bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatial Vector Solitons in Nonlinear Photonic Crystal Fibers
Authors: Salgueiro José R. , Kivshar Yuri S. , Pelinovsky Dmitry E. , Simón Verónica , Michinel Humberto
Published: July 2005

We study spatial vector solitons in a photonic crystal fiber (PCF) made of a material with the focusing Kerr nonlinearity. We show that such two‐component localized nonlinear waves consist of two mutually trapped components confined by the PCF linear and the self‐induced nonlinear refractive indices, and they bifurcate from the corresponding scalar solitons. We demonstrate that, in a sharp contrast with an entirely homogeneous nonlinear Kerr medium where both scalar and vector spatial solitons are unstable and may collapse, the periodic structure of PCF can stabilize the otherwise unstable two‐dimensional spatial optical solitons. We apply the matrix criterion for stability of these two‐parameter solitons, and verify it by direct numerical simulations.
Partially Coherent Waves in Nonlinear Periodic Lattices
Authors: Buljan H. , Bartal G. , Cohen O. , Schwartz T. , Manela O. , Carmon T. , Segev M. , Fleischer J. W. , Christodoulides D. N.
Published: July 2005

We study the propagation of partially coherent (random‐phase) waves in nonlinear periodic lattices. The dynamics in these systems is governed by the threefold interplay between the nonlinearity, the lattice properties, and the statistical (coherence) properties of the waves. Such dynamic interplay is reflected in the characteristic properties of nonlinear wave phenomena (e.g., solitons) in these systems. While the propagation of partially coherent waves in nonlinear periodic systems is a universal problem, we analyze it in the context of nonlinear photonic lattices, where recent experiments have proven their existence.
Optical Soliton Bullets in (2+1)D Nonlinear Bragg Resonant Periodic Geometries
Authors: Dohnal Tomáš , Aceves Alejandro B.
Published: July 2005

We consider light propagation in a Kerr‐nonlinear 2D waveguide with a Bragg grating in the propagation direction and homogeneous in the transverse direction. Using Newton's iteration method we construct both stationary and travelling solitary wave solutions of the corresponding mathematical model, the 2D nonlinear coupled mode equations (2D CME). We call these solutions 2D gap solitons due to their similarity with the gap solitons of 1D CME (fiber grating). Long‐time stable evolution preserving the solitary fashion is demonstrated numerically despite the fact that, as we show, for the 2D CME no local constrained minima of the Hamiltonian functional exist. Building on the 1D study of [1], we demonstrate trapping of slow enough 2D gap solitons at localized defects. We explain the mechanism of trapping as resonant transfer of energy from the soliton to one or more nonlinear defect modes. For a special class of defects, we construct a family of nonlinear defect modes by numerically following a bifurcation curve starting at analytically or numerically known linear defect modes. Compared to 1D the dynamics of trapping are harder to fully analyze and the existence of many defect modes for a given defect potential causes that slow solitons store a part of their energy for virtually all of the studied attractive defects.
Dynamic Photonic Structures: Stopping, Storage, and Time Reversal of Light
Authors: Yanik Mehmet F. , Fan Shanhui
Published: July 2005

The use of dynamic photonic structures opens fascinating new possibilities for controlling the properties of light. The general idea is to create a coupled resonator array such that a light pulse can be held in the structure for a sufficiently long time, and to modulate the refractive index of the system while the pulse is in the system. Doing so allows the spectrum of the pulse to be molded almost arbitrarily with small refractive index modulations, leading to highly nontrivial information‐processing capabilities on chip. As examples of such capabilities, here we show that light pulses can be stopped, stored, and time‐reversed with these dynamic systems.
Poor relief, labourers’ households and living standards in rural England c.1770–1834: a Bedfordshire case study1
Authors: WILLIAMS SAMANTHA
Published: July 2005

This article estimates the contribution of poor relief to the household economies of the labouring poor in the two case‐study communities of Campton and Shefford, east Bedfordshire, and thereby throws further light on the standard of living of workers during industrialization in the south and east. Utilizing the technique of nominal record linkage between poor law sources and family reconstitution for the period c.1770—c.1834, the article charts the growth in social welfare and estimates the proportion of inhabitants benefiting from regular relief payments, the changing family circumstances of recipients, and the proportion of total income made up by poor relief.
Capital deepening and the rise of the factory: the American experience during the nineteenth century1
Authors: ATACK JEREMY , BATEMAN FRED , MARGO ROBERT A.
Published: July 2005

Between 1850 and 1880, capital per worker in United States manufacturing increased on average by at least 75 per cent, even after taking account of declining capital goods prices. During this same period, production shifted from small, labour‐intensive artisan shops to large capital‐intensive factories. Similar changes have occurred in many other countries at the same stage of industrialization. Establishment‐level data from the federal censuses of manufacturing, however, reveal that the shift in production in the United States accounts for a modest amount of the increased capital per worker. There, at least, capital deepening seems to have occurred in almost all firms everywhere.
Local transfer of prostaglandin E2 into the ovary and its retrograde transfer into the uterus in early pregnant sows
Authors: Stefańczyk‐Krzymowska Stanisława , Chłopek Jolanta , Grzegorzewski Waldemar , Radomski Michał
Published: July 2005

