bluuebunny/crossref_metadata_2025 huggingface dataset:
Going Local or Global: The Case of Online Daily Deal Company TicketMonster
Authors: Jeon Seongmin , Yoo Byungjoon
Published: March 2015

TicketMonster is a deal-of-the-day coupon site which utilizes the Internet and mobile infrastructure to offer deals in Seoul and other cities around Korea on services at restaurants, cafes, spas, and so forth. Following the company's rapid expansion, management made the decision to expand the scope of TicketMonster beyond Korea's borders with the aim of taking on other Asian markets. To this end, TicketMonster acquired Everyday.com.my, the biggest social shopping site in Malaysia. However, it was believed that simply competing in markets across Asia would not enable TicketMonster to claim sufficient market share in light of the international expansion of Groupon and LivingSocial, two online daily deal global giants.

Furthermore, competition in the online daily deal sector in Korea had escalated as local, regional and international players vied for consumer awareness and loyalty. On top of an advertising war, competition grew to the point where several sites began selling coupons while knowingly taking a loss by lowering commissions in order to attract competitive products or services for their respective deals and at times paying for the services themselves. In mid-2011, U.S.-based LivingSocial made an offer to buy TicketMonster in order to strengthen its presence in Asia.

Considering these changes and challenges, what are the strategic issues regarding TicketMonster and how should the company deal with the offer to deploy its transfer of ownership to LivingSocial? This case will help readers form an opinion on the related management issues and analyses.
Contrasting geochemistry of orogenic gold deposits in Yukon, Canada and Otago, New Zealand
Authors: Craw Dave , Mortensen Jim , MacKenzie Doug , Pitcairn Iain
Published: February 2015

The Yukon-Tanana Terrane (YTT) of western Yukon Territory in NW Canada and Otago Schist belt (OSB) of South Island, New Zealand share similar geological evolutionary histories as convergent orogenic belts. Both belts host orogenic gold deposits of mainly Jurassic to Early Cretaceous age. Jurassic mineralization in the YTT occurred during convergent orogenesis and stacking of previously-metamorphosed (Palaeozoic) greenschist-amphibolite facies metasediments, metavolcanic rocks, and metagranitoids. Early Cretaceous OSB mineralization occurred in the latter stages of terrane accretion of un-metamorphosed turbidites with minor basaltic rocks. Metamorphism of the OSB turbidites mobilised background levels of Au (0.6–1.3 ppb), As (2–20 ppm), Sb (0.1–1 ppm), and W (< 10 ppm), primarily under greenschist to lower amphibolite facies conditions when diagenetic pyrite (Au
c
. 0.5–2 ppm; As
c
. 500–10 000 ppm) transformed to pyrrhotite on a regional scale. In contrast, the previously-metamorphosed YTT rocks had generally low background As contents (1–2 ppm) apart from some As-rich quartzites (up to 100 ppm As). Consequently, there was less As available for orogenic mobilisation, and YTT Au deposits generally have lower concentrations of this pathfinder element compared to the OSB. YTT host rocks, especially metagranitoids, have anomalous levels of Mo (10–300 ppm), and many orogenic deposits contain elevated Mo, locally including molybdenite. OSB turbidites have elevated Mo (2–200 ppm), along with elevated Au and As, in diagenetic pyrite, but this Mo became largely dispersed through the metamorphic pile as metamorphic grade increased and pyrite transformed to pyrrhotite. OSB orogenic deposits have only marginally elevated Mo (
c
. 1 ppm), no molybdenite, and accessory scheelite in these deposits is distinctly Mo-poor. Only minor mobilisation of base metals occurred in these orogenic belts, and orogenic Au deposits contain sparse base metal sulphides. Orogenic deposits in the YTT and OSB differ in that Au (and other associated elements) in many of the orogenic deposits in the YTT was remobilised from relatively local sources (e.g. pre-existing Cu-Mo-Au porphyry or volcanogenic sulphide mineralization) whereas Au in the OSB was mobilised from larger volumes of homogeneous rock at depth.
Geochemistry in prospectivity modelling: investigating gold mineralization in the Taupo Volcanic Zone, New Zealand
Authors: Payne Constance E. , Peters Katie J.
Published: February 2015

Prospectivity modelling of epithermal gold mineralization has been completed over the Taupo Volcanic Zone (TVZ), North Island, New Zealand. The TVZ is unique in that it is a present-day analogue of the environment in which many epithermal ore deposits, such as in the adjacent Hauraki Goldfield in the Coromandel Volcanic Zone, are formed. The model utilizes compiled digital data including: historical exploration data; geological data from the Institute of Geological and Nuclear Sciences Quarter Million Mapping Programme over Rotorua, Hawkes Bay and Taranaki; recent Glass Earth Gold Ltd geophysical data; and historic exploration geochemical data from rock-chip and stream sediment samples. The weights of evidence modelling technique was used to determine spatial correlations between known gold prospects and predictive maps, created from the available data, representing each component of the currently accepted mineral system model for epithermal gold. Despite the limited coverage of several data-sets, the resulting prospectivity model over the TVZ confirms potential for gold mineralization. The most prospective areas are those associated with active and inactive hydrothermal systems represented by areas of hydrothermal alteration. The Rotokawa and Waiotapu hydrothermal centres have been identified as particularly prospective, suggesting these systems may represent modern analogues of epithermal gold mineralization.
Biogeochemical exploration using
Triodia pungens
in the Tanami Desert, Australia
Authors: Hodkinson Ian P. , Dunn Colin E. , Waldron Helen M. , Scarlett Ryan , Vose Christopher P.
Published: February 2015

