bluuebunny/crossref_metadata_2025 huggingface dataset:
Cathodal stimulation in the recovery phase of a propagating planar wave in the rabbit heart reveals four stimulation mechanisms
Authors: Sidorov Veniamin Y. , Woods Marcella C. , Baudenbacher Franz
Published: June 2007

The stimulation of cardiac tissue in the recovery phase has significant importance in relation to reentry induction. In the theoretical experiment proposed by Winfree, termed the ‘pinwheel' experiment, a point stimulus (S2) is applied in the wake of a freely propagating planar wave (S1). Reentry induced from this S1–S2 pinwheel protocol has been observed experimentally in heart preparations. However, in these experiments, which focused on activation outcomes, only mapping of extracellular voltages has been conducted. The lack of transmembrane potential (Vm) distribution data makes it impossible to analyse the underlying stimulation mechanisms which precede the reentry induction. In this work we sought to elucidate the stimulation mechanisms throughout the heart cycle using the pinwheel protocol. We examined the cardiac tissue responses during and immediately after cathodal stimulation in the refractory wake of a propagating planar wave. The voltage‐sensitive dye di‐4‐ANEPPS was utilized to measure Vm directly from quasi two‐dimensional preparations of cryoablated Langendorff‐perfused rabbit hearts. Four stimulation mechanisms were observed that depended on the Vm magnitude during S2 cathodal stimulation. Make stimulation always occurred during diastolic stimulation. When stimulation was at the beginning of the relative refractory period (RRP), transitional make–break stimulation was detected. During the RRP the excitation was due to the break mechanism. While approaching the effective refractory period (ERP), the tissue response is characterized by a damped wave mediated response. These four stimulation mechanisms were observed in all hearts whether the S1 planar wave propagation was parallel or perpendicular to the fibre direction. This study is the first examination of Vm and the stimulation mechanisms throughout the cardiac cycle using the pinwheel protocol, and the results have implications in the development and improvement of pacing protocols for artificial cardiostimulators.
Four Climate Cycles of Recurring Deep and Surface Water Destabilizations on the Iberian Margin
Authors: Martrat Belen , Grimalt Joan O. , Shackleton Nicholas J. , de Abreu Lucia , Hutterli Manuel A. , Stocker Thomas F.
Published: June 2007

Centennial climate variability over the last ice age exhibits clear bipolar behavior. High-resolution analyses of marine sediment cores from the Iberian margin trace a number of associated changes simultaneously. Proxies of sea surface temperature and water mass distribution, as well as relative biomarker content, demonstrate that this typical north-south coupling was pervasive for the cold phases of climate during the past 420,000 years. Cold episodes after relatively warm and largely ice-free periods occurred when the predominance of deep water formation changed from northern to southern sources. These results reinforce the connection between rapid climate changes at Mediterranean latitudes and century-to-millennial variability in northern and southern polar regions.
Noise in Gene Expression Determines Cell Fate in
Bacillus subtilis
Authors: Maamar Hédia , Raj Arjun , Dubnau David
Published: June 2007

Random cell-to-cell variations in gene expression within an isogenic population can lead to transitions between alternative states of gene expression. Little is known about how these variations (noise) in natural systems affect such transitions. In
Bacillus subtilis
, noise in ComK, the protein that regulates competence for DNA uptake, is thought to cause cells to transition to the competent state in which genes encoding DNA uptake proteins are expressed. We demonstrate that noise in
comK
expression selects cells for competence and that experimental reduction of this noise decreases the number of competent cells. We also show that transitions are limited temporally by a reduction in
comK
transcription. These results illustrate how such stochastic transitions are regulated in a natural system and suggest that noise characteristics are subject to evolutionary forces.
Remnants of the Early Solar System Water Enriched in Heavy Oxygen Isotopes
Authors: Sakamoto Naoya , Seto Yusuke , Itoh Shoichi , Kuramoto Kiyoshi , Fujino Kiyoshi , Nagashima Kazuhide , Krot Alexander N. , Yurimoto Hisayoshi
Published: June 2007

Oxygen isotopic composition of our solar system is believed to have resulted from mixing of two isotopically distinct nebular reservoirs,
16
O-rich and
17,18
O-rich relative to Earth. The nature and composition of the
17,18
O-rich reservoir are poorly constrained. We report an in situ discovery of a chemically and isotopically unique material distributed ubiquitously in fine-grained matrix of a primitive carbonaceous chondrite Acfer 094. This material formed by oxidation of Fe,Ni-metal and sulfides by water either in the solar nebula or on a planetesimal. Oxygen isotopic composition of this material indicates that the water was highly enriched in
17
O and
18
O (δ
17,18
O
SMOW
= +180‰ per mil), providing the first evidence for an extremely
17,18
O-rich reservoir in the early solar system.
Reciprocal T
H
17 and Regulatory T Cell Differentiation Mediated by Retinoic Acid
Authors: Mucida Daniel , Park Yunji , Kim Gisen , Turovskaya Olga , Scott Iain , Kronenberg Mitchell , Cheroutre Hilde
Published: June 2007

The cytokine transforming growth factor–β (TGF-β) converts naïve T cells into regulatory T (Treg) cells that prevent autoimmunity. However, in the presence of interleukin-6 (IL-6), TGF-β has also been found to promote the differentiation of naïve T lymphocytes into proinflammatory IL-17 cytokine-producing T helper 17 (T
H
17) cells, which promote autoimmunity and inflammation. This raises the question of how TGF-β can generate such distinct outcomes. We identified the vitamin A metabolite retinoic acid as a key regulator of TGF-β–dependent immune responses, capable of inhibiting the IL-6–driven induction of proinflammatory T
H
17 cells and promoting anti-inflammatory Treg cell differentiation. These findings indicate that a common metabolite can regulate the balance between pro- and anti-inflammatory immunity.
Upregulation of cellular triacylglycerol – free fatty acid cycling by oleate is associated with long-term serum-free survival of human breast cancer cells
Authors: Przybytkowski Ewa , Joly Érik , Nolan Christopher J. , Hardy Serge , Francoeur Ann-Michele , Langelier Yves , Prentki Marc
Published: June 2007

