bluuebunny/crossref_metadata_2025 huggingface dataset:
RELATIONAL EXPLOITATION: THE INFORMAL ORGANIZATION OF DAY LABOR AGENCIES
Authors: Bartley Tim , Roberts Wade T.
Published: February 2006

Recent controversies have drawn attention to the growing day labor industry in the U.S. While academics and activists have documented and criticized day labor agencies’ practice of externalizing costs onto the workforce, less attention has been paid to the informal organization of this form of work. At first glance, the day labor industry may appear to be little more than an anonymous “spot market,” but this glosses over the subtle relational and reputational dynamics at play. This article uses qualitative and quantitative evidence to uncover the informal order of the day labor hall, as experienced by homeless workers. Dispatcher discretion over the allocation of jobs leads day laborers to adopt several strategies for combating anonymity in this market. We argue that dispatchers’ perceptions of workers’ loyalty and reliability shape the allocation of rewards, thus inserting a small measure of stability into this highly contingent form of work.
BUILDING A MOVEMENT FOR HEALTH CARE: KEY TO ORGANIZING THE UNORGANIZED?
Authors: Nealis Wayne
Published: February 2006

History shows that labor union membership increased rapidly in the United States in the last century only during periods when broad movements for social justice also existed. One of these movements was the fight for basic social benefits during the Great Depression; the other was the struggle to secure democratic rights and dignity for African–Americans during the Civil Rights movement. This article presents an argument as to why labor should join in leading an offensive for single‐payer national health insurance (NHI), not only to win health care for all, but to help jump start a broader social and economic justice movement that could create a socio‐political climate that is more conducive to organizing the unorganized.
“THEY WANT TO DESTROY ME”: HOW CALIFORNIA'S FISCAL CRISIS BECAME A WAR ON “BIG GOVERNMENT UNIONS”
Authors: Mitchell Daniel J. B.
Published: February 2006

In 2003, California voters recalled their governor and elected movie actor Arnold Schwarzenegger in his place. Two crises triggered this event: large ongoing state budget deficits and a failed electricity deregulation plan. In his first year, Governor Schwarzenegger dealt with the budget through large‐scale borrowing and had a reasonably cooperative relationship with the legislature. But in 2005, with the budget still in deficit, he threatened to go to the voters with a budget solution. That decision somehow morphed into a gubernatorial campaign against “big government unions.” Ultimately, after vast sums were spent on a November 2005 special election, all the governor's initiatives lost, including one offering “paycheck protection” to public union members. The decision to antagonize unions seemed to result from excess delegation of authority by the governor to outsiders and lack of control of his own staff.
Optimisation of plumbosolvency control using a computational model
Authors: Hayes C. R. , Bates A. J. , Jones L. , Cuthill A. D. , Van der Leer D. , Weatherill N. P.
Published: February 2006

Computational modelling has been used in plumbosolvency control optimisation studies involving three English water companies. A zonal model simulates lead emissions across an entire area of supply; it utilises a single pipe model that simulates the lead concentration in drinking water over a 24 h period. A sampling model then simulates the results of random daytime sampling and the results are compared with those obtained by the water company, as a means of validating the zonal model. The simulated zone is created by the random ascription of a range of variables (lead pipe length, pipe diameter, water use, pattern of flow events, etc.), based on the Monte Carlo method. The conditions of the zones that were investigated were wide ranging, and included both low and high alkalinity waters, before and after the dosing of ortho‐phosphate to reduce plumbosolvency. Excellent validation was achieved, which enabled the models to be used with confidence for predictive purposes. To achieve the optimisation criteria set by the Drinking Water Inspectorate in 2001, plumbosolvency reductions of between 65 and 91% were found to be required. The minimum length of the 12 mm internal diameter lead pipe that was predicted to continue to fail the 10 μg/L standard, once phosphate dosing had been optimised, ranged from 40 to 50 m, providing a possible basis for selective replacement. Cross‐referencing the zonal modelling results to laboratory treatment tests indicated that the optimum average ortho‐phosphate dose varied from 0.9 to 2.0 mg/L (P), dependent on water‐specific requirements.
Post‐hypoxic hypoperfusion is associated with suppression of cerebral metabolism and increased tissue oxygenation in near‐term fetal sheep
Authors: Jensen E. C. , Bennet L. , Hunter C. J. , Power G. C. , Gunn A. J.
Published: February 2006

Secondary cerebral hypoperfusion is common following perinatal hypoxia–ischaemia. However, it remains unclear whether this represents a true failure to provide sufficient oxygen and nutrients to tissues, or whether it is simply a consequence of reduced cerebral metabolic demand. We therefore examined the hypothesis that cerebral oxygenation would be reduced during hypoperfusion after severe asphyxia, and further, that the greater neural injury associated with blockade of the adenosine A1 receptor during the insult would be associated with greater hypoperfusion and deoxygenation. Sixteen near‐term fetal sheep received either vehicle or 8‐cyclopentyl‐1,3‐dipropylxanthine (DPCPX) for 1 h, followed by 10 min of severe asphyxia induced by complete occlusion of the umbilical cord. Infusions were discontinued at the end of the occlusion and data were analysed for the following 8 h. A transient, secondary fall in carotid artery blood flow and laser Doppler flow was seen from approximately 1–4 h after occlusion (P < 0.001), with no significant differences between vehicle and DPCPX. Changes in laser Doppler blood flow were highly correlated with carotid blood flow (r2= 0.81, P < 0.001). Cortical metabolism was suppressed, reaching a nadir 1 h after occlusion and then resolving. Cortical tissue P was significantly increased at 1, 2 and 3 h after occlusion compared to baseline, and inversely correlated with carotid blood flow (r2= 0.69, P < 0.001). In conclusion, contrary to our initial hypothesis, delayed posthypoxic hypoperfusion was associated with suppression of cerebral metabolism and increased tissue P, and was not significantly affected by preceding adenosine A1 blockade. These data suggest that posthypoxic hypoperfusion is actively mediated and reflects suppressed cerebral metabolism.
Effect of culturing mouse embryos under different oxygen concentrations on subsequent fetal and placental development
Authors: Feil Deanne , Lane Michelle , Roberts Claire T. , Kelley Rebecca L. , Edwards Lisa J. , Thompson Jeremy G. , Kind Karen L.
Published: February 2006

