bluuebunny/crossref_metadata_2025 huggingface dataset:
Receptor‐specific inhibition of GABAB‐activated K+ currents by muscarinic and metabotropic glutamate receptors in immature rat hippocampus
Authors: Sohn Jong‐Woo , Lee Doyun , Cho Hana , Lim Wonil , Shin Hee‐Sup , Lee Suk‐Ho , Ho Won‐Kyung
Published: January 2007

It has been shown that the activation of Gq‐coupled receptors (GqPCRs) in cardiac myocytes inhibits the G protein‐gated inwardly rectifying K+ current (IGIRK) via receptor‐specific depletion of phosphatidylinositol 4,5‐bisphosphate (PIP2). In this study, we investigated the mechanism of the receptor‐mediated regulation of IGIRK in acutely isolated hippocampal CA1 neurons by the muscarinic receptor agonist, carbachol (CCh), and the group I metabotropic glutamate receptor (mGluR) agonist, 3,5‐dihydroxyphenylglycine (DHPG). IGIRK was activated by the GABAB receptor agonist, baclofen. When baclofen was repetitively applied at intervals of 2–3 min, the amplitude of the second IGIRK was 92.3 ± 1.7% of the first IGIRK in control. Pretreatment of neurons with CCh or DHPG prior to the second application of baclofen caused a reduction in the amplitude of the second IGIRK to 54.8 ± 1.3% and 51.4 ± 0.6%, respectively. In PLCβ1 knockout mice, the effect of CCh on IGIRK was significantly reduced, whereas the effect of DHPG remained unchanged. The CCh‐mediated inhibition of IGIRK was almost completely abolished by PKC inhibitors and pipette solutions containing BAPTA. The DHPG‐mediated inhibition of IGIRK was attenuated by the inhibition of phospholipase A2 (PLA2), or the sequestration of arachidonic acid. We confirmed that DHPG eliminated the inhibition of IGIRK by arachidonic acid. These results indicate that muscarinic inhibition of IGIRK is mediated by the PLC/PKC signalling pathway, while group I mGluR inhibition of IGIRK occurs via the PLA2‐dependent production of arachidonic acid. These results present a novel receptor‐specific mechanism for crosstalk between GqPCRs and GABAB receptors.
Emulating Membrane Protein Evolution by Rational Design
Authors: Rapp Mikaela , Seppälä Susanna , Granseth Erik , von Heijne Gunnar
Published: January 2007

How do integral membrane proteins evolve in size and complexity? Using the small multidrug-resistance protein EmrE from
Escherichia coli
as a model, we experimentally demonstrated that the evolution of membrane proteins composed of two homologous but oppositely oriented domains can occur in a small number of steps: An original dual-topology protein evolves, through a gene-duplication event, to a heterodimer formed by two oppositely oriented monomers. This simple evolutionary pathway can explain the frequent occurrence of membrane proteins with an internal pseudo–two-fold symmetry axis in the plane of the membrane.
Quantum Hall Effect in Polar Oxide Heterostructures
Authors: Tsukazaki A. , Ohtomo A. , Kita T. , Ohno Y. , Ohno H. , Kawasaki M.
Published: January 2007

We observed Shubnikov–de Haas oscillation and the quantum Hall effect in a high-mobility two-dimensional electron gas in polar ZnO/Mg

x

Zn

1–
x

O heterostructures grown by laser molecular beam epitaxy. The electron density could be controlled in a range of 0.7 × 10
12
to 3.7 × 10
12
per square centimeter by tuning the magnesium content in the barriers and the growth polarity. From the temperature dependence of the oscillation amplitude, the effective mass of the two-dimensional electrons was derived as 0.32 ± 0.03 times the free electron mass. Demonstration of the quantum Hall effect in an oxide heterostructure presents the possibility of combining quantum Hall physics with the versatile functionality of metal oxides in complex heterostructures.
Development of a Semiquantitative Degenerate Real-Time PCR-Based Assay for Estimation of Numbers of Butyryl-Coenzyme A (CoA) CoA Transferase Genes in Complex Bacterial Samples
Authors: Louis Petra , Flint Harry J.
Published: January 2007

We describe a new degenerate real-time PCR approach to simultaneously quantify phylogenetically different butyrate-producing bacteria based on the detection of butyryl-coenzyme A (CoA) CoA transferase genes. This pathway is present in numerically important groups of butyrate producers within the human colon, and thus this assay estimates the butyrate-producing ability of the microbiota.
REPRESENTATIVE ENSEMBLES IN STATISTICAL MECHANICS
Authors: YUKALOV V. I.
Published: January 2007

The notion of representative statistical ensembles, correctly representing statistical systems, is strictly formulated. This notion allows for a proper description of statistical systems, avoiding inconsistencies in theory. As an illustration, a Bose-condensed system is considered. It is shown that a self-consistent treatment of the latter, using a representative ensemble, always yields a conserving and gapless theory.
LOCALIZATION OF PLANE WAVES IN DILUTE BOSE–EINSTEIN GASES
Authors: CHU A. KWANG-HUA
Published: January 2007

Discrete Uehling–Uhlenbeck models together with the introduction of the disorder or an orientation-free parameter are adopted to study the possible localization of plane waves propagating in dilute hard-sphere Bose–Einstein gases under very-low temperature environment based on the acoustical analog. The curves of the localization length versus the disorder and Pauli-blocking measure we obtained here resemble qualitatively those proposed before.
THREE-DIMENSIONAL THERMAL LATTICE BOLTZMANN SIMULATION OF NATURAL CONVECTION IN A CUBIC CAVITY
Authors: NOR AZWADI C. S. , TANAHASHI T.
Published: January 2007

