 μm) induced epileptiform discharges. We conclude from these results that in the immature hippocampus, activation of glycine receptors can mediate both pro- and anticonvulsive effects, but that a persistent activation of glycine receptors is required to suppress epileptiform activity. In summary, our study elucidated the important role of glycine receptors in the control of neuronal excitability in the immature hippocampus. PMID:24665103

  19. Restoring wtp53 activity in HIPK2 depleted MCF7 cells by modulating metallothionein and zinc.

    Puca, Rosa; Nardinocchi, Lavinia; Bossi, Gianluca; Sacchi, Ada; Rechavi, Gideon; Givol, David; D'Orazi, Gabriella

    2009-01-01

    The maintenance of p53 transactivation activity is important for p53 apoptotic function. We have shown that stable knockdown of HIPK2 induces p53 misfolding with inhibition of p53 target gene transcription. In this study we established a lentiviral-based system for doxycyclin (Dox)-induced conditional interference of HIPK2 expression to evaluate the molecular mechanisms involved in p53 deregulation. We found that HIPK2 knockdown induced metallothionein 2A (MT2A) upregulation as assessed by RT-PCR analysis, increased promoter acetylation, and increased promoter luciferase activity. The MT2A upregulation correlated with resistance to Adriamycin (ADR)-driven apoptosis and with p53 inhibition. Thus, acute knockdown of HIPK2 (HIPK2i) induced misfolded p53 protein in MCF7 breast cancer cells and inhibited p53 DNA-binding and transcription activities in response to ADR treatment. Previous works show that MT may modulate p53 activity through zinc exchange. Here, we found that inhibition of MT2A expression by siRNA in the HIPK2i cells restored p53 transcription activity. Similarly zinc supplementation to HIPK2i cells restored p53 transcription activity and drug-induced apoptosis. These data support the notion that MT2A is involved in p53 deregulation and strengthen the possibility that combination of chemotherapy and zinc might be useful to treat tumors with inactive wtp53. PMID:18996371

  20. Chromospheric activity and rotational modulation on the young, single K2 dwarf LQ Hya

    High-resolution echelle spectra of LQ Hya, obtained during several observing runs from 2006 to 2012, have been analyzed to study its chromospheric activity. Using the spectral subtraction technique, we derived information about chromospheric activity of LQ Hya from several optical chromospheric activity indicators (including the Hβ, He I D3, Na I D1, D2, Hα, and Ca II infrared triplet (IRT) lines). No optical flares were found during our observations. The equivalent widths (EWs) of the excess emissions in the chromospheric activity lines have been measured. The ratios of EW8542/EW8498 are generally small, which indicates that the Ca II IRT emission arises from plage-like regions, while the E Hα/E Hβ values suggest that the emission of the Balmer lines is due to both plage and prominence structures for the observations in 2012. We find that clear rotational modulation of chromospheric emission exists, which suggests the presence and change of chromospheric active regions over the surface of LQ Hya. Moreover, the active regions were associated with the photospheric spots in spatial structure.

  1. Phasic and tonic mGlu7 receptor activity modulates the thalamocortical network

    Valériane eTassin

    2016-04-01

    Full Text Available Mutation of the metabotropic glutamate receptor type 7 (mGlu7 induces absence-like epileptic seizures, but its precise role in the somatosensory thalamocortical network remains unknown. By combining electrophysiological recordings, optogenetics and pharmacology we dissected the contribution of the mGlu7 receptor at mouse thalamic synapses. We found that mGlu7 is functionally expressed at both glutamatergic and GABAergic synapses, where it can inhibit neurotransmission and regulate short-term plasticity. These effects depend on the PDZ-ligand of the receptor, as they are lost in mutant mice. Interestingly, the very low affinity of mGlu7 receptors for glutamate raises the question of how it can be activated, namely at GABAergic synapses and in basal conditions. Inactivation of the receptor activity with the mGlu7 negative allosteric modulator (NAM, ADX71743, enhances thalamic synaptic transmission. In vivo administration of the NAM induces a lethargic state with spindle and/or spike-and-wave discharges accompanied by a behavioral arrest typical of absence epileptic seizures. This provides evidence for mGlu7 receptor-mediated tonic modulation of a physiological function in vivo preventing synchronous and potentially pathological oscillations.

  2. Phasic and Tonic mGlu7 Receptor Activity Modulates the Thalamocortical Network.

    Tassin, Valériane; Girard, Benoît; Chotte, Apolline; Fontanaud, Pierre; Rigault, Delphine; Kalinichev, Mikhail; Perroy, Julie; Acher, Francine; Fagni, Laurent; Bertaso, Federica

    2016-01-01

    Mutation of the metabotropic glutamate receptor type 7 (mGlu7) induces absence-like epileptic seizures, but its precise role in the somatosensory thalamocortical network remains unknown. By combining electrophysiological recordings, optogenetics, and pharmacology, we dissected the contribution of the mGlu7 receptor at mouse thalamic synapses. We found that mGlu7 is functionally expressed at both glutamatergic and GABAergic synapses, where it can inhibit neurotransmission and regulate short-term plasticity. These effects depend on the PDZ-ligand of the receptor, as they are lost in mutant mice. Interestingly, the very low affinity of mGlu7 receptors for glutamate raises the question of how it can be activated, namely at GABAergic synapses and in basal conditions. Inactivation of the receptor activity with the mGlu7 negative allosteric modulator (NAM), ADX71743, enhances thalamic synaptic transmission. In vivo administration of the NAM induces a lethargic state with spindle and/or spike-and-wave discharges accompanied by a behavioral arrest typical of absence epileptic seizures. This provides evidence for mGlu7 receptor-mediated tonic modulation of a physiological function in vivo preventing synchronous and potentially pathological oscillations. PMID:27199672

  3. Lung protease/anti-protease network and modulation of mucus production and surfactant activity.

    Garcia-Verdugo, Ignacio; Descamps, Delphyne; Chignard, Michel; Touqui, Lhousseine; Sallenave, Jean-Michel

    2010-11-01

    Lung epithelium guarantees gas-exchange (performed in the alveoli) and protects from external insults (pathogens, pollutants…) present within inhaled air. Both functions are facilitated by secretions lining airway surface liquid, mucus (in the upper airways) and pulmonary surfactant (in the alveoli). Mucins, the main glycoproteins present within the mucus, are responsible for its rheologic properties and participate in lung defense mechanisms. In parallel, lung collectins are pattern recognition molecules present in pulmonary surfactant that also modulate lung defense. During chronic airways diseases, excessive protease activity can promote mucus hypersecretion and degradation of lung collectins and therefore contribute to the pathophysiology of these diseases. Importantly, secretion of local and systemic anti-proteases might be crucial to equilibrate the protease/anti-protease unbalance and therefore preserve the function of lung host defense compounds and airway surface liquid homeostasis. In this review we will present information relative to proteases able to modulate mucin production and lung collectin integrity, two important compounds of innate immune defense. One strategy to preserve physiological mucus production and collectin integrity during chronic airways diseases might be the over-expression of local 'alarm' anti-proteases such as SLPI and elafin. Interestingly, a cross-talk between lung collectins and anti-protease activity has recently been described, implicating the presence within the lung of a complex network between proteases, anti-proteases and pattern recognition molecules, which aims to keep or restore homeostasis in resting or inflamed lungs. PMID:20493919

  4. White noise improves learning by modulating activity in dopaminergic midbrain regions and right superior temporal sulcus.

    Rausch, Vanessa H; Bauch, Eva M; Bunzeck, Nico

    2014-07-01

    In neural systems, information processing can be facilitated by adding an optimal level of white noise. Although this phenomenon, the so-called stochastic resonance, has traditionally been linked with perception, recent evidence indicates that white noise may also exert positive effects on cognitive functions, such as learning and memory. The underlying neural mechanisms, however, remain unclear. Here, on the basis of recent theories, we tested the hypothesis that auditory white noise, when presented during the encoding of scene images, enhances subsequent recognition memory performance and modulates activity within the dopaminergic midbrain (i.e., substantia nigra/ventral tegmental area, SN/VTA). Indeed, in a behavioral experiment, we can show in healthy humans that auditory white noise-but not control sounds, such as a sinus tone-slightly improves recognition memory. In an fMRI experiment, white noise selectively enhances stimulus-driven phasic activity in the SN/VTA and auditory cortex. Moreover, it induces stronger connectivity between SN/VTA and right STS, which, in addition, exhibited a positive correlation with subsequent memory improvement by white noise. Our results suggest that the beneficial effects of auditory white noise on learning depend on dopaminergic neuromodulation and enhanced connectivity between midbrain regions and the STS-a key player in attention modulation. Moreover, they indicate that white noise could be particularly useful to facilitate learning in conditions where changes of the mesolimbic system are causally related to memory deficits including healthy and pathological aging. PMID:24345178

  5. Epigenetic modulations in activated cells early after HIV-1 infection and their possible functional consequences.

    Juliana T Maricato

    Full Text Available Epigenetic modifications refer to a number of biological processes which alter the structure of chromatin and its transcriptional activity such as DNA methylation and histone post-translational processing. Studies have tried to elucidate how the viral genome and its products are affected by epigenetic modifications imposed by cell machinery and how it affects the ability of the virus to either, replicate and produce a viable progeny or be driven to latency. The purpose of this study was to evaluate epigenetic modifications in PBMCs and CD4+ cells after HIV-1 infection analyzing three approaches: (i global DNA- methylation; (ii qPCR array and (iii western blot. HIV-1 infection led to methylation increases in the cellular DNA regardless the activation status of PBMCs. The analysis of H3K9me3 and H3K27me3 suggested a trend towards transcriptional repression in activated cells after HIV-1 infection. Using a qPCR array, we detected genes related to epigenetic processes highly modulated in activated HIV-1 infected cells. SETDB2 and RSK2 transcripts showed highest up-regulation levels. SETDB2 signaling is related to transcriptional silencing while RSK2 is related to either silencing or activation of gene expression depending on the signaling pathway triggered down-stream. In addition, activated cells infected by HIV-1 showed lower CD69 expression and a decrease of IL-2, IFN-γ and metabolism-related factors transcripts indicating a possible functional consequence towards global transcriptional repression found in HIV-1 infected cells. Conversely, based on epigenetic markers studied here, non-stimulated cells infected by HIV-1, showed signs of global transcriptional activation. Our results suggest that HIV-1 infection exerts epigenetic modulations in activated cells that may lead these cells to transcriptional repression with important functional consequences. Moreover, non-stimulated cells seem to increase gene transcription after HIV-1 infection

  6. Predicting chemically-induced skin reactions. Part II: QSAR models of skin permeability and the relationships between skin permeability and skin sensitization

    Skin permeability is widely considered to be mechanistically implicated in chemically-induced skin sensitization. Although many chemicals have been identified as skin sensitizers, there have been very few reports analyzing the relationships between molecular structure and skin permeability of sensitizers and non-sensitizers. The goals of this study were to: (i) compile, curate, and integrate the largest publicly available dataset of chemicals studied for their skin permeability; (ii) develop and rigorously validate QSAR models to predict skin permeability; and (iii) explore the complex relationships between skin sensitization and skin permeability. Based on the largest publicly available dataset compiled in this study, we found no overall correlation between skin permeability and skin sensitization. In addition, cross-species correlation coefficient between human and rodent permeability data was found to be as low as R2 = 0.44. Human skin permeability models based on the random forest method have been developed and validated using OECD-compliant QSAR modeling workflow. Their external accuracy was high (Q2ext = 0.73 for 63% of external compounds inside the applicability domain). The extended analysis using both experimentally-measured and QSAR-imputed data still confirmed the absence of any overall concordance between skin permeability and skin sensitization. This observation suggests that chemical modifications that affect skin permeability should not be presumed a priori to modulate the sensitization potential of chemicals. The models reported herein as well as those developed in the companion paper on skin sensitization suggest that it may be possible to rationally design compounds with the desired high skin permeability but low sensitization potential. - Highlights: • It was compiled the largest publicly-available skin permeability dataset. • Predictive QSAR models were developed for skin permeability. • No concordance between skin sensitization and skin

  7. Predicting chemically-induced skin reactions. Part II: QSAR models of skin permeability and the relationships between skin permeability and skin sensitization

    Alves, Vinicius M. [Laboratory of Molecular Modeling and Design, Faculty of Pharmacy, Federal University of Goiás, Goiânia, GO 74605-220 (Brazil); Laboratory for Molecular Modeling, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599 (United States); Muratov, Eugene [Laboratory for Molecular Modeling, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599 (United States); Laboratory of Theoretical Chemistry, A.V. Bogatsky Physical–Chemical Institute NAS of Ukraine, Odessa 65080 (Ukraine); Fourches, Denis [Laboratory for Molecular Modeling, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599 (United States); Strickland, Judy; Kleinstreuer, Nicole [ILS/Contractor supporting the NTP Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM), P.O. Box 13501, Research Triangle Park, NC 27709 (United States); Andrade, Carolina H. [Laboratory of Molecular Modeling and Design, Faculty of Pharmacy, Federal University of Goiás, Goiânia, GO 74605-220 (Brazil); Tropsha, Alexander, E-mail: alex_tropsha@unc.edu [Laboratory for Molecular Modeling, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599 (United States)

    2015-04-15

    Skin permeability is widely considered to be mechanistically implicated in chemically-induced skin sensitization. Although many chemicals have been identified as skin sensitizers, there have been very few reports analyzing the relationships between molecular structure and skin permeability of sensitizers and non-sensitizers. The goals of this study were to: (i) compile, curate, and integrate the largest publicly available dataset of chemicals studied for their skin permeability; (ii) develop and rigorously validate QSAR models to predict skin permeability; and (iii) explore the complex relationships between skin sensitization and skin permeability. Based on the largest publicly available dataset compiled in this study, we found no overall correlation between skin permeability and skin sensitization. In addition, cross-species correlation coefficient between human and rodent permeability data was found to be as low as R{sup 2} = 0.44. Human skin permeability models based on the random forest method have been developed and validated using OECD-compliant QSAR modeling workflow. Their external accuracy was high (Q{sup 2}{sub ext} = 0.73 for 63% of external compounds inside the applicability domain). The extended analysis using both experimentally-measured and QSAR-imputed data still confirmed the absence of any overall concordance between skin permeability and skin sensitization. This observation suggests that chemical modifications that affect skin permeability should not be presumed a priori to modulate the sensitization potential of chemicals. The models reported herein as well as those developed in the companion paper on skin sensitization suggest that it may be possible to rationally design compounds with the desired high skin permeability but low sensitization potential. - Highlights: • It was compiled the largest publicly-available skin permeability dataset. • Predictive QSAR models were developed for skin permeability. • No concordance between skin

  8. Aurora kinase B activity is modulated by thyroid hormone during transcriptional activation of pituitary genes

    Tardáguila, Manuel; González-Gugel, Elena; Sánchez-Pacheco, Aurora

    2011-01-01

    Covalent histone modifications clearly play an essential role in ligand-dependent transcriptional regulation by nuclear receptors. One of the predominant mechanisms used by nuclear receptors to activate or repress target-gene transcription is the recruitment of coregulatory factors capable of covalently modify the amino terminal ends of histones. Here we show that the thyroid hormone (T3) produces a rapid increase in histone H3Ser10 phosphorylation (H3Ser10ph) concomitant to the rapid displac...

  9. Osthole inhibits histamine-dependent itch via modulating TRPV1 activity.

    Yang, Niu-Niu; Shi, Hao; Yu, Guang; Wang, Chang-Ming; Zhu, Chan; Yang, Yan; Yuan, Xiao-Lin; Tang, Min; Wang, Zhong-Li; Gegen, Tana; He, Qian; Tang, Kehua; Lan, Lei; Wu, Guan-Yi; Tang, Zong-Xiang

    2016-01-01

    Osthole, an active coumarin isolated from Cnidium monnieri (L.) Cusson, has long been used in China as an antipruritic herbal medicine; however, the antipruitic mechanism of osthole is unknown. We studied the molecular mechanism of osthole in histamine-dependent itch by behavioral test, Ca(2+) imaging, and electrophysiological experiments. First, osthole clearly remitted the scratching behaviors of mice induced with histamine, HTMT, and VUF8430. Second, in cultured dorsal root ganglion (DRG) neurons, osthole showed a dose-dependent inhibitory effect to histamine. On the same neurons, osthole also decreased the response to capsaicin and histamine. In further tests, the capsaicin-induced inward currents were inhibited by osthole. These results revealed that osthole inhibited histamine-dependent itch by modulating TRPV1 activity. This study will be helpful in understanding how osthole exerts anti-pruritus effects and suggests that osthole may be a useful treatment medicine for histamine-dependent itch. PMID:27160770

  10. Amygdala activity can be modulated by unexpected chord functions during music listening.

    Koelsch, Stefan; Fritz, Thomas; Schlaug, Gottfried

    2008-12-01

    Numerous earlier studies have investigated the cognitive processing of musical syntax with regular and irregular chord sequences. However, irregular sequences may also be perceived as unexpected, and therefore have a different emotional valence than regular sequences. We provide behavioral data showing that irregular chord functions presented in chord sequence paradigms are perceived as less pleasant than regular sequences. A reanalysis of functional MRI data showed increased blood oxygen level-dependent signal changes bilaterally in the amygdala in response to music-syntactically irregular (compared with regular) chord functions. The combined data indicate that music-syntactically irregular events elicit brain activity related to emotional processes, and that, in addition to intensely pleasurable music or highly unpleasant music, single chord functions can also modulate amygdala activity. PMID:19050462

  11. Reward expectation differentially modulates attentional behavior and activity in visual area V4.

    Baruni, Jalal K; Lau, Brian; Salzman, C Daniel

    2015-11-01

    Neural activity in visual area V4 is enhanced when attention is directed into neuronal receptive fields. However, the source of this enhancement is unclear, as most physiological studies have manipulated attention by changing the absolute reward associated with a particular location as well as its value relative to other locations. We trained monkeys to discriminate the orientation of two stimuli presented simultaneously in different hemifields while we independently varied the reward magnitude associated with correct discrimination at each location. Behavioral measures of attention were controlled by the relative value of each location. By contrast, neurons in V4 were consistently modulated by absolute reward value, exhibiting increased activity, increased gamma-band power and decreased trial-to-trial variability whenever receptive field locations were associated with large rewards. These data challenge the notion that the perceptual benefits of spatial attention rely on increased signal-to-noise in V4. Instead, these benefits likely derive from downstream selection mechanisms. PMID:26479590

  12. Electro-optic light modulation and THz generation in locally plasma-activated silicon nanophotonic devices.

    Matheisen, Christopher; Waldow, Michael; Chmielak, Bartos; Sawallich, Simon; Wahlbrink, Thorsten; Bolten, Jens; Nagel, Michael; Kurz, Heinrich

    2014-03-10

    Silicon is not an electro-optic material by itself but the required second-order optical nonlinearity can be induced by breaking the inversion symmetry of the crystal lattice. Recently, an attractive approach has been demonstrated based on a surface-activation in a CMOS-compatible HBr dry etching process. In this work, we further investigate and quantify the second-order nonlinearity induced by this process. Using THz near-field probing we demonstrate that this simple and versatile process can be applied to locally equip silicon nanophotonic chips with micro-scale areas of electro-optic activity. The realization of a first fully integrated Mach-Zehnder modulator device - based on this process - is applied to quantify the nonlinearity to an effective χ((2)) of 9 ± 1 pm/V. Analysis of the thermal stability of the induced nonlinearity reveals post-processing limitations and paths for further efficiency improvements. PMID:24663865

  13. Effect of hypnotic pain modulation on brain activity in patients with temporomandibular disorder pain

    Abrahamsen, Randi; Dietz, Martin; Lodahl, Sanne;

    2010-01-01

    Hypnosis modulates pain perception but the associated brain mechanisms in chronic pain conditions are poorly understood. Brain activity evoked by painful repetitive pin-prick stimulation of the left mental nerve region was investigated with use of fMRI in 19 patients with painful temporomandibular...... disorders (TMD) during hypnotic hypoalgesia and hyperalgesia and a control condition. Pain intensity and unpleasantness of the painful stimulation was scored on a 0-10 Numerical Rating Scale (NRS). NRS pain and unpleasantness scores during hypnotic hypoalgesia were significantly lower than in the control...... condition and significantly higher in the hypnotic hyperalgesia condition. In the control condition, painful stimulation caused significant activation of right posterior insula, primary somatosensory cortex (SI), BA21, and BA6, and left BA40 and BA4. Painful stimulation during hypnotic hyperalgesia...

  14. Peptides complementary to the active loop of porin P2 from Haemophilus influenzae modulate its activity

    Galdiero S

    2012-05-01

    Full Text Available Marco Cantisani,1 Mariateresa Vitiello,2 Annarita Falanga,1 Emiliana Finamore,2 Marilena Galdiero,2 Stefania Galdiero11Department of Biological Sciences, CIRPeB and IBB CNR, University of Naples "Federico II," Napoli, Italy; 2Department of Experimental Medicine, II University of Naples, Napoli, ItalyAbstract: Haemophilus influenzae type b (Hib is one of the leading causes of invasive bacterial infection in young children. It is characterized by inflammation that is mainly mediated by cytokines and chemokines. One of the most abundant components of the Hib outer membrane is the P2 porin, which has been shown to induce the release of several inflammatory cytokines. A synthetic peptide corresponding to loop L7 of the porin activates JNK and p38 mitogen-activated protein kinase (MAPK pathways. We report a novel use of the complementary peptide approach to design a peptide that is able to bind selectively to the protein P2, thereby reducing its activity. This work provides insights into essential molecular details of P2 that may affect the pathogenesis of Hib infections where interruption of the signaling cascade could represent an attractive therapeutic strategy.Keywords: complementary-peptide, rational design, porin

  15. Cannabinoid activation of peroxisome proliferator-activated receptors: potential for modulation of inflammatory disease.

    O'Sullivan, S E; Kendall, D A

    2010-08-01

    Cannabinoids act via cell surface G protein-coupled receptors (CB(1) and CB(2)) and the ion channel receptor TRPV1. Evidence has now emerged suggesting that an additional target is the peroxisome proliferator-activated receptor (PPAR) family of nuclear receptors. There are three PPAR subtypes alpha, delta (also known as beta) and gamma, which regulate cell differentiation, metabolism and immune function. The major endocannabinoids, anandamide and 2-arachidonoylglycerol, and ajulemic acid, a structural analogue of the phytocannabinoid Delta(9)-tetrahydrocannabinol (THC), have anti-inflammatory properties mediated by PPARgamma. Other cannabinoids which activate PPARgamma include N-arachidonoyl-dopamine, THC, cannabidiol, HU210, WIN55212-2 and CP55940. The endogenous acylethanolamines, oleoylethanolamide and palmitoylethanolamide regulate feeding and body weight, stimulate fat utilization and have neuroprotective effects mediated through PPARalpha. Other endocannabinoids that activate PPARalpha include anandamide, virodhamine and noladin ether. There is, as yet, little direct evidence for interactions of cannabinoids with PPARdelta. There is a convergence of effects of cannabinoids, acting via cell surface and nuclear receptors, on immune cell function which provides promise for the targeted therapy of a variety of immune, particularly neuroinflammatory, diseases. PMID:19833407

  16. Docosahexaenoic acid and palmitic acid reciprocally modulate monocyte activation in part through endoplasmic reticulum stress.

    Snodgrass, Ryan G; Huang, Shurong; Namgaladze, Dmitry; Jandali, Ola; Shao, Tiffany; Sama, Spandana; Brüne, Bernhard; Hwang, Daniel H

    2016-06-01

    Palmitic acid (C16:0) and TLR2 ligand induce, but docosahexaenoic acid (DHA) inhibits monocyte activation. C16:0 and TLR2 or TLR4 ligand induce certain ER stress markers; thus, we determined whether ER stress induced by these agonists is sufficient to induce monocyte activation, and whether the ER stress is inhibited by DHA which is known to inhibit C16:0- or ligand-induced TLR activation. Monocyte activation and ER stress were assessed by TLR/inflammasome-induced IL-1β production, and phosphorylation of IRE-1 and eIF2 and expression of CHOP, respectively in THP-1 cells. TLR2 ligand Pam3CSK4 induced phosphorylation of eIF2, but not phosphorylation of IRE-1 and CHOP expression. LPS also induced phosphorylation of both IRE-1 and eIF2 but not CHOP expression suggesting that TLR2 or TLR4 ligand, or C16:0 induces different ER stress responses. C16:0-, Pam3CSK4-, or LPS-induced IL-1β production was inhibited by 4-phenylbutyric acid, an inhibitor of ER stress suggesting that IL-1β production induced by these agonists is partly mediated through ER stress. Among two ER stress-inducing molecules, thapsigargin but not tunicamycin led to the expression of pro-IL-1β and secretion of IL-1β. Thus, not all types of ER stress are sufficient to induce inflammasome-mediated IL-1β secretion in monocytes. Although both C16:0 and thapsigargin-induced IL-1β secretion was inhibited by DHA, only C16:0-mediated ER stress was responsive to DHA. These findings suggest that the anti-inflammatory effects of DHA are at least in part mediated through modulating ER homeostasis and that the propensity of ER stress can be differentially modulated by the types of dietary fat we consume. PMID:27142735

  17. Compound A, a selective glucocorticoid receptor modulator, enhances heat shock protein Hsp70 gene promoter activation.

    Ilse M Beck

    Full Text Available Compound A possesses glucocorticoid receptor (GR-dependent anti-inflammatory properties. Just like classical GR ligands, Compound A can repress NF-κB-mediated gene expression. However, the monomeric Compound A-activated GR is unable to trigger glucocorticoid response element-regulated gene expression. The heat shock response potently activates heat shock factor 1 (HSF1, upregulates Hsp70, a known GR chaperone, and also modulates various aspects of inflammation. We found that the selective GR modulator Compound A and heat shock trigger similar cellular effects in A549 lung epithelial cells. With regard to their anti-inflammatory mechanism, heat shock and Compound A are both able to reduce TNF-stimulated IκBα degradation and NF-κB p65 nuclear translocation. We established an interaction between Compound A-activated GR and Hsp70, but remarkably, although the presence of the Hsp70 chaperone as such appears pivotal for the Compound A-mediated inflammatory gene repression, subsequent novel Hsp70 protein synthesis is uncoupled from an observed CpdA-induced Hsp70 mRNA upregulation and hence obsolete in mediating CpdA's anti-inflammatory effect. The lack of a Compound A-induced increase in Hsp70 protein levels in A549 cells is not mediated by a rapid proteasomal degradation of Hsp70 or by a Compound A-induced general block on translation. Similar to heat shock, Compound A can upregulate transcription of Hsp70 genes in various cell lines and BALB/c mice. Interestingly, whereas Compound A-dependent Hsp70 promoter activation is GR-dependent but HSF1-independent, heat shock-induced Hsp70 expression alternatively occurs in a GR-independent and HSF1-dependent manner in A549 lung epithelial cells.

