bluuebunny/crossref_metadata_2025 huggingface dataset:
Combined Fatigue Life Test and Extrapolation of Turbine Disk Mortise at Elevated Temperature
Authors: Wang Rongqiao , Cho Chongdu , Nie Jingxu
Published: September 2005

To investigate the crack failure of a certain turbine disc mortise, a test system with a new low- and high-cycle noninterfering loading scheme was established to study the low- and high-cycle combined fatigue (L-HCCF) of fir-tree mortise at elevated temperature. Then, for 50 and 100Hz vibrations with constant stress amplitude superimposed on the same low cycle loading, respectively, the contrast L-HCCF life tests of light- and serious-corrosive disc mortises were carried out. Through real-time crack detection of the first teeth, the crack propagation rule of fir-tree mortise, a typical multiple load path structure, was obtained. Finally, a new method, two-frequency-ratio method, was presented to relate the load and life of laboratory test to the equivalent those of service in order to help the definition of the failure criteria for serious-corrosive discs in actual practice. The extrapolative results show that the life policies in use for light-corrosive turbine disc can not be applied to serious-corrosive disc directly because its reliable life is greatly less than an overhaul schedule, and it is urgent to establish criteria for withdrawal from service of the serious-corrosive discs to assure the structural integrity of this aeroengine.
Effect of the Specific Heat Ratio on the Aerodynamic Performance of Turbomachinery
Authors: Roberts Stephen K. , Sjolander Steen A.
Published: September 2005

Many gases, including carbon dioxide and argon, have been considered as alternative working fluids to air in a number of design studies for closed and semi-closed gas turbine engines. In many of these studies, it has been assumed that if the gas constant R and specific heat ratio γ are included in the speed and flow parameters, the compressor map or turbine characteristic is applicable to other working fluids. However, similarity arguments show that the isentropic exponent itself is a criterion of similarity and that the turbomachinery characteristics, even when appropriately nondimensionalized, will, in principle, vary as the γ of the working fluid varies. This paper examines the effect of γ on turbomachinery characteristics, mainly in terms of compressors. The performance of a centrifugal compressor stage was measured using air (γ=1.4), CO2(γ=1.29), and argon (γ=1.67). For the same values of the nondimensional speed, the pressure ratio, efficiency, and choking mass flow were found to be significantly different for the three test gases. The experimental results have been found to be consistent with a CFD analysis of the impeller. Finally, it is shown that the changes in performance can be predicted reasonably well with simple arguments based mainly on one-dimensional isentropic flow. These arguments form the basis for correction procedures that can be used to project compressor characteristics measured for one value of γ to those for a gas with a different value.
Acid-Induced Activation of the Urease Promoters Is Mediated Directly by the ArsRS Two-Component System of
Helicobacter pylori
Authors: Pflock Michael , Kennard Simone , Delany Isabel , Scarlato Vincenzo , Beier Dagmar
Published: September 2005

The nickel-containing enzyme urease is an essential colonization factor of the human gastric pathogen
Helicobacter pylori
which enables the bacteria to survive the low-pH conditions of the stomach. Transcription of the urease genes is positively controlled in response to increasing concentrations of nickel ions and acidic pH. Here we demonstrate that acid-induced transcription of the urease genes is mediated directly by the ArsRS two-component system. Footprint analyses identify binding sites of the phosphorylated ArsR response regulator within the
ureA
and
ureI
promoters. Furthermore, deletion of a distal upstream ArsR binding site of the
ureA
promoter demonstrates its role in acid-dependent activation of the promoter. In addition, acid-induced transcription of the
ureA
gene is unaltered in a
nikR
mutant, providing evidence that pH-responsive regulation and nickel-responsive regulation of the
ureA
promoter are mediated by independent mechanisms involving the ArsR response regulator and the NikR protein.
Working Mechanism of Immunoglobulin A1 (IgA1) Protease: Cleavage of IgA1 Antibody toNeisseria meningitidisPorA Requires De Novo Synthesis of IgA1 Protease
Authors: Vidarsson Gestur , Overbeeke Natasja , Stemerding Annette M. , van den Dobbelsteen Germie , van Ulsen Peter , van der Ley Peter , Kilian Mogens , van de Winkel Jan G. J.
Published: September 2005

Neisseria meningitidissecretes a protease that specifically cleaves the hinge region of immunoglobulin A1 (IgA1), releasing the effector (Fc) domain of IgA1 from the antigen binding (Fab) determinants. Theoretically, the remaining Fab fragments can block pathogen receptors or toxins and still provide protection. Here, we describe binding of V-gene-matched human IgA1 and IgA2 to PorA of strain H44/76. On live meningococci, efficient cleavage of IgA1, but not cleavage of IgA2, was observed, and up to ∼80% of the IgA1 Fc tails were lost from the meningococcal surface within 30 min. No cleavage of IgA1 was found on an isogenic H44/76 strain lacking IgA1 protease. Furthermore, our data indicate that PorA-bound IgA1 is masked by the serogroup B polysaccharide capsule, rendering the IgA1 less accessible to degradation by secreted IgA1 protease present in the bacterial surroundings. Experiments with protein synthesis inhibitors showed that de novo production of IgA1 protease was responsible for cleavage of PorA-bound IgA1 on encapsulated bacteria. Finally, our data suggest that cleavage of IgA1 by IgA1 protease releases a significant proportion of Fab fragments from the bacterium, probably as a result of their reduced avidity compared to that of whole antibodies.
Bacillus anthracisEdema Toxin InhibitsStaphylococcus aureusEnterotoxin B Effects In Vitro: a Potential Protein Therapeutic?
Authors: Krakauer Teresa , Little Stephen F. , Stiles Bradley G.
Published: September 2005