The oxygen concentration used during embryo culture can influence embryo development and quality. Reducing the oxygen concentration in the atmosphere to 2% during post‐compaction culture of mouse embryos perturbs embryonic gene expression. This study examined the effect of culturing mouse embryos under different oxygen concentrations on subsequent fetal and placental development. Embryos were cultured from the zygote to morula stage under 7% oxygen, followed by 20, 7 or 2% oxygen to the blastocyst stage. Cultured and in vivo developed blastocysts were transferred into pseudopregnant recipients. Fetal and placental outcomes were analysed at day 18 of pregnancy. Implantation rate was not influenced by embryo culture conditions, but resorption rates were increased in embryos cultured under 2% oxygen, compared with 7% oxygen. Day 18 fetal weights were reduced following culture under 2%, compared with 7 or 20% oxygen, or in vivo development. Placental weight was not influenced by culture conditions. No differences in the proportion of junctional or labyrinthine exchange regions within the placenta or the morphometry of the labyrinthine region were detected. Surface density (surface area/gram labyrinth) of trophoblast available for exchange was reduced in placentas developed from embryos cultured under 2% oxygen, compared with 7% oxygen. Placental gene expression of Slc2a1, Slc2a3, Igf2, Igf2r and H19 was not influenced by oxygen conditions during embryo culture. Thus, exposure to 2% oxygen during post‐compaction pre‐implantation embryo development has adverse consequences for fetal development in the mouse. Oxygen is a significant component of the embryonic environment and reductions in oxygen availability can influence both embryonic gene expression and subsequent fetal development.
Gene expression profile differences in left and right liver lobes from mid‐gestation fetal baboons: a cautionary tale
Authors: Cox Laura A. , Schlabritz‐Loutsevitch Natalia , Hubbard Gene B. , Nijland Mark J. , McDonald Thomas J. , Nathanielsz Peter W.
Published: February 2006

Interpretation of gene array data presents many potential pitfalls in adult tissues. Gene array techniques applied to fetal tissues present additional confounding pitfalls. The left lobe of the fetal liver is supplied with blood containing more oxygen than the right lobe. Since synthetic activity and cell function are oxygen dependent, we hypothesized major differences in mRNA expression between the fetal right and left liver lobes. Our aim was to demonstrate the need to evaluate RNA samples from both lobes. We performed whole genome expression profiling on left and right liver lobe RNA from six 90‐day gestation baboon fetuses (term 180 days). Comparing right with left, we found 875 differentially expressed genes – 312 genes were up‐regulated and 563 down‐regulated. Pathways for damaged DNA binding, endonuclease activity, interleukin binding and receptor activity were up‐regulated in right lobe; ontological pathways related to cell signalling, cell organization, cell biogenesis, development, intracellular transport, phospholipid metabolism, protein biosynthesis, protein localization, protein metabolism, translational regulation and vesicle mediated transport were down‐regulated in right lobe. Molecular pathway analysis showed down‐regulation of pathways related to heat shock protein binding, ion channel and transporter activities, oxygen binding and transporter activities, translation initiation and translation regulator activities. Genes involved in amino acid biosynthesis, lipid biosynthesis and oxygen transport were also differentially expressed. This is the first demonstration of RNA differences between the two lobes of the fetal liver. The data support the argument that a complete interpretation of gene expression in the developing liver requires data from both lobes.
Physiological roles of ATP‐sensitive K+ channels in smooth muscle
Authors: Teramoto Noriyoshi
Published: February 2006

Potassium channels that are inhibited by intracellular ATP (ATPi) were first identified in ventricular myocytes, and are referred to as ATP‐sensitive K+ channels (i.e. KATP channels). Subsequently, K+ channels with similar characteristics have been demonstrated in many other tissues (pancreatic β‐cells, skeletal muscle, central neurones, smooth muscle). Approximately one decade ago, KATP channels were cloned and were found to be composed of at least two subunits: an inwardly rectifying K+ channel six family (Kir6.x) that forms the ion conducting pore and a modulatory sulphonylurea receptor (SUR) that accounts for several pharmacological properties. Various types of native KATP channels have been identified in a number of visceral and vascular smooth muscles in single‐channel recordings. However, little attention has been paid to the molecular properties of the subunits in KATP channels and it is important to determine the relative expression of KATP channel components which give rise to native KATP channels in smooth muscle. The aim of this review is to briefly discuss the current knowledge available for KATP channels with the main interest in the molecular basis of native KATP channels, and to discuss their possible linkage with physiological functions in smooth muscle.
Cytoplasmic overexpression of ALCAM is prognostic of disease progression in breast cancer
Authors: Burkhardt M , Mayordomo E , Winzer K-J , Fritzsche F , Gansukh T , Pahl S , Weichert W , Denkert C , Guski H , Dietel M , Kristiansen G
Published: February 2006

Background:Activated leucocyte cell adhesion molecule (ALCAM, CD166) is a cell surface member of the immunoglobulin superfamily. ALCAM expression has prognostic relevance in prostate and colon cancer.

