bluuebunny/crossref_metadata_2025 huggingface dataset:
Input and Design Optimization Under Uncertainty to Minimize the Impact Velocity of an Electrostatically Actuated MEMS Switch
Authors: Allen M. S. , Massad J. E. , Field R. V. , Dyck C. W.
Published: March 2008

The dynamic response of a radio-frequency (RF) microelectromechanical system to a time-varying electrostatic force is optimized to enhance robustness to variations in material properties and geometry. The device functions as an electrical switch, where an applied voltage is used to close a circuit. The objective is to minimize the severity of the mechanical impact that occurs each time the switch closes because severe impacts have been found to significantly decrease the life of these switches. Previous works have demonstrated that a classical vibro-impact model, a single-degree-of-freedom oscillator subject to mechanical impact with a single rigid barrier, captures the relevant physics adequately. Certain model parameters are described as random variables to represent the significant unit-to-unit variability observed during fabrication and testing of a collection of nominally identical switches; these models for unit-to-unit variability are calibrated to available experimental data. Our objective is to design the shape and duration of the voltage waveform so that impact kinetic energy at switch closure is minimized for the collection of nominally identical switches, subject to design constraints. A voltage waveform designed using a deterministic model for the RF switch is found to perform poorly on the ensemble. An alternative waveform is generated using the proposed optimization procedure with a probabilistic model and is found to decrease the maximum impact velocity by a factor of 2 relative to the waveform designed deterministically. The methodology is also applied to evaluate a design change that reduces the impact velocity further and to predict the effect of fabrication process improvements.
Suppression of Brake Squeal Using Shunted Piezoceramics
Authors: Neubauer Marcus , Oleskiewicz Robert
Published: March 2008

Due to increased interest in comfort features, considerable effort is spent by brake manufacturers in order to suppress brake squeal. This process can be shortened by eliminating the remaining squealing with shunted piezoceramics that are embedded into the brake system. The piezoceramics offers the unique ability to convert mechanical energy into electrical energy and vice versa. The damping performance is determined by the connected shunt. This paper presents a multibody system model of a brake, which is capable of reproducing important features of brake squeal. It includes the dynamics of a piezoceramics that is shunted with a passive LR shunt or a negative capacitance LRC shunt. Analytical stability analysis is carried out to obtain optimal shunt parameters. The performance increase with a negative capacitance is studied in detail. The simulations are validated with measurements on an automotive disk brake.
Mechanism of Self-Sterility in a Hermaphroditic Chordate
Authors: Harada Yoshito , Takagaki Yuhei , Sunagawa Masahiko , Saito Takako , Yamada Lixy , Taniguchi Hisaaki , Shoguchi Eiichi , Sawada Hitoshi
Published: March 2008

Hermaphroditic organisms avoid inbreeding by a system of self-incompatibility (SI). A primitive chordate (ascidian)
Ciona intestinalis
is an example of such an organism, but the molecular mechanism underlying its SI system is not known. Here, we show that the SI system is governed by two gene loci that act cooperatively. Each locus contains a tightly linked pair of polycystin 1–related receptor (
s-Themis
) and fibrinogen-like ligand (
v-Themis
) genes, the latter of which is located in the first intron of
s-Themis
but transcribed in the opposite direction. These genes may encode male- and female-side self-recognition molecules. The SI system of
C. intestinalis
has a similar framework to that of flowering plants but utilizing different molecules.
Metabolic Diversification—Independent Assembly of Operon-Like Gene Clusters in Different Plants
Authors: Field Ben , Osbourn Anne E.
Published: March 2008

Operons are clusters of unrelated genes with related functions that are a feature of prokaryotic genomes. Here, we report on an operon-like gene cluster in the plant
Arabidopsis thaliana
that is required for triterpene synthesis (the thalianol pathway). The clustered genes are coexpressed, as in bacterial operons. However, despite the resemblance to a bacterial operon, this gene cluster has been assembled from plant genes by gene duplication, neofunctionalization, and genome reorganization, rather than by horizontal gene transfer from bacteria. Furthermore, recent assembly of operon-like gene clusters for triterpene synthesis has occurred independently in divergent plant lineages (
Arabidopsis
and oat). Thus, selection pressure may act during the formation of certain plant metabolic pathways to drive gene clustering.
Point-of-Care Diagnostics for Global Health
Authors: Yager Paul , Domingo Gonzalo J. , Gerdes John
Published: March 2008

Biomedical engineers have traditionally developed technologies in response to the needs of the developed world's medical community. As a result, the diagnostic systems on which they have worked have met the requirements of well-funded laboratories in highly regulated and quality-assessed environments. However, such approaches do not address the needs of the majority of the world's people afflicted with infectious diseases, who have, at best, access to poorly resourced health care facilities with almost no supporting clinical laboratory infrastructure. A major challenge for the biomedical engineering community is to develop diagnostic tests to meet the needs of these people, the majority of whom are in the developing world. We here review the context in which the diagnostics must operate, some of the appropriate diagnostic technologies already in distribution, and some emerging technologies that promise to address this challenge. However, there is much room for innovation, adaptation, and cost reduction before these technologies can impact health care in the developing world.
Effect of the nitric oxide donor V-PYRRO/NO on portal pressure and sinusoidal dynamics in normal and cirrhotic mice
Authors: Edwards Claire , Feng Hong-Qiang , Reynolds Christopher , Mao Lan , Rockey Don C.
Published: March 2008