This study was designed to establish (a) whether prostaglandin E2 (PGE2) can reach the ovary and oviduct by a local pathway and what is the contribution of lymphatic vessels to this transfer, and (b) whether PGE2 can permeate from venous and lymphatic vessels of the mesometrium to arterial blood and be delivered to the uterine horn during maternal recognition of pregnancy in gilts. The reproductive tract was excised from gilts (n= 10) on day 14 after mating. The uterine horn was isolated with the ovary and broad ligament and perfused with warmed and oxygenated autologous blood. A total dose of 5.5 × 107 disintegrations per min (d.p.m.) (49 ng) [3H]PGE2 was infused into the small branches of the uterine vein on the broad ligament or into the lymphatic vessels. Frequent blood samples were collected from the branch of the uterine artery and from the venous effluent. Tissue samples were collected from the uterine horn, the ovary and the broad ligament. The concentration of [3H]PGE2 was significantly higher in the ovary (P < 0.001), oviduct (P < 0.01), endometrium (P < 0.01), myometrium (P < 0.001) and mesometrium (P < 0.001) after infusion of [3H]PGE2 into lymphatic vessels than into the branches of the uterine vein. In contrast, the concentration of [3H]PGE2 was significantly higher in arterial blood supplying the uterine horn (P < 0.01) and in the venous effluent (P < 0.001) after infusion of [3H]PGE2 into the branches of the uterine vein than into lymphatic vessels. These results demonstrated local transfer of [3H]PGE2 into the ovary, oviduct and uterine horn from lymphatic and venous vessels of the mesometrium. However, the efficiency of this transfer was considerably higher after infusion into lymphatic vessels than into branches of the ovarian vein. We conclude that the lymphatic pathway is a fundamental mechanism in the local transfer of PGE2 from the uterus to the ovary and oviduct during early pregnancy in the pig.
Factors mediating powerful voltage attenuation along CA1 pyramidal neuron dendrites
Authors: Golding Nace L. , Mickus Timothy J. , Katz Yael , Kath William L. , Spruston Nelson
Published: July 2005

We performed simultaneous patch‐electrode recordings from the soma and apical dendrite of CA1 pyramidal neurons in hippocampal slices, in order to determine the degree of voltage attenuation along CA1 dendrites. Fifty per cent attenuation of steady‐state somatic voltage changes occurred at a distance of 238 μm from the soma in control and 409 μm after blocking the hyperpolarization‐activated (H) conductance. The morphology of three neurons was reconstructed and used to generate computer models, which were adjusted to fit the somatic and dendritic voltage responses. These models identify several factors contributing to the voltage attenuation along CA1 dendrites, including high axial cytoplasmic resistivity, low membrane resistivity, and large H conductance. In most cells the resting membrane conductances, including the H conductances, were larger in the dendrites than the soma. Simulations suggest that synaptic potentials attenuate enormously as they propagate from the dendrite to the soma, with greater than 100‐fold attenuation for synapses on many small, distal dendrites. A prediction of this powerful EPSP attenuation is that distal synaptic inputs are likely only to be effective in the presence of conductance scaling, dendritic excitability, or both.
Proton sensitivity of ASIC1 appeared with the rise of fishes by changes of residues in the region that follows TM1 in the ectodomain of the channel
Authors: Coric Tatjana , Zheng Deyou , Gerstein Mark , Canessa Cecilia M.
Published: July 2005

The acid‐sensitive ion channel 1 (ASIC1) is a neuronal Na+ channel insensitive to changes in membrane potential but is gated by external protons. Proton sensitivity is believed to be essential for the role of ASIC1 in modulating synaptic transmission and nociception in the mammalian nervous system. To examine the structural determinants that confer proton sensitivity, we cloned and functionally characterized ASIC1 from different species of the chordate lineage: lamprey, shark, toadfish and chicken. We observed that ASIC1s from early vertebrates (lamprey and shark) were proton insensitive in spite of a high degree of amino acid conservation (66–67%) with their mammalian counterparts. Sequence analysis showed that proton‐sensitive ASIC1s could not be distinguished from proton‐insensitive channels by any signature in the protein sequence. Chimeras made with rat ASIC1 (rASIC1) and lamprey or shark indicated that most of the ectodomain of rASIC1 was required to confer proton sensitivity and the distinct kinetics of activation and desensitization of the rat channel. Proton‐sensitive chimeras contained the segment D78–E136, together with residues D351, Q358 and E359 of the rat sequence. However, none of the functional chimeras containing only part of the rat extracellular domain retained the kinetics of activation and desensitization of rASIC1, suggesting that residues distributed in several regions of the ectodomain contribute to allosteric changes underlying activation and desensitization. The results also demonstrate that gating by protons is not a feature common to all ASIC1 channels. Proton sensitivity arose recently in evolution, implying that agonists different from protons activate ASIC1 in lower vertebrates.
No effect of growth hormone administration on substrate oxidation during exercise in young, lean men
Authors: Hansen Mette , Morthorst Rikke , Larsson Benny , Dall Rolf , Flyvbjerg Allan , Rasmussen Michael Højby , Ørskov Hans , Kjær Michael , Lange Kai Henrik Wiborg
Published: July 2005

The purpose of this study was to examine the effects of increased fat availability induced by growth hormone (GH) administration on the oxidative metabolism during exercise. Seven well‐trained males (age 25 ± 2 years (mean ±s.e.m.); peak oxygen consumption : 62 ± 1 ml min−1 kg−1 (completed four randomised trials: 120 min bicycling at 55% 4 h after receiving either 7.5 IU (2.5 mg) GH or placebo (Plc), and during rest after receiving either GH or Plc. In all studies a standardized meal was given 2 h after GH or Plc injection. GH administration resulted in an ∼60‐fold increase in serum GH concentration at rest (P < 0.0001) and during exercise (P < 0.0001). The increase in serum GH was followed by an increase in circulating glycerol at rest (8%, P < 0.0001). When combined with exercise the increase in plasma glycerol was more pronounced (GH: 716% of baseline versus Plc: 328%, P < 0.0001). However, this increase in fat mobilization did not increase fat oxidation during exercise (indirect calorimetry). In conclusion, GH administration combined with aerobic exercise increased lipolytic parameters substantially more than exercise alone, but did not further augment whole body fat oxidation.
Shortening velocity of human triceps surae muscle measured with the slack test in vivo
Authors: Sasaki Kazushige , Ishii Naokata
Published: July 2005

