bluuebunny/crossref_metadata_2025 huggingface dataset:
NON-BREAKABLE DATA ENCRYPTION WITH CLASSICAL INFORMATION
Authors: KISH LASZLO B. , SETHURAMAN SWAMINATHAN
Published: July 2004

Secure encryption of data is one of the most important parts of information technology and major concern of data security, military, defense and homeland security applications. The main aim of the paper is to propose a new way of approach to encryption. We propose a new possible approach [1] to encryption, which could be a fast, simple, inexpensive, robust, flexible, and mobile way of data encryption for absolutely secure data transmission by using classical digital information. The Eavesdropper is allowed to know the received signal thus the method has a higher level of protection than that of quantum encryption. Factorization algorithms do not help to break the code. Proper scrambling operators, which are necessary for the method, are study of current research.
FLUCTUATIONS OF OPTICAL AND ELECTRICAL PARAMETERS OF DISTRIBUTED FEEDBACK LASERS AND THEIR RELIABILITY
Authors: PRALGAUSKAITE S. , PALENSKIS V. , MATUKAS J.
Published: July 2004

Comprehensive experimental optical and electrical noises and their mutual correlation factor characteristic investigations of distributed feedback (DFB) InGaAsP / InP multiple-quantum well laser diodes (LDs) are presented. At the lasing operation, both optical and electrical noises of DFB LDs are 1/f type and are caused by the defects. Worse operation characteristics and short lifetime of some LDs are caused by the presence of defects in the interfaces with the active region. These defects increase leakage that leads to the larger LD threshold; and, during the ageing, they migrate, form clusters and deteriorate the laser characteristics. Noise characteristics (especially the correlation factor between optical and electrical fluctuations at the threshold) have been found to be suitable for semiconductor lasers quality and reliability prediction.
Phosphatidylinositol 3-kinase regulates Ca2+signaling in pancreatic acinar cells through inhibition of sarco(endo)plasmic reticulum Ca2+-ATPase
Authors: Fischer L. , Gukovskaya A. S. , Young S. H. , Gukovsky I. , Lugea A. , Buechler P. , Penninger J. M. , Friess H. , Pandol S. J.
Published: July 2004

Calcium is a key mediator of hormone-induced enzyme secretion in pancreatic acinar cells. At the same time, abnormal Ca2+responses are associated with pancreatitis. We have recently shown that inhibition of phosphatidylinositol 3-kinase (PI3-kinase) by LY-294002 and wortmannin, as well as genetic deletion of PI3-kinase-γ, regulates Ca2+responses and the Ca2+-sensitive trypsinogen activation in pancreatic acinar cells. The present study sought to determine the mechanisms of PI3-kinase involvement in Ca2+responses induced in these cells by CCK and carbachol. The PI3-kinase inhibitors inhibited both Ca2+influx and mobilization from intracellular stores induced by stimulation of acini with physiological and pathological concentrations of CCK, as well as with carbachol. PI3-kinase inhibition facilitated the decay of cytosolic free Ca2+concentration ([Ca2+]i) oscillations observed in individual acinar cells. The PI3-kinase inhibitors decreased neither CCK-induced inositol 1,4,5-trisphosphate [Ins( 1 , 4 , 5 )P3] production nor Ins( 1 , 4 , 5 )P3-induced Ca2+mobilization, suggesting that the effect of PI3-kinase inhibition is not through Ins( 1 , 4 , 5 )P3or Ins( 1 , 4 , 5 )P3receptors. PI3-kinase inhibition did not affect Ca2+mobilization induced by thapsigargin, a specific inhibitor of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA). Moreover, SERCA blockade with thapsigargin abolished the effects of pharmacological and genetic PI3-kinase inhibition on [Ca2+]isignals, suggesting SERCA as a downstream target of PI3-kinase. Both pharmacological PI3-kinase inhibition and genetic deletion of PI3-kinase-γ increased the amount of Ca2+in intracellular stores during CCK stimulation. Finally, addition of the PI3-kinase product phosphatidylinositol 3,4,5-trisphosphate to permeabilized acini significantly attenuated Ca2+reloading into the endoplasmic reticulum. The results indicate that PI3-kinase regulates Ca2+signaling in pancreatic acinar cells through its inhibitory effect on SERCA.
Orexin-A does not stimulate food intake in old rats
Authors: Takano Saeko , Kanai Setsuko , Hosoya Hiroko , Ohta Minoru , Uematsu Hiroshi , Miyasaka Kyoko
Published: July 2004

Aging is associated with a progressive decrease in appetite and food intake. Both A and B orexins, expressed in specific neurons of the lateral hypothalamic area, have been implicated in the regulation of sleep and feeding. In this study, the stimulatory effect of intracerebroventricular administration of the orexins on food intake was compared between young (4-mo-old) and old (25- to 27-mo-old) male Wistar rats. A stainless steel cannula was implanted stereotactically into the left lateral ventricle. After a 7-day recovery period, different doses (0–30 nmol) of orexins were injected into the left lateral ventricle without anesthesia. Food and water consumptions were measured at 1, 2, and 4 h after injection. The protein levels of orexin receptors, a specific receptor for orexin-A (OX1R) and a receptor for both orexin-A and -B (OX2R), in the hypothalamus were determined by Western blot analysis and compared between young and old rats. Intracerebroventricular administration of orexin-A stimulated food intake in a dose-dependent manner in young rats. However, no effects were observed at any dose in old rats. The protein level of OX1R in the hypothalamus was significantly lower in old rats than in young rats, although the protein level of OX2R was comparable between groups. Results of the present study indicate that the function of the orexin system is diminished in old rats. The decrease in the OX1R protein level in the hypothalamus could be responsible for orexin-A's lack of stimulation of food intake in old rats.
Protein kinase C-α-induced hypertrophy of neonatal rat ventricular myocytes
Authors: Vijayan Kalpana , Szotek Erika L. , Martin Jody L. , Samarel Allen M.
Published: July 2004