We previously showed that exogenous oleate protects human breast cancer cells against palmitate-induced apoptosis in part by increasing esterification of this free fatty acid (FFA) into triacylglycerol (TG). Here, we studied the mechanism whereby oleate protects these cells against apoptosis induced by serum withdrawal. The metabolism of FFA, TG, and glucose, in parallel with long-term cell survival in the absence of serum, was investigated in a panel of human breast cancer cell lines and in nontransformed MCF-10A cells after treatment with exogenous oleate. Short-term (3–24 h) exposure of MDA-MB-231 human breast cancer cells to exogenous oleate resulted in a dose-dependent long-term (10 day) serum-free survival that correlated with the accumulation of TG in lipid droplets and with upregulation of lipolysis. Both effects persisted for several days after oleate removal. Rapid TG lipolysis and FFA re-esterification, supported by high rates of glycolysis that provide the glycerol backbone for TG synthesis, are consistent with the presence of very active TG–FFA cycling in human breast cancer cells. Only the cancer cell lines capable of accumulating TG showed long-term serum-free survival after oleate treatment. The results suggest that upregulation of TG–FFA cycling induced by oleate may be involved in maintenance of human breast cancer cell survival.
Metabolic and molecular aspects of ethanolamine phospholipid biosynthesis: the role of CTP:phosphoethanolamine cytidylyltransferase (Pcyt2)
Authors: Bakovic Marica , Fullerton Morgan D. , Michel Vera
Published: June 2007

The CDP-ethanolamine branch of the Kennedy pathway is the major route for the formation of ethanolamine-derived phospholipids, including diacyl phosphatidylethanolamine and alkenylacyl phosphatidylethanolamine derivatives, known as plasmalogens. Ethanolamine phospholipids are essential structural components of the cell membranes and play regulatory roles in cell division, cell signaling, activation, autophagy, and phagocytosis. The physiological importance of plasmalogens has not been not fully elucidated, although they are known for their antioxidant properties and deficiencies in a number of inherited peroxisomal disorders. This review highlights important aspects of ethanolamine phospholipid metabolism and reports current molecular information on 1 of the regulatory enzymes in their synthesis, CTP:phosphoethanolamine cytidylyltransferase (Pcyt2). Pcyt2 is encoded by a single, nonredundant gene in animal species that could be alternatively spliced into 2 potential protein products. We describe properties of the mouse and human Pcyt2 genes and their regulatory promoters and provide molecular evidence for the existence of 2 distinct Pcyt2 proteins. The goal is to obtain more insight into Pcyt2 catalytic function and regulation to facilitate a better understanding of the production of ethanolamine phospholipids via the CDP-ethanolamine branch of the Kennedy pathway.
Evidence that estrogen receptor β enhances MMP-13 promoter activity in HIG-82 cells and that this enhancement can be influenced by ligands and involves specific promoter sites
Authors: Lu Ting , Achari Yamini , Rattner Jerome B. , Hart David A.
Published: June 2007

Degradation of articular cartilage is characteristic of osteoarthritis, and matrix metalloproteinase-13 (MMP-13) has been implicated in this condition. Estrogen receptors (ERs) are present in connective tissues, indicating these tissues' potential responsiveness to estrogen. We based this study on the hypothesis that estrogen receptor β (ERβ) can modulate MMP-13 promoter activity. Transfection of cells with ERβ constructs led to the induction of the endogenous MMP-13 gene, as evidenced by increased mRNA levels. The results also indicated that MMP-13 promoter construct activity in the HIG-82 cell line significantly increased when ERβ was present, and that estrogen downregulated this response in a dose-dependent manner. ERβ was shown to enhance MMP-13 expression somewhat more strongly than ERα, and the impact of a number of selective ER modulators (tamoxifen, raloxifene, and ICI 182,780) on ERβ enhancement of promoter activity was found to be significantly less than that of estrogen. Furthermore, transcription regulatory sites in the MMP-13 promoter, specifically AP-1 and PEA-3, were shown to act in conjunction to mediate ERβ effects. Thus, ERβ likely influences MMP-13 promoter expression in normal and disease processes.
Yeast actin with a subdomain 4 mutation (A204C) exhibits increased pointed-end critical concentration
Authors: Teal David J. , Dawson John F.
Published: June 2007

Characterizing mutants of actin that do not polymerize will advance our understanding of the mechanism of actin polymerization and will be invaluable for the production of short F-actin structures for structural studies. To circumvent the problem of expressing dominant lethal nonpolymerizing actin in yeast, we adopted a cysteine engineering strategy. Here we report the characterization of a mutant of yeast actin, AC-actin, possessing a single pointed-end mutation, A204C. Expression of this mutant in yeast results in actin-polymerization-deficient phenotypes. When copolymerized with wild-type actin, ATP–AC-actin is incorporated into filaments. ADP–AC-actin participates in the nucleation and elongation of wild-type filaments only at very high concentrations. At low concentrations, ADP–AC-actin appears to participate only in the nucleation of wild-type filaments, suggesting that Ala-204 is involved in modulating the critical concentration of the pointed end of actin.
Probing the role of the conserved β-II turn Pro-76/Gly-77 of mitochondrial cytochromec
Authors: Black Karen M. , Wallace Carmichael J.A.
Published: June 2007