Unloaded shortening velocity (V0) of human triceps surae muscle was measured in vivo by applying the ‘slack test’, originally developed for determining V0 of single muscle fibres, to voluntary contractions at varied activation levels (ALs). V0 was measured from 10 subjects at five different ALs defined as a fraction (5, 10, 20, 40 and 60%) of the maximum voluntary contraction (MVC) torque. Although individual variability was apparent, V0 tended to increase with AL (R2= 0.089; P= 0.035) up to 60%MVC (8.6 ± 2.6 rad s−1). This value of V0 at 60%MVC was comparable to the maximum shortening velocity of plantar flexors reported in the previous studies. Electromyographic analysis showed that the activities of soleus, medial gastrocnemius and lateral gastrocnemius muscles increased with AL during isometric contraction and after the application of quick release in a similar manner. Also, it showed that the activity of an antagonist, tibialis anterior muscle, was negligible, even though a slight increase took place after the quick release of agonist. Correlation analysis showed that there were no significant correlations between V0 and MVC torque normalized with respect to body mass, although the correlation coefficient was relatively high at low ALs. The results suggest that in human muscle, V0 represents the unloaded velocity of the fastest muscle fibres recruited, and increases with AL possibly because of progressive recruitment of faster fibres. Individual variability may be explained, at least partially, by the difference in fibre‐type composition.
Mechanisms of stretch‐induced muscle damage in normal and dystrophic muscle: role of ionic changes
Authors: Allen D. G. , Whitehead N. P. , Yeung E. W.
Published: July 2005

Muscle damage, characterized by prolonged weakness and delayed onset of stiffness and soreness, is common following contractions in which the muscles are stretched. Stretch‐induced damage of this sort is more pronounced in the muscular dystrophies and the profound muscle damage observed in these conditions may involve similar pathways. It has been known for many years that damaged muscles accumulate calcium and that elevating calcium in normal muscles simulates many aspects of muscle damage. The changes in intracellular calcium, sodium and pH following stretched contractions are reviewed and the various pathways which have been proposed to allow ion entry are discussed. One possibility is that TRPC1 (transient receptor potential, canonical), a protein which seems to form both a stretch‐activated channel and a store‐operated channel, is the main source of Ca2+ entry. The mechanisms by which the changes in intracellular ions contribute to reduced force production, to increased protein breakdown and to increased membrane permeability are considered. A hypothetical scheme for muscle damage which incorporates these ideas is presented.
Zinc inhibits human ClC‐1 muscle chloride channel by interacting with its common gating mechanism
Authors: Duffield Michael D. , Rychkov Grigori Y. , Bretag Allan H. , Roberts Michael L.
Published: July 2005

Transition metals block the muscle Cl− channel ClC‐1, which belongs to a large family of double‐barreled Cl− channels and transporters. In the Torpedo Cl− channel ClC‐0, Zn2+ block is closely related to the common gating mechanism that opens and closes both pores of the channel simultaneously, and the mutation C212S, which locks the common gate open, also eliminates the block. In ClC‐1, however, previous results suggested that Zn2+ block is independent of gating, and that the cysteine residues involved in Zn2+ binding are in different positions to those that confer Zn2+ sensitivity on ClC‐0. In this work, we show that Zn2+ block of ClC‐1 is faster at hyperpolarized potentials where the channel is more likely to be in the closed state. Mutation C277S, equivalent to C212S in ClC‐0, which locks the common gate in ClC‐1 open, virtually eliminates Zn2+ block. A mutation, V321A, which reduces open probability of the common gate, facilitated Zn2+ block. These results demonstrate that Zn2+ block is state dependent, acting on the common gate. The extent of the block, however, is not a simple function of the open probability of the common gate. The Q10 of ∼13 of the time course of Zn2+ block, which is significantly higher than the Q10 of common gating transitions in WT ClC‐1, suggests that Zn2+ binds to a very high temperature‐dependent low‐probability closed substate of the common gate, which has not yet been characterized in this channel.
The GABAergic projection of the dentate gyrus to hippocampal area CA3 of the rat: pre‐ and postsynaptic actions after seizures
Authors: Treviño Mario , Gutiérrez Rafael
Published: July 2005