Protein kinase C (PKC) isoenzymes play a critical role in cardiomyocyte hypertrophy. At least three different phorbol ester-sensitive PKC isoenzymes are expressed in neonatal rat ventricular myocytes (NRVMs): PKC-α, -δ, and -ε. Using replication-defective adenoviruses (AdVs) that express wild-type (WT) and dominant-negative (DN) PKC-α together with phorbol myristate acetate (PMA), which is a hypertrophic agonist and activator of all three PKC isoenzymes, we studied the role of PKC-α in signaling-specific aspects of the hypertrophic phenotype. PMA induced nuclear translocation of endogenous and AdV-WT PKC-α in NRVMs. WT PKC-α overexpression increased protein synthesis and the protein-to-DNA (P/D) ratio but did not affect cell surface area (CSA) or cell shape compared with uninfected or control AdV β-galactosidase (AdV βgal)-infected cells. PMA-treated uninfected cells displayed increased protein synthesis, P/D ratio, and CSA and elongated morphology. PMA did not further enhance protein synthesis or P/D ratio in AdV-WT PKC-α-infected cells. To assess the requirement of PKC-α for these PMA-induced changes, AdV-DN PKC-α or AdV βgal-infected NRVMs were stimulated with PMA. Without PMA, AdV-DN PKC-α had no effects on protein synthesis, P/D ratio, CSA, or shape vs. AdV βgal-infected NRVMs. PMA increased protein synthesis, P/D ratio, and CSA in AdV βgal-infected cells, but these parameters were significantly reduced in PMA-stimulated AdV-DN PKC-α-infected NRVMs. Overexpression of DN PKC-α enhanced PMA-induced cell elongation. Neither WT PKC-α nor DN PKC-α affected atrial natriuretic factor gene expression. Insulin-like growth factor-1 also induced nuclear translocation of endogenous PKC-α. PMA but not WT PKC-α overexpression induced ERK1/2 activation. However, AdV-DN PKC-α partially blocked PMA-induced ERK activation. Thus PKC-α is necessary for certain aspects of PMA-induced NRVM hypertrophy.
Decreased cardiac mitochondrial NADP+-isocitrate dehydrogenase activity and expression: a marker of oxidative stress in hypertrophy development
Authors: Benderdour Mohamed , Charron Guy , Comte Blandine , Ayoub Riwa , Beaudry Diane , Foisy Sylvain , deBlois Denis , Des Rosiers Christine
Published: July 2004

Mitochondrial dysfunction subsequent to increased oxidative stress and alterations in energy metabolism is considered to play a role in the development of cardiac hypertrophy and its progression to failure, although the sequence of events remains to be elucidated. This study aimed at characterizing the impact of hypertrophy development on the activity and expression of mitochondrial NADP+-isocitrate dehydrogenase (mNADP+-ICDH), a metabolic enzyme that controls redox and energy status. We expanded on our previous finding of its inactivation through posttranslational modification by the lipid peroxidation product 4-hydroxynonenal (HNE) in 7-wk-old spontaneously hypertensive rat (SHR) hearts before hypertrophy development (Benderdour et al. J Biol Chem 278: 45154–45159, 2003). In this study, we used 7-, 15-, and 30-wk-old SHR and Sprague-Dawley (SD) rats with abdominal aortic coarctation. Compared with age-matched control Wistar-Kyoto (WKY) rats, SHR hearts showed a significant 25% decrease of mNADP+-ICDH activity, which preceded in time 1) the decline in its protein and mRNA expression levels (between 10% and 35%) and 2) the increase in hypertrophy markers. The chronic and persistent loss of mNADP+-ICDH activity in SHR was associated with enhanced tissue accumulation of HNE-mNADP+-ICDH and total HNE-protein adducts at all ages and contrasted with the profile of changes in the activity of other mitochondrial enzymes involved in antioxidant or energy metabolism. Two-way ANOVA of the data also revealed a significant effect of age on most parameters measured in SHR and WKY hearts. The mNADP+-ICDH activity, protein, and mRNA expression were reduced between 25% and 35% in coarctated SD rats and were normalized by treatment of SHR or coarctated SD rats with renin-angiotensin system inhibitors, which prevented or attenuated hypertrophy. Altogether, our data show that cardiac mNADP+-ICDH activity and expression are differentially and sequentially affected in hypertrophy development and, to a lesser extent, with aging. Decreased cardiac mNADP+-ICDH activity, which is attributed at least in part to HNE adduct formation, appears to be a relevant early and persistent marker of mitochondrial oxidative stress-related alterations in hypertrophy development. Potentially, this could also contribute to the aetiology of cardiomyopathy.
Heterogeneity of action potential durations in isolated mouse left and right atria recorded using voltage-sensitive dye mapping
Authors: Nygren Anders , Lomax Alan E. , Giles Wayne R.
Published: July 2004

An imaging system for di-4-ANEPPS (4-[β-[2-(di- n-butylamino)-6-naphthylvinyl]pyridinium]) voltage-sensitive dye recordings has been adapted for recording from an in vitro mouse heart preparation that consists of both atria in isolation. This approach has been used to study inter- and intra-atrial activation and conduction and to monitor action potential durations (APDs) in the left and right atrium. The findings from this study confirm some of our previous findings in isolated mouse atrial myocytes and demonstrate that many electrophysiological properties of mouse atria closely resemble those of larger mammals. Specifically, we made the following observations: 1) Activation in mouse atria originates in the sinoatrial node and spreads into the right atrium and, after a delay, into the left atrium. 2) APD in the left atrium is shorter than in the right atrium. 3) Sites in the posterior walls have longer APDs than sites in the atrial appendages. 4) Superfusion of this preparation with 4-aminopyridine and tetraethylammonium resulted in increases in APD, consistent with their inhibitory effects on the K+ currents known to be expressed in mouse atria. 5) The muscarinic agonist carbachol shortened APD in all areas of the preparation, except the left atrial appendage, in which carbachol had no statistically significant effect on APD. These results validate a new approach for monitoring activation, conduction, and repolarization in mouse atria and demonstrate that the physiological and pharmacological properties of mouse atria are sufficiently similar to those of larger animals to warrant further studies using this preparation.
Time course of changes in collateral blood flow and isolated vessel size and gene expression after femoral artery occlusion in rats
Authors: Prior Barry M. , Lloyd Pamela G. , Ren Jie , Li Han , Yang H. T. , Laughlin M. Harold , Terjung Ronald L.
Published: July 2004

