bluuebunny/crossref_metadata_2025 huggingface dataset:
Physiology and Posttranscriptional Regulation of Methanol:Coenzyme M Methyltransferase Isozymes in
Methanosarcina acetivorans
C2A
Authors: Opulencia Rina B. , Bose Arpita , Metcalf William W.
Published: September 2009

Methanosarcina
species possess three operons (
mtaCB1
,
mtaCB2
, and
mtaCB3
) encoding methanol-specific methyltransferase 1 (MT1) isozymes and two genes (
mtaA1
and
mtaA2
) with the potential to encode a methanol-specific methyltransferase 2 (MT2). Previous genetic studies showed that these genes are differentially regulated and encode enzymes with distinct levels of methyltransferase activity. Here, the effects of promoter strength on growth and on the rate of methane production were examined by constructing strains in which the
mtaCB
promoters were exchanged. When expressed from the strong P
mtaC1
or P
mtaC2
promoter, each of the MtaC and MtaB proteins supported growth and methane production at wild-type levels. In contrast, all
mtaCB
operons exhibited poorer growth and lower rates of methane production when P
mtaC3
controlled their expression. Thus, previously observed phenotypic differences can be attributed largely to differences in promoter activity. Strains carrying various combinations of
mtaC
,
mtaB
, and
mtaA
expressed from the strong, tetracycline-regulated P
mcrB
(
tetO1
) promoter exhibited similar growth characteristics on methanol, showing that all combinations of MtaC, MtaB, and MtaA can form functional MT1/MT2 complexes. However, an in vitro assay of coupled MT1/MT2 activity showed significant variation between the strains. Surprisingly, these variations in activity correlated with differences in protein abundance, despite the fact that all the encoding genes were expressed from the same promoter. Quantitative reverse transcriptase PCR and reporter gene fusion data suggest that the
mtaCBA
transcripts show different stabilities, which are strongly influenced by the growth substrate.
A Novel Regulatory Protein Involved in Motility of
Vibrio cholerae
Authors: Moisi Manuel , Jenul Christian , Butler Susan M. , New Aaron , Tutz Sarah , Reidl Joachim , Klose Karl E. , Camilli Andrew , Schild Stefan
Published: September 2009

The facultative pathogen
Vibrio cholerae
is the causative agent of the human intestinal disease cholera. Both motility and chemotaxis of
V. cholerae
have been shown to contribute to the virulence and spread of cholera. The flagellar gene operons are organized into a hierarchy composed of four classes (I to IV) based on their temporal expression patterns. Some regulatory elements involved in flagellar gene expression have been elucidated, but regulation is complex and flagellar biogenesis in
V. cholerae
is not completely understood. In this study, we determined that the virulence defect of a
V. cholerae cheW1
deletion mutant was due to polar effects on the downstream open reading frame VC2058 (
flrD
). Expression of
flrD
in
trans
restored the virulence defect of the
cheW1
deletion mutant, and deletion of
flrD
resulted in a
V. cholerae
strain attenuated for virulence, as determined by using the infant mouse intestinal colonization model. The
flrD
mutant strain exhibited decreased transcription of class III and IV flagellar genes and reduced motility. Transcription of the
flrD
promoter, which lies within the coding sequence of
cheW1
, is independent of the flagellar transcriptional activators FlrA and RpoN, which activate class II genes, indicating that
flrD
does not fit into any of the four flagellar gene classes. Genetic epistasis studies revealed that the two-component system FlrBC, which is required for class III and IV flagellar gene transcription, acts downstream of
flrD
. We hypothesize that the inner membrane protein FlrD interacts with the cytoplasmic FlrBC complex to activate class III and IV gene transcription.
Role of the Transcriptional Regulator RamB (Rv0465c) in the Control of the Glyoxylate Cycle in
Mycobacterium tuberculosis
Authors: Micklinghoff Julia C. , Breitinger Katrin J. , Schmidt Mascha , Geffers Robert , Eikmanns Bernhard J. , Bange Franz-Christoph
Published: September 2009

Mycobacterium tuberculosis
generally is assumed to depend on lipids as a major carbon and energy source when persisting within the host. The utilization of fatty acids requires a functional glyoxylate cycle with the key enzymes isocitrate lyase (Icl) and malate synthase. The open reading frame Rv0465c of
M. tuberculosis
H37Rv encodes a protein with significant sequence similarity to the transcriptional regulator RamB, which in
Corynebacterium glutamicum
controls the expression of several genes involved in acetate metabolism, i.e., those encoding enzymes of acetate activation and the glyoxylate cycle. We show here that the
M. tuberculosis
Rv0465c protein can functionally complement RamB in
C. glutamicum
and that it binds to the promoter regions of
M. tuberculosis icl1
and Rv0465c. Construction and subsequent transcriptional and enzymatic analysis of a defined Rv0465c deletion mutant in
M. tuberculosis
revealed that the Rv0465c protein, now designated RamB, represses
icl1
expression during growth with glucose and negatively autoregulates the expression of its own operon. Whole-genome microarray analysis of the
M. tuberculosis ramB
(

ramB
MT

) mutant and the wild type furthermore showed that apart from
icl1
and the

ramB
MT

operon, the expression of all other
M. tuberculosis
genes involved in acetate metabolism remain unchanged in the mutant. Thus, RamB
MT
has a more specific regulatory function as RamB from
C. glutamicum
and is confined to expression control of
icl1
and the

ramB
MT

operon.
Complete Genome Sequence of the Ethanol Producer
Zymomonas mobilis
NCIMB 11163
Authors: Kouvelis Vassili N. , Saunders Elizabeth , Brettin Thomas S. , Bruce David , Detter Chris , Han Cliff , Typas Milton A. , Pappas Katherine M.
Published: September 2009