  18. Vagal modulation of pre-inspiratory activity in hypoglossal discharge in the decerebrate rat.

    Ghali, Michael George Zaki

    2015-08-15

    Respiration consists of three phases--inspiration (I), post-inspiration (post-I), and late expiration (E2). Pre-I is a subphase occurring at the end of E2. Hypoglossal (XII) discharge contains I and occasionally pre-I activity. Functionally, XII pre-I underlies tongue muscle contraction and expansion of the upper airway, causing a decrease in airway resistance in anticipation of the succeeding inspiratory effort. It has been shown that vagotomy causes an increase in pre-I activity in XII in anesthetized animals. Also, in anesthetized artificially-ventilated animals, XII onset is synchronized with that of inspiratory phrenic nerve (PhN) activity. Therefore, we sought to systematically test the hypothesis that XII pre-I is present in vagus-intact unanesthetized decerebrate animals and vagal afferents negatively modulate XII pre-I discharge in decerebrate rats, in the absence of confounding anesthesia. Experiments were performed on seven Sprague-Dawley unanesthetized decerebrate adult male rats and bilateral PhN and XII recordings performed. In three animals, vagotomy was performed during PhN recordings and one animal was vagotomized during initial surgical preparation prior to recordings. In vagus-intact animals, XII pre-I duration averaged 12.4 ms. Vagotomy was associated with greater XII pre-I duration, expressed in absolute time (89.5 vs. 12.4 ms; p<0.01) as well as relative to the XII bursting period (18.9 vs. 3.4%; p<0.01). Vagal deafferentation was also associated with a larger relative amplitude of the pre-I XII activity relative to total XII discharge (12.4 vs. 2.1%; p<0.01). We conclude that pre-I discharge is present in vagus-intact artificially-ventilated unanesthetized decerebrate animals and is negatively modulated by vagal afferents. PMID:25979456

  19. Multiple monoaminergic modulation of posturo-locomotor network activity in the newborn rat spinal cord

    Lauriane eBeliez

    2014-08-01

    Full Text Available Studies devoted to understanding locomotor control have mainly addressed the functioning of the neural circuits controlling leg movements and relatively little is known of the operation of networks that activate trunk muscles in coordination with limb movements. The aim of the present work was (1 to identify the exogenous neurotransmitter cocktail that most strongly activates postural thoracic circuitry; (2 to investigate how the biogenic amines serotonin (5-HT, dopamine (DA and noradrenaline (NA modulate the coordination between limb and axial motor networks. Experiments were carried out on in vitro isolated spinal cord preparations from newborn rats. We recorded from ventral roots to monitor hindlimb locomotor and axial postural network activity. Each combination of the three amines with excitatory amino acids (EAAs elicited coordinated rhythmic motor activity at all segmental levels with specific characteristics. The variability in cycle period was similar with 5-HT and DA while it was significantly higher with NA. DA elicited motor bursts of smaller amplitude in thoracic segments compared to 5-HT and NA, while both DA and NA elicited motor bursts of higher amplitude than 5-HT in the lumbar and sacral segments. The amines modulated the phase relationships of bursts in various segments with respect to the reference lumbar segment. At the thoracic level there was a phase lag between all recorded segments in the presence of 5-HT, while DA and NA elicited synchronous bursting. At the sacral level, 5-HT and DA induced an intersegmental phase shift while relationships became phase-locked with NA. Various combinations of EAAs with two or even all three amines elicited rhythmic motor output that was more variable than with one amine alone. Our results provide new data on the coordinating processes between spinal cord networks, demonstrating that each amine has a characteristic signature regarding its specific effect on intersegmental phase

  20. Evaluation of monovalent and multivalent iminosugars to modulate Candida albicans β-1,2-mannosyltransferase activities.

    Hurtaux, Thomas; Sfihi-Loualia, Ghenima; Brissonnet, Yoan; Bouckaert, Julie; Mallet, Jean-Maurice; Sendid, Boualem; Delplace, Florence; Fabre, Emeline; Gouin, Sébastien G; Guérardel, Yann

    2016-06-24

    β-1,2-Linked oligomannosides substitute the cell wall of numerous yeast species. Several of those including Candida albicans may cause severe infections associated with high rates of morbidity and mortality, especially in immunocompromised patients. β-1,2-Mannosides are known to be involved in the pathogenic process and to elicit an immune response from the host. In C. albicans, the synthesis of β-mannosides is under the control of a family of nine genes coding for putative β-mannosyltransferases. Two of them, CaBmt1 and CaBmt3, have been shown to initiate and prime the elongation of the β-mannosides on the cell-wall mannan core. In the present study, we have assessed the modulating activities of monovalent and multivalent iminosugar analogs on these enzymes in order to control the enzymatic bio-synthesis of β-mannosides. We have identified a monovalent deoxynojirimycin (DNJ) derivative that inhibits the CaBmt1-catalyzed initiating activity, and mono-, tetra- and polyvalent deoxymannojirimycin (DMJ) that modulate the CaBmt1 activity toward the formation of a single major product. Analysis of the aggregating properties of the multivalent iminosugars showed their ability to elicit clusterization of both CaBmt1 and CaBmt3, without affecting their activity. These results suggest promising roles for multivalent iminosugars as controlling agents for the biosynthesis of β-1,2 mannosides and for monovalent DNJ derivative as a first target for the design of future β-mannosyltransferase inhibitors. PMID:26852253

  1. Generic phosphatase activity detection using zinc mediated aggregation modulation of polypeptide-modified gold nanoparticles

    Selegård, Robert; Enander, Karin; Aili, Daniel

    2014-11-01

    A challenge in the design of plasmonic nanoparticle-based colorimetric assays is that the change in colloidal stability, which generates the colorimetric response, is often directly linked to the biomolecular recognition event. New assay strategies are hence required for every type of substrate and enzyme of interest. Here, a generic strategy for monitoring of phosphatase activity is presented where substrate recognition is completely decoupled from the nanoparticle stability modulation mechanism, which enables detection of a wide range of enzymes using different natural substrates with a single simple detection scheme. Phosphatase activity generates inorganic phosphate that forms an insoluble complex with Zn2+. In a sample containing a preset concentration of Zn2+, phosphatase activity will markedly reduce the concentration of dissolved Zn2+ from the original value, which in turn affects the aggregation of gold nanoparticles functionalized with a designed Zn2+ responsive polypeptide. The change in nanoparticle stability thus provides a rapid and sensitive readout of the phosphatase activity. The assay is not limited to a particular enzyme or enzyme substrate, which is demonstrated using three completely different phosphatases and five different substrates, and thus constitutes a highly interesting system for drug screening and diagnostics.A challenge in the design of plasmonic nanoparticle-based colorimetric assays is that the change in colloidal stability, which generates the colorimetric response, is often directly linked to the biomolecular recognition event. New assay strategies are hence required for every type of substrate and enzyme of interest. Here, a generic strategy for monitoring of phosphatase activity is presented where substrate recognition is completely decoupled from the nanoparticle stability modulation mechanism, which enables detection of a wide range of enzymes using different natural substrates with a single simple detection scheme

  2. Bile Salts Modulate the Mucin-Activated Type VI Secretion System of Pandemic Vibrio cholerae.

    Verena Bachmann

    Full Text Available The causative agent of cholera, Vibrio cholerae, regulates its diverse virulence factors to thrive in the human small intestine and environmental reservoirs. Among this pathogen's arsenal of virulence factors is the tightly regulated type VI secretion system (T6SS. This system acts as an inverted bacteriophage to inject toxins into competing bacteria and eukaryotic phagocytes. V. cholerae strains responsible for the current 7th pandemic activate their T6SS within the host. We established that T6SS-mediated competition occurs upon T6SS activation in the infant mouse, and that this system is functional under anaerobic conditions. When investigating the intestinal host factors mucins (a glycoprotein component of mucus and bile for potential regulatory roles in controlling the T6SS, we discovered that once mucins activate the T6SS, bile acids can further modulate T6SS activity. Microbiota modify bile acids to inhibit T6SS-mediated killing of commensal bacteria. This interplay is a novel interaction between commensal bacteria, host factors, and the V. cholerae T6SS, showing an active host role in infection.

  3. The psychedelic state induced by ayahuasca modulates the activity and connectivity of the default mode network.

    Fernanda Palhano-Fontes

    Full Text Available The experiences induced by psychedelics share a wide variety of subjective features, related to the complex changes in perception and cognition induced by this class of drugs. A remarkable increase in introspection is at the core of these altered states of consciousness. Self-oriented mental activity has been consistently linked to the Default Mode Network (DMN, a set of brain regions more active during rest than during the execution of a goal-directed task. Here we used fMRI technique to inspect the DMN during the psychedelic state induced by Ayahuasca in ten experienced subjects. Ayahuasca is a potion traditionally used by Amazonian Amerindians composed by a mixture of compounds that increase monoaminergic transmission. In particular, we examined whether Ayahuasca changes the activity and connectivity of the DMN and the connection between the DMN and the task-positive network (TPN. Ayahuasca caused a significant decrease in activity through most parts of the DMN, including its most consistent hubs: the Posterior Cingulate Cortex (PCC/Precuneus and the medial Prefrontal Cortex (mPFC. Functional connectivity within the PCC/Precuneus decreased after Ayahuasca intake. No significant change was observed in the DMN-TPN orthogonality. Altogether, our results support the notion that the altered state of consciousness induced by Ayahuasca, like those induced by psilocybin (another serotonergic psychedelic, meditation and sleep, is linked to the modulation of the activity and the connectivity of the DMN.

  4. The psychedelic state induced by ayahuasca modulates the activity and connectivity of the default mode network.

    Palhano-Fontes, Fernanda; Andrade, Katia C; Tofoli, Luis F; Santos, Antonio C; Crippa, Jose Alexandre S; Hallak, Jaime E C; Ribeiro, Sidarta; de Araujo, Draulio B

    2015-01-01

    The experiences induced by psychedelics share a wide variety of subjective features, related to the complex changes in perception and cognition induced by this class of drugs. A remarkable increase in introspection is at the core of these altered states of consciousness. Self-oriented mental activity has been consistently linked to the Default Mode Network (DMN), a set of brain regions more active during rest than during the execution of a goal-directed task. Here we used fMRI technique to inspect the DMN during the psychedelic state induced by Ayahuasca in ten experienced subjects. Ayahuasca is a potion traditionally used by Amazonian Amerindians composed by a mixture of compounds that increase monoaminergic transmission. In particular, we examined whether Ayahuasca changes the activity and connectivity of the DMN and the connection between the DMN and the task-positive network (TPN). Ayahuasca caused a significant decrease in activity through most parts of the DMN, including its most consistent hubs: the Posterior Cingulate Cortex (PCC)/Precuneus and the medial Prefrontal Cortex (mPFC). Functional connectivity within the PCC/Precuneus decreased after Ayahuasca intake. No significant change was observed in the DMN-TPN orthogonality. Altogether, our results support the notion that the altered state of consciousness induced by Ayahuasca, like those induced by psilocybin (another serotonergic psychedelic), meditation and sleep, is linked to the modulation of the activity and the connectivity of the DMN. PMID:25693169

  5. Modulation of phase-II enzyme activities in benzene treated ovariectomized rats.

    Verma, Yeshvandra; Rana, S V S

    2011-05-01

    The aim of the study was to determine the influence of ovariectomy on phase II enzymes viz. glutathione-S-transferase (GST), glutathione peroxidase (GPX) and catalase (CAT) in liver and kidney of female rats treated with benzene. The results showed the significant decrease of the GST and GPX activity in benzene treated rats after ovariectomy. However progesterone supplementation stimulated the activity of GST and GPX in liver and kidney of benzene treated non ovariectomized and ovariectomized rats. Progesterone supplementation to benzene treated ovariectomized rats helps to gain in CAT activity. Our results on DNA damage using single cell gel electrophoresis also confirmed our findings on antioxidant enzymes. The results showed that lack of protective progesterone against benzene toxicity is reflected in alterations in antioxidant enzyme activities. However progesterone therapy to benzene treated ovariectomized rats results in activating the antioxidant defence system. Since female workers are engaged in industrial sector, these results are important from occupational health point of view. Benzene exposure affects their reproductive health. Nevertheless, it could be modulated by suitable hormonal therapy. PMID:21787707

  6. Sumoylation of p35 modulates p35/cyclin-dependent kinase (Cdk) 5 complex activity.

    Büchner, Anja; Krumova, Petranka; Ganesan, Sundar; Bähr, Mathias; Eckermann, Katrin; Weishaupt, Jochen H

    2015-03-01

    Cyclin-dependent kinase (Cdk) 5 is critical for central nervous system development and neuron-specific functions including neurite outgrowth as well as synaptic function and plasticity. Cdk5 activity requires association with one of the two regulatory subunits, called p35 and p39. p35 redistribution as well as misregulation of Cdk5 activity is followed by cell death in several models of neurodegeneration. Posttranslational protein modification by small ubiquitin-related modifier (SUMO) proteins (sumoylation) has emerged as key regulator of protein targeting and protein/protein interaction. Under cell-free in vitro conditions, we found p35 covalently modified by SUMO1. Using both biochemical and FRET-/FLIM-based approaches, we demonstrated that SUMO2 is robustly conjugated to p35 in cells and identified the two major SUMO acceptor lysines in p35, K246 and K290. Furthermore, different degrees of oxidative stress resulted in differential p35 sumoylation, linking oxidative stress that is encountered in neurodegenerative diseases to the altered activity of Cdk5. Functionally, sumoylation of p35 increased the activity of the p35/Cdk5 complex. We thus identified a novel neuronal SUMO target and show that sumoylation is a likely candidate mechanism for the rapid modulation of p35/Cdk5 activity in physiological situations as well as in disease. PMID:25391294

  7. Arrestin orchestrates cross-talk between GPCRs to modulate the spatiotemporal activation of ERK MAPK

    Cervantes, David; Crosby, Catherine; Xiang, Yang

    2009-01-01

    Rationale G protein-coupled receptors (GPCRs) respond to diversified extracellular stimuli to modulate cellular function. Despite extensive studies investigating the regulation of single GPCR signaling cascades, the effects of concomitant GPCR activation on downstream signaling and cellular function remain unclear. Objective We aim to characterize the cellular mechanism by which GPCR cross-talk regulates MAPK activation. Methods and Results Adrenergic receptors on cardiac fibroblasts were manipulated to examine the role of arrestin in the spatiotemporal regulation of ERK1/2 MAPK signaling. We show a general mechanism in which arrestin activation by one GPCR is capable of regulating signaling originating from another GPCR. Activation of Gq-coupled receptor signaling leads to prolonged ERK1/2 MAPK phosphorylation, nuclear accumulation and cellular proliferation. Interestingly, co-activation of these receptors with the β adrenergic receptors (ARs) induced transient ERK signaling localized within the cytosol, which attenuated cell proliferation. Further studies revealed that recruitment of arrestin3 to the β2AR orchestrates the sequestration of Gq-coupled receptor-induced ERK to the cytosol through direct binding of ERK to arrestin. Conclusion This is the first evidence showing that arrestin3 acts as a coordinator to integrate signals from multiple GPCRs. Our studies not only provide a novel mechanism explaining the integration of mitogenic signaling elicited by different GPCRs, but also underscore the critical role of signaling cross-talk among GPCRs in vivo. PMID:19926878

  8. Electrokinetic effects and fluid permeability

    G. Berryman, James

    2003-10-01

    Fluid permeability of porous media depends mainly on connectivity of the pore space and two physical parameters: porosity and a pertinent length-scale parameter. Electrical imaging methods typically establish connectivity and directly measure electrical conductivity, which can then often be related to porosity by Archie's law. When electrical phase measurements are made in addition to the amplitude measurements, information about the pertinent length scale can then be obtained. Since fluid permeability controls the ability to flush unwanted fluid contaminants from the subsurface, inexpensive maps of permeability could improve planning strategies for remediation efforts. Detailed knowledge of fluid permeability is also important for oil field exploitation, where knowledge of permeability distribution in three dimensions is a common requirement for petroleum reservoir simulation and analysis, as well as for estimates on the economics of recovery.

  9. The availability of attentional resources modulates the inhibitory strength related to weakly activated priming.

    Wang, Yongchun; Wang, Yonghui; Liu, Peng; Dai, Dongyang; Di, Meilin; Chen, Qiang

    2016-08-01

    The current study investigated the role of attention in inhibitory processes (the inhibitory processes described in the current study refer only to those associated with masked or flanked priming) using a mixed paradigm involving the negative compatibility effect (NCE) and object-based attention. Accumulating evidence suggests that attention can be spread more easily within the same object, which increases the availability of attentional resources, than across different objects. Accordingly, we manipulated distractor location (with primes presented in the same object versus presented in different objects) together with prime/target compatibility (compatible versus incompatible) and prime-distractor stimulus onset asynchrony (SOA, 23 ms vs 70 ms). The aim was to investigate whether inhibitory processes related to weakly activated priming, which have been previously assumed to be automatic, depend on the availability of attentional resources. The results of Experiment 1 showed a significant NCE for the 70-ms SOA when the prime and distractor were presented in the same object (greater attentional resource availability); however, reversed NCEs were obtained for all other conditions. Experiment 2 was designed to disentangle whether the results of Experiment 1 were affected by the prime position, and the results indicated that the prime position did not modulate the NCE in Experiment 1. Together, these results are consistent with the claim that the availability of attentional resources modulates the inhibitory strength related to weakly activated priming. Specifically, if attentional resources are assigned to the distractor when it is presented in the same object as the prime, the strength of the inhibition elicited by the distractor may increase and reverse the activation elicited by the prime, which could lead to a significant NCE. PMID:27198916

  10. Coumestrol, Bisphenol-A, DDT, and TCDD Modulation of Interleukin-2 Expression in Activated CD+4 Jurkat T Cells

    McMurray, Robert W.; Tchounwou, Paul B.; Kenneth Ndebele

    2004-01-01

    Endogenous estrogens are known to modulate several components of immune response, including interleukin-2 (IL-2) production. IL-2 is a cytokine that plays an important role in adaptive immune responses. These responses may be modulated by xenoestrogens such as coumestrol, bisphenol A (BPA), DDT, and TCDD. In this research, we examined the effects and potential mechanisms of action of these estrogenic compounds on IL-2 production in activated CD4+ Jurkat T cells. IL-2 production was analyzed b...

  11. DOPAMINE RECEPTOR ACTIVATION CAN REDUCE VOLTAGE-GATED Na+ CURRENT BY MODULATING BOTH ENTRY INTO AND RECOVERY FROM INACTIVATION

    Hayashida, Yuki; Ishida, Andrew T.

    2004-01-01

    We tested whether dopamine receptor activation modulates the voltage-gated Na+ current of goldfish retinal ganglion cells, using a fast voltage-clamp amplifier, perforated-patch whole-cell mode, and a physiological extracellular Na+ concentration. As found in other cells, activators of D1-type dopamine receptors and of protein kinase A reduced the amplitude of current activated by depolarizations from resting potential, without altering the current kinetics or activation range. However, D1-ty...

  12. Temporal expectation and attention jointly modulate auditory oscillatory activity in the beta band.

    Ana Todorovic

    Full Text Available The neural response to a stimulus is influenced by endogenous factors such as expectation and attention. Current research suggests that expectation and attention exert their effects in opposite directions, where expectation decreases neural activity in sensory areas, while attention increases it. However, expectation and attention are usually studied either in isolation or confounded with each other. A recent study suggests that expectation and attention may act jointly on sensory processing, by increasing the neural response to expected events when they are attended, but decreasing it when they are unattended. Here we test this hypothesis in an auditory temporal cueing paradigm using magnetoencephalography in humans. In our study participants attended to, or away from, tones that could arrive at expected or unexpected moments. We found a decrease in auditory beta band synchrony to expected (versus unexpected tones if they were unattended, but no difference if they were attended. Modulations in beta power were already evident prior to the expected onset times of the tones. These findings suggest that expectation and attention jointly modulate sensory processing.

  13. Tumor-Suppressive Activity of Lunatic Fringe in Prostate through Differential Modulation of Notch Receptor Activation

    Shubing Zhang

    2014-02-01

    Full Text Available Elevated Notch ligand and receptor expression has been associated with aggressive forms of prostate cancer, suggesting a role for Notch signaling in regulation of prostate tumor initiation and progression. Here, we report a critical role for Lunatic Fringe (Lfng, which encodes an O-fucosylpeptide 3-ß-N-acetylglucosaminyltransferase known to modify epidermal growth factor repeats of Notch receptor proteins, in regulation of prostate epithelial differentiation and proliferation, as well as in prostate tumor suppression. Deletion of Lfng in mice caused altered Notch activation in the prostate, associated with elevated accumulation of Notch1, Notch2, and Notch4 intracellular domains, decreased levels of the putative Notch3 intracellular fragment, as well as increased expression of Hes1, Hes5, and Hey2. Loss of Lfng resulted in expansion of the basal layer, increased proliferation of both luminal and basal cells, and ultimately, prostatic intraepithelial neoplasia. The Lfng-null prostate showed down-regulation of prostatic tumor suppressor gene NKX3.1 and increased androgen receptor expression. Interestingly, expression of LFNG and NKX3.1 were positively correlated in publically available human prostate cancer data sets. Knockdown of LFNG in DU-145 prostate cancer cells led to expansion of CD44+CD24− and CD49f+CD24− stem/progenitor-like cell population associated with enhanced prostatosphere-forming capacity. Taken together, these data revealed a tumor-suppressive role for Lfng in the prostate through differential regulation of Notch signaling.

  14. Brexpiprazole I: in vitro and in vivo characterization of a novel serotonin-dopamine activity modulator.

    Maeda, Kenji; Sugino, Haruhiko; Akazawa, Hitomi; Amada, Naoki; Shimada, Jun; Futamura, Takashi; Yamashita, Hiroshi; Ito, Nobuaki; McQuade, Robert D; Mørk, Arne; Pehrson, Alan L; Hentzer, Morten; Nielsen, Vibeke; Bundgaard, Christoffer; Arnt, Jørn; Stensbøl, Tine Bryan; Kikuchi, Tetsuro

    2014-09-01

    Brexpiprazole (OPC-34712, 7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1H)-one) is a novel drug candidate in clinical development for psychiatric disorders with high affinity for serotonin, dopamine, and noradrenaline receptors. In particular, it bound with high affinity (Ki 1000 nM). Brexpiprazole potently bound to rat 5-HT2A and D2 receptors in vivo, and ex vivo binding studies further confirmed high 5-HT1A receptor binding potency. Brexpiprazole inhibited DOI (2,5-dimethoxy-4-iodoamphetamine)-induced head twitches in rats, suggestive of 5-HT2A antagonism. Furthermore, in vivo D2 partial agonist activity of brexpiprazole was confirmed by its inhibitory effect on reserpine-induced DOPA accumulation in rats. In rat microdialysis studies, brexpiprazole slightly reduced extracellular dopamine in nucleus accumbens but not in prefrontal cortex, whereas moderate increases of the dopamine metabolites, homovanillic acid and DOPAC (3,4-dihydroxy-phenyl-acetic acid), in these areas also suggested in vivo D2 partial agonist activity. In particular, based on a lower intrinsic activity at D2 receptors and higher binding affinities for 5-HT1A/2A receptors than aripiprazole, brexpiprazole would have a favorable antipsychotic potential without D2 receptor agonist- and antagonist-related adverse effects. In conclusion, brexpiprazole is a serotonin-dopamine activity modulator with a unique pharmacology, which may offer novel treatment options across a broad spectrum of central nervous system disorders. PMID:24947465

  15. Tetraspanin CD9 modulates human lymphoma cellular proliferation via histone deacetylase activity

    Herr, Michael J. [Vascular Biology Center of Excellence, The University of Tennessee Health Science Center, Memphis, TN 38163 (United States); Department of Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163 (United States); Department of Molecular Sciences, The University of Tennessee Health Science Center, Memphis, TN 38163 (United States); Department of Surgery, The University of Tennessee Health Science Center, Memphis, TN 38163 (United States); Longhurst, Celia M.; Baker, Benjamin [Vascular Biology Center of Excellence, The University of Tennessee Health Science Center, Memphis, TN 38163 (United States); Homayouni, Ramin [Department of Biology, Bioinformatics Program, University of Memphis, Memphis, TN 38152 (United States); Speich, Henry E.; Kotha, Jayaprakash [Vascular Biology Center of Excellence, The University of Tennessee Health Science Center, Memphis, TN 38163 (United States); Jennings, Lisa K., E-mail: ljennings@uthsc.edu [Vascular Biology Center of Excellence, The University of Tennessee Health Science Center, Memphis, TN 38163 (United States); Department of Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163 (United States); Department of Molecular Sciences, The University of Tennessee Health Science Center, Memphis, TN 38163 (United States); Department of Surgery, The University of Tennessee Health Science Center, Memphis, TN 38163 (United States); Department of Biology, Bioinformatics Program, University of Memphis, Memphis, TN 38152 (United States)

    2014-05-16

    Highlights: • CD9 is differentially expressed in human Burkitt’s lymphoma cells. • We found that CD9 expression promotes these cells proliferation. • CD9 expression also increases HDAC activity. • HDAC inhibition decreased both cell proliferation and importantly CD9 expression. • CD9 may dictate HDAC efficacy and play a role in HDAC regulation. - Abstract: Non-Hodgkin Lymphoma (NHL) is a type of hematological malignancy that affects two percent of the overall population in the United States. Tetraspanin CD9 is a cell surface protein that has been thoroughly demonstrated to be a molecular facilitator of cellular phenotype. CD9 expression varies in two human lymphoma cell lines, Raji and BJAB. In this report, we investigated the functional relationship between CD9 and cell proliferation regulated by histone deacetylase (HDAC) activity in these two cell lines. Introduction of CD9 expression in Raji cells resulted in significantly increased cell proliferation and HDAC activity compared to Mock transfected Raji cells. The increase in CD9–Raji cell proliferation was significantly inhibited by HDAC inhibitor (HDACi) treatment. Pretreatment of BJAB cells with HDAC inhibitors resulted in a significant decrease in endogenous CD9 mRNA and cell surface expression. BJAB cells also displayed decreased cell proliferation after HDACi treatment. These results suggest a significant relationship between CD9 expression and cell proliferation in human lymphoma cells that may be modulated by HDAC activity.

  16. Modulation of CP2 family transcriptional activity by CRTR-1 and sumoylation.

    Sarah To

    Full Text Available CRTR-1 is a member of the CP2 family of transcription factors. Unlike other members of the family which are widely expressed, CRTR-1 expression shows specific spatio-temporal regulation. Gene targeting demonstrates that CRTR-1 plays a central role in the maturation and function of the salivary glands and the kidney. CRTR-1 has also recently been identified as a component of the complex transcriptional network that maintains pluripotency in embryonic stem (ES cells. CRTR-1 was previously shown to be a repressor of transcription. We examine the activity of CRTR-1 in ES and other cells and show that CRTR-1 is generally an activator of transcription and that it modulates the activity of other family members, CP2, NF2d9 and altNF2d9, in a cell specific manner. We also demonstrate that CRTR-1 activity is regulated by sumoylation at a single major site, residue K30. These findings imply that functional redundancy with other family members may mask important roles for CRTR-1 in other tissues, including the blastocyst stage embryo and embryonic stem cells.