Objective:To evaluate ALCAM protein expression in breast cancer by immunohistochemistry and to correlate expression levels with clinicopathological data.

Methods:162 primary breast carcinomas with a mean clinical follow up time of 53 months were immunostained using a monoclonal ALCAM antibody. The staining was evaluated as an immunoreactive score (IRS) and grouped into lowvhigh for both membranous and cytoplasmic staining.

Results:Intraductal and invasive carcinomas showed a higher ALCAM expression (median IRS 4 and 6 respectively) than normal breast tissue (IRS 2). In univariate survival analyses a significant association of high cytoplasmic ALCAM expression with shortened patient disease-free survival (mean (SD) five year non-progression rate, 69.4 (4.6)%v49.4 (11.1)%, p = 0.0142) was found. In multivariate analyses of disease-free survival times, high cytoplasmic ALCAM expression (relative risk (RR) = 2.086, p = 0.026) and nodal status (RR = 2.246, p = 0.035) were significantly associated with earlier disease progression, whereas tumour grading (RR = 1.6, p = 0.052) was of borderline significance.

Conclusions:The data suggest that strong cytoplasmic ALCAM expression in primary breast cancer, as detected by immunohistochemistry, might be a new marker for a more aggressive breast cancer biology.
ACHIEVING ANALOG ACCURACY IN NANOMETER CMOS
Authors: FLYNN MICHAEL P. , PARK SUNGHYUN , LEE CHUN C.
Published: February 2006

This paper reviews causes of and trends in MOS transistor mismatch, and assesses the implications for analog circuit design in the nanometer régime. The current understanding of MOS transistor mismatch is reviewed. In most cases, transistor mismatch is dominated by threshold voltage mismatch. Although, there is strong evidence that VT matching is improving as CMOS technology evolves, these improvements are countered by reductions in power supply that also accompany process scaling. In fact, the power consumption of analog circuits based on current design styles will increase with scaling to finer processes. It has long been known that thermal noise causes the power consumption of analog circuits to increase with scaling. However, unlike the case with thermal noise, new circuit techniques can break the accuracy-power constraints related to mismatch. These techniques are based on analog circuit redundancy, and take advantage of the tremendous transistor density offered by nanometer CMOS. This paper is primarily concerned with comparators, and in particular, with the use of comparators in flash ADCs; however, the analysis is also applicable to other circuits and applications.
SELF-INDUCED NOISE IN INTEGRATED CIRCUITS
Authors: GHARPUREY RANJIT , NARAGHI SHAHRZAD
Published: February 2006

Circuits with diverse electrical behavior are often placed in close physical proximity in order to achieve high-levels of on-chip integration. The activity of certain types of circuits can generate harmful interference, and degrade the performance of the system through electromagnetic coupling. Considerable effort in system-on-a-chip implementations is in fact related to technology and architectural considerations for minimizing this interference. This is especially the case in systems that have exacting requirements on the dynamic range such as those for wireless applications.

In this paper, we will discuss the evolution of techniques for modeling and analyzing these sources of noise generation and interference. We will provide a physical description of the problem. Techniques for extraction of electrical models to represent the media that support these noise sources will be covered. Macromodeling techniques will be discussed. Finally we will introduce the concept of functional modeling of circuit functions and present such a model for an integrated flash analog-to-digital converter.
HIGH-SPEED OVERSAMPLING ANALOG-TO-DIGITAL CONVERTERS
Authors: GHARBIYA AHMED , CALDWELL TREVOR C. , JOHNS D. A.
Published: February 2006

This paper is mainly tutorial in nature and discusses architectures for oversampling converters with a particular emphasis on those which are well suited for high frequency input signal bandwidths. The first part of the paper looks at various architectures for discrete-time modulators and looks at their performance when attempting high speed operation. The second part of this paper presents some recent advancements in time-interleaved oversampling converters. The next section describes the design and challenges in continuous-time modulators. Finally, conclusions are made and a brief summary of the recent state of the art of high-speed converters is presented.
SOME CHARACTERIZATIONS OF DESARGUESIAN TRANSLATION PLANES
Authors: BROZOVIC DOUGLAS P. , HO CHAT YIN
Published: February 2006

In this note we consider finite translation planes with large translation complements. In particular, we characterize finite affine Desarguesian translation planes in two ways, according to the existence of subgroups in the translation complement that are divisible by relatively large integers, together with modest additional restrictions.
SINGLE-MOLECULE ANALYSIS OF RNA POLYMERASE TRANSCRIPTION
Authors: Bai Lu , Santangelo Thomas J. , Wang Michelle D.
Published: February 2006

The kinetics and mechanisms of transcription are now being investigated by a repertoire of single-molecule techniques, including optical and magnetic tweezers, high-sensitivity fluorescence techniques, and atomic force microscopy. Single-molecule techniques complement traditional biochemical and crystallographic approaches, are capable of detecting the motions and dynamics of individual RNAP molecules and transcription complexes in real time, and make it possible to directly measure RNAP binding to and unwinding of template DNA, as well as RNAP translocation along the DNA during transcript synthesis.
PARTY IDENTIFICATION: Unmoved Mover or Sum of Preferences?
Authors: Johnston Richard
Published: February 2006