The Palaeoproterozoic Granites–Tanami Province in Western Australia and the Northern Territory contains numerous significant gold deposits, but recent exploration for additional deposits has been hampered by deep weathering of the basement and extensive Tertiary and Quaternary cover. Biogeochemical exploration has rarely been attempted in this environment, with soil sampling and drilling being the principal exploration methods. This paper outlines the methodology and results of a biogeochemical exploration programme utilizing
Triodia pungens
(soft spinifex), a perennial, hummock-forming grass, widely found throughout much of arid and semi-arid Australia. The species possesses several attributes which make it suitable for biogeochemical exploration, being ubiquitous in the area, readily harvested and capable of the uptake of trace elements useful in geochemistry. Systematic sampling has been undertaken at 50 m intervals on widely spaced lines over several prospect areas. Collection of large samples from several plants at each sample station is desirable to try to obtain a representative sample. Initial multi-element analytical work utilizing small samples (
c
. 2.5 g) of dried and shredded vegetation did not allow sufficient resolution of anomalies, with most results for Au and Pt being below detection levels. However, preconcentration by ashing of substantially larger samples (
c
. 30 g) has allowed anomaly thresholds for those elements to be more readily defined. The species displays extensive geochemical variability for precious metals, pathfinders, base metals and major cations suggesting it offers much promise as a sampling medium. Test sampling traverses across known gold occurrences confirm the effectiveness of the technique in areas of thick cover sequences.
Low-Complexity Implementation of RAID Based on Reed-Solomon Codes
Authors: Trifonov P.
Published: March 2015

Fast algorithms are proposed for encoding and reconstructing data in RAID based on Reed-Solomon codes. The proposed approach is based on the cyclotomic fast Fourier transform algorithm and enables one to significantly reduce the number of expensive Galois field multiplications required. The complexity of the obtained algorithms is much lower than those for existing MDS array codes. Software implementation of the proposed algorithms is discussed. The performance results show that the new algorithms provide substantially better performance compared with the standard algorithm.
Traffic engineering with forward fault correction
Authors: Liu Hongqiang Harry , Kandula Srikanth , Mahajan Ratul , Zhang Ming , Gelernter David
Published: March 2015

Faults such as link failures and high switch configuration delays can cause heavy congestion and packet loss. Because it takes time to detect and react to faults, these conditions can last long---even tens of seconds. We propose forward fault correction (FFC), a proactive approach to handling faults. FFC spreads network traffic such that freedom from congestion is guaranteed under arbitrary combinations of up to k faults. We show how FFC can be practically realized by compactly encoding the constraints that arise from this large number of possible faults and solving them efficiently using sorting networks. Experiments with data from real networks show that, with negligible loss in overall network throughput, FFC can reduce data loss by a factor of 7--130 in well-provisioned networks, and reduce the loss of high-priority traffic to almost zero in well-utilized networks.
Protection against diet-induced obesity and obesity- related insulin resistance in Group 1B PLA2-deficient mice
Authors: Huggins Kevin W. , Boileau Amy C. , Hui David Y.
Published: March 2015

Group 1B phospholipase A2(PLA2) is an abundant lipolytic enzyme that is well characterized biochemically and structurally. Because of its high level of expression in the pancreas, it has been presumed that PLA2plays a role in the digestion of dietary lipids, but in vivo data have been lacking to support this theory. Our initial study on mice lacking PLA2demonstrated no abnormalities in dietary lipid absorption in mice consuming a chow diet. However, the effects of PLA2deficiency on animals consuming a high-fat diet have not been studied. To investigate this, PLA2+/+and PLA2−/−mice were fed a western diet for 16 wk. The results showed that PLA2−/−mice were resistant to high-fat diet-induced obesity. This observed weight difference was due to decreased adiposity present in the PLA2−/−mice. Compared with PLA2+/+mice, the PLA2−/−mice had 60% lower plasma insulin and 72% lower plasma leptin levels after high-fat diet feeding. The PLA2−/−mice also did not exhibit impaired glucose tolerance associated with the development of obesity-related insulin resistance as observed in the PLA2+/+mice. To investigate the mechanism by which PLA2−/−mice exhibit decreased weight gain while on a high-fat diet, fat absorption studies were performed. The PLA2−/−mice displayed 50 and 35% decreased plasma [3H]triglyceride concentrations 4 and 6 h, respectively, after feeding on a lipid-rich meal containing [3H]triolein. The PLA2−/−mice also displayed increased lipid content in the stool, thus indicating decreased fat absorption in these animals. These results suggest a novel role for PLA2in the protection against diet-induced obesity and obesity-related insulin resistance, thereby offering a new target for treatment of obesity and diabetes.
AICAR and phlorizin reverse the hypoglycemia-specific defect in glucagon secretion in the diabetic BB rat
Authors: McCrimmon R. J. , Evans M. L. , Jacob R. J. , Fan X. , Zhu Y. , Shulman G. I. , Sherwin R. S.
Published: March 2015