  17. Cell-permeable Carboxyl-terminal p27Kip1 Peptide Exhibits Anti-tumor Activity by Inhibiting Pim-1 Kinase*

    Morishita, Daisuke; Takami, Miho; Yoshikawa, Seiko; Katayama, Ryohei; Sato, Shigeo; Kukimoto-Niino, Mutsuko; Umehara, Takashi; Shirouzu, Mikako; Sekimizu, Kazuhisa; Yokoyama, Shigeyuki; Fujita, Naoya

    2011-01-01

    The incidence and death rate of prostate cancer is increasing rapidly. In addition, the low sensitivity of prostate cancer to chemotherapy makes it difficult to treat this condition. The serine/threonine kinase Pim-1 plays an important role in cell cycle progression and apoptosis inhibition, resulting in prostate tumorigenesis. Therefore, Pim-1 inhibition has been expected to be an attractive target for developing new anti-cancer drugs. However, no small compounds targeting Pim-1 have progressed to clinical use because of their lack of specificity. Here, we have reported a new cell-permeable Pim-1 inhibitory p27Kip1 peptide that could interfere with the binding of Pim-1 to its substrates and act as an anti-cancer drug. The peptide could bind to Pim-1 and inhibit phosphorylation of endogenous p27Kip1 and Bad by Pim-1. Treatment of prostate cancer with the peptide induces G1 arrest and subsequently apoptosis in vitro. However, the peptide showed almost no growth inhibitory or apoptosis-inducing effects in normal cells. The peptide could inhibit tumor growth in in vivo prostate cancer xenograft models. Moreover, the peptide treatment could overcome resistance to taxol, one of the first line chemotherapeutic agents for prostate cancer, and a combination of the peptide with taxol synergistically inhibited prostate cancer growth in vivo. These results indicate that a Pim-1 inhibitory p27Kip1 peptide could be developed as an anti-cancer drug against prostate cancer. PMID:21062737

  18. Water permeability of elastomers.

    Held, H R; Landi, S

    1977-01-01

    In a previous study it has been shown that the free moisture content in freeze-dried BCG vaccine dispensed in vials sealed with rubber stoppers increased during storage. The search for the source of this increase led us to explore the possibility that this additional moisture could originate from the rubber stoppers themselves. Therefore, the water permeability of various rubber stoppers has been studied, and the water content of grey butyl stoppers during some operations (autoclaving, oven-drying, freeze-drying, storage) used in the manufacturing of BCG vaccine has been determined. Our experiments showed: rapid water uptake during steam-autoclaving and rapid water release during subsequent oven-drying of the stoppers; a slow water uptake of the stoppers during freeze-drying and a slow water permeation through the stoppers when vials containing Indicating Drierite were stored in a water-saturated atmosphere. Among 12 types of rubber stoppers tested, the grey butyl stoppers and the silicone stoppers showed the lowest water uptake. Moisture-resistant wrappings decreased significantly the moisture uptake of Drierite. To delay moisture from reaching the vaccine it is recommended that the stoppers employed be as dry as possible. PMID:881425

  19. Impaired Peroxisome Proliferator-activated Receptor-γ Contributes to Phenotypic Modulation of Vascular Smooth Muscle Cells during Hypertension*

    Zhang, Lili; Xie, Peng; Wang, Jingzhou; Yang, Qingwu; Fang, Chuanqin; Zhou, Shuang; Li, Jingcheng

    2010-01-01

    The phenotypic modulation of vascular smooth muscle cells (VSMCs) plays a pivotal role in hypertension-induced vascular changes including vascular remodeling. The precise mechanisms underlying VSMC phenotypic modulation remain elusive. Here we test the role of peroxisome proliferator-activated receptor (PPAR)-γ in the VSMC phenotypic modulation during hypertension. Both spontaneously hypertensive rat (SHR) aortas and SHR-derived VSMCs exhibited reduced PPAR-γ expression and excessive VSMC phenotypic modulation identified by reduced contractile proteins, α-smooth muscle actin (α-SMA) and smooth muscle 22α (SM22α), and enhanced proliferation and migration. PPAR-γ overexpression rescued the expression of α-SMA and SM22α, and inhibited the proliferation and migration in SHR-derived VSMCs. In contrast, PPAR-γ silencing exerted the opposite effect. Activating PPAR-γ using rosiglitazone in vivo up-regulated aortic α-SMA and SM22α expression and attenuated aortic remodeling in SHRs. Increased activation of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling was observed in SHR-derived VSMCs. PI3K inhibitor LY294002 rescued the impaired expression of contractile proteins, and inhibited proliferation and migration in VSMCs from SHRs, whereas constitutively active PI3K mutant had the opposite effect. Overexpression or silencing of PPAR-γ inhibited or excited PI3K/Akt activity, respectively. LY294002 counteracted the PPAR-γ silencing induced proliferation and migration in SHR-derived VSMCs, whereas active PI3K mutant had the opposite effect. In contrast, reduced proliferation and migration by PPAR-γ overexpression were reversed by the active PI3K mutant, and further inhibited by LY294002. We conclude that PPAR-γ inhibits VSMC phenotypic modulation through inhibiting PI3K/Akt signaling. Impaired PPAR-γ expression is responsible for VSMC phenotypic modulation during hypertension. These findings highlight an attractive therapeutic target for

  20. The self-pleasantness judgment modulates the encoding performance and the Default Mode Network activity

    Perrone-Bertolotti eMarcela

    2016-03-01

    Full Text Available In this functional magnetic resonance imaging (fMRI study, we evaluated the effect of self-relevance on cerebral activity and behavioral performance during an incidental encoding task. Recent findings suggest that pleasantness judgments reliably induce self-oriented (internal thoughts and increase default mode network (DMN activity. We hypothesized that this increase in DMN activity would relate to increased memory recognition for pleasantly-judged stimuli (which depend on internally-oriented attention but decreased recognition for unpleasantly-judged items (which depend on externally-oriented attention. To test this hypothesis, brain activity was recorded from 21 healthy participants while they performed a pleasantness judgment requiring them to rate visual stimuli as pleasant or unpleasant. One hour later, participants performed a surprise memory recognition test outside of the scanner. Thus, we were able to evaluate the effects of pleasant and unpleasant judgments on cerebral activity and incidental encoding. The behavioral results showed that memory recognition was better for items rated as pleasant than items rated as unpleasant. The whole brain analysis indicated that successful encoding activates the inferior frontal and lateral temporal cortices, whereas unsuccessful encoding recruits two key medial posterior DMN regions, the posterior cingulate cortex and precuneus. A region of interest analysis including classic DMN areas, revealed significantly greater involvement of the medial Prefrontal Cortex in pleasant compared to unpleasant judgments, suggesting this region’s involvement in self-referential (i.e., internal processing. This area may be responsible for the greater recognition performance seen for pleasant stimuli. Furthermore, a significant interaction between the encoding performance (successful vs. unsuccessful and pleasantness was observed for the posterior cingulate cortex, precuneus and inferior frontal gyrus. Overall, our

  1. Modulation of Ca2+ oscillation and melatonin secretion by BKCa channel activity in rat pinealocytes.

    Mizutani, Hiroya; Yamamura, Hisao; Muramatsu, Makoto; Hagihara, Yumiko; Suzuki, Yoshiaki; Imaizumi, Yuji

    2016-05-01

    The pineal glands regulate circadian rhythm through the synthesis and secretion of melatonin. The stimulation of nicotinic acetylcholine receptor due to parasympathetic nerve activity causes an increase in intracellular Ca(2+) concentration and eventually downregulates melatonin production. Our previous report shows that rat pinealocytes have spontaneous and nicotine-induced Ca(2+) oscillations that are evoked by membrane depolarization followed by Ca(2+) influx through voltage-dependent Ca(2+) channels (VDCCs). These Ca(2+) oscillations are supposed to contribute to the inhibitory mechanism of melatonin secretion. Here we examined the involvement of large-conductance Ca(2+)-activated K(+) (BKCa) channel conductance on the regulation of Ca(2+) oscillation and melatonin production in rat pinealocytes. Spontaneous Ca(2+) oscillations were markedly enhanced by BKCa channel blockers (1 μM paxilline or 100 nM iberiotoxin). Nicotine (100 μM)-induced Ca(2+) oscillations were also augmented by paxilline. In contrast, spontaneous Ca(2+) oscillations were abolished by BKCa channel opener [3 μM 12,14-dichlorodehydroabietic acid (diCl-DHAA)]. Under whole cell voltage-clamp configurations, depolarization-elicited outward currents were significantly activated by diCl-DHAA and blocked by paxilline. Expression analyses revealed that the α and β3 subunits of BKCa channel were highly expressed in rat pinealocytes. Importantly, the activity of BKCa channels modulated melatonin secretion from whole pineal gland of the rat. Taken together, BKCa channel activation attenuates these Ca(2+) oscillations due to depolarization-synchronized Ca(2+) influx through VDCCs and results in a recovery of reduced melatonin secretion during parasympathetic nerve activity. BKCa channels may play a physiological role for melatonin production via a negative-feedback mechanism. PMID:26791489

  2. Pathogenic Mycobacterium bovis strains differ in their ability to modulate the proinflammatory activation phenotype of macrophages

    Andrade Marcelle RM

    2012-08-01

    Full Text Available Abstract Background Tuberculosis, caused by Mycobacterium tuberculosis or Mycobacterium bovis, remains one of the leading infectious diseases worldwide. The ability of mycobacteria to rapidly grow in host macrophages is a factor contributing to enhanced virulence of the bacteria and disease progression. Bactericidal functions of phagocytes are strictly dependent on activation status of these cells, regulated by the infecting agent and cytokines. Pathogenic mycobacteria can survive the hostile environment of the phagosome through interference with activation of bactericidal responses. To study the mechanisms employed by highly virulent mycobacteria to promote their intracellular survival, we investigated modulating effects of two pathogenic M. bovis isolates and a reference M. tuberculosis H37Rv strain, differing in their ability to multiply in macrophages, on activation phenotypes of the cells primed with major cytokines regulating proinflammatory macrophage activity. Results Bone marrow- derived macrophages obtained from C57BL/6 mice were infected by mycobacteria after a period of cell incubation with or without treatment with IFN-γ, inducing proinflammatory type-1 macrophages (M1, or IL-10, inducing anti-inflammatory type-2 cells (M2. Phenotypic profiling of M1 and M2 was then evaluated. The M. bovis strain MP287/03 was able to grow more efficiently in the untreated macrophages, compared with the strains B2 or H37Rv. This strain induced weaker secretion of proinflammatory cytokines, coinciding with higher expression of M2 cell markers, mannose receptor (MR and arginase-1 (Arg-1. Treatment of macrophages with IFN-γ and infection by the strains B2 and H37Rv synergistically induced M1 polarization, leading to high levels of inducible nitric oxide synthase (iNOS expression, and reduced expression of the Arg-1. In contrast, the cells infected with the strain MP287/03 expressed high levels of Arg-1 which competed with iNOS for the common substrate

  3. Permeability testing of biomaterial membranes

    Dreesmann, L; Hajosch, R; Nuernberger, J Vaz; Schlosshauer, B [NMI Natural and Medical Sciences Institute at University Tuebingen, Markwiesenstr. 55, D-72770 Reutlingen (Germany); Ahlers, M [GELITA AG, Gammelsbacher Str. 2, D-69412 Eberbach (Germany)], E-mail: schlosshauer@nmi.de

    2008-09-01

    The permeability characteristics of biomaterials are critical parameters for a variety of implants. To analyse the permeability of membranes made from crosslinked ultrathin gelatin membranes and the transmigration of cells across the membranes, we combined three technical approaches: (1) a two-chamber-based permeability assay, (2) cell culturing with cytochemical analysis and (3) biochemical enzyme electrophoresis (zymography). Based on the diffusion of a coloured marker molecule in conjunction with photometric quantification, permeability data for a gelatin membrane were determined in the presence or absence of gelatin degrading fibroblasts. Cytochemical evaluation after cryosectioning of the membranes was used to ascertain whether fibroblasts had infiltrated the membrane inside. Zymography was used to investigate the potential release of proteases from fibroblasts, which are known to degrade collagen derivatives such as gelatin. Our data show that the diffusion equilibrium of a low molecular weight dye across the selected gelatin membrane is approached after about 6-8 h. Fibroblasts increase the permeability due to cavity formation in the membrane inside without penetrating the membrane for an extended time period (>21 days in vitro). Zymography indicates that cavity formation is most likely due to the secretion of matrix metalloproteinases. In summary, the combination of the depicted methods promises to facilitate a more rational development of biomaterials, because it provides a rapid means of determining permeability characteristics and bridges the gap between descriptive methodology and the mechanistic understanding of permeability alterations due to biological degradation.

  4. Permeability testing of biomaterial membranes

    The permeability characteristics of biomaterials are critical parameters for a variety of implants. To analyse the permeability of membranes made from crosslinked ultrathin gelatin membranes and the transmigration of cells across the membranes, we combined three technical approaches: (1) a two-chamber-based permeability assay, (2) cell culturing with cytochemical analysis and (3) biochemical enzyme electrophoresis (zymography). Based on the diffusion of a coloured marker molecule in conjunction with photometric quantification, permeability data for a gelatin membrane were determined in the presence or absence of gelatin degrading fibroblasts. Cytochemical evaluation after cryosectioning of the membranes was used to ascertain whether fibroblasts had infiltrated the membrane inside. Zymography was used to investigate the potential release of proteases from fibroblasts, which are known to degrade collagen derivatives such as gelatin. Our data show that the diffusion equilibrium of a low molecular weight dye across the selected gelatin membrane is approached after about 6-8 h. Fibroblasts increase the permeability due to cavity formation in the membrane inside without penetrating the membrane for an extended time period (>21 days in vitro). Zymography indicates that cavity formation is most likely due to the secretion of matrix metalloproteinases. In summary, the combination of the depicted methods promises to facilitate a more rational development of biomaterials, because it provides a rapid means of determining permeability characteristics and bridges the gap between descriptive methodology and the mechanistic understanding of permeability alterations due to biological degradation

  5. Designed modulation of sex steroid signaling inhibits telomerase activity and proliferation of human prostate cancer cells

    Verma, Vikas; Sharma, Vikas; Singh, Vishal [Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226 031 (India); Sharma, Siddharth; Bishnoi, Ajay Kumar [Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226 031 (India); Chandra, Vishal; Maikhuri, J.P.; Dwivedi, Anila [Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226 031 (India); Kumar, Atul [Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226 031 (India); Gupta, Gopal, E-mail: g_gupta@cdri.res.in [Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226 031 (India)

    2014-10-15

    The predominant estrogen-receptor (ER)-β signaling in normal prostate is countered by increased ER-α signaling in prostate cancer (CaP), which in association with androgen-receptor (AR) signaling results in pathogenesis of the disease. However CaP treatments mostly target AR signaling which is initially effective but eventually leads to androgen resistance, hence simultaneous targeting of ERs has been proposed. A novel series of molecules were designed with multiple sex-steroid receptor modulating capabilities by coalescing the pharmacophores of known anti-CaP molecules that act via modulation of ER(α/β) and/or AR, viz. 3,3′diindolylmethane (DIM), mifepristone, toremifene, tamoxifen and raloxifene. N,N-diethyl-4-((2-(4-methoxyphenyl)-1H-indol-3-yl)methyl) aniline (DIMA) was identified as the most promising structure of this new series. DIMA increased annexin-V labelling, cell-cycle arrest and caspase-3 activity, and decreased expression of AR and prostate specific antigen in LNCaP cells, in vitro. Concurrently, DIMA increased ER-β, p21 and p27 protein levels in LNCaP cells and exhibited ∼ 5 times more selective binding for ER-β than ER-α, in comparison to raloxifene. DIMA exhibited a dose-dependent ER-β agonism and ER-α antagonism in classical gene reporter assay and decreased hTERT (catalytic subunit of telomerase) transcript levels in LNCaP at 3.0 μM (P < 0.05). DIMA also dose-dependently decreased telomerase enzyme activity in prostate cancer cells. It is thus concluded that DIMA acts as a multi-steroid receptor modulator and effectively inhibits proliferation of prostate cancer cells through ER-β mediated telomerase inhibition, by countering actions of ER-α and AR. Its unique molecular design can serve as a lead structure for generation of potent agents against endocrine malignancies like the CaP.

  6. Designed modulation of sex steroid signaling inhibits telomerase activity and proliferation of human prostate cancer cells

    The predominant estrogen-receptor (ER)-β signaling in normal prostate is countered by increased ER-α signaling in prostate cancer (CaP), which in association with androgen-receptor (AR) signaling results in pathogenesis of the disease. However CaP treatments mostly target AR signaling which is initially effective but eventually leads to androgen resistance, hence simultaneous targeting of ERs has been proposed. A novel series of molecules were designed with multiple sex-steroid receptor modulating capabilities by coalescing the pharmacophores of known anti-CaP molecules that act via modulation of ER(α/β) and/or AR, viz. 3,3′diindolylmethane (DIM), mifepristone, toremifene, tamoxifen and raloxifene. N,N-diethyl-4-((2-(4-methoxyphenyl)-1H-indol-3-yl)methyl) aniline (DIMA) was identified as the most promising structure of this new series. DIMA increased annexin-V labelling, cell-cycle arrest and caspase-3 activity, and decreased expression of AR and prostate specific antigen in LNCaP cells, in vitro. Concurrently, DIMA increased ER-β, p21 and p27 protein levels in LNCaP cells and exhibited ∼ 5 times more selective binding for ER-β than ER-α, in comparison to raloxifene. DIMA exhibited a dose-dependent ER-β agonism and ER-α antagonism in classical gene reporter assay and decreased hTERT (catalytic subunit of telomerase) transcript levels in LNCaP at 3.0 μM (P < 0.05). DIMA also dose-dependently decreased telomerase enzyme activity in prostate cancer cells. It is thus concluded that DIMA acts as a multi-steroid receptor modulator and effectively inhibits proliferation of prostate cancer cells through ER-β mediated telomerase inhibition, by countering actions of ER-α and AR. Its unique molecular design can serve as a lead structure for generation of potent agents against endocrine malignancies like the CaP

  7. Relative Permeability of Fractured Rock

    Mark D. Habana

    2002-06-30

    Contemporary understanding of multiphase flow through fractures is limited. Different studies using synthetic fractures and various fluids have yielded different relative permeability-saturation relations. This study aimed to extend the understanding of multiphase flow by conducting nitrogen-water relative permeability experiments on a naturally-fractured rock from The Geysers geothermal field. The steady-state approach was used. However, steady state was achieved only at the endpoint saturations. Several difficulties were encountered that are attributed to phase interference and changes in fracture aperture and surface roughness, along with fracture propagation/initiation. Absolute permeabilities were determined using nitrogen and water. The permeability values obtained change with the number of load cycles. Determining the absolute permeability of a core is especially important in a fractured rock. The rock may change as asperities are destroyed and fractures propagate or st rain harden as the net stresses vary. Pressure spikes occurred in water a solute permeability experiments. Conceptual models of an elastic fracture network can explain the pressure spike behavior. At the endpoint saturations the water relative permeabilities obtained are much less than the nitrogen gas relative permeabilities. Saturations were determined by weighing and by resistivity calculations. The resistivity-saturation relationship developed for the core gave saturation values that differ by 5% from the value determined by weighing. Further work is required to complete the relative permeability curve. The steady-state experimental approach encountered difficulties due to phase interference and fracture change. Steady state may not be reached until an impractical length of time. Thus, unsteady-state methods should be pursued. In unsteady-state experiments the challenge will be in quantifying rock fracture change in addition to fluid flow changes.

  8. Modulation of Na+/K+ ATPase Activity by Hydrogen Peroxide Generated through Heme in L. amazonensis.

    Nathália Rocco-Machado

    Full Text Available Leishmania amazonensis is a protozoan parasite that occurs in many areas of Brazil and causes skin lesions. Using this parasite, our group showed the activation of Na+/K+ ATPase through a signaling cascade that involves the presence of heme and protein kinase C (PKC activity. Heme is an important biomolecule that has pro-oxidant activity and signaling capacity. Reactive oxygen species (ROS can act as second messengers, which are required in various signaling cascades. Our goal in this work is to investigate the role of hydrogen peroxide (H2O2 generated in the presence of heme in the Na+/K+ ATPase activity of L. amazonensis. Our results show that increasing concentrations of heme stimulates the production of H2O2 in a dose-dependent manner until a concentration of 2.5 μM heme. To confirm that the effect of heme on the Na+/K+ ATPase is through the generation of H2O2, we measured enzyme activity using increasing concentrations of H2O2 and, as expected, the activity increased in a dose-dependent manner until a concentration of 0.1 μM H2O2. To investigate the role of PKC in this signaling pathway, we observed the production of H2O2 in the presence of its activator phorbol 12-myristate 13-acetate (PMA and its inhibitor calphostin C. Both showed no effect on the generation of H2O2. Furthermore, we found that PKC activity is increased in the presence of H2O2, and that in the presence of calphostin C, H2O2 is unable to activate the Na+/K+ ATPase. 100 μM of Mito-TEMPO was capable of abolishing the stimulatory effect of heme on Na+/K+ ATPase activity, indicating that mitochondria might be the source of the hydrogen peroxide production induced by heme. The modulation of L. amazonensis Na+/K+ ATPase by H2O2 opens new possibilities for understanding the signaling pathways of this parasite.

  9. Modulation of Na+/K+ ATPase Activity by Hydrogen Peroxide Generated through Heme in L. amazonensis.

    Rocco-Machado, Nathália; Cosentino-Gomes, Daniela; Meyer-Fernandes, José Roberto

    2015-01-01

    Leishmania amazonensis is a protozoan parasite that occurs in many areas of Brazil and causes skin lesions. Using this parasite, our group showed the activation of Na+/K+ ATPase through a signaling cascade that involves the presence of heme and protein kinase C (PKC) activity. Heme is an important biomolecule that has pro-oxidant activity and signaling capacity. Reactive oxygen species (ROS) can act as second messengers, which are required in various signaling cascades. Our goal in this work is to investigate the role of hydrogen peroxide (H2O2) generated in the presence of heme in the Na+/K+ ATPase activity of L. amazonensis. Our results show that increasing concentrations of heme stimulates the production of H2O2 in a dose-dependent manner until a concentration of 2.5 μM heme. To confirm that the effect of heme on the Na+/K+ ATPase is through the generation of H2O2, we measured enzyme activity using increasing concentrations of H2O2 and, as expected, the activity increased in a dose-dependent manner until a concentration of 0.1 μM H2O2. To investigate the role of PKC in this signaling pathway, we observed the production of H2O2 in the presence of its activator phorbol 12-myristate 13-acetate (PMA) and its inhibitor calphostin C. Both showed no effect on the generation of H2O2. Furthermore, we found that PKC activity is increased in the presence of H2O2, and that in the presence of calphostin C, H2O2 is unable to activate the Na+/K+ ATPase. 100 μM of Mito-TEMPO was capable of abolishing the stimulatory effect of heme on Na+/K+ ATPase activity, indicating that mitochondria might be the source of the hydrogen peroxide production induced by heme. The modulation of L. amazonensis Na+/K+ ATPase by H2O2 opens new possibilities for understanding the signaling pathways of this parasite. PMID:26070143

  10. Modulation of C-nociceptive Activities by Inputs from Myelinated Fibers.

    Wan-Ru, Duan; Yi-Kuan, Xie

    2016-01-01

    To understand the mechanisms of neuropathic pain caused by demyelination, a rapid-onset, completed but reversible demyelination of peripheral A-fibers and neuropathic pain behaviors in adult rats by single injection of cobra venom into the sciatic nerve, was created. Microfilament recording revealed that cobra venom selectively blocked A-fibers, but not C-fibers. Selective blockade of A-fibers may result from A-fiber demyelination at the site of venom injection as demonstrated by microscope examination. Neuropathic pain behaviors including inflammatory response appeared almost immediately after venom injection and lasted about 3 weeks. Electrophysiological studies indicated that venom injection induced loss of conduction in A-fibers, increased sensitivity of C-polymodal nociceptors to innocuous stimuli, and triggered spontaneous activity from peripheral and central terminals of C-fiber nociceptors. Neurogenic inflammatory responses were also observed in the affected skin via Evans blue extravasation experiments. Both antidromic C-fiber spontaneous activity and neurogenic inflammation were substantially decreased by continuous A-fiber threshold electric stimuli applied proximally to the venom injection site. The data suggest that normal activity of peripheral A-fibers may produce inhibitory modulation of C-polymodal nociceptors. Removal of inhibition to C-fiber polymodal nociceptors following demyelination of A-fibers may result in pain and neurogenic inflammation in the affected receptive field. PMID:26900061

  11. Inflows towards active regions and the modulation of the solar cycle: a parameter study

    Martin-Belda, David

    2016-01-01

    Aims: We aim to investigate how converging flows towards active regions affect the surface transport of magnetic flux, as well as their impact on the generation of the Sun's poloidal field. The inflows constitute a potential non-linear mechanism for the saturation of the global dynamo and may contribute to the modulation of the solar cycle in the Babcock-Leighton framework. Methods: We build a surface flux transport code incorporating a parametrized model of the inflows and run simulations spanning several cycles. We carry out a parameter study to assess how the strength and extension of the inflows affect the build-up of the global dipole field. We also perform simulations with different levels of activity to investigate the potential role of the inflows in the saturation of the global dynamo. Results: We find that the interaction of neighbouring active regions can lead to the occasional formation of single-polarity magnetic flux clumps inconsistent with observations. We propose the darkening caused by pores...

  12. Prediction-error in the context of real social relationships modulates reward system activity

    Joshua ePoore

    2012-08-01

    Full Text Available The human reward system is sensitive to both social (e.g., validation and non-social rewards (e.g., money and is likely integral for relationship development and reputation building. However, data is sparse on the question of whether implicit social reward processing meaningfully contributes to explicit social representations such as trust and attachment security in pre-existing relationships. This event-related fMRI experiment examined reward system prediction-error activity in response to a potent social reward—social validation—and this activity’s relation to both attachment security and trust in the context of real romantic relationships. During the experiment, participants’ expectations for their romantic partners’ positive regard of them were confirmed (validated or violated, in either positive or negative directions. Primary analyses were conducted using predefined regions of interest, the locations of which were taken from previously published research. Results indicate that activity for mid-brain and striatal reward system regions of interest was modulated by social reward expectation violation in ways consistent with prior research on reward prediction-error. Additionally, activity in the striatum during viewing of disconfirmatory information was associated with both increases in post-scan reports of attachment anxiety and decreases in post-scan trust, a finding that follows directly from representational models of attachment and trust.

  13. Activity-dependent modulation of odorant receptor gene expression in the mouse olfactory epithelium.

    Shaohua Zhao

    Full Text Available Activity plays critical roles in development and maintenance of the olfactory system, which undergoes considerable neurogenesis throughout life. In the mouse olfactory epithelium, each olfactory sensory neuron (OSN stably expresses a single odorant receptor (OR type out of a repertoire of ∼1200 and the OSNs with the same OR identity are distributed within one of the few broadly-defined zones. However, it remains elusive whether and how activity modulates such OR expression patterns. Here we addressed this question by investigating OR gene expression via in situ hybridization when sensory experience or neuronal excitability is manipulated. We first examined the expression patterns of fifteen OR genes in mice which underwent neonatal, unilateral naris closure. After four-week occlusion, the cell density in the closed (sensory-deprived side was significantly lower (for four ORs, similar (for three ORs, or significantly higher (for eight ORs as compared to that in the open (over-stimulated side, suggesting that sensory inputs have differential effects on OSNs expressing different OR genes. We next examined the expression patterns of seven OR genes in transgenic mice in which mature OSNs had reduced neuronal excitability. Neuronal silencing led to a significant reduction in the cell density for most OR genes tested and thinner olfactory epithelium with an increased density of apoptotic cells. These results suggest that sensory experience plays important roles in shaping OR gene expression patterns and the neuronal activity is critical for survival of OSNs.

  14. 3β-Acetyl Tormentic Acid (3ATA a Novel Modulator of ABCC Proteins Activity

    Cerli Rocha Gattass

    2012-06-01

    Full Text Available Multidrug resistance (MDR is considered the main cause of cancer chemotherapy failure and patient relapse. The active drug efflux mediated by transporter proteins of the ABC (ATP-binding cassette family is the most investigated mechanism leading to MDR. With the aim of inhibiting this transport and circumventing MDR, a great amount of work has been dedicated to identifying pharmacological inhibitors of specific ABC transporters. We recently showed that 3β-acetyl tormentic acid (3ATA had no effect on P-gp/ABCB1 activity. Herein, we show that 3ATA strongly inhibited the activity of MRP1/ABCC1. In the B16/F10 and Ma104 cell lines, this effect was either 20X higher or similar to that observed with MK571, respectively. Nevertheless, the low inhibitory effect of 3ATA on A549, a cell line that expresses MRP1-5, suggests that it may not inhibit other MRPs. The use of cells transfected with ABCC2, ABCC3 or ABCC4 showed that 3ATA was also able to modulate these transporters, though with an inhibition ratio lower than that observed for MRP1/ABCC1. These data point to 3ATA as a new ABCC inhibitor and call attention to its potential use as a tool to investigate the function of MRP/ABCC proteins or as a co-adjuvant in the treatment of MDR tumors.

  15. Disintegrins: integrin selective ligands which activate integrin-coupled signaling and modulate leukocyte functions

    Barja-Fidalgo C.