The glutamatergic granule cells of the dentate gyrus transiently express GABAergic markers after seizures. Here we show that when this occurs, their activation produces (i) GABAA receptor‐mediated synaptic field responses in CA3, with the physiological and pharmacological characteristics of mossy fibre transmission, and (ii) GABAA receptor‐mediated collateral inhibition. Control hippocampal slices present, on stimulation of the dentate gyrus, population responses in stratum lucidum, which are blocked by ionotropic glutamate receptor antagonists. By contrast, in slices from rats subjected to seizures in vivo, dentate activation additionally produces GABAA receptor‐mediated field synaptic responses in the presence of glutamate receptor antagonists. One‐dimensional current source density analysis confirmed the spatial coincidence of the glutamatergic and GABAergic dendritic currents. The GABAA receptor‐mediated field responses show frequency‐dependent facilitation and strong inhibition during activation of metabotropic glutamate receptors. In the presence of glutamate receptor blockers, a conditioning pulse delivered to one site of the dentate gyrus inhibits the population synaptic response and the afferent volley provoked by the activation of a second site, in a bicuculline‐sensitive manner. In accordance with this, antidromic responses evoked by mossy fibre activation were enhanced by perfusion of bicuculline. Our results suggest that, for GABA receptor‐dependent field potentials to be detected, a considerable number of boutons of a well‐defined GABAergic pathway should simultaneously release GABA to act on a large number of receptors. Therefore, putative GABA release from the mossy fibres acts on pre‐ and postsynaptic sites to affect hippocampal activity at the network level after seizures.
Discovery of Very High Energy Gamma Rays Associated with an X-ray Binary
Authors: Aharonian F. , Akhperjanian A. G. , Aye K.-M. , Bazer-Bachi A. R. , Beilicke M. , Benbow W. , Berge D. , Berghaus P. , Bernlöhr K. , Boisson C. , Bolz O. , Borrel V. , Braun I. , Breitling F. , Brown A. M. , Gordo J. Bussons , Chadwick P. M. , Chounet L.-M. , Cornils R. , Costamante L. , Degrange B. , Dickinson H. J. , Djannati-Ataï A. , Drury L. O'C. , Dubus G. , Emmanoulopoulos D. , Espigat P. , Feinstein F. , Fleury P. , Fontaine G. , Fuchs Y. , Funk S. , Gallant Y. A. , Giebels B. , Gillessen S. , Glicenstein J. F. , Goret P. , Hadjichristidis C. , Hauser M. , Heinzelmann G. , Henri G. , Hermann G. , Hinton J. A. , Hofmann W. , Holleran M. , Horns D. , Jacholkowska A. , de Jager O. C. , Khélifi B. , Komin Nu. , Konopelko A. , Latham I. J. , Le Gallou R. , Lemière A. , Lemoine-Goumard M. , Leroy N. , Lohse T. , Marcowith A. , Martin J.-M. , Martineau-Huynh O. , Masterson C. , McComb T. J. L. , de Naurois M. , Nolan S. J. , Noutsos A. , Orford K. J. , Osborne J. L. , Ouchrif M. , Panter M. , Pelletier G. , Pita S. , Pühlhofer G. , Punch M. , Raubenheimer B. C. , Raue M. , Raux J. , Rayner S. M. , Reimer A. , Reimer O. , Ripken J. , Rob L. , Rolland L. , Rowell G. , Sahakian V. , Saugé L. , Schlenker S. , Schlickeiser R. , Schuster C. , Schwanke U. , Siewert M. , Sol H. , Spangler D. , Steenkamp R. , Stegmann C. , Tavernet J.-P. , Terrier R. , Théoret C. G. , Tluczykont M. , Vasileiadis G. , Venter C. , Vincent P. , Völk H. J. , Wagner S. J.
Published: July 2005

X-ray binaries are composed of a normal star in orbit around a neutron star or stellar-mass black hole. Radio and x-ray observations have led to the presumption that some x-ray binaries called microquasars behave as scaled-down active galactic nuclei. Microquasars have resolved radio emission that is thought to arise from a relativistic outflow akin to active galactic nuclei jets, in which particles can be accelerated to large energies. Very high energy γ-rays produced by the interactions of these particles have been observed from several active galactic nuclei. Using the High Energy Stereoscopic System, we find evidence for gamma-ray emission of >100 gigaelectron volts from a candidate microquasar, LS 5039, showing that particles are also accelerated to very high energies in these systems.
Voltage Sensor of Kv1.2: Structural Basis of Electromechanical Coupling
Authors: Long Stephen B. , Campbell Ernest B. , MacKinnon Roderick
Published: July 2005

Voltage-dependent ion channels contain voltage sensors that allow them to switch between nonconductive and conductive states over the narrow range of a few hundredths of a volt. We investigated the mechanism by which these channels sense cell membrane voltage by determining the x-ray crystal structure of a mammalian
Shaker
family potassium ion (K
+
) channel. The voltage-dependent K
+
channel Kv1.2 grew three-dimensional crystals, with an internal arrangement that left the voltage sensors in an apparently native conformation, allowing us to reach three important conclusions. First, the voltage sensors are essentially independent domains inside the membrane. Second, they perform mechanical work on the pore through the S4-S5 linker helices, which are positioned to constrict or dilate the S6 inner helices of the pore. Third, in the open conformation, two of the four conserved Arg residues on S4 are on a lipid-facing surface and two are buried in the voltage sensor. The structure offers a simple picture of how membrane voltage influences the open probability of the channel.
HIGHER DIMENSIONAL GLOBAL MONOPOLE WITH COSMOLOGICAL TERM
Authors: RAHAMAN F. , GHOSH P. , KALAM M. , GAYEN K.
Published: July 2005

We investigate the spacetime of a global monopole in a five-dimensional spacetime in the presence of the cosmological term. Also the gravitational properties of the monopole solution are discussed.
SUPERFLUID STATES OF NUCLEAR MATTER BEYOND THE BCS APPROXIMATION
Authors: LOMBARDO UMBERTO , SHEN CAIWAN , SCHULZE HANS-JOSEF , ZUO WEI
Published: July 2005