Reduced sinusoidal endothelial nitric oxide (NO) production contributes to increased intrahepatic resistance and portal hypertension after liver injury. We hypothesized that V-PYRRO/NO, an NO donor prodrug metabolized “specifically” in the liver, would reduce portal venous pressure (PVP) without affecting the systemic vasculature. Liver injury was induced in male BALB/c mice by weekly CCl4gavage. PVP and mean arterial pressure were recorded during intravenous administration of V-PYRRO/NO. In vivo microscopy was used to monitor sinusoidal diameter and flow during drug administration. Mean PVP was increased in CCl4-treated mice compared with sham-treated mice. In dose-response experiments, the minimum dose of PYRRO/NO required to acutely lower PVP by 20%, the amount believed to yield a clinically meaningful outcome, was 200 nmol/kg. This dose decreased portal pressure in cirrhotic (23.4 ± 2.0%, P < 0.001 vs. vehicle) and sham-treated (19.5 ± 2.3%, P < 0.001 vs. vehicle) animals by a similar magnitude. This concentration also led to dilation of hepatic sinusoids and an increase in sinusoidal volumetric flow, consistent with a reduction of intrahepatic resistance. The effect of V-PYRRO/NO on mean arterial pressure was significant at all concentrations tested, including the lowest, 30 nmol/kg ( P < 0.001 vs. vehicle for all doses). We conclude that V-PYRRO/NO had widespread vascular effects and, as such, is unlikely to be suitable for treatment of portal hypertension. As the potential of this or other similar compounds for treatment of portal hypertension is evaluated, effects on the systemic vasculature will also need to be considered.
Toll-like receptor 2 is upregulated by hog confinement dust in an IL-6-dependent manner in the airway epithelium
Authors: Bailey K. L. , Poole J. A. , Mathisen T. L. , Wyatt T. A. , Von Essen S. G. , Romberger D. J.
Published: March 2008

Hog confinement workers are at high risk to develop chronic bronchitis as a result of their exposure to organic dust. Chronic bronchitis is characterized by inflammatory changes of the airway epithelium. A key mediator in inflammation is Toll-like receptor 2 (TLR2). We investigated the role of TLR2 in pulmonary inflammation induced by hog confinement dust. Normal human bronchial epithelial cells (NHBE) were grown in culture and exposed to hog confinement dust extract. Hog confinement dust upregulated airway epithelial cell TLR2 mRNA in a concentration- and time-dependent manner using real-time PCR. There was a similar increase in TLR2 protein at 48 h as shown by Western blot. TLR2 was upregulated on the surface of airway epithelial cells as shown by flow cytometry. A similar upregulation of pulmonary TLR2 mRNA and protein was shown in a murine model of hog confinement dust exposure. Hog confinement dust is known to stimulate epithelial cells to produce IL-6. To determine whether TLR2 expression was being regulated by IL-6, the production of IL-6 was blocked using an IL-6-neutralizing antibody. This resulted in attenuation of the dust-induced upregulation of TLR2. To further demonstrate the importance of IL-6 in the regulation of TLR2, NHBE were directly stimulated with recombinant human IL-6. IL-6 alone was able to upregulate TLR2 in airway epithelial cells. Hog confinement dust upregulates TLR2 in the airway epithelium through an IL-6-dependent mechanism.
Downregulation of carbon monoxide as well as nitric oxide contributes to peripheral chemoreflex hypersensitivity in heart failure rabbits
Authors: Ding Yanfeng , Li Yu-Long , Schultz Harold D.
Published: March 2008

Peripheral chemoreflex sensitivity is potentiated in clinical and experimental chronic heart failure (CHF). Downregulation of nitric oxide (NO) synthase (NOS) in the carotid body (CB) is involved in this effect. However, it remains poorly understood whether carbon monoxide (CO) also contributes to the altered peripheral chemoreflex sensitivity in CHF. This work highlights the effect of NO and CO on renal sympathetic nerve activity (RSNA) in response to graded hypoxia in conscious rabbits. Renal sympathetic nerve responses to graded hypoxia were enhanced in CHF rabbits compared with sham rabbits. The NO donor S-nitroso- N-acetylpenicillamine (SNAP, 1.2 μg·kg−1·min−1) and the CO-releasing molecule tricarbonyldichlororuthenium (II) dimer {[Ru(CO)3Cl2]2, 3.0 μg·kg−1·min−1} each attenuated hypoxia-induced RSNA increases in CHF rabbits ( P < 0.05), but the degree of attenuation of RSNA induced by SNAP or [Ru(CO)3Cl2]2 was smaller than that induced by SNAP + [Ru(CO)3Cl2]2. Conversely, treatment with the NOS inhibitor Nω-nitro-l-arginine (30 mg/kg) + the heme oxygenase (HO) inhibitor Cr (III) mesoporphyrin IX chloride (0.5 mg/kg) augmented the renal sympathetic nerve response to hypoxia in sham rabbits to a greater extent than treatment with either inhibitor alone and was without effect in CHF rabbits. In addition, using immunostaining and Western blot analyses, we found that expression of neuronal NOS, endothelial NOS, and HO-2 protein (expressed as the ratio of NOS or HO-2 expression to β-tubulin protein expression) was lower in CBs from CHF (0.19 ± 0.04, 0.17 ± 0.06, and 0.15 ± 0.02, respectively) than sham (0.63 ± 0.04, 0.56 ± 0.06, and 0.27 ± 0.03, respectively) rabbits ( P < 0.05). These results suggest that a deficiency of NO and CO in the CBs augments peripheral chemoreflex sensitivity to hypoxia in CHF.
Pulmonary Thromboembolism Secondary to Left Spermatic Vein Thrombosis: A Case Report
Authors: Castillo Octavio A. , Diaz Manuel , Vitagliano Gonzalo J. , Metrebian Esteban
Published: March 2008