Various in vitro effects of staphylococcal enterotoxin B (SEB) on human peripheral blood mononuclear cells were mitigated byBacillus anthracisedema toxin. In particular, levels of some SEB-induced cytokines (tumor necrosis factor alpha, gamma interferon) and chemokines (monocyte chemoattractant protein 1, macrophage inflammatory protein 1 alpha [MIP-1α], MIP-1β) were significantly diminished or even nonexistent, depending upon the timing of edema toxin administration. Overall, these results suggest a novel use ofB. anthracisedema toxin against a bacterial superantigen.
Analyses of CIA5, the master regulator of the carbon-concentrating mechanism in Chlamydomonas reinhardtii, and its control of gene expression
Authors: Wang Ying , Sun Zhaohui , Horken Kempton M , Im Chung-Soon , Xiang Youbin , Grossman Arthur R , Weeks Donald P
Published: September 2005

In numerous studies, the CIA5 gene of Chlamydomonas reinhardtii Dangeard has been shown to control the expression of several "CO2-responsive genes" when cells are shifted to higher or lower levels of CO2. Using DNA microarray analyses with arrays containing 2764 unique cDNA sequences, we have demonstrated that several additional genes are controlled by the CIA5 gene, some increasing in expression when CO2 levels are lowered and others decreasing. Not all genes that respond to changes in CO2 concentrations are controlled by CIA5. For example, the RH1 gene, is markedly induced when both wild-type and cia5 mutant cells are shifted to high levels of CO2. We demonstrate that cycloheximide (an inhibitor of cytoplasmic protein synthesis) has no apparent effect on the initial induction of CO2-responsive genes, suggesting constitutive presence of all the molecular machinery needed by the cell to immediately respond to changes in CO2 levels. This observation is consistent with our earlier suggestions that CIA5 or another key component(s) of the carbon-concentrating mechanism must be rapidly "activated" (or "inactivated") as part of the response of C. reinhardtii to changes in external CO2 levels. We present new, direct evidence that CIA5 is localized to the nucleus in both low- and high-CO2 conditions.Key words: CIA5, CCM, carbon-concentrating mechanism, photosynthesis, gene regulation, Chlamydomonas reinhardtii, CO2.
Adaptation of a Chlamydomonas mutant with reduced rate of photorespiration to different concentrations of CO2
Authors: Suzuki Kensaku , Onodera Hidenori
Published: September 2005

It has been widely accepted that Chlamydomonas reinhardtii cells utilize inorganic carbon very efficiently for photosynthesis by operating a CO2-concentrating mechanism (CCM) under conditions of limited CO2. To help define the mechanism, 7FR2N, one of the suppressor double mutants of phosphoglycolate phosphatase-deficient (pgp1) mutants that have a reduced photorespiration rate (RPR) was crossed with wild-type strains to generate the strain N21 as a single RPR mutant. The comparison of photosynthetic characteristics with wild-type strains after the cells adapted to different concentrations of CO2 revealed that photosynthetic affinity for inorganic carbon was higher than that in wild-type strains after adaptation to concentrations between 50 µL·L1 CO2 and 5% CO2. Chlorophyll fluorescence parameters were also compared, and the biggest difference between N21 and the wild-type strains was observed in the photochemical quenching and effective quantum yield of photosystem II (ΔF/Fm′) at the CO2 compensation point. These values in N21 increased in a similar manner to the photosynthetic affinity for CO2, and increased significantly when the cells adapted to low-CO2 levels, whereas the values in the wild-type strains were apparently lower without any significant changes, regardless of the CO2 concentrations to which they were adapted. Although it was not clear if a nonphotochemical quenching parameter (NPQ) in N21 was higher than that in wild-type strains, NPQ increased coincidentally with the increase in photosynthetic affinity for inorganic carbon when the CO2 concentrations to which the strains were adapted decreased, in both the mutant and wild-type strain, suggesting that this form of NPQ reflects the operation of CCM in certain conditions. Possible candidates for the RPR mutation and the relationship between CCM and photosynthetic electron flow are discussed.Key words: Chlamydomonas reinhardtii, chlorophyll fluorescence, CO2-concentrating mechanism, low-CO2 responsive gene, phosphoglycolate phosphatase, photorespiration.
Regulation of inorganic carbon acquisition by phosphorus limitation in the green algaChlorella emersonii
Authors: Beardall John , Roberts Simon , Raven John A
Published: September 2005

Inorganic phosphate (Pi) plays a central role in cellular energy transduction. As a consequence, limitation of growth by phosphate availability can have an important impact on various aspects of metabolism. Since carbon acquisition via CO2-concentrating mechanisms (CCMs) in most microalgae is an active process, requiring ATP, it might be expected that phosphate limitation could have an indirect regulatory influence on CCM activity. We grew the green alga Chlorella emersonii Shihira et Krauss in semicontinuous or continuous cultures in nutrient-replete conditions or with orthophosphate as the limiting nutrient. CCM activity was down-regulated by P limitation. K0.5(dissolved inorganic carbon) values increased from approximately 4.5 µmol·L1in cells growing at close to maximal rates to >12 µmol·L1in cells growing at 0.2 d1. Maximal rates of photosynthesis decreased by approximately half over the same range of growth rates. Direct measurements of CCM activity showed that internal CO2: external CO2ratio was markedly decreased under P limitation, and concurrent measurements of stable carbon isotope discrimination were consistent with decreased CCM activity in the P-limited cells.Key words: phosphate, CCM, CO2-concentrating mechanism, Chlorella, inorganic carbon acquisition.
Mechanisms of inorganic carbon acquisition in twoEuglenaspecies
Authors: Colman Brian , Balkos Konstantine D
Published: September 2005

The mechanism of inorganic carbon uptake was examined in Euglena gracilis Klebs. and the acidophilic species Euglena mutabilis Schmitz. Both species, whether grown in acidic (pH 3.5) or alkaline (pH 7.5) media lack external carbonic anhydrase. Acid-grown E. gracilis was shown to have no capacity for bicarbonate transport, but transport was induced on transfer to alkaline medium (pH 7.5) in the light over a period of 8 h. In contrast, acid-grown E. mutabilis appears to have no capacity for bicarbonate transport even at neutral pH. The overall internal pH of the cells was determined by equilibration with14C-labelled benzoic acid over the pH range 3.55.0 and with14C-labelled 5,5-dimethyloxazolidine-2,4-dione over the range pH 5.57.5. The acidophilic species maintains an internal pH range of 6.66.8 in an external pH range of 3.55.5, whereas the acid-tolerant species E. gracilis maintains a neutral internal pH in an external pH range of 3.57.5. Measurement, by mass spectrometry, of the fluxes of CO2and O2in photosynthesizing cells at pH 3.5 demonstrated a rapid uptake of CO2by both species that was completely blocked by iodoacetamide, an inhibitor of CO2fixation. Uptake of CO2by E. gracilis, grown at pH 7.5, was not completely inhibited by iodoacetamide and O2evolution was sustained when the cells reached the CO2compensation concentration, indicating a direct uptake of bicarbonate. These data indicate that the acidophilic species, E. mutabilis, takes up CO2by diffusion, whereas the acid-tolerant species, E. gracilis, takes up CO2by diffusion at acid pH levels but has some capacity for active bicarbonate uptake when grown at alkaline pH levels.Key words: acidophilic alga, acidotolerant alga, bicarbonate uptake, CO2uptake, Euglena gracilis, Euglena mutabilis, internal pH.
Inorganic carbon acquisition by Chlamydomonas acidophila across a pH range
Authors: Spijkerman Elly
Published: September 2005

Chlamydomonas acidophila Negoro had a higher maximum growth rate upon aeration with 5% CO2 (v/v) than in nonaerated conditions at an external pH above 2. In medium with a pH of 1.0 or 2.0, a decrease in the maximum growth rate was observed upon CO2 aeration in comparison with nonaerated conditions. At both very low and very high external pH conditions, an induction of external carbonic anhydrase was detected; this being more pronounced in CO2-aerated cells than in nonaerated cells. It is therefore suggested that the induction of carbonic anhydrase is part of a stress response in Chlamydomonas acidophila. Comparison of some physiological characteristics of Chlamydomonas acidophila acclimated at pH 2.65 and at pH 6.0, revealed that CO2 aeration increased gross maximum photosynthesis at both pHs, whereas respiration, light acclimation, and photoinhibition were not effected. At pH 2.65, Chlamydomonas acidophila was found to have a carbon-concentrating mechanism under nonaerated conditions, whereas it did not under CO2-aerated conditions at pH 6. The affinity for CO2 use in O2 production was not dependent on CO2 aeration, but it was much lower at pH 6 than it was at pH 2.65. CO2 kinetic characteristics indicate that the photosynthesis of Chlamydomonas acidophila in its natural environment is not limited by inorganic carbon.Key words: Chlamydomonas acidophila, CCM, external carbonic anhydrase, photosynthesis, growth rates, pH stress, CO2.
Molecular characterization of autoinduction of bioluminescence in the Microtox® indicator strain Vibrio fischeri ATCC 49387
Authors: Perry Lynda L , Bright Nathan G , Carroll, Jr. Richard J , Scott M Cathy , Allen Michael S , Applegate Bruce M
Published: September 2005

Repeated attempts to clone the luxI from Vibrio fischeri ATCC 49387 failed to produce a clone carrying a functional LuxI. Sequence data from the clones revealed the presence of a polymorphism when compared with previously published luxI sequences, prompting further characterization of bioluminescence regulation in V. fischeri ATCC 49387. Further investigation of V. fischeri ATCC 49387 revealed that its LuxI protein lacks detectable LuxI activity due to the presence of a glutamine residue at position 125 in the deduced amino acid sequence. Specific bioluminescence in V. fischeri ATCC 49387 increases with increasing cell density, indicative of a typical autoinduction response. However, conditioned medium from this strain does not induce bioluminescence in an ATCC 49387 luxR-plux-based acyl homoserine lactone reporter strain, but does induce bioluminescence in ATCC 49387. It has been previously shown that a V. fischeri MJ-1 luxI mutant exhibits autoinduction of bioluminescence through N-octanoyl-L-homoserine lactone, the product of the AinS autoinducer synthase. However, a bioreporter based on luxR-plux from V. fischeri ATCC 49387 responded poorly to conditioned medium from V. fischeri ATCC 49387 and also responded poorly to authentic N-octanoyl-DL-homoserine lactone. A similar MJ-1-based bioreporter showed significant induction under the same conditions. A putative ainS gene cloned from ATCC 49387, unlike luxI from ATCC 49387, expresses V. fischeri autoinducer synthase activity in Escherichia coli. This study suggests that a regulatory mechanism independent of LuxR and LuxI but possibly involving AinS is responsible for the control of autoinduction of bioluminescence in V. fischeri ATCC 49387.Key words: quorum sensing, bioluminescence, Vibrio fischeri.
Community structure of free-floating filamentous cyanobacterial mats from the Wonder Lake geothermal springs in the Philippines
Authors: Lacap Donnabella C , Smith Gavin J.D , Warren-Rhodes Kimberley , Pointing Stephen B
Published: September 2005

Cyanobacterial mats were characterized from pools of 45–60 °C in near-neutral pH, low-sulphide geothermal springs in the Philippines. Mat structure did not vary with temperature. All mats possessed highly ordered layers of airspaces at both the macroscopic and microscopic level, and these appear to be an adaptation to a free-floating growth habit. Upper mat layers supported biomass with elevated carotenoid:chlorophyll a ratios and an as yet uncharacterized waxy layer on the dorsal surface. Microscopic examination revealed mats comprised a single Fischerella morphotype, with abundant heterocysts throughout mats at all temperatures. Molecular analysis of mat community structure only partly matched morphological identification. All samples supported greater 16S rDNA-defined diversity than morphology suggested, with a progressive loss in the number of genotypes with increasing temperature. Fischerella-like sequences were recovered from mats occurring at all temperatures, but some mats also yielded Oscillatoria-like sequences, although corresponding phenotypes were not observed. Phylogenetic analysis revealed that Fischerella-like sequences were most closely affiliated with Fischerella major and the Oscillatoria-like sequences with Oscillatoria amphigranulata.Key words: cyanobacteria, Fischerella, geothermal springs, microbial mats, Oscillatoria.
THE IMPACT OF ELECTION RESULTS ON THE MEMBER NUMBERS OF THE LARGE PARTIES IN BAVARIA AND GERMANY
Authors: SCHNEIDER JOHANNES J. , HIRTREITER CHRISTIAN
Published: September 2005

In this paper, we investigate the relations between the numbers of members of various parties and their results in the elections in Bavaria and in Germany. Deriving from the finding that there is a strong time-delayed correlation between these data-sets for the two largest parties in Bavaria, we show in a simulation based on the Sznajd model that such a correlation leads to very stable majorities, just as in Bavaria.
3D ISING NONUNIVERSALITY: A MONTE CARLO STUDY
Authors: SCHULTE MELANIE , DROPE CAROLINE
Published: September 2005

We investigate as a member of the Ising universality class the Next-Nearest Neighbor Ising model without external field on a simple cubic lattice by using the Monte Carlo Metropolis Algorithm. The Binder cumulant and the susceptibility ratio, which should be universal quantities at the critical point, were shown to vary for small negative next-nearest neighbor interactions.
DIRECTED SPIRAL PERCOLATION HULL ON THE SQUARE AND TRIANGULAR LATTICES
Authors: SINHA SANTANU , SANTRA S. B.
Published: September 2005

Critical properties of hulls of directed spiral percolation clusters are studied on the square and triangular lattices in two dimensions (2D). The hull fractal dimension (dH) and some of the critical exponents associated with different moments of the hull size distribution function of the anisotropic DSP clusters are reported here. The values of dH and other critical exponents are found the same within error bars on both the lattices. The universality of the hull's critical exponents then holds true between the square and triangular lattices in 2D unlike the cluster's critical exponents which exhibit a breakdown of universality. The hull fractal dimension (dH ≈ 1.46) is also found close to 4/3 and away from 7/4, that of ordinary percolation cluster hull. A new conjecture is proposed for dH in terms of two connectivity length exponents (ν‖ and ν⊥) of the anisotropic clusters generated here. The values of dH and other critical exponents obtained here are very close to that of the spiral percolation cluster hull. The hull properties of the DSP clusters are then mostly determined by the rotational constraint and almost independent of the directional constraint present in the model.
EFFECT OF THE NUMBER OF ENERGY LEVELS OF A DEMON FOR THE SIMULATION OF THE FOUR-DIMENSIONAL ISING MODEL ON THE CREUTZ CELLULAR AUTOMATON
Authors: MERDAN Z. , GUNEN A. , MULAZIMOGLU G.
Published: September 2005

The four-dimensional Ising model is simulated on the Creutz cellular automaton by using three- and four-bit demons. The simulations result in overlapping curves for both the order parameter, the magnetic susceptibility, the internal energy and the Binder cumulant. However, the specific heat curves overlap above and at Tc as the number of energy levels of a demon or the number of bits increases, but below Tc they are strongly violated. The critical exponents for the order parameter and the magnetic susceptibility as the number of bits increases are obtained by analyzing the data according to the finite-size scaling relations available.
NUMERICAL STABILITY AND THE SIGN PROBLEM IN THE DETERMINANT QUANTUM MONTE CARLO METHOD
Authors: LOH E. Y. , GUBERNATIS J. E. , SCALETTAR R. T. , WHITE S. R. , SCALAPINO D. J. , SUGAR R. L.
Published: September 2005

A recent paper by Matuttis and Ito questions the numerical accuracy of a widely-used fermion Monte Carlo algorithm. They also claim that the increase in the d-wave pairfield susceptibility χd(T) of a doped 4×4 Hubbard model at low temperature, previously found using this algorithm, is an artifact due to numerical errors. Here, we provide tests which show that this algorithm is numerically accurate and show that the simulation of χd for a 2×2 lattice agrees with exact diagonalization results. We also provide more complete data for χd on a 4×4 lattice that is consistent with our previous results.
SIMULATIONS OF FINANCIAL MARKETS IN A POTTS-LIKE MODEL
Authors: TAKAISHI TETSUYA
Published: September 2005

A three-state model based on the Potts model is proposed to simulate financial markets. The three states are assigned to "buy", "sell" and "inactive" states. The model shows the main stylized facts observed in the financial market: fat-tailed distributions of returns and long time correlations in the absolute returns. At low inactivity rate, the model effectively reduces to the two-state model of Bornholdt and shows similar results to the Bornholdt model. As the inactivity increases, we observe the exponential distributions of returns.
SELF-ORGANIZING SOCIAL HIERARCHIES ON SCALE-FREE NETWORKS
Authors: GALLOS LAZAROS K.
Published: September 2005

In this work, we extend the model of Bonabeau et al. in the case of scale-free networks. A sharp transition is observed from an egalitarian to an hierarchical society, with a very low population density threshold. The exact threshold value also depends on the network size. We find that in an hierarchical society the number of individuals with strong winning attitude is much lower than the number of the community members that have a low winning probability.
VALENCE AND METAL-INSULATOR TRANSITIONS IN THE SPINLESS FALICOV–KIMBALL MODEL INDUCED BY DOPING
Authors: FARKAŠOVSKÝ PAVOL , ČENČARIKOVÁ HANA
Published: September 2005

The influence of doping on valence and metal-insulator transitions in the spinless Falicov–Kimball model is studied by the well-controlled numerical method. Two types of doping are examined, and namely, the substitution of rare-earth ions by non-magnetic ions that introduce (i) one or (ii) no additional electron (per non-magnetic ion) into the conduction band. It is found that the first type of substitution increases the average f-state occupancy of rare-earth ions, whereas the second type of substitution has the opposite effect. In both cases valence changes are accompanied by a doping induced insulator-metal transition. The results obtained are used to describe valence and metal-insulator transitions in the samarium hexaboride solid solutions.
Intraindividual validation of heart rate variability indexes to measure vagal effects on hearts
Authors: Martinmäki Kaisu , Rusko Heikki , Kooistra Libbe , Kettunen Joni , Saalasti Sami
Published: September 2005

Heart rate variability (HRV) has been widely used as a measure of vagal activation in physiological, psychological, and clinical examinations. We studied the within-subject quantitative relationship between HRV and vagal effects on the heart in different body postures during a gradually decreasing vagal blockade. Electrocardiogram and respiratory frequency were measured in subjects (8 endurance athletes and 10 participants of nonendurance sports) in supine, sitting, and standing postures before the blockade, under vagal blockade (atropine sulfate, 0.04 mg/kg), and four times during a 150-min recovery from the blockade. Fast Fourier transform was used to calculate low-frequency power (LFP, 0.04–0.15 Hz), high-frequency power (HFP, 0.15–0.40 Hz), and total power (TP, 0.04–0.40 Hz). A within-subject linear regression analysis of recovery time on each HRV index was conducted. Complete vagal blockade decreased all HRV significantly, particularly HFP ( P < 0.001). A linear fit explained a large portion of the within-subject variance between recovery time and natural log-transformed (ln) HRV indexes in every posture, with coefficients of determination ( R2) in the supine posture [means (SD)]: 98 (SD 2)% for mean R-R interval, 87 (SD 10)% for lnLFP, 87 (SD 13)% for lnHFP, and 91 (SD 10)% for lnTP. Neither body posture nor endurance-training background had an impact on R2 values. There was marked between-subject variation in the R2 values, slopes, and intercepts. In conclusion, all HRV, particularly HFP, is predominantly under vagal control. Within subjects, lnLFP, lnHFP, and lnTP increased linearly with the gradually decreasing vagal blockade in all postures.
Calcitonin gene-related peptide activates different signaling pathways in mesenteric lymphatics of guinea pigs
Authors: Hosaka Kayoko , Rayner Sharyn E. , von der Weid Pierre-Yves , Zhao Jun , Imtiaz Mohammad S. , van Helden Dirk F.
Published: September 2005

The effects of calcitonin gene-related peptide (CGRP) on constriction frequency, smooth muscle membrane potential ( Vm), and endothelial Vm of guinea pig mesenteric lymphatics were examined in vitro. CGRP (1–100 nM) caused an endothelium-dependent decrease in the constriction frequency of perfused lymphatic vessels. The endothelium-dependent CGRP response was abolished by the CGRP-1 receptor antagonist CGRP-(8–37) (1 μM) and pertussis toxin (100 ng/ml). This action of CGRP was also blocked by the nitric oxide (NO) synthase inhibitor NG-nitro-l-arginine (l-NNA; 10 μM), an action that was reversed by the addition of l-arginine (100 μM). cGMP, adenylate cyclase, cAMP-dependent protein kinase (PKA), and ATP-sensitive K+ (KATP+) channels were all implicated in the endothelium-dependent CGRP response because it was abolished by methylene blue (20 μM), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (10 μM), dideoxyadenosine (10 μM), N-[2-( p-bromociannamylamino)-ethyl]-5-isoquinolinesulfonamide-dichloride (H89; 1 μM) and glibenclamide (10 μM). CGRP (100 nM), unlike acetylcholine, did not alter endothelial intracellular Ca2+ concentration or Vm. CGRP (100 nM) hyperpolarized the smooth muscle Vm, an effect inhibited by l-NNA, H89, or glibenclamide. CGRP (500 nM) also caused a decrease in constriction frequency. However, this was no longer blocked by CGRP-(8–37). CGRP (500 nM) also caused smooth muscle hyperpolarization, an action that was now not blocked by l-NNA (100 μM). It was most likely mediated by the activation of the cAMP/PKA pathway and the opening of KATP+ channels because it was abolished by H89 or glibenclamide. We conclude that CGRP, at low to moderate concentrations (i.e., 1–100 nM), decreases lymphatic constriction frequency primarily by the stimulation of CGRP-1 receptors coupled to pertussis toxin-sensitive G proteins and the release of NO from the endothelium or enhancement of the actions of endogenous NO. At high concentrations (i.e., 500 nM), CGRP also directly activates the smooth muscle independent of NO. Both mechanisms of activation ultimately cause the PKA-mediated opening of KATP+ channels and resultant hyperpolarization.
Selective right, but not left, coronary endothelial dysfunction precedes development of pulmonary hypertension and right heart hypertrophy in rats
Authors: Sun Xiaowei , Ku David D.
Published: September 2005

We investigated a causal role for coronary endothelial dysfunction in development of monocrotaline (MCT)-induced pulmonary hypertension and right heart hypertrophy in rats. Significant increases in pulmonary pressure and right ventricular weight did not occur until 3 wk after 60 mg/kg MCT injection (34 ± 4 vs. 19 ± 2 mmHg and 37 ± 2 vs. 25 ± 1% septum + left ventricular weight in controls, respectively). Isolated right coronary arteries (RCA) showed significant decreases in acetylcholine-induced NO dilation in both 1-wk (33 ± 3% with 0.3 μM; n = 5) and 3-wk (18 ± 3%; n = 11) MCT rats compared with control rats (71 ± 8%, n = 10). Septal coronary arteries (SCA) showed a smaller decrease in acetylcholine dilation (55 ± 8% and 33 ± 7%, respectively, vs. 73 ± 8% in controls). No significant change was found in the left coronary arteries (LCA; 88 ± 6% and 81 ± 6%, respectively, vs. 87 ± 3% in controls). Nitro-l-arginine methyl ester-induced vasoconstriction, an estimate of spontaneous endothelial NO-mediated dilation, was not significantly altered in MCT-treated SCA or LCA but was increased in RCA after 1 wk of MCT (−41 ± 6%) and decreased after 3 wk (−18 ± 3% vs. −27 ± 3% in controls). A marked enhancement to 30 nM U-46619-induced constriction was also noted in RCA of 3-wk (−28 ± 6% vs. −9 ± 2% in controls) but not 1-wk (−12 ± 7%) MCT rats. Sodium nitroprusside-induced vasodilation was not different between control and MCT rats. Together, our findings show that a selective impairment of right, but not left, coronary endothelial function is associated with and precedes development of MCT-induced pulmonary hypertension and right heart hypertrophy in rats.
Cellular and molecular mechanisms underlying LPS-associated myocyte impairment
Authors: Tavener Samantha A. , Kubes Paul
Published: September 2005

Recently we reported that Toll-like receptor 4 (TLR4)-positive immune cells of unknown identity were responsible for the LPS-induced depression of cardiac myocyte shortening. The aim of this study is to identify the TLR4-positive cell type that is responsible for the LPS-induced cardiac dysfunction. Neither neutrophil depletion alone nor mast cell deficiency had any impact on the impairment of myocyte shortening during LPS treatment. In contrast, LPS-treated, macrophage-deficient mice demonstrated a partial reduction in shortening compared with saline-treated, macrophage-deficient mice. Because the removal of macrophages could only partially restore myocyte shortening, we also investigated the effects of removing both neutrophils and macrophages on myocyte shortening. Interestingly, endotoxemic, neutrophil-depleted, and macrophage-deficient mice had completely restored myocyte shortening. Because both macrophages and neutrophils can produce nitric oxide (NO) and TNF-α, we examined LPS-treated inducible NO synthase knockout (iNOSKO) mice and TNF receptor (TNFR)-deficient mice. Eliminating both TNFR1 and TNFR2 was required to restore myocyte shortening during LPS treatment, whereas iNOS deficiency had no effect. These data suggest that macrophages and to a lesser degree neutrophils cause cardiac impairment, presumably via TNF-α.
Differential expression and regulation of murine CD40 in regional vascular beds
Authors: Vowinkel Thorsten , Wood Katherine C. , Stokes Karen Y. , Russell Janice , Krieglstein Christian F. , Granger D. Neil
Published: September 2005

There is emerging evidence for a role of the CD40/CD40 ligand (CD40L) dyad as a signaling mechanism in different inflammatory conditions. The aims of this study were to 1) quantify the constitutive and induced expression of CD40 in different regional vascular beds of the mouse and 2) assess the role of CD40L as a modulator of vascular endothelial CD40 expression. The dual radiolabeled monoclonal antibody technique was used to quantify the expression of endothelial CD40 in control and LPS-challenged wild-type (WT) mice. Significant constitutive CD40 expression was detected in several vascular beds of WT mice with lung, kidney, and small intestine exhibiting the highest expression, whereas the liver and stomach showed no detectable baseline expression. LPS administration elicited two- to sevenfold increases in CD40 expression in several tissues (heart, kidney, and intestine) within 4 h, whereas other organs (brain) required up to 48 h to exhibit CD40 upregulation. CD40 expression was not detected in unstimulated or LPS-challenged CD40−/−mice. Constitutive expression of CD40 was profoundly reduced in unstimulated CD40L−/−mice, but the LPS-induced CD40 upregulation did not differ between CD40L−/−and WT mice. Depletion of platelets or T lymphocytes, the major CD40L-expressing cells in blood, also resulted in a profound reduction in basal CD40 expression. These findings demonstrate significant endothelial expression of CD40 under basal conditions in different vascular beds and increased CD40 expression after endothelial cell activation with LPS. Platelet- and T-lymphocyte-associated CD40L appears to play a major role in regulating the density of CD40 expression on vascular endothelial cells in vivo.
Effects of red blood cell aggregation on myocardial hematocrit gradient using two approaches to increase aggregation
Authors: Yalcin Ozlem , Aydin Funda , Ulker Pinar , Uyuklu Mehmet , Gungor Firat , Armstrong Jonathan K. , Meiselman Herbert J. , Baskurt Oguz K.
Published: September 2005