The recent progress in the pairing problem and the superfluidity of neutron stars is reviewed. The theory of superfluidity in nuclear and neutron matter is developed beyond the BCS approximation. In particular, the dispersion effects including the depletion of the Fermi surface and the core polarization are discussed within the Brueckner theory. In addition, the effects of vertex correction to the pairing interaction, based on RPA, are incorporated in the generalized gap equation. The isospin singlet (neutron–proton) pairing is investigated in connection with the low-density crossover from a superfluid Fermi system to a Bose–Einstein condensate and the isospin suppression of pairing in neutron-rich matter. The onset of different superfluid states of neutron–neutron and proton–proton pairing in neutron stars is discussed in the context of application to rotational motion and cooling process.
PSEUDORAPIDITY DISTRIBUTION OF CHARGED PARTICLES IN $p\bar p$ AND AA COLLISIONS AT HIGH ENERGIES
Authors: SONG FU , LIU FU-HU
Published: July 2005

The pseudorapidity distributions of charged particles produced in [Formula: see text] annihilations and AA collisions at high energies are investigated by using a revised thermalized cylinder model. The Monte Carlo calculated results are compared and found to be in good agreement with the experimental data of [Formula: see text] annihilations at center-of-mass energy [Formula: see text], 546, 200, and 53 GeV, Au–Au collisions at [Formula: see text] and 130 A GeV, and Pb–Pb collisions at [Formula: see text].
A COMPARATIVE STUDY OF THE 12C+24Mg SYSTEM WITH DEEP AND SHALLOW POTENTIALS
Authors: BOZTOSUN I. , BAYRAK O. , DAGDEMIR Y.
Published: July 2005

Studying nuclear reactions near the Coulomb barrier shows a number of problems which have remained unsolved for a long time: The out-of-phase problem between theoretical predictions and experimental data; the reproductions of the oscillatory structure near the Coulomb barrier; the consistent description of angular distributions together with the excitation functions data are just some of these problems. In order to address and overcome these problems, by considering a comparative study of the shallow and deep optical potentials, the elastic scattering angular distributions and excitation functions data of the 12 C +24 Mg reaction have been analyzed within the framework of the optical model over a wide energy range. The potential depths near the Coulomb barrier according to the increasing energy and threshold anomaly are discussed in terms of the shallow and deep potentials. Excellent agreement between theoretical results and measured data is obtained by using the optical model.
NUCLEAR HALO AND THE COHERENT NUCLEAR INTERACTION
Authors: ALZETTA RENZO , LIBERTI GIUSEPPE , ZAFFINO ROSA LETIZIA
Published: July 2005

The unusual structure of11Li , the first halo nucleus found, is analyzed by the Preparata model of nuclear structure. By applying coherent nucleus theory, we derive a new interaction potential for the halo-neutrons that correctly reproduces the fundamental state of the system.
Role of nuclear receptors and hepatocyte-enriched transcription factors for Ntcp repression in biliary obstruction in mouse liver
Authors: Zollner Gernot , Wagner Martin , Fickert Peter , Geier Andreas , Fuchsbichler Andrea , Silbert Dagmar , Gumhold Judith , Zatloukal Kurt , Kaser Arthur , Tilg Herbert , Denk Helmut , Trauner Michael
Published: July 2005

Expression of the main hepatic bile acid uptake system, the Na+-taurocholate cotransporter (Ntcp), is downregulated during cholestasis. Bile acid-induced, farnesoid X receptor (FXR)-mediated induction of the nuclear repressor short heterodimer partner (SHP) has been proposed as a key mechanism reducing Ntcp expression. However, the role of FXR and SHP or other nuclear receptors and hepatocyte-enriched transcription factors in mediating Ntcp repression in obstructive cholestasis is unclear. FXR knockout (FXR−/−) and wild-type (FXR+/+) mice were subjected to common bile duct ligation (CBDL). Cholic acid (CA)-fed and LPS-treated FXR−/− and FXR+/+ mice were studied for comparison. mRNA levels of Ntcp and SHP and nuclear protein levels of hepatocyte nuclear factor (HNF)-1α, HNF-3β, HNF-4α, retinoid X receptor (RXR)-α, and retinoic acid receptor (RAR)-α and their DNA binding were assessed. Hepatic cytokine mRNA levels were also measured. CBDL and CA led to Ntcp repression in FXR+/+, but not FXR−/−, mice, whereas LPS reduced Ntcp expression in both genotypes. CBDL and LPS but not CA induced cytokine expression and reduced levels of HNF-1α, HNF-3β, HNF-4α, RXRα, and RARα to similar extents in FXR+/+ and FXR−/−. DNA binding of these transactivators was unaffected by CA in FXR+/+ mice but was markedly reduced in FXR−/− mice. In conclusion, Ntcp repression by CBDL and CA is mediated by accumulating bile acids via FXR and does not depend on cytokines, whereas Ntcp repression by LPS is independent of FXR. Reduced levels of HNF-1α, RXRα, and RARα in CBDL FXR−/− mice and reduced DNA binding in CA-fed FXR−/− mice, despite unchanged Ntcp levels, indicate that these factors may have a minor role in regulation of mouse Ntcp during cholestasis.
Intracellular Ca2+and Zn2+signals during monochloramine-induced oxidative stress in isolated rat colon crypts
Authors: Cima Robert R. , Dubach J. Matthew , Wieland Aaron M. , Walsh Breda M. , Soybel David I.
Published: July 2005