Spermatic vein thrombosis is a particularly rare entity which can be difficult to diagnose. Pulmonary embolism associated with spermatic vein thrombosis is rarely seen. We report the diagnosis and management of a case at our institution and recommend spermatic vein ligation as the definite treatment for thrombosed spermatic veins associated with pulmonary thromboembolism. We prefer laparoscopy as a minimally invasive approach because of its clear advantages over open surgery.
Spinal Intramedullary Arachnoid Cyst in Children
Authors: Lmejjati Mohamed , Aniba Khalid , Haddi Mustapha , Hakkou Mohamed , Ghannane Houssine , Ait Ben Ali Said
Published: March 2008

The authors report an unusual case of a child who presented with progressive paraparesis that lasted 15 days, revealing an intramedullary cystic lesion extending from T3 to T4 as detected with spine magnetic resonance imaging. A laminotomy from T3 to T4 was performed and the lesion removed. Histopathological findings confirmed the diagnosis of arachnoid cyst. After surgery, the patient’s neurological status improved. At the 4-month follow-up examination, the results of his neurological examinations remained normal. Arachnoid cyst is an entity that should be included in the differential diagnosis of intramedullary cystic lesions.
Interactions between XIAP Associated Factor 1 and a Nuclear Co-Activator, CBP, in Colon Cancer Cells
Authors: Sun Yunwei , Qiao Liang , Zou Bing , Xia Harry Hua-Xiang , Gu Qing , Ma Juan , Lin Marie C.M. , Zhu Qi , Zhu Senlin , Dai Yun , Wong Benjamin C.Y.
Published: March 2008

Background/Aims: XIAP-associated factor 1 (XAF1) is a nuclear protein. CBP, the cAMP response element binding protein (CREB)-binding protein, plays an important role as a multifunctional transcriptional co-activator. In this investigation, we aimed to study the putative interaction between XAF1 and CBP in colon cancer cells. Methods: Expressions of XAF1 and CBP were detected by Western blot and RT-PCR. The interaction between XAF1 and CBP was investigated by the glutathione S-transferase (GST) pull-down assay, colocalization and co-immunoprecipitation analysis. Cell proliferation was examined by cell number counting. Results: Both XAF1 and CBP were co-localized in the nuclei of colon cancer cells and they demonstrated a physical interaction, as revealed by GST pull-down assay and co-immunoprecipitation analysis. CBP I peptide (residues 1–1098) was the interacting domain for XAF1 binding. The functional implication of the interaction between XAF1 and CBP was demonstrated by the finding that cell growth inhibition by XAF1 was potentiated by cotransfection with CBP. Furthermore, a reporter assay demonstrated that cotransfection with XAF1 and CBP led to marked reduction in phorbol ester 12-O-tetradecanoylphorbol-13-acetate (PMA)-stimulated adaptor-related protein complex 1 activity. Conclusions: CBP is a novel binding partner of XAF1, and the interaction between XAF1 and CBP and their functional consequence were mediated by adaptor-related protein complex 1.
Mechanisms by Which S-Albuterol Induces Human Bronchial Smooth Muscle Cell Proliferation
Authors: Ibe Basil O. , Abdallah May F. , Raj J. Usha
Published: March 2008

Background: Racemic albuterol is a 50:50 mixture of the R-isomer, levalbuterol, and the S-isomer, S-albuterol. S-Albuterol increases airway hyperresponsiveness to spasmogens, exacerbates asthmatic conditions and stimulates cell growth, whereas levalbuterol attenuates cell growth in culture. The mechanisms of S-albuterol-induced cell proliferation are not well understood. We studied the role of albuterol isomers and intracellular cell cycle regulators on proliferation of human bronchial smooth muscle cells. Methods: Serum-starved cells (72 h) were fed test agents for 24 h and cell proliferation was measured. The expression of nuclear factor-ĸB inhibitory protein IĸBα, nuclear factor-ĸB, cyclin-dependent kinases 2 and 4, interleukin (IL)-6, and retinoblastoma and platelet-activating factor (PAF) receptor protein were measured by Western blotting. Results:S-Albuterol, PAF and platelet-derived growth factor stimulated cell proliferation, but levalbuterol and the racemic mixture inhibited cell proliferation compared with the effect of 5% fetal bovine serum alone. The proliferative effect of platelet-derived growth factor on S-albuterol was not additive, suggesting that the 2 mediators act by different mechanisms. S-Albuterol induced greater expression of all the measured proteins than either levalbuterol, the racemic mixture or 5% fetal bovine serum. S-Albuterol stimulated IL-6 secretion and abolished the ability of levalbuterol to inhibit IL-6 secretion. Conclusion: Our data show that S-albuterol stimulates cell proliferation by activating expression and phosphorylation of several intracellular mitogenic proteins and may exacerbate asthma by stimulating the release of IL-6. Induction of PAF receptor protein expression by S-albuterol strongly suggests that S-albuterol may exert its adverse effects by binding to a G protein-coupled receptor such as the PAF receptor.
Uric Acid Levels Are Associated With All-Cause and Cardiovascular Disease Mortality Independent of Systemic Inflammation in Men From the General Population
Authors: Meisinger Christa , Koenig Wolfgang , Baumert Jens , Döring Angela
Published: March 2008

Objective—

The purpose of this study was to assess whether increasing serum uric acid (UA) levels are related to cardiovascular disease (CVD) mortality, all-cause mortality, and incident (fatal and nonfatal) myocardial infarction (MI) in men from the general population taking into account C-reactive protein (CRP), a sensitive marker of systemic inflammation.

Methods and Results—

The study was based on 3604 men (45 to 74 years of age) who participated in 1 of the 3 MONICA Augsburg surveys between 1984 and 1995. All participants were prospectively followed within the framework of the Cooperative Health Research in the Region of Augsburg (KORA). Up to December 31, 2002, there occurred 809 total deaths, 359 CVD deaths, and 297 incident MIs. In a Cox model, comparing extreme quartiles of the UA distribution, the hazard ratio for CVD mortality was 1.44 (95% confidence interval [CI] 1.04 to 2.0), and for all-cause mortality it was 1.40 (95% CI 1.13 to 1.74) after adjustment for conventional cardiovascular risk factors, CRP, and diuretic intake. However, UA was not associated with incident MI after multivariable adjustment.

Conclusions—

High UA levels were independently associated with CVD mortality as well as all-cause mortality but not with incident MI in middle-aged men from the general population.
Cardiovascular Events With Increased Lipoprotein-Associated Phospholipase A
2
and Low High-Density Lipoprotein-Cholesterol
Authors: Robins Sander J. , Collins Dorothea , Nelson Jeanenne J. , Bloomfield Hanna E. , Asztalos Bela F.
Published: March 2008

Objective—

Lipoprotein-associated phospholipase A
2
(Lp-PLA
2
), a proinflammatory enzyme that predominantly circulates with low-density lipoprotein (LDL), has been shown in general populations to predict cardiovascular (CV) events. We sought to determine whether increased Lp-PLA
2
would also predict CV events in the absence of high LDL-cholesterol (LDL-C), in a population with low high-density lipoprotein-cholesterol (HDL-C).

Methods and Results—

Plasma Lp-PLA
2
activity was measured at baseline and after 6 months on-trial in 1451 men with low HDL-C (mean, 32 mg/dL) and low LDL-C (mean 110 mg/dL), randomized to either placebo or gemfibrozil therapy in the Veterans Affairs HDL Intervention Trial (VA-HIT). Over a quartile range of increasing Lp-PLA
2
there was a significant increase in LDL-C and decrease in HDL-C (
P
<0.0001), and an increased percentage of myocardial infarction (MI), stroke, or CHD death (
P
=0.03 for trend). In Cox models, adjusted for major CV risk factors, a 1-SD increase in Lp-PLA
2
was associated with a significant increase in CV events (hazard ratio [HR] 1.17 95% CI 1.04 to 1.32). Although gemfibrozil reduced Lp-PLA
2
only modestly (6.6%), at higher levels of Lp-PLA
2
gemfibrozil produced a significant reduction in CV events.

Conclusions—

In VA-HIT, a population with low HDL-C and LDL-C, high Lp-PLA
2
independently predicted CV events that were reduced by gemfibrozil.
Increased ADAM17 mRNA Expression and Activity Is Associated With Atherosclerosis Resistance in LDL-Receptor Deficient Mice
Authors: Holdt Lesca M. , Thiery Joachim , Breslow Jan L. , Teupser Daniel
Published: March 2008

Background—

We have previously identified an atherosclerosis quantitative trait locus (QTL) on mouse chromosome (Chr) 12 in an F2-intercross of atherosclerosis-resistant FVB and atherosclerosis-susceptible C57BL/6 (B6) mice on the LDL-receptor deficient (LDL
−/−
) background. The aim of the present study was to identify potentially causative genes at this locus.

Methods and Results—

Expression QTL (eQTL) analysis of candidate genes in livers of F2-mice revealed that
a disintegrin and metalloproteinase 17 (ADAM17
) mRNA expression mapped to the physical position of
ADAM17
on proximal Chr12 (21.6 Mb, LOD 3.3) and colocalized with the atherosclerosis QTL. The FVB allele was associated with significantly higher
ADAM17
mRNA expression (39%) than the B6 allele. Likewise,
ADAM17
mRNA levels in the parental strains were significantly elevated in FVB.LDLR
−/−
compared to B6.LDLR
−/−
mice in liver, macrophages, and aorta (68%, 58%, and 32%, respectively). Reporter gene assays revealed a genetic variant that might explain these expression differences. Moreover, FVB.LDLR
−/−
macrophages showed 5-fold increased PMA-induced shedding of tumor necrosis factor (TNF)-α and 32% increased release of TNF-receptor I compared to B6.LDLR
−/−
. The atherosclerosis locus and expression differences were confirmed in Chr12 interval-specific congenic mice.

Conclusion—

Our data provide functional evidence for ADAM17 as a candidate gene of atherosclerosis susceptibility at the murine Chr12 QTL.
Inhibition of Mitochondrial Permeability Transition Pore Opening by Ischemic Preconditioning Is Probably Mediated by Reduction of Oxidative Stress Rather Than Mitochondrial Protein Phosphorylation
Authors: Clarke Samantha J. , Khaliulin Igor , Das Manika , Parker Joanne E. , Heesom Kate J. , Halestrap Andrew P.
Published: March 2008

Inhibition of mitochondrial permeability transition pore (MPTP) opening at reperfusion is critical for cardioprotection by ischemic preconditioning (IP). Some studies have implicated mitochondrial protein phosphorylation in this effect. Here we confirm that mitochondria rapidly isolated from preischemic control and IP hearts show no significant difference in calcium-mediated MPTP opening, whereas IP inhibits MPTP opening in mitochondria isolated from IP hearts following 30 minutes of global normothermic ischemia or 3 minutes of reperfusion. Analysis of protein phosphorylation in density-gradient purified mitochondria was performed using both 2D and 1D electrophoresis, with detection of phosphoproteins using Pro-Q Diamond or phospho-amino-specific antibodies. Several phosphoproteins were detected, including voltage-dependent anion channels isoforms 1 and 2, but none showed significant IP-mediated changes either before ischemia or during ischemia and reperfusion, and neither Western blotting nor 2D fluorescence difference gel electrophoresis detected translocation of protein kinase C (α, ε, or δ isoforms), glycogen synthase kinase 3β, or Akt to the mitochondria following IP. In freeze-clamped hearts, changes in phosphorylation of GSK3β, Akt, and AMP-activated protein kinase were detected following ischemia and reperfusion but no IP-mediated changes correlated with MPTP inhibition or cardioprotection. However, measurement of mitochondrial protein carbonylation, a surrogate marker for oxidative stress, suggested that a reduction in mitochondrial oxidative stress at the end of ischemia and during reperfusion may account for IP-mediated inhibition of MPTP. The signaling pathways mediating this effect and maintaining it during reperfusion are discussed.
Salt-Sensitive Hypertension Induced by Decoy of Transcription Factor Hypoxia-Inducible Factor-1α in the Renal Medulla
Authors: Li Ningjun , Chen Li , Yi Fan , Xia Min , Li Pin-Lan
Published: March 2008

Hypoxia inducible factor (HIF)-1α, a transcription factor, is abundantly expressed in the renal medulla and regulates many oxygen-sensitive genes such as nitric oxide synthase, cyclooxygenase-2, and heme oxygenase-1. Given the important roles of these genes in the control of arterial pressure, the present study was to test the hypothesis that HIF-1α–mediated gene activation serves as an antihypertensive pathway by regulating renal medullary function and sodium excretion. HIF-1α decoy oligodeoxynucleotides (ODNs) or scrambled ODNs were transfected into the renal medulla in uninephrectomized Sprague–Dawley rats. Two weeks after ODN transfection, the HIF-1α binding activities were significantly inhibited by 45%, and high salt–induced increases of nitric oxide synthase-2 and heme oxygenase-1 transcriptions were also inhibited by 70% and 61% in the renal medulla from decoy rats. The natriuretic responses and increases of renal medullary blood flow responding to the elevations of renal perfusion pressure were significantly blunted by 50% and 37% in decoy rats. Intravenously acute sodium loading increased medullary blood flow and urinary sodium excretion, which was remarkably attenuated in decoy rats. In decoy rats, high salt intake caused a greater positive sodium balance. Consequently, arterial pressure was remarkably increased (from 118±1.9 to 154±6.3 mm Hg) in decoy rats but not in control rats when the rats were challenged with a high salt diet. There was no blood pressure change in decoy rats that were maintained in normal salt diet. In conclusion, HIF-1α–mediated gene activation importantly participates in the regulation of renal medullary function and long-term arterial blood pressure.
Role of Ca
V
β Subunits, and Lack of Functional Reserve, in Protein Kinase A Modulation of Cardiac Ca
V
1.2 Channels
Authors: Miriyala Jayalakshmi , Nguyen Trang , Yue David T. , Colecraft Henry M.
Published: March 2008

Protein kinase A (PKA)-mediated enhancement of L-type calcium currents (
I
Ca,L
) is essential for sympathetic regulation of the heartbeat and is the classic example of channel regulation by phosphorylation, and its loss is a common hallmark of heart failure. Mechanistic understanding of how distinct Ca
V
channel subunits contribute to PKA modulation of
I
Ca,L
has been intensely pursued yet remains elusive. Moreover, critical features of this regulation such as its functional reserve (the surplus capacity available for modulation) in the heart are unknown. Here, we use an overexpression paradigm in heart cells to simultaneously identify the impact of auxiliary Ca
V
βs on PKA modulation of
I
Ca,L
and to gauge the functional reserve of this regulation in the heart. Ca
V
1.2 channels containing wild-type β
2a
or a phosphorylation-deficient mutant (β
2a,AAA
) were equally upregulated by PKA, discounting a necessary role for β phosphorylation. Nevertheless, channels reconstituted with β
2a
displayed a significantly diminished PKA response compared with other β isoforms, an effect explainable by a uniquely higher basal
P
o
of β
2a
channels. Overexpression of all βs increased basal current density, accompanied by a concomitant decrease in the magnitude of PKA regulation. Scatter plots of fold increase in current against basal current density revealed an inverse relationship that was conserved across species and conformed to a model in which a large fraction of channels remained unmodified after PKA activation. These results redefine the role of β subunits in PKA modulation of Ca
V
1.2 channels and uncover a new design principle of this phenomenon in the heart, vis à vis a limited functional reserve.
Phospholemman-Mediated Activation of Na/K-ATPase Limits [Na]
i
and Inotropic State During β-Adrenergic Stimulation in Mouse Ventricular Myocytes
Authors: Despa Sanda , Tucker Amy L. , Bers Donald M.
Published: March 2008

Background—

Cardiac Na/K-ATPase (NKA) regulates intracellular Na ([Na]
i
), which in turn affects intracellular Ca and thus contractility via Na/Ca exchange. Recent evidence shows that phosphorylation of the NKA-associated small transmembrane protein phospholemman (PLM) mediates β-adrenergic–induced NKA stimulation.