The objectives of this study were to assess the time course of enlargement and gene expression of a collateral vessel that enlarges following occlusion of the femoral artery and to relate these responses to the increases in collateral-dependent blood flow to the calf muscles in vivo. We employed exercise training to stimulate collateral vessel development. Rats were exercise trained or kept sedentary for various times of up to 25 days postbilateral occlusion ( n = ∼9/time point). Collateral blood flow to the calf muscles, determined with microspheres, increased modestly over the first few days to ∼40 ml·min−1·100 g−1 in sedentary animals; the increase continued over time to ∼80 ml·min−1·100 g−1 in the trained animals. Diameters of the isolated collateral vessels increased progressively over time, whereas an increased vessel compliance observed at low pressures was similar across time. These responses were greater in the trained animals. The time course of upregulation of vascular endotheial growth factor and placental growth factor, and particularly endothelial nitric oxide synthase and fms-like tyrosine kinase 1, mRNAs in the isolated collateral vessel implicates these factors as integral to the arteriogenic process. Collateral vessel enlargement and increased compliance at low pressures contribute to the enlarged circuit available for collateral blood flow. However, modulation of the functioning collateral vessel diameter, by smooth muscle tone, must occur to account for the observed increases in collateral blood flow measured in vivo.
FKBP12.6 overexpression decreases Ca2+ spark amplitude but enhances [Ca2+]i transient in rat cardiac myocytes
Authors: Gómez Ana M. , Schuster Iris , Fauconnier Jérémy , Prestle Jürgen , Hasenfuss Gerd , Richard Sylvain
Published: July 2004

Ryanodine receptors/Ca2+-release channels (RyR2) from the sarcoplasmic reticulum (SR) provide the Ca2+ required for contraction at each cardiac twitch. RyR2 are regulated by a variety of proteins, including the immunophilin FK506 binding protein (FKBP12.6). FKBP12.6 seems to be important for coupled gating of RyR2 and its deficit and alteration may be involved in heart failure. The role of FKBP12.6 on Ca2+ release has not been analyzed directly, but rather it was inferred from the effects of immunophilins, such us FK506 and rapamycin, which, among other effects, dissociates FKBP12.6 from the RyR2. Here, we investigated directly the effects of FKBP12.6 on local (Ca2+ sparks) and global {intracellular Ca2+ concentration ([Ca2+]i) transients} Ca2+ release in single rat cardiac myocytes. The FKBP12.6 gene was transfected in single myocytes using the adenovirus technique with a reporter gene strategy based on green fluorescent protein (GFP) to check out the success of transfections. Control myocytes were transfected with only GFP (Ad-GFP). Rhod-2 was used as the Ca2+ indicator, and cells were viewed with a confocal microscope. We found that overexpression of FKBP12.6 decreases the occurrence, amplitude, duration, and width of spontaneous Ca2+ sparks. FK506 had diametrically opposed effects. However, overexpression of FKBP12.6 increased the [Ca2+]i transient amplitude and accelerated its decay in field-stimulated cells. The associated cell shortening was increased. SR Ca2+ load, estimated by rapid caffeine application, was increased. In conclusion, FKBP12.6 overexpression decreases spontaneous Ca2+ sparks but increases [Ca2+]i transients, in relation with enhanced SR Ca2+ load, therefore improving excitation-contraction coupling.
Biphasic modulation of vascular nitric oxide catabolism by oxygen
Authors: Liu Xiaoping , Cheng Crystal , Zorko Nicholas , Cronin Scott , Chen Yeong-Renn , Zweier Jay L.
Published: July 2004

Endothelium-derived nitric oxide (NO) plays an important role in the regulation of vascular tone. Lack of NO bioavailability can result in cardiovascular disease. NO bioavailability is determined by its rates of generation and catabolism; however, it is not known how the NO catabolism rate is regulated in the vascular wall under normoxic, hypoxic, and anaerobic conditions. To investigate NO catabolism under different oxygen concentrations, studies of NO and O2consumption by the isolated rat aorta were performed using electrochemical sensors. Under normoxic conditions, the rate of NO consumption in solution was enhanced in the presence of the rat aorta. Under hypoxic conditions, NO consumption decreased in parallel with the O2concentration. Like the inhibition of mitochondrial respiration by NO, the inhibitory effects of NO on aortic O2consumption increased as O2concentration decreased. Under anaerobic conditions, however, a paradoxical reacceleration of NO consumption occurred. This increased anaerobic NO consumption was inhibited by the cytochrome c oxidase inhibitor NaCN but not by the free iron chelator deferoxamine, the flavoprotein inhibitor diphenylene iodonium (10 μM), or superoxide dismutase (200 U/ml). The effect of O2on the NO consumption could be reproduced by purified cytochrome c oxidase (CcO), implying that CcO is involved in aortic NO catabolism. This reduced NO catabolism at low O2tensions supports the maintenance of effective NO levels in the vascular wall, reducing the resistance of blood vessels. The increased anaerobic NO catabolism may be important for removing excess NO accumulation in ischemic tissues.
Increase of PTP levels in vascular injury and in cultured aortic smooth muscle cells treated with specific growth factors
Authors: Chang Yingzi , Zhuang Daming , Zhang Chunxiang , Hassid Aviv
Published: July 2004