During acute exacerbations of inflammatory bowel diseases, oxidants are generated through the interactions of bacteria in the lumen, activated granulocytes, and cells of the colon mucosa. In this study we explored the ability of one such class of oxidants, represented by monochloramine (NH2Cl), to serve as agonists of Ca2+and Zn2+accumulation within the colonocyte. Individual colon crypts prepared from Sprague-Dawley rats were mounted in perfusion chambers after loading with fluorescent reporters fura 2-AM and fluozin 3-AM. These reporters were characterized, in situ, for responsiveness to Ca2+and Zn2+in the cytoplasm. Responses to different concentrations of NH2Cl (50, 100, and 200 μM) were monitored. Subsequent studies were designed to identify the sources and mechanisms of NH2Cl-induced increases in Ca2+and Zn2+in the cytoplasm. Exposure to NH2Cl led to dose-dependent increases in intracellular Ca2+concentration ([Ca2+]i) in the range of 200–400 nM above baseline levels. Further studies indicated that NH2Cl-induced accumulation of Ca2+in the cytoplasm is the result of release from intracellular stores and basolateral entry of extracellular Ca2+through store-operated channels. In addition, exposure to NH2Cl resulted in dose-dependent and sustained increases in intracellular Zn2+concentration ([Zn2+]i) in the nanomolar range. These alterations were neutralized by dithiothreitol, which shields intracellular thiol groups from oxidation. We conclude that Ca2+- and Zn2+-handling proteins are susceptible to oxidation by chloramines, leading to sustained, but not necessarily toxic, increases in [Ca2+]iand [Zn2+]i. Under certain conditions, NH2Cl may act not as a toxin but as an agent that activates intracellular signaling pathways.
Canine model of paroxysmal atrial fibrillation and paroxysmal atrial tachycardia
Authors: Swissa Moshe , Zhou Shengmei , Paz Offir , Fishbein Michael C. , Chen Lan S. , Chen Peng-Sheng
Published: July 2005

Both autonomic nerve activity and electrical remodeling are important in atrial arrhythmogenesis. Therefore, dogs with sympathetic hyperinnervation, myocardial infarction (MI), and complete atrioventricular block (CAVB) may have a high incidence of atrial arrhythmias. We studied eight dogs (experimental group) with MI, CAVB, and sympathetic hyperinnervation induced either by nerve growth factor infusion ( n = 4 dogs) or subthreshold electrical stimulation ( n = 4 dogs) of the left stellate ganglion. Cardiac rhythm was continuously monitored by a Data Sciences International transmitter for 48 (SD 27) days. Three normal control dogs were also monitored. Six additional normal dogs were used for histology control. Paroxysmal atrial fibrillation (PAF) and paroxysmal atrial tachycardia (PAT) were documented in all dogs in the experimental group, with an average of 3.8 (SD 3) episodes/day, including 1.3 (SD 1.6) episodes of PAF and 2.5 (SD 2.2) episodes of PAT. The duration averaged 298 (SD 745) s (range, 7–4,000 s). There was a circadian pattern of arrhythmia onset ( P < 0.01). Of 576 episodes of PAF and PAT, 236 (41%) episodes occurred during either sustained or nonsustained ventricular tachycardia (VT). Among these 236 episodes, 53% started before VT, whereas 47% started after the onset of VT. Normal dogs did not have either PAF or PAT. The hearts from the experimental group had a higher density of nerve structures immunopositive ( P < 0.01) for three different nerve specific markers in both right and left atria than those of the control dogs. We conclude that the induction of nerve sprouting and sympathetic hyperinnervation in dogs with CAVB and MI creates a high yield model of PAF and PAT.
Vasoconstriction during venous congestion: effects of venoarteriolar response, myogenic reflexes, and hemodynamics of changing perfusion pressure
Authors: Okazaki Kazunobu , Fu Qi , Martini Emily R. , Shook Robin , Conner Colin , Zhang Rong , Crandall Craig G. , Levine Benjamin D.
Published: July 2005

We dissected the relative contribution of arteriovenous hemodynamics, the venoarteriolar response (VAR), and the myogenic reflex toward a decrease in local blood flow induced by venous congestion. Skin blood flow (SkBF) was measured in 12 supine subjects via laser-Doppler flowmetry 1) over areas of forearm and calf skin, in which the VAR was blocked by using eutectic mixture of local anesthetics (EMLA sites) and 2) over the contralateral forearm or calf skin (control sites), using two different techniques: limb dependency of 23–37 cm below the heart and cuff inflation to 40 mmHg. During limb dependency, SkBF decreased at the control sites, whereas it remained unchanged at the EMLA sites. In contrast, during cuff inflation, SkBF decreased at the control sites and also decreased at the EMLA sites. The percent change in SkBF from baseline was greater during cuff inflation than limb dependency at both the control sites and the EMLA sites. Estimated skin vascular resistance remained unchanged at the EMLA sites during cuff inflation, as well as limb dependency. Thus the decrease in SkBF during venous congestion with cuff inflation is not solely due to the cutaneous VAR but also to a reduction in local perfusion pressure. The VAR is therefore most specifically quantified by venous congestion induced by limb dependency, rather than cuff inflation. Finally, from both techniques, we calculated that during venous congestion induced by limb dependency (calf), ∼45% of the nonbaroreflex vasoconstriction is induced by the VAR and ∼55% by the myogenic reflex.
Characterization of vasopressin V2 receptor mutants in nephrogenic diabetes insipidus in a polarized cell model
Authors: Robben J. H. , Knoers N. V. A. M. , Deen P. M. T.
Published: July 2005