Zymomonas mobilis
is an ethanol-producing alphaproteobacterium currently considered a major candidate organism for bioethanol production. Here we report the finished and annotated genome sequence of
Z. mobilis
subsp.
mobilis
strain NCIMB 11163, a British ale-infecting isolate. This is the first
Z. mobilis
strain whose genome, chromosomal and plasmid, is presented in its entirety.
Occupational exposure to silica and lung cancer risk in the Netherlands
Authors: Preller Liesbeth , van den Bosch Linda M C , van den Brandt Piet A , Kauppinen T , Goldbohm Alexandra
Published: September 2009

Objectives

The lung cancer carcinogenicity of crystalline silica dust remains the subject of discussion. Epidemiological evidence is based on occupational cohort studies and population-based case–control studies. The aim of this study was to assess associations between male lung cancer risk and silica exposure in a population-based cohort study.

Methods

The study was conducted among men aged 55–69 years (n=58 279) from the Netherlands Cohort Study, which included self-reported, life-time job histories. Job titles were linked to the occupational groups of the external Finnish Job Exposure Matrix (FINJEM), including probability and level of silica exposure, each for specific time periods. 1667 incident lung cancer cases with known silica exposure status (210 exposed) were available after 11.3 years of follow-up. Risks were estimated based on a case–cohort design, and using Cox proportional hazards models.

Results

Adjusted for smoking and other confounders, elevated risks were observed for exposure duration (RR 1.65, 95% CI 1.14 to 2.41 for 26–51 years vs no exposure) and cumulative exposure (RR 1.47, 95% CI 0.93 to 2.33 for ≥3 vs <3 mg/m3.year). Associations with average exposure levels were weaker. Associations were stronger for occupations with an exposure probability of ≥90%. Adjustment for asbestos exposure slightly increased the risk.

Conclusions

Results from this prospective population-based cohort study corroborate the classification of crystalline silica as a lung carcinogen. Associations could not be explained by smoking or by asbestos exposure.
ON THE POWER OF COOPERATING MORPHISMS VIA REACHABILITY PROBLEMS
Authors: KARHUMÄKI JUHANI
Published: September 2009

The goal of this presentation is to analyze the equality mechanism of cooperating morphisms of free monoids, and to point out how it can be used to define the reachability problems leading to important undecidability results and easy characterizations of recursively enumerable languages. In particular, we aim to show, which subconstructions are needed in such results. Moreover, we recall that in some cases the undecidability of the reachability is achieved although the sets of all reachable objects are simple, or more formally, regular languages.
SWITCHING GRAPHS
Authors: GROOTE JAN FRISO , PLOEGER BAS
Published: September 2009

Switching graphs are graphs that contain switches. A switch is a pair of edges that start in the same vertex and of which precisely one edge is enabled at any time. By using a Boolean function called a switch setting, the switches in a switching graph can be put in a fixed direction to obtain an ordinary graph. For many problems, switching graphs are a remarkable straightforward and natural model, but they have hardly been studied. We study the complexity of several natural questions in switching graphs of which some are polynomial, and others are NP-complete. We started investigating switching graphs because they turned out to be a natural framework for studying the problem of solving Boolean equation systems, which is equivalent to model checking of the modal µ-calculus and deciding the winner in parity games. We give direct, polynomial encodings of Boolean equation systems in switching graphs and vice versa, and prove correctness of the encodings.
DOPING INDUCED ELECTRONIC PHASE SEPARATION AND COULOMB BUBBLES IN LAYERED SUPERCONDUCTORS
Authors: SAARELA M. , KUSMARTSEV F. V.
Published: September 2009

We study properties of charge fluids with random impurities or heavy polarons using a microscopic Hamiltonian with the full many-body Coulomb interaction. At zero temperature and high enough density the bosonic fluid is superconducting, but when density decreases the Coulomb interaction will be strongly over-screened and impurities or polarons begin to trap charge carriers forming bound quasiparticle like clusters, which we call Coulomb bubbles or clumps. These bubbles are embedded inside the superconductor and form nuclei of a new insulating state. The growth of a bubble is terminated by the Coulomb force. The fluid contains two groups of charge carriers associated with free and localized states. The insulating state arises via a percolation of the insulating islands of bubbles, which cluster and prevent the flow of the electrical supercurrent through the system.

Our results are applicable to HTSC. There the Coulomb fluids discussed in the paper correspond to mobile holes located on Cu sites and heavy polarons or charged impurities located on Oxygen sites. As a result of our calculations the following two-componet picture of two competing orders in cuprates arise. The mobile and localized states are competing with each other and their balance is controlled by doping. At high doping a large Fermi surface is open. There the density of real charge carriers is significantly larger than the density of the doped ones. When doping decreases more and more carriers are localized as Coulomb clumps which are creating around heavy polarons localized on Oxygen sites and forming a regular lattice. The picture is consistent with the Gorkov and Teitelbaum (GT) analysis 1,2 of the transport, Hall effect data and the ARPES spectra as well as with nanoscale superstructures observed in Scanning Tunneling Microscope(STM) experiments [3-8]. The scenario of the clump formation may be also applicable to pnictides, where two types of clumps may arise even at very high temperatures.
RPA APPROACH TO NON-LINEAR TRANSPORT IN QUANTUM DOTS
Authors: TANATAR B. , MOLDOVEANU V.
Published: September 2009

An accurate theoretical treatment of electron-electron interactions in mesoscopic systems is available in very few cases and approximation schemes are developed in most of the applications, especially for many-level quantum dots. Here we present transport calculations within the random-phase approximation for the Coulomb interaction using the Keldysh Green's functions formalism. We describe the quantum dot systems by a tight-binding Hamiltonian. Our method is similar to the one used by Faleev and Stockman [Phys. Rev. B 66 085318 (2002)] in their study of the equilibrium properties of a homogeneous 2D electron gas. The important extension at the formal level is that we combine the RPA and the Keldysh formalism for studying non-linear transport properties of open quantum dots. Within the Keldysh formalism the polarization operator becomes a contour-ordered quantity that should be computed either from the non-interacting Green functions of the coupled quantum dot (the so-called G0W approximation) either self-consistently (GW approximation). We performed both non-selfconsistent and self-consistent calculations and compare the results. In particular we recover the Coulomb diamonds for interacting quantum dots and we discuss the charge sensing effects in parallel quantum dots.
Effects of Ion Irradiation on the Performance of Solid Oxide Fuel Cells
Authors: Crabb Kevin M. , Chao Cheng-Chieh , Park Joon Seok , Prinz F B.
Published: September 2009

In this paper, the effects of ion irradiation at the cathode-electrolyte interface of solid oxide fuel cells (SOFCs) are studied. In particular, the IV performance is studied as a function of irradiation species, energy, and dose. Impedance spectroscopy is used to determine the type of loss most affected by the irradiation. Results indicate that xenon ion irradiation produces an increase of more than 100% in the peak power density at 400{degree sign}C (under multiple irradiation conditions) by reducing the activation losses of the SOFCs, while lithium, and sodium irradiation produce either little effect, or significantly worse performance, depending upon the ion irradiation conditions used. Additionally, transmission electron microscopy (TEM) is used to visualize the damage created in the electrolyte substrates under various irradiation conditions.
Polarization of Anode-Supported Solid Oxide Fuel Cells Studied by Pt Reference Electrode in Symmetric and Asymmetric Configurations
Authors: Xiao Haiming , Rottmayer Michael , Seibert T. , Reitz Thomas
Published: September 2009

A symmetric three-electrode configuration was applied to an anode-supported solid oxide fuel cell to study electrode polarization and the results were compared with those obtained via an asymmetric reference configuration. In this study, Ni/YSZ was used as the anode, LSM/YSZ as the cathode, Pt as the reference electrode, and thin YSZ film as the electrolyte. The cells were polarized potentiostatically at - 0.2 V, - 0.4 V, - 0.6 V and - 0.8 V with respect to open circuit voltage (OCV) and the potential changes of the anode and the cathode were measured via reference electrode simultaneously. The data from both symmetric and asymmetric configurations indicated cathode overpotentials was much larger than that observed on the anode. The cathode overpotentials decreased with increasing temperature. At low polarizations, cell overpotentials were disproportionately cathodic but the difference between anode and cathode polarization decreased with increasing polarization. The relative contribution of anodic overpotentials compared to cathodic was also observed to increase with increasing cell temperature.
The Effect of Particle Size on the Microstructure and the Effective Reaction Zone of SOFC Cermet Anodes
Authors: Fukunaga Hiroshi , Azuma Junji , Takatsuka Toru , Koyama Michihisa
Published: September 2009

Ni-SDC cermet SOFC anodes with different microstructures were prepared and the overpotential and the ohmic loss were measured. Anodes with coarse particles and small pores showed intermediate performance and little dependence on flow rate, whereas that with large pores showed a large dependence on flow rate and high performance at high flow rate. Anodes with fine particles showed lowest overpotential at low current density. Ohmic loss was large for the thick electrode with small pores, and for that with large pores, when flow rate was low. It is considered that different particle size and pore size lead to the difference in effective reaction zone, thus showing different dependence to the flow rate.
Improved Performance of Nickel / Gadolinium-doped Ceria Anode by Infiltration of Proton Conductor (SrCe0.95Yb0.05O3-α) in Hydrogen and Dry Methane Fuels
Authors: Yasutake Hiroyuki , Jin Yongcheng , Yamahara Keij , Ihara Manabu
Published: September 2009

Ni/Gd0.2Ce0.8O2-δ(GDC) anodes were infiltrated with the proton-conductor SrCe0.95Yb0.05O3-α (SCYb) to improve the performance of SOFCs. First, the electrochemical characteristics of Ni/GDC and Ni/GDC-SCYb anodes were evaluated in humidified hydrogen (1 % H2O) fuel and in dry methane fuel at 1173 K, and then the tolerance of the anodes against dry methane was evaluated using accelerated degradation tests. Results revealed that the maximum power density of the Ni/GDC-SCYb anode was 50 % higher than that of the Ni/GDC anode; namely, maximum Power density of 0.648 W/cm2 in humidified H2 and 0.438 W/cm2 in dry methane. In conclusion, performance of Ni/GDC anodes can be improved in humidified hydrogen and dry methane fuels by infiltration with SCYb.
Electric-Field Effects in Solid-State Ionic Devices
Authors: Blackburn Bryan M. , Van Assche F. Martin , Wachsman E. D.
Published: September 2009

The performance of solid-state ionic devices is often dependent on chemisorption and surface reactions. Due to the nature of these processes, they can be influenced with electric fields. The primary focus of this work is to explore the use of externally-generated (i.e., not directly biased) electric fields to modify the behavior and performance of solid-state gas sensors. This electric-field effect was displayed using a planar gas sensor, which consisted of sensing electrodes exposed to the same environment. The effect was further investigated using an air-reference sample to simultaneously monitor changes in the electrical properties of a semiconducting oxide/electrolyte couple and changes in gas composition as a result of the electric field. In order to gauge effects to the semiconducting oxide alone, temperature programmed desorption (TPD) experiments were conducted. Changes in catalytic conversion, shifts in adsorption energies, and modifications to the sensor signals are discussed.
Enhanced Proton Conductivity of Amorphous Silicate Nanofilms
Authors: Aoki Yoshitaka , Habazaki Hiroki , Kunitake Toyoki
Published: September 2009

AlxSi1-xOn films exhibit a drastic change of proton conductivity across the film by reducing its thickness to less than 100 nm. The temperature- and humidity-dependence of conductivity of the sub-100 nm films is quite different from those of the thicker films. Furthermore, in the former thickness range, the value of conductivity markedly increases with reducing the film thickness, and its thickness dependence follows a power law with a fixed index of -2.1. This size-scaling effect can be explained by the percolation conductivity model that the probability for percolating of the conductive moiety in AlxSi1-xOn films increases with decreasing the thickness.
The Design Concept for High-Temperature Photo-Electronic Devices using SrTiO3
Authors: Horikiri Fumimasa , Sato Kazuhisa , Yashiro Keiji , Kawada Tatsuya , Mizusaki Junichiro
Published: September 2009

Quantum electronic discussion was made on metal/SrTiO3 hetero-structure to obtain the design concept for high-temperature photo-electronic devices using SrTiO3. The current density ratios were calculated between tunneling and thermionic emission component across the hetero-interface, which indicates how much dopant concentration is required for ohmic or Schottky contact. WKB approximation and Gamow transmission coefficient were used in calculation of the tunneling coefficient. The calculated results show good agreement with experimental results. The possibility of high-temperature photo-electronic devices using SrTiO3 was shown both in theoretical and experimental approach.
siRNA-mediated knockdown ofh-caldesmon in vascular smooth muscle
Authors: Smolock Elaine M. , Trappanese Danielle M. , Chang Shaohua , Wang Tanchun , Titchenell Paul , Moreland Robert S.
Published: September 2009

Smooth muscle contraction involves phosphorylation of the regulatory myosin light chain. However, this thick-filament system of regulation cannot account for all aspects of a smooth muscle contraction. An alternate site of contractile regulation may be in the thin-filament-associated proteins, in particular caldesmon. Caldesmon has been proposed to be an inhibitory protein that acts either as a brake to stop any increase in resting or basal tone, or as a modulatory protein during contraction. The goal of this study was to use short interfering RNA technology to decrease the levels of the smooth muscle-specific isoform of caldesmon in intact vascular smooth muscle tissue to determine more carefully what role(s) caldesmon has in smooth muscle regulation. Intact strips of vascular tissue depleted of caldesmon produced significant levels of shortening velocity, indicative of cross-bridge cycling, in the unstimulated tissue and exhibited lower levels of contractile force to histamine. Our results also suggest that caldesmon does not play a role in the cooperative activation of unphosphorylated cross bridges by phosphorylated cross bridges. The velocity of shortening of the constitutively active tissue and the high basal values of myosin light chain phosphorylation suggest that h-caldesmon in vivo acts as a brake against contractions due to basally phosphorylated myosin. It is also possible that phosphorylation of h-caldesmon alone in the resting state may be a mechanism to produce increases in force without stimulation and increases in calcium. Disinhibition of h-caldesmon by phosphorylation would then allow force to be developed by activated myosin in the resting state.
eNOS uncoupling and endothelial dysfunction in aged vessels
Authors: Yang Yang-Ming , Huang An , Kaley Gabor , Sun Dong
Published: September 2009

Endothelial nitric oxide synthase (eNOS) uncoupling is a mechanism that leads to endothelial dysfunction. Previously, we reported that shear stress-induced release of nitric oxide in vessels of aged rats was significantly reduced and was accompanied by increased production of superoxide ( 18 , 27 ). In the present study, we investigated the influence of aging on eNOS uncoupling. Mesenteric arteries were isolated from young (3 mo) and aged (24 mo) C57 BL/6J mice. The expression of eNOS protein in young vs. aged mice was not significantly different. However, the aged mice had remarkable increases in the ratio of eNOS monomers to dimers and Nω-nitro-l-arginine methyl ester-inhibitable superoxide formation. The level of nitrotyrosine in the total protein and precipitated eNOS of aged vessels was increased compared with that in young vessels. HPLC analysis indicated a reduced level of tetrahydrobiopterin (BH4), an essential cofactor for eNOS, in the mesenteric arteries of aged mice. Quantitative PCR results implied that the diminished BH4 may result from the decreased expressions of GTP cyclohydrolase I and sepiapterin reductase, enzymes involved in BH4 biosynthesis. When isolated and cannulated second-order mesenteric arteries (∼150 μm) from aged mice were treated with sepiapterin, acetylcholine-induced, endothelium-dependent vasodilation improved significantly, which was accompanied by stabilization of the eNOS dimer. These data suggest that eNOS uncoupling and increased nitrosylation of eNOS, decreased expressions of GTP cyclohydrolase I and sepiapterin reductase, and subsequent reduced BH4 bioavailability may be important contributors of endothelial dysfunction in aged vessels.
A high-fat diet increases adiposity but maintains mitochondrial oxidative enzymes without affecting development of heart failure with pressure overload
Authors: Chess David J. , Khairallah Ramzi J. , O'Shea Karen M. , Xu Wenhong , Stanley William C.
Published: September 2009

A high-fat diet can increase adiposity, leptin secretion, and plasma fatty acid concentration. In hypertension, this scenario may accelerate cardiac hypertrophy and development of heart failure but could be protective by activating peroxisome proliferator-activated receptors and expression of mitochondrial oxidative enzymes. We assessed the effects of a high-fat diet on the development of left ventricular hypertrophy, remodeling, contractile dysfunction, and the activity of mitochondrial oxidative enzymes. Mice ( n = 10–12/group) underwent transverse aortic constriction (TAC) or sham surgery and were fed either a low-fat diet (10% of energy intake as fat) or a high-fat diet (45% fat) for 6 wk. The high-fat diet increased adipose tissue mass and plasma leptin and insulin. Left ventricular mass and chamber size were unaffected by diet in sham animals. TAC increased left ventricular mass (∼70%) and end-systolic and end-diastolic areas (∼100% and ∼45%, respectively) to the same extent in both dietary groups. The high-fat diet increased plasma free fatty acid concentration and prevented the decline in the activity of the mitochondrial enzymes medium chain acyl-coenzyme A dehydrogenase (MCAD) and citrate synthase that was observed with TAC animals on a low-fat diet. In conclusion, a high-fat diet did not worsen cardiac hypertrophy or left ventricular chamber enlargement despite increases in fat mass and insulin and leptin concentrations. Furthermore, a high-fat diet preserved MCAD and citrate synthase activities during pressure overload, suggesting that it may help maintain mitochondrial oxidative capacity in failing myocardium.
Endogenous regulation of cardiovascular function by apelin-APJ
Authors: Charo David N. , Ho Michael , Fajardo Giovanni , Kawana Masataka , Kundu Ramendra K. , Sheikh Ahmad Y. , Finsterbach Thomas P. , Leeper Nicholas J. , Ernst Kavita V. , Chen Mary M. , Ho Yen Dong , Chun Hyung J. , Bernstein Daniel , Ashley Euan A. , Quertermous Thomas
Published: September 2009

Studies have shown significant cardiovascular effects of exogenous apelin administration, including the potent activation of cardiac contraction. However, the role of the endogenous apelin-APJ pathway is less clear. To study the loss of endogenous apelin-APJ signaling, we generated mice lacking either the ligand (apelin) or the receptor (APJ). Apelin-deficient mice were viable, fertile, and showed normal development. In contrast, APJ-deficient mice were not born in the expected Mendelian ratio, and many showed cardiovascular developmental defects. Under basal conditions, both apelin and APJ null mice that survived to adulthood manifested modest decrements in contractile function. However, with exercise stress both mutant lines demonstrated consistent and striking decreases in exercise capacity. To explain these findings, we explored the role of autocrine signaling in vitro using field stimulation of isolated left ventricular cardiomyocytes lacking either apelin or APJ. Both groups manifested less sarcomeric shortening and impaired velocity of contraction and relaxation with no difference in calcium transient. Taken together, these results demonstrate that endogenous apelin-APJ signaling plays a modest role in maintaining basal cardiac function in adult mice with a more substantive role during conditions of stress. In addition, an autocrine pathway seems to exist in myocardial cells, the ablation of which reduces cellular contraction without change in calcium transient. Finally, differences in the developmental phenotype between apelin and APJ null mice suggest the possibility of undiscovered APJ ligands or ligand-independent effects of APJ.
Biological evidence for the acute health effects of secondhand smoke exposure
Authors: Flouris Andreas D. , Vardavas Constantine I. , Metsios Giorgos S. , Tsatsakis Aristidis M. , Koutedakis Yiannis
Published: September 2009

A vast number of studies on the unfavorable effects of secondhand smoke (SHS) exist within the international literature, the majority of which evaluate longitudinal epidemiological data. Although limited, the experimental studies that assess the acute and short-term effects of exposure to SHS are also increasing in number. They include cellular, animal, and human studies that indicate a number of pathophysiological mechanisms through which the deleterious effects of SHS may arise. This current review evaluates the existing biological evidence regarding the acute health effects of SHS exposure. Analyses on the inhaled toxicants and the carcinogenicity of SHS are included as well as in-depth discussions on the evidence for acute SHS-induced respiratory, cardiovascular, metabolic, endocrine and immune effects, and SHS-induced influences on oxygen delivery and exercise. The influence of the length of exposure and the duration of the observed effects is also described. Moreover, recent findings regarding the underlying pathophysiological mechanisms related to SHS are depicted so as to generate models that describe the SHS-induced effects on different systems within the human body. Based on the presented biological evidence, it is concluded that brief, acute, transient exposures to SHS may cause significant adverse effects on several systems of the human body and represent a significant and acute health hazard. Future research directions in this area include research on the concentrations of tobacco smoke constituents in the alveolar milieu following SHS exposure, individual susceptibility to SHS, as well as the effects of SHS on neurobehavioral activity, brain cell development, synaptic development, and function.
Sustained hypoxia leads to the emergence of cells with enhanced growth, migratory, and promitogenic potentials within the distal pulmonary artery wall
Authors: Frid Maria G. , Li Min , Gnanasekharan Meena , Burke Danielle L. , Fragoso Miguel , Strassheim Derek , Sylman Joanna L. , Stenmark Kurt R.
Published: September 2009

All forms of chronic pulmonary hypertension (PH) are characterized by structural remodeling of the pulmonary artery (PA) media, a process previously attributed solely to changes in the phenotype of resident smooth muscle cells (SMC). However, recent experimental evidence in both systemic and pulmonary circulations suggests that other cell types, including circulating and local progenitors, contribute significantly to this process. The goal of this study was to determine if hypoxia-induced remodeling of distal PA (dPA) media involves the emergence of cells with phenotypic and functional characteristics distinct from those of resident dPA SMC and fibroblasts. In vivo, in contrast to the phenotypically uniform SMC composition of dPA media in control calves, the remodeled dPA media of neonatal calves with severe hypoxia-induced PH comprised cells exhibiting a distinct phenotype, including the expression of hematopoetic (CD45), leukocytic/monocytic (CD11b, CD14), progenitor (cKit), and motility-associated (S100A4) cell markers. Consistent with these in vivo observations, primary cell cultures isolated from dPA media of hypertensive calves yielded not only differentiated SMC, but also smaller, morphologically rhomboidal (thus termed here “R”) cells that transiently expressed CD11b, constitutively expressed the mesenchymal cell marker type I procollagen, expressed high mRNA levels of progenitor cell markers cKit, CD34, CD73, as well as for inflammatory mediators, IL-6 and MCP-1, and, with time in culture, gained expression of a myofibroblast marker, α-SM-actin. R cells exhibited highly augmented proliferative, migratory, invasive, and potent promitogenic capabilities, which were due, at least in part, to the production of PDGFs, SDF-1/CXCL12, and S100A4. These data suggest that the cellular mechanisms of dPA remodeling include the emergence of cells with phenotypic and functional characteristics markedly distinct from those of resident dPA cells.
Encoding of Reward and Space During a Working Memory Task in the Orbitofrontal Cortex and Anterior Cingulate Sulcus
Authors: Kennerley Steven W. , Wallis Jonathan D.
Published: September 2009

Several lines of research indicate that emotional and motivational information may be useful in guiding the allocation of attentional resources. Two areas of the frontal lobe that are particularly implicated in the encoding of motivational information are the orbital prefrontal cortex (PFo) and the dorsomedial region of prefrontal cortex, specifically the anterior cingulate sulcus (PFcs). However, it remains unclear whether these areas use this information to influence spatial attention. We used single-unit neurophysiology to examine whether, at the level of individual neurons, there was evidence for integration between reward information and spatial attention. We trained two subjects to perform a task that required them to attend to a spatial location across a delay under different expectancies of reward for correct performance. We balanced the order of presentation of spatial and reward information so we could assess the neuronal encoding of the two pieces of information independently and conjointly. We found little evidence for encoding of the spatial location in either PFo or PFcs. In contrast, both areas encoded the expected reward. Furthermore, PFo consistently encoded reward more quickly than PFcs, although reward encoding was subsequently more prevalent and stronger in PFcs. These results suggest a differential contribution of PFo and PFcs to reward encoding, with PFo potentially more important for initially determining the value of rewards predicted by sensory stimuli. They also suggest that neither PFo nor PFcs play a direct role in the control of spatial attention.
Modulation of Visual Signals in Macaque MT and MST Neurons During Pursuit Eye Movement
Authors: Chukoskie Leanne , Movshon J. Anthony
Published: September 2009

Retinal image motion is produced with each eye movement, yet we usually do not perceive this self-produced “reafferent” motion, nor are motion judgments much impaired when the eyes move. To understand the neural mechanisms involved in processing reafferent motion and distinguishing it from the motion of objects in the world, we studied the visual responses of single cells in middle temporal (MT) and medial superior temporal (MST) areas during steady fixation and smooth-pursuit eye movements in awake, behaving macaques. We measured neuronal responses to random-dot patterns moving at different speeds in a stimulus window that moved with the pursuit target and the eyes. This allowed us to control retinal image motion at all eye velocities. We found the expected high proportion of cells selective for the direction of visual motion. Pursuit tracking changed both response amplitude and preferred retinal speed for some cells. The changes in preferred speed were on average weakly but systematically related to the speed of pursuit for area MST cells, as would be expected if the shifts in speed selectivity were compensating for reafferent input. In area MT, speed tuning did not change systematically during pursuit. Many cells in both areas also changed response amplitude during pursuit; the most common form of modulation was response suppression when pursuit was opposite in direction to the cell's preferred direction. These results suggest that some cells in area MST encode retinal image motion veridically during eye movements, whereas others in both MT and MST contribute to the suppression of visual responses to reafferent motion.
Pulmonary Vascular Destabilization in the Premetastatic Phase Facilitates Lung Metastasis
Authors: Huang Yujie , Song Nan , Ding Yanping , Yuan Shaopeng , Li Xuhui , Cai Hongchen , Shi Hubing , Luo Yongzhang
Published: September 2009

Before metastasis, certain organs have already been influenced by primary tumors. However, the exact alterations and regulatory mechanisms of the premetastatic organs remain poorly understood. Here, we report that, in the premetastatic stage, angiopoietin 2 (Angpt2), matrix metalloproteinase (MMP) 3, and MMP10 are up-regulated in the lung by primary B16/F10 tumor, which leads to the increased permeability of pulmonary vasculatures and extravasation of circulating tumor cells. Subsequent studies show that Angpt2, MMP3, and MMP10 have a synergistic effect on disrupting vascular integrity in both in vitro and in vivo models. Lentivirus-based in vivo RNA interference of Angpt2, MMP3, and MMP10 attenuates the pulmonary vascular permeability and suppresses the infiltration of myeloid cells in the premetastatic lung. Moreover, knocking down these factors significantly inhibits the spontaneous lung metastasis in the model by orthotopic implantation of MDA-MB-231-Luc-D3H1 cells in nude mice. Further investigations reveal that the malignancy of tumor cells is positively correlated with their capabilities to induce the expression of Angpt2, MMP3, and MMP10. Luciferase reporter assay and chromatin immunoprecipitation assay also suggest that transforming growth factor-β1 and tumor necrosis factor-α signaling are involved in the regulation of these premetastatic factors. Our study shows that pulmonary vascular destabilization in the premetastatic phase promotes the extravasation of tumor cells and facilitates lung metastasis, which may provide potential targets for clinical prevention of metastasis. [Cancer Res 2009;69(19):7529–37]
Variable effects of alpha v suppression on VEGFR-2 expression in endothelial cells of different vascular beds
Authors: Livnat Tami , Seligsohn Uri , Dardik Rima
Published: September 2009

Integrins αvβ3 and αvβ5 have been long considered as proangiogenic receptors, yet genetic ablation studies demonstrated enhanced angiogenesis in mice lacking αvβ3 and αvβ5 integrins, which was attributed to increased expression of vascular endothelial growth factor receptor-2 (VEGFR-2). In this study, we determined the effect of αvβ3 and αvβ5 suppression in endothelial cells (EC) on vascular endothelial growth factor (VEGF) and VEGFR-2 expression. αv was suppressed by shRNA in HUVEC (venous endothelial cells) and HMVEC (microvascular endothelial cells).VEGFR-2 was significantly upregulated by αv suppression in HUVEC and downregulated in HMVEC at both mRNA and protein levels,as assessed by real-time PCR and flow cytometry,respectively.HMVEC displayed completely abolished Sp1 binding to the VEGFR-2 promoter, and HUVEC exhibited enhanced binding to the –170 E- Box element in the VEGFR-2 promoter, assessed by electrophoretic mobility shift assay. Realtime PCR also revealed opposite effects on the expression of 5 additional important genes involved in angiogenesis in the two cell types.VEGF mRNA expression was enhanced in HUVEC and reduced in HMVEC; however, these alterations were not statistically significant.VEGF-induced proliferation was upregulated in HUVEC and reduced in HMVEC following αv suppression. No tube formation on Matrigel was observed in αv suppressed cells, regardless of their origin.These results indicate that suppression of αv integrins can either augment or inhibit VEGFR-2 levels and VEGF-induced proliferation in EC from different vascular beds. Hence, therapeutic antiangiogenic intervention by siRN-Amediated suppression of αv integrins should take into account variable and potentially hazardous responses in different vascular beds.
Contribution of Genome-Wide Significant Single-Nucleotide Polymorphisms and Antiretroviral Therapy to Dyslipidemia in HIV-Infected Individuals
Authors: Rotger Margalida , Bayard Cornelia , Taffé Patrick , Martinez Raquel , Cavassini Matthias , Bernasconi Enos , Battegay Manuel , Hirschel Bernard , Furrer Hansjakob , Witteck Andrea , Weber Rainer , Ledergerber Bruno , Telenti Amalio , Tarr Philip E. ,   the Swiss HIV Cohort Study
Published: September 2009

Background—

HIV-infected individuals have an increased risk of myocardial infarction. Antiretroviral therapy (ART) is regarded as a major determinant of dyslipidemia in HIV-infected individuals. Previous genetic studies have been limited by the validity of the single-nucleotide polymorphisms (SNPs) interrogated and by cross-sectional design. Recent genome-wide association studies have reliably associated common SNPs to dyslipidemia in the general population.

Methods and Results—

We validated the contribution of 42 SNPs (33 identified in genome-wide association studies and 9 previously reported SNPs not included in genome-wide association study chips) and of longitudinally measured key nongenetic variables (ART, underlying conditions, sex, age, ethnicity, and HIV disease parameters) to dyslipidemia in 745 HIV-infected study participants (n=34 565 lipid measurements; median follow-up, 7.6 years). The relative impact of SNPs and ART to lipid variation in the study population and their cumulative influence on sustained dyslipidemia at the level of the individual were calculated. SNPs were associated with lipid changes consistent with genome-wide association study estimates. SNPs explained up to 7.6% (non–high-density lipoprotein cholesterol), 6.2% (high-density lipoprotein cholesterol), and 6.8% (triglycerides) of lipid variation; ART explained 3.9% (non–high-density lipoprotein cholesterol), 1.5% (high-density lipoprotein cholesterol), and 6.2% (triglycerides). An individual with the most dyslipidemic antiretroviral and genetic background had an ≈3- to 5-fold increased risk of sustained dyslipidemia compared with an individual with the least dyslipidemic therapy and genetic background.

Conclusions—

In the HIV-infected population treated with ART, the weight of the contribution of common SNPs and ART to dyslipidemia was similar. When selecting an ART regimen, genetic information should be considered in addition to the dyslipidemic effects of ART agents.
Urocortin 2 Inhibits Furosemide-Induced Activation of Renin and Enhances Renal Function and Diuretic Responsiveness in Experimental Heart Failure
Authors: Rademaker Miriam T. , Charles Christopher J. , Nicholls M. Gary , Richards A. Mark
Published: September 2009

Background—

Urocortin 2 (Ucn2), a novel peptide with therapeutic potential in heart failure, and diuretics have opposing effects on renal function and the renin-angiotensin-aldosterone system. Because any prospective new treatment is likely to be used in conjunction with standard diuretic therapy, it is necessary to investigate the combined effects of these agents.

Methods and Results—

Ucn2 and furosemide were administered for 3 hours, both singly and combined, in 7 sheep with pacing-induced heart failure. Compared with time-matched controls, separate Ucn2 and furosemide administration significantly increased urine output (furosemide>Ucn2), urine sodium (furosemide>Ucn2), potassium (furosemide>Ucn2), and creatinine excretion (Ucn2>furosemide) and creatinine clearance (Ucn2>furosemide). Compared with furosemide treatment alone, Ucn2+furosemide produced a further diuresis (
P
<0.05), natriuresis (
P
<0.05), and a sustained increase in creatinine excretion (
P
<0.05) and clearance (
P
<0.05), without additional potassium elimination. All active treatments reduced mean arterial pressure (Ucn2+furosemide=furosemide>Ucn2), left atrial pressure (Ucn2+furosemide>Ucn2>furosemide), and peripheral resistance (Ucn2+furosemide=Ucn2>furosemide), whereas only Ucn2, singly and in combination with furosemide, increased cardiac output and dP/dt(max). In contrast to the increase in plasma renin activity elicited by furosemide alone, Ucn2 and Ucn2+furosemide markedly reduced plasma renin activity. All active treatments decreased plasma aldosterone (Ucn2+furosemide=Ucn2>furosemide), whereas only Ucn2 and Ucn2+furosemide reduced vasopressin and natriuretic peptide concentrations.

Conclusion—

Ucn2 cotreatment with furosemide enhanced hemodynamic and renal function and diuretic responsiveness (without additional potassium depletion) in experimental heart failure. Furthermore, Ucn2 reversed furosemide-induced increases in plasma renin activity and induced greater decreases in plasma aldosterone and vasopressin. These data indicate that adjunct Ucn2 therapy with diuretics in heart failure is beneficial.
Clinical Significance of Echo Signal Attenuation on Intravascular Ultrasound in Patients With Coronary Artery Disease
Authors: Kimura Shigeki , Kakuta Tsunekazu , Yonetsu Taishi , Suzuki Asami , Iesaka Yoshito , Fujiwara Hideomi , Isobe Mitsuaki
Published: September 2009

Background—

Atherosclerotic plaque that shows echo signal attenuation (EA) without associated bright echoes is sometimes observed by intravascular ultrasound but its clinical significance remains unclear. We investigated the impact of EA on coronary perfusion and evaluated the pathological features of plaque with EA.

Methods and Results—

We studied 687 native coronary lesions in 687 consecutive patients (336 with acute coronary syndrome and 351 with stable angina pectoris) who underwent intravascular ultrasound before percutaneous coronary intervention. By subgroup analysis, 60 lesions (30 lesions with EA) treated with directional coronary atherectomy underwent pathological examination. The Thrombolysis in Myocardial Infarction (TIMI) flow grade and myocardial blush grade after percutaneous coronary intervention were compared between lesions with and without EA in 627 lesions except directional coronary atherectomy subgroup. EA was observed in 245 lesions (35.7%), and coronary flow after percutaneous coronary intervention was worse for lesions with EA than without (final TIMI grade of 0 to 2: 15.4% versus 2.4%,
P
<0.001; final myocardial blush grade of 0 to 2: 45.6% versus 21.4%,
P
<0.001). Multivariate analysis revealed a significant association between no reflow (TIMI grade 0 to 2) and EA (odds ratio, 5.59; 95% CI, 2.64 to 11.85;
P
<0.001), a baseline TIMI grade of 0 to 2 (odds ratio, 5.91; 95% CI, 2.79 to 12.5;
P
<0.001), and a large reference area (odds ratio, 3.08; 95% CI, 1.40 to 6.76;
P
=0.005) after controlling for other associated factors. Pathological examination revealed a significantly higher frequency of lipid-rich plaque with microcalcification in lesions with EA.

Conclusions—

Atherosclerotic plaque with EA showed a significant association with no reflow after percutaneous coronary intervention, suggesting the existence of fragile components susceptible to distal embolization.