bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activation of cardiac chloride conductance by the tyrosine kinase inhibitor, genistein
Authors: Shuba Lesya M. , Asai Tatsuya , Pelzer Siegried , McDonald Terence F. 
Published: July 2012

Genistein (GST), an inhibitor of protein tyrosine kinase (PTK), Na3VO4 (VO4), an inhibitor of phosphotyrosine phosphatase (PTPase), and forskolin (FSK), an activator of the cyclic AMP‐dependent, cystic fibrosis transmembrane conductance regulator (CFTR) Cl− channel, were applied to guinea‐pig ventricular myocytes to probe for a possible role of tyrosine phosphorylation in the regulation of cardiac Cl− channels.
Myocytes in the standard whole‐cell configuration were pulsed to various potentials and Cl− current (IC1) measured as the difference from control background current. GST (1–500 μm) activated a current that had similar biophysical properties (time‐ and voltage‐independent; Cl−‐dependent reversal potential and outward rectification) as IC1 activated by 5 μm FSK. The EC50 for activation of Cl− conductance (gC1) by GST was approximately 100 μm, and gC1 activated by GST (500 μm) was as large as gC1 activated by maximally‐effective FSK (5 μm). Daidzein, a GST analogue with little effect on PTK, was at least one order less effective than GST.
GST responses were rapidly and reversibly inhibited by 0.1‐1 mM VO4 treatments that had little effect on FSK‐activated IC1.
Niflumic acid (100–200 μm) reversibly depressed GST (100 μm)‐activated gC1 by 55%.
GST (50 μm) strongly incremented current in myocytes with cyclic AMP‐dependent CFTR IC1 already activated by maximally‐effective FSK 5 μm.
Based on these results, and on evidence of a synergistic interaction between GST and FSK, we conclude that inhibition of tyrosine phosphorylation by GST causes an activation of cardiac CFTR that is not mediated by an elevation of cyclic AMP.
The effect of PPADS as an antagonist of inositol (1,4,5)trisphosphate induced intracellular calcium mobilization
Authors: Vigne Paul , Pacaud Pierre , Urbach Valérie , Feolde Erick , Breittmayer Jean Philippe , Frelin Christian 
Published: July 2012

Brain capillary endothelial cells responded to uridine 5′‐triphosphate (UTP) and adenosine 5′‐triphosphate (ATP) by activation of phospholipase C and by large changes in [Ca2+]i. These cells expressed mRNA sequences identical to the sequence of the P2Y2‐purinoceptor of rat pituitaries.
Pyridoxalphosphate‐6‐azophenyl‐2′,4′‐disulphonic acid (PPADS) at 100 μm did not prevent UTP and ATP induced accumulations of total [3H]‐inositol (poly)phosphates. It inhibited UTP and ATP induced intracellular Ca2+ mobilization (IC50 = 30 γm) by non competitive mechanism.
PPADS (100 μm) inhibited endothelin‐1 induced accumulation of total [3H]‐inositol (poly)phosphates by less than 20% and prevented most of endothelin‐1 induced intracellular Ca2+ mobilization (IC50 = 30 μm).
PPADS (100 μm) had no action on ionomycin induced intracellular Ca2+ mobilization.
Microinjection of inositol (1,4,5)trisphosphate (InsP3) into Xenopus oocytes induced large Ca2+ activated Cl− currents that were prevented by heparin and by PPADS.
It is concluded that PPADS does not recognize rat P2Y2‐purinoceptors and prevents UTP and ATP induced intracellular Ca2+ mobilization by a non‐specific mechanism that could involve the inhibition of InsP3 channels.
Evidence for mediation of L‐2‐chloropropionic acid‐induced delayed neuronal cell death by activation of a constitutive nitric oxide synthase
Authors: Widdowson P.S. , Farnworth M. , Moore R.B. , Dunn D. , Wyatt I. 
Published: July 2012