Methods and Results—

Here, we tested whether PLM phosphorylation during β-adrenergic activation limits the rise in [Na]
i
, Ca transient amplitude, and triggered arrhythmias in mouse ventricular myocytes. In myocytes from wild-type (WT) mice, [Na]
i
increased on field stimulation at 2 Hz from 11.1±1.8 mmol/L to a plateau of 15.2±1.5 mmol/L. Isoproterenol induced a decrease in [Na]
i
to 12.0±1.2 mmol/L. In PLM knockout (PLM-KO) mice in which β-adrenergic stimulation does not activate NKA, [Na]
i
also increased at 2 Hz (from 10.4±1.2 to 17.0±1.5 mmol/L) but was unaltered by isoproterenol. The PLM-mediated decrease in [Na]
i
in WT mice could limit the isoproterenol-induced inotropic state. Indeed, the isoproterenol-induced increase in the amplitude of Ca transients was significantly smaller in the WT mice (5.2±0.4- versus 7.1±0.5-fold in PLM-KO mice). This also was the case for the sarcoplasmic reticulum Ca content, which increased by 1.27±0.09-fold in WT mice versus 1.53±0.09-fold in PLM-KO mice. The higher sarcoplasmic reticulum Ca content in PLM-KO versus WT mice was associated with an increased propensity for spontaneous Ca transients and contractions in PLM-KO mice.

Conclusions—

These data suggest that PLM phosphorylation and NKA stimulation are an integral part of the sympathetic fight-or-flight response, tempering the rise in [Na]
i
and cellular Ca loading and perhaps limiting Ca overload–induced arrhythmias.
Angiotensin II Type 2 Receptor Deletion Enhances Vascular Senescence by Methyl Methanesulfonate Sensitive 2 Inhibition
Authors: Min Li-Juan , Mogi Masaki , Iwanami Jun , Li Jian-Mei , Sakata Akiko , Fujita Teppei , Tsukuda Kana , Iwai Masaru , Horiuchi Masatsugu
Published: March 2008

Vascular senescence is closely associated with age-related vascular disorders and is enhanced by angiotensin (Ang) II type 1 receptor stimulation. However, the role of Ang II type 2 receptor activation in vascular senescence is still an enigma. Ang II stimulation significantly increased senescence-associated β-galactosidase activity and the level of 8-hydroxy-2′-deoxyguanosine, with enhancement of oxidative stress and expression of Ki-ras2A, p53, and p21 in vascular smooth muscle cells (VSMCs) from wild-type (
Agtr2
+
) mice, whereas these effects of Ang II were enhanced in VSMCs from Ang II type 2 receptor null (
Agtr2
−
) mice. Administration of an Ang II type 1 receptor blocker, valsartan, attenuated these parameters, with less effect in
Agtr2
−
VSMCs. Ang II stimulation increased methyl methanesulfonate sensitive 2 (MMS2) expression in
Agtr2
+
VSMCs but not in
Agtr2
−
VSMCs. MMS2 small-interfering RNA treatment enhanced Ang II–induced senescence-associated β-galactosidase activity and 8-hydroxy-2′-deoxyguanosine level with no significant changes in oxidative stress markers and the expression of Ki-ras2A, p53, and p21. Moreover, exposure of
Agtr2
+
VSMCs to hydrogen peroxide and ultraviolet irradiation induced marked increases in senescence-associated β-galactosidase activity and 8-hydroxy-2′-deoxyguanosine level, which were further enhanced in
Agtr2
−
and MMS2 small-interfering RNA–treated
Agtr2
+
VSMCs.
Agtr2
+
mice exposed to x-ray irradiation showed increases in senescence-associated β-galactosidase activity and 8-hydroxy-2′-deoxyguanosine level in the aorta, which were further exaggerated in the aorta of
Agtr2
−
mice with a lower MMS2 level. These findings suggest that Ang II type 2 receptor signaling attenuates DNA damage and consequent vascular senescence at least in part through MMS2 transactivation and propose the beneficial effects of Ang II type 2 receptor stimulation with Ang II type 1 receptor blockers in age-related vascular disorders.
A Pilot Randomized Clinical Safety Study of Sonothrombolysis Augmentation With Ultrasound-Activated Perflutren-Lipid Microspheres for Acute Ischemic Stroke
Authors: Alexandrov Andrei V. , Mikulik Robert , Ribo Marc , Sharma Vijay K. , Lao Annabelle Y. , Tsivgoulis Georgios , Sugg Rebecca M. , Barreto Andrew , Sierzenski Paul , Malkoff Marc D. , Grotta James C.
Published: March 2008

Background and Purpose—

Ultrasound transiently expands perflutren-lipid microspheres (μS), transmitting energy momentum to surrounding fluids. We report a pilot safety/feasibility study of ultrasound-activated μS with systemic tissue plasminogen activator (tPA).

Methods—

Stroke subjects treated within 3 hours had abnormal Thrombolysis in Brain Ischemia (TIBI) residual flow grades 0 to 3 before tPA on transcranial Doppler (TCD). Randomization included Controls (tPA+TCD) or Target (tPA+TCD+2.8 mL μS). The primary safety end point was symptomatic intracranial hemorrhage (sICH) with worsening by ≥4 NIHSS points within 72 hours.

Results—

Fifteen subjects were randomized 3:1 to Target, n=12 or Control, n=3. After treatment, asymptomatic ICH occurred in 3 Target and 1 Control, and sICH was not seen in any study subject. μS reached MCA occlusions in all Target subjects at velocities higher than surrounding residual red blood cell flow: 39.8±11.3 vs 28.8±13.8 cm/s, P<0.001. In 75% of subjects, μS permeated to areas with no pretreatment residual flow, and in 83% residual flow velocity improved at a median of 30 minutes from start of μS infusion (range 30 s to 120 minutes) by a median of 17 cm/s (118% above pretreatment values). To provide perspective, current study recanalization rates were compared with the tPA control arm of the CLOTBUST trial: complete recanalization 50% versus 18%, partial 33% versus 33%, none 17% versus 49%,
P
=0.028. At 2 hours, sustained complete recanalization was 42% versus 13%,
P
=0.003, and NIHSS scores 0 to 3 were reached by 17% versus 8%,
P
=0.456.

Conclusions—

Perflutren μS reached and permeated beyond intracranial occlusions with no increase in sICH after systemic thrombolysis suggesting feasibility of further μS dose-escalation studies and development of drug delivery to tissues with compromised perfusion.
Modeling and Measuring Individuals' Mental Representations of Complex Spatio-Temporal Decision Problems
Authors: Arentze Theo A. , Dellaert Benedict G. C. , Timmermans Harry J. P.
Published: March 2008

Based on mental model theory, we expect individuals to construct a mental representation of the system they interact with which tends to be a strong reduction of reality and is tailored to the specific situation and task at hand. Such reductions may be particularly significant in complex decision situations involved in local spatial choice behavior. In this article, we develop a method to model and measure mental representations of decision problems involving individual spatio-temporal choice behavior in different situations. The so-called CNET method consists of an interview protocol to elicit the structures at the individual level as a causal network. We test the proposed method in a case study involving 180 respondents and an experimental shopping-trip planning task. The results indicate that the method is an adequate way of eliciting mental representations. We show how the networks revealed can be used to model and simulate reasoning and decision-making processes.
Associations Between Neighborhood Open Space Attributes and Quality of Life for Older People in Britain
Authors: Sugiyama Takemi , Thompson Catharine Ward , Alves Susana
Published: March 2008

The existing literature suggests that neighborhood open space (NOS) may play an important role for older people in maintaining and enhancing their quality of life (QoL). However, little is known as to what attributes of such places are relevant to QoL in late life. This study explored what aspects of NOS are associated with health, life satisfaction, and outdoor activity (walking) for older people. A cross-sectional survey was conducted to collect data from 284 people aged 65 years or older, living in Britain. The results indicate that the pleasantness and safety of open spaces were relevant to participants' life satisfaction, whereas the quality of paths to open spaces was associated with walking behavior. The distance to NOS was also correlated with life satisfaction. However, no NOS attributes were associated with participants' health status. These results are further discussed in the context of designing NOS to enhance older people's QoL.
Knowledge and Confidence in Knowledge About Climate Change Among Experts, Journalists, Politicians, and Laypersons
Authors: Sundblad Eva-Lotta , Biel Anders , Gärling Tommy
Published: March 2008

Knowledge and confidence in one's own knowledge of climate change was investigated among experts, journalists, politicians, and laypersons. Subsamples of 65 experts, 72 environmental journalists, 145 politicians being chairs of environmental committees, and 621 laypersons in Sweden responded to survey questions concerning current climate state, causes, and consequences of climate change. Experts presented the highest level of knowledge, followed by journalists, politicians, and laypersons. In all the groups, knowledge of causes was greater than that of climate state and of future consequences, and among the latter knowledge was less of health consequences than that of weather and sea/glacier consequences. Also, experts expressed the highest level of confidence in their own knowledge, followed by journalists, politicians, and laypersons. Nevertheless, the adjustment of confidence in one's own knowledge to actual knowledge was somewhat higher among journalists than among experts.
A Job for Urban Social Planners in Developing Countries
Authors: Judd Joe
Published: March 2008

[Is there an important contribution urban social planners could make to help improve the praspects of the urban poor? This article presents a task analyses of a iob for urban social planners in neighbourhood improvement programmes, and analyses both the potentials and problems to be faced in site selection, data collection and analysis, preparing and setting a social plan, and monitoring and evaluation. Perhaps urban social planners can contribufie to the alleviation of urban proverty but it will take a substantial effort for them to legitimize their roles in the eyes of poticy-makers, fellow bureaucrats, and the urban poor.]
Conflict in Human Services Organizations: Resource or Liability?
Authors: Singleton Carole A. , Henkin Alan B.
Published: March 2008

[The authors examine dimensions of conflict in the context of complex organixa tions in general and human services organizations in particular. The implications of theory and related research on conflict for the human services are discussed and some potentialities of controlled conflict as an organizational utility are suggested].
Circles of Freedom and Maturation in Hannah Crafts’ The Bondwoman’s Narrative
Authors: Jua Roselyne M.
Published: March 2008

Posthumously published in 2002 and providentially so according to Henry Louis Gates Jr.’s account, Hannah Crafts’ The Bondwoman’s Narrative, written circa 1855, seems to possess more than one life. It simply refused to die in obscurity or, as Marcia Ann Gillespie has opined, to be “shrouded in silence.” Does the narrative simply converge with other slave narratives of the 19th century as it depicts Hannah’s flight from slavery to freedom, or can Crafts’ novel be situated at the very beginnings of Black feminism? Further interrogation of the narrative discloses that Crafts weaves themes of growth and embraces symbols such as houses, sleep, and journeys in the typical 19th-century manner of mainstream writers like Samuel Richardson, Daniel Defoe, and Charles Dickens in England and Edgar Allan Poe, Nathaniel Hawthorne, Herman Melville, and Walt Whitman in America to situate her work within the American literary renaissance.
The Other Side of the Model Minority Story
Authors: Qin Desirée Boalian , Way Niobe , Mukherjee Preetika
Published: March 2008