The normal transmyocardial tissue hematocrit distribution (i.e., subepicardial greater than subendocardial) is known to be affected by red blood cell (RBC) aggregation. Prior studies employing the use of infused large macromolecules to increase erythrocyte aggregation are complicated by both increased plasma viscosity and dilution of plasma. Using a new technique to specifically alter the aggregation behavior by covalent attachment of Pluronic F-98 to the surface of the RBC, we have determined the effects of only enhanced aggregation (i.e., Pluronic F-98-coated RBCs) versus enhanced aggregation with increased plasma viscosity (i.e., an addition of 500 kDa dextran) on myocardial tissue hematocrit in rapidly frozen guinea pig hearts. Although both approaches equally increased aggregation, tissue hematocrit profiles differed markedly: 1) when Pluronic F-98-coated cells were used, the normal transmyocardial gradient was abolished, and 2) when dextran was added, the hematocrit remained at subepicardial levels for about one-half the thickness of the myocardium and then rapidly decreased to the control level in the subendocardial layer. Our results indicate that myocardial hematocrit profiles are sensitive to both RBC aggregation and to changes of plasma viscosity associated with increased RBC aggregation. Furthermore, they suggest the need for additional studies to explore the mechanisms affecting RBC distribution in three-dimensional vascular beds.
Biphasic effects of ANP infusion in conscious, euvolumic rats: roles of AQP2 and ENaC trafficking
Authors: Wang Weidong , Li Chunling , Nejsum Lene N. , Li Hongyan , Kim Soo Wan , Kwon Tae-Hwan , Jonassen Thomas E. N. , Knepper Mark A. , Thomsen Klaus , Frøkiær Jørgen , Nielsen Søren
Published: September 2005

Atrial natriuretic peptide (ANP) acutely promotes water and sodium excretion, whereas subchronic effects involve water retention. Renal hemodynamics, water and sodium excretion, and aquaporin-2 (AQP2) and epithelial Na channel (ENaC) subcellular trafficking were determined in response to continuous ANP infusion in conscious rats, where body sodium and fluid balance was constantly maintained. ANP (0.5 μg·kg−1·min−1) evoked a transient (peak at 10 min) fivefold diuresis followed by reduced urine production to control levels (30- to 90-min period). The fractional distal water excretion was significantly increased initially and then decreased in response to ANP. There was no change in the subcellular localization of AQP2 and AQP2 phosphorylated in PKA consensus site S256 (p-AQP2) 10 min after ANP infusion. In contrast, after 90 min a marked increase in apical labeling of AQP2 and p-AQP2 was observed in the inner and outer medullary collecting ducts but not in cortical collecting ducts. In support of this, ANP induced plasma membrane targeting of AQP2 in transiently AQP2-transfected cells. ANP infusion evoked an instant increase in renal sodium excretion, which persisted for 90 min. Ten minutes of ANP infusion induced no changes in the subcellular localization of ENaC subunits, whereas a marked increase in apical targeting of α- and γ-subunits was observed after 90 min. In conclusion, 1) ANP infusion induced a sustained natriuresis and transient diuresis; 2) there were no changes in the subcellular localization of AQP2 and ENaC subunits after 10 min of ANP infusion; and 3) there was a marked increase in apical targeting of AQP2, p-AQP2, and α- and γ-ENaC after 90 min of ANP infusion. The increased targeting of ENaC and AQP2 likely represents direct or compensatory effects to increase sodium and water reabsorption and to prevent volume depletion in response to prolonged ANP infusion.
A Strategy for Integrative Computational Physiology
Authors: Hunter Peter , Nielsen Poul
Published: September 2005

Organ function (the heart beat for example) can only be understood through knowledge of molecular and cellular processes within the constraints of structure-function relations at the tissue level. A quantitative modeling framework that can deal with these multiscale issues is described here under the banner of the International Union of Physiological Sciences Physiome Project.
Proglucagon-Derived Peptides: Mechanisms of Action and Therapeutic Potential
Authors: Sinclair Elaine M , Drucker Daniel J.
Published: September 2005

Glucagon is used for the treatment of hypoglycemia, and glucagon receptor antagonists are under development for the treatment of type 2 diabetes. Moreover, glucagon-like peptide (GLP)-1 and GLP-2 receptor agonists appear to be promising therapies for the treatment of type 2 diabetes and intestinal disorders, respectively. This review discusses the physiological, pharmacological, and therapeutic actions of the proglucagon-derived peptides, with an emphasis on clinical relevance of the peptides for the treatment of human disease.
On convergence of a global search strategy for reverse convex problems
Authors: Strekalovsky Alexander
Published: September 2005

On the base of global optimality conditions for RCP we develop the
global search strategy (GSS) and focus on the global convergence
of GSS giving a variant of the proof.
Quality improvement in an inventory model with finite-range stochastic lead times
Authors: Paknejad Javad , Nasri Farrokh , Affisco John F.
Published: September 2005

Typically, traditional inventory models operate under the
assumption of perfect quality. In this paper we modify an
inventory model with finite-range stochastic lead time to allow
for a random number of defective units in a lot. However, there
is an extra cost for holding the defective items in the lot for
the period before it is returned to the supplier. This paper also
considers the option of investment to improve quality.
Closed-form relationships are obtained for a quality-adjusted
model as well as a quality improvement model. Numerical examples
confirm that the option of investment in quality improvement
results in significant cost savings. Sensitivity analysis shows
that the quality improvement model is robust.
The Cyclin-dependent Kinase Inhibitor CYC202 (R-Roscovitine) Inhibits Retinoblastoma Protein Phosphorylation, Causes Loss of Cyclin D1, and Activates the Mitogen-activated Protein Kinase Pathway
Authors: Whittaker Steven R. , Walton Mike I. , Garrett Michelle D. , Workman Paul
Published: September 2005