Migration and proliferation of vascular smooth muscle cells are key events in injury-induced neointima formation. Several growth factors and ANG II are thought to be involved in neointima formation. A recent report indicated that vascular injury is associated with increased mRNA levels of protein tyrosine phosphatase (PTP)-1B (PTP-1B). In the present study, we tested the following hypotheses: 1) rat carotid artery injury induces the expression of PTP-1B, Src homology-2 domain phosphatase (SHP-2), and PTP-proline, glutamate, serine, and threonine sequence (PEST) protein; and 2) polypeptide growth factors as well as ANG II increase the levels of tyrosine phosphatases in cultured rat aortic smooth muscle cells. We found that vascular injury induced by balloon catheter increases the protein levels of aforementioned phosphatases and that these effects occur in a PTP specific, as well as temporally and regionally specific, manner. Moreover, treatment of cultured primary rat aortic smooth muscle cells with PDGF or bFGF, but not with IGF1, EGF, or ANG II, increases PTP-1B, SHP-2, and PTP-PEST protein levels. These results suggest that increased PDGF and bFGF levels, occurring after vascular injury, may induce expression of several PTPs.
cAMP protects endothelial barrier functions by preventing Rac-1 inhibition
Authors: Waschke J. , Drenckhahn D. , Adamson R. H. , Barth H. , Curry F. E.
Published: July 2004

cAMP enhances endothelial barrier properties and is protective against various inflammatory mediators both in vivo and in vitro. However, the mechanisms whereby cAMP stabilizes the endothelial barrier are largely unknown. Recently we demonstrated that the Rho family GTPase Rac-1 is required for maintenance of endothelial barrier functions in vivo and in vitro. Therefore, in the present study we investigated the effect of forskolin (5 μM)- and rolipram (10 μM)-induced cAMP increase on reduction of barrier functions in response to Rac-1 inhibition by Clostridium sordellii lethal toxin (LT). Forskolin and rolipram treatment blocked LT (200 ng/ml)-induced hydraulic conductivity ( Lp) increase in mesenteric microvessels in vivo. Likewise, LT-induced intercellular gap formation in monolayers of cultured microvascular myocardial endothelial (MyEnd) cells and LT-induced loss of adhesion of vascular endothelial cadherin-coated microbeads were abolished. Inhibition of PKA by myristoylated inhibitor peptide (14–22) of PKA (100 μM) reduced the protective effect of cAMP on LT-induced Lpincrease in vivo and gap formation in vitro, indicating that the effect of cAMP on Rac-1 inhibition was PKA dependent. Glucosylation assays demonstrated that cAMP prevents inhibitory Rac-1 glucosylation by LT, indicating that one way that cAMP enhances endothelial barrier functions may be by regulating Rac-1 signaling. Our study suggests that cAMP may provide its well-established protective effects at least in part by regulation of Rho proteins.
Combined NO and PG inhibition augments α-adrenergic vasoconstriction in contracting human skeletal muscle
Authors: Dinenno Frank A. , Joyner Michael J.
Published: July 2004

Sympathetic α-adrenergic vasoconstrictor responses are blunted in the vascular beds of contracting muscle (functional sympatholysis). We tested the hypothesis that combined inhibition of nitric oxide (NO) and prostaglandins (PGs) restores sympathetic vasoconstriction in contracting human muscle. We measured forearm blood flow via Doppler ultrasound and calculated the reduction in forearm vascular conductance in response to α-adrenergic receptor stimulation during rhythmic handgrip exercise (6.4 kg) and during a control nonexercise vasodilator condition (using intra-arterial adenosine) before and after combined local inhibition of NO synthase (NOS; via NG-nitro-l-arginine methyl ester) and cyclooxygenase (via ketorolac) in healthy men. Before combined inhibition of NO and PGs, the forearm vasoconstrictor responses to intra-arterial tyramine (which evoked endogenous noradrenaline release), phenylephrine (a selective α1-agonist), and clonidine (an α2-agonist) were significantly blunted during exercise compared with adenosine treatment. After combined inhibition of NO and PGs, the vasoconstrictor responses to all α-adrenergic receptor stimuli were augmented by ∼10% in contracting muscle ( P < 0.05), whereas the responses to phenylephrine and clonidine were also augmented by ∼10% during passive vasodilation in resting muscle ( P < 0.05). In six additional subjects, PG inhibition alone did not alter the vasoconstrictor responses in resting or contracting muscles. Thus in light of our previous findings, it appears that inhibition of either NO or PGs alone does not affect functional sympatholysis in healthy humans. However, the results from the present study indicate that combined inhibition of NO and PGs augments α-adrenergic vasoconstriction in contracting muscle but does not completely restore the vasoconstrictor responses compared with those observed during passive vasodilation in resting muscle.
Cardiotrophin-1 alters airway smooth muscle structure and mechanical properties in airway explants
Authors: Zheng Xueyan , Zhou Danyi , Seow Chun Y. , Bai Tony R
Published: July 2004