Individuals with type 1 diabetes demonstrate a hypoglycemia-specific defect in glucagon secretion. To determine whether intraislet hyperinsulinemia plays a role in the genesis of this defect, glucagon-secretory responses to moderate hypoglycemia induced by either insulin or a novel combination of the noninsulin glucose-lowering agents 5-aminoimidazole-4-carboxamide (AICAR) and phlorizin were compared in diabetic BB rats (an animal model of type 1 diabetes) and nondiabetic BB rats. The phlorizin-AICAR combination was able to induce moderate and equivalent hypoglycemia in both diabetic and nondiabetic BB rats in the absence of marked hyperinsulinemia. Diabetic BB rats demonstrated impaired glucagon and epinephrine responses during insulin-induced hypoglycemia compared with nondiabetic rats. In contrast, both glucagon (9- to 10-fold increase) and epinephrine (5- to 6-fold increase) responses were markedly improved during phlorizin-AICAR hypoglycemia. Combining phlorizin, AICAR, and insulin attenuated the glucagon response to hypoglycemia by 70% in the diabetic BB rat. Phlorizin plus AICAR had no effect on counterregulatory hormones under euglycemic conditions. We conclude that α-cell glucagon secretion in response to hypoglycemia is not defective if intraislet hyperinsulinemia is prevented. This suggests that exogenous insulin plays a pivotal role in the etiology of this defect.
Mice with targeted deletion of eNOS develop hyperdynamic circulation associated with portal hypertension
Authors: Iwakiri Yasuko , Cadelina Gregory , Sessa William C. , Groszmann Roberto J.
Published: March 2015

Systemic vasodilation is the initiating event of the hyperdynamic circulatory state, being most likely triggered by increased levels of vasodilators, primarily nitric oxide (NO). Endothelial NO synthase (eNOS) is responsible for this event. We tested the hypothesis that gene deletion of eNOS and inducible NOS (iNOS) may inhibit the development of the hyperdynamic circulatory state in portal hypertensive animals. To test this hypothesis, we used mice lacking eNOS (eNOS−/−) or eNOS/iNOS (eNOS/iNOS−/−) genes. A partial portal vein ligation (PVL) was used to induce portal hypertension. Sham-operated animals were used as a control. Hemodynamic characteristics were tested 2 wk after surgery. As opposed to our hypothesis, PVL also caused significant reduction in peripheral resistance in eNOS−/− compared with sham animals (0.33 ± 0.02 vs. 0.41 ± 0.03 mmHg · min · kg body wt · ml−1; P = 0.04) and in eNOS/iNOS−/− animals with PVL compared with that of the sham-operated group (0.44 ± 0.02 vs. 0.54 ± 0.04; P = 0.03). This demonstrates that, despite gene deletion of eNOS, the knockout mice developed hyperdynamic circulation. Compensatory vasodilator molecule(s) are upregulated in place of NO in the systemic and splanchnic circulation in portal hypertensive animals.
Glutathione and thioredoxin redox during differentiation in human colon epithelial (Caco-2) cells
Authors: Nkabyo Yvonne S. , Ziegler Thomas R. , Gu Li H. , Watson Walter H. , Jones Dean P.
Published: March 2015

Cellular redox, maintained by the glutathione (GSH)- and thioredoxin (Trx)-dependent systems, has been implicated in the regulation of a variety of biological processes. The redox state of the GSH system becomes oxidized when cells are induced to differentiate by chemical agents. The aim of this study was to determine the redox state of cellular GSH/glutathione disulfide (GSH/GSSG) and Trx as a consequence of progression from proliferation to contact inhibition and spontaneous differentiation in colon carcinoma (Caco-2) cells. Results showed a significant decrease in GSH concentration, accompanied by a 40-mV oxidation of the cellular GSH/GSSG redox state and a 28-mV oxidation of the extracellular cysteine/cystine redox state in association with confluency and increase in differentiation markers. The redox state of Trx did not change. Thus the two central cellular antioxidant and redox-regulating systems (GSH and Trx) were independently controlled. According to the Nernst equation, a 30-mV oxidation is associated with a 10-fold change in the reduced/oxidized ratio of a redox-sensitive dithiol motif. Therefore, the measured 40-mV oxidation of the cellular GSH/GSSG couple or the 28-mV oxidation of the extracellular cysteine/cystine couple should be sufficient to function in signaling or regulation of differentiation in Caco-2 cells.
Polyamines are required for activation of c-Jun NH2-terminal kinase and apoptosis in response to TNF-α in IEC-6 cells
Authors: Bhattacharya Sujoy , Ray Ramesh M. , Viar Mary Jane , Johnson Leonard R.
Published: March 2015

Intracellular polyamine homeostasis is important for the regulation of cell proliferation and apoptosis and is necessary for the balanced growth of cells and tissues. Polyamines have been shown to play a role in the regulation of apoptosis in many cell types, including IEC-6 cells, but the mechanism is not clear. In this study, we analyzed the mechanism by which polyamines regulate the process of apoptosis in response to tumor necrosis factor-α (TNF-α). TNF-α or cycloheximide (CHX) alone did not induce apoptosis in IEC-6 cells. Significant apoptosis was observed when CHX was given along with TNF-α, as indicated by a significant increase in the detachment of cells, caspase-3 activity, and DNA fragmentation. Polyamine depletion by treatment with α-difluoromethylornithine significantly reduced the level of apoptosis, as judged by DNA fragmentation and the caspase-3 activity of attached cells. Apoptosis in IEC-6 cells was accompanied by the activation of upstream caspases-6, -8, and -9 and NH2-terminal c-Jun kinase (JNK). Inhibition of JNK activation prevented caspase-9 activation. Polyamine depletion prevented the activation of JNK and of caspases-6, -8, -9, and -3. SP-600125, a specific inhibitor of JNK activation, prevented cytochrome c release from mitochondria, JNK activation, DNA fragmentation, and caspase-9 activation in response to TNF-α/CHX. In conclusion, we have shown that polyamine depletion delays and decreases TNF-α-induced apoptosis in IEC-6 cells and that apoptosis is accompanied by the release of cytochrome c, the activation of JNK, and of upstream caspases as well as caspase-3. Polyamine depletion prevented JNK activation, which may confer protection against apoptosis by modulation of upstream caspase-9 activation.
T cell substance P receptor governs antigen-elicited IFN-γ production
Authors: Blum Arthur M. , Metwali Ahmed , Elliott David E. , Weinstock Joel V.
Published: March 2015