The loop segment comprising residues 70–84 in mitochondrial cytochrome c serves to direct the polypeptide backbone to permit the functionally required heme Fe – S (Met-80) co-ordination. The primary sequence here is highly conserved, which is something rarely observed in surface loop segments and suggests that its purpose is more complex than its obvious structural role. The β-II turn formed by Pro-76 and Gly-77 is postulated to be key to the redirection of the peptide backbone required to execute the loop. We assessed the importance of Pro-76 and Gly-77 by mutating 1 or both of these residues to alanine such that the range of allowable dihedral angles was altered, and this resulted in significant changes in physicochemical properties and biological activities. We observed structural perturbations using circular dichroism spectroscopy and thermal denaturation studies. Based on these changes, we propose that the Pro-76/Gly-77 β-II turn precisely orients the 70s loop, not only to maintain the backbone orientation required for the formation of the axial heme ligand, but also to provide a complementary surface to physiological partners.
RNase A – tRNA binding alters protein conformation
Authors: N’soukpoé-Kossi C.N. , Ragi C. , Tajmir-Riahi H.A.
Published: June 2007

Bovine pancreatic ribonuclease A (RNase A) catalyzes the cleavage of P-O5′ bonds in RNA on the 3′ side of pyrimidine to form cyclic 2′,5′-phosphates. Even though extensive structural information is available on RNase A complexes with mononucleotides and oligonucleotides, the interaction of RNase A with tRNA has not been fully investigated. We report the complexation of tRNA with RNase A in aqueous solution under physiological conditions, using a constant RNA concentration and various amounts of RNase A. Fourier transform infrared, UV-visible, and circular dichroism spectroscopic methods were used to determine the RNase binding mode, binding constant, sequence preference, and biopolymer secondary structural changes in the RNase–tRNA complexes. Spectroscopic results showed 2 major binding sites for RNase A on tRNA, with an overall binding constant of K = 4.0 × 105(mol/L)–1. The 2 binding sites were located at the G-C base pairs and the backbone PO2group. Protein–RNA interaction alters RNase secondary structure, with a major reduction in α helix and β sheets and an increase in the turn and random coil structures, while tRNA remains in the A conformation upon protein interaction. No tRNA digestion was observed upon RNase A complexation.
Valosin-containing protein from the hard tick Haemaphysalis longicornis: effects of dsRNA-mediated HlVCP gene silencing
Authors: Boldbaatar Damdinsuren , Battsetseg Badgar , Hatta Takeshi , Miyoshi Takeharu , Tsuji Naotoshi , Xuan Xuenan , Fujisaki Kozo
Published: June 2007

We report the cloning and characterization of a cDNA encoding the valosin-containing protein (VCP) from the Haemaphysalis longicornis tick (HlVCP). The full-length HlVCP is 2782 bp and codes for 808 amino acids of a deduced protein with a predicted molecular mass of 89.9 kDa. The domain structure analysis revealed that the deduced protein has 2 Walker A domains, 2 Walker B domains, a Cdc48 domain, and a polyQ-binding domain. The mouse anti-HlVCP serum recognized a 97 kDa native protein in the salivary glands, midgut, and synganglion. RT–PCR analysis revealed that the native VCP was expressed throughout the developing stages and in tick organs. HlVCP silencing resulted in a decrease in tick body mass after blood feeding. This study not only contributes to a growing understanding of the ATPase gene family but also lays the groundwork for future studies on protein secretion and host–tick interaction. This study is the first report of the VCP gene from Chelicerata, which include spiders, scorpions, and ticks.
TRACE ELEMENT ANALYSIS IN CANINE TEETH OF NORTHERN FUR SEALS — RELATIONSHIP BETWEEN MOTHER AND FETUS
Authors: TANAKA SHINO , ARAI NOBUAKI , YOSHIDA KOJI , BABA NORIHISA , SAKAMOTO WATARU
Published: June 2007

Canine teeth of northern fur seals were analyzed by PIXE to examine relationship between trace elements in fetal teeth and those in mother's teeth. The trace elements including Mn , Fe , Zn and Sr were detected in all the sample. No significant difference was detected in the mean concentration of Mn between fetal teeth and mother's teeth. On the other hand, significant difference was detected in the mean concentration of Fe , Zn and Sr between the enamel tissue in fetal teeth and the enamel tissue in mother's teeth. Additionally, difference in the change of concentration was detected among elements: Fe concentration in enamel tissue has no relation to ages, Zn concentration in enamel tissue decreases with age and Sr concentration in enamel tissue increases with age. The fluctuation of trace elements is possibly affected by seal's migration route and / or the mechanism of the element transfer from maternal sera to fetus through the placenta.
ELEMENTAL DISTRIBUTION IN ORGANS OF MEDAKA, Oryzias laptipes, BURDENED WITH X-RAY IRRADIATION AND SALTY WATER
Authors: YUKAWA MASAE , ISHIKAWA YUJI , IMASEKI HITOSHI , AOKI KAZUKO
Published: June 2007