In this paper, a three-dimensional (3D) thermal lattice Boltzmann model is proposed to simulate 3D incompressible thermal flow problem. Our model is based on the double-distribution function approach. We found that a new and simple lattice type of eight-velocity model for the internal energy density distribution function can be developed, where the viscous and compressive heating effects are negligible. Numerical results of 3D natural convection flow in a cubic cavity are presented.
ON THE THERMAL EXPANSION OF MgB2 AT NORMAL STATE
Authors: MEENA DEVI J. , RAMACHANDRAN K.
Published: January 2007

Thermal expansion of MgB 2 at normal state is measured experimentally in the temperature range 300–400 K. Lattice and electronic contribution to the thermal expansion is determined from the Gruneisen relation using electronic and lattice specific heat. This is compared with the low temperature measurements for predicting superconducting transition.
TLBM MODEL FOR THE VISCOUS HEAT DISSIPATION IN INCOMPRESSIBLE LIMIT
Authors: ZHENG LIN , SHI BAO CHANG , CHAI ZHEN HUA
Published: January 2007

The viscous dissipation term in energy equation is investigated with the lattice Boltzmann method, and the double distribution functions (DDF) are applied, respectively, to simulate the velocity and the temperature fields. Compared with other existing models, the complicated evolution equation is simplified and the energy equilibrium density function is completely independent of the density distribution function in present model [unlike the authors He et al. [J. Comput. Phys.146, 282 (1998)]], when dealing with viscous dissipation term problem. In this paper, the viscous dissipation term is directly treated as a source term and the complex space discretion in the evolution equation can also be avoided by special method in part 2. Efficiency and accuracy of present model is validated through numerical experiments on Couette and natural convection flows.
BOSONIC GUTZWILLER PROJECTION APPROACH FOR THE BOSE–HUBBARD MODEL
Authors: KOU SU-PENG , LI RONG-HUA
Published: January 2007

In this paper, a new Bosonic Gutzwiller projection approach is proposed to study the strongly correlated bosons in optical lattice. In this method, there exist many variational parameters which make us calculate the physical characters of states, including the double occupation rate and the higher occupation rates. Based on this approach, a quantum phase transition from superfluid state to Mott insulator state is obtained for the homogenous phase at unit filling.
INVESTIGATIONS ON THE SPIN HAMILTONIAN PARAMETERS FORNd3+INThGeO4
Authors: WU SHAO-YI , DONG HUI-NING
Published: January 2007

The spin Hamiltonian parameters, g factors g‖and g⊥, for Nd3+in ThGeO4are theoretically investigated from the perturbation formulas of the g factors for a 4f3ion in tetragonal symmetry. In these formulas, the contributions to the g factors from the second-order perturbation terms and the admixture of various states are taken into account. It is found that the calculated g factors of this work are smaller than the experimental results, but close to those in the previous theoretical studies by Gutowska et al. Moreover, the calculated hyperfine structure constants A‖and A⊥as well as the energies of the4I9/2Stark levels in this work are also consistent with those in the previous investigations. The discrepancy between theoretical and experimental g factors is discussed.
A CORRECTED SCALAR COUPLED-MODE THEORY FOR THE ANISOTROPIC WAVEGUIDE
Authors: LI DENG-FENG , DONG HUI-NING , ZU XIAO-TAO , QIU YI-SHEN
Published: January 2007

A new coupled-mode formulation based on scalar modes is developed for the anisotropic optical waveguide. In the new formulation, the birefringence property of the material is represented as additional coupling to the coupling due to the refractive-index perturbations. The theory is applied to the direction coupler made of parallel slab waveguides. The numerical results show that the numerical value of the birefringence coupling correction is around 10% as much as that of the refractive-index perturbation coupling for the special case.
SQUEEZING AND AMPLITUDE-SQUARED SQUEEZING IN THE MODEL OF TWO NONIDENTICAL TWO-LEVEL ATOMS
Authors: BASHKIROV E. K.
Published: January 2007

Squeezing and amplitude-squared squeezing for two two-level nonidentical atoms in lossless cavity has been investigated assuming the field to be initially in the coherent state. The time-dependent squeezing parameters have been calculated. The influence of the relative difference of two coupling constants on the squeezing parameters has been analyzed.
OUT-OF-PLANE PSEUDOGAP IN Bi2Sr2CaCu2Oy THIN FILMS GROWN ON SrTiO3 VICINAL SURFACES
Authors: TOMA V. , RAFFY H.
Published: January 2007

The out-of-plane resistivity ρc(T) is measured for Bi 2 Sr 2 CaCu 2 O 8 superconducting thin films successfully deposited by in situ magnetron RF–sputtering on vicinal (100) SrTiO 3 substrates. Oriented film with c-axis inclined with respect to the basal plane by a tilt angle α≈4° was obtained. The oxygen content of the film was changed from maximally overdoped state to strongly underdoped nonsuperconducting states. It was found that the temperature corresponding to the minimum between metallic and semiconductive behavior appears to reflect the opening of the pseudogap for transport along c-axis. We found that the opening of the pseudogap along c-axis does not coincide with pseudogap seen in ab plane.
REVISITING THE FRÖHLICH-TYPE TRANSFORMATION WHEN DEGENERATE STATES ARE PRESENT
Authors: ACQUARONE M. , VENTURA C. I.
Published: January 2007