Substance P (SP) enhances antigen-dependent T cell IFN-γ production. It was determined if a T cell neurokinin-1 receptor (NK-1R) was critical for IFN-γ regulation. T cells from schistosome-infected mice were mixed with splenocytes from uninfected NK-1R knockout (KO) animals. Thus only the schistosome egg antigen-specific T cells expressed NK-1R. The cells were cultured 18 h with or without SP. SP enhanced antigen-induced IFN-γ production fourfold without affecting IL-4 or IL-5 secretion. NK-1R inhibitor blocked this stimulation. Neither purified T cells nor naı̈ve KO splenocytes cultured alone responded to antigen. To further define the importance of T cell NK-1R, we developed a T cell-selective NK-1R KO mouse by reconstituting T cell-deficient Rag mice with NK-1R KO T cells. These mice challanged with schistosomiasis developed abnormal liver granulomas. Granuloma size was smaller in T cell-selective NK-1R KO mice compared with granulomas in Rag reconstituted with normal T cells. Splenocytes and granuloma cells from NK-1R KO mice made less IFN-γ. The mice also made less IgG2a. Thus T cell NK-1R is important for IFN-γ regulation.
Effect of CCK and intracellular calcium to regulate eIF2B and protein synthesis in rat pancreatic acinar cells
Authors: Sans Maria Dolors , Kimball Scot R. , Williams John A.
Published: March 2015

Pancreatic secretagogues enhance acinar protein synthesis at physiological concentrations and inhibit protein synthesis at high concentrations. We investigated the potential role in this process of the eukaryotic translation initiation factor (eIF)2B. Cholecystokinin (CCK) at 10–100 pM did not significantly affect eIF2B activity, which averaged 35.4 nmol guanosine 5′-diphosphate exchanged per minute per milligram protein under control conditions; higher CCK concentrations reduced eIF2B activity to 38.2% of control. Carbamylcholine chloride (Carbachol, CCh), A-23187, and thapsigargin also inhibited eIF2B and protein synthesis, whereas bombesin and the CCK analog JMV-180 were without effect. Previous studies have shown that eIF2B can be negatively regulated by glycogen synthase kinase-3 (GSK-3). However, GSK-3 activity, as assessed by phosphorylation state, was inhibited at high concentrations of CCK, an effect that should have stimulated, rather than repressed, eIF2B activity. An alternative mechanism for regulating eIF2B is through phosphorylation of the α-subunit of eIF2, which converts it into an inhibitor of eIF2B. CCK, CCh, A-23187, and thapsigargin all enhanced eIF2α phosphorylation, suggesting that eIF2B activity is regulated by eIF2α phosphorylation under these conditions. Removal of Ca2+from the medium enhanced the inhibitory action of CCK on both protein synthesis and eIF2B activity as well as further increasing eIF2α phosphorylation. Although it is likely that other mechanisms account for the stimulation of acinar protein synthesis, these results suggest that the inhibition of acinar protein synthesis by CCK occurs as a result of depletion of Ca2+from the endoplasmic reticulum lumen leading to phosphorylation of eIF2α and inhibition of eIF2B.
Putative effect ofHelicobacter pyloriand gastritis on gastric acid secretion in cat
Authors: Sobhani Iradj , Canedo Sergio , Alchepo Beatriz , Vissuzaine Christiane , Chevalier Catherine , Buyse Marion , Moizo Laurent , Laigneau J. Pierre , Mignon Michel , Lewin J. Miguel , Bado André
Published: March 2015

Helicobacter pylori may increase or inhibit gastric acid. We studied acid variations and plasma gastrin in cats harboring Helicobacter felis, harboring H. pylori, or free of gastric pathogens with reference to thioperamide (H3receptor antagonist) and SR-27417A (PAF receptor antagonist). In cats harboring H. felis, gastric mucosa were histologically normal. After H. feliseradication, pentagastrin-stimulated acid secretion was increased (40%) compared with the situation before eradication. Thioperamide abolished this inhibitory effect of H. felis, whereas SR-27417A did not. Basal and meal-stimulated plasma gastrin levels were not affected by eradication therapy. Acid secretion was inhibited (−80%) in week 3, increased from weeks 5 to 9, and remained constant for up to 42 weeks after H. pylori infection. SR-27417A had no effect on acid secretion before week 8 but inhibited it thereafter, and thioperamide increased it (20%) only before week 7 in those cats. Helicobacter inhibits gastric acid via an H3receptor pathway. Inflammatory mediators are thus involved in adaptation to the inhibitory effects of H. pylori on acid secretion.
Circumferential, not longitudinal, colonic stretch increases synaptic input to mouse prevertebral ganglion neurons
Authors: Miller Steven M. , Szurszewski J. H.
Published: March 2015

The relationship between longitudinal and circular muscle tension in the mouse colon and mechanosensory excitatory synaptic input to neurons in the superior mesenteric ganglion (SMG) was investigated in vitro. Electrical activity was recorded intracellularly from SMG neurons, and muscle tension was simultaneously monitored in the longitudinal, circumferential, or both axes. Colonic intraluminal pressure and volume changes were also monitored simultaneously with muscle tension changes. The results showed that the frequency of fast excitatory postsynaptic potentials (fEPSPs) in SMG neurons increased when colonic muscle tension decreased, when the colon relaxed and refilled with fluid after contraction, and during receptive relaxation preceding spontaneous colonic contractions. In contrast, fEPSP frequency decreased when colonic muscle tension increased during spontaneous colonic contraction and emptying. Manual stretch of the colon wall to 10-15% beyond resting length in the circumferential axis of flat sheet preparations increased fEPSP frequency in SMG neurons, but stretch in the longitudinal axis to 15% beyond resting length in the same preparations did not. There was no increase in synaptic input when tubular colon segments were stretched in their long axes up to 20% beyond their resting length. The circumferential stretch-sensitive increase in the frequency of synaptic input to SMG neurons persisted when the colonic muscles were relaxed pharmacologically by nifedipine (2 μM) or nicardipine (3 μM). These results suggest that colonic mechanosensory afferent nerves projecting to the SMG function as length or stretch detectors in parallel to the circular muscle layer.
Erk1/2- and p38 MAP kinase-dependent phosphorylation and activation of cPLA2by m3 and m2 receptors
Authors: Zhou Huiping , Das Sankar , Murthy Karnam S.
Published: March 2015