Delayed neuronal cell death elicited by excess excitatory amino acid concentrations has been strongly implicated in many neurological disorders including head trauma, stroke, motor neurone disease and Huntington's disease. We have used the neurotoxin, L‐2‐chloropropionic acid (L‐CPA) to model cellular events in vivo leading to delayed neuronal cell loss which is confined to the cerebellar cortex and can be prevented by inhibitors of nitric oxide synthase such as NG‐nitro‐L‐arginine methyl ester.
Experiments were performed to determine whether the constitutive nitric oxide synthase (NOS) or inducible form of NOS (iNOS) was responsible for the neuronal cell death. Activation of NOS was confirmed by a 39% increase in cerebellar total nitrate and nitrite concentrations in L‐CPA‐treated brains, as compared to controls (controls = 2.53 ± 0.10; L‐CPA treated = 3.51 ± 0.31 nmol mg−1 protein, P < 0.01 Student's t tests, n = 6, mean ± s.e.mean). Biochemical measurements of total NOS activity were made in homogenates of cerebellum 6 h and 48 h following L‐CPA administration, times at which L‐CPA concentrations are maximal in brain and a time when there is a high proportion of cerebellar granule cell death, respectively. NOS activity as measured by the amount of [3H]‐arginine converted to [3H]‐citrulline, did not reveal any difference between controls (rats dosed with water) and animals dosed with L‐CPA at either 6 or 48 h following dosing. Furthermore the ability of three NOS inhibitors, NG‐nitro‐L‐arginine, 7‐bromo‐3‐nitroindazole and S‐methylisothiourea to block the conversion of [3H]‐citrulline to [3H]‐arginine was identical at 6 and 48 h time points in control and L‐CPA treated rats.
Quantitative autoradiography using [3H]‐NG‐nitro‐L‐arginine was used to measure the relative anatomical distribution and amount of NOS enzyme in the cerebellum of controls and L‐CPA‐treated rats 48 h following dosing. There was no significant alteration in the binding of [3H]‐NG‐nitro‐L‐arginine to granular and molecular layers of the cerebellum of control and L‐CPA‐treated rat brains.
Western blotting using antibodies against the inducible NOS enzyme failed to detect the protein in cerebellums of L‐CPA‐treated rats when measured 48 h after L‐CPA dosing.
In conclusion, the increase in cerebellar nitrate/nitrite concentrations in L‐CPA‐treated rats provides further evidence for activation of NOS in the cerebellum following administration of L‐CPA. The failure to demonstrate an increase in NOS activity at 6 or 48 h in L‐CPA‐treated rats as compared to controls suggests that the source of nitric oxide responsible for the granule cell death must originate from the constitutive NOS enzyme, probably the neuronal form which is highly enriched in the cerebellum. This hypothesis was further substantiated by Western blotting and quantitative autoradiography.
Interactions between nitric oxide and prostanoids in isolated perfused kidneys of the rat
Authors: Ziyyat Abderrahim , Zhang Bei‐Li , Benzoni Daniel 
Published: July 2012

The present study was aimed to assess the interaction between nitric oxide (NO) and thromboxane (Tx) A2‐prostaglandin (PG) H2 in single‐pass perfused isolated kidneys of the rat.
Noradrenaline (NA, 63 and 110 nM) dose‐dependently elevated the renal vascular resistance (RVR), the glomerular filtration rate (GFR) and the urinary excretion of sodium (UNaV). Infusion of Nγ‐nitro‐L‐arginine methyl ester (L‐NAME, 100 μm), an inhibitor of NO synthesis, enhanced the effects of NA on RVR and on UNaV, but decreased those on GFR. The TxA2‐PGH2 (TP) receptor blockade by GR32191B (10 μm) attenuated this potentiating effect of L‐NAME.
When renal perfusion pressure was stepwise increased from 90 to 150 mmHg, L‐NAME similarly decreased renal perfusion flow rate and GFR.
The venous excretion of TxB2 and 6‐keto‐PGF1α was increased by L‐NAME in baseline conditions as well as after NA or increasing renal perfusion pressure (RPP).
These results suggest that: (1) TxA2 and PGH2 play an important role in the overall effect of the renal prostanoids, (2) NO strongly interacts with the cyclo‐oxygenase pathway and reduces the prostanoid synthesis in the kidney, and (3) the pressor effect of L‐NAME partly relies upon the vasoconstrictor effect of TxA2 and PGH2.
Regulation of human basophil function by phosphatase inhibitors
Authors: Peirce Matthew J. , Warner Jane A. , Munday Michael R. , Peachell Peter T. 
Published: July 2012

Okadaic acid, a cell permeant inhibitor of protein serine/threonine phosphatases (PPs), attenuated the IgE‐mediated release of the pre‐formed mediator, histamine from human basophils in a time‐ and dose‐dependent manner. Optimal inhibition (77 ± 4%,P< 0.0001) of histamine release was observed following a 2 h incubation with 1 μmokadaic acid.Okadaic acid and two analogues of okadaic acid were also studied and were found to inhibit the IgE‐dependent release of histamine. Concentrations required to inhibit release by 50% (IC50) were 0.6 μmfor okadaic acid and 7.5 μmfor okadaol, whereas okadaone was inactive.The structurally‐unrelated PP inhibitor, calyculin A, also inhibited IgE‐dependent histamine release from basophils dose‐dependently and was approximately six fold more potent than okadaic acid.The IgE‐mediated generation of sulphopeptidoleukotrienes (sLT) from basophils was inhibited by okadaic acid and related analogues with the following rank order of potency; okadaic acid (approx. IC500.3 μm) > okadaol (3 μm) > okadaone (inactive).Okadaic acid, okadaol and okadaone (all at 3 μm) inhibited the IgE‐mediated generation of the cytokine interleukin 4 (IL4) from human basophils by 67 ± 9% (P< 0.002), 48 ± 14% (P< 0.05) and 8 ± 7% (P= 0.31), respectively.Extracts of purified human basophils liberated32P from radiolabeled glycogen phosphorylase and this PP activity was inhibited by 17 ± 3% (P< 0.0005) by a low (2 nM) concentration of okadaic acid and was inhibited by 96 ± 1% (P< 0.0001) by a higher (5 μm) concentration of okadaic acid. Because a low (2 nM) concentration of okadaic acid inhibits PP2A selectively whereas a higher (5 μm) concentration inhibits both PP1 and PP2A, these findings suggest that both PP1 and PP2A are present in basophils.In total these data suggest that PPs are resident in human basophils and that PPs may be important in the regulation of basophil function.
Pharmacological characterization of the inwardly‐rectifying current in the smooth muscle cells of the rat bladder
Authors: Green Michelle E. , Edwards Gillian , Kirkup Anthony J. , Miller Martin , Weston Arthur H. 
Published: July 2012

In freshly‐isolated single cells of the rat bladder detrusor, outwardly‐rectifying and inwardly‐rectifying membrane currents were identified by the whole‐cell voltage‐clamp technique.
The inwardly‐rectifying current (IIR) exhibited features of a cation current permeable to both K+ and Na+ but it was unaffected by changes in extracellular Ca2+. It had an activation threshold close to −60 mV and an estimated reversal potential of −29 mV.
IIR activated slowly with a voltage‐sensitive time‐constant of 69 ms at −140 mV and 209 ms at −100 mV but it did not exhibit time‐dependent inactivation.
IIR was unaffected by tetraethylammonium (up to 20 mM) but it was reduced by extracellular Ba2+(1 mM) and by extracellular Cs+ (1 mM).
IIR was reduced by terikalant (100 μm) and markedly inhibited by ciclazindol (100 μm) although at these concentrations, both agents also reduced outward currents.
IIR was inhibited by ZD7288 (10–100 μm) in a concentration‐dependent manner. At concentrations up to 30 μm, ZD7288 did not reduce the magnitude of outward currents but these were inhibited by 100 μm ZD7288.
In strips of bladder detrusor, spontaneous mechanical activity was increased by ZD7288 (0.3–100 μm) and by ciclazindol (0.3–100 μm) but was unaffected by glibenclamide (1–10 μm).
It is concluded that IIR closely resembles the hyperpolarization‐activated current, Ih, previously described in the smooth muscle of rabbit jejunum and in a variety of other cell types. This current may play an important role in modulating detrusor excitability but this could not be confirmed using the inhibitors ZD7288 and ciclazindol.
Noradrenaline synthesis after sympathetic nerve activation in rat atria and its dependence on calcium but not CAM kinase II and protein kinases A or C
Authors: Kotsonis P. , Binko J. , Majewski H. 
Published: July 2012

The biosynthesis of noradrenaline following sympathetic nerve activation was investigated in rat atria. In particular the time course of noradrenaline synthesis changes, the relationship of changes in synthesis to transmitter release and the possible roles of second messengers and protein kinases were examined.
Rat atria incubated with the precursor [3H]‐tyrosine synthesized [3H]‐noradrenaline. Synthesis was enhanced following pulsatile electrical field stimulation (3 Hz for 5 min) with the bulk of the increase occurring in the first 45 min after the commencement of electrical stimulation. In separate experiments rat atria were pre‐incubated with [3H]‐noradrenaline and the radioactive outflow in response to electrical field stimulation (3 Hz for 5 min) was taken as an index of noradrenaline release.
Stimulation‐induced (S‐I) noradrenaline synthesis was significantly correlated to S‐I noradrenaline release for a variety of procedures which modulate noradrenaline release by mechanisms altering Ca2+ entry into the neurone (r2 = 0.99): those which decreased release: tetrodotoxin (0.3 μm), Ca2+‐free medium, lowering the frequency of nerve activation to 1 Hz, and those which increased release, tetraethylammonium (0.3 mM), phentolamine (1 μm) and the combination of phentolamine (1 μm) and adenosine (10 μm). On the strength of this relationship we suggest that Ca2+ entry is a determining factor in S‐I synthesis changes rather than the amount of noradrenaline released. Indeed the reduction in noradrenaline release with the calmodulin‐dependent protein (CAM) kinase II inhibitor KN‐62 (10 μm) which acts subsequent to Ca2+ entry, did not affect S‐I synthesis.
The cell permeable cyclic AMP analogue, 8‐bromoadenosine 3′, 5′‐monophosphate (BrcAMP, 90 and 270 μm), dose‐dependently increased basal [3H]‐noradrenaline synthesis in unstimulated rat atria. This effect was antagonized by the selective protein kinase A (PKA) antagonist, Rp‐8‐chloroadenosine 3′, 5′‐cyclic monophosphorothioate (RClcAMPS, 300 μm), suggesting that PKA activation enhances basal noradrenaline biosynthesis in sympathetic nerve terminals.
The protein kinase inhibitors, KN‐62 (CAM kinase II, 10 μm), RClcAMPS (PKA, 300 μm), polymyxin B (protein kinase C (PKC), 21 μm) and staurosporine (PKC, PKA and CAM kinase II, 0.1 μm) did not affect S‐I synthesis, although KN‐62, polymyxin B and staurosporine decreased S‐I release. We conclude that S‐I synthesis is triggered by Ca2+ entering the neurone but that the signalling pathway does not involve classical protein kinases and appears distinct from the steps involved in transmitter release.
The inhibitory effects of α2‐adrenoceptor agonists on gastrointestinal transit during croton oil‐induced intestinal inflammation
Authors: Pol Olga , Valle Lluis , Ferrer Isidre , Puig Margarita M. 
Published: July 2012

The peripheral effects of α2‐adrenoceptor agonists were investigated in a model of intestinal inflammation induced by intragastric administration of croton oil (CO). Our hypothesis was that inflammation would ‘sensitize’ adrenoceptors in peripheral and/or central terminals of myenteric and submucous plexus neurones, and enhance systemic effects of α2‐adrenoceptor agonists.
Male swiss CD‐1 mice, received intragastrically CO (0.05 ml), castor oil (CA, 0.1 ml) or saline (SS) 3 h before the study: gastrointestinal transit (GIT) was evaluated 20 min afterwards with a charcoal meal. The presence of inflammation was assessed by electron microscopy.
The intragastric administration of CA or CO caused an increase in GIT and weight loss, but only CO induced an inflammatory response. Both clonidine (imidazoline1/α2‐agonist) and UK‐14304 (α2‐agonist) produced dose‐related inhibitions of GIT in all groups. During inflammatory diarrhoea (CO), potencies of systemic (s.c.) clonidine and UK‐14304 were significantly increased 3.5 and 2.1 times, respectively, while potencies remained unaltered in the presence of diarrhoea without inflammation (CA). The effects were reversed by administration (s.c.) of receptor‐specific adrenoceptor antagonists, but not by naloxone.
Clonidine was 8.3 (SS) and 2.8 (CO) times more potent when administered intracerebroventricularly (i.c.v.), than when administered s.c. Inflammation of the gut did not alter the potency of i.c.v. clonidine, demonstrating that enhanced effects of s.c. clonidine are mediated by peripheral receptors. During inflammation, i.c.v. efaroxan did not antagonize low doses of s.c. clonidine (ED20 and ED50s), but partially reversed ED80s, further supporting the peripheral effects of the agonists in CO treated animals.
The results demonstrate that inflammation of the gut enhances the potency of α2‐adrenoceptor agonists by a peripheral mechanism. The results also suggest that the inflammatory response induces an up‐regulation or sensitization of α‐adrenoceptors and/or imidazoline receptors.
Associations between infections and clinical outcome parameters in status epilepticus: A retrospective 5‐year cohort study
Authors: Sutter Raoul , Tschudin‐Sutter Sarah , Grize Leticia , Fuhr Peter , Bonten Marc J. M. , Widmer Andreas F. , Marsch Stephan , Rüegg Stephan 
Published: July 2012