X-linked nephrogenic diabetes insipidus (NDI) is caused by mutations in the gene encoding the vasopressin V2 receptor (V2R). For the development of a tailored therapy for NDI, knowledge of the cellular fate of V2R mutants is needed. It would be useful when this fate could be predicted from the location and type of mutation. To identify similarities and differences in localization, maturation, stability, and degradation of COOH-terminal GFP-tagged V2R mutants, we stably expressed nine mutants in polarized Madin-Darby canine kidney cells. The mutants V2R-L44P, -Δ62–64, -I130F, -S167T, -S167L, and -V206D were mainly expressed in the endoplasmic reticulum (ER) as immature proteins. These mutants had relatively short half-lives due to proteasomal degradation, except for V2R-Δ62–64. In contrast, V2R-R113W, -G201D, and -T204N were expressed in the ER and in the basolateral membrane as immature, high-mannose glycosylated, and mature complex-glycosylated proteins. The immature forms of V2R-R113W and -T204N, but not V2R-G201D, were rapidly degraded. The mature forms varied extensively in their stability and were degraded by only lysosomes (V2R-T204N and wild-type V2R) or lysosomes and proteasomes (V2R-G201D, -R113W). These data reveal that most missense V2R mutations lead to retention in the ER and suggest that mutations that likely distort a transmembrane domain or introduce a charged amino acid close to it make a V2R mutant more prone to ER retention. Because six of the mutants tested showed significant increases in intracellular cAMP levels on transient expression in COS cells, activation of these six receptors following rescue of cell-surface expression might provide a cure for NDI patients.
Tumor necrosis factor-α and malnutrition-induced inhibition of diaphragm fiber growth in young rats
Authors: Lewis Michael I. , Da Xiaoyu , Li Hongmei , Fournier Mario
Published: July 2005

Tumor necrosis factor (TNF)-α has been implicated in several muscle-wasting disorders, with increased levels of the cytokine reported in malnourished children. The role of TNF-α in mediating malnutrition-induced inhibition of diaphragm (DIA) muscle growth in young growing rats was evaluated. Three groups of rats were studied: 1) control (CTL); 2) nutritional deprivation (ND; 50% of normal food intake for 7 days); and 3) ND + rat specific anti-TNF-α antibody. DIA fiber cross-sectional areas were determined. Serum and muscle TNF-α levels were measured by real-time PCR, ELISA, and immunohistochemistry. Body weights decreased 20% in ND rats and increased 46% in CTL animals. Anti-TNF-α had no effect on body weight or on DIA mass in ND animals. ND significantly reduced cross-sectional areas of all fiber types (33–46%). Anti-TNF-α failed to attenuate ND-induced inhibition of DIA fiber growth. Serum TNF-α levels increased 2.6-fold in ND animals, with levels suppressed to below CTL values with anti-TNF-α. DIA TNF-α mRNA and protein levels increased two- to threefold in ND rats. Anti-TNF-α antibodies suppressed muscle levels of the cytokine in ND animals to near CTL values. TNF-α immunoreactivity in all DIA fibers revealed similar directions of change in both ND groups. Direction and magnitude of change in DIA phosphorylated p38 MAPK (a likely second messenger of TNF-α) tracked those of TNF-α. Muscle levels of IGF-I mRNA and phosphorylated Akt were markedly reduced in ND animals with no change following anti-TNF-α therapy. Thus rat anti-TNF-α at a dose known to neutralize the cytokine failed to attenuate or reverse ND-induced inhibition of DIA fiber growth in our model.
Exercise flow-volume loops in prepubescent aerobically trained children
Authors: Nourry Cédric , Deruelle Fabien , Fabre Claudine , Baquet Georges , Bart Frédéric , Grosbois Jean-Marie , Berthoin Serge , Mucci Patrick
Published: July 2005

We studied mechanical ventilatory constraints in 13 aerobically trained (Tr) and 11 untrained (UT) prepubescent children by plotting the exercise flow-volume (F-V) loops within the maximal F-V loop (MFVL) measured at rest. The MFVL allowed to determine forced vital capacity (FVC) and maximal expiratory flows. Expiratory and inspiratory reserve volumes relative to FVC (ERV/FVC and IRV/FVC, respectively) were measured during a progressive exercise test until exhaustion. Breathing reserve (BR) and expiratory flow limitation (expFL), expressed in percentage of tidal volume (Vt) and defined as the part of the tidal breath meeting the boundary of the MFVL, were measured. Higher FVC and maximal expiratory flows were found in Tr than UT ( P < 0.05) at rest. Our results have shown that during exercise, excepting one subject, all Tr regulated their Vt within FVC similarly during exercise, by breathing at low lung volume at the beginning of exercise followed breathing at high lung volume at strenuous exercise. In UT, ERV/FVC and IRV/FVC were regulated during exercise in many ways. The proportion of children who presented an expFL was nearly the same in both groups (∼70% with a range of 14 to 65% of Vt), and no significant difference was found during exercise concerning expFL. However, higher ventilation (V̇e), ERV/FVC, and dyspnea associated with lower BR, IRV/FVC, and SaO2 were reported at peak power in Tr than UT ( P < 0.05). These results suggest that, because of their higher V̇e level, trained children presented higher ventilatory constraints than untrained. These may influence negatively the SaO2 level and dyspnea during strenuous exercise.
NADPH oxidase p22phox gene variants are associated with systemic oxidative stress biomarker responses to exercise training
Authors: Park Joon-Young , Ferrell Robert E. , Park Jung-Jun , Hagberg James M. , Phares Dana A. , Jones Jennifer M. , Brown Michael D.
Published: July 2005