    2005-01-01

    Full Text Available Extracellular matrix proteins and cell adhesion receptors (integrins play essential roles in the regulation of cell adhesion and migration. Interactions of integrins with the extracellular matrix proteins lead to phosphorylation of several intracellular proteins such as focal adhesion kinase, activating different signaling pathways responsible for the regulation of a variety of cell functions, including cytoskeleton mobilization. Once leukocytes are guided to sites of infection, inflammation, or antigen presentation, integrins can participate in the initiation, maintenance, or termination of the immune and inflammatory responses. The modulation of neutrophil activation through integrin-mediated pathways is important in the homeostatic control of the resolution of inflammatory states. In addition, during recirculation, T lymphocyte movement through distinct microenvironments is mediated by integrins, which are critical for cell cycle, differentiation and gene expression. Disintegrins are a family of low-molecular weight, cysteine-rich peptides first identified in snake venom, usually containing an RGD (Arg-Gly-Asp motif, which confers the ability to selectively bind to integrins, inhibiting integrin-related functions in different cell systems. In this review we show that, depending on the cell type and the microenvironment, disintegrins are able to antagonize the effects of integrins or to act agonistically by activating integrin-mediated signaling. Disintegrins have proven useful as tools to improve the understanding of the molecular events regulated by integrin signaling in leukocytes and prototypes in order to design therapies able to interfere with integrin-mediated effects.

  16. Intracellular modulation, extracellular disposal and serum increase of MiR-150 mark lymphocyte activation.

    Paola de Candia

    Full Text Available Activated lymphocytes release nano-sized vesicles (exosomes containing microRNAs that can be monitored in the bloodstream. We asked whether elicitation of immune responses is followed by release of lymphocyte-specific microRNAs. We found that, upon activation in vitro, human and mouse lymphocytes down-modulate intracellular miR-150 and accumulate it in exosomes. In vivo, miR-150 levels increased significantly in serum of humans immunized with flu vaccines and in mice immunized with ovalbumin, and this increase correlated with elevation of antibody titers. Immunization of immune-deficient mice, lacking MHCII, resulted neither in antibody production nor in elevation of circulating miR-150. This study provides proof of concept that serum microRNAs can be detected, with minimally invasive procedure, as biomarkers of vaccination and more in general of adaptive immune responses. Furthermore, the prompt reduction of intracellular level of miR-150, a key regulator of mRNAs critical for lymphocyte differentiation and functions, linked to its release in the external milieu suggests that the selective extracellular disposal of microRNAs can be a rapid way to regulate gene expression during lymphocyte activation.

  17. Modulation of inflammasome activity by Porphyromonas gingivalis in periodontitis and associated systemic diseases.

    Olsen, Ingar; Yilmaz, Özlem

    2016-01-01

    Inflammasomes are large multiprotein complexes localized in the cytoplasm of the cell. They are responsible for the maturation of pro-inflammatory cytokines such as interleukin-1β (IL-1β) and IL-18 as well as for the activation of inflammatory cell death, the so-called pyroptosis. Inflammasomes assemble in response to cellular infection, cellular stress, or tissue damage; promote inflammatory responses and are of great importance in regulating the innate immune system in chronic inflammatory diseases such as periodontitis and several chronic systemic diseases. In addition to sensing cellular integrity, inflammasomes are involved in the homeostatic mutualism between the indigenous microbiota and the host. There are several types of inflammasomes of which NLRP3 is best characterized in microbial pathogenesis. Many opportunistic bacteria try to evade the innate immune system in order to survive in the host cells. One of these is the periodontopathogen Porphyromonas gingivalis which has been shown to have several mechanisms of modulating innate immunity by limiting the activation of the NLRP3 inflammasome. Among them, ATP-/P2X7- signaling is recently associated not only with periodontitis but also with development of several systemic diseases. The present paper reviews multiple mechanisms through which P. gingivalis can modify innate immunity by affecting inflammasome activity. PMID:26850450

  18. Modulation of inflammasome activity by Porphyromonas gingivalis in periodontitis and associated systemic diseases

    Ingar Olsen

    2016-02-01

    Full Text Available Inflammasomes are large multiprotein complexes localized in the cytoplasm of the cell. They are responsible for the maturation of pro-inflammatory cytokines such as interleukin-1β (IL-1β and IL-18 as well as for the activation of inflammatory cell death, the so-called pyroptosis. Inflammasomes assemble in response to cellular infection, cellular stress, or tissue damage; promote inflammatory responses and are of great importance in regulating the innate immune system in chronic inflammatory diseases such as periodontitis and several chronic systemic diseases. In addition to sensing cellular integrity, inflammasomes are involved in the homeostatic mutualism between the indigenous microbiota and the host. There are several types of inflammasomes of which NLRP3 is best characterized in microbial pathogenesis. Many opportunistic bacteria try to evade the innate immune system in order to survive in the host cells. One of these is the periodontopathogen Porphyromonas gingivalis which has been shown to have several mechanisms of modulating innate immunity by limiting the activation of the NLRP3 inflammasome. Among them, ATP-/P2X7- signaling is recently associated not only with periodontitis but also with development of several systemic diseases. The present paper reviews multiple mechanisms through which P. gingivalis can modify innate immunity by affecting inflammasome activity.

  19. Structure-function analysis indicates that sumoylation modulates DNA-binding activity of STAT1

    Grönholm Juha

    2012-10-01

    Full Text Available Abstract Background STAT1 is an essential transcription factor for interferon-γ-mediated gene responses. A distinct sumoylation consensus site (ψKxE 702IKTE705 is localized in the C-terminal region of STAT1, where Lys703 is a target for PIAS-induced SUMO modification. Several studies indicate that sumoylation has an inhibitory role on STAT1-mediated gene expression but the molecular mechanisms are not fully understood. Results Here, we have performed a structural and functional analysis of sumoylation in STAT1. We show that deconjugation of SUMO by SENP1 enhances the transcriptional activity of STAT1, confirming a negative regulatory effect of sumoylation on STAT1 activity. Inspection of molecular model indicated that consensus site is well exposed to SUMO-conjugation in STAT1 homodimer and that the conjugated SUMO moiety is directed towards DNA, thus able to form a sterical hindrance affecting promoter binding of dimeric STAT1. In addition, oligoprecipitation experiments indicated that sumoylation deficient STAT1 E705Q mutant has higher DNA-binding activity on STAT1 responsive gene promoters than wild-type STAT1. Furthermore, sumoylation deficient STAT1 E705Q mutant displayed enhanced histone H4 acetylation on interferon-γ-responsive promoter compared to wild-type STAT1. Conclusions Our results suggest that sumoylation participates in regulation of STAT1 responses by modulating DNA-binding properties of STAT1.

  20. Multi-Senses Explication Activities Module for Dyslexic Children in Malaysia

    Vijayaletchumy Subramaniam

    2013-05-01

    Full Text Available Dyslexic children are having abnormal difficulties in reading, spelling and writing. The awareness on these problems leads researcher to conduct a case study in the psycholinguistic field about the multi-senses explication activities in the words mastery among the dyslexic children in Sekolah Kebangsaan Padang Temu Melaka. Starting from the Information Processing Theory by Robert M. Gagne (1975 as the theoretical framework, this research aims to produce a module on the multi-senses explication activities for the dyslexic children in Malaysia. The subjects are five dyslexic children from Sekolah Kebangsaan Padang Temu Melaka. They are in the middle of following through the Dyslexia Specific Learning Problem Integration Programme in that particular school. Data were gathered from Test 1 and Test 2, questionnaire, interview sessions and observations conducted. The findings showed that the multi-senses explication activities could provide the language learning mode, especially on the mastery of the suitable words based on the dyslexic children’s mind. Besides that, researcher also emphasized on the language game element in the students’ learning of the Malay language. The interview sessions and the observations showed the improvised language learning game managed to pull the attention of the students and trigger the fun feelings of the dyslexic children in learning the Malay language which they felt difficult to master previously.

  1. Early intervention with human albumin to reduce the tissue plasminogen activator-mediated blood-brain barrier permeability damaged by delayed reperfusion: an experimental study in rats

    Objective: To clarify whether early use of high-dose human albumin can reduce the permeability of blood-brain barrier (BBB) damaged by delayed thrombolysis or not, and, in tun, reduce the vasogenic brain edema. Methods: A total of 138 male SD rats weighing 320-380 grams were randomly divided into 4 groups: sham operation group (n=3), control group (n=45), albumin group (n=45) and albumin+rt-PA group (n=45). According to the reperfusion time after the onset of middle cerebral artery occlusion (MCAO), each group, except sham operation group, was divided into three subgroups of 2 h, 3 h and 4 h with 15 rats in each subgroup. Rats in albumin group and albumin+rt-PA group received an intravenous infusion of 20% human albumin (2.5 g/kg) 2 hours after the onset of MCAO, and rats in albumin+rt-PA group received an intravenous infusion of rt-PA (10 mg/kg) at all points of reperfusion time via the rat's femoral vein immediately after the reperfusion. All rats were sacrificed 24 hours after MCAO, the infarct volume of the brain was determined with TTC dye method, the leakage extent of BBB was quantitatively estimated by using Evans blue method, and the matrix metalloproteinase-9 (MMP-9) expression was assessed with immunohistochemistry technique. Results: Early intervention with the use of high-dose human albumin could significantly improve the neurological score at 24 h. In MCAO 3 h albumin group, MCAO 4 h albumin group and MCAO 3 h albumin+rt-PA group, neurological score was significantly better than that in the control group (P0.05). The volume of the infarct tissue was also significantly smaller in all the treated groups with high-dose human albumin groups (P<0.05) when compared with the control group. The infarct volume of the MCAO 4 h in albumin group and albumin+rt-PA group was reduced by 23% and by 17.3%, respectively. Cerebral hemorrhage transformation occurred in two rats of MCAO 4 h control group, in one rat of MCAO 4 h albumin group and in one rat of MCAO 4 h

  2. Commensal Streptococcus salivarius Modulates PPARγ Transcriptional Activity in Human Intestinal Epithelial Cells.

    Benoît Couvigny

    Full Text Available The impact of commensal bacteria in eukaryotic transcriptional regulation has increasingly been demonstrated over the last decades. A multitude of studies have shown direct effects of commensal bacteria from local transcriptional activity to systemic impact. The commensal bacterium Streptococcus salivarius is one of the early bacteria colonizing the oral and gut mucosal surfaces. It has been shown to down-regulate nuclear transcription factor (NF-кB in human intestinal cells, a central regulator of the host mucosal immune system response to the microbiota. In order to evaluate its impact on a further important transcription factor shown to link metabolism and inflammation in the intestine, namely PPARγ (peroxisome proliferator-activated receptor, we used human intestinal epithelial cell-lines engineered to monitor PPARγ transcriptional activity in response to a wide range of S. salivarius strains. We demonstrated that different strains from this bacterial group share the property to inhibit PPARγ activation independently of the ligand used. First attempts to identify the nature of the active compounds showed that it is a low-molecular-weight, DNase-, proteases- and heat-resistant metabolite secreted by S. salivarius strains. Among PPARγ-targeted metabolic genes, I-FABP and Angptl4 expression levels were dramatically reduced in intestinal epithelial cells exposed to S. salivarius supernatant. Both gene products modulate lipid accumulation in cells and down-regulating their expression might consequently affect host health. Our study shows that species belonging to the salivarius group of streptococci impact both host inflammatory and metabolic regulation suggesting a possible role in the host homeostasis and health.

  3. Commensal Streptococcus salivarius Modulates PPARγ Transcriptional Activity in Human Intestinal Epithelial Cells.

    Couvigny, Benoît; de Wouters, Tomas; Kaci, Ghalia; Jacouton, Elsa; Delorme, Christine; Doré, Joël; Renault, Pierre; Blottière, Hervé M; Guédon, Eric; Lapaque, Nicolas

    2015-01-01

    The impact of commensal bacteria in eukaryotic transcriptional regulation has increasingly been demonstrated over the last decades. A multitude of studies have shown direct effects of commensal bacteria from local transcriptional activity to systemic impact. The commensal bacterium Streptococcus salivarius is one of the early bacteria colonizing the oral and gut mucosal surfaces. It has been shown to down-regulate nuclear transcription factor (NF-кB) in human intestinal cells, a central regulator of the host mucosal immune system response to the microbiota. In order to evaluate its impact on a further important transcription factor shown to link metabolism and inflammation in the intestine, namely PPARγ (peroxisome proliferator-activated receptor), we used human intestinal epithelial cell-lines engineered to monitor PPARγ transcriptional activity in response to a wide range of S. salivarius strains. We demonstrated that different strains from this bacterial group share the property to inhibit PPARγ activation independently of the ligand used. First attempts to identify the nature of the active compounds showed that it is a low-molecular-weight, DNase-, proteases- and heat-resistant metabolite secreted by S. salivarius strains. Among PPARγ-targeted metabolic genes, I-FABP and Angptl4 expression levels were dramatically reduced in intestinal epithelial cells exposed to S. salivarius supernatant. Both gene products modulate lipid accumulation in cells and down-regulating their expression might consequently affect host health. Our study shows that species belonging to the salivarius group of streptococci impact both host inflammatory and metabolic regulation suggesting a possible role in the host homeostasis and health. PMID:25946041

  4. Cytosolic phospholipase A2α regulates G1 progression through modulating FOXO1 activity.

    Naini, Said Movahedi; Choukroun, Gabriel J; Ryan, James R; Hentschel, Dirk M; Shah, Jagesh V; Bonventre, Joseph V

    2016-03-01

    Group IVA phospholipase A2 [cytosolic phospholipase A2α (cPLA2α)] is a key mediator of inflammation and tumorigenesis. In this study, by using a combination of chemical inhibition and genetic approaches in zebrafish and murine cells, we identify a mechanism by which cPLA2α promotes cell proliferation. We identified 2 cpla2α genes in zebrafish, cpla2αa and cpla2αb, with conserved phospholipase activity. In zebrafish, loss of cpla2α expression or inhibition of cpla2α activity diminished G1 progression through the cell cycle. This phenotype was also seen in both mouse embryonic fibroblasts and mesangial cells. G1 progression was rescued by the addition of arachidonic acid or prostaglandin E2 (PGE2), indicating a phospholipase-dependent mechanism. We further show that PGE2, through PI3K/AKT activation, promoted Forkhead box protein O1 (FOXO1) phosphorylation and FOXO1 nuclear export. This led to up-regulation of cyclin D1 and down-regulation of p27(Kip1), thus promoting G1 progression. Finally, using pharmacologic inhibitors, we show that cPLA2α, rapidly accelerated fibrosarcoma (RAF)/MEK/ERK, and PI3K/AKT signaling pathways cooperatively regulate G1 progression in response to platelet-derived growth factor stimulation. In summary, these data indicate that cPLA2α, through its phospholipase activity, is a critical effector of G1 phase progression through the cell cycle and suggest that pharmacological targeting of this enzyme may have important therapeutic benefits in disease mechanisms that involve excessive cell proliferation, in particular, cancer and proliferative glomerulopathies.-Naini, S. M., Choukroun, G. J., Ryan, J. R., Hentschel, D. M., Shah, J. V., Bonventre, J. V. Cytosolic phospholipase A2α regulates G1 progression through modulating FOXO1 activity. PMID:26644349

  5. Transcranial Direct Current Stimulation Modulates Cortical Neuronal Activity in Alzheimer's Disease

    Marceglia, Sara; Mrakic-Sposta, Simona; Rosa, Manuela; Ferrucci, Roberta; Mameli, Francesca; Vergari, Maurizio; Arlotti, Mattia; Ruggiero, Fabiana; Scarpini, Elio; Galimberti, Daniela; Barbieri, Sergio; Priori, Alberto

    2016-01-01

    . Our findings disclosed that tDCS induces significant modulations in the cortical EEG activity in AD patients. The abnormal pattern of EEG activity observed in AD during memory processing is partially reversed by applying anodal tDCS, suggesting that anodal tDCS benefits in AD patients during working memory tasks are supported by the modulation of cortical activity. PMID:27065792

  6. PRE-ACTIVITY MODULATION OF LOWER EXTREMITY MUSCLES WITHIN DIFFERENT TYPES AND HEIGHTS OF DEEP JUMP

    Vladimir Mrdakovic

    2008-06-01

    Full Text Available The purpose of this study was to determine modulation of pre- activity related to different types and heights of deep jump. Sixteen male soccer players without experience in deep jumps training (the national competition; 15.0 ± 0.5yrs; weight 61.9 ± 6.1kg; height 1.77 ± 0.07m, who participated in the study, performed three types of deep jump (bounce landing, counter landing, and bounce drop jump from three different heights (40cm, 60cm, and 80cm. Surface EMG device (1000Hz was used to estimate muscle activity (maximal amplitude of EMG - AmaxEMG; integral EMG signal - iEMG of five muscles (mm.gastrocnemii, m.soleus, m.tibialis anterior, m.vastus lateralis within 150ms before touchdown. All the muscles, except m. gastrocnemius medialis, showed systematic increase in pre-activity when platform height was raised. For most of the lower extremity muscles, the most significant differences were between values of pre-activity obtained for 40 cm and 80 cm platforms. While the amount of muscle pre-activity in deep jumps from the heights above and beneath the optimal one did not differ significantly from that generated in deep jumps from the optimal drop height of 60 cm, the patterns of muscle pre-activity obtained for the heights above the optimal one did differ from those obtained for the optimal drop height. That suggests that deep jumps from the heights above the optimal one do not seem to be an adequate exercise for adjusting muscle activity for the impact. Muscle pre-activity in bounce drop jumps differed significantly from that in counter landing and bounce landing respectively, which should indicate that a higher amount of pre-activity generated during bounce drop jumps was used for performing take-offs. As this study included the subjects who were not familiar with deep jumps training, the prospective studies should reveal the results of athletes with previous experience

  7. Plasminogen N-terminal activation peptide modulates the activity of angiostatin-related peptides on endothelial cell proliferation and migration.

    Hayashi, Moyuru; Tamura, Yosuke; Dohmae, Naoshi; Kojima, Soichi; Shimonaka, Motoyuki

    2008-05-01

    Angiostatin, a potent inhibitor of angiogenesis, is derived from the fibrinolytic proenzyme, plasminogen, by enzymatic processing. Plasminogen N-terminal activation peptide (PAP) is one of the products concomitantly released aside from angiostatin (kringles 1-4) and mini-plasminogen (kringle 5 plus the catalytic domain) when plasminogen is processed. To determine whether PAP alone or together with the angiostatin-related peptides derived from the processing of plasminogen modulate the proliferation and motility of endothelial cells, we have generated a recombinant PAP and used it to study its effects on endothelial cells in the presence and absence of the angiostatin-related peptides. Our results showed that PAP alone slightly increased the migration but not the proliferation of endothelial cells. However, in the presence of the angiostatin-related peptides, PAP attenuated the inhibitory activity of the angiostatin-related peptides on the proliferation and migration of endothelial cells. The inhibitory effect of PAP on the angiostatin-related peptides could be due to its binding to the kringle domains of the latter peptides. PMID:18294956

  8. Plasminogen N-terminal activation peptide modulates the activity of angiostatin-related peptides on endothelial cell proliferation and migration

    Angiostatin, a potent inhibitor of angiogenesis, is derived from the fibrinolytic proenzyme, plasminogen, by enzymatic processing. Plasminogen N-terminal activation peptide (PAP) is one of the products concomitantly released aside from angiostatin (kringles 1-4) and mini-plasminogen (kringle 5 plus the catalytic domain) when plasminogen is processed. To determine whether PAP alone or together with the angiostatin-related peptides derived from the processing of plasminogen modulate the proliferation and motility of endothelial cells, we have generated a recombinant PAP and used it to study its effects on endothelial cells in the presence and absence of the angiostatin-related peptides. Our results showed that PAP alone slightly increased the migration but not the proliferation of endothelial cells. However, in the presence of the angiostatin-related peptides, PAP attenuated the inhibitory activity of the angiostatin-related peptides on the proliferation and migration of endothelial cells. The inhibitory effect of PAP on the angiostatin-related peptides could be due to its binding to the kringle domains of the latter peptides

  9. Modulation of functionally localized right insular cortex activity using real-time fMRI-based neurofeedback

    Berman, Brian D.; Horovitz, Silvina G.; Hallett, Mark

    2013-01-01

    The capacity for subjects to learn to volitionally control localized brain activity using neurofeedback is actively being investigated. We aimed to investigate the ability of healthy volunteers to quickly learn to use visual feedback during real-time functional MRI (rtfMRI) to modulate brain activity within their anterior right insular cortex (RIC) localized during a blink suppression task, an approach of possible interest in the use of rtfMRI to reduce urges. The RIC region of interest (RIC-...

  10. Geothermal Permeability Enhancement - Final Report

    Joe Beall; Mark Walters

    2009-06-30

    The overall objective is to apply known permeability enhancement techniques to reduce the number of wells needed and demonstrate the applicability of the techniques to other undeveloped or under-developed fields. The Enhanced Geothermal System (EGS) concept presented in this project enhances energy extraction from reduced permeability zones in the super-heated, vapor-dominated Aidlin Field of the The Geysers geothermal reservoir. Numerous geothermal reservoirs worldwide, over a wide temperature range, contain zones of low permeability which limit the development potential and the efficient recovery of heat from these reservoirs. Low permeability results from poorly connected fractures or the lack of fractures. The Enhanced Geothermal System concept presented here expands these technologies by applying and evaluating them in a systematic, integrated program.

  11. Permeability of soils in Mississippi

    O'Hara, Charles G.

    1994-01-01

    The permeability of soils in Mississippi was determined and mapped using a geographic information system (GIS). Soil permeabilities in Mississippi were determined to range in value from nearly 0.0 to values exceeding 5.0 inches per hour. The U.S. Soil Conservation Service's State Soil Geographic Data Base (STATSGO) was used as the primary source of data for the determination of area-weighted soil permeability. STATSGO provides soil layer properties that are spatially referenced to mapped areas. These mapped areas are referred to as polygons in the GIS. The polygons arc boundaries of soils mapped as a group and are given unique Map Unit Identifiers (MUIDs). The data describing the physical characteristics of the soils within each polygon are stored in a tabular data base format and are referred to as attributes. The U.S. Soil Conservation Service developed STATSGO to be primarily used as a guide for regional resource planning, management, and monitoring. STATSGO was designed so that soil information could be extracted from properties tables at the layer level, combined by component, and statistically expanded to cover the entire map unit. The results of this study provide a mapped value for permeability which is representative of the vertical permeability of soils in that area. The resultant permeability map provides a representative vertical soil permeability for a given area sufficient for county, multi- county, and area planning, and will be used as the soil permeability data component in the evaluation of the susceptibility of major aquifers to contami- nation in Mississippi.

  12. Permeability within basaltic oceanic crust

    Fisher, Andrew T.

    1998-05-01

    Water-rock interactions within the seafloor are responsible for significant energy and solute fluxes between basaltic oceanic crust and the overlying ocean. Permeability is the primary hydrologic property controlling the form, intensity, and duration of seafloor fluid circulation, but after several decades of characterizing shallow oceanic basement, we are still learning how permeability is created and distributed and how it changes as the crust ages. Core-scale measurements of basaltic oceanic crust yield permeabilities that are quite low (generally 10-22 to 10-17 m²), while in situ measurements in boreholes suggest an overlapping range of values extending several orders of magnitude higher (10-18 to 10-13 m²). Additional indirect estimates include calculations made from borehole temperature and flow meter logs (10-16 to 10-11 m²), numerical models of coupled heat and fluid flow at the ridge crest and within ridge flanks (10-16 to 10-9 m²), and several other methods. Qualitative indications of permeability within the basaltic oceanic crust come from an improved understanding of crustal stratigraphy and patterns of alteration and tectonic modification seen in ophiolites, seafloor samples and boreholes. Difficulties in reconciling the wide range of estimated permeabilities arise from differences in experimental scale and critical assumptions regarding the nature and distribution of fluid flow. Many observations and experimental and modeling results are consistent with permeability varying with depth into basement and with primary basement lithology. Permeability also seems to be highly heterogeneous and anisotropic throughout much of the basaltic crust, as within crystalline rocks in general. A series of focused experiments is required to resolve permeability in shallow oceanic basement and to directly couple upper crustal hydrogeology to magmatic, tectonic, and geochemical crustal evolution.

  13. Reducing Dilution and Analysis Time in Online Comprehensive Two-Dimensional Liquid Chromatography by Active Modulation.

    Gargano, Andrea F G; Duffin, Mike; Navarro, Pablo; Schoenmakers, Peter J

    2016-02-01

    Online comprehensive two-dimensional liquid chromatography (LC × LC) offers ways to achieve high-performance separations in terms of peak capacity (exceeding 1000) and additional selectivity to realize applications that cannot be addressed with one-dimensional chromatography (1D-LC). However, the greater resolving power of LC × LC comes at the price of higher dilutions (thus, reduced sensitivity) and, often, long analysis times (>100 min). The need to preserve the separation attained in the first dimension ((1)D) causes greater dilution for LC × LC, in comparison with 1D-LC, and long analysis times to sample the (1)D with an adequate number of second dimension separations. A way to significantly reduce these downsides is to introduce a concentration step between the two chromatographic dimensions. In this work we present a possible active-modulation approach to concentrate the fractions of (1)D effluent. A typical LC × LC system is used with the addition of a dilution flow to decrease the strength of the (1)D effluent and a modulation unit that uses trap columns. The potential of this approach is demonstrated for the separation of tristyrylphenol ethoxylate phosphate surfactants, using a combination of hydrophilic interaction and reversed-phase liquid chromatography. The modified LC × LC system enabled us to halve the analysis time necessary to obtain a similar degree of separation efficiency with respect to UHPLC based LC × LC and of 5 times with respect to HPLC instrumentation (40 compared with 80 and 200 min, respectively), while at the same time reducing dilution (DF of 142, 299, and 1529, respectively) and solvent consumption per analysis (78, 120, and 800 mL, respectively). PMID:26709410

  14. Modulation of peritoneal macrophage activity by the saturation state of the fatty acid moiety of phosphatidylcholine

    F.C.C. Grando

    2009-07-01

    Full Text Available To determine the effects of saturated and unsaturated fatty acids in phosphatidylcholine (PC on macrophage activity, peritoneal lavage cells were cultured in the presence of phosphatidylcholine rich in saturated or unsaturated fatty acids (sat PC and unsat PC, respectively, both used at concentrations of 32 and 64 µM. The treatment of peritoneal macrophages with 64 µM unsat PC increased the production of hydrogen peroxide by 48.3% compared to control (148.3 ± 16.3 vs 100.0 ± 1.8%, N = 15, and both doses of unsat PC increased adhesion capacity by nearly 50%. Moreover, 64 µM unsat PC decreased neutral red uptake by lysosomes by 32.5% compared to the untreated group (67.5 ± 6.8 vs 100.0 ± 5.5%, N = 15, while both 32 and 64 µM unsat PC decreased the production of lipopolysaccharide-elicited nitric oxide by 30.4% (13.5 ± 2.6 vs 19.4 ± 2.5 µM and 46.4% (10.4 ± 3.1 vs 19.4 ± 2.5 µM, respectively. Unsat PC did not affect anion production in non-stimulated cells or phagocytosis of unopsonized zymosan particles. A different result pattern was obtained for macrophages treated with sat PC. Phorbol 12-miristate 13-acetate-elicited superoxide production and neutral red uptake were decreased by nearly 25% by 32 and 64 µM sat PC, respectively. Sat PC did not affect nitric oxide or hydrogen peroxide production, adhesion capacity or zymosan phagocytosis. Thus, PC modifies macrophage activity, but this effect depends on cell activation state, fatty acid saturation and esterification to PC molecule and PC concentration. Taken together, these results indicate that the fatty acid moiety of PC modulates macrophage activity and, consequently, is likely to affect immune system regulation in vivo.