SummaryPurpose:  Status epilepticus (SE) represents a life‐threatening condition, requiring pharmacologic therapy and neurointensive care. Infectious complications in SE are suspected to be frequent and worsen outcome. However, little is known about their incidence during SE and their impact on course and outcome. The aim of this study was to determine the incidence and time of onset of infections during SE, as well as their association with particular SE courses, length of hospitalization, intensive care unit (ICU) stay, and outcome.Methods:  All consecutive ICU patients hospitalized due to SE from 2005 to 2009 at the University Hospital Basel were included. Electroencephalography (EEG) recordings and microbiologic data were extracted from two prospectively established databases. Length of SE, ICU, and hospital stay; development of refractory status epilepticus (RSE); and destinations at discharge or death were assessed by comprehensive medical chart review.Key Findings:  Of 160 patients, 23% had infections during SE. Of those, 94% were respiratory tract infections, 29% were ventilator‐associated pneumonias. Patients with infections during SE had longer SE duration (p < 0.0001), longer ICU stay (p = 0.0041), higher risk of RSE (odds ratio [OR] 4.8, p = 0.0002), and higher mortality (OR 5.2, p = 0.0003) than those without infectious complications. Infections during the first 3 days after SE onset were significantly associated with longer SE duration, higher rate of RSE, and higher mortality compared to infections detected before SE.Significance:  Infections during SE are frequent and associated with higher mortality, prolonged ICU stay, and higher rates of RSE. Further trials are needed to provide evidence of a causative relation between infections and outcomes of SE, followed by investigations on underlying mechanisms and preventive strategies.
Technological Growth and Asset Pricing
Authors: GÂRLEANU NICOLAE , PANAGEAS STAVROS , YU JIANFENG 
Published: July 2012

ABSTRACTWe study the asset‐pricing implications of technological growth in a model with “small,” disembodied productivity shocks and “large,” infrequent technological innovations, which are embodied into new capital vintages. The technological‐adoption process leads to endogenous cycles in output and asset valuations. This process can help explain stylized asset‐valuation patterns around major technological innovations. More importantly, it can help provide a unified, investment‐based theory for numerous well‐documented facts related to excess‐return predictability. To illustrate the distinguishing features of our theory, we highlight novel implications pertaining to the joint time‐series properties of consumption and excess returns.
Mutual Fund Trading Pressure: Firm‐Level Stock Price Impact and Timing of SEOs
Authors: KHAN MOZAFFAR , KOGAN LEONID , SERAFEIM GEORGE 
Published: July 2012

ABSTRACTWe use price pressure resulting from purchases by mutual funds with large capital inflows to identify overvalued equity. This is a relatively exogenous overvaluation indicator as it is associated with who is buying—buyers with excess liquidity—rather than what is being purchased. We document substantial stock price impact associated with purchases by high‐inflow mutual funds, and find the probability of a seasoned equity offering (SEO), insider sales, and the probability of a stock‐based acquisition increase significantly in the four quarters following the mutual fund buying pressure. These results provide new evidence that firm managers are able to identify and exploit overvalued equity.
Real Options, Volatility, and Stock Returns
Authors: GRULLON GUSTAVO , LYANDRES EVGENY , ZHDANOV ALEXEI 
Published: July 2012

ABSTRACTWe provide evidence that the positive relation between firm‐level stock returns and firm‐level return volatility is due to firms’ real options. Consistent with real option theory, we find that the positive volatility‐return relation is much stronger for firms with more real options and that the sensitivity of firm value to changes in volatility declines significantly after firms exercise their real options. We reconcile the evidence at the aggregate and firm levels by showing that the negative relation at the aggregate level may be due to aggregate market conditions that simultaneously affect both market returns and return volatility.
Effect of Y‐α‐Sialon Seeding and Holding Time on the Formation of Elongated (Ca,Dy)‐α‐Sialon Crystals Prepared via Carbothermal Reduction and Nitridation
Authors: Huang Juntong , Zhou Heping , Huang Zhaohui , Liu Guanghua , Fang Minghao , Liu Yan'gai 
Published: July 2012

Single‐phase (Ca,Dy)‐α‐Sialon with elongated crystals and high aspect ratios was prepared at 1700°C by carbothermal reduction and nitridation (CRN) with Y‐α‐Sialon seed crystals. Effects of Y‐α‐Sialon seeding and holding time on the phase assemblage and crystal morphology of CRN products were discussed. The results showed that adding seed crystals and prolonging holding time could facilitate not only phase transformation, but also crystal refinement. Moreover, they resulted in the increase of the aspect ratios of α‐Sialon crystals, due to the decreasing range in the crystal width exceeding that in the length. In addition, a highly unusual phenomenon of crystal size reduction during reaction was observed in the seeded samples with the holding time extending from 2 to 4 h. Crystallization from liquid phase and growth followed by nucleation based on the surface of existing large crystals were the growth modes of elongated α‐Sialon crystals.