This study examined the upstream signaling pathways initiated by muscarinic m2 and m3 receptors that mediate sustained ERK1/2- and p38 MAP kinase-dependent phosphorylation and activation of the 85-kDa cytosolic phospholipase (cPL)A2in smooth muscle. The pathway initiated by m2 receptors involved sequential activation of Gβγi3, phosphatidylinositol (PI)3-kinase, Cdc42, and Rac1, p21-activated kinase (PAK1), p38 mitogen-activated protein (MAP) kinase, and cPLA2, and phosphorylation of cPLA2at Ser505. cPLA2activity was inhibited to the same extent (61 ± 5 to 72 ± 4%) by the m2 antagonist methoctramine, Gβ antibody, pertussis toxin, the PI3-kinase inhibitor LY 294002, PAK1 antibody, the p38 MAP kinase inhibitor SB-203580, and a Cdc42/Rac1 GEF (Vav2) antibody and by coexpression of dominant-negative Cdc42 and Rac1 mutants. The pathway initiated by m3 receptors involved sequential activation of Gαq, PLC-β1, PKC, ERK1/2, and cPLA2, and phosphorylation of cPLA2at Ser505. cPLA2activity was inhibited to the same extent (35 ± 3 to 41 ± 5%) by the m3 antagonist 4-diphenylacetoxy- N-methylpiperdine (4-DAMP), the phosphoinositide hydrolysis inhibitor U-73122, the PKC inhibitor bisindolylmaleimide, and the ERK1/2 inhibitor PD 98059. cPLA2activity was not affected in cells coexpressing dominant-negative RhoA and PLC-δ1 mutants, implying that PKC was not derived from phosphatidylcholine hydrolysis. The effects of ERK1/2 and p38 MAP kinase on cPLA2activity were additive and accounted fully for activation and phosphorylation of cPLA2.
Relationship between esophageal muscle thickness and intraluminal pressure in patients with esophageal spasm
Authors: Pehlivanov Nonko , Liu Jianmin , Kassab Ghassan S. , Beaumont Cheryl , Mittal Ravinder K.
Published: March 2015

We previously showed, in normal subjects, a positive correlation between the esophageal contraction amplitude and peak muscle thickness. The goal of this study was to determine the relationship between esophageal muscle thickness and contraction amplitude in patients with high-amplitude peristaltic and simultaneous contractions. Eleven patients with high-amplitude peristaltic contractions, 8 with diffuse esophageal spasm (DES), 7 with nonspecific (NS) motor disorder of the esophagus, and 10 normal subjects were studied using simultaneous pressure and ultrasound imaging. Pressure was recorded by manometry and ultrasound imaging with a high-frequency ultrasound probe catheter. Recordings were performed in the lower esophageal sphincter (LES) and at 2, 4, 6, 8, and 10 cm above the LES during resting state and swallow-induced contractions. Baseline esophageal muscle was thicker in the distal, compared with the proximal esophagus both in normal subjects and patient groups. Patients with DES and nutcracker esophagus (NC) have a higher baseline muscle thickness compared with normal and NS patients. Correlation between the peak pressure and the peak muscle thickness was weaker in patients with NC and DES compared with normal subjects and patients with NS. Whereas normal subjects have good correlation between delta (difference between peak and baseline) muscle thickness and peak pressures, this relationship was absent in patients with NC and DES. Increase in contraction amplitude in patients with NC and DES was associated with an increase in baseline thickness of esophageal muscularis propria. Increase in baseline thickness was specific to patients with spastic motor disorders and was not seen in patients with NS.
Stimulatory effects of bilirubin on amylase release from isolated rat pancreatic acini
Authors: Hirohata Yoshihide , Fujii Masatoshi , Okabayashi Yoshinori , Nagashio Yoshikuni , Tashiro Mitsuo , Imoto Issei , Akiyama Toshiharu , Otsuki Makoto
Published: March 2015

Considered to be an etiologic factor of acute pancreatitis, hypersecretion of pancreatic juice and digestive enzymes is often associated with hyperbilirubinemia. We explored the intracellular mechanisms through which bilirubin affects pancreatic exocrine secretory function by examining the effect of bilirubin on isolated rat pancreatic acini. Bilirubin stimulated amylase release in a concentration- and time-dependent manner, significantly increasing amylase release at concentrations >5 mg/100 ml and after 15 min of incubation. Coincubation of bilirubin with vasoactive intestinal polypeptide, 8-bromo-cAMP, or A-23187 had a synergistic effect on amylase release, whereas coincubation with CCK-8, carbamylcholine, or 12- O-tetradecanoylphorbol 13-acetate had an additive effect. Bilirubin did not affect acinar cAMP content or Ca2+efflux. Intracellular Ca2+pool depletion had no influence on bilirubin-evoked amylase release. The protein kinase C (PKC) inhibitors staurosporine and calphostin C partially but significantly inhibited bilirubin-stimulated amylase release, whereas the PKA inhibitor H-89 did not. The tyrosine kinase (TK) inhibitor genistein, phospholipase A2(PLA2) inhibitor indoxam, and PLC inhibitor U-73122 also inhibited amylase release. Bilirubin significantly translocated PKC activity from the cytosol to the membrane fraction and activated TK in cytosol and membrane fractions. These results indicate that bilirubin stimulates amylase release by activating PKC and TK in rat pancreatic acini and that PLC and PLA2partly mediate this process.
Curcumin attenuates DNB-induced murine colitis
Authors: Salh B. , Assi K. , Templeman V. , Parhar K. , Owen D. , Gómez-Muñoz A. , Jacobson K.
Published: March 2015