  15. Aqueous Extracts of Selected Potentilla Species Modulate Biological Activity of Human Normal Colon Cells.

    Paduch, Roman; Wiater, Adrian; Locatelli, Marcello; Pleszczyńska, Malgorzata; Tomczyk, Michal

    2015-01-01

    Potentilla L. (Rosaceae) species have been used in traditional and in folk medicine for many years. This study characterized the activity of extracts from aerial parts of selected Potentilla species: P. argentea, P. anserina, P. grandiflora and P. erecta as well as one species of closely related to the genus Potentilla, Drymocallis rupestris (syn. P. rupestris). The biological activities were analyzed using MTT, NR and DPPH assays on CCD 841 CoTr and CCD-18Co cells. Moreover, cell morphology and cytoskeletal actin F-filaments organization and IL-6 and IL-10 levels by ELISA were analyzed after 24 h of incubation. Potentilla extracts at dose levels between 25 and 250 µg/mL were analyzed. For ELISA, 15 µg/mL and 30 μg/mL were chosen. When mitochondrial succinyl dehydrogenase activity was tested (MTT assay) only extract obtained from P. erecta at lower concentrations (up to 125 µg/mL) suppressed metabolism of myofibroblasts, while epithelial cells mitochondrial enzyme activity increased after incubation with all extracts. In Neutral Red (NR) method cellular membrane disturbance of both cell cultures was found after D. rupestris and P. grandiflora addition. Moreover, strong influence on epithelial cells was also found for P. anserina. All extracts showed similar, concentration-dependent free radical scavenging (DPPH) effect. Potentilla extracts, especially at lower concentration, decreased IL-6 production in myofibroblasts but the level of the cytokine was found to be stable in epithelial cells. IL-10 analysis revealed that P. argentea, D. rupestris, P. erecta extracts decrease cytokine level in myofibroblasts, while only when higher concentration were applied, decreased cytokine level produced by epithelial cells was found. F-actin filaments staining revealed that Potentilla extracts significantly influence on cellular cytoskeleton organization. Potentilla extracts influence on cells of human colon wall lining modulating the main features of them (viability

  16. Modulation of the firing activity of female dorsal raphe nucleus serotonergic neurons by neuroactive steroids.

    Robichaud, M; Debonnel, G

    2004-07-01

    Important gender differences in mood disorders result in a greater susceptibility for women. Accumulating evidence suggests a reciprocal modulation between the 5-hydroxytryptamine (5-HT) system and neuroactive steroids. Previous data from our laboratory have shown that during pregnancy, the firing activity of 5-HT neurons increases in parallel with progesterone levels. This study was undertaken to evaluate the putative modulation of the 5-HT neuronal firing activity by different neurosteroids. Female rats received i.c.v. for 7 days a dose of 50 micro g/kg per day of one of the following steroids: progesterone, pregnenolone, 5beta-pregnane-3,20-dione (5beta-DHP), 5beta-pregnan-3alpha-ol,20-one, 5beta-pregnan-3beta-ol,20-one, 5alpha-pregnane-3,20-dione, 5alpha-pregnan-3alpha-ol,20-one (allopregnanolone, 3alpha,5alpha-THP), 5alpha-pregnane-3beta-ol,20-one and dehydroepiandrosterone (DHEA). 5beta-DHP and DHEA were also administered for 14 and 21 days (50 micro g/kg per day, i.c.v.) as well as concomitantly with the selective sigma 1 (sigma1) receptor antagonist NE-100. In vivo, extracellular unitary recording of 5-HT neurons performed in the dorsal raphe nucleus of these rats revealed that DHEA, 5beta-DHP and 3alpha,5alpha-THP significantly increased the firing activity of the 5-HT neurons. Interestingly, 5beta-DHP and DHEA showed different time-frames for their effects with 5beta-DHP having its greatest effect after 7 days to return to control values after 21 days, whereas DHEA demonstrated a sustained effect over the 21 day period. NE-100 prevented the effect of DHEA but not of 5beta-DHP, thus indicating that its sigma1 receptors mediate the effect of DHEA but not that of 5beta-DHP. In conclusion, our results offer a cellular basis for potential antidepressant effects of neurosteroids, which may prove important particularly for women with affective disorders. PMID:15225127

  17. Diuretic effect of compounds from Hibiscus sabdariffa by modulation of the aldosterone activity.

    Jiménez-Ferrer, Enrique; Alarcón-Alonso, Javier; Aguilar-Rojas, Arturo; Zamilpa, Alejandro; Jiménez-Ferrer C, Itzia; Tortoriello, Jaime; Herrera-Ruiz, Maribel

    2012-12-01

    acetonitrile extract significantly decreased the expression of this protein.The conclusion of this work is that the diuretic, natriuretic, and potassium sparing effects of Hibiscus sabdariffa are due in part to the modulation of aldosterone activity by the presence in the extract of this plant of compounds potentially responsible for this modulation, as anthocyanins, flavonoids, and chlorogenic acid. PMID:23150077

  18. Bone Microenvironment Modulates Expression and Activity of Cathepsin B in Prostate Cancer

    Izabela Podgorski

    2005-03-01

    Full Text Available Prostate cancers metastasize to bone leading to osteolysis. Here we assessed proteolysis of DOcollagen I (a bone matrix protein and, for comparison, DO-collagen IV, by living human prostate carcinoma cells in vitro. Both collagens were degraded, this degradation was reduced by inhibitors of matrix metallo, serine, cysteine proteases. Because secretion of the cysteine protease cathepsin B is increased in human breast fibroblasts grown on collagen I gels, we analyzed cathepsin B levels and secretion in prostate cells grown on collagen I gels. Levels and secretion were increased only in DU145 cells-cells that expressed the highest baseline levels of cathepsin B. Secretion of cathepsin B was also elevated in DU145 cells grown in vitro on human bone fragments. We further investigated the effect of the bone microenvironment on cathepsin B expression and activity in vivo in a SCID-human model of prostate bone metastasis. High levels of cathepsin B protein and activity were found in DU145, PC3, LNCaP bone tumors, although the PC3 and LNCaP cells had exhibited low cathepsin B expression in vitro. Our results suggest that tumor-stromal interactions in the context of the bone microenvironment can modulate the expression of the cysteine protease cathepsin B.

  19. Rupture force of cell adhesion ligand tethers modulates biological activities of a cell-laden hydrogel.

    Lee, Min Kyung; Park, Jooyeon; Wang, Xuefeng; Roein-Peikar, Mehdi; Ko, Eunkyung; Qin, Ellen; Lee, Jonghwi; Ha, Taekjip; Kong, Hyunjoon

    2016-04-01

    Recent efforts to design a synthetic extracellular matrix for cell culture, engineering, and therapies greatly contributed to addressing biological roles of types and spatial organization of cell adhesion ligands. It is often suggested that ligand-matrix bond strength is another path to regulate cell adhesion and activities; however tools are lacking. To this end, this study demonstrates that a hydrogel coupled with integrin-binding deoxyribonucleic acid (DNA) tethers with pre-defined rupture forces can modulate cell adhesion, differentiation, and secretion activities due to the changes in the number and, likely, force of cells adhered to a gel. The rupture force of DNA tethers was tuned by altering the spatial arrangement of matrix-binding biotin groups. The DNA tethers were immobilized on a hydrogel of alginate grafted with biotin using avidin. Mesenchymal stem cells showed enhanced adhesion, neural differentiation, and paracrine secretion when cultured on the gel coupled with DNA tethers with higher rupture forces. Such innovative cell-matrix interface engineering would be broadly useful for a series of materials used for fundamental and applied studies on biological cells. PMID:26912186

  20. FBXL5 modulates HIF-1α transcriptional activity by degradation of CITED2.

    Machado-Oliveira, Gisela; Guerreiro, Eduarda; Matias, Ana Catarina; Facucho-Oliveira, João; Pacheco-Leyva, Ivette; Bragança, José

    2015-06-15

    CITED2 is a ubiquitously expressed nuclear protein exhibiting a high affinity for the cysteine-histidine-rich domain 1 (CH1) of the transcriptional co-activators CBP/p300. CITED2 is particularly efficient in the inhibition of the hypoxia-inducible factor-1α (HIF-1α) dependent transcription by competing with it for the interaction with the CH1 domain. Here we report a direct and specific interaction between CITED2 and the F-box and leucine rich repeat protein 5 (FBXL5), a substrate adaptor protein which is part of E3 ubiquitin ligase complexes mediating protein degradation by the proteasome. We demonstrated that depletion of FBXL5 by RNA interference led to an increase of CITED2 protein levels. Conversely, overexpression of FBXL5 caused the decrease of CITED2 protein levels in a proteasome-dependent manner, and impaired the interaction between CITED2 and the CH1 domain of p300 in living cells. In undifferentiated mouse embryonic stem cells, the overexpression of FBXL5 also reduced Cited2 protein levels. Finally, we evidenced that FBXL5 overexpression and the consequent degradation of CITED2 enabled the transcriptional activity of the N-terminal transactivation domain of HIF-1α. Collectively, our results highlighted a novel molecular interaction between CITED2 and FBXL5, which might regulate the steady state CITED2 protein levels and contribute to the modulation of gene expression by HIF-1α. PMID:25956243

  1. Green Tea and Bone Marrow Transplantation: From Antioxidant Activity to Enzymatic and Multidrug-resistance Modulation.

    Peluso, Ilaria; Palmery, Maura; Vitalone, Annabella

    2016-10-25

    Epigallocatechin-3-gallate (EGCG), the main flavonoid of green tea (GT), could play an active role in the prevention of oxidative-stress-related diseases, such as hematologic malignancies. Some effects of EGCG are not imputable to antioxidant activity, but involve modulation of antioxidant enzymes and uric acid (UA) levels. The latter is the major factor responsible of the plasma non-enzymatic antioxidant capacity (NEAC). However, hyperuricemia is a frequent clinical feature caused by tumor lysis syndrome or cyclosporine side effects, both before and after bone marrow transplantation (BMT). Besides this, food-drug interactions could be associated with GT consumption and could have clinical implications. The molecular mechanisms involved in the redox and drug metabolizing/transporting pathways were discussed, with particular reference to the potential role of GT and EGCG in BMT. Moreover, on reviewing data on NEAC, isoprostanes, uric acid, and various enzymes from human studies on GT, its extract, or EGCG, an increase in NEAC, without effect on isoprostanes, and contrasting results on UA and enzymes were observed. Currently, few and contrasting available evidences suggest caution for GT consumption in BMT patients and more studies are needed to better understand the potential impact of EGCG on oxidative stress and metabolizing/transporting systems. PMID:26047551

  2. A biased activation theory of the cognitive and attentional modulation of emotion

    Edmund eRolls

    2013-03-01

    Full Text Available Cognition can influence emotion by biasing neural activity in the first cortical region in which the reward value and subjective pleasantness of stimuli is made explicit in the representation, the orbitofrontal cortex. The same effect occurs in a second cortical tier for emotion, the anterior cingulate cortex. Similar effects are found for selective attention, to for example the pleasantness vs the intensity of stimuli, which modulates representations of reward value and affect in the orbitofrontal and anterior cingulate cortices. The mechanisms for the effects of cognition and attention on emotion are top-down biased competition and top-down biased activation. Affective and mood states can in turn influence memory and perception, by backprojected biasing influences. Emotion-related decision systems operate to choose between gene-specified rewards such as taste, touch, and beauty. Reasoning processes capable of planning ahead with multiple steps held in working memory in the explicit system can allow the gene-specified rewards not to be selected, or to be deferred. The stochastic, noisy, dynamics of decision-making systems in the brain may influence whether decisions are made by the selfish-gene-specified reward emotion system, or by the cognitive reasoning system that explicitly calculates reward values that are in the interests of the individual, the phenotype.

  3. Anthropogenically-Induced Superficial Seismic Activity Modulated By Slow-Slip Events in Guerrero, Mexico

    Frank, W.; Shapiro, N.; Husker, A. L.; Kostoglodov, V.; Campillo, M.

    2014-12-01

    We use the data of the MASE seismic experiment operated during 2.5 years in Guerrero, Mexico to create a large catalog of seismic multiplets. This catalog is dominated by families of Low-Frequency Earthquakes (LFE) occurring in vicinity of the main subduction interface. In addition to more than one thousand LFE families, we detected nine repeating seismic event families that are located in the upper crust and are anthropogenically induced (AI) by mining blasts. Analysis of the recurrence of these AI events in time shows that their activity significantly increases during the strong Slow-Slip Event (SSE) in 2006. Modeled static stress perturbations induced by the SSE at the surface are ~5 kPa that is on the same order of magnitude as dynamic stress perturbations observed to trigger other low stress drop phenomena, such as tectonic tremor. We propose therefore that strong SSEs in Guerrero impose an extensional regime throughout the continental crust, modifying the stress field near the surface and increasing AI activity. This modulation of the recurrence of the crustal seismic events by the SSE-induced stress might be related to another recent observation: the SSE-induced reduction of seismic velocities linked to nonlinear elastic effects caused by opening of cracks (Rivet et al., 2011, 2014).

  4. Cannabinoid Modulation of Frontolimbic Activation and Connectivity During Volitional Regulation of Negative Affect.

    Gorka, Stephanie M; Phan, K Luan; Lyons, Maryssa; Mori, Shoko; Angstadt, Mike; Rabinak, Christine A

    2016-06-01

    Behavioral and brain research indicates that administration of Δ(9)-tetrahydrocannabinol (THC) alters threat perception and enhances the suppression of conditioned fear responses via modulation of the frontolimbic circuit. No prior studies, however, have examined whether THC also affects volitional forms of emotion processing such as cognitive reappraisal. The aim of the current study was therefore to examine the effects of THC on frontolimbic activation and functional connectivity during cognitive reappraisal in a sample of healthy adults. The study was a randomized, double-blind, placebo-controlled, between-subject design and all participants ingested either an oral dose of synthetic THC (n=41) or placebo (n=37) before completion of an emotion regulation task during functional magnetic resonance imaging (fMRI). Functional connectivity was assessed using generalized psychophysiological interaction (gPPI) analyses. Results indicated that although there were no group differences in self-reported attenuation of negative affect during cognitive reappraisal, relative to placebo, THC increased amygdala activation and reduced amygdala and dorsolateral prefrontal cortex (dlPFC) functional coupling during cognitive reappraisal of emotionally negative pictures. This suggests that in addition to automatic emotional processes, THC affects frontolimbic functioning during cognitive reappraisal. PMID:26647971

  5. Active optics null test system based on a liquid crystal programmable spatial light modulator

    Ares, Miguel; Royo, Santiago; Sergievskaya, Irina; Riu, Jordi

    2010-11-10

    We present an active null test system adapted to test lenses and wavefronts with complex shapes and strong local deformations. This system provides greater flexibility than conventional static null tests that match only a precisely positioned, individual wavefront. The system is based on a cylindrical Shack-Hartmann wavefront sensor, a commercial liquid crystal programmable phase modulator (PPM), which acts as the active null corrector, enabling the compensation of large strokes with high fidelity in a single iteration, and a spatial filter to remove unmodulated light when steep phase changes are compensated. We have evaluated the PPM's phase response at 635 nm and checked its performance by measuring its capability to generate different amounts of defocus aberration, finding root mean squared errors below {lambda}/18 for spherical wavefronts with peak-to-valley heights of up to 78.7{lambda}, which stands as the limit from which diffractive artifacts created by the PPM have been found to be critical under no spatial filtering. Results of a null test for a complex lens (an ophthalmic customized progressive addition lens) are presented and discussed.

  6. Polyamines cause plasma membrane depolarization, activate Ca2+-, and modulate H+-ATPase pump activity in pea roots.

    Pottosin, Igor; Velarde-Buendía, Ana María; Bose, Jayakumar; Fuglsang, Anja T; Shabala, Sergey

    2014-06-01

    Polyamines regulate a variety of cation and K(+) channels, but their potential effects on cation-transporting ATPases are underexplored. In this work, noninvasive microelectrode ion flux estimation and conventional microelectrode techniques were applied to study the effects of polyamines on Ca(2+) and H(+) transport and membrane potential in pea roots. Externally applied spermine or putrescine (1mM) equally activated eosin yellow (EY)-sensitive Ca(2+) pumping across the root epidermis and caused net H(+) influx or efflux. Proton influx induced by spermine was suppressed by EY, supporting the mechanism in which Ca(2+) pump imports 2 H(+) per each exported Ca(2+). Suppression of the Ca(2+) pump by EY diminished putrescine-induced net H(+) efflux instead of increasing it. Thus, activities of Ca(2+) and H(+) pumps were coupled, likely due to the H(+)-pump inhibition by intracellular Ca(2+). Additionally, spermine but not putrescine caused a direct inhibition of H(+) pumping in isolated plasma membrane vesicles. Spermine, spermidine, and putrescine (1mM) induced membrane depolarization by 70, 50, and 35 mV, respectively. Spermine-induced depolarization was abolished by cation transport blocker Gd(3+), was insensitive to anion channels' blocker niflumate, and was dependent on external Ca(2+). Further analysis showed that uptake of polyamines but not polyamine-induced cationic (K(+)+Ca(2+)+H(+)) fluxes were a main cause of membrane depolarization. Polyamine increase is a common component of plant stress responses. Activation of Ca(2+) efflux by polyamines and contrasting effects of polyamines on net H(+) fluxes and membrane potential can contribute to Ca(2+) signalling and modulate a variety of transport processes across the plasma membrane under stress. PMID:24723394

  7. Electrostatically gated membrane permeability in inorganic protocells

    Li, Mei; Harbron, Rachel L.; Weaver, Jonathan V. M.; Binks, Bernard P.; Mann, Stephen

    2013-06-01

    Although several strategies are now available to produce functional microcompartments analogous to primitive cell-like structures, little progress has been made in generating protocell constructs with self-controlled membrane permeability. Here we describe the preparation of water-dispersible colloidosomes based on silica nanoparticles and delineated by a continuous semipermeable inorganic membrane capable of self-activated, electrostatically gated permeability. We use crosslinking and covalent grafting of a pH-responsive copolymer to generate an ultrathin elastic membrane that exhibits selective release and uptake of small molecules. This behaviour, which depends on the charge of the copolymer coronal layer, serves to trigger enzymatic dephosphorylation reactions specifically within the protocell aqueous interior. This system represents a step towards the design and construction of alternative types of artificial chemical cells and protocell models based on spontaneous processes of inorganic self-organization.

  8. West Nile virus-induced cell adhesion molecules on human brain microvascular endothelial cells regulate leukocyte adhesion and modulate permeability of the in vitro blood-brain barrier model.

    Kelsey Roe

    Full Text Available Characterizing the mechanisms by which West Nile virus (WNV causes blood-brain barrier (BBB disruption, leukocyte infiltration into the brain and neuroinflammation is important to understand the pathogenesis of WNV encephalitis. Here, we examined the role of endothelial cell adhesion molecules (CAMs in mediating the adhesion and transendothelial migration of leukocytes across human brain microvascular endothelial cells (HBMVE. Infection with WNV (NY99 strain significantly induced ICAM-1, VCAM-1, and E-selectin in human endothelial cells and infected mice brain, although the levels of their ligands on leukocytes (VLA-4, LFA-1and MAC-1 did not alter. The permeability of the in vitro BBB model increased dramatically following the transmigration of monocytes and lymphocytes across the models infected with WNV, which was reversed in the presence of a cocktail of blocking antibodies against ICAM-1, VCAM-1, and E-selectin. Further, WNV infection of HBMVE significantly increased leukocyte adhesion to the HBMVE monolayer and transmigration across the infected BBB model. The blockade of these CAMs reduced the adhesion and transmigration of leukocytes across the infected BBB model. Further, comparison of infection with highly neuroinvasive NY99 and non-lethal (Eg101 strain of WNV demonstrated similar level of virus replication and fold-increase of CAMs in HBMVE cells suggesting that the non-neuropathogenic response of Eg101 is not because of its inability to infect HBMVE cells. Collectively, these results suggest that increased expression of specific CAMs is a pathological event associated with WNV infection and may contribute to leukocyte infiltration and BBB disruption in vivo. Our data further implicate that strategies to block CAMs to reduce BBB disruption may limit neuroinflammation and virus-CNS entry via 'Trojan horse' route, and improve WNV disease outcome.

  9. Activation and Allosteric Modulation of Human μ Opioid Receptor in Molecular Dynamics.

    Bartuzi, Damian; Kaczor, Agnieszka A; Matosiuk, Dariusz

    2015-11-23

    Allosteric protein modulation has gained increasing attention in drug design. Its application as a mechanism of action could bring forth safer and more effective medicines. Targeting opioid receptors with allosteric modulators can result in better treatment of pain, depression, and respiratory and immune disorders. In this work we use recent reports on negative modulators of μ opioid receptor as a starting point for identification of allosteric sites and mechanisms of opioid receptor modulation using homology modeling and docking and molecular dynamics studies. An allosteric binding site description is presented. Results suggest a shared binding region for lipophilic allosteric ligands, reveal possible differences in the modulation mechanism between cannabinoids and salvinorin A, and show ambiguous properties of the latter. Also, they emphasize the importance of native-like environment in molecular dynamics simulations and uncover relationships between modulator and orthosteric ligand binding and receptor behavior. Relationships between ligands, transmission switch, and hydrophobic lock are analyzed. PMID:26517559

  10. Thrombospondin-1 modulates vascular endothelial growth factor activity at the receptor level

    Zhang, Xuefeng; Kazerounian, Shideh; Duquette, Mark; Perruzzi, Carole; Nagy, Janice A.; Dvorak, Harold F.; Parangi, Sareh; Lawler, Jack

    2009-01-01

    Vascular endothelial growth factor (VEGF) is a well-established stimulator of vascular permeability and angiogenesis, whereas thrombospondin-1 (TSP-1) is a potent angiogenic inhibitor. In this study, we have found that the TSP-1 receptors CD36 and β1 integrin associate with the VEGF receptor 2 (VEGFR2). The coclustering of receptors that regulate angiogenesis may provide the endothelial cell with a platform for integration of positive and negative signals in the plane of the membrane. Thus, t...

  11. The Self-Pleasantness Judgment Modulates the Encoding Performance and the Default Mode Network Activity.

    Perrone-Bertolotti, Marcela; Cerles, Melanie; Ramdeen, Kylee T; Boudiaf, Naila; Pichat, Cedric; Hot, Pascal; Baciu, Monica

    2016-01-01

    In this functional magnetic resonance imaging (fMRI) study, we evaluated the effect of self-relevance on cerebral activity and behavioral performance during an incidental encoding task. Recent findings suggest that pleasantness judgments reliably induce self-oriented (internal) thoughts and increase default mode network (DMN) activity. We hypothesized that this increase in DMN activity would relate to increased memory recognition for pleasantly-judged stimuli (which depend on internally-oriented attention) but decreased recognition for unpleasantly-judged items (which depend on externally-oriented attention). To test this hypothesis, brain activity was recorded from 21 healthy participants while they performed a pleasantness judgment requiring them to rate visual stimuli as pleasant or unpleasant. One hour later, participants performed a surprise memory recognition test outside of the scanner. Thus, we were able to evaluate the effects of pleasant and unpleasant judgments on cerebral activity and incidental encoding. The behavioral results showed that memory recognition was better for items rated as pleasant than items rated as unpleasant. The whole brain analysis indicated that successful encoding (SE) activates the inferior frontal and lateral temporal cortices, whereas unsuccessful encoding (UE) recruits two key medial posterior DMN regions, the posterior cingulate cortex (PCC) and precuneus (PCU). A region of interest (ROI) analysis including classic DMN areas, revealed significantly greater involvement of the medial prefrontal cortex (mPFC) in pleasant compared to unpleasant judgments, suggesting this region's involvement in self-referential (i.e., internal) processing. This area may be responsible for the greater recognition performance seen for pleasant stimuli. Furthermore, a significant interaction between the encoding performance (successful vs. unsuccessful) and pleasantness was observed for the PCC, PCU and inferior frontal gyrus (IFG). Overall, our

  12. Chronic activation of NPFFR2 stimulates the stress-related depressive behaviors through HPA axis modulation.

    Lin, Ya-Tin; Liu, Tzu-Yu; Yang, Ching-Yao; Yu, Yu-Lian; Chen, Ting-Chun; Day, Yuan-Ji; Chang, Che-Chien; Huang, Guo-Jen; Chen, Jin-Chung

    2016-09-01

    Neuropeptide FF (NPFF) is a morphine-modulating peptide that regulates the analgesic effect of opioids, and also controls food consumption and cardiovascular function through its interaction with two cognate receptors, NPFFR1 and NPFFR2. In the present study, we explore a novel modulatory role for NPFF-NPFFR2 in stress-related depressive behaviors. In a mouse model of chronic mild stress (CMS)-induced depression, the expression of NPFF significantly increased in the hypothalamus, hippocampus, medial prefrontal cortex (mPFC) and amygdala. In addition, transgenic (Tg) mice over-expressing NPFFR2 displayed clear depression and anxiety-like behaviors with hyperactivity in the hypothalamic-pituitary-adrenal (HPA) axis, reduced expression of glucocorticoid receptor (GR) and neurogenesis in the hippocampus. Furthermore, acute treatment of NPFFR2 agonists in wild-type (WT) mice enhanced the activity of the HPA axis, and chronic administration resulted in depressive and anxiety-like behaviors. Chronic stimulation of NPFFR2 also decreased the expression of hippocampal GR and led to persistent activation of the HPA axis. Strikingly, bilateral intra-paraventricular nucleus (PVN) injection of NPFFR2 shRNA predominately inhibits the depressive-like behavior in CMS-exposed mice. Antidepressants, fluoxetine and ketamine, effectively relieved the depressive behaviors of NPFFR2-Tg mice. We speculate that persistent NPFFR2 activation, in particular in the hypothalamus, up-regulates the HPA axis and results in long-lasting increases in circulating corticosterone (CORT), consequently damaging hippocampal function. This novel role of NPFFR2 in regulating the HPA axis and hippocampal function provides a new avenue for combating depression and anxiety-like disorder. PMID:27243477

  13. Belief about Nicotine Modulates Subjective Craving and Insula Activity in Deprived Smokers

    Gu, Xiaosi; Lohrenz, Terry; Salas, Ramiro; Baldwin, Philip R.; Soltani, Alireza; Kirk, Ulrich; Cinciripini, Paul M.; Montague, P. Read

    2016-01-01

    Little is known about the specific neural mechanisms through which cognitive factors influence craving and associated brain responses, despite the initial success of cognitive therapies in treating drug addiction. In this study, we investigated how cognitive factors such as beliefs influence subjective craving and neural activities in nicotine-addicted individuals using model-based functional magnetic resonance imaging (fMRI) and neuropharmacology. Deprived smokers (N = 24) participated in a two-by-two balanced placebo design, which crossed beliefs about nicotine (told “nicotine” vs. told “no nicotine”) with the nicotine content in a cigarette (nicotine vs. placebo) which participants smoked immediately before performing a fMRI task involving reward learning. Subjects’ reported craving was measured both before smoking and after the fMRI session. We found that first, in the presence of nicotine, smokers demonstrated significantly reduced craving after smoking when told “nicotine in cigarette” but showed no change in craving when told “no nicotine.” Second, neural activity in the insular cortex related to craving was only significant when smokers were told “nicotine” but not when told “no nicotine.” Both effects were absent in the placebo condition. Third, insula activation related to computational learning signals was modulated by belief about nicotine regardless of nicotine’s presence. These results suggest that belief about nicotine has a strong impact on subjective craving and insula responses related to both craving and learning in deprived smokers, providing insights into the complex nature of belief–drug interactions. PMID:27468271

  14. CHD7 targets active gene enhancer elements to modulate ES cell-specific gene expression.

    Michael P Schnetz

    2010-07-01

    Full Text Available CHD7 is one of nine members of the chromodomain helicase DNA-binding domain family of ATP-dependent chromatin remodeling enzymes found in mammalian cells. De novo mutation of CHD7 is a major cause of CHARGE syndrome, a genetic condition characterized by multiple congenital anomalies. To gain insights to the function of CHD7, we used the technique of chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP-Seq to map CHD7 sites in mouse ES cells. We identified 10,483 sites on chromatin bound by CHD7 at high confidence. Most of the CHD7 sites show features of gene enhancer elements. Specifically, CHD7 sites are predominantly located distal to transcription start sites, contain high levels of H3K4 mono-methylation, found within open chromatin that is hypersensitive to DNase I digestion, and correlate with ES cell-specific gene expression. Moreover, CHD7 co-localizes with P300, a known enhancer-binding protein and strong predictor of enhancer activity. Correlations with 18 other factors mapped by ChIP-seq in mouse ES cells indicate that CHD7 also co-localizes with ES cell master regulators OCT4, SOX2, and NANOG. Correlations between CHD7 sites and global gene expression profiles obtained from Chd7(+/+, Chd7(+/-, and Chd7(-/- ES cells indicate that CHD7 functions at enhancers as a transcriptional rheostat to modulate, or fine-tune the expression levels of ES-specific genes. CHD7 can modulate genes in either the positive or negative direction, although negative regulation appears to be the more direct effect of CHD7 binding. These data indicate that enhancer-binding proteins can limit gene expression and are not necessarily co-activators. Although ES cells are not likely to be affected in CHARGE syndrome, we propose that enhancer-mediated gene dysregulation contributes to disease pathogenesis and that the critical CHD7 target genes may be subject to positive or negative regulation.