▪ Abstract  Are party identifications relatively fixed features on the political landscape in the United States and elsewhere? If they are relatively fixed, do identifications move substantive issue preferences, perceptions of candidates, and perceptions of the link between candidates and issues? Early studies in the United States answered these questions in the affirmative. The track record for other systems is spotty, and each question occasioned repeated controversy in the decades since the 1960s. Much of the apparent lability and cross-national variation in party ties can be laid at the feet of measurement error, but not all. The claim that party identification moves other features on the political landscape is remarkably robust.
Suppression of early growth response factor-1 with egr-1 antisense oligodeoxynucleotide aggravates experimental duodenal ulcers
Authors: Khomenko Tetyana , Szabo Sandor , Deng Xiaoming , Jadus Martin R. , Ishikawa Hideki , Osapay Klara , Sandor Zsuzsa , Chen Longchuan
Published: February 2006

Previously, we demonstrated that cysteamine releases endothelin-1 in the rat duodenal mucosa, followed by increased expression of early growth response factor-1 (egr-1). We hypothesized that egr-1 is a key mediator gene in the multifactorial mechanisms of duodenal ulcer development and healing because its protein, transcription factor product Egr-1, regulates the expression of angiogenic growth factors. We wanted to determine the effect of egr-1 antisense oligonucleotide on cysteamine-induced duodenal ulcers as well as on the expression of bFGF, PDGF, and VEGF, of which synthesis is modulated by Egr-1. An antisense oligonucleotide to egr-1 was used to inhibit the synthesis of Egr-1 and to determine its effect on ulcer formation in the rat model of cysteamine-induced duodenal ulceration. Real-time RT-PCR and Western blot analysis were used to assess the expression of Egr-1 mRNA and protein as well as ERK, bFGF, PDGF, and VEGF. The antisense Egr-1 oligonucleotide inhibited the expression of egr-1 mRNA and protein and increased the duodenal ulcer size from 8.1 ± 1.8 mm2 in controls to 20.7 ± 4.0 mm2 ( P < 0.01). Cysteamine induced phosphorylation of ERK1/2 and enhanced the synthesis of bFGF, PDGF, and VEGF in the preulcerogenic stages of duodenal ulceration, whereas egr-1 antisense oligonucleotide markedly decreased the expression of these growth factors in the duodenal mucosa. We also demonstrated that Egr-1 expression relates to the ulcerogenic effect of cysteamine because these actions were not exerted by the toxic analog ethanolamine. Thus Egr-1 seems to play a critical role in duodenal ulceration because Egr-1 downregulation aggravates experimental duodenal ulcers, most likely through the transcriptional inhibition of bFGF, PDGF, and VEGF synthesis.
ANG II-induced cardiac molecular and cellular events: role of aldosterone
Authors: Zhao Wenyuan , Ahokas Robert A. , Weber Karl T. , Sun Yao
Published: February 2006

Chronic elevation of circulating ANG II is associated with cardiac remodeling in patients with hypertension and heart failure. The underlying mechanisms, however, are not completely defined. Herein, we studied ANG II-induced molecular and cellular events in the rat heart as well as their links to the redox state. We also addressed the potential contribution of aldosterone (ALDO) on ANG II-induced cardiac remodeling. In ANG II-treated rats, and compared with controls, we found: 1) the expression of proinflammatory/profibrogenic mediators was significantly increased in the perivascular space and at the sites of microscopic injury in both ventricles; 2) macrophages and myofibroblasts were primary repairing cells at these sites, together with increased fibrillar collagen volume; 3) apoptotic macrophages and myofibroblasts were evident at the same sites; 4) NADPH oxidase (gp91phox) was significantly enhanced at these regions and primarily expressed by macrophages, whereas superoxide dismutase and catalase levels remained unchanged; 5) plasma 8-isoprostane levels were significantly increased; and 6) blood pressure was significantly elevated. Losartan treatment completely prevented cardiac oxidative stress as well as molecular/cellular responses and normalized blood pressure. Spironolactone treatment partially suppressed the cardiac inflammatory/fibrogenic responses and redox state. Thus chronic elevation of circulating ANG II is accompanied by a proinflammatory/profibrogenic phenotype involving vascular and myocardial remodeling in both ventricles. Enhanced reactive oxygen species production at these sites and increased plasma 8-isoprostane indicate the involvement of oxidative stress in ANG II-induced cardiac injury. ALDO contributes, in part, to ANG II-induced cardiac molecular and cellular responses.
Multiple coherence of cerebral blood flow velocity in humans
Authors: Panerai Ronney B. , Eames Penelope J. , Potter John F.
Published: February 2006