We focus on the definition of the unitary transformation leading to an effective second order Hamiltonian, inside degenerate eigensubspaces of the non-perturbed Hamiltonian. We shall prove, by working out in detail the Su–Schrieffer–Heeger Hamiltonian case, that the presence of degenerate states, including fermions and bosons, which might seemingly pose an obstacle toward the determination of such "Fröhlich-transformed" Hamiltonian, in fact does not: we explicitly show how degenerate states may be harmlessly included in the treatment, as they contribute with vanishing matrix elements to the effective Hamiltonian matrix. In such a way, one can use without difficulty the eigenvalues of the effective Hamiltonian to describe the renormalized energies of the real excitations in the interacting system. Our argument applies also to few-body systems where one may not invoke the thermodynamic limit to get rid of the "dangerous" perturbation terms.
ALIGNING SOFTWARE PROJECT DECISIONS: A CASE STUDY
Authors: AURUM AYBÜKE , WOHLIN CLAES , PORTER ANDREW
Published: January 2007

Recent research in software engineering has highlighted the need to ensure alignment between business objectives, customer requirements and product development. If the business is to meet its strategic objectives, the Requirements Engineering (RE) activities must be executed in a manner such that they support these higher level objectives. A clear alignment between RE activities and the strategic objectives of the organization should underscore the merit of IT investment and the opportunities for competitive advantage that can be pursued as a result by the organization. This research begins with a detailed investigation of the complexity of decision-making during RE activities on business, product and project levels. Secondly, it investigates "in-project" level RE decisions and provides empirical findings from an industrial case study. The findings show that RE project related decisions are influenced by business and product requirements. Although the software developers in this study recognized the importance of developing software products that meet customer requirements and that are aligned with business objectives, they found it difficult to achieve this when the customer was external and the communication was a major problem. A lack of understanding the business strategy and a lack of communication between business, product and project level stakeholders were among the problems that are highlighted by this study.
CASE STUDIES IN PROCESS IMPROVEMENT THROUGH RETROSPECTIVE ANALYSIS OF RELEASE PLANNING DECISIONS
Authors: KARLSSON LENA , REGNELL BJÖRN , THELIN THOMAS
Published: January 2007

The process of selecting requirements for a release of a software product is challenging as the decision-making is based on uncertain predictions of customer value and development cost. This paper presents a method aimed at supporting software product development organisations in the identification of process improvement proposals to increase requirements selection quality. The method is based on an in-depth analysis of requirements selection decision outcomes after the release has been launched to the users. The method is validated in two separate case studies involving real requirements and industrial requirements engineering experts. The conclusions from the two case studies are that the method seems valuable in situations with complex release planning decisions, such as in market-driven projects. It also appears essential that participants with different viewpoints attend the root cause discussion. Requirements interdependencies seem to play a big role in release planning decision-making. In addition, successful projects can also be a source of learning.
ICRAD: AN INTEGRATED PROCESS FOR THE SOLUTION OF REQUIREMENTS CONFLICTS AND ARCHITECTURAL DESIGN
Authors: HERRMANN ANDREA , PAECH BARBARA , PLAZA DAMIAN
Published: January 2007

In order to solve requirements conflicts when developing or enhancing an IT system, it is essential to understand its architecture. Frequently, the costs for the realization of certain requirements are a decision criterion. Requirements negotiation and architectural design must be treated together, as conflicts cannot be solved before the architecture has been designed. So far, no integrated process exists which clearly defines input and output among these activities, and which takes into account a variety of different types of dependencies among requirements and between requirements and architecture.

In this paper, we develop a detailed iterative process named ICRAD (Integrated Conflict Resolution and Architectural Design). ICRAD integrates requirements negotiation and architectural design and takes into account nine types of dependencies. We define three types of requirements conflicts. We also present a case study.
BRINGING THE AGILE PHILOSOPHY TO FORMAL SPECIFICATION SETTINGS
Authors: LÓPEZ-NORES MARTÍN , PAZOS-ARIAS JOSÉ J. , GARCÍA-DUQUE JORGE , BLANCO-FERNÁNDEZ YOLANDA , DÍAZ-REDONDO REBECA P. , FERNÁNDEZ-VILAS ANA , GIL-SOLLA ALBERTO , RAMOS-CABRER MANUEL
Published: January 2007

Software development can be seen as a process of knowledge acquisition, in which human beings progressively learn about the intended behavior of the desired systems. Thereby, development is subject to considerable amounts of uncertainty and variability, that make it impossible to proceed in a purely incremental fashion — at some points, the need always arises to reconsider part of the accumulated knowledge. With this problem in mind, agile development methodologies have been gaining popularity in recent years as a means to enhance productivity, and there have been attempts to supplement them with formal techniques for better reliability. However, the existing approaches to agile formal methods have practically limited themselves to adopting recommended practices of agile development, with no particular contribution from the employed formalisms. Compared to that, this paper advocates the use of formalisms intended for evolutionary development, with a two-fold objective: first, to exploit the knowledge acquired up to any given stage as a means to cope with frequent and numerous changes; and, second, to introduce support for the creative development tasks through an interactive procedure that helps taking steps forward.
Exercise-induced activation of cardiac sympathetic nerve triggers cardioprotection via redox-sensitive activation of eNOS and upregulation of iNOS
Authors: Akita Yuzo , Otani Hajime , Matsuhisa Seiji , Kyoi Shiori , Enoki Chiharu , Hattori Reiji , Imamura Hiroji , Kamihata Hiroshi , Kimura Yutaka , Iwasaka Toshiji
Published: January 2007

We investigated the mechanism of exercise-induced late cardioprotection against ischemia-reperfusion (I/R) injury. C57BL/6 mice received treadmill exercise (60 min/day) for 7 days at a work rate of 60–70% maximal oxygen uptake. Exercise transiently increased oxidative stress and activated endothelial isoform of nitric oxide synthase (eNOS) during exercise and increased expression of inducible isoform of NOS (iNOS) in the heart after 7 days of exercise. The mice were subjected to regional ischemia by 30 min of occlusion of the left coronary artery, followed by 2 h of reperfusion. Infarct size was significantly smaller in the exercised mice. Ablation of cardiac sympathetic nerve by topical application of phenol abolished oxidative stress, activation of eNOS, upregulation of iNOS, and cardioprotection mediated by exercise. Treatment with the antioxidant N-(2-mercaptopropionyl)-glycine during exercise also inhibited activation of eNOS, upregulation of iNOS, and cardioprotection. In eNOS−/− mice, exercise-induced oxidative stress was conserved, but upregulation of iNOS and cardioprotection was lost. Exercise did not confer cardioprotection when the iNOS selective inhibitor 1400W was administered just before coronary artery occlusion or when iNOS−/− mice were employed. These results suggest that exercise stimulates cardiac sympathetic nerves that provoke redox-sensitive activation of eNOS, leading to upregulation of iNOS, which acts as a mediator of late cardioprotection against I/R injury.
Expression of nestin in the podocytes of normal and diseased human kidneys
Authors: Su Wei , Chen Jing , Yang Haichun , You Li , Xu Lan , Wang Xiang , Li Ruixi , Gao Lu , Gu Yong , Lin Shanyan , Xu Hong , Breyer Matthew D. , Hao Chuan-Ming
Published: January 2007

The complex cyto-architecture of the podocyte is critical for glomerular permselectivity. The present study characterizes the expression of nestin, an intermediate filament protein, in human kidneys. In normal kidneys, nestin was detected at the periphery of glomerular capillary loops. Colabeling showed nestin was expressed in WT1-positive cells. Within the podocyte, nestin immunoreactivity was present in the cell body and primary process. This was supported by immunoelectron microscopy. Nestin also colocalized with vimentin in the periphery of capillary loops but not in the mesangium. Nestin was not detected in other structures of the adult human kidney. To determine the potential role of nestin in proteinuria, nestin was examined in kidney biopsies from patients with or without proteinuria. These patients were diagnosed with IgA nephropathy with mild mesangial expansion but without proteinuria, IgA nephropathy with proteinuria, membranous nephropathy (MN), and focal segmental glomerular sclerosis (FSGS). The distribution of nestin in these biopsies was similar to that in the normal kidney. Semiquantitative analysis of immunostaining showed that glomerular nestin expression in IgA nephropathy without proteinuria was not different from normal kidney; however, nestin expression in kidneys of patients with IgA nephropathy and proteinuria, or MN and FSGS with proteinuria was significantly reduced compared with normal kidney ( P < 0.01). Reduced nestin mRNA expression in the patients with IgA nephropathy with proteinuria and FSGN was also observed by quantitative real-time PCR. These studies suggest that nestin may play an important role in maintaining normal podocyte function in the human kidney.
Scaling of postcontractile phosphocreatine recovery in fish white muscle: effect of intracellular diffusion
Authors: Nyack Albert C. , Locke Bruce R. , Valencia Alejandro , Dillaman Richard M. , Kinsey Stephen T.
Published: January 2007

In some fish, hypertrophic growth of white muscle leads to very large fibers. The associated low-fiber surface area-to-volume ratio (SA/V) and potentially long intracellular diffusion distances may influence the rate of aerobic processes. We examined the effect of intracellular metabolite diffusion on mass-specific scaling of aerobic capacity and an aerobic process, phosphocreatine (PCr) recovery, in isolated white muscle from black sea bass ( Centropristis striata). Muscle fiber diameter increased during growth and was >250 μm in adult fish. Mitochondrial volume density and cytochrome- c oxidase activity had similar small scaling exponents with increasing body mass (−0.06 and −0.10, respectively). However, the mitochondria were more clustered at the sarcolemmal membrane in large fibers, which may offset the low SA/V, but leads to greater intracellular diffusion distances between mitochondrial clusters and ATPases. Despite large differences in intracellular diffusion distances, the postcontractile rate of PCr recovery was largely size independent, with a small scaling exponent for the maximal rate (−0.07) similar to that found for the indicators of aerobic capacity. Consistent with this finding, a mathematical reaction-diffusion analysis indicated that the resynthesis of PCr (and other metabolites) was too slow to be substantially limited by diffusion. These results suggest that the recovery rate in these fibers is primarily limited by low mitochondrial density. Additionally, the change in mitochondrial distribution with increasing fiber size suggests that low SA/V and limited O2flux are more influential design constraints in fish white muscle, and perhaps other fast-twitch vertebrate muscles, than is intracellular metabolite diffusive flux.
Investigation of the mechanisms by which chronic infusion of an acutely subpressor dose of angiotensin II induces hypertension
Authors: Hood S. G. , Cochrane T. , McKinley M. J. , May C. N.
Published: January 2007

The mechanisms by which chronic infusion of an initially subpressor low dose of angiotensin II (ANG II) causes a progressive and sustained hypertension remain unclear. In conscious sheep ( n = 6), intravenous infusion of ANG II (2 μg/h) gradually increased mean arterial pressure (MAP) from 82 ± 3 to 96 ± 5 mmHg over 7 days ( P < 0.001). This was accompanied by peripheral vasoconstriction; total peripheral conductance decreased from 44.6 ± 6.4 to 38.2 ± 6.7 ml·min−1·mmHg−1 ( P < 0.001). Cardiac output and heart rate were unchanged. In the regional circulation, mesenteric, renal, and iliac conductances decreased but blood flows were unchanged. There was no coronary vasoconstriction, and coronary blood flow increased. Ganglion blockade (125 mg/h hexamethonium for 4 h) reduced MAP by 13 ± 1 mmHg in the control period and by 7 ± 2 mmHg on day 8 of ANG II treatment. Inhibition of central AT1 receptors by intracerebroventricular infusion of losartan (1 mg/h for 3 h) had no effect on MAP in the control period or after 7 days of ANG II infusion. Pressor responsiveness to incremental doses of intravenous ANG II (5, 10, 20 μg/h, each for 15 min) was unchanged after 7 days of ANG II infusion. ANG II caused no sodium or water retention. In summary, hypertension due to infusion of a low dose of ANG II was accompanied by generalized peripheral vasoconstriction. Indirect evidence suggested that the hypertension was not neurogenic, but measurement of sympathetic nerve activity is required to confirm this conclusion. There was no evidence for a role for central angiotensinergic mechanisms, increased pressor responsiveness to ANG II, or sodium and fluid retention.
Rest-inserted loading rapidly amplifies the response of bone to small increases in strain and load cycles
Authors: Srinivasan Sundar , Ausk Brandon J. , Poliachik Sandra L. , Warner Sarah E. , Richardson Thomas S. , Gross Ted S.
Published: January 2007

We hypothesized that a 10-s rest interval (at zero load) inserted between each load cycle would increase the osteogenic effects of mechanical loading near previously identified thresholds for strain magnitude and cycle numbers. We tested our hypothesis by subjecting the right tibiae of female C57BL/6J mice (16 wk, n = 70) to exogenous mechanical loading within a peri-threshold physiological range of strain magnitudes and load cycle numbers using a noninvasive murine tibia loading device. Bone responses to mechanical loading were determined via dynamic histomorphometry. More specifically, we contrasted bone formation induced by cyclic vs. rest-inserted loading (10-s rest at zero load inserted between each load cycle) by first varying peak strains (1,000, 1,250, or 1,600 με) at fixed cycle numbers (50 cycles/day, 3 days/wk for 3 wk) and then varying cycle numbers (10, 50, or 250 cycles/day) at a fixed strain magnitude (1,250 με). Within the range of strain magnitudes tested, the slope of periosteal bone formation rate (p.BFR/BS) with increasing strain magnitudes was significantly increased by rest-inserted compared with cyclical loading. Within the range of load cycles tested, the slope of p.BFR/BS with increasing load cycles of rest-inserted loading was also significantly increased by rest-inserted compared with cyclical loading. In sum, the data of this study indicate that inserting a 10-s rest interval between each load cycle amplifies bone's response to mechanical loading, even within a peri-threshold range of strain magnitudes and cycle numbers.
In vivo characterization of lung morphology and function in anesthetized free-breathing mice using micro-computed tomography
Authors: Ford N. L. , Martin E. L. , Lewis J. F. , Veldhuizen R. A. W. , Drangova M. , Holdsworth D. W.
Published: January 2007

Lung morphology and function in human subjects can be monitored with computed tomography (CT). Because many human respiratory diseases are routinely modeled in rodents, a means of monitoring the changes in the structure and function of the rodent lung is desired. High-resolution images of the rodent lung can be attained with specialized micro-CT equipment, which provides a means of monitoring rodent models of lung disease noninvasively with a clinically relevant method. Previous studies have shown respiratory-gated images of intubated and respirated mice. Although the image quality and resolution are sufficient in these studies to make quantitative measurements, these measurements of lung structure will depend on the settings of the ventilator and not on the respiratory mechanics of the individual animals. In addition, intubation and ventilation can have unnatural effects on the respiratory dynamics of the animal, because the airway pressure, tidal volume, and respiratory rate are selected by the operator. In these experiments, important information about the symptoms of the respiratory disease being studied may be missed because the respiration is forced to conform to the ventilator settings. In this study, we implement a method of respiratory-gated micro-CT for use with anesthetized free-breathing rodents. From the micro-CT images, quantitative analysis of the structure of the lungs of healthy unconscious mice was performed to obtain airway diameters, lung and airway volumes, and CT densities at end expiration and during inspiration. Because the animals were free breathing, we were able to calculate tidal volume (0.09 ± 0.03 ml) and functional residual capacity (0.16 ± 0.03 ml).
Endurance training restores peritoneal macrophage function in post-MI congestive heart failure rats
Authors: Batista M. L. , Santos R. V. T. , Oliveira E. M. , Seelaender M. C. L. , Costa Rosa L. F. B. P.
Published: January 2007

Congestive heart failure (CHF) induces a state of immune activation, and peritoneal macrophages (Mφs) may play an important role in the development and progression of one such condition. Moderate endurance training modulates peritoneal Mφ function. We evaluated the effect of endurance training on different stages of the phagocytic process and in the production of interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) after LPS stimulation. Either ligation of the left coronary artery or Sham operations were performed in adult Wistar rats. After 4 wk, control (Sham operated) and MI (ligation of the left coronary artery) animals were randomly assigned to either a sedentary (Sham-operated sedentary, n = 7 and MI sedentary, n = 10) or a trained group (Sham-operated trained, n = 8 and MI trained, n = 8). Trained rats ran on a treadmill (0% grade at 13–20 m/min) for 60 min/day, 5 days/wk, for 8–10 wk, whereas sedentary rats had only limited activity. Training increased maximal oxygen uptake normalized for body weight (ml·kg−1·min−1), as well as skeletal muscle citrate synthase maximal activity, when compared with sedentary groups. The resident and total cell number, the chemotaxis index, and the production of TNF-α stimulated by LPS were significantly higher in the MI sedentary group when compared with the Sham sedentary group. Moderate endurance training reversed these alterations promoted by post-MI. These results demonstrate that moderate intensity exercise training modulates peritoneal Mφ function and induces beneficial metabolic effects in rats with post-MI CHF.
Adapter molecule DOC-2 is differentially expressed in pressure and volume overload hypertrophy and inhibits collagen synthesis in cardiac fibroblasts
Authors: Kumbar Deepa H. , VanBergen Andrew , Ocampo Catherina , Muangmingsuk Sunthorn , Griffin Andrew J. , Gupta Madhu
Published: January 2007

DOC-2 (differentially expressed in ovarian carcinoma) is involved in Ras-, β-integrin-, PKC-, and transforming growth factor-β-mediated cell signaling. These pathways are implicated in the accumulation of extracellular matrix proteins during progression of hypertrophy to heart failure; however, the role of DOC-2 in cardiac pathophysiology has never been examined. This study was undertaken to 1) analyze DOC-2 expression in primary cultures of cardiac fibroblasts and cardiac myocytes and in the heart following different types of hemodynamic overloads and 2) examine its role in growth factor-mediated ERK activation and collagen production. Pressure overload and volume overload were induced for 10 wk in Sprague-Dawley rats by aortic constriction and by aortocaval shunt, respectively. ANG II (0.3 mg·kg−1·day−1) was infused for 2 wk. Results showed that, compared with myocytes, DOC-2 was found abundantly expressed in cardiac fibroblasts. Treatment of cardiac fibroblasts with ANG II and TPA resulted in increased expression of DOC-2. Overexpression of DOC-2 in cardiac fibroblasts led to inhibition of hypertrophy agonist-stimulated ERK activation and collagen expression. An inverse correlation between collagen and DOC-2 was observed in in vivo models of cardiac hypertrophy; in pressure overload and after ANG II infusion, increased collagen mRNA correlated with reduced DOC-2 levels, whereas in volume overload increased DOC-2 levels were accompanied by unchanged collagen mRNA. These data for the first time describe expression of DOC-2 in the heart and demonstrate its modulation by growth-promoting agents in cultured cardiac fibroblasts and in in vivo models of heart hypertrophy. Results suggest a role of DOC-2 in cardiac remodeling involving collagen expression during chronic hemodynamic overload.
Role of ischemia and deformation in the onset of compression-induced deep tissue injury: MRI-based studies in a rat model
Authors: Stekelenburg Anke , Strijkers Gustav J. , Parusel Henry , Bader Dan L. , Nicolay Klaas , Oomens Cees W.
Published: January 2007

A rat model was used to distinguish between the different factors that contribute to muscle tissue damage related to deep pressure ulcers that develop after compressive loading. The separate and combined effects of ischemia and deformation were studied. Loading was applied to the hindlimb of rats for 2 h. Muscle tissue was examined using MR imaging (MRI) and histology. An MR-compatible loading device allowed simultaneous loading and measurement of tissue status. Two separate loading protocols incorporated uniaxial loading, resulting in tissue compression and ischemic loading. Uniaxial loading was applied to the tibialis anterior by means of an indenter, and ischemic loading was accomplished with an inflatable tourniquet. Deformation of the muscle tissue during uniaxial loading was measured using MR tagging. Compression of the tissues for 2 h led to increased T2 values, which were correlated to necrotic regions in the tibialis anterior. Perfusion measurements, by means of contrast-enhanced MRI, indicated a large ischemic region during indentation. Pure ischemic loading for 2 h led to reversible tissue changes. From the MR-tagging experiments, local strain fields were calculated. A 4.5-mm deformation, corresponding to a surface pressure of 150 kPa, resulted in maximum shear strain up to 1.0. There was a good correlation between the location of damage and the location of high shear strain. It was concluded that the large deformations, in conjunction with ischemia, provided the main trigger for irreversible muscle damage.
Programmed Cell Death-4 Tumor Suppressor Protein Contributes to Retinoic Acid–Induced Terminal Granulocytic Differentiation of Human Myeloid Leukemia Cells
Authors: Ozpolat Bulent , Akar Ugur , Steiner Michael , Zorrilla-Calancha Isabel , Tirado-Gomez Maribel , Colburn Nancy , Danilenko Michael , Kornblau Steven , Lopez Berestein Gabriel
Published: January 2007