Deregulation of the cell cycle commonly occurs during tumorigenesis, resulting in unrestricted cell proliferation and independence from mitogens. Cyclin-dependent kinase inhibitors have the potential to induce cell cycle arrest and apoptosis in cancer cells. CYC202 (R-roscovitine) is a potent inhibitor of CDK2/cyclin E that is undergoing clinical trials. Drugs selected to act on a particular molecular target may exert additional or alternative effects in intact cells. We therefore studied the molecular pharmacology of CYC202 in human colon cancer cells. Treatment of HT29 and KM12 colon carcinoma cell lines with CYC202 decreased both retinoblastoma protein phosphorylation and total retinoblastoma protein. In addition, an increase in the phosphorylation of extracellular signal-regulated kinases 1/2 was observed. As a result, downstream activation of the mitogen-activated protein kinase pathway occurred, as demonstrated by an increase in ELK-1 phosphorylation and in c-FOS expression. Use of mitogen-activated protein kinase kinases 1/2 inhibitors showed that the CYC202-induced extracellular signal-regulated kinases 1/2 phosphorylation was mitogen-activated protein kinase kinases 1/2 dependent but did not contribute to the cell cycle effects of the drug, which included a reduction of cells in G1, inhibition of bromodeoxyuridine incorporation during S-phase, and a moderate increase in G2-M phase. Despite activation of the mitogen-activated protein kinase pathway, cyclin D1 protein levels were decreased by CYC202, an effect that occurred simultaneously with loss of retinoblastoma protein phosphorylation and inhibition of cell cycle progression. The reduced expression of cyclin D1 protein was independent of the p38SAPK and phosphatidylinositol 3-kinase pathways, which are known regulators of cyclin D1 protein. Interestingly, CYC202 caused a clear reduction in cyclins D1, A, and B1 mRNA, whereas c-FOS mRNA increased by 2-fold. This was accompanied by a loss of RNA polymerase II phosphorylation and total RNA polymerase II protein, suggesting that CYC202 was inhibiting transcription, possibly via inhibition of CDK7 and CDK9 complexes. It can be concluded that although CYC202 can act as a CDK2 inhibitor, it also has the potential to inhibit CDK4 and CDK1 activities in cancer cells through the down-regulation of the corresponding cyclin partners. This provides a possible mechanism by which CYC202 can cause a reduction in retinoblastoma protein phosphorylation at multiple sites and cell cycle arrest in G1, S, and G2-M phases. In addition to providing useful insights into the molecular pharmacology of CYC202 in human cancer cells, the results also suggest potential pharmacodynamic end points for use in clinical trials with the drug.
The Adrenal Androgen Androstenediol Is Present in Prostate Cancer Tissue after Androgen Deprivation Therapy and Activates Mutated Androgen Receptor
Authors: Mizokami Atsushi , Koh Eitetsu , Fujita Hiroshi , Maeda Yuji , Egawa Masayuki , Koshida Kiyoshi , Honma Seijiro , Keller Evan T. , Namiki Mikio
Published: September 2005

Despite an initial response to androgen deprivation therapy, prostate cancer (PCa) progresses eventually from an androgen-dependent to an androgen-independent phenotype. One of the mechanisms of relapse is antiandrogen withdrawal phenomenon caused by mutation of 877th amino acid of androgen receptor (AR). In the present study, we established a method to measure the concentration of androstenediol (adiol) in prostate tissue. We found that adiol maintains a high concentration in PCa tissue even after androgen deprivation therapy. Furthermore, adiol is a stronger activator of mutant AR in LNCaP PCa cells and induces more cell proliferation, prostate-specific antigen (PSA) mRNA expression, and PSA promoter than dihydrotestosterone (DHT). Because antiandrogen, bicalutamide, blocked adiol activity in LNCaP cells, it was suggested that adiol effect was mediated through AR. However, high concentration of bicalutamide was necessary to block completely adiol activity. These effects were specific to LNCaP cells because adiol had less effect in PC-3 PCa cells transfected with wild-type AR than DHT and had similar effect in PC-3 cells transfected with mutant AR. The mechanism that adiol activates mutant AR in LNCaP cells did not result from the increased affinity to mutant AR or from AR’s association with coactivator ARA70. However, low concentration of adiol induced more AR nuclear translocation than DHT in LNCaP cells and not PC-3 cells transfected with AR. These results indicate that adiol may cause the progression of PCa even after hormone therapy.
neu Antigen-Negative Variants Can Be Generated after neu-Specific Antibody Therapy in neu Transgenic Mice
Authors: Knutson Keith L. , Almand Bond , Dang Yushe , Disis Mary L.
Published: September 2005

Prolonged administration of HER-2/neu-specific monoclonal antibody therapy is now widely used for the treatment of HER-2/neu-overexpressing tumors in advanced-stage breast cancer patients. Monoclonal antibody therapy has the potential to promote reduced tumor expression of HER-2/neu by receptor down-modulation and/or the generation of antigen-negative variants. Loss of antigen by either mechanism could potentially impact subsequent therapeutic strategies targeting HER-2/neu. In this study, the effects of chronic neu-specific monoclonal antibody therapy on tumor growth and neu protein expression were examined in a murine model of neu-overexpressing breast cancer. Treatment of neu-overexpressing tumors with neu-specific antibody, in vitro or in vivo, resulted in significant tumor growth inhibition. When neu antibody was used to treat neu-overexpressing tumor cells both in vitro and in vivo in tumor-bearing mice, neu receptor expression was not diminished after cessation of therapy. However, in the setting of clinically undetectable disease in a fraction of animals, antigen-negative variants were generated. An understanding of the effects of monoclonal antibodies on target antigen expression is critical for the future design and testing of novel HER-2/neu-targeted therapies administered in combination with or after HER-2/neu-specific monoclonal antibody therapy.