  15. Modulation of Posterior Alpha Activity by Spatial Attention Allows for Controlling A Continuous Brain-Computer Interface

    Horschig, J.M.; Oosterheert, W.; Oostenveld, R.; Jensen, O.

    2014-01-01

    Here we report that the modulation of alpha activity by covert attention can be used as a control signal in an online brain-computer interface, that it is reliable, and that it is robust. Subjects were instructed to orient covert visual attention to the left or right hemifield. We decoded the direct

  16. Combining Functional Neuroimaging with Off-Line Brain Stimulation: Modulation of Task-Related Activity in Language Areas

    Andoh, Jamila; Paus, Tomas

    2011-01-01

    Repetitive TMS (rTMS) provides a noninvasive tool for modulating neural activity in the human brain. In healthy participants, rTMS applied over the language-related areas in the left hemisphere, including the left posterior temporal area of Wernicke (LTMP) and inferior frontal area of Broca, have been shown to affect performance on word…

  17. MSFC Skylab airlock module, volume 2. [systems design and performance, systems support activity, and reliability and safety programs

    1974-01-01

    System design and performance of the Skylab Airlock Module and Payload Shroud are presented for the communication and caution and warning systems. Crew station and storage, crew trainers, experiments, ground support equipment, and system support activities are also reviewed. Other areas documented include the reliability and safety programs, test philosophy, engineering project management, and mission operations support.

  18. Two dimensional distribution of tritium breeding ratio and induced activity in Japanese water cooled and helium cooled test blanket modules

    Solid breeder blankets are regarded as a near-at-hand blanket concept for a fusion power demonstration plant in Japan. Test blanket module (TBM) to be tested in ITER is the most important milestone to establish the fusion demonstration blanket. For the candidate TBM's, two types of TBM, water cooled solid breeder TBM, and a helium gas cooled solid breeder TBM have been proposed and designed in JAERI. For detailed performance study under operation and after shut down, detailed neutronics analysis gives the most important design conditions, such as, distribution of tritium breeding ratio, nuclear heating rate during operation, and induced activation and decay heat after termination of irradiation. In the analysis, neutron and gamma transportation was calculated by two dimensional analysis code, DOT3.5, for two TBMs. Nuclear reaction rate and induced activation rate were evaluated by APPLE-3 and ACT-4, respectively. The analysis model included configurations of thermo-mechanical test modules and surrounding common frames for both of He cooled and water cooled TBMs. By the neutronics analysis, TBR and contact dose rate by induced activation till one year after termination of the module testing have been evaluated. For the evaluation of induced activation level change and decay heat change, the transient decreases in one year after termination of the module testing have been calculated. The time duration of the module testing before termination of testing is assumed to be 133 continuous days of full power operation. The result of TBR analysis showed that TBR distribution in the toroidal direction of TBM is not significant, however, the neutron flux decreases in the region of sidewall of common frame made of SS and water. This result shows that there is relatively large neutron loss from the TBM to the common frame. Thus, it is considered that the TBR value observed in the TBM testing may be smaller than the estimation by one dimensional neutronics analysis which does

  19. Determination of the distribution of catalyst activity across a permeable membrane containing an immobilized enzyme. Indeterminacy of a functional approach to a structural problem.

    Bunow, B.; Caplan, S R

    1984-01-01

    Porous membranes were fabricated from collodion and impregnated with papain, inhomogeneously through the thickness of the membrane. These membranes were placed between reservoirs containing N-alpha-benzoyl arginineamide, a substrate for the enzyme papain. The progress of the reaction was monitored by sampling the reservoirs on each side for ammonia, a reaction product. From these data the diffusion coefficient, enzyme activity, and distribution of enzyme activity of the membrane were estimate...

  20. CITED2 modulates estrogen receptor transcriptional activity in breast cancer cells

    Lau, Wen Min; Doucet, Michele; Huang, David; Weber, Kristy L.; Kominsky, Scott L., E-mail: kominsc@jhmi.edu

    2013-07-26

    Highlights: •The effects of elevated CITED2 on ER function in breast cancer cells are examined. •CITED2 enhances cell growth in the absence of estrogen and presence of tamoxifen. •CITED2 functions as a transcriptional co-activator of ER in breast cancer cells. -- Abstract: Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (CITED2) is a member of the CITED family of non-DNA binding transcriptional co-activators of the p300/CBP-mediated transcription complex. Previously, we identified CITED2 as being overexpressed in human breast tumors relative to normal mammary epithelium. Upon further investigation within the estrogen receptor (ER)-positive subset of these breast tumor samples, we found that CITED2 mRNA expression was elevated in those associated with poor survival. In light of this observation, we investigated the effect of elevated CITED2 levels on ER function. While ectopic overexpression of CITED2 in three ER-positive breast cancer cell lines (MCF-7, T47D, and CAMA-1) did not alter cell proliferation in complete media, growth was markedly enhanced in the absence of exogenous estrogen. Correspondingly, cells overexpressing CITED2 demonstrated reduced sensitivity to the growth inhibitory effects of the selective estrogen receptor modulator, 4-hydroxytamoxifen. Subsequent studies revealed that basal ER transcriptional activity was elevated in CITED2-overexpressing cells and was further increased upon the addition of estrogen. Similarly, basal and estrogen-induced expression of the ER-regulated genes trefoil factor 1 (TFF1) and progesterone receptor (PGR) was higher in cells overexpressing CITED2. Concordant with this observation, ChIP analysis revealed higher basal levels of CITED2 localized to the TFF-1 and PGR promoters in cells with ectopic overexpression of CITED2, and these levels were elevated further in response to estrogen stimulation. Taken together, these data indicate that CITED2 functions as a transcriptional co-activator

  1. CITED2 modulates estrogen receptor transcriptional activity in breast cancer cells

    Highlights: •The effects of elevated CITED2 on ER function in breast cancer cells are examined. •CITED2 enhances cell growth in the absence of estrogen and presence of tamoxifen. •CITED2 functions as a transcriptional co-activator of ER in breast cancer cells. -- Abstract: Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (CITED2) is a member of the CITED family of non-DNA binding transcriptional co-activators of the p300/CBP-mediated transcription complex. Previously, we identified CITED2 as being overexpressed in human breast tumors relative to normal mammary epithelium. Upon further investigation within the estrogen receptor (ER)-positive subset of these breast tumor samples, we found that CITED2 mRNA expression was elevated in those associated with poor survival. In light of this observation, we investigated the effect of elevated CITED2 levels on ER function. While ectopic overexpression of CITED2 in three ER-positive breast cancer cell lines (MCF-7, T47D, and CAMA-1) did not alter cell proliferation in complete media, growth was markedly enhanced in the absence of exogenous estrogen. Correspondingly, cells overexpressing CITED2 demonstrated reduced sensitivity to the growth inhibitory effects of the selective estrogen receptor modulator, 4-hydroxytamoxifen. Subsequent studies revealed that basal ER transcriptional activity was elevated in CITED2-overexpressing cells and was further increased upon the addition of estrogen. Similarly, basal and estrogen-induced expression of the ER-regulated genes trefoil factor 1 (TFF1) and progesterone receptor (PGR) was higher in cells overexpressing CITED2. Concordant with this observation, ChIP analysis revealed higher basal levels of CITED2 localized to the TFF-1 and PGR promoters in cells with ectopic overexpression of CITED2, and these levels were elevated further in response to estrogen stimulation. Taken together, these data indicate that CITED2 functions as a transcriptional co-activator

  2. Scorpion venom component III inhibits cell proliferation by modulating NF-κB activation in human leukemia cells

    SONG, XIANGFENG; Zhang, Guojun; SUN, AIPING; Guo, Jiqiang; TIAN, ZHONGWEI; Wang, Hui; Liu, Yufeng

    2012-01-01

    Scorpion venom contains various groups of compounds that exhibit anticancer activity against a variety of malignancies through a poorly understood mechanism. While the aberrant activation of nuclear factor κB (NF-κB) has been linked with hematopoietic malignancies, we hypothesized that scorpion venom mediates its effects by modulating the NF-κB signaling pathway. In the present study, we examined the effects of scorpion venom component III (SVCIII) on the human leukemia cell lines THP-1 and J...

  3. dTRPA1 in Non-circadian Neurons Modulates Temperature-dependent Rhythmic Activity in Drosophila melanogaster.

    Das, Antara; Holmes, Todd C; Sheeba, Vasu

    2016-06-01

    In fruit flies Drosophila melanogaster, environmental cycles of light and temperature are known to influence behavioral rhythms through dedicated sensory receptors. But the thermosensory pathways and molecular receptors by which thermal cycles modulate locomotor activity rhythms remain unclear. Here, we report that neurons expressing warmth-activated ion channel Drosophila Transient Receptor Potential-A1 (dTRPA1) modulate distinct aspects of the rhythmic activity/rest rhythm in a light-dependent manner. Under light/dark (LD) cycles paired with constantly warm ambient conditions, flies deficient in dTRPA1 expression are unable to phase morning and evening activity bouts appropriately. Correspondingly, we show that electrical activity of a few neurons targeted by the dTRPA1(SH)-GAL4 driver modulates temperature-dependent phasing of activity/rest rhythm under LD cycles. The expression of dTRPA1 also affects behavior responses to temperature cycles combined with constant dark (DD) or light (LL) conditions. We demonstrate that the mid-day "siesta" exhibited by flies under temperature cycles in DD is dependent on dTRPA1 expression in a small number of neurons that include thermosensory anterior cell neurons. Although a small subset of circadian pacemaker neurons may express dTRPA1, we show that CRY-negative dTRPA1(SH)-GAL4 driven neurons are critical for the suppression of mid-thermophase activity, thus enabling flies to exhibit siesta. In contrast to temperature cycles in DD, under LL, dTRPA1 is not required for exhibiting siesta but is important for phasing of evening peak. Our studies show that activity/rest rhythms are modulated in a temperature-dependent manner via signals from dTRPA1(SH)-GAL4 driven neurons. Taken together, these results emphasize the differential influence of thermoreceptors on rhythmic behavior in fruit flies in coordination with light inputs. PMID:26868037

  4. Modulation of Irisin and Physical Activity on Executive Functions in Obesity and Morbid obesity.

    Fagundo, A B; Jiménez-Murcia, S; Giner-Bartolomé, C; Agüera, Z; Sauchelli, S; Pardo, M; Crujeiras, A B; Granero, R; Baños, R; Botella, C; de la Torre, R; Fernández-Real, J M; Fernández-García, J C; Frühbeck, G; Rodríguez, A; Mallorquí-Bagué, N; Tárrega, S; Tinahones, F J; Rodriguez, R; Ortega, F; Menchón, J M; Casanueva, F F; Fernández-Aranda, F

    2016-01-01

    Whether the executive profile is different between obesity (OB) and morbid obesity (MO) remains unclear. Recent evidence suggests that physical activity (PA) can act as a cognitive enhancer. Irisin is a recently discovered hormone associated with some of the positive effects of PA. The objective of the study was to investigate the executive profile in OB and MO, and to explore the role of PA and irisin. 114 participants were included (21 OB, 44 MO and 49 healthy controls-HC) in the study and assessed with the Wisconsin Card Sorting Test, Stroop Color and Word Test, and Iowa Gambling Task. All participants were female, aged between 18 and 60 years. Results showed a similar dysfunctional profile on decision making in OB and MO compared with HC. Thus, no specific neuropsychological profiles between OB and MO can be clearly observed in our sample. However, a negative correlation was found between irisin and executive functioning. These results demonstrate a specific executive profile in OB and a relevant and negative modulation of irisin on executive functioning. Although irisin might be a promising target for the treatment of obesity, its effects on cognition might be considered when thinking about its therapeutic use. PMID:27476477

  5. Modulation of NADPH oxidase activation in cerebral ischemia/reperfusion injury in rats.

    Genovese, Tiziana; Mazzon, Emanuela; Paterniti, Irene; Esposito, Emanuela; Bramanti, Placido; Cuzzocrea, Salvatore

    2011-02-01

    NADPH oxidase is a major complex that produces reactive oxygen species (ROSs) during the ischemic period and aggravates brain damage and cell death after ischemic injury. Although many approaches have been tested for preventing production of ROSs by NADPH oxidase in ischemic brain injury, the regulatory mechanisms of NADPH oxidase activity after cerebral ischemia are still unclear. The aim of this study is identifying apocynin as a critical modulator of NADPH oxidase and elucidating its role as a neuroprotectant in an experimental model of brain ischemia in rat. Treatment of apocynin 5min before of reperfusion attenuated cerebral ischemia in rats. Administration of apocynin showed marked reduction in infarct size compared with that of control rats. Medial carotid artery occlusion (MCAo)-induced cerebral ischemia was also associated with an increase in, nitrotyrosine formation, as well as IL-1β expression, IκB degradation and ICAM expression in ischemic regions. These expressions were markedly inhibited by the treatment of apocynin. We also demonstrated that apocynin reduces levels of apoptosis (TUNEL, Bax and Bcl-2 expression) resulting in a reduction in the infarct volume in ischemia-reperfusion brain injury. This new understanding of apocynin induced adaptation to ischemic stress and inflammation could suggest novel avenues for clinical intervention during ischemic and inflammatory diseases. PMID:21138737

  6. Modulation of activity of the adipocyte aquaglyceroporin channel by plant extracts.

    Cals-Grierson, M-M

    2007-02-01

    The plasma membrane protein, aquaglyceroporin-7 (AQP7) is exclusively expressed in adipocytes and appears to be a channel for glycerol entry and exit. It is possible that by facilitating the opening of these channels, the loss of intracellular glycerol could be encouraged and thus reduce the size of the lipid reservoir. Human preadipocytes and mouse 3T3-L1 preadipocytes were induced to develop an adipocytic phenotype by culture in a semi-defined medium. After 7 days, the expression of AQP7 message had increased by 37-fold, a level which could be further up-regulated by troglitazone or retinoic acid or down-regulated by insulin. The mature adipocytes also expressed immunoreactive aquaporin (AQP) channel protein as assessed by immunocytochemistry and Western blot. The addition of adrenaline to the culture medium stimulated the release of glycerol (blockable by HgCl(2)). Plant extracts, with potential anti-cellulite properties, were tested for their effect on glycerol elimination. These included wild yam root (Dioscorea opposita), cocoa bean (Theobroma cacao), horse chestnut tree (Aesculus hippocastanum) seed and bark and tomato (Solanum lycopersicum). Of these, D. opposita appeared to induce a dose-dependent glycerol release. The results show that our assay can help to identify modulators of AQP7 channel expression and activation in adipocytes. PMID:18489306

  7. Event-related power modulations of brain activity preceding visually guided saccades.

    Brignani, Debora; Maioli, Claudio; Maria Rossini, Paolo; Miniussi, Carlo

    2007-03-01

    To analyze the characteristics of the event-related desynchronization (ERD) and synchronization (ERS) of cortical rhythms during the preparation and execution of a lateralized eye movement, EEG was recorded in normal subjects during a visually guided task. Alpha and beta bands were investigated in three temporal intervals: a sensory period, a delay period and a saccade preparation period time locked with saccade onset. Modulations of ERD/ERS power, coupled with the task, reached the largest amplitudes over the frontal and parieto-occipital regions. Differences of oscillatory activity in the alpha bands revealed an intriguing pattern of asymmetry in parieto-occipital areas. Rightward saccades induced a larger desynchronization with respect to the leftward saccades in the left hemisphere, but not in the right. If representative, these findings are congruent to the established right-hemisphere dominance of the brain areas that direct attention. Moreover differences between the two alpha types emerged in the frontal areas before and during the saccade preparation periods, indicative of differential engagement of these areas depending on the task demands. In conclusion, the present approach shows that planning eye movements is linked with covert orienting of spatial attention and may supply a useful method for studying eye movements and selective attention-related processes. PMID:17196943

  8. Perhexiline activates KLF14 and reduces atherosclerosis by modulating ApoA-I production.

    Guo, Yanhong; Fan, Yanbo; Zhang, Jifeng; Lomberk, Gwen A; Zhou, Zhou; Sun, Lijie; Mathison, Angela J; Garcia-Barrio, Minerva T; Zhang, Ji; Zeng, Lixia; Li, Lei; Pennathur, Subramaniam; Willer, Cristen J; Rader, Daniel J; Urrutia, Raul; Chen, Y Eugene

    2015-10-01

    Recent genome-wide association studies have revealed that variations near the gene locus encoding the transcription factor Krüppel-like factor 14 (KLF14) are strongly associated with HDL cholesterol (HDL-C) levels, metabolic syndrome, and coronary heart disease. However, the precise mechanisms by which KLF14 regulates lipid metabolism and affects atherosclerosis remain largely unexplored. Here, we report that KLF14 is dysregulated in the liver of 2 dyslipidemia mouse models. We evaluated the effects of both KLF14 overexpression and genetic inactivation and determined that KLF14 regulates plasma HDL-C levels and cholesterol efflux capacity by modulating hepatic ApoA-I production. Hepatic-specific Klf14 deletion in mice resulted in decreased circulating HDL-C levels. In an attempt to pharmacologically target KLF14 as an experimental therapeutic approach, we identified perhexiline, an approved therapeutic small molecule presently in clinical use to treat angina and heart failure, as a KLF14 activator. Indeed, in WT mice, treatment with perhexiline increased HDL-C levels and cholesterol efflux capacity via KLF14-mediated upregulation of ApoA-I expression. Moreover, perhexiline administration reduced atherosclerotic lesion development in apolipoprotein E-deficient mice. Together, these results provide comprehensive insight into the KLF14-dependent regulation of HDL-C and subsequent atherosclerosis and indicate that interventions that target the KLF14 pathway should be further explored for the treatment of atherosclerosis. PMID:26368306

  9. Modulating Composition and Metabolic Activity of the Gut Microbiota in IBD Patients.

    Matijašić, Mario; Meštrović, Tomislav; Perić, Mihaela; Čipčić Paljetak, Hana; Panek, Marina; Vranešić Bender, Darija; Ljubas Kelečić, Dina; Krznarić, Željko; Verbanac, Donatella

    2016-01-01

    The healthy intestine represents a remarkable interface where sterile host tissues come in contact with gut microbiota, in a balanced state of homeostasis. The imbalance of gut homeostasis is associated with the onset of many severe pathological conditions, such as inflammatory bowel disease (IBD), a chronic gastrointestinal disorder increasing in incidence and severely influencing affected individuals. Despite the recent development of next generation sequencing and bioinformatics, the current scientific knowledge of specific triggers and diagnostic markers to improve interventional approaches in IBD is still scarce. In this review we present and discuss currently available and emerging therapeutic options in modulating composition and metabolic activity of gut microbiota in patients affected by IBD. Therapeutic approaches at the microbiota level, such as dietary interventions alone or with probiotics, prebiotics and synbiotics, administration of antibiotics, performing fecal microbiota transplantation (FMT) and the use of nematodes, all represent a promising opportunities towards establishing and maintaining of well-being as well as improving underlying IBD symptoms. PMID:27104515

  10. Modulating Composition and Metabolic Activity of the Gut Microbiota in IBD Patients

    Mario Matijašić

    2016-04-01

    Full Text Available The healthy intestine represents a remarkable interface where sterile host tissues come in contact with gut microbiota, in a balanced state of homeostasis. The imbalance of gut homeostasis is associated with the onset of many severe pathological conditions, such as inflammatory bowel disease (IBD, a chronic gastrointestinal disorder increasing in incidence and severely influencing affected individuals. Despite the recent development of next generation sequencing and bioinformatics, the current scientific knowledge of specific triggers and diagnostic markers to improve interventional approaches in IBD is still scarce. In this review we present and discuss currently available and emerging therapeutic options in modulating composition and metabolic activity of gut microbiota in patients affected by IBD. Therapeutic approaches at the microbiota level, such as dietary interventions alone or with probiotics, prebiotics and synbiotics, administration of antibiotics, performing fecal microbiota transplantation (FMT and the use of nematodes, all represent a promising opportunities towards establishing and maintaining of well-being as well as improving underlying IBD symptoms.

  11. 2D surface temperature measurement of plasma facing components with modulated active pyrometry

    In nuclear fusion devices, such as Tore Supra, the plasma facing components (PFC) are in carbon. Such components are exposed to very high heat flux and the surface temperature measurement is mandatory for the safety of the device and also for efficient plasma scenario development. Besides this measurement is essential to evaluate these heat fluxes for a better knowledge of the physics of plasma-wall interaction, it is also required to monitor the fatigue of PFCs. Infrared system (IR) is used to manage to measure surface temperature in real time. For carbon PFCs, the emissivity is high and known (ε ∼ 0.8), therefore the contribution of the reflected flux from environment and collected by the IR cameras can be neglected. However, the future tokamaks such as WEST and ITER will be equipped with PFCs in metal (W and Be/W, respectively) with low and variable emissivities (ε ∼ 0.1–0.4). Consequently, the reflected flux will contribute significantly in the collected flux by IR camera. The modulated active pyrometry, using a bicolor camera, proposed in this paper allows a 2D surface temperature measurement independently of the reflected fluxes and the emissivity. Experimental results with Tungsten sample are reported and compared with simultaneous measurement performed with classical pyrometry (monochromatic and bichromatic) with and without reflective flux demonstrating the efficiency of this method for surface temperature measurement independently of the reflected flux and the emissivity

  12. 2D surface temperature measurement of plasma facing components with modulated active pyrometry

    Amiel, S.; Loarer, T.; Pocheau, C.; Roche, H.; Gauthier, E.; Aumeunier, M.-H.; Courtois, X.; Jouve, M.; Balorin, C.; Moncada, V. [CEA, IRFM, F-13108 Saint-Paul-lez-Durance (France); Le Niliot, C.; Rigollet, F. [Aix-Marseille Univ, IUSTI, UMR CNRS 7343, F-13453 Marseille (France)

    2014-10-01

    In nuclear fusion devices, such as Tore Supra, the plasma facing components (PFC) are in carbon. Such components are exposed to very high heat flux and the surface temperature measurement is mandatory for the safety of the device and also for efficient plasma scenario development. Besides this measurement is essential to evaluate these heat fluxes for a better knowledge of the physics of plasma-wall interaction, it is also required to monitor the fatigue of PFCs. Infrared system (IR) is used to manage to measure surface temperature in real time. For carbon PFCs, the emissivity is high and known (ε ~ 0.8), therefore the contribution of the reflected flux from environment and collected by the IR cameras can be neglected. However, the future tokamaks such as WEST and ITER will be equipped with PFCs in metal (W and Be/W, respectively) with low and variable emissivities (ε ~ 0.1–0.4). Consequently, the reflected flux will contribute significantly in the collected flux by IR camera. The modulated active pyrometry, using a bicolor camera, proposed in this paper allows a 2D surface temperature measurement independently of the reflected fluxes and the emissivity. Experimental results with Tungsten sample are reported and compared with simultaneous measurement performed with classical pyrometry (monochromatic and bichromatic) with and without reflective flux demonstrating the efficiency of this method for surface temperature measurement independently of the reflected flux and the emissivity.

  13. Decreased modulation by the risk level on the brain activation during decision making in adolescents with internet gaming disorder

    Yongxin Yang

    2015-11-01

    Full Text Available Greater impulse and risk-taking and reduced decision-making ability were reported as the main behavioral impairments in individuals with Internet gaming disorder (IGD, which has become a serious mental health issue worldwide. However, it is not clear to date how the risk level modulates brain activity during the decision-making process in IGD individuals. In this study, 23 adolescents with IGD and 24 healthy controls (HCs without IGD were recruited, and the Balloon Analog Risk Task (BART was used in a functional magnetic resonance imaging (fMRI experiment to evaluate the modulation of the risk level (the probability of balloon explosion on brain activity during risky decisionmaking in IGD adolescents. Reduced modulation of the risk level on the activation of the right dorsolateral prefrontal cortex (DLPFC during the active BART was found in IGD group compared to the HCs. In the IGD group, there was a significant negative correlation between the risk-related DLPFC activation during the active BART and the Barratt impulsivity scale (BIS-11 scores, which were significantly higher in IGD group compared with the HCs. Our study demonstrated that, as a critical decision-making-related brain region, the right DLPFC is less sensitive to risk in IGD adolescents compared with the HCs, which may contribute to the higher impulsivity level in IGD adolescents.

  14. Quantifying tight-gas sandstone permeability via critical path analysis

    Ghanbarian, Behzad; Torres-Verdín, Carlos; Skaggs, Todd H.

    2016-06-01

    Rock permeability has been actively investigated over the past several decades by the geosciences community. However, its accurate estimation still presents significant technical challenges, particularly in spatially complex rocks. In this short communication, we apply critical path analysis (CPA) to estimate permeability in porous rocks from measured mercury intrusion porosimetry and electrical conductivity data. Theoretical estimations of various CPA-based models are then compared to experimental measurements using eighteen tight-gas sandstones. Except for two of the samples, we find permeability estimations performed with the Skaggs model (assuming pore diameter independent of its length) more accurate than other models, within a factor of two of the measured permeabilities. We discuss some plausible sources of the uncertainties.

  15. Differential water permeability and regulation of three aquaporin 4 isoforms

    Fenton, Robert A.; Moeller, Hanne B; Zelenina, Marina;

    2010-01-01

    Aquaporin 4 (AQP4) is expressed in the perivascular glial endfeet and is an important pathway for water during formation and resolution of brain edema. In this study, we examined the functional properties and relative unit water permeability of three functional isoforms of AQP4 expressed...... in the brain (M1, M23, Mz). The M23 isoform gave rise to square arrays when expressed in Xenopus laevis oocytes. The relative unit water permeability differed significantly between the isoforms in the order of M1 > Mz > M23. None of the three isoforms were permeable to small osmolytes nor were they affected...... by changes in external K(+) concentration. Upon protein kinase C (PKC) activation, oocytes expressing the three isoforms demonstrated rapid reduction of water permeability, which correlated with AQP4 internalization. The M23 isoform was more sensitive to PKC regulation than the longer isoforms...

  16. 论情感教育在幼儿音乐活动中的渗透%Affective education permeability in children music activities

    高英杰

    2013-01-01

      The music is the most direct expression of human feelings in art, it does not require any media, than the more direct language. Take music activities of preschool children as an example, discuss from the music activities and children's age characteristics, the penetration in emotional education of music activities.%  音乐是最能直接表达人类感情的艺术,它不需要任何媒介,比语言更为直接。本文以学龄前幼儿音乐活动为例,从音乐活动形式、幼儿年龄特点等方面对情感教育在幼儿音乐活动中的渗透进行论述。

  17. Air permeability of polyester nonwoven fabrics

    Zhu Guocheng; Kremenakova Dana; Wang Yan; Militky Jiri

    2015-01-01

    Air permeability is one of the most important properties of non-woven fabrics in many applications. This paper aims to investigate the effects of thickness, porosity and density on the air permeability of needle-punched non-woven fabrics and compare the experimental values with two models which are based on hydraulic radius theory and drag theory, respectively. The air permeability of the samples was measured by an air permeability tester FX3300. The results showed that the air permeability o...