Induction of hypertrophy and inhibition of apoptosis may be important mechanisms contributing to increased airway smooth muscle (ASM) mass in asthma. Data from our laboratory indicate that cardiotrophin-1 (CT-1) induces hypertrophy and inhibits apoptosis in isolated human ASM cells. To determine whether these novel effects of CT-1 also occur in the airway tissue milieu and to determine whether structural changes are accompanied by functional changes, matched pairs of guinea pig airway explants were treated with or without CT-1 for 7 days, and structural features as well as isometric and isotonic contractile and relaxant mechanical properties were measured. CT-1 (0.2–5 ng/ml) increased both myocyte mass and extracellular matrix in a concentration-dependent fashion. CT-1 (10 ng/ml)-treated tissues exhibited a significant increase in passive tension at all lengths on day 7; at optimal length, passive tension generated by CT-1-treated tissues was 1.72 ± 0.12 vs. 1.0 ± 0.1 g for control. Maximal isometric stress was decreased in the CT-1-treated group on day 7 (0.39 ± 0.10 kg/cm2) vs. control (0.77 ± 0.15 kg/cm2, P < 0.05). Isoproterenol-induced relaxant potency was reduced in CT-1-treated tissues, log EC50 being −7.28 ± 0.34 vs. −8.12 ± 0.25 M in control, P < 0.05. These data indicate that CT-1 alters ASM structural and mechanical properties in the tissue environment and suggest that structural changes found in the airway wall in asthma are not necessarily associated with increased responsiveness.
Exaggerated IL-8 and IL-6 responses to TNF-α by parainfluenza virus type 4-infected NCI-H292 cells
Authors: Roger Thierry , Bresser Paul , Snoek Mieke , van der Sluijs Koen , van den Berg Arjen , Nijhuis Monique , Jansen Henk M. , Lutter René
Published: July 2004

Respiratory viruses induce and potentiate airway inflammation, which is related to the induction of proinflammatory mediators such as interleukin (IL)-8 and IL-6. Here we report on mechanisms implicated in IL-8 and IL-6 production by airway epithelium-like NCI-H292 cells exposed to parainfluenza virus type 4a (PIV-4). PIV-4 readily infected NCI-H292 cells as reflected by intracellular PIV-4 antigen expression. PIV-4 infection triggered a biphasic IL-8 and IL-6 mRNA response. Transient transfection with truncated and mutated promoter constructs identified NF-κB and activator protein (AP)-1, and CCAAT-enhancer binding protein (C/EBP) as the relevant transcription factors for PIV-4-induced IL-8 and IL-6 gene transcription, respectively. An increase of DNA-binding activities for NF-κB and C/EBP paralleled the induction of the first and second IL-8 and IL-6 mRNA peaks, whereas the onset of AP-1 paralleled the first IL-8 mRNA peak only. The second mRNA peak, apparently dependent on viral replication, coincided also with a marked reduction of IL-8 and IL-6 mRNA degradation. Importantly, cells at the time of the reduced mRNA degradation displayed an exaggerated IL-8 and IL-6 protein production to a secondary stimulus, as exemplified by steeper dose-response curves to TNF-α. Thus PIV-4 infection enhances epithelial IL-8 and IL-6 production by transcriptional and posttranscriptional mechanisms. The previously unrecognized phase of reduced IL-8 and IL-6 mRNA degradation and the concurrent amplified epithelial IL-8 and IL-6 responses may play an important role in virus-induced potentiation of airway inflammation.
Rat brain and liver mitochondria develop oxidative stress and lose enzymatic activities on aging
Authors: Navarro Ana , Boveris Alberto
Published: July 2004

The mitochondrial mass of rat brain and liver remained unchanged on aging in young adults, old adults, and senescent animals (28, 60, and 92 wk of age); the values were 15–17 and 29–31 mg protein/g for brain and liver, respectively. The whole aging process was associated with an increased content of the oxidation products, thiobarbituric acid-reactive substances and protein carbonyls, by 61–69% in brain and 36–45% in liver, respectively. The activities of critical enzymes for mitochondrial function, mitochondrial nitric oxide synthase, Mn-superoxide dismutase, complex I, and complex IV, decreased progressively during aging with activity losses of 73, 37, 29, and 28%, respectively, in the brain and 47, 46, 30, and 24% in the liver of senescent rats compared with young adults. Brain mitochondria isolated from aged rats showed increased mitochondrial fragility, as assayed by mitochondrial marker enzyme activities in the postmitochondrial supernatant, and increased volume and water permeability, as assayed by light scattering. Liver mitochondria isolated from young and old rats did not show differences in fragility and water permeability. A subpopulation of brain mitochondria with increased size and fragility was differentiated in aging rats, whereas liver showed a homogeneous mitochondrial population.
Leptin action is modified by an interaction between dietary fat content and ambient temperature
Authors: Haltiner Andrea L. , Mitchell Tiffany D. , Harris Ruth B. S.
Published: July 2004

Mice adapted to a high-fat diet are reported to be leptin resistant; however, we previously reported that mice fed a high-fat (HF) diet and housed at 23°C remained sensitive to peripheral leptin and specifically lost body fat. This study tested whether leptin action was impaired by a combination of elevated environmental temperature and a HF diet. Male C57BL/6 mice were adapted to low-fat (LF) or HF diet from 10 days of age and were housed at 27°C from 28 days of age. From 35 days of age, baseline food intake and body weight were recorded for 1 wk and then mice on each diet were infused with 10 μg leptin/day or PBS from an intraperitoneal miniosmotic pump for 13 days. HF-fed mice had a higher energy intake than LF-fed mice and were heavier but not fatter. Serum leptin was lower in PBS-infused HF- than LF-fed mice. Leptin significantly inhibited energy intake of both LF-fed and HF-fed mice, and this was associated with a significant increase in hypothalamic long-form leptin receptors with no change in short-form leptin receptor or brown fat uncoupling protein-1 mRNA expression. Leptin significantly inhibited weight gain in both LF- and HF-fed mice but reduced the percentage of body fat mass only in LF-fed mice. The percentage of lean and fat tissue in HF-fed mice did not change, implying that overall growth had been inhibited. These results suggest that dietary fat modifies the mechanisms responsible for leptin-induced changes in body fat content and that those in HF-fed mice are sensitive to environmental temperature.
Quantitative assessment of hemoglobin-induced endothelial barrier dysfunction
Authors: Dull Randal O. , DeWitt Bracken J. , Dinavahi Ramani , Schwartz Larry , Hubert Christopher , Pace Nathan , Fronticelli Clara
Published: July 2004