Numerous therapies used for inflammatory bowel disease (IBD) target the transcription factor NF-κB, which is involved in the production of cytokines and chemokines integral for inflammation. Here we show that curcumin, a component of the spice turmeric, is able to attenuate colitis in the dinitrobenzene sulfonic acid (DNB)-induced murine model of colitis. When given before the induction of colitis it reduced macroscopic damage scores and NF-κB activation. This was accompanied by a reduction in myeloperoxidase activity, and using semiquantitative RT-PCR, an attenuation of the DNB-induced message for IL-1β was detected. Western blotting analysis revealed that there was a reproducible DNB-induced activation of p38 MAPK detected in intestinal lysates by using a phosphospecific antibody. This signal was significantly attenuated by curcumin. Furthermore, we show that the immunohistochemical signal is dramatically attenuated at the level of the mucosa by curcumin. We conclude that the widely used food additive curcumin is able to attenuate experimental colitis through a mechanism correlated with the inhibition of the activation of NF-κB and effects a reduction in the activity of p38 MAPK. We propose that this agent may have therapeutic implications for human IBD.
Thrombin stimulates dissociation and induction of HSP27 via p38 MAPK in vascular smooth muscle cells
Authors: Hirade Kouseki , Kozawa Osamu , Tanabe Kumiko , Niwa Masayuki , Matsuno Hiroyuki , Oiso Yutaka , Akamatsu Shigeru , Ito Hidenori , Kato Kanefusa , Katagiri Yoshihiro , Uematsu Toshihiko
Published: March 2015

We investigated the effects of thrombin on the induction of heat shock proteins (HSP) 70 and 27, and the mechanism behind the induction in aortic smooth muscle A10 cells. Thrombin increased the level of HSP27 but had little effect on the level of HSP70. Thrombin stimulated the accumulation of HSP27 dose dependently between 0.01 and 1 U/ml and cycloheximide reduced the accumulation. Thrombin stimulated an increase in the level of HSP27 mRNA and actinomycin D suppressed the thrombin-increased mRNA level. Thrombin induced the phosphorylation of p38 mitogen-activated protein kinase (MAPK). The HSP27 accumulation by thrombin was reduced by SB-203580 and PD-169316 but not by SB-202474. SB-203580 and PD-169316 suppressed the thrombin-induced phosphorylation of p38 MAPK. SB-203580 reduced the thrombin-increased level of HSP27 mRNA. Dissociation of the aggregated HSP27 to the dissociated HSP27 was induced by thrombin. Dissociation was inhibited by SB-203580. Thrombin induced the phosphorylation of HSP27 and the phosphorylation was suppressed by SB-203580. These results indicate that thrombin stimulates not only the dissociation of HSP27 but also the induction of HSP27 via p38 MAPK activation in aortic smooth muscle cells.
Initiation and propagation of ectopic waves: insights from an in vitro model of ischemia-reperfusion injury
Authors: Arutunyan Ara , Swift Luther M. , Sarvazyan Narine
Published: March 2015

The objective of the present study was to directly visualize ectopic activity associated with ischemia-reperfusion and its progression to arrhythmia. To accomplish this goal, we employed a two-dimensional network of neonatal rat cardiomyocytes and a recently developed model of localized ischemia-reperfusion. Washout of the ischemia-like solution resulted in tachyarrhythmic episodes lasting 15–200 s. These episodes were preceded by the appearance of multiple ectopic sources and propagation of ectopic activity along the border of the former ischemic zone. The ectopic sources exhibited a slow rise in diastolic calcium, which disappeared upon return to the original pacing pattern. Border zone propagation of ectopic activity was followed by its escape into the surrounding control network, generating arrhythmias. Together, these observations suggest that upon reperfusion, a distinct layer, which consists of ectopically active, poorly coupled cells, is formed transiently over an injured area. Despite being neighbored by a conductive and excitable tissue, this transient functional layer is capable of sustaining autonomous waves and serving as a special conductive medium through which ectopic activity can propagate before spreading into the surrounding healthy tissue.
Targeting αvβ3 and α5β1 for gene delivery to proliferating VSMCs: synergistic effect of TGF-β1
Authors: Li Jian-Mei , Fan Lampson M. , Shah Ajay , Brooks Gavin
Published: March 2015