Balance of essential elements in organisms is possibly changed by environmental stresses. Small toleost fish, Medaka, was burdened with X-ray irradiation (total dose: 17 Gy ) and salty water (70% NaCl of sea water). These stresses are not lethal dose. Essential elements in various organs in the fish were. measured by PIXE method and compared with a control fish to determine the effect of two types of the burdens in the elemental contents. Fe , Cu , Zn and Mn are examined in brain, eye, liver, ovary, spleen and intestine. In the liver and spleen, the contents of these elements in stressed fishes are higher than in the control fish. The change of the contents of the elements in brain was small in both cases of X-ray and salty water. It is provided that the balance shift of essential elements occurred in Medaka with the stresses can be observed using PIXE method.
PIXE MEASUREMENT OF ATMOSPHERIC PARTICULATE MATTER IN A RESIDENTIAL AREA NEAR A MAJOR URBAN HIGHWAY
Authors: Oguri Y. , Yamashita T. , Ebihara A. , Kambe N. , Hasegawa J.
Published: June 2007

In order to study influence of automobile traffic on a local urban atmospheric environment, we have investigated suspended particulate matter (SPM) collected at sampling sites in a region which includes a major highway and a residential area in the southern part of Tokyo during August - November 1999. The atomic composition of each sample was measured by means of PIXE analysis using a 2.0 MeV proton beam. Sixteen elements were quantitatively measured. The positional dependence of SPM loading was determined for each element using samples simultaneously collected at three different sites. For the experimental results obtained for downwind conditions, the measured concentration as a function of the distance from the highway was compared with a simple calculation based on the Gaussian plume model. The concentration distribution of some heavy elements in the fine fraction is well reproduced by this analysis. It has been found that for ordinary moderate downwind conditions the area within 300-400 m from the highway is directly affected by emission due to the automobile traffic.
RAPID MONITORING OF INDUSTRIAL WASTEWATER BY PIXE AND ANION CHROMATOGRAPHY
Authors: Tsuji M. , Kawasaki K. , Niizeki T.
Published: June 2007

Selenium in industrial wastewater at sub-ppm level was determined by PIXE spectrometry at the Tokyo Institute of Technology Van de Graaff Laboratory using a 2.5 MeV proton beam. A chemical concentration method was applied for elemental analysis. Other elements ( Mn , Fe , Ni , Cu , Zn , Pb , Hg , Cd , As ) were also found simultaneously. Anion chromatography revealed that selenium forms an oxyanion SeO 32- in wastewater studied. Pb , As and Se of these chemical species are required to lower below the discharge standard to the public water, 0.1ppm, while that of Hg is 0.005ppm. The combined use of these two analysis tools will help for rapid monitoring of the quality in the public water environment.
DIFFERENTIAL RESPONSES OF COPPER(I) AND COPPER(II) ON LIVER COPPER ACCUMULATION IN THE LONG-EVANS CINNAMON (LEC) RATS STUDIED BY PIXE DETERMINATION
Authors: Ohta A. , Bu G. , Matsubayashi T. , Mihara H. , Nemoto N. , Miyazawa S. , Furukawa K. , Katou T. , Oda E. , Sera K. , Futatsugawa S. , Hatakeyama S. , Saitou Y.
Published: June 2007

Effects of supplementation by copper(I) and copper (II) in Long-Evans Cinnamon(LEC) rats and life survival of rats are given. Long-Evans Cinnamon(LEC) strain rats were used at age of 8 weeks. The rats were randomly assigned to either copper(I) chloride or copper (II) chloride group. We have performed x-ray emissivite determination of copper in liver of LEC rats using PIXE and detected increase in copper in liver at early stage which could be supplemented by copper(I) and copper (II). During the supplementation period, clinical deterioration continued accompanied by daily body sway. The rats lost an undetermined amount of body weight and died approximately fourteen days later.
SUBMILLIMETER CORRECTIONS TO GRAVITY AND THE METASTABILITY OF WHITE DWARF AND NEUTRON STARS
Authors: AZAM MOFAZZAL , SAMI M.
Published: June 2007

The string inspired higher dimensional theories suggest modification of Newton's law at submillimeter length scales. Inter-particle distances in white dwarf and neutron stars are 10-10 cms and 10-13 cms respectively, and therefore, the effects of short distance corrections to gravity deserve investigation. We show, by carrying out explicit analytical many-body calculations that, in the presence of corrections, the normal state of these compact stars become metastable. The actual quantum mechanical ground state of the stars turns out to be unstable. However, the tunneling probability to the unstable ground state is so small that the stars may remain trapped in the metastable state practically forever.
PROBING HIGGS-SECTOR CP VIOLATION AT A PHOTON COLLIDER
Authors: LEE JAE SIK
Published: June 2007

In this review we demonstrate physics potential of a photon linear collider by studying the neutral Higgs–boson sector of the MSSM in which interesting CP-violating Higgs mixing could arise via radiative corrections.
Cholecystokinin-8s excites identified rat pancreatic-projecting vagal motoneurons
Authors: Wan Shuxia , Coleman F. Holly , Travagli R. Alberto
Published: June 2007