The image of the model minority dominates scholarly and public discourse on Asian American children and adolescents. However, recent research has shown that despite their high levels of educational achievement Asian American students report poor psychological and social adjustment. Using an ecological framework, this article sought to explore the family and peer experiences of Chinese American adolescents as these are the two most critical contexts influencing adolescents' psychological and social adjustment. Drawing on longitudinal data collected from two studies conducted in Boston and New York on 120 first- and second-generation Chinese American students, our analyses suggested that many Chinese American adolescents feel alienated from their parents and peers. The alienation from parents was due to factors such as language barriers, parenting work schedules, and high parental educational expectations. Alienation from peers was due to ongoing peer discrimination from both Chinese and non-Chinese peers. Implications and future research are also discussed.
If You Build It, Will They Come?
Authors: Weitzman Beth C. , Mijanovich Tod , Silver Diana , Brazill Caitlyn
Published: March 2008

Telephone-survey data were gathered from parents and youth in five of America's largest and most distressed cities to estimate unmet demand for after-school programs. Unmet demand was conceptualized as a function of low utilization and dissatisfaction with one's current arrangement; furthermore, the authors argue that dissatisfaction must stem from something that can be addressed through changes in policy or programs. Large numbers of parents of children who infrequently use after-school programs were found to indicate that they would increase utilization if there were improvements in the quality, access, or types of programming. However, large numbers of parents whose children do not participate or participate infrequently in after-school programs were also found to express satisfaction with their arrangement and indicated that they do not wish to change it. Expanding services with the assumption that children from these families will participate may be misguided.
Maternal Gate Closing and Gate Opening in Postdivorce Families
Authors: Trinder Liz
Published: March 2008

This study explores the processes by which custodial mothers can support and inhibit fathers' relationships following divorce and separation. It draws on qualitative interviews with resident mothers and nonresident fathers from 54 separated families, including 22 sets of former couples. The study found that mothers adopt a range of strategies, from proactive gate opening to gate closing, and that these strategies appear influential. Maternal perceptions of paternal competence and child welfare beliefs, parental relationship quality, and parental role bargains were strongly linked to different types of maternal gatekeeping. Informed by systems theory, the interviews of former couples suggest that gate work, whether gate opening or gate closing, can be a dynamic transactional process rather than a linear and unidirectional process running from mothers to fathers.
“A Kotex and a Smile”
Authors: Lee Janet
Published: March 2008

This article explores the menarche or first-period narratives of 155 young women, focusing on their relationships with their mothers at this time. It finds that maternal scripts are changing as young women of this cohort, most of whom started their periods around the new millennium, recalled supportive mothers who were emotionally engaged with them. Although such support is related to positive experiences of menarche, it is not a guarantee, as substantial numbers of women with warm maternal support recalled negative memories of menarche. Still, this study suggests that emotionally connected mothers are able to mitigate feelings of shame and humiliation associated with the discourses of menstruation in contemporary culture. Finally, although White women and the more affluent are overrepresented among celebratory and emotionally connected mothers, women of color and, to some extent, the less affluent are overrepresented among the helpful, less demonstrative mothers. The latter seem to facilitate the least negative menarcheal responses on the part of daughters.
Economic Assessment of Rural District Heating by Bio-Steam Supplied by a Paper Mill in Canada
Authors: Marinova Mariya , Beaudry Catherine , Taoussi Abdelaziz , Trépanier Martin , Paris Jean
Published: March 2008

The article investigates the feasibility of district heating in a small town adjacent to a Kraft pulp mill in eastern Canada. A detailed heat demand analysis is performed for all buildings using a geographical information system and archived data provided by the municipality. The study shows that the entire space heating requirement of the town can be supplied by steam from the mill, even during exceptional peak demands. A screening test based on load density indicators, however, reveals that a district heating serving the entire town would probably not be economically viable. An economic analysis of partial districts show that a district covering about half of the town can be economically viable with a proper balance between the price of the steam sold by the mill to the district operator and the cost of the energy sold to customers.
Incorporation of Process Preferences within the QALY Framework: A Study of Alternative Methods
Authors: McNamee Paul , Seymour Janelle
Published: March 2008

Objective. This article explores the implications of incorporating process preferences using time tradeoff and standard gamble methods to assess the benefits of health care. Methods. Data were derived from 2 sources: a randomized controlled trial of alternative palliative care treatments (plastic stents, thermal ablation, or brachytherapy) for esophageal cancer, and a valuation survey conducted among individuals who had previously undergone curative treatment for such cancer. Costs and quality-adjusted life years (QALYs) associated with different palliative treatments in terms of health outcome values were compared to costs and QALYs based on process values derived from 3 different treatment allocation methods: 1) receipt of most preferred treatment; 2) receipt of least preferred treatment; and 3) mean process values. Results. Process values produced a different number of QALYs and QALY gains compared to those derived from health outcome values. However, treatment recommendations based on process values corresponded with those based on health outcome values: brachytherapy was identified as the more cost-effective treatment in terms of the incremental cost-per-QALY ratio by both the standard health outcome values approach and methods based on process values. These findings were supported by probabilistic analysis using the net monetary benefit framework. Conclusions. Estimation of process preferences provides additional information to policy makers in judgments over the cost-effectiveness of health care programs. These methods offer a promising alternative to standard cost-per-QALY estimation using health outcomes. However, further research examining the role of process preferences in decision making in other clinical applications appears warranted.
Local Knowledge in Visually Mediated Practice
Authors: Van Herzele Ann , van Woerkum Cees M. J.
Published: March 2008

Visualization tools such as maps, models, and computer images are used increasingly as means of involving people more effectively. We examine how a visualization tool in the form of a map-based model may shape the knowledge local people bring to the planning table. The analysis was guided by the concept of mediated action as it has been developed in sociocultural theory. We found that local knowledge was conditioned by a complexity of factors, including the dynamic of actions that develop around the tool and the way of looking imposed by map-based representation. The suggestion being made is that visualization tools, although bringing people closer to the planning process, also disconnect them from their local knowledge base.