Systemic oxidative stress plays a role in many degenerative diseases. Although regular physical activity has been known as the most effective nonpharmacological intervention to alleviate the oxidative stress, the beneficial effect varies between individuals. We investigated whether NADPH oxidase p22phox gene C242T and A640G polymorphisms are associated with systemic oxidative stress level response to exercise training (ExTr). Fifty-nine sedentary middle-aged to older Caucasians with relatively high cardiovascular disease risk factors underwent a 6-mo standardized ExTr program. Body mass index, plasma lipoprotein-lipid profiles, cardiovascular fitness, and plasma thiobarbituric acid reactive substances (TBARS) were measured before and after ExTr. Demographic and initial levels of cardiovascular disease risk factors were similar among genotype groups for both polymorphisms. Overall, TBARS was decreased by 16% with ExTr in the entire group ( P < 0.001). There was no significant difference in TBARS changes with ExTr among the C242T genotype groups. However, A allele carriers showed greater reduction in TBARS than noncarriers at the A640G locus ( P = 0.05). There was a significant interaction ( P = 0.05) between ExTr and A640G polymorphism in TBARS changes with ExTr. This interaction remained after accounting for age and baseline TBARS level. Furthermore, diplotype analysis showed that TBARS was decreased to a greater extent in the C242/A640 haplotype carriers compared with the noncarriers ( P < 0.05). We found that p22phox polymorphisms, especially A640G, were associated with differential changes in systemic oxidative stress with aerobic exercise training.
Age-related changes in ATP-producing pathways in human skeletal muscle in vivo
Authors: Lanza Ian R. , Befroy Douglas E. , Kent-Braun Jane A.
Published: July 2005

Energy for muscle contractions is supplied by ATP generated from 1) the net hydrolysis of phosphocreatine (PCr) through the creatine kinase reaction, 2) oxidative phosphorylation, and 3) anaerobic glycolysis. The effect of old age on these pathways is unclear. The purpose of this study was to examine whether age may affect ATP synthesis rates from these pathways during maximal voluntary isometric contractions (MVIC). Phosphorus magnetic resonance spectroscopy was used to assess high-energy phosphate metabolite concentrations in skeletal muscle of eight young (20–35 yr) and eight older (65–80 yr) men. Oxidative capacity was assessed from PCr recovery after a 16-s MVIC. We determined the contribution of each pathway to total ATP synthesis during a 60-s MVIC. Oxidative capacity was similar across age groups. Similar rates of ATP synthesis from PCr hydrolysis and oxidative phosphorylation were observed in young and older men during the 60-s MVIC. Glycolytic flux was higher in young than older men during the 60-s contraction ( P < 0.001). When expressed relative to the overall ATP synthesis rate, older men relied on oxidative phosphorylation more than young men ( P = 0.014) and derived a smaller proportion of ATP from anaerobic glycolysis ( P < 0.001). These data demonstrate that although oxidative capacity was unaltered with age, peak glycolytic flux and overall ATP production from anaerobic glycolysis were lower in older men during a high-intensity contraction. Whether this represents an age-related limitation in glycolytic metabolism or a preferential reliance on oxidative ATP production remains to be determined.
Extraesophageal Reflux and Upper Aerodigestive Tract Diseases
Authors: Jecker Peter , Orloff Lisa A. , Mann Wolf J.
Published: July 2005

Reflux disease can cause multiple disorders not only of the esophagus but also of the upper aerodigestive tract. In the last decade, an association between reflux disease and multiple head and neck diseases was described, including those of the larynx and pharynx as well as those of the nose, the sinuses and the middle ear. The present article summarizes these different diseases and possible pathomechanisms are explained. In particular, there is a need to differentiate between the classical gastroesophageal reflux disease (GERD) and the extraesophageal manifestation of the reflux disease, called extraesophageal reflux (EER). Both diseases are characterized by different symptoms and can cause different disorders. To differentiate between GERD and EER, double-probe pH monitoring is mandatory. At last, some aspects of reflux therapy are explained.
Impact of Missing Genotype Data on Monte-Carlo Simulation Based Haplotype Analysis
Authors: Becker Tim , Knapp Michael
Published: July 2005

In the context of haplotype association analysis of unphased genotype data, methods based on Monte-Carlo simulations are often used to compensate for missing or inappropriate asymptotic theory. Moreover, such methods are an indispensable means to deal with multiple testing problems. We want to call attention to a potential trap in this usually useful approach: The simulation approach may lead to strongly inflated type I errors in the presence of different missing rates between cases and controls, depending on the chosen test statistic. Here, we consider four different testing strategies for haplotype analysis of case-control data. We recommend to interpret results for data sets with non-comparable distributions of missing genotypes with special caution, in case the test statistic is based on inferred haplotypes per individual. Moreover, our results are important for the conduction and interpretation of genome-wide association studies.
Linear Parameter Haplotype Models with Stratification
Authors: Bergemann T.L. , Clarkson D.B.
Published: July 2005

Objectives: The question of interest is estimating the relationship between haplotypes and an outcome measure, based upon unphased genotypes. The outcome of interest might be predicting the presence of disease in a logistic model, predicting a numeric drug response in a linear model, or predicting survival time in a parametric survival model with censoring. Explanatory variables may include phased haplotype design variables, environmental variables, or interactions between them. Methods: We extend existing generalized linear haplotype models to parametric survival outcomes. To improve the stability of model variance estimates, a profile likelihood solution is proposed. An adjustment for population stratification is also considered. Here we investigate data sampled from known ‘strata’ (e.g., gender or ethnicity) that influence haplotype prior probabilities and thus the regression model weights. Differing linear model variance estimates, and the effect of stratification and departures from Hardy-Weinberg Equilibrium (HWE) on parameter estimates, are compared and contrasted via simulation. Results: From simulations, we observed an improvement in statistical power when using a solution to profile likelihood equations. We also saw that stratification had little impact on estimates. Haplotypes that are not in HWE had a negative impact on power to test hypotheses. Finally, profile likelihood solutions for haplotypes deviating from HWE had improved power and confidence interval coverage of regression model coefficients.