It is known that cholecystokinin (CCK) acts in a paracrine fashion to increase pancreatic exocrine secretion via vagal circuits. Recent evidence, however, suggests that CCK-8s actions are not restricted to afferent vagal fibers, but also affect brain stem structures directly. Within the brain stem, preganglionic neurons of the dorsal motor nucleus of the vagus (DMV) send efferent fibers to subdiaphragmatic viscera, including the pancreas. Our aims were to investigate whether DMV neurons responded to exogenously applied CCK-8s and, if so, the mechanism of action. Using whole cell patch-clamp recordings we show that perfusion with CCK-8s induced a concentration-dependent excitation in ∼60% of identified pancreas-projecting DMV neurons. The depolarization was significantly reduced by tetrodotoxin, suggesting both direct (on the DMV membrane) and indirect (on local synaptic circuits) effects. Indeed, CCK-8s increased the frequency of miniature excitatory currents onto DMV neurons. The CCK-A antagonist, lorglumide, prevented the CCK-8s-mediated excitation whereas the CCK-B preferring agonist, CCK-nonsulfated, had no effect, suggesting the involvement of CCK-A receptors only. In voltage clamp, the CCK-8s-induced inward current reversed at −106 ± 3 mV and the input resistance increased by 150 ± 15%, suggesting an effect mediated by the closure of a potassium conductance. Indeed, CCK-8s reduced both the amplitude and the time constant of decay of a calcium-dependent potassium conductance. When tested with pancreatic polypeptide (which reduces pancreatic exocrine secretion), cells that responded to CCK-8s with an excitation were, instead, inhibited by pancreatic polypeptide. These data indicate that CCK-8s may control pancreas-exocrine secretion also via an effect on pancreas-projecting DMV neurons.
Vagally mediated, nonparacrine effects of cholecystokinin-8s on rat pancreatic exocrine secretion
Authors: Viard Eddy , Zheng Zhongling , Wan Shuxia , Travagli R. Alberto
Published: June 2007

Cholecystokinin (CCK) has been proposed to act in a vagally dependent manner to increase pancreatic exocrine secretion via actions exclusively at peripheral vagal afferent fibers. Recent evidence, however, suggests the CCK-8s may also affect brain stem structures directly. We used an in vivo preparation with the aims of 1) investigating whether the actions of intraduodenal casein perfusion to increase pancreatic protein secretion also involved direct actions of CCK at the level of the brain stem and, if so, 2) determining whether, in the absence of vagal afferent inputs, CCK-8s applied to the dorsal vagal complex (DVC) can also modulate pancreatic exocrine secretion (PES). Sprague-Dawley rats (250–400 g) were anesthetized and the common bile-pancreatic duct was cannulated to collect PES. Both vagal deafferentation and pretreatment with the CCK-A antagonist lorglumide on the floor of the fourth ventricle decreased the casein-induced increase in PES output. CCK-8s microinjection (450 pmol) in the DVC significantly increased PES; the increase was larger when CCK-8s was injected in the left side of the DVC. Protein secretion returned to baseline levels within 30 min. Microinjection of CCK-8s increased PES (although to a lower extent) also in rats that underwent complete vagal deafferentation. These data indicate that, as well as activating peripheral vagal afferents, CCK-8s increases pancreatic exocrine secretion via an action in the DVC. Our data suggest that the CCK-8s-induced increases in PES are due mainly to a paracrine effect of CCK; however, a relevant portion of the effects of CCK is due also to an effect of the peptide on brain stem vagal circuits.
Modulatory role of phosphoinositide 3-kinase in gastric acid secretion
Authors: Mettler S. E. , Ghayouri S. , Christensen G. P. , Forte J. G.
Published: June 2007

The gastric parietal cell is responsible for the secretion of HCl into the lumen of the stomach mainly due to stimulation by histamine via the cAMP pathway. However, the participation of several other receptors and pathways have been discovered to influence both stimulation and inhibition of acid secretion (e.g., cholinergic). Here we examine the role of phosphoinositide 3-kinase (PI3K) in the modulation of acid secretion. Treatment of isolated gastric glands and parietal cells with the PI3K inhibitor, LY294002 (LY), potentiated acid secretion in response to histamine to nearly the maximal secretion obtained with histamine plus phosphodiesterase inhibitors. As cAMP levels were elevated in response to histamine plus LY, but other means of elevating cAMP (e.g., forskolin, dbcAMP) were not influenced by LY, we posited that the effect might require activation of G-protein-coupled histamine H2receptors, possibly through the protein kinase B pathway (also known as Akt). Study of downstream effectors of PI3K showed that histaminergic stimulation increased Akt phosphorylation, which in turn was blocked by inhibition of PI3K. Expression studies showed that high expression of active Akt decreased acid secretion, whereas dominant-negative Akt increased acid secretion. Taken together, these data suggest stimulation with histamine increases the activity of PI3K leading to increased activity of Akt and decreased levels of cAMP in the parietal cell.
Proteoglycan fragmentation and respiratory mechanics in mechanically ventilated healthy rats
Authors: Moriondo Andrea , Pelosi Paolo , Passi Alberto , Viola Manuela , Marcozzi Cristiana , Severgnini Paolo , Ottani Vittoria , Quaranta Marilisa , Negrini Daniela
Published: June 2007

This research investigated whether stretching of lung tissue due to increased positive alveolar pressure swings during mechanical ventilation (MV) at various tidal volumes (Vt) might affect the composition and/or structure of the glycosaminoglycan (GAG) components of pulmonary extracellular proteoglycans. Experiments were performed in 30 healthy rats: 1) anesthetized and immediately killed (controls, C-0); 2) anesthetized and spontaneously breathing for 4 h (C-4h); and 3) anesthetized, paralyzed, and mechanically ventilated for 4 h with air at 0-cmH2O end-expiratory pressure and Vt of 8 ml/kg (MV-1), 16 ml/kg (MV-2), 24 ml/kg (MV-3), or 32 ml/kg (MV-4), adjusting respiratory rates at a minute ventilation of 270 ml/min. Compared with C-0 and C-4h, a significant reduction of dynamic and static compliance of the respiratory system and of the lung was observed only in MV-4, while extravascular lung water significantly increased in MV-3 and MV-4, but not in MV-1 and MV-2. However, even in MV-1, MV induced a significant fragmentation of pulmonary GAGs. Extraction of covalently bound GAGs and wash out of loosely bound or fragmented GAGs progressively increased with increasing Vt and was associated with increased expression of local (matrix metalloproteinase-2) and systemic (matrix metalloproteinase-9) activated metalloproteases. We conclude that 1) MV, even at “physiological” low Vt, severely affects the pulmonary extracellular architecture, exposing the lung parenchyma to development of ventilator-induced lung injury; and 2) respiratory mechanics is not a reliable clinical tool for early detection of lung injury.
Blood flow restriction during low-intensity resistance exercise increases S6K1 phosphorylation and muscle protein synthesis
Authors: Fujita Satoshi , Abe Takashi , Drummond Micah J. , Cadenas Jerson G. , Dreyer Hans C. , Sato Yoshiaki , Volpi Elena , Rasmussen Blake B.
Published: June 2007