Hemoglobin (Hb)-based O2 carriers (HBOC) are undergoing extensive development as potential “blood substitutes.” A major problem associated with these molecules is an increase in microvascular permeability and peripheral vascular resistance. In this paper, we utilized bovine lung microvascular endothelial cell monolayers and simultaneously measured Hb-induced changes in transendothelial electrical resistance, diffusive albumin permeability, and diffusive Hb permeability ( PDH) for three forms of Hb: natural tetrameric human Hb-A and two polymerized recombinant HBOCs containing α-human and β-bovine chains designated Hb-Polytaur (molecular mass: 500 kDa) and Hb-(Polytaur)n (molecular mass: ∼1,000,000 Da), respectively. Hb-Polytaur and Hb-(Polytaur)n are being evaluated for clinical use as HBOCs. All three Hb molecules induce a rapid decline of transendothelial electrical resistance to 30% of baseline. Diffusive albumin permeabiltiy increases, on average, approximately ninefold (2.78 × 10−7 vs. 2.47 × 10−6 cm/s) in response to Hb exposure. All three Hb molecules induce an increase in their own permeability, a process that we have called Hb-induced Hb permeability. The magnitude of change of PDH is also related to Hb size. When PDH is corrected for the diffusive coefficient for each Hb species, no evidence of restricted diffusion is found. Immunofluorescent images demonstrate Hb-induced actin stress fiber formation and large intercellular gaps. These data provide the first quantitative assessment of the effect of polymerized HBOC on their own diffusion rates over time. We discuss the importance of these findings in terms of Hb extravasation rates, molecular sieving, and clinical consequences of HBOC use.
Respiratory response to passive limb movement is suppressed by a cognitive task
Authors: Bell Harold J. , Duffin James
Published: July 2004

Feedback from muscles stimulates ventilation at the onset of passive movement. We hypothesized that central neural activity via a cognitive task source would interact with afferent feedback, and we tested this hypothesis by examining the fast changes in ventilation at the transition from rest to passive leg movement, under two conditions: 1) no task and 2) solving a computer-based puzzle. Resting breathing was greater in condition 2 than in condition 1, evidenced by an increase in mean ± SE breathing frequency (18.2 ± 1.1 vs. 15.0 ± 1.2 breaths/min, P = 0.004) and ventilation (10.93 ± 1.16 vs. 9.11 ± 1.17 l/min, P < 0.001). In condition 1, the onset of passive movement produced a fast increase in mean ± SE breathing frequency (change of 2.9 ± 0.4 breaths/min, P < 0.001), tidal volume (change of 233 ± 95 ml, P < 0.001), and ventilation (change of 6.00 ± 1.76 l/min, P < 0.001). However, in condition 2, the onset of passive movement only produced a fast increase in mean ± SE breathing frequency (change of 1.3 ± 0.4 breaths/min, P = 0.045), significantly smaller than in condition 1 ( P = 0.007). These findings provide evidence for an interaction between central neural cognitive activity and the afferent feedback mechanism, and we conclude that the performance of a cognitive task suppresses the respiratory response to passive movement.
Passive triceps surae stretch inhibits vasoconstriction in the nonexercised limb during posthandgrip muscle ischemia
Authors: Tokizawa Ken , Mizuno Masaki , Nakamura Yoshio , Muraoka Isao
Published: July 2004

We investigated whether selective muscle mechanoreceptor activation in the lower limb opposes arm muscle metaboreceptor activation-mediated limb vasoconstriction. Seven subjects completed two trials: one control trial and one stretch trial. Both trials included 2 min of handgrip and 2 min of posthandgrip exercise muscle ischemia (PEMI). In the stretch trial, a 2-min sustained triceps surae stretch, by brief passive dorsiflexion of the right foot, was performed simultaneously during PEMI. Mean arterial pressure, heart rate, and forearm blood flow (FBF) in the nonexercised arm and forearm vascular conductance (FVC) in the nonexercised arm were measured. During PEMI in the control trial, mean arterial pressure was significantly greater and FBF and FVC were significantly lower than baseline values ( P < 0.05 for each). In contrast, FBF and FVC during PEMI in the stretch trial exhibited different responses than in the control trial. FBF and FVC were significantly greater in the stretch trial than in the control trial (FBF, 5.5 ± 0.4 vs. 3.8 ± 0.4 ml·100 ml−1·min−1; FVC, 0.048 ± 0.004 vs. 0.033 ± 0.003 unit, respectively; P < 0.05). These results indicate that passive triceps surae stretch can inhibit vasoconstriction in the nonexercised forearm mediated via muscle metaboreceptor activation in the exercised arm.
Cellular distribution of GPR14 and the positive inotropic role of urotensin II in the myocardium in adult rat
Authors: Gong Hui , Wang Yan-Xia , Zhu Yi-Zhun , Wang Wen-Wei , Wang Ming-Jie , Yao Tai , Zhu Yi-Chun
Published: July 2004

Urotensin II is a cyclic neuropeptide recently shown to play a role via its receptor GPR14 in regulating vascular tone in the mammalian cardiovascular system. The existence of GPR14 in rat heart has been validated by ligand binding assay and RT-PCR. In the present study, we investigated the cellular distribution of GPR14 protein in rat heart by using immunohistochemistry and confocal microscopic immunofluorescence double staining with antipeptide polyclonal antibodies against GPR14 and cell type markers for myocytes and endothelial cells. The direct effect of urotensin II on left ventricular contractility was further evaluated in isolated left ventricular papillary muscles of the rat. In paraffin-embedded heart sections, positive immunohistochemical staining was observed in the left ventricle but not in the right ventricle and atria. Immunofluorescence double staining revealed the cardiac myocyte as the only cell type expressing GPR14 protein in frozen heart sections as well as in isolated cardiac myocytes. There was no visible signal for GPR14 in intramyocardial coronary arteries and capillaries. The existence of GPR14 protein in rat heart was further validated by immunoprecipitation and Western blot analysis. In isolated rat left ventricular papillary muscle preparations, urotensin II induced an increase in active contractile force. GPR14 mRNA was also detected in rat heart by RT-PCR. These data provide the first direct evidence for the cellular localization of GPR14 receptor protein and a positive inotropic effect of urotensin II in normal rat heart.
Effects of midodrine on exercise-induced hypotension and blood pressure recovery in autonomic failure
Authors: Schrage William G. , Eisenach John H. , Dinenno Frank A. , Roberts Shelly K. , Johnson Christopher P. , Sandroni Paola , Low Philip A. , Joyner Michael J.
Published: July 2004