  18. Cannabinoid modulation of prefrontal-limbic activation during fear extinction learning and recall in humans.

    Rabinak, Christine A; Angstadt, Mike; Lyons, Maryssa; Mori, Shoko; Milad, Mohammed R; Liberzon, Israel; Phan, K Luan

    2014-09-01

    Pre-extinction administration of Δ9-tetrahydrocannibinol (THC) facilitates recall of extinction in healthy humans, and evidence from animal studies suggest that this likely occurs via enhancement of the cannabinoid system within the ventromedial prefrontal cortex (vmPFC) and hippocampus (HIPP), brain structures critical to fear extinction. However, the effect of cannabinoids on the underlying neural circuitry of extinction memory recall in humans has not been demonstrated. We conducted a functional magnetic resonance imaging (fMRI) study using a randomized, double-blind, placebo-controlled, between-subjects design (N=14/group) coupled with a standard Pavlovian fear extinction paradigm and an acute pharmacological challenge with oral dronabinol (synthetic THC) in healthy adult volunteers. We examined the effects of THC on vmPFC and HIPP activation when tested for recall of extinction learning 24 h after extinction learning. Compared to subjects who received placebo, participants who received THC showed increased vmPFC and HIPP activation to a previously extinguished conditioned stimulus (CS+E) during extinction memory recall. This study provides the first evidence that pre-extinction administration of THC modulates prefrontal-limbic circuits during fear extinction in humans and prompts future investigation to test if cannabinoid agonists can rescue or correct the impaired behavioral and neural function during extinction recall in patients with PTSD. Ultimately, the cannabinoid system may serve as a promising target for innovative intervention strategies (e.g. pharmacological enhancement of exposure-based therapy) in PTSD and other fear learning-related disorders. PMID:24055595

  19. Learning to modulate one's own brain activity: The effect of spontaneous mental strategies

    Silvia Erika Kober

    2013-10-01

    Full Text Available Using neurofeedback (NF, individuals can learn to modulate their own brain activity, in most cases electroencephalographic (EEG rhythms. Although a large body of literature reports positive effects of NF training on behavior and cognitive functions, there are hardly any reports on how participants can successfully learn to gain control over their own brain activity. About one third of people fail to gain significant control over their brain signals even after repeated training sessions. The reasons for this failure are still largely unknown. In this context, we investigated the effects of spontaneous mental strategies on NF performance. Twenty healthy participants performed either a SMR (sensorimotor rhythm, 12-15 Hz based or a Gamma (40-43 Hz based NF training over ten sessions. After the first and the last training session, they were asked to write down which mental strategy they have used for self-regulating their EEG. After the first session, all participants reported the use of various types of mental strategies such as visual strategies, concentration, or relaxation. After the last NF training session, four participants of the SMR group reported to employ no specific strategy. These four participants showed linear improvements in NF performance over the ten training sessions. In contrast, participants still reporting the use of specific mental strategies in the last NF session showed no changes in SMR based NF performance over the ten sessions. This effect could not be observed in the Gamma group. The Gamma group showed no prominent changes in Gamma power over the NF training sessions, regardless of the mental strategies used. These results indicate that successful SMR based NF performance is associated with implicit learning mechanisms. Participants stating vivid reports on strategies to control their SMR probably overload cognitive resources, which might be counterproductive in terms of increasing SMR power.

  20. Quasi-biennial modulation of solar neutrino flux: connections with solar activity

    Vecchio, A.; Laurenza, M.; D'alessi, L.; Carbone, V.; Storini, M.

    2011-12-01

    A quasi-biennial periodicity has been recently found (Vecchio et al., 2010) in the solar neutrino flux, as detected at the Homestake experiment, as well as in the flux of solar energetic protons, by means of the Empirical Modes Decomposition technique. Moreover, both fluxes have been found to be significantly correlated at the quasi-biennial timescale, thus supporting the hypothesis of a connection between solar neutrinos and solar activity. The origin of this connection is investigated, by modeling how the standard Mikheyev-Smirnov-Wolfenstein (MSW) effect (the process for which the well-known neutrino flavor oscillations are modified in passing through the material) could be influenced by matter fluctuations. As proposed by Burgess et al., 2004, by introducing a background magnetic field in the helioseismic model, density fluctuations can be excited in the radiative zone by the resonance between helioseismic g-modes and Alfvén waves. In particular, with reasonable values of the background magnetic field (10-100 kG), the distance between resonant layers could be of the same order of neutrino oscillation length. We study the effect over this distance of a background magnetic field which is variable with a ~2 yr period, in agreement with typical variations of solar activity. Our findings suggest that the quasi-biennial modulation of the neutrino flux is theoretically possible as a consequence of the magnetic field variations in the solar interior. A. Vecchio, M. Laurenza, V. Carbone, M. Storini, The Astrophysical Journal Letters, 709, L1-L5 (2010). C. Burgess, N. S. Dzhalilov, T. I. Rashba, V., B.Semikoz, J. W. F. Valle, Mon. Not. R. Astron. Soc., 348, 609-624 (2004).

  1. Chimeric RXFP1 and RXFP2 Receptors Highlight the Similar Mechanism of Activation Utilizing Their N-Terminal Low-Density Lipoprotein Class A Modules

    Bruell, Shoni; Kong, Roy C. K.; Petrie, Emma J.; Hoare, Brad; John D Wade; Scott, Daniel J.; Gooley, Paul R.; Bathgate, Ross A. D.

    2013-01-01

    Relaxin family peptide (RXFP) receptors 1 and 2 are unique G-protein coupled receptors in that they contain an N-terminal low-density lipoprotein type A (LDLa) module which is necessary for receptor activation. The current hypothesis suggests that upon ligand binding the LDLa module interacts with the transmembrane (TM) domain of a homodimer partner receptor to induce the active receptor conformations. We recently demonstrated that three residues in the N-terminus of the RXFP1 LDLa module are...

  2. Chimeric RXFP1 and RXFP2 receptors highlight the similar mechanism of activation utilizing their N-terminal low density lipoprotein class A modules

    RossBathgate; EmmaJunePetrie; JohnDWade

    2013-01-01

    Relaxin family peptide (RXFP) receptors 1 and 2 are unique G-protein coupled receptors in that they contain an N-terminal low density lipoprotein type A (LDLa) module which is necessary for receptor activation. The current hypothesis suggests that upon ligand binding the LDLa module interacts with the transmembrane (TM) domain of a homodimer partner receptor to induce the active receptor conformations. We recently demonstrated that three residues in the N-terminus of the RXFP1 LDLa module are...

  3. Timescales for permeability reduction and strength recovery in densifying magma

    Heap, M. J.; Farquharson, J. I.; Wadsworth, F. B.; Kolzenburg, S.; Russell, J. K.

    2015-11-01

    Transitions between effusive and explosive behaviour are routine for many active volcanoes. The permeability of the system, thought to help regulate eruption style, is likely therefore in a state of constant change. Viscous densification of conduit magma during effusive periods, resulting in physical and textural property modifications, may reduce permeability to that preparatory for an explosive eruption. We present here a study designed to estimate timescales of permeability reduction and strength recovery during viscous magma densification by coupling measurements of permeability and strength (using samples from a suite of variably welded, yet compositionally identical, volcanic deposits) with a rheological model for viscous compaction and a micromechanical model, respectively. Bayesian Information Criterion analysis confirms that our porosity-permeability data are best described by two power laws that intersect at a porosity of 0.155 (the "changepoint" porosity). Above and below this changepoint, the permeability-porosity relationship has a power law exponent of 8.8 and 1.0, respectively. Quantitative pore size analysis and micromechanical modelling highlight that the high exponent above the changepoint is due to the closure of wide (∼200-300 μm) inter-granular flow channels during viscous densification and that, below the changepoint, the fluid pathway is restricted to narrow (∼50 μm) channels. The large number of such narrow channels allows porosity loss without considerable permeability reduction, explaining the switch to a lower exponent. Using these data, our modelling predicts a permeability reduction of four orders of magnitude (for volcanically relevant temperatures and depths) and a strength increase of a factor of six on the order of days to weeks. This discrepancy suggests that, while the viscous densification of conduit magma will inhibit outgassing efficiency over time, the regions of the conduit prone to fracturing, such as the margins, will

  4. Permeability anisotropy of serpentinite and fluid migration in subduction zones

    Kawano, S.; Katayama, I.; Okazaki, K.

    2010-12-01

    Subduction zones are the place where water is transported into the Earth's interior and causes arc volcanism and seismic activities. Subducting slabs release most of the water to the mantle wedge by the dehydration reactions, and the expelled water reacts with mantle rocks, forming serpentinite at the plate interface. The existence of hydrous layer has been detected by low- velocity anomaly and high-Poison's ratio in several subduction zones (Kamiya and Kobayashi 2000 ; Brocher et al. 2003). The migration of water is generally considered to move upward by buoyancy in the mantle. However, if the hydrous layer is extensively deformed, the migration of water can be controlled by the deformation plane within such layer. In order to test this hypothesis, we analyzed the permeability anisotropy of serpentinite with a strongly-developed schistosity and discuss fluid migration in the subduction systems. Serpentinite samples were collected from Nishisonogi metamorphic terrane in Nagasaki, which schistosity is well-defined developed. Two types of experimental samples were prepared: one is parallel to schistosity and the other is perpendicular. We used intra-vessel deformation and fluid- flow apparatus (IVA) in Hiroshima University to measure the permeability. In this study, we measured gas permeability using nitrogen gas and water permeability under isotropic pressure. Gas permeability was measured using the constant flow method, and water permeability was similar to gas and the transient pulse method was also used. The experiments were conducted at confining pressures up to 50 MPa, pore pressures up to 8 MPa at room temperature. We converted gas permeability to intrinsic permeability with Klinkenberg effect. The permeability decreased with increasing confining pressure, and intrinsic permeability of samples parallel to schistosity were about 10^-20 m2 at confining pressure of 50 MPa. We observed two types of pressure effect: one is significant decline due to crack filling

  5. Mass spectrometry reveals thioredoxin-1 as a new partner of ADAM17 that can modulate its sheddase activity

    Aragao, A.Z.B.; Simabuco, F.M.; Smetana, J.H.C. [Laboratorio Nacional de Biociencias - LNBIO, Campinas, SP (Brazil); Yokoo, S.; Paes Leme, A.F. [Laboratorio Nacional de Luz Sincrotron (LNLS), Campinas, SP (Brazil); Rodrigues, E.; Mercadante, A.Z. [Universidade Estadual de Campinas (UNICAMP), SP (Brazil)

    2012-07-01

    Full text: ADAMs are a family of membrane-associated metalloproteinases with a complex multi-domain structure: a metalloproteinase domain, a disintegrin domain, a cysteine-rich region, an epidermal growth factor-like repeat, a transmembrane domain and a cytoplasmic tail. These proteases are responsible for shedding the ectodomains of cell surface proteins, modulating regulatory mechanisms. Many ADAMs are highly associated with tumorigenesis and tumor progression. The aim of this study is identify novel binding partners that can modulate ADAM17 activation via cytoplasmatic domain. We performed the cloning and overexpression of the ADAM17 cytoplasmic tail in HEK-293 cell line and the ligands were determined by LC-MS/MS after proteins immunoprecipitation (IP) with anti-FLAG M2 Affinity Gel (Sigma). Thioredoxin-1 (Trx-1) and others ligands were identified at least in two independent experiments, and this binding is independent of phosphorylation. The IP of Trx-1 was confirmed by Western blot, furthermore Trx-1 immunolocalized with full length ADAM17-HA and cytoplasmic tail-FLAG recombinant proteins in HEK293 and HeLa cells. Trx-1 is part of the system peroxiredoxin/thioredoxin/thioredoxin reductase, one of the mechanisms by which cells maintain the reduced cellular environment, inactivating the reactive oxygen species (ROS). We investigate whether ADAM17 activity is modulate by Trx-1 on AP reporter assay that was performed using HEK293 and SCC-9 cells transfected stably with HB-EGF-AP in co-transfection with transient recombinant Trx-1-HA. The results indicate that Trx-1 can modulate negatively the activity or maturation of ADAM17 in presence of PMA, which is known to increase ROS. In summary, this study identifies Trx-1 and suggest that this protein can modulate ADAM17 activity in normal and tumorigenic cells lines. (author)

  6. Mass spectrometry reveals thioredoxin-1 as a new partner of ADAM17 that can modulate its sheddase activity

    Full text: ADAMs are a family of membrane-associated metalloproteinases with a complex multi-domain structure: a metalloproteinase domain, a disintegrin domain, a cysteine-rich region, an epidermal growth factor-like repeat, a transmembrane domain and a cytoplasmic tail. These proteases are responsible for shedding the ectodomains of cell surface proteins, modulating regulatory mechanisms. Many ADAMs are highly associated with tumorigenesis and tumor progression. The aim of this study is identify novel binding partners that can modulate ADAM17 activation via cytoplasmatic domain. We performed the cloning and overexpression of the ADAM17 cytoplasmic tail in HEK-293 cell line and the ligands were determined by LC-MS/MS after proteins immunoprecipitation (IP) with anti-FLAG M2 Affinity Gel (Sigma). Thioredoxin-1 (Trx-1) and others ligands were identified at least in two independent experiments, and this binding is independent of phosphorylation. The IP of Trx-1 was confirmed by Western blot, furthermore Trx-1 immunolocalized with full length ADAM17-HA and cytoplasmic tail-FLAG recombinant proteins in HEK293 and HeLa cells. Trx-1 is part of the system peroxiredoxin/thioredoxin/thioredoxin reductase, one of the mechanisms by which cells maintain the reduced cellular environment, inactivating the reactive oxygen species (ROS). We investigate whether ADAM17 activity is modulate by Trx-1 on AP reporter assay that was performed using HEK293 and SCC-9 cells transfected stably with HB-EGF-AP in co-transfection with transient recombinant Trx-1-HA. The results indicate that Trx-1 can modulate negatively the activity or maturation of ADAM17 in presence of PMA, which is known to increase ROS. In summary, this study identifies Trx-1 and suggest that this protein can modulate ADAM17 activity in normal and tumorigenic cells lines. (author)

  7. Gap Junction Protein Connexin43 Exacerbates Lung Vascular Permeability

    O’Donnell, James J.; Birukova, Anna A.; Beyer, Eric C.; Birukov, Konstantin G.

    2014-01-01

    Increased vascular permeability causes pulmonary edema that impairs arterial oxygenation and thus contributes to morbidity and mortality associated with Acute Respiratory Distress Syndrome and sepsis. Although components of intercellular adhesive and tight junctions are critical for maintaining the endothelial barrier, there has been limited study of the roles of gap junctions and their component proteins (connexins). Since connexins can modulate inflammatory signaling in other systems, we hy...

  8. Magnetically controlled permeability membranes

    Kosel, Jurgen

    2013-10-31

    A bioactive material delivery system can include a thermoresponsive polymer membrane and nanowires distributed within the thermoresponsive polymer membrane. Magnetic activation of a thermoresponsive polymer membrane can take place via altering the magnetization or dimensions of nanowires dispersed or ordered within the membrane matrix.

  9. Nutritional strategies to modulate inflammation and oxidative stress pathways via activation of the master antioxidant switch Nrf2.

    Cardozo, Ludmila F M F; Pedruzzi, Liliana M; Stenvinkel, Peter; Stockler-Pinto, Milena B; Daleprane, Julio B; Leite, Maurilo; Mafra, Denise

    2013-08-01

    The nuclear factor E2-related factor 2 (Nrf2) plays an important role in cellular protection against cancer, renal, pulmonary, cardiovascular and neurodegenerative diseases where oxidative stress and inflammation are common conditions. The Nrf2 regulates the expression of detoxifying enzymes by recognizing the human Antioxidant Response Element (ARE) binding site and it can regulate antioxidant and anti-inflammatory cellular responses, playing an important protective role on the development of the diseases. Studies designed to investigate how effective Nrf2 activators or modulators are need to be initiated. Several recent studies have shown that nutritional compounds can modulate the activation of Nrf2-Keap1 system. This review aims to discuss some of the key nutritional compounds that promote the activation of Nrf2, which may have impact on the human health. PMID:23643732

  10. Development of Active External Network Topology Module for Floodlight SDN Controller

    A. A. Noskov

    2015-01-01

    Full Text Available Traditional network architecture is inflexible and complicated. This observation has led to a paradigm shift towards software-defined networking (SDN, where network management level is separated from data forwarding level. This change was made possible by control plane transfer from the switching equipment to software modules that run on a dedicated server, called the controller (or network operating system, or network applications, that work with this controller. Methods of representation, storage and communication interfaces with network topology elements are the most important aspects of network operating systems available to SDN user because performance of some key controller modules is heavily dependent on internal representation of the network topology. Notably, firewall and routing modules are examples of such modules. This article describes the methods used for presentation and storage of network topologies, as well as interface to the corresponding Floodlight modules. An alternative algorithm has been suggested and developed for message exchange conveying network topology alterations between the controller and network applications. Proposed algorithm makes implementation of module alerting based on subscription to the relevant events. API for interaction between controller and network applications has been developed. This algorithm and API formed the base for Topology Tracker module capable to inform network applications about the changes that had occurred in the network topology and also stores compact representation of the network to speed up the interaction process.

  11. The Nucleosome Remodeling and Deacetylase Complex NuRD Is Built from Preformed Catalytically Active Sub-modules.

    Zhang, W; Aubert, A; Gomez de Segura, J M; Karuppasamy, M; Basu, S; Murthy, A S; Diamante, A; Drury, T A; Balmer, J; Cramard, J; Watson, A A; Lando, D; Lee, S F; Palayret, M; Kloet, S L; Smits, A H; Deery, M J; Vermeulen, M; Hendrich, B; Klenerman, D; Schaffitzel, C; Berger, I; Laue, E D

    2016-07-17

    The nucleosome remodeling deacetylase (NuRD) complex is a highly conserved regulator of chromatin structure and transcription. Structural studies have shed light on this and other chromatin modifying machines, but much less is known about how they assemble and whether stable and functional sub-modules exist that retain enzymatic activity. Purification of the endogenous Drosophila NuRD complex shows that it consists of a stable core of subunits, while others, in particular the chromatin remodeler CHD4, associate transiently. To dissect the assembly and activity of NuRD, we systematically produced all possible combinations of different components using the MultiBac system, and determined their activity and biophysical properties. We carried out single-molecule imaging of CHD4 in live mouse embryonic stem cells, in the presence and absence of one of core components (MBD3), to show how the core deacetylase and chromatin-remodeling sub-modules associate in vivo. Our experiments suggest a pathway for the assembly of NuRD via preformed and active sub-modules. These retain enzymatic activity and are present in both the nucleus and the cytosol, an outcome with important implications for understanding NuRD function. PMID:27117189

  12. Permeability enhancement by shock cooling

    Griffiths, Luke; Heap, Michael; Reuschlé, Thierry; Baud, Patrick; Schmittbuhl, Jean

    2015-04-01

    The permeability of an efficient reservoir, e.g. a geothermal reservoir, should be sufficient to permit the circulation of fluids. Generally speaking, permeability decreases over the life cycle of the geothermal system. As a result, is usually necessary to artificially maintain and enhance the natural permeability of these systems. One of the methods of enhancement -- studied here -- is thermal stimulation (injecting cold water at low pressure). This goal of this method is to encourage new thermal cracks within the reservoir host rocks, thereby increasing reservoir permeability. To investigate the development of thermal microcracking in the laboratory we selected two granites: a fine-grained (Garibaldi Grey granite, grain size = 0.5 mm) and a course-grained granite (Lanhelin granite, grain size = 2 mm). Both granites have an initial porosity of about 1%. Our samples were heated to a range of temperatures (100-1000 °C) and were either cooled slowly (1 °C/min) or shock cooled (100 °C/s). A systematic microstructural (2D crack area density, using standard stereological techniques, and 3D BET specific surface area measurements) and rock physical property (porosity, P-wave velocity, uniaxial compressive strength, and permeability) analysis was undertaken to understand the influence of slow and shock cooling on our reservoir granites. Microstructurally, we observe that the 2D crack surface area per unit volume and the specific surface area increase as a result of thermal stressing, and, for the same maximum temperature, crack surface area is higher in the shock cooled samples. This observation is echoed by our rock physical property measurements: we see greater changes for the shock cooled samples. We can conclude that shock cooling is an extremely efficient method of generating thermal microcracks and modifying rock physical properties. Our study highlights that thermal treatments are likely to be an efficient method for the "matrix" permeability enhancement of

  13. All-trans retinoic acid modulates mitogen-activated protein kinase pathway activation in human scleral fibroblasts through retinoic acid receptor beta

    Huo, Lijun; Cui, Dongmei; Yang, Xiao; Gao, Zhenya; Trier, Klaus; Zeng, Junwen

    2013-01-01

    Purpose All-trans retinoic acid (ATRA) is known to inhibit the proliferation of human scleral fibroblasts (HSFs) and to modulate the scleral intercellular matrix composition, and may therefore serve as a mediator for controlling eye growth. Cell proliferation is regulated by the mitogen-activated protein kinase (MAPK) pathway. The aim of the current study was to investigate whether changed activation of the MAPK pathway could be involved in the response of HSFs exposed to ATRA. Methods HSFs w...

  14. Capillary permeability in adipose tissue

    Paaske, W P; Nielsen, S L

    1976-01-01

    A method for measurement of capillary permeability using external registration of gamma emitting isotopes after close arterial bolus injection was applied to the isolated inguinal fat pad in slightly fasting rabbits. An average extraction of 26 per cent for 51Cr-EDTA was found at a plasma flow of...... about 7 ml/100 g-min. This corresponds to a capillary diffusion capacity of 2.0 ml/100 g-min which is half the value reported for vasodilated skeletal muscle having approximately twice as great capillary surface area. Thus, adipose tissue has about the same capillary permeability during slight metabolic...

  15. Nitric oxide activation by distal redox modulation in tetranuclear iron nitrosyl complexes.

    de Ruiter, Graham; Thompson, Niklas B; Lionetti, Davide; Agapie, Theodor

    2015-11-11

    A series of tetranuclear iron complexes displaying a site-differentiated metal center was synthesized. Three of the metal centers are coordinated to our previously reported ligand, based on a 1,3,5-triarylbenzene motif with nitrogen and oxygen donors. The fourth (apical) iron center is coordinatively unsaturated and appended to the trinuclear core through three bridging pyrazolates and an interstitial μ4-oxide moiety. Electrochemical studies of complex [LFe3(PhPz)3OFe][OTf]2 revealed three reversible redox events assigned to the Fe(II)4/Fe(II)3Fe(III) (-1.733 V), Fe(II)3Fe(III)/Fe(II)2Fe(III)2 (-0.727 V), and Fe(II)2Fe(III)2/Fe(II)Fe(III)3 (0.018 V) redox couples. Combined Mössbauer and crystallographic studies indicate that the change in oxidation state is exclusively localized at the triiron core, without changing the oxidation state of the apical metal center. This phenomenon is assigned to differences in the coordination environment of the two metal sites and provides a strategy for storing electron and hole equivalents without affecting the oxidation state of the coordinatively unsaturated metal. The presence of a ligand-binding site allowed the effect of redox modulation on nitric oxide activation by an Fe(II) metal center to be studied. Treatment of the clusters with nitric oxide resulted in binding of NO to the apical iron center, generating a {FeNO}(7) moiety. As with the NO-free precursors, the three reversible redox events are localized at the iron centers distal from the NO ligand. Altering the redox state of the triiron core resulted in significant change in the NO stretching frequency, by as much as 100 cm(-1). The increased activation of NO is attributed to structural changes within the clusters, in particular, those related to the interaction of the metal centers with the interstitial atom. The differences in NO activation were further shown to lead to differential reactivity, with NO disproportionation and N2O formation performed by the more

  16. MPTP-meditated hippocampal dopamine deprivation modulates synaptic transmission and activity-dependent synaptic plasticity

    Parkinson's disease (PD)-like symptoms including learning deficits are inducible by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Therefore, it is possible that MPTP may disturb hippocampal memory processing by modulation of dopamine (DA)- and activity-dependent synaptic plasticity. We demonstrate here that intraperitoneal (i.p.) MPTP injection reduces the number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra (SN) within 7 days. Subsequently, the TH expression level in SN and hippocampus and the amount of DA and its metabolite DOPAC in striatum and hippocampus decrease. DA depletion does not alter basal synaptic transmission and changes pair-pulse facilitation (PPF) of field excitatory postsynaptic potentials (fEPSPs) only at the 30 ms inter-pulse interval. In addition, the induction of long-term potentiation (LTP) is impaired whereas the duration of long-term depression (LTD) becomes prolonged. Since both LTP and LTD depend critically on activation of NMDA and DA receptors, we also tested the effect of DA depletion on NMDA receptor-mediated synaptic transmission. Seven days after MPTP injection, the NMDA receptor-mediated fEPSPs are decreased by about 23%. Blocking the NMDA receptor-mediated fEPSP does not mimic the MPTP-LTP. Only co-application of D1/D5 and NMDA receptor antagonists during tetanization resembled the time course of fEPSP potentiation as observed 7 days after i.p. MPTP injection. Together, our data demonstrate that MPTP-induced degeneration of DA neurons and the subsequent hippocampal DA depletion alter NMDA receptor-mediated synaptic transmission and activity-dependent synaptic plasticity. - Highlights: → I.p. MPTP-injection mediates death of dopaminergic neurons. → I.p. MPTP-injection depletes DA and DOPAC in striatum and hippocampus. → I.p. MPTP-injection does not alter basal synaptic transmission. → Reduction of LTP and enhancement of LTD after i.p. MPTP-injection. → Attenuation of NMDA-receptors mediated

  17. Identification and characterization of the host protein DNAJC14 as a broadly active flavivirus replication modulator.

    Zhigang Yi

    Full Text Available Viruses in the Flavivirus genus of the Flaviviridae family are arthropod-transmitted and contribute to staggering numbers of human infections and significant deaths annually across the globe. To identify cellular factors with antiviral activity against flaviviruses, we screened a cDNA library using an iterative approach. We identified a mammalian Hsp40 chaperone protein (DNAJC14 that when overexpressed was able to mediate protection from yellow fever virus (YFV-induced cell death. Further studies revealed that DNAJC14 inhibits YFV at the step of viral RNA replication. Since replication of bovine viral diarrhea virus (BVDV, a member of the related Pestivirus genus, is also known to be modulated by DNAJC14, we tested the effect of this host factor on diverse Flaviviridae family members. Flaviviruses, including the pathogenic Asibi strain of YFV, Kunjin, and tick-borne Langat virus, as well as a Hepacivirus, hepatitis C virus (HCV, all were inhibited by overexpression of DNAJC14. Mutagenesis showed that both the J-domain and the C-terminal domain, which mediates self-interaction, are required for anti-YFV activity. We found that DNAJC14 does not block YFV nor HCV NS2-3 cleavage, and using non-inhibitory mutants demonstrate that DNAJC14 is recruited to YFV replication complexes. Immunofluorescence analysis demonstrated that endogenous DNAJC14 rearranges during infection and is found in replication complexes identified by dsRNA staining. Interestingly, silencing of endogenous DNAJC14 results in impaired YFV replication suggesting a requirement for DNAJC14 in YFV replication complex assembly. Finally, the antiviral activity of overexpressed DNAJC14 occurs in a time- and dose-dependent manner. DNAJC14 overexpression may disrupt the proper stoichiometry resulting in inhibition, which can be overcome upon restoration of the optimal ratios due to the accumulation of viral nonstructural proteins. Our findings, together with previously published work

  18. Lithium ions in nanomolar concentration modulate glycine-activated chloride current in rat hippocampal neurons.

    Solntseva, E I; Bukanova, J V; Kondratenko, R V; Skrebitsky, V G

    2016-03-01

    Lithium salts are successfully used to treat bipolar disorder. At the same time, according to recent data lithium may be considered as a candidate medication for the treatment of neurodegenerative disorders. The mechanisms of therapeutic action of lithium have not been fully elucidated. In particular, in the literature there are no data on the effect of lithium on the glycine receptors. In the present study we investigated the effect of Li(+) on glycine-activated chloride current (IGly) in rat isolated pyramidal hippocampal neurons using patch-clamp technique. The effects of Li(+) were studied with two glycine concentrations: 100 μM (EC50) and 500 μM (nearly saturating). Li(+) was applied to the cell in two ways: first, by 600 ms co-application with glycine through micropipette (short application), and, second, by addition to an extracellular perfusate for 10 min (longer application). Li(+) was used in the range of concentrations of 1 nM-1 mM. Short application of Li(+) caused two effects: (1) an acceleration of desensitization (a decrease in the time of half-decay, or "τ") of IGly induced by both 100 μM and 500 μM glycine, and (2) a reduction of the peak amplitude of the IGly, induced by 100 μM, but not by 500 μM glycine. Both effects were not voltage-dependent. Dose-response curves for both effects were N-shaped with two maximums at 100 nM and 1 mM of Li(+) and a minimum at 1 μM of Li(+). This complex form of dose-response may indicate that the process activated by high concentrations of lithium inhibits the process that is sensitive to low concentrations of lithium. Longer application of Li(+)caused similar effects, but in this case 1 μM lithium was effective and the dose-effect curves were not N-shaped. The inhibitory effect of lithium ions on glycine-activated current suggests that lithium in low concentrations is able to modulate tonic inhibition in the hippocampus. This important property of lithium should be considered when using this drug as a

  19. Probing permeability and microstructure: Unravelling the role of a low-permeability dome on the explosivity of Merapi (Indonesia)

    Kushnir, Alexandra R. L.; Martel, Caroline; Bourdier, Jean-Louis; Heap, Michael J.; Reuschlé, Thierry; Erdmann, Saskia; Komorowski, Jean-Christophe; Cholik, Noer

    2016-04-01

    Low permeability dome rocks may contribute to conduit overpressure development in volcanic systems, indirectly abetting explosive activity. The permeability of dome-forming rocks is primarily controlled by the volume, type (vesicles and/or microcracks), and connectivity of the void space present. Here we investigate the permeability-porosity relationship of dome-forming rocks and pumice clasts from Merapi's 1888 to 2013 eruptions and assess their possible role in eruptive processes, with particular emphasis on the 2010 paroxysmal eruption. Rocks are divided into three simple field classifications common to all eruptions: Type 1 samples have low bulk density and are pumiceous in texture; Type 2 samples, ubiquitous to the 2010 eruption, are dark grey to black in hand sample and vary greatly in vesicularity; and Type 3 samples are weakly vesicular, light grey in hand sample, and are the only samples that contain cristobalite. Type 2 and Type 3 rocks are present in all eruptions and their permeability and porosity data define similar power law relationships, whereas data for Type 1 samples are clearly discontinuous from these trends. A compilation of permeability and porosity data for andesites and basaltic andesites with published values highlights two microstructural transitions that exert control on permeability, confirmed by modified Bayesian Information Criterion (BIC) analysis. Permeability is microcrack- and diktytaxitic-controlled at connected porosities, φc, 31 vol.%. Type 3 basaltic andesites, the least permeable of the measured samples and therefore the most likely to have originated in the uppermost low-permeability dome, are identified as relicts of terminal domes (the last dome extruded prior to quiescence). Cristobalite commonly found in the voids of Type 3 blocks may not contribute significantly to the reduction of the permeability of these samples, mainly because it is associated with an extensive microporous, diktytaxitic texture. Indeed, the low

  20. FRET measurements of intracellular cAMP concentrations and cAMP analog permeability in intact cells.

    Börner, Sebastian; Schwede, Frank; Schlipp, Angela; Berisha, Filip; Calebiro, Davide; Lohse, Martin J; Nikolaev, Viacheslav O

    2011-04-01

    Real-time measurements of second messengers in living cells, such as cAMP, are usually performed by ratiometric fluorescence resonance energy transfer (FRET) imaging. However, correct calibration of FRET ratios, accurate calculations of absolute cAMP levels and actual permeabilities of different cAMP analogs have been challenging. Here we present a protocol that allows precise measurements of cAMP concentrations and kinetics by expressing FRET-based cAMP sensors in cells and modulating them with an inhibitor of adenylyl cyclase activity and a cell-permeable cAMP analog that fully inhibits and activates the sensors, respectively. Using this protocol, we observed different basal cAMP levels in primary mouse cardiomyocytes, thyroid cells and in 293A cells. The protocol can be generally applied for calibration of second messenger or metabolite concentrations measured by FRET, and for studying kinetics and pharmacological properties of their membrane-permeable analogs. The complete procedure, including cell preparation and FRET measurements, takes 3-6 d. PMID:21412271

  1. Dopaminergic modulation of synaptic transmission and neuronal activity patterns in the zebrafish homolog of olfactory cortex

    Schärer, Yan-Ping Zhang; Shum, Jennifer; Moressis, Anastasios; Friedrich, Rainer W.

    2012-01-01

    Dopamine (DA) is an important modulator of synaptic transmission and plasticity that is causally involved in fundamental brain functions and dysfunctions. We examined the dopaminergic modulation of synaptic transmission and sensory responses in telencephalic area Dp of zebrafish, the homolog of olfactory cortex. By combining anatomical tracing and immunohistochemistry, we detected no DA neurons in Dp itself but long-range dopaminergic input from multiple other brain areas. Whole-cell recordin...

  2. Dopaminergic modulation of synaptic transmission and neuronal activity patterns in the zebrafish homolog of olfactory cortex

    Friedrich, Rainer W.

    2012-01-01

    Dopamine (DA) is an important modulator of synaptic transmission and plasticity that is causally involved in fundamental brain functions and dysfunctions. We examined the dopaminergic modulation of synaptic transmission and sensory responses in telencephalic area Dp of zebrafish, the homologue of olfactory cortex. By combining anatomical tracing and immunohistochemistry, we detected no DA neurons in Dp itself but long-range dopaminergic input from multiple other brain areas. Whole-cell record...

  3. Co-activation patterns distinguish cortical modules, their connectivity and functional differentiation

    Eickhoff, Simon B; Bzdok, Danilo; Laird, Angela R.; Roski, Christian; Caspers, Svenja; Zilles, Karl; Fox, Peter T.

    2011-01-01

    The organisation of the cerebral cortex into distinct modules may be described along several dimensions, most importantly, structure, connectivity and function. Identification of cortical modules by differences in whole-brain connectivity profiles derived from diffusion tensor imaging or resting state correlations have already been shown. These approaches, however, carry no task-related information. Hence, inference on the functional relevance of the ensuing parcellation remains tentative. He...

  4. Cells in the monkey ponto-medullary reticular formation modulate their activity with slow finger movements

    Soteropoulos, Demetris S.; Williams, Elizabeth R.; Baker, Stuart N.

    2012-01-01

    Recent work has shown that the primate reticulospinal tract can influence spinal interneurons and motoneurons involved in control of the hand. However, demonstrating connectivity does not reveal whether reticular outputs are modulated during the control of different types of hand movement. Here, we investigated how single unit discharge in the pontomedullary reticular formation (PMRF) modulated during performance of a slow finger movement task in macaque monkeys. Two animals performed an inde...

  5. Temporal and Tight Hepatitis C Virus Gene Activation in Cultured Human Hepatoma Cells Mediated by a Cell-Permeable Cre Recombinase

    Dong XIAO; Kang XU; Ying YUE; Zhong-Min GUO; Bing HUANG; Xin-Yan DENG; Huan TANG; Xi-Gu CHEN

    2004-01-01

    Conditional gene expression has greatly facilitated the examination of the functions of particular gene products. Using the Cre/lox P switching expression system, we plan to develop efficient conditional transgene activation of hepatitis C virus core protein (HCV-C) cDNA (nucleotide 342-914) in the transgenic mice to overcome "immune tolerance" formed during the embryonic period and "immune escape" against hepatitis virus antigen in our project. To use this system in vivo, the dormant transgenic construct, i.e.,pApoE-SCS-EGFP-HCV-C, was generated using techniques of standard molecular biology. The liverspecific human apoE promoter was here used to target expression of genes of interest (EGFP and HCV-C) to murine liver. Prior to generating the transgenic mice, the availability of Cre/lox P system and construct functionality were successfully verified by a cell-free recombination system and via checking the expression of EGFP and HCV-C in the human hepatoma cells at the mRNA and protein levels. These results suggest that the Cre/lox P system could tightly control expression of EGFP and HCV-C in vitro, which laid a solid foundation to conditionally activate expression of target gene(s) in transgenic mice by Cre-mediated site-specific recombination.

  6. Modulation of telomerase activity in fish muscle by biological and environmental factors.

    Peterson, Drew Ryan; Mok, Helen Oi Lam; Au, Doris Wai Ting

    2015-12-01

    Telomerase expression has long been linked to promotion of tumor growth and cell proliferation in mammals. Interestingly, telomerase activity (TA) has been detected in skeletal muscle for a variety of fish species. Despite this being a unique feature in fish, very few studies have investigated the potential role of TA in muscle. The present study was set to prove the concepts that muscle telomerase in fish is related to body growth, and more specifically, to muscle cell proliferation and apoptosis in vivo. Moreover, muscle TA can be influenced by biotic factors and modulated by environmental stress. Using three fish species, mangrove red snapper (Lutjanus argentimaculatus), orange-spotted grouper (Epinephelus coioides), and marine medaka (Oryzias melastigma), the present work reports for the first time that fish muscle TA was sensitive to the environmental stresses of starvation, foodborne exposure to benzo[a]pyrene, and hypoxia. In marine medaka, muscle TA was coupled with fish growth during early life stages. Upon sexual maturation, muscle TA was confounded by sex (female>male). Muscle TA was significantly correlated with telomerase reverse transcriptase (TERT) protein expression (Pearson correlation r=0.892; p≤0.05), which was coupled with proliferating cell nuclear antigen (PCNA) cell proliferation, but not associated with apoptosis (omBax/omBcl2 ratio) in muscle tissue. The results reported here have bridged the knowledge gap between the existence and function of telomerase in fish muscle. The underlying regulatory mechanisms of muscle TA in fish warrant further exploration for comparison with telomerase regulation in mammals. PMID:26400776

  7. Modulation of agonist-activated calcium influx by extracellular pH in rat pancreatic acini

    The biochemical and Ca2+ transport pathways involved in generating the hormone-evoked Ca2+ signal are reported to be influenced by pH. The present study was designed to determine the effect of extracellular pH (pHo) and intracellular pH (pHi) on hormone-stimulated Ca2+ transport. We used rat pancreatic acini and measured free cytosolic Ca2+ concentration ([Ca2+]i) with fura-2, pHi with 2,7-bis(carboxyethyl)-5(6)-carboxyfluorescein (BCECF), and Ca2+ fluxes with 45Ca2+. In the presence of external Ca2+, increasing pHo increased steady-state [Ca2+]i during sustained agonist stimulation; in the absence of external Ca2+, this increase in [Ca2+]i did not occur. The addition of an antagonist or blocking plasma membrane Ca2+ influx with La3+ in stimulated cells suspended at pHo 8.2 resulted in a reduction in [Ca2+]i. Increasing pHo increased the rate and extent of 45Ca2+ uptake into stimulated cells and the rate and extent of Ca2+ reloading of intracellular stores. The increased Ca2+ content of the intracellular stores with increased pHo indicated that at physiological pHo and pHi the agonist-mobilizable internal stores are not saturated with Ca2+. Changes in pHo affected pHi. However, changes in pHi at constant pHo had no effect on hormone-evoked [Ca2+]i increase, reduction in [Ca2+]i after hormone stimulation, or reloading of intracellular stores. We conclude that the hormone-activated plasma membrane Ca2+ entry pathway responsible for Ca2+ reloading is directly modulated by external H+

  8. Brain-computer interfacing using modulations of alpha activity induced by covert shifts of attention

    Schmidt Nico M

    2011-05-01

    Full Text Available Abstract Background Visual brain-computer interfaces (BCIs often yield high performance only when targets are fixated with the eyes. Furthermore, many paradigms use intense visual stimulation, which can be irritating especially in long BCI sessions. However, BCIs can more directly directly tap the neural processes underlying visual attention. Covert shifts of visual attention induce changes in oscillatory alpha activity in posterior cortex, even in the absence of visual stimulation. The aim was to investigate whether different pairs of directions of attention shifts can be reliably differentiated based on the electroencephalogram. To this end, healthy participants (N = 8 had to strictly fixate a central dot and covertly shift visual attention to one out of six cued directions. Results Covert attention shifts induced a prolonged alpha synchronization over posterior electrode sites (PO and O electrodes. Spectral changes had specific topographies so that different pairs of directions could be differentiated. There was substantial variation across participants with respect to the direction pairs that could be reliably classified. Mean accuracy for the best-classifiable pair amounted to 74.6%. Furthermore, an alpha power index obtained during a relaxation measurement showed to be predictive of peak BCI performance (r = .66. Conclusions Results confirm posterior alpha power modulations as a viable input modality for gaze-independent EEG-based BCIs. The pair of directions yielding optimal performance varies across participants. Consequently, participants with low control for standard directions such as left-right might resort to other pairs of directions including top and bottom. Additionally, a simple alpha index was shown to predict prospective BCI performance.

  9. Modulation of NR2B-regulated contextual fear in the hippocampus by the tissue plasminogen activator system

    Norris, Erin H.; Strickland, Sidney

    2007-01-01

    Contextual fear conditioning is regulated by the hippocampus, and NR2B, a subunit of the NMDA receptor (NR), is involved in this process. We show that acute stress modulates tissue plasminogen activator (tPA) activity in the hippocampus by inducing expression of its inhibitor, plasminogen activator inhibitor-1. Acute stress increases NR2B expression and ERK1/2 phosphorylation, a classical marker of postsynaptic plasticity, in the hippocampus. tPA forms a complex with NR2B and is necessary for...

  10. Cognitive emotion regulation in children: Reappraisal of emotional faces modulates neural source activity in a frontoparietal network

    Ida Wessing

    2015-06-01

    Full Text Available Emotion regulation has an important role in child development and psychopathology. Reappraisal as cognitive regulation technique can be used effectively by children. Moreover, an ERP component known to reflect emotional processing called late positive potential (LPP can be modulated by children using reappraisal and this modulation is also related to children's emotional adjustment. The present study seeks to elucidate the neural generators of such LPP effects. To this end, children aged 8–14 years reappraised emotional faces, while neural activity in an LPP time window was estimated using magnetoencephalography-based source localization. Additionally, neural activity was correlated with two indexes of emotional adjustment and age. Reappraisal reduced activity in the left dorsolateral prefrontal cortex during down-regulation and enhanced activity in the right parietal cortex during up-regulation. Activity in the visual cortex decreased with increasing age, more adaptive emotion regulation and less anxiety. Results demonstrate that reappraisal changed activity within a frontoparietal network in children. Decreasing activity in the visual cortex with increasing age is suggested to reflect neural maturation. A similar decrease with adaptive emotion regulation and less anxiety implies that better emotional adjustment may be associated with an advance in neural maturation.

  11. Shallow hydrothermal alteration and permeability changes in pyroclastic deposits: a case study at La Fossa cone (Vulcano island, Italy):

    Cangemi, Marianna; Madonia, Paolo; Speziale, Sergio; Oliveri, Ygor

    2016-04-01

    La Fossa cone at Vulcano, the southernmost island of the Aeolian volcanic archipelago (Italy), has been characterized by an intense fumarolic activity since its last eruption dated 1888-90. Mineralogical alteration induced by shallow hydrothermal circulation has significantly reduced the permeability of the volcanic products, causing important feedbacks on the circulation of fluids in the shallowest portion of the volcanic edifice. The summit area of the cone is sealed by a quite continuous coating surface, fostering the condensation of hydrothermal fluids inside the volcanic edifice. The combination of fractures and volcano-stratigraphic discontinuities, conveying hydrothermal fluids, makes significant rock volumes prone to slide seaward, as occurred in 1988 during the main unrest experienced by Vulcano island since its last eruption. Similar instability conditions are found over the Forgia Vecchia crater rim area, formed by phreatic activity on the NE flank of the cone, where tensile fracturing and hydrothermal circulation interacts with mutual negative feedbacks. In the behalf of the DPC-INGV V3 Project 2012-15 we investigated the mineralogical composition and the hydraulic conductivity (under saturated conditions) of volcanic deposits potentially prone to hydrothermal fluid circulation, for evaluating their ability in retaining water, creating favourable conditions for gravitational instability. We also measured rainfall rate and volumetric soil moisture content in two automated stations located in different areas, with and without active hydrothermal circulation. We found that hydrothermal alteration transforms volcanic products into clay minerals, significantly reducing permeability of volcanic deposits. Argillified volcanic materials show background water contents, modulated by impulsive increments following rainfalls, higher than unaltered pyroclastic deposits, due to the combination of lower permeability and direct condensation of hydrothermal vapour. The

  12. High membrane permeability for melatonin.

    Yu, Haijie; Dickson, Eamonn J; Jung, Seung-Ryoung; Koh, Duk-Su; Hille, Bertil

    2016-01-01

    The pineal gland, an endocrine organ in the brain, synthesizes and secretes the circulating night hormone melatonin throughout the night. The literature states that this hormone is secreted by simple diffusion across the pinealocyte plasma membrane, but a direct quantitative measurement of membrane permeability has not been made. Experiments were designed to compare the cell membrane permeability to three indoleamines: melatonin and its precursors N-acetylserotonin (NAS) and serotonin (5-HT). The three experimental approaches were (1) to measure the concentration of effluxing indoleamines amperometrically in the bath while cells were being dialyzed internally by a patch pipette, (2) to measure the rise of intracellular indoleamine fluorescence as the compound was perfused in the bath, and (3) to measure the rate of quenching of intracellular fura-2 dye fluorescence as indoleamines were perfused in the bath. These measures showed that permeabilities of melatonin and NAS are high (both are uncharged molecules), whereas that for 5-HT (mostly charged) is much lower. Comparisons were made with predictions of solubility-diffusion theory and compounds of known permeability, and a diffusion model was made to simulate all of the measurements. In short, extracellular melatonin equilibrates with the cytoplasm in 3.5 s, has a membrane permeability of ∼1.7 µm/s, and could not be retained in secretory vesicles. Thus, it and NAS will be "secreted" from pineal cells by membrane diffusion. Circumstances are suggested when 5-HT and possibly catecholamines may also appear in the extracellular space passively by membrane diffusion. PMID:26712850

  13. Increased pulmonary and intestinal permeability in Crohn's disease.

    Adenis, A; Colombel, J F; Lecouffe, P; Wallaert, B; Hecquet, B; Marchandise, X; Cortot, A

    1992-01-01

    We tested the hypothesis that an increased epithelial permeability may affect sites other than the intestine in patients with Crohn's disease by simultaneously evaluating their pulmonary and intestinal permeability. Pulmonary and intestinal permeability were measured by clearance of inhaled technetium-99m diethylene triamine pentacetate (99mTc-DTPA) and by urinary recovery of chromium-51 ethylene diamine tetracetate respectively in 22 patients with Crohn's disease. The half time clearance of 99mTc-DTPA from lung to blood (t1/2LB) was decreased--that is pulmonary permeability increased--in the whole group of patients with Crohn's disease as compared with 13 controls (median 45.5 minutes (8-160) v 85 minutes (34-130) (p less than 0.003)). When analysed separately only patients with active Crohn's disease (n = 15) had a decreased t1/2 lung to blood v controls (42 minutes (8-160) v 85 minutes (34-130) (p less than 0.0025)). Among patients with active Crohn's disease, six were studied again when their disease was quiescent and their t1/2 lung to blood did not differ significantly. The intestinal permeability was increased in the whole group of Crohn's disease patients as compared with 15 controls (5.25% (1.2-24) v 1.7% (0.65-5.75) (p less than 0.0002)). When analysed separately both patients with active and inactive Crohn's disease had increased intestinal permeability v controls (8.1% (1.6-24) and 3.5% (1.2.9.2) v 1.7% (0.65-5.75)) (p less than 0.0001, p = 0.05 respectively). Six patients with active Crohn's disease were studied again when their disease was quiescent and their intestinal permeability decreased significantly p less than 0.04). Pulmonary permeability was increased in patients with Crohn's disease but was not greatly influenced by Crohn's disease activity as opposed to intestinal permeability. The mechanism of this increase is unknown, but may be related in some patients to the presence of an alveolitis. PMID:1612487

  14. Modulation of p53 activities by the prolyl-isomerase PIN1 and the bromodomain protein BRD7

    Tocco, Francesca

    2008-01-01

    ABSTRACT: MODULATION OF p53 ACTIVITIES BY THE PROLYL-ISOMERASE PIN1 AND THE BROMODOMAIN PROTEIN BRD7 The tumour suppressor p53 belongs to a family of transcription factors that play key roles in maintaining genomic stability and cellular homeostasis. The orchestration of the appropriate cellular responses depends on the fine regulation of p53’s functions through post-translational modifications and interaction with other proteins. In many years of intense study a considerable knowledge on...

  15. Decreased modulation by the risk level on the brain activation during decision making in adolescents with internet gaming disorder

    Qi, Xin; Du, Xin; Yang, Yongxin; Du, Guijin; Gao, Peihong; Zhang, Yang; Qin, Wen; Li, Xiaodong; Zhang, Quan

    2015-01-01

    Greater impulse and risk-taking and reduced decision-making ability were reported as the main behavioral impairments in individuals with internet gaming disorder (IGD), which has become a serious mental health issue worldwide. However, it is not clear to date how the risk level modulates brain activity during the decision-making process in IGD individuals. In this study, 23 adolescents with IGD and 24 healthy controls (HCs) without IGD were recruited, and the balloon analog risk task (BART) w...

  16. Decreased modulation by the risk level on the brain activation during decision making in adolescents with internet gaming disorder

    Yongxin Yang; Guijin Du; Quan Zhang

    2015-01-01

    Greater impulse and risk-taking and reduced decision-making ability were reported as the main behavioral impairments in individuals with Internet gaming disorder (IGD), which has become a serious mental health issue worldwide. However, it is not clear to date how the risk level modulates brain activity during the decision-making process in IGD individuals. In this study, 23 adolescents with IGD and 24 healthy controls (HCs) without IGD were recruited, and the Balloon Analog Risk Task (BART) w...

  17. MicroRNA-214 controls skin and hair follicle development by modulating the activity of the Wnt pathway

    Ahmed, Mohammed I.; Alam, Majid; Emelianov, Vladimir U.; Poterlowicz, Krzysztof; Patel, Ankit; Sharov, Andrey A.; Mardaryev, Andrei N.; Botchkareva, Natalia V.

    2014-01-01

    Skin development is governed by complex programs of gene activation and silencing, including microRNA-dependent modulation of gene expression. Here, we show that miR-214 regulates skin morphogenesis and hair follicle (HF) cycling by targeting β-catenin, a key component of the Wnt signaling pathway. miR-214 exhibits differential expression patterns in the skin epithelium, and its inducible overexpression in keratinocytes inhibited proliferation, which resulted in formation of fewer HFs with de...

  18. Steroid modulation of the chloride ionophore in rat brain: structure-activity requirements, regional dependence and mechanism of action

    Gee, K.W.; Bolger, M.B.; Brinton, R.E.; Coirini, H.; McEwen, B.S.

    1988-08-01

    Further in vitro studies of steroids active at the gamma-aminobutyric acidA (GABAA) receptor regulated Cl- channel labeled by (35S)-t-butylbicyclophosphorothionate ((35S)TBPS) reveal additional structural requirements necessary for activity. Evaluation of selected steroids for activity against TBPS-induced convulsions show similar requirements for activity. Interestingly, steroids (e.g., 5 alpha-pregnan-3 alpha, 20 alpha-diol) were identified that have high potency but limited efficacy as modulators of (35S)TBPS binding. These characteristics are reminiscent of the clinically useful benzodiazepines (BZs) such as clonazepam. However, interactions between the prototypical anesthetic-barbiturate, sodium pentobarbital, and steroids active at the Cl- channel suggest that they do not share a common site of action as allosteric modulators of (35S)TBPS and BZ receptor binding. The most potent steroid evaluated, 5 alpha-pregnan-3 alpha-ol-20-one, modulates (35S)TBPS binding at low concentrations (IC50 approximately 17 nM) in a regionally dependent manner. All (35S)TBPS binding sites appear to be functionally coupled to a steroid modulatory site. Because several of the active steroids are metabolites of progesterone, their ability to inhibit the binding of (3H)promegestrone to the cytosolic progestin receptor in rat uterus was evaluated. Those steroids showing potent activity at the GABAA receptor-Cl- ionophore were inactive at the intracellular progestin receptor. Such specificity coupled with their high potency provide additional support for the hypothesis that some of these steroids may be involved in the homeostatic regulation of brain excitability via the GABAA-BZ receptor complex.

  19. Steroid modulation of the chloride ionophore in rat brain: structure-activity requirements, regional dependence and mechanism of action

    Further in vitro studies of steroids active at the gamma-aminobutyric acidA (GABAA) receptor regulated Cl- channel labeled by [35S]-t-butylbicyclophosphorothionate ([35S]TBPS) reveal additional structural requirements necessary for activity. Evaluation of selected steroids for activity against TBPS-induced convulsions show similar requirements for activity. Interestingly, steroids (e.g., 5 alpha-pregnan-3 alpha, 20 alpha-diol) were identified that have high potency but limited efficacy as modulators of [35S]TBPS binding. These characteristics are reminiscent of the clinically useful benzodiazepines (BZs) such as clonazepam. However, interactions between the prototypical anesthetic-barbiturate, sodium pentobarbital, and steroids active at the Cl- channel suggest that they do not share a common site of action as allosteric modulators of [35S]TBPS and BZ receptor binding. The most potent steroid evaluated, 5 alpha-pregnan-3 alpha-ol-20-one, modulates [35S]TBPS binding at low concentrations (IC50 approximately 17 nM) in a regionally dependent manner. All [35S]TBPS binding sites appear to be functionally coupled to a steroid modulatory site. Because several of the active steroids are metabolites of progesterone, their ability to inhibit the binding of [3H]promegestrone to the cytosolic progestin receptor in rat uterus was evaluated. Those steroids showing potent activity at the GABAA receptor-Cl- ionophore were inactive at the intracellular progestin receptor. Such specificity coupled with their high potency provide additional support for the hypothesis that some of these steroids may be involved in the homeostatic regulation of brain excitability via the GABAA-BZ receptor complex

  20. Motion sickness is associated with an increase in vestibular modulation of skin but not muscle sympathetic nerve activity.

    Klingberg, Danielle; Hammam, Elie; Macefield, Vaughan G

    2015-08-01

    We have previously shown that sinusoidal galvanic vestibular stimulation (sGVS), delivered bilaterally at frequencies of 0.08-2.00 Hz, causes a pronounced modulation of muscle sympathetic nerve activity (MSNA) and skin sympathetic nerve activity (SSNA), together with robust frequency-dependent illusions of side-to-side motion. At low frequencies of sGVS (≤0.2 Hz), some subjects report nausea, so we tested the hypothesis that vestibular modulation of MSNA and SSNA is augmented in individuals reporting nausea. MSNA was recorded via tungsten microelectrodes inserted into the left common peroneal nerve in 22 awake, seated subjects; SSNA was recorded in 14 subjects. Bipolar binaural sGVS (±2 mA, 100 cycles) was applied to the mastoid processes at 0.08, 0.13, and 0.18 Hz. Nausea was reported by 21 out of 36 subjects (58 %), but across frequencies of sGVS there was no difference in the magnitude of the vestibular modulation of MSNA in subjects who reported nausea (27.1 ± 1.8 %) and those who did not (30.4 ± 2.9 %). This contrasts with the significantly greater vestibular modulation of SSNA with nausea (41.1 ± 2.0 vs. 28.7 ± 3.1 %) and indicates an organ-specific modulation of sympathetic outflow via the vestibular system during motion sickness. PMID:26025612