Low-intensity resistance exercise training combined with blood flow restriction (REFR) increases muscle size and strength as much as conventional resistance exercise with high loads. However, the cellular mechanism(s) underlying the hypertrophy and strength gains induced by REFR are unknown. We have recently shown that both the mammalian target of rapamycin (mTOR) signaling pathway and muscle protein synthesis (MPS) were stimulated after an acute bout of high-intensity resistance exercise in humans. Therefore, we hypothesized that an acute bout of REFR would enhance mTOR signaling and stimulate MPS. We measured MPS and phosphorylation status of mTOR-associated signaling proteins in six young male subjects. Subjects were studied once during blood flow restriction (REFR, bilateral leg extension exercise at 20% of 1 repetition maximum while a pressure cuff was placed on the proximal end of both thighs and inflated at 200 mmHg) and a second time using the same exercise protocol but without the pressure cuff [control (Ctrl)]. MPS in the vastus lateralis muscle was measured by using stable isotope techniques, and the phosphorylation status of signaling proteins was determined by immunoblotting. Blood lactate, cortisol, and growth hormone were higher following REFR compared with Ctrl ( P < 0.05). Ribosomal S6 kinase 1 (S6K1) phosphorylation, a downstream target of mTOR, increased concurrently with a decreased eukaryotic translation elongation factor 2 (eEF2) phosphorylation and a 46% increase in MPS following REFR ( P < 0.05). MPS and S6K1 phosphorylation were unchanged in the Ctrl group postexercise. We conclude that the activation of the mTOR signaling pathway appears to be an important cellular mechanism that may help explain the enhanced muscle protein synthesis during REFR.
Lung density is not altered following intense normobaric hypoxic interval training in competitive female cyclists
Authors: Guenette Jordan A. , Sporer Benjamin C. , MacNutt Meaghan J. , Coxson Harvey O. , Sheel A. William , Mayo John R. , McKenzie Donald C.
Published: June 2007

Noninvasive imaging techniques have been used to assess pulmonary edema following exercise but results remain equivocal. Most studies examining this phenomenon have used male subjects while the female response has received little attention. Some suggest that women, by virtue of their smaller lungs, airways, and diffusion surface areas may be more susceptible to pulmonary limitations during exercise. Accordingly, the purpose of this study was to determine if intense normobaric hypoxic exercise could induce pulmonary edema in women. Baseline lung density was obtained in eight highly trained female cyclists (mean ± SD: age = 26 ± 7 yr; height = 172.2 ± 6.7 cm; mass = 64.1 ± 6.7 kg; V̇o2max = 52.2 ± 2.2 ml·kg−1·min−1) using computed tomography (CT). CT scans were obtained at the level of the aortic arch, the tracheal carina, and the superior end plate of the tenth thoracic vertebra. While breathing 15% O2, subjects then performed five 2.5-km cycling intervals [mean power = 212 ± 31 W; heart rate (HR) = 94.5 ± 2.2%HRmax] separated by 5 min of recovery. Throughout the intervals, subjects desaturated to 82 ± 4%, which was 13 ± 2% below resting hypoxic levels. Scans were repeated 44 ± 8 min following exercise. Mean lung density did not change from pre (0.138 ± 0.014 g/ml)- to postexercise (0.137 ± 0.011 g/ml). These findings suggest that pulmonary edema does not occur in highly trained females following intense normobaric hypoxic exercise.
Exercise-induced HSP-72 elevation and cardioprotection against infarct and apoptosis
Authors: Quindry John C. , Hamilton Karyn L. , French Joel P. , Lee Youngil , Murlasits Zsolt , Tumer Nihal , Powers Scott K.
Published: June 2007

Successive bouts of endurance exercise are associated with both increased cardiac levels of heat shock protein-72 (HSP-72) and improved cardioprotection against ischemia-reperfusion (I/R)-induced cardiac cell death. Although overexpression of HSP-72 has been shown to be cardioprotective in transgenic animals, it is unclear whether increased levels of HSP-72 are essential for exercise-induced cardioprotection against I/R-mediated cell death. We tested the hypothesis that exercise-induced increases in myocardial levels of HSP-72 are required to achieve exercise-mediated protection against I/R-induced cardiac cell death. To test this postulate, we investigated the effect of preventing the exercise-induced increase in cardiac HSP-72 on myocardial infarction and apoptosis after 50 min of in vivo ischemia and 120 min of reperfusion. Adult male rats remained sedentary or performed successive bouts of endurance exercise in cold (8°C) or warm (22°C) environments. We found that, compared with sedentary control animals, exercise in a warm environment significantly increased myocardial HSP-72 content. In contrast, exercise in the cold environment prevented the exercise-induced increase in myocardial HSP-72 levels. After in vivo myocardial I/R, infarct size was reduced in both exercised groups compared with sedentary animals. Furthermore, compared with sedentary rats, I/R-induced myocardial apoptosis (as indicated by terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling-positive nuclei and caspase-3 activity) was attenuated in both groups of exercised animals. Therefore, although HSP-72 has cardioprotective properties, our results reveal that increased myocardial levels of HSP-72 (above control) are not essential for exercise-induced protection against I/R-induced myocardial infarction and apoptosis.
Pulmonary perfusion in the prone and supine postures in the normal human lung
Authors: Prisk G. Kim , Yamada Kei , Henderson A. Cortney , Arai Tatsuya J. , Levin David L. , Buxton Richard B. , Hopkins Susan R.
Published: June 2007

Prone posture increases cardiac output and improves pulmonary gas exchange. We hypothesized that, in the supine posture, greater compression of dependent lung limits regional blood flow. To test this, MRI-based measures of regional lung density, MRI arterial spin labeling quantification of pulmonary perfusion, and density-normalized perfusion were made in six healthy subjects. Measurements were made in both the prone and supine posture at functional residual capacity. Data were acquired in three nonoverlapping 15-mm sagittal slices covering most of the right lung: central, middle, and lateral, which were further divided into vertical zones: anterior, intermediate, and posterior. The density of the entire lung was not different between prone and supine, but the increase in lung density in the anterior lung with prone posture was less than the decrease in the posterior lung (change: +0.07 g/cm3 anterior, −0.11 posterior; P < 0.0001), indicating greater compression of dependent lung in supine posture, principally in the central lung slice ( P < 0.0001). Overall, density-normalized perfusion was significantly greater in prone posture (7.9 ± 3.6 ml·min−1·g−1 prone, 5.1 ± 1.8 supine, a 55% increase; P < 0.05) and showed the largest increase in the posterior lung as it became nondependent (change: +71% posterior, +58% intermediate, +31% anterior; P = 0.08), most marked in the central lung slice ( P < 0.05). These data indicate that central posterior portions of the lung are more compressed in the supine posture, likely by the heart and adjacent structures, than are central anterior portions in the prone and that this limits regional perfusion in the supine posture.
Progressive decrease of heart period variability entropy-based complexity during graded head-up tilt
Authors: Porta Alberto , Gnecchi-Ruscone Tomaso , Tobaldini Eleonora , Guzzetti Stefano , Furlan Raffaello , Montano Nicola
Published: June 2007

Complexity (or its opposite, regularity) of heart period variability has been related to age and disease but never linked to a progressive shift of the sympathovagal balance. We compare several well established estimates of complexity of heart period variability based on entropy rates [i.e., approximate entropy (ApEn), sample entropy (SampEn), and correct conditional entropy (CCE)] during an experimental protocol known to produce a gradual shift of the sympathovagal balance toward sympathetic activation and vagal withdrawal (i.e., the graded head-up tilt test). Complexity analysis was carried out in 17 healthy subjects over short heart period variability series (∼250 cardiac beats) derived from ECG recordings during head-up tilt with table inclination randomly chosen inside the set {0, 15, 30, 45, 60, 75, 90}. We found that 1) ApEn does not change significantly during the protocol; 2) all indices measuring complexity based on entropy rates, including ad hoc corrections of the bias arising from their evaluation over short data sequences (i.e., corrected ApEn, SampEn, CCE), evidence a progressive decrease of complexity as a function of the tilt table inclination, thus indicating that complexity is under control of the autonomic nervous system; 3) corrected ApEn, SampEn, and CCE provide global indices that can be helpful to monitor sympathovagal balance.
The mechanical behavior of activated skeletal muscle during stretch: effects of muscle unloading and MyHC isoform shifts
Authors: Caiozzo Vincent J. , Richmond Heather , Kaska Serge , Valeroso Dahlia
Published: June 2007

The response of activated skeletal muscle to a ramp stretch is complex. Force rises rapidly above the isometric plateau during the initial phase of stretch. However, after a strain of ∼1–2%, force yields and continues to rise but with a slower slope. The resistance to stretch during the initial phase can be characterized by the stiffness of the muscle and/or the preyield modulus ( Epre). Similarly, a measure of modulus also can be used to characterize the postyield modulus response ( Epost). This study examined the effects of muscle atrophy and altered myosin heavy chain (MyHC) isoform composition on both Epreand Epost. Female Sprague-Dawley rats were assigned to 1) control group, 2) a hypothyroid group, 3) a hyperthyroid group, 4) a hindlimb suspension group, and 5) a hindlimb suspension + hyperthyroid group. These interventions were used either to alter the MyHC isoform composition of the muscle or to induce atrophy. Soleus muscles were stretched at strain rates that ranged from ∼0.15 to 1.25 muscle length/s. The findings of this study demonstrate that 4 wk of hindlimb suspension can produce a large (i.e., 40–60%) reduction in Epre. Hindlimb suspension did not produce a proportional change in Epost. Analyses of the Epre-strain rate relationship demonstrated that there was little dependence on MyHC isoform composition. In summary, the disproportionate decrease in Epreof atrophied muscle has important implications with respect to issues related to joint stability, especially under dynamic conditions and conditions where the static joint stabilizers (i.e., ligaments) have been compromised by injury.
Ventilation-perfusion relationships following experimental pulmonary contusion
Authors: Batchinsky Andriy I. , Weiss William B. , Jordan Bryan S. , Dick Edward J. , Cancelada David A. , Cancio Leopoldo C.
Published: June 2007