We tested the hypothesis that the oral α1-adrenergic agonist, midodrine, would limit the fall in arterial pressure observed during exercise in patients with pure autonomic failure (PAF). Fourteen subjects with PAF underwent a stand test, incremental supine cycling exercise (25, 50, and 75 W), and ischemic calf exercise, before (control) and 1 h after ingesting 10 mg midodrine. Heart rate (ECG), beat-to-beat blood pressure (MAP, arterial catheter), cardiac output (Q̇, open-circuit acetylene breathing), forearm blood flow (FBF, Doppler ultrasound), and calf blood flow (CBF, venous occlusion plethysmography) were measured. The fall in MAP after standing for 2 min was similar (∼60 mmHg; P = 0.62). Supine MAP immediately before cycling was greater after midodrine (124 ± 6 vs 117 ± 6 mmHg; P < 0.03), but cycling caused a workload-dependent hypotension ( P < 0.001), whereas increases in Q̇ were modest but similar. Midodrine increased MAP and total peripheral resistance (TPR) during exercise ( P < 0.04), but the exercise-induced fall in MAP and TPR were similar during control and midodrine ( P = 0.27 and 0.14). FBF during cycling was not significantly reduced by midodrine ( P > 0.2). By contrast, recovery of MAP after cycling was faster ( P < 0.04) after midodrine (∼25 mmHg higher after 5 min). Ischemic calf exercise evoked similar peak CBF in both trials, but midodrine reduced the hyperemic response over 5 min of recovery ( P < 0.02). We conclude midodrine improves blood pressure and TPR during exercise and dramatically improves the recovery of MAP after exercise.
Geometrical and topological foundations of theoretical physics: from gauge theories to string program
Authors: Boi Luciano
Published: July 2004

We study the role of geometrical and topological concepts in the
recent developments of theoretical physics, notably in non‐Abelian
gauge theories and superstring theory, and further we show the
great significance of these concepts for a deeper understanding
of the dynamical laws of physics. This work aims to demonstrate
that the global topological properties of the manifold′s model of
spacetime play a major role in quantum field theory and that,
therefore, several physical quantum effects arise from the
nonlocal metrical and topological structure of this manifold. We
mathematically argue the need for building new structures of space
with different topology. This means, in particular, that the “hidden” symmetries of fundamental physics can be related to the phenomenon of topological change of certain classes of
(presumably) nonsmooth manifolds.
Effect of Exposure to Cigarette Smoke on Carotid Artery Intimal Thickening
Authors: Anazawa Takeo , Dimayuga Paul C. , Li Hongyan , Tani Shigemasa , Bradfield Jason , Chyu Kuang-Yuh , Kaul Sanjay , Shah Prediman K. , Cercek Bojan
Published: July 2004

Objective—

We investigated the role of inducible NO synthase (iNOS) in intimal thickening with exposure to cigarette smoke (CS).

Methods and Results—

Intimal thickening in wild-type (WT) and iNOS-deficient (iNOS−/−) mice subjected to CS exposure was induced by placement of a cuff around the carotid artery. CS exposure in WT mice was associated with increased arterial iNOS expression, superoxide production, activator protein-1 (AP-1) activation, and serum NO. Intimal thickening 21 days after cuff placement was significantly greater in mice exposed to CS compared with air (0.023±0.013 mm
2
versus 0.009±0.008 mm
2
;
P
<0.05). iNOS inhibitor mercaptoethylguanidine-treated WT mice exposed to CS had reduced iNOS activity and intimal thickening (0.006±0.005 mm
2
;
P
<0.05). Intimal thickening was significantly less in iNOS−/− mice compared with WT mice (0.006±0.005 mm
2
;
P
<0.01) and was not augmented with CS (0.002±0.002 mm
2
). The aryl hydrocarbon receptor (AhR) was detected in arteries in vivo and in smooth muscle cells (SMCs) in vitro. CS condensate treatment of SMCs increased AhR binding to the core xenobiotic-responsive element of the iNOS promoter and increased iNOS expression.

Conclusions—

Increased arterial expression of iNOS, mediated at least in part by AhR signaling, may be an important mechanism by which CS increases carotid intimal thickening. CS exposure in mice was associated with increased arterial iNOS expression, superoxide production, AP-1 activation, serum NO expression, and intimal thickening. Inhibition or deletion of iNOS abrogated the effects of CS.
Angiotensin II–Induced Insulin Resistance and Protein Tyrosine Phosphatases
Authors: Marrero Mario B. , Fulton David , Stepp David , Stern David M.
Published: July 2004

Although the importance of protein tyrosine phosphorylation by tyrosine kinases in mitogenic signaling is well-accepted, recent studies also suggest that tyrosine dephosphorylation by protein tyrosine phosphatases (PTPases) play an equally important role. For example, both angiotensin II (Ang II) and insulin are known to mediate protein tyrosine phosphorylation and dephosphorylation events. These apparently paradoxical effects of Ang II and insulin suggest that both convergent and divergent intracellular signaling cascades are stimulated downstream of their respective receptors, producing diverse cellular responses. In this review, we discuss the hypothesis that the protein tyrosine phosphatase (PTPase), PTP-1B, plays a central role in Ang II-induced insulin resistance by inhibiting activation of the insulin receptor. We hypothesize that Ang II-induced PTP-1B activation leads to dephosphorylation of the insulin receptor and that this signaling pathway underlies the maladaptive responses observed in diabetic vascular and renal tissue during type II diabetes.
C-Reactive Protein Genotypes Affect Baseline, but not Exercise Training–Induced Changes, in C-Reactive Protein Levels
Authors: Obisesan Thomas O. , Leeuwenburgh Christiaan , Phillips Tracey , Ferrell Robert E. , Phares Dana A. , Prior Steven J. , Hagberg James M.
Published: July 2004

Objective—

The goal of this study is to determine whether C-reactive protein (CRP) gene variants affect baseline and training-induced changes in plasma CRP levels.

Methods and Results—

Sixty-three sedentary men and women aged 50 to 75 years old underwent baseline testing (V
o
max, body composition, CRP levels). They repeated these tests after 24 weeks of exercise training while on a low-fat diet. The CRP +219G/A variant significantly associated with CRP levels before and after training after accounting for the effects of demographic and biological variables. CRP −732A/G genotype was significantly related on a univariate basis to CRP levels after training. The CRP +29T/A variant did not affect CRP levels before or after training. In regression analyses, the +219 and −732 variants each had significant effects on CRP levels before and after training. Subjects homozygous for the common A/G −732/+219 haplotype exhibited the highest CRP levels, and having the rare allele at either site was associated with significantly lower CRP levels. CRP levels decreased significantly with training (−0.38±0.18 mg/L;
P
=0.03). However, none of the CRP variants was associated with the training-induced CRP changes.

Conclusion—

CRP +219G/A and −732A/G genotypes and haplotypes and exercise training appear to modulate CRP levels. However, training-induced CRP reductions appear to be independent of genotype at these loci.
Proinflammatory Cytokines Regulate LOX-1 Expression in Vascular Smooth Muscle Cells
Authors: Hofnagel Oliver , Luechtenborg Birgit , Stolle Katrin , Lorkowski Stefan , Eschert Heike , Plenz Gabriele , Robenek Horst
Published: July 2004

Objective—Atherogenesis represents a type of chronic inflammation and involves elements of the immune response, eg, the expression of proinflammatory cytokines. In advanced atherosclerotic lesions, lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is expressed in endothelial cells, macrophages, and smooth muscle cells (SMCs). In vitro, the expression of LOX-1 is induced by inflammatory cytokines like TNF-α and transforming growth factor (TGF)-β. Therefore, LOX-1 is thought to be upregulated locally in response to cytokines in vivo.

Methods and Results—We determined by reverse-transcription polymerase chain reaction (PCR) and Western blot analysis whether the mediators of the acute phase response in inflammation, IL-1α, IL-1β, and TNF-α, regulate LOX-1 expression in cultured SMC, and whether this regulation is influenced by peroxisome proliferator-activated receptor γ (PPARγ). We studied by immunohistochemistry whether these cytokines are spatially correlated with LOX-1 expression in advanced atherosclerotic lesions. We found upregulation of LOX-1 expression in SMC in a dose- and time-dependent manner after incubation with IL-1α, IL-1β, and TNF-α. Simultaneous incubation with these cytokines at saturated concentrations had an additive effect on LOX-1 expression. The PPARγ activator, 15d-PGJ2, however, inhibited IL-1β–induced upregulation of LOX-1. In the intima of atherosclerotic lesions regions of IL-1α, IL-1β, and TNF-α expression corresponded to regions of LOX-1 expression.

Conclusion—We suppose that upregulated LOX-1 expression in SMC of advanced atherosclerotic lesions is a response to these proinflammatory cytokines. Moreover, the proinflammatory effects of these cytokines can be decreased by the antiinflammatory effect of PPARγ.
Leukotriene B4Strongly Increases Monocyte Chemoattractant Protein-1 in Human Monocytes
Authors: Huang Li , Zhao Annie , Wong Frederick , Ayala Julia M. , Struthers Mary , Ujjainwalla Feroze , Wright Samuel D. , Springer Marty S. , Evans Jilly , Cui Jisong
Published: July 2004

Objective—Leukotriene B4(LTB4), a product of the 5-lipoxygenase (5-LO) pathway of arachidonic acid metabolism, has been implicated in atherosclerosis. However, the molecular mechanisms for the atherogenic effect of LTB4are not well understood. This study is to determine candidate mechanisms.

Method and Results—Primary human monocytes were treated with LTB4and the supernatant was analyzed for cytokine/chemokine production by an immuno-protein array. This analysis revealed a strong increase of the monocyte chemoattractant protein-1 (MCP-1), a proinflammatory cytokine. Follow-up analyses with MCP-1 enzyme-linked immunosorbent assay (for quantitation of MCP-1 protein) and real-time polymerase chain reaction (PCR) (for MCP-1 mRNA) demonstrated that LTB4strongly induced expression of MCP-1 protein and mRNA in a time-dependent and dose-dependent fashion. This induction was effectively abolished by CP-105,696, an antagonist for the LTB4receptor BLT1. Selective inhibitors of ERK1/2 or JNK MAPK effectively blocked the LTB4-induced MCP-1 production. Furthermore, LTB4increased NF-κB DNA binding activity, which was blocked by CP-105,696.

Conclusions—LTB4strongly induces MCP-1 production in primary human monocytes. This induction is mediated through the BLT1pathway increasing MCP-1 transcription. Activation of ERK1/2 or JNK MAPK is essential for this induction. The NF-κB activation may be involved in LTB4-increased MCP-1 expression. The LTB4-induced MCP-1 in human monocytes may play a critical role in the atherogenicity of LTB4.