Programmed cell death-4 (PDCD4) is a recently discovered tumor suppressor protein that inhibits protein synthesis by suppression of translation initiation. We investigated the role and the regulation of PDCD4 in the terminal differentiation of acute myeloid leukemia (AML) cells. Expression of PDCD4 was markedly up-regulated during all-trans retinoic acid (ATRA)–induced granulocytic differentiation in NB4 and HL60 AML cell lines and in primary human promyelocytic leukemia (AML-M3) and CD34+ hematopoietic progenitor cells but not in differentiation-resistant NB4.R1 and HL60R cells. Induction of PDCD4 expression was associated with nuclear translocation of PDCD4 in NB4 cells undergoing granulocytic differentiation but not in NB4.R1 cells. Other granulocytic differentiation inducers such as DMSO and arsenic trioxide also induced PDCD4 expression in NB4 cells. In contrast, PDCD4 was not up-regulated during monocytic/macrophagic differentiation induced by 1,25-dihydroxyvitamin D3 or 12-O-tetradecanoyl-phorbol-13-acetate in NB4 cells or by ATRA in THP1 myelomonoblastic cells. Knockdown of PDCD4 by RNA interference (siRNA) inhibited ATRA-induced granulocytic differentiation and reduced expression of key proteins known to be regulated by ATRA, including p27Kip1 and DAP5/p97, and induced c-myc and Wilms' tumor 1, but did not alter expression of c-jun, p21Waf1/Cip1, and tissue transglutaminase (TG2). Phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway was found to regulate PDCD4 expression because inhibition of PI3K by LY294002 and wortmannin or of mTOR by rapamycin induced PDCD4 protein and mRNA expression. In conclusion, our data suggest that PDCD4 expression contributes to ATRA-induced granulocytic but not monocytic/macrophagic differentiation. The PI3K/Akt/mTOR pathway constitutively represses PDCD4 expression in AML, and ATRA induces PDCD4 through inhibition of this pathway. (Mol Cancer Res 2007;5(1):95–108)
Regulation of IκB Kinase ε Expression by the Androgen Receptor and the Nuclear Factor-κB Transcription Factor in Prostate Cancer
Authors: Péant Benjamin , Diallo Jean-Simon , Lessard Laurent , Delvoye Nathalie , Le Page Cécile , Saad Fred , Mes-Masson Anne-Marie
Published: January 2007

Although several genes have been associated with prostate cancer progression, it is clear that we are far from understanding all the molecular events implicated in the initiation and progression of the disease to a hormone-refractory state. The androgen receptor is a central player in the initiation and proliferation of prostate cancer and its response to hormone therapy. Nuclear factor-κB has important proliferative and antiapoptotic activities that could contribute to the development and progression of cancer cells as well as resistance to therapy. In this study, we report that IκB kinase ε (IKKε), which is controlled by nuclear factor-κB in human chondrocytes, is expressed in human prostate cancer cells. We show that IKKε gene expression is stimulated by tumor necrosis factor-α treatment in LNCaP cells and is inhibited by transfection of a dominant-negative form of IκBα, which prevents the nuclear translocation of p65. Furthermore, we found that tumor necrosis factor-α–induced IKKε expression is inhibited by an androgen analogue (R1881) in androgen-sensitive prostate cancer cells and that this inhibition correlates with the modulation of IκBα expression by R1881. We also noted constitutive IKKε expression in androgen-independent PC-3 and DU145 cells. To our knowledge, this is the first report of an IκB kinase family member whose expression is modulated by androgen and deregulated in androgen receptor–negative cells. (Mol Cancer Res 2007;5(1):87–94)
Roles of Aurora Kinases in Mitosis and Tumorigenesis
Authors: Fu Jingyan , Bian Minglei , Jiang Qing , Zhang Chuanmao
Published: January 2007

Aurora kinases, which have been implicated in several vital events in mitosis, represent a protein kinase family highly conserved during evolution. The activity of Aurora kinases is delicately regulated, mainly by phosphorylation and degradation. Deregulation of Aurora kinase activity can result in mitotic abnormality and genetic instability, leading to defects in centrosome function, spindle assembly, chromosome alignment, and cytokinesis. Both the expression level and the kinase activity of Aurora kinases are found to be up-regulated in many human cancers, indicating that these kinases might serve as useful targets for the development of anticancer drugs. This review focuses on recent progress on the roles of Aurora kinases in mitosis and tumorigenesis. (Mol Cancer Res 2007;5(1):1–10)
Estrogen-Related Receptor α1 Transcriptional Activities Are Regulated in Part via the ErbB2/HER2 Signaling Pathway
Authors: Ariazi Eric A. , Kraus Richard J. , Farrell Michael L. , Jordan V. Craig , Mertz Janet E.
Published: January 2007

We previously showed that (a) estrogen-related receptor α1 (ERRα1) down-modulates estrogen receptor (ER)–stimulated transcription in low ErbB2–expressing MCF-7 mammary carcinoma cells, and (b) ERRα and ErbB2 mRNA levels positively correlate in clinical breast tumors. We show here that ERRα1 represses ERα-mediated activation in MCF-7 cells because it failed to recruit the coactivator glucocorticoid receptor interacting protein 1 (GRIP1) when bound to an estrogen response element. In contrast, ERRα1 activated estrogen response element– and ERR response element–mediated transcription in ERα-positive, high ErbB2–expressing BT-474 mammary carcinoma cells, activation that was enhanced by overexpression of GRIP1. Likewise, regulation of the endogenous genes pS2, progesterone receptor, and ErbB2 by ERRα1 reflected the cell type–specific differences observed with our reporter plasmids. Importantly, overexpression of activated ErbB2 in MCF-7 cells led to transcriptional activation, rather than repression, by ERRα1. Two-dimensional PAGE of radiophosphate-labeled ERRα1 indicated that it was hyperphosphorylated in BT-474 relative to MCF-7 cells; incubation of these cells with anti-ErbB2 antibody led to reduction in the extent of ERRα1 phosphorylation. Additionally, mitogen-activated protein kinases (MAPK) and Akts, components of the ErbB2 pathway, phosphorylated ERRα1 in vitro. ERRα1-activated transcription in BT-474 cells was inhibited by disruption of ErbB2/epidermal growth factor receptor signaling with trastuzumab or gefitinib or inactivation of downstream components of this signaling, MAPK kinase/MAPK, and phosphatidylinositol-3-OH kinase/Akt, with U0126 or LY294002, respectively. Thus, ERRα1 activities are regulated, in part, via ErbB2 signaling, with ERRα1 likely positively feedback-regulating ErbB2 expression. Taken together, we conclude that ERRα1 phosphorylation status shows potential as a biomarker of clinical course and antihormonal- and ErbB2-based treatment options, with ERRα1 serving as a novel target for drug development. (Mol Cancer Res 2007;5(1):71–86)
Functional Characterization of a Novel BRCA1-Null Ovarian Cancer Cell Line in Response to Ionizing Radiation
Authors: DelloRusso Christiana , Welcsh Piri L. , Wang Weixin , Garcia Rochelle L. , King Mary-Claire , Swisher Elizabeth M.
Published: January 2007

The breast and ovarian cancer susceptibility gene BRCA1 plays a major role in the DNA damage response pathway. The lack of well-characterized human BRCA1-null cell lines has limited the investigation of BRCA1 function, particularly with regard to its role in ovarian cancer. We propagated a novel BRCA1-null human ovarian cancer cell line UWB1.289 from a tumor of papillary serous histology, the most common form of ovarian carcinoma. UWB1.289 carries a germline BRCA1 mutation within exon 11 and has a deletion of the wild-type allele. UWB1.289 is estrogen and progesterone receptor negative and has an acquired somatic mutation in p53, similar to the commonly used BRCA1-null breast cancer cell line HCC1937. We used ionizing radiation to induce DNA damage in both UWB1.289 and in a stable UWB1.289 line in which wild-type BRCA1 was restored. We examined several responses to DNA damage in these cell lines, including sensitivity to radiation, cell cycle checkpoint function, and changes in gene expression using microarray analysis. We observed that UWB1.289 is sensitive to ionizing radiation and lacks cell cycle checkpoint functions that are a normal part of the DNA damage response. Restoration of wild-type BRCA1 function in these cells partially restores DNA damage responses. Expression array analysis not only supports this partial functional correction but also reveals interesting new information regarding BRCA1-positive regulation of the expression of claudin 6 and other metastasis-associated genes and negative regulation of multiple IFN-inducible genes. (Mol Cancer Res 2007;5(1):35–45)
Renal Effects of Long-Term Ciclosporin A Treatment in a Large Animal Model
Authors: Cibulskyte Donata , Samsoe Engberg Anne , Hanefelt Kristensen Daniel , Ellingsen Anne Ringer , Pedersen Michael , Hoerlyck Arne , Flyvbjerg Allan , Marcussen Niels , Hansen Hans Erik , Madsen Melvin , Mortensen Jens
Published: January 2007

Background: Most experimental studies of chronic ciclosporin A (CsA) nephrotoxicity have been performed in rodents; however, the pig possesses several advantages. The aim of this study was to investigate renal functional and structural changes during CsA treatment with 20 mg/kg/day for 6 months in a pig model. Methods: Göttingen minipigs were randomized to oral CsA treatment or as controls. At 0, 5, 10, 15, 20 and 25 weeks body weight, blood pressure, serum creatinine, and whole blood CsA levels were measured. Magnetic resonance imaging was used to estimate relative glomerular filtration rate (rGFR), renal blood flow (RBF), kidney length and volume. Renal vascular resistance (RVR) was calculated. Kidney tissue biopsies were taken and volume fraction of cortical interstitial tissue estimated by a stereology-based method. Results: CsA induced significant increases in serum creatinine, blood pressure, RVR, and a significant decrease in RBF. Furthermore, renal volume increased significantly. This finding was inversely related to the decrease in RBF and initially followed by an increase in rGFR, which then decreased. No significant histopathological kidney changes were observed. Conclusion: CsA treatment with 20 mg/kg/day for 6 months causes increased serum creatinine, blood pressure, RVR, and renal volume along with a decrease in RBF in accordance with data obtained in humans. The initial temporal changes in renal volume and function during CsA administration have similarities to the functional changes seen in early diabetes.
Natural History of Postobstructive Nephropathy: A Single-Center Retrospective Study
Authors: Ravanan Rommel , Tomson Charles R.V.
Published: January 2007

Background: There is extensive published material on the effects of experimental ureteric obstruction. In contrast, there is very little literature on the natural history of postobstructive renal disease in patients. Methods: Patients presenting with obstructive nephropathy and renal impairment in a tertiary renal unit, and whose obstruction was successfully relieved, were identified, and the Modification of Diet in Renal Disease equation was used to calculate the glomerular filtration rate (GFR) at presentation and after relief of obstruction. Results: 104 patients were identified (79 male). There were 9 deaths at 12 months and a further 4 deaths by 3 years; losses to follow-up were 7 and 20 at the same time points. The mean GFR was 9.2 ± (SEM) 0.9 ml/min at presentation (n = 104), 27.8 ± 1.7 ml/min at 3 months (n = 98), 29.0 ± 1.8 ml/min at 12 months (n = 79), and 30.0 ± 2.2 ml/min at 3 years (n = 61). Of 28 patients initially requiring dialysis, 6 were dialysis dependent at 3 months; 3 further patients, all with GFR <10 ml/min after relief of obstruction, required dialysis by 12 months and 1 further patient by 3 years. Conclusions: Progressive deterioration in renal function is unusual after relief of obstruction in the majority of patients over a 3-year period. This relative stability in human postobstructive nephropathy contrasts with the course of remnant nephropathy in animal models.