Ventilation-perfusion changes after right-sided pulmonary contusion (PC) in swine were investigated by means of the multiple inert gas elimination technique (MIGET). Anesthetized swine (injury, n = 8; control, n = 6) sustained a right-chest PC by a captive-bolt apparatus. This was followed by a 12-ml/kg hemorrhage, resuscitation, and reinfusion of shed blood. MIGET and thoracic computed tomography (CT) were performed before and 6 h after injury. Three-dimensional CT scan reconstruction enabled determination of the combined fractional volume of poorly aerated and non-aerated lung tissue (VOL), and the mean gray-scale density (MGSD). Six hours after PC in injured animals, PaO2 decreased from 234.9 ± 5.1 to 113.9 ± 13.0 mmHg. Shunt (QS) increased (2.7 ± 0.4 to 12.3 ± 2.2%) at the expense of blood flow to normal ventilation/perfusion compartments (97.1 ± 0.4 to 87.4 ± 2.2%). Dead space ventilation (VD/VT) increased (58.7 ± 1.7% to 67.2 ± 1.2%). MGSD increased (−696.7 ± 6.1 to −565.0 ± 24.3 Hounsfield units), as did VOL (4.3 ± 0.5 to 33.5 ± 3.2%). Multivariate linear regression of MGSD, VOL, VD/VT, and QS vs. PaO2 retained VOL and QS ( r2 = .835) as independent covariates of PaO2. An increase in QS characterizes lung failure 6 h after pulmonary contusion; QS and VOL correlate independently with PaO2.
The influence of episodic hypoxia on upper airway collapsibility in subjects with obstructive sleep apnea
Authors: Rowley James A. , Deebajah Ihab , Parikh Swapna , Najar Ali , Saha Rajib , Badr M. Safwan
Published: June 2007

We have previously shown that in subjects with obstructive sleep apnea, repetitive hypoxia is associated with long-term facilitation as manifested by decreased upper airway resistance (Rua). Our objective was to study the influence of long-term facilitation on upper airway collapsibility as measured by the critical closing pressure (Pcrit) model and to determine whether changes in Rua correlated with changes in collapsibility. We studied 13 subjects (10 men, 3 women) with a mean apnea-hypopnea index of 43.9 ± 24.0 events/h. In the first protocol with 11 subjects, we measured collapsibility using a Pcrit protocol before and after episodic hypoxia. Brief (3 min) isocapnic hypoxia (inspired O2fraction = 8%) followed by 5 min of room air was induced 10 times. A sham study without hypoxia was performed on eight subjects. Ventilatory parameters, Rua, and Pcrit before and after episodic hypoxia were measured. At 20 min of recovery, there was no change in minute ventilation but there was a significant decrease in Rua compared with the control period (control, 8.6 ± 4.8 cmH2O·l−1·s vs. recovery, 5.9 ± 3.8 cmH2O·l−1·s; P < 0.05). However, there was no change in Pcrit between the control (2.3 ± 1.9 cmH2O) and recovery (2.7 ± 3.2 cmH2O) periods. No changes in Rua or Pcrit were observed in the sham protocol. We conclude that long-term facilitation of upper airway dilators is not associated with changes in upper airway collapsibility in subjects with obstructive sleep apnea. These results corroborate previous evidence that changes in upper airway resistance and caliber can be dissociated from changes in upper airway collapsibility.
Predictors of 2-Year Drinking Outcomes in a Swedish Treatment Sample
Authors: Bodin Maria C. , Romelsjö Anders
Published: June 2007

Background: Few studies have investigated predictors of short- and longer-term outcomes in relatively well functioning treatment samples. Methods: Multivariate logistic regression analyses were used to identify predictors of continuous abstinence in 188 individuals during their 2nd year after private 12-step treatment in Sweden, and findings are related to a previous report on 1-year outcomes. Results: Individual baseline characteristics were not directly related to 2nd year outcomes, while a higher 1st-year drinking severity decreased the likelihood of 2nd-year abstinence. Satisfaction with treatment and affiliation with Alcoholics Anonymous, but not program aftercare during the 1st year increased the likelihood of 2nd-year abstinence. Conclusion: Results are consistent with previous studies showing that shorter-term outcomes are likely to be maintained, and that baseline characteristics and treatment factors account less for outcomes over longer terms.
Report of an International Survey of Molecular Genetic Testing Laboratories
Authors: McGovern Margaret M. , Elles Rob , Beretta Isabella , Somerville Martin J. , Hoefler Gerald , Keinanen Mauri , Barton David , Carson Nancy , Dequeker Elisabeth , Brdicka Radim , Blazkova Alena , Aymé Ségolène , Schnieders Birgit , Müller Clemens R. , Dalen Vibeke , Martinez Armando Albert , Kristoffersson Ulf , Ozguc Meral , Mueller Hansjakob , Boone Joe , Lubin Ira M. , Sequeiros Jorge , Taruscio Domenica , Williamson Bob , Mainland Lynn , Yoshikura Hiroshi , Ronchi Elettra
Published: June 2007

Objective: To collect data on the practices of molecular genetic testing (MGT) laboratories for the development of national and international policies for quality assurance (QA). Methods: A web-based survey of MGT laboratory directors (n = 827; response rate 63%) in 18 countries on 3 continents. QA and reporting indices were developed and calculated for each responding laboratory. Results: Laboratory setting varied among and within countries, as did qualifications of the directors. Respondents in every country indicated that their laboratory receives specimens from outside their national borders (64%, n = 529). Pair-wise comparisons of the QA index revealed a significant association with the director having formal training in molecular genetics (p < 0.005), affiliation with a genetics unit (p = 0.003), accreditation of the laboratory (p < 0.005) and participation in proficiency testing (p < 0.005). Research labs had a lower mean report score compared to all other settings (p < 0.05) as did laboratories accessioning <150 samples per year. Conclusion: MGT is provided under widely varying conditions and regulatory frameworks. The data provided here may be a useful guide for policy action at both governmental and professional levels.