The coherence function has been used in transfer function analysis of dynamic cerebral autoregulation to assess the statistical significance of spectral estimates of gain and phase frequency response. Interpretation of the coherence function and choice of confidence limits has not taken into account the intrinsic nonlinearity represented by changes in cerebrovascular resistance due to vasomotor activity. For small spontaneous changes in arterial blood pressure (ABP), the relationship between ABP and cerebral blood flow velocity (CBFV) can be linearized, showing that corresponding changes in cerebrovascular resistance should be included as a second input variable. In this case, the standard univariate coherence function needs to be replaced by the multiple coherence, which takes into account the contribution of both inputs to explain CBFV variability. With the use of two different indicators of cerebrovascular resistance index [CVRI = ABP/CBFV and the resistance-area product (RAP)], multiple coherences were calculated for 42 healthy control subjects, aged 20 to 40 yr (28 ± 4.6 yr, mean ± SD), at rest in the supine position. CBFV was measured in both middle cerebral arteries, and ABP was recorded noninvasively by finger photoplethysmography. Results for the ABP + RAP inputs show that the multiple coherence of CBFV for frequencies <0.05 Hz is significantly higher than the corresponding values obtained for univariate coherence ( P < 10−5). Corresponding results for the ABP + CVRI inputs confirm the principle of multiple coherence but are less useful due to the interdependence between CVRI, ABP, and CBFV. The main conclusion is that values of univariate coherence between ABP and CBFV should not be used to reject spectral estimates of gain and phase, derived from small fluctuations in ABP, because the true explained power of CBFV in healthy subjects is much higher than what has been usually predicted by the univariate coherence functions.
Maternal low-protein diet programs cardiac β-adrenergic response and signaling in 3-mo-old male offspring
Authors: Fernandez-Twinn Denise S. , Ekizoglou Sofia , Wayman Adrian , Petry Clive J. , Ozanne Susan E.
Published: February 2006

Low birth weight in humans is associated with an increased risk of cardiovascular disease. Humans with heart failure have a reduced β-adrenergic response. The aim of this study was to investigate the hemodynamic response to the β-adrenergic agonist isoproterenol and to identify molecular deficiencies that may be predictive of cardiac failure in a low-birth weight rodent model that develops insulin resistance and type 2 diabetes in adulthood. Wistar rats were fed a control or a low-protein (LP) diet throughout pregnancy and lactation. The resting heart rate and blood pressure of the 3-mo-old male offspring of these dams, termed “control” and “LP” groups, respectively, and their responses to isoproterenol (ISO) infusion were monitored by radiotelemetry. The protein expression of β-adrenergic signaling components was also measured by Western blot analysis. Basal heart rate was increased in LP offspring ( P < 0.04), although mean arterial pressure was comparable with controls. Chronotropic effects of ISO were blunted in LP offspring with significant delays to maximal response ( P = 0.01), a shorter duration of response ( P = 0.03), and a delayed return to baseline ( P = 0.01) at the lower dose (0.1 μg·kg−1·min−1). At the higher dose (1.0 μg·kg−1·min−1ISO), inotropic response was blunted ( P = 0.03) but quicker ( P = 0.001). In heart tissue of LP offspring, β1-adrenergic receptor expression was reduced ( P < 0.03). β1-Adrenergic receptor kinase and both stimulatory and inhibitory G protein levels remained unchanged, whereas β-arrestin levels were higher ( P < 0.03). Finally, insulin receptor-β expression was reduced in LP offspring ( P < 0.012). LP offspring have reduced β-adrenergic responsiveness and attenuated adrenergic and insulin signaling, suggesting that intrauterine undernutrition alters heart failure risk.
Physiology and pathophysiology of Na+/H+exchange and Na+-K+-2Cl−cotransport in the heart, brain, and blood
Authors: Pedersen S. F. , O'Donnell M. E. , Anderson S. E. , Cala P. M.
Published: February 2006

Maintenance of a stable cell volume and intracellular pH is critical for normal cell function. Arguably, two of the most important ion transporters involved in these processes are the Na+/H+exchanger isoform 1 (NHE1) and Na+-K+-2Cl−cotransporter isoform 1 (NKCC1). Both NHE1 and NKCC1 are stimulated by cell shrinkage and by numerous other stimuli, including a wide range of hormones and growth factors, and for NHE1, intracellular acidification. Both transporters can be important regulators of cell volume, yet their activity also, directly or indirectly, affects the intracellular concentrations of Na+, Ca2+, Cl−, K+, and H+. Conversely, when either transporter responds to a stimulus other than cell shrinkage and when the driving force is directed to promote Na+entry, one consequence may be cell swelling. Thus stimulation of NHE1 and/or NKCC1 by a deviation from homeostasis of a given parameter may regulate that parameter at the expense of compromising others, a coupling that may contribute to irreversible cell damage in a number of pathophysiological conditions. This review addresses the roles of NHE1 and NKCC1 in the cellular responses to physiological and pathophysiological stress. The aim is to provide a comprehensive overview of the mechanisms and consequences of stress-induced stimulation of these transporters with focus on the heart, brain, and blood. The physiological stressors reviewed are metabolic/exercise stress, osmotic stress, and mechanical stress, conditions in which NHE1 and NKCC1 play important physiological roles. With respect to pathophysiology, the focus is on ischemia and severe hypoxia where the roles of NHE1 and NKCC1 have been widely studied yet remain controversial and incompletely elucidated.
Identification of neural circuits involved in female genital responses in the rat: a dual virus and anterograde tracing study
Authors: Marson L. , Murphy A. Z.
Published: February 2006