TGF-β1 levels increase after vascular injury and promote vascular smooth muscle cell (VSMC) proliferation. We define a nonviral gene delivery system that targets αvβ3 and α5β1 integrins that are expressed on proliferating VSMCs and strongly induced by TGF-β1. A 15-amino acid RGDNP-containing peptide from American Pit Viper venom was linked to a Lys(16) peptide as vector (molossin vector) and complexed with Lipofectamine or fusogenic peptide for delivery of luciferase or β-galactosidase reporter genes to primary cultures of human, rabbit, and rat VSMCs. Preincubation of VSMCs with TGF-β1 for 24 h, but not with PDGF-BB, interferon-γ, TNF-α, nor PMA, increased αvβ3 and α5β1 expressions on VSMCs and enhanced gene delivery of molossin vector. Thus β-galactosidase activity increased from 35 ± 5% (controls) to 75 ± 5% after TGF-β1 treatment, and luciferase activity increased fourfold over control values. Potential use of this system in vessel bypass surgery was examined in an ex vivo rat aortic organ culture model after endothelial damage. Molossin vector system delivered β-galactosidase to VSMCs in the vessel wall that remained for up to 12 days posttransfection. The molossin vector system, when combined with TGF-β1, enhances gene delivery to proliferating VSMCs and might have clinical applications for certain vasculoproliferative diseases.
Myocardial oxygenation and high-energy phosphate levels during KATP channel blockade
Authors: Zhang Jianyi , From Arthur H. L. , Ugurbil Kamil , Bache Robert J.
Published: March 2015

Inhibition of ATP-sensitive K+ (KATP) channel activity has previously been demonstrated to result in coronary vasoconstriction with decreased myocardial blood flow and loss of phosphocreatine (PCr). This study was performed to determine whether the high-energy phosphate abnormality during KATP channel blockade can be ascribed to oxygen insufficiency. Myocardial blood flow and oxygen extraction were measured in open-chest dogs during KATP channel blockade with intracoronary glibenclamide, whereas high-energy phosphates were examined with 31P magnetic resonance spectroscopy (MRS), and myocardial deoxymyoglobin (Mb-δ) was determined with 1H MRS. Glibenclamide resulted in a 20 ± 8% decrease of myocardial blood flow that was associated with a loss of phosphocreatine (PCr) and accumulation of inorganic phosphate. Mb-δ was undetectable during basal conditions but increased to 58 ± 5% of total myoglobin during glibenclamide administration. This degree of myoglobin desaturation during glibenclamide was far greater than we previously observed during a similar reduction of blood flow produced by a coronary stenosis (22% of myoglobin deoxygenated during stenosis). The findings suggest that reduction of coronary blood flow with an arterial stenosis was associated with a decrease of myocardial energy demands and that this response to hypoperfusion was inhibited by KATP channel blockade.
dl-3-Hydroxybutyrate administration prevents myocardial damage after coronary occlusion in rat hearts
Authors: Zou Zhitian , Sasaguri Shiro , Rajesh Katare Gopalrao , Suzuki Ryoko
Published: March 2015

To investigate the role of high concentrations of dl-3-hydroxybutyrate (DL-3-HB) in preventing heart damage after prolonged fasting, infarct size and the incidence of apoptosis caused by ischemia-reperfusion were determined in four groups of Wistar rats. Fed rats (±DL-3-HB group) and fasted rats (±DL-3-HB group) were subjected to 30 min of left coronary artery occlusion and 120 min of reperfusion. DL-3-HB was administered intravenously 60 min before the coronary artery occlusion. Infarct size, defined by triphenylyetrazolium chloride (TTC) staining, was reduced from 72 ± 3% (fed group), 75 ± 5% (fed + DL-3-HB group), and 70 ± 5% (fasting group), respectively, to 26 ± 4% ( P < 0.01 vs. fasting + DL-3-HB group). Apoptosis, as defined by single-stranded DNA staining, was significantly reduced in the subendocardial region in the fasting + DL-3-HB group (9 ± 2%) compared with the other groups (39 ± 6% in the fed group, 37 ± 5% in the fed + DL-3-HB group, and 34 ± 3% in the fasting group; P < 0.01). In addition, levels of ATP in the fasting + DL-3-HB group were significantly higher compared with other groups after 30 min of ischemia and 120 min of reperfusion ( P < 0.01). In conclusion, the present study demonstrates that high concentrations of DL-3-HB reduces myocardial infarction size and apoptosis induced by ischemia-reperfusion, possibly by providing increased energy substrate to the fasted rat myocardium.
Reverse flux through cardiac NADP+-isocitrate dehydrogenase under normoxia and ischemia
Authors: Comte Blandine , Vincent Geneviève , Bouchard Bertrand , Benderdour Mohamed , Des Rosiers Christine
Published: March 2015

Little is known about the role of mitochondrial NADP+-isocitrate dehydrogenase (NADP+-ICDH) in the heart, where this enzyme shows its highest expression and activity. We tested the hypothesis that in the heart, NADP+-ICDH operates in the reverse direction of the citric acid cycle (CAC) and thereby may contribute to the fine regulation of CAC activity (Sazanov and Jackson, FEBS Lett344: 109–116, 1994). We documented a reverse flux through this enzyme in rat hearts perfused with the medium-chain fatty acid octanoate using [U-13C5]glutamate and mass isotopomer analysis of tissue citrate (Comte et al., J Biol Chem 272: 26117–26124, 1997). In this study, we assessed the significance of our previous finding by perfusing hearts with long-chain fatty acids and tested the effects of changes in O2supply. We showed that under all of these conditions citrate was enriched in an isotopomer containing five13C atoms. This isotopomer can only be explained by substrate flux through reversal of the NADP+-ICDH reaction, which is evaluated at 3–7% of flux through citrate synthase. Small variations in reversal fluxes induced by low-flow ischemia that mimicked hibernation occurred despite major changes in contractile function and O2consumption of the heart as well as citrate and succinate release rates and tissue levels. Our data show a reverse flux through NADP+-ICDH and support its hypothesized role in the fine regulation of CAC activity in the normoxic and O2-deprived heart.
Inhibition of vascular ATP-sensitive K+channels does not affect reactive hyperemia in human forearm
Authors: Farouque H. M. Omar , Meredith Ian T.
Published: March 2015

The extent to which ATP-sensitive K+channels contribute to reactive hyperemia in humans is unresolved. We examined the role of ATP-sensitive K+channels in regulating reactive hyperemia induced by 5 min of forearm ischemia. Thirty-one healthy subjects had forearm blood flow measured with venous occlusion plethysmography. Reactive hyperemia could be reproducibly induced ( n = 9). The contribution of vascular ATP-sensitive K+channels to reactive hyperemia was determined by measuring forearm blood flow before and during brachial artery infusion of glibenclamide, an ATP-sensitive K+channel inhibitor ( n = 12). To document ATP-sensitive K+channel inhibition with glibenclamide, coinfusion with diazoxide, an ATP-sensitive K+channel opener, was undertaken ( n = 10). Glibenclamide did not significantly alter resting forearm blood flow or the initial and sustained phases of reactive hyperemia. However, glibenclamide attenuated the hyperemic response induced by diazoxide. These data suggest that ATP-sensitive K+channels do not play an important role in controlling forearm reactive hyperemia and that other mechanisms are active in this adaptive response.
Mechanics of the human femoral adventitia including the high-pressure response
Authors: Schulze-Bauer Christian A. J. , Regitnig Peter , Holzapfel Gerhard A.
Published: March 2015

Adventitial mechanics were studied on the basis of adventitial tube tests and associated stress analyses utilizing a thin-walled model. Inflation tests of 11 nonstenotic human femoral arteries (79.3 ± 8.2 yr, means ± SD) were performed during autopsy. Adventitial tubes were separated anatomically and underwent cyclic, quasistatic extension-inflation tests using physiological pressures and high pressures up to 100 kPa. Associated circumferential and axial stretches were typically <20%, indicating “adventitiosclerosis.” Adventitias behaved nearly elastically for both loading domains, demonstrating high tensile strengths (>1 MPa). The anisotropic and strongly nonlinear mechanical responses were represented appropriately by two-dimensional Fung-type stored-energy functions. At physiological pressure (13.3 kPa), adventitias carry ∼25% of the pressure load in situ, whereas their circumferential and axial stresses were similar to the total wall stresses (∼50 kPa in both directions), supporting a “uniform stress hypothesis.” At higher pressures, they became the mechanically predominant layer, carrying >50% of the pressure load. These significant load-carrying capabilities depended strongly on circumferential and axial in-vessel prestretches (mean values: 0.95 and 1.08). On the basis of these results, the mechanical role of the adventitia at physiological and hypertensive states and during balloon angioplasty was characterized.
Exercise pressor reflex in decerebrate and anesthetized rats
Authors: Hayashi Naoyuki
Published: March 2015

I investigated whether muscular contraction evokes cardiorespiratory increases (exercise pressor reflex) in α-chloralose- and chloral hydrate-anesthetized and precollicular, midcollicular, and postcollicular decerebrated rats. Mean arterial pressure (MAP), heart rate (HR), and minute ventilation (V˙e) were recorded before and during 1-min sciatic nerve stimulation, which induced static contraction of the triceps surae muscles, and during 1-min stretch of the calcaneal tendon, which selectively stimulated mechanosensitive receptors in the muscles. Anesthetized rats showed various patterns of MAP response to both stimuli, i.e., biphasic, depressor, pressor, and no response. Sciatic nerve stimulation to muscle in precollicular decerebrated rats always evoked spontaneous running, so the exercise pressor reflex was not determined from these preparations. None of the postcollicular decerebrated rats showed a MAP response or spontaneous running. Midcollicular decerebrated rats consistently showed biphasic blood pressure response to both stimulations. The increases in MAP, HR, and V˙e were related to the tension developed. The static contractions in midcollicular decerebrated rats (381 ± 65 g developed tension) significantly increased MAP, HR, andV˙e from 103 ± 12 to 119 ± 24 mmHg, from 386 ± 30 to 406 ± 83 beats/min, and from 122 ± 7 to 133 ± 25 ml/min, respectively. After paralysis, sciatic nerve stimulation had no effect on MAP, HR, or V˙e. These results indicate that the midcollicular decerebrated rat can be a model for the study of the exercise pressor reflex.
Myocardial fibrosis blunts nitric oxide synthase-related preload reserve in human dilated cardiomyopathy
Authors: Bronzwaer Jean G. F. , Heymes Christophe , Visser Cees A. , Paulus Walter J.
Published: March 2015

The purpose of the study was to investigate interactions between myocardial nitric oxide synthase (NOS) and myocardial fibrosis, both of which determine left ventricular (LV) preload reserve in patients with nonischemic dilated cardiomyopathy (DCM). In previous animal experiments, chronic inhibition of NOS induced myocardial fibrosis and limited LV preload reserve. Twenty-eight DCM patients underwent LV catheterization, balloon caval occlusions (BCO; n = 8), intracoronary substance P infusion ( n = 8), and procurement of LV endomyocardial biopsies for determinations of collagen volume fraction (CVF), of gene expression of NOS2, NOS3, heme oxygenase (HO)-1, and TNF-α, and of NOS2 protein. CVF was unrelated to the intensity of NOS2, NOS3, HO-1, or TNF-α gene expression or of NOS2 protein expression. Preload recruitable LV stroke work (PR-LVSW) correlated directly with NOS2 gene expression ( P = 0.001) and inversely with CVF ( P = 0.04). High CVF (>10%) reduced baseline LVSW and PR-LVSW at each level of NOS2 gene expression. In DCM, myocardial fibrosis is unrelated to the intensity of myocardial gene expression of NOS, antioxidative enzymes (HO-1), or cytokines (TNF-α) and blunts NOS2-related recruitment of LV preload reserve.