The spinal and peripheral innervation of the clitoris and vagina are fairly well understood. However, little is known regarding supraspinal control of these pelvic structures. The multisynaptic tracer pseudorabies virus (PRV) was used to map the brain neurons that innervate the clitoris and vagina. To delineate forebrain input on PRV-labeled cells, the anterograde tracer biotinylated dextran amine was injected in the medial preoptic area (MPO), ventromedial nucleus of the hypothalamus (VMN), or the midbrain periaqueductal gray (PAG) 10 days before viral injections. These brain regions have been intimately linked to various aspects of female reproductive behavior. After viral injections (4 days) in the vagina and clitoris, PRV-labeled cells were observed in the paraventricular nucleus (PVN), Barrington’s nucleus, the A5 region, and the nucleus paragigantocellularis (nPGi). At 5 days postviral administration, additional PRV-labeled cells were observed within the preoptic region, VMN, PAG, and lateral hypothalamus. Anterograde labeling from the MPO terminated among PRV-positive cells primarily within the dorsal PVN of the hypothalamus, ventrolateral VMN (VMNvl), caudal PAG, and nPGi. Anterograde labeling from the VMN terminated among PRV-positive cells in the MPO and lateral/ventrolateral PAG. Anterograde labeling from the PAG terminated among PRV-positive cells in the PVN, ventral hypothalamus, and nPGi. Transynaptically labeled cells in the lateral hypothalamus, Barrington’s nucleus, and ventromedial medulla received innervation from all three sources. These studies, together, identify several central nervous system (CNS) sites participating in the neural control of female sexual responses. They also provide the first data demonstrating a link between the MPO, VMNvl, and PAG and CNS regions innervating the clitoris and vagina, providing support that these areas play a major role in female genital responses.
Central administration of neuropeptide Y induces wakefulness in rats
Authors: Szentirmai E. , Krueger J. M.
Published: February 2006

Neuropeptide Y (NPY) is a well-characterized neuromodulator in the central nervous system, primarily implicated in the regulation of feeding. NPY, orexins, and ghrelin form a hypothalamic food intake regulatory circuit. Orexin and ghrelin are also implicated in sleep-wake regulation. In the present experiments, we studied the sleep-modulating effects of central administration of NPY in rats. Rats received intracerebroventricular injection of physiological saline or three different doses of NPY (0.4, 2, and 10 μg in a volume of 4 μl) at light onset. Another group of rats received bilateral microinjection of saline or 2 μg NPY in the lateral hypothalamus in a volume of 0.2 μl. Sleep-wake activity and motor activity were recorded for 23 h. Food intake after the control and treatment injections was also measured on separate days. Intracerebroventricular and lateral hypothalamic administration of NPY suppressed non-rapid-eye-movement sleep and rapid-eye-movement sleep in rats during the first hour after the injection and also induced changes in electroencephalogram delta power spectra. NPY stimulated food intake in the first hour after both routes of administration. Data are consistent with the hypothesis that NPY has a role in the integration of feeding, metabolism, and sleep regulation.
Activation pattern of MAPK signaling in the hearts of trained and untrained rats following a single bout of exercise
Authors: Iemitsu Motoyuki , Maeda Seiji , Jesmin Subrina , Otsuki Takeshi , Kasuya Yoshitoshi , Miyauchi Takashi
Published: February 2006

Since exercise training causes cardiac hypertrophy and a single bout induces mechanical stress to the heart, the present study aimed to characterize the activation patterns of multiple MAPK signaling pathways in the heart after a single bout of exercise or chronic exercises. The hearts of untrained rats received 5, 15, and 30 min of treadmill running exercise (Ex5 to Ex30) and rested for 0.5, 1, 3, 6, 12, and 24 h (PostEx0.5 to PostEx24) before subjecting them to the following different experiments. Activation of MAPKs (ERK, JNK, and p38) and MAPKKs (MEK1/2, SEK, and MKK3/6) increased immediately after acute exercise in a time-dependent manner, with ERK, JNK, and p38 peaking at Ex15, Ex15, and Ex30, respectively. Expression of immediate early genes ( c-fos, c-jun, and c-myc) was augmented and activator protein-1 DNA binding activity was enhanced in untrained rats immediately after a single bout of exercise. The elevated levels of MAPKs declined to the resting levels within 24 h after exercise. In another set of experiments, following 4, 8, and 12 wk of exercise training, the rats exhibited significant cardiac hypertrophy by week 12. Activation of MAPKs in the 4-wk-trained rats increased after a 30-min single bout of exercise but decreased in the 8-wk group. Finally, the activity of MAPKs signaling in the 12-wk-trained rats exposed to an acute bout of exercise was unaltered. We conclude that exercise induces the activation of multiple MAPK (ERK, JNK, and p38) pathways in the heart, an effect that gradually declines with the development of exercise-induced cardiac hypertrophy.
Matrix metalloproteinase-2 activity, protein, mRNA, and tissue inhibitors in small arteries from pregnant and relaxin-treated nonpregnant rats
Authors: Jeyabalan Arundhathi , Kerchner Laurie J. , Fisher Michelle C. , McGuane Jonathan T. , Doty Ketah D. , Conrad Kirk P.
Published: February 2006

Vascular gelatinase activity is essential for pregnancy- and relaxin (Rlx)-induced renal vasodilation and hyperfiltration in rats. The objective of this study was to further elucidate the mechanisms for the increase in vascular matrix metalloproteinase (MMP)-2 activity caused by pregnancy and Rlx. We first corroborated our earlier work by showing that pro- and active forms of MMP-2 were increased in small renal arteries from pregnant compared with virgin rats and Rlx-treated compared with vehicle-treated nonpregnant rats. We next investigated other artery types and showed that MMP-2 activity was upregulated in mesenteric arteries from pregnant rats (pro-MMP-2 by 50% and active MMP-2 by 40%, both P < 0.05) and from Rlx-treated nonpregnant rats (pro-MMP-2 by 50% and active MMP-2 by 90%, both P < 0.005) compared with their respective controls. To corroborate these results obtained by gelatin zymography, pro-MMP-2 protein was determined by Western analysis in the same small arteries. Pro-MMP-2 protein was increased in small renal arteries from pregnant compared with virgin rats and from Rlx- compared with vehicle-treated nonpregnant rats: pro-MMP-2-to-β-actin ratio = 0.29 vs. 0.21 ( P < 0.01) and 0.43 vs. 0.32 ( P < 0.005). Findings were similar for mesenteric arteries. MMP-2 mRNA as measured by real-time PCR was increased in small renal arteries from pregnant and Rlx-treated nonpregnant rats compared with their respective controls. There were no significant differences in tissue inhibitor of metalloproteinase (TIMP-1 or TIMP-2) activity by reverse zymography in small renal arteries. Thus increases in MMP-2 mRNA and protein expression are major factors contributing to increased MMP-2 activity in small arteries from pregnant and Rlx-treated nonpregnant rats.
Inhibition of serotonergic medullary raphe obscurus neurons suppresses genioglossus and diaphragm activities in anesthetized but not conscious rats
Authors: Sood Sandeep , Raddatz Eric , Liu Xia , Liu Hattie , Horner Richard L.
Published: February 2006

Although exogenous serotonin at the hypoglossal motor nucleus (HMN) activates the genioglossus muscle, endogenous serotonin plays a minimal role in modulating genioglossus activity in awake and sleeping rats (Sood S, Morrison JL, Liu H, and Horner RL. Am J Respir Crit Care Med 172: 1338–1347, 2005). This result therefore implies that medullary raphe neurons also play a minimal role in the normal physiological control of the HMN, but this has not yet been established because raphe neurons release other excitatory neurotransmitters onto respiratory motoneurons in addition to serotonin. This study tests the hypothesis that inhibition of medullary raphe serotonergic neurons with 8-hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT) suppresses genioglossus and diaphragm activities in awake and sleeping rats. Ten rats were implanted with electrodes to record sleep-wake states and genioglossus and diaphragm activities. Microdialysis probes were also implanted into the nucleus raphe obscurus (NRO). Experiments in 10 anesthetized and vagotomized rats were also performed using the same methodology. In anesthetized rats, microdialysis perfusion of 0.1 mM 8-OH-DPAT into the NRO decreased genioglossus activity by 60.7 ± 9.0% and diaphragm activity by 13.3 ± 3.4%. Diaphragm responses to 7.5% CO2 were also significantly reduced by 8-OH-DPAT. However, despite the robust effects observed in anesthetized and vagotomized rats, there was no effect of 0.1 mM 8-OH-DPAT on genioglossus or diaphragm activities in conscious rats awake or asleep. The results support the concept that endogenously active serotonergic medullary raphe neurons play a minimal role in modulating respiratory motor activity across natural sleep-wake states in freely behaving rodents. This result has implications for pharmacological strategies aiming to manipulate raphe neurons and endogenous serotonin in obstructive sleep apnea.
ErbB2 Increases Vascular Endothelial Growth Factor Protein Synthesis via Activation of Mammalian Target of Rapamycin/p70S6K Leading to Increased Angiogenesis and Spontaneous Metastasis of Human Breast Cancer Cells
Authors: Klos Kristine S. , Wyszomierski Shannon L. , Sun Menghong , Tan Ming , Zhou Xiaoyan , Li Ping , Yang Wentao , Yin Guosheng , Hittelman Walter N. , Yu Dihua
Published: February 2006

ErbB2 overexpression in breast tumors results in increased metastasis and angiogenesis and reduced survival. To study ErbB2 signaling mechanisms in metastasis and angiogenesis, we did a spontaneous metastasis assay using MDA-MB-435 human breast cancer cells stably transfected with constitutively active ErbB2 kinase (V659E), a kinase-dead mutant of ErbB2 (K753M), or vector control (neo). Mice injected with V659E had increased metastasis incidence and tumor microvessel density than mice injected with K753M or control. Increased angiogenesis in vivo from the V659E transfectants paralleled increased angiogenic potential in vitro. V659E produced increased vascular endothelial growth factor (VEGF) through increased VEGF protein synthesis. This was mediated through signaling events involving extracellular signal-regulated kinase, phosphatidylinositol 3-kinase/Akt, mammalian target of rapamycin (mTOR), and p70S6K. The V659E xenografts also had significantly increased phosphorylated Akt, phosphorylated p70S6K, and VEGF compared with controls. To validate the clinical relevance of these findings, we examined 155 human breast tumor samples. Human tumors that overexpressed ErbB2, which have been previously shown to have higher VEGF expression, showed significantly higher p70S6K phosphorylation as well. Increased VEGF expression also significantly correlated with higher levels of Akt and mTOR phosphorylation. Additionally, patients with tumors having increased p70S6K phosphorylation showed a trend for worse disease-free survival and increased metastasis. Our findings show that ErbB2 increases VEGF protein production by activating p70S6K in cell lines, xenografts, and in human cancers and suggest that these signaling molecules may serve as targets for antiangiogenic and antimetastatic therapies. (Cancer Res 2006; 66(4): 2028-37)
Sprouty 2, an Inhibitor of Mitogen-Activated Protein Kinase Signaling, Is Down-Regulated in Hepatocellular Carcinoma
Authors: Fong Chee Wai , Chua Mei-Sze , McKie Arthur B. , Ling Sharon Hee Ming , Mason Veronica , Li Rui , Yusoff Permeen , Lo Ting Ling , Leung Hing Y. , So Samuel K.S. , Guy Graeme R.
Published: February 2006

The Sprouty proteins are increasingly being recognized to be deregulated in various types of cancers. This deregulation is often associated with aberrant signaling of receptor tyrosine kinases and its downstream effectors, leading to the mitogen-activated protein kinase (MAPK) signaling pathway. In human hepatocellular carcinoma, where the MAPK activity is enhanced via multiple hepatocarcinogenic factors, we observed a consistent reduced expression of the sprouty 2 (Spry2) transcript and protein in malignant hepatocytes compared with normal or cirrhotic hepatocytes. The expression pattern of Spry2 in hepatocellular carcinoma resembles that of several potential tumor markers of hepatocellular carcinoma and also that of several angiogenic factors and growth factor receptors. In contrast to previous studies of Spry2 down-regulation in other cancers, we have ruled out loss of heterozygosity or the methylation of promoter sites, two common mechanisms responsible for the silencing of genes with tumor suppressor properties. Functionally, we show that Spry2 inhibits both extracellular signal-regulated kinase signaling as well as proliferation in hepatocellular carcinoma cell lines, whereas knocking down Spry2 levels in NIH3T3 cells causes mild transformation. Our study clearly indicates a role for Spry2 in hepatocellular carcinoma, and an understanding of the regulatory controls of its expression could provide new means of regulating the angiogenic switch in this hypervascular tumor, thereby potentially controlling tumor growth. (Cancer Res 2006; 66(4): 2048-58)
Mammary Tumorigenesis following Transgenic Expression of a Dominant Negative CHK2 Mutant
Authors: Kwak Eunice L. , Kim Sang , Zhang Jianmin , Cardiff Robert D. , Schmidt Emmett V. , Haber Daniel A.
Published: February 2006

A truncating allele of the cell cycle checkpoint kinase CHK2 is present in 1% of the population, conferring a moderate increase in breast cancer risk, and inactivation of chk2 enhances mammary tumorigenesis in mice with targeted inactivation of brca1. We used the mouse mammary tumor virus (MMTV) promoter to target expression of a kinase-dead CHK2 allele (D347A). Mammary tumors, of predominantly micropapillary histology, developed in 40% of MMTV-CHK2-D347A transgenic mice with an average latency of 20 months. Tumors metastasized to lung and spleen; tumor-derived cell lines were frequently aneuploid and showed suppression of irradiation-induced p53 function. Primary hematopoietic malignancies were also observed in the spleen, another site of MMTV expression. The increased rate of tumor formation in MMTV-CHK2-D347A mice, compared with the relatively low incidence in chk2-null mice, provides a model to study modifiers of CHK2-dependent transformation. (Cancer Res 2006; 66(4) 1923-8)
Use of a Chemically Modified Antisense Oligonucleotide Library to Identify and Validate Eg5 (Kinesin-Like 1) as a Target for Antineoplastic Drug Development
Authors: Koller Erich , Propp Stephanie , Zhang Hong , Zhao Chenguang , Xiao Xiaokun , Chang MingYi , Hirsch Scott A. , Shepard Peter J. , Koo Seongjoon , Murphy Cain , Glazer Robert I. , Dean Nicholas M.
Published: February 2006

A library of 2′-methoxyethyl-modified antisense oligonucleotides (2′MOE ASO) targeting 1,510 different genes has been developed, validated, and used to identify cell cycle regulatory genes. The most effective molecular target identified was Eg5 (kinesin-like-1), which when inhibited gave the largest increase in 4N DNA in various tumor cells. The Eg5 ASO reduced Eg5 levels, inhibited proliferation, increased apoptosis, and altered the expression of other cell cycle proteins, including survivin and Aurora-A. To examine the therapeutic utility of the Eg5 ASO, the compound was also evaluated in xenograft models. Treatment with Eg5 ASO produced a statistically significant reduction of tumor growth, reduction in Eg5 expression in the tumors, and changes in histone phosphorylation, consistent with a loss of Eg5 protein expression. These data show, for the first time, the utility of a 2′MOE ASO library for high-throughput cell culture–based functional assays and suggest that an Eg5 ASO also has potential in a therapeutic strategy. (Cancer Res 2006; (66)4: 2059-66)
The Ligand Status of the Aromatic Hydrocarbon Receptor Modulates Transcriptional Activation of BRCA-1 Promoter by Estrogen
Authors: Hockings Jennifer K. , Thorne Patricia A. , Kemp Michael Q. , Morgan Sherif S. , Selmin Ornella , Romagnolo Donato F.
Published: February 2006

In sporadic breast cancers, BRCA-1 expression is down-regulated in the absence of mutations in the BRCA-1 gene. This suggests that disruption of BRCA-1 expression may contribute to the onset of mammary tumors. Environmental contaminants found in industrial pollution, tobacco smoke, and cooked foods include benzo(a)pyrene [B(a)P] and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which have been shown to act as endocrine disruptors and tumor promoters. In previous studies, we documented that estrogen (E2) induced BRCA-1 transcription through the recruitment of an activator protein-1/estrogen receptor-α (ERα) complex to the proximal BRCA-1 promoter. Here, we report that activation of BRCA-1 transcription by E2 requires occupancy of the BRCA-1 promoter by the unliganded aromatic hydrocarbon receptor (AhR). The stimulatory effects of E2 on BRCA-1 transcription are counteracted by (a) cotreatment with the AhR antagonist 3′-methoxy-4′-nitroflavone; (b) transient expression in ERα-negative HeLa cells of ERα lacking the protein-binding domain for the AhR; and (c) mutation of two consensus xenobiotic-responsive elements (XRE, 5′-GCGTG-3′) located upstream of the ERα-binding region. These results suggest that the physical interaction between the unliganded AhR and the liganded ERα plays a positive role in E2-dependent activation of BRCA-1 transcription. Conversely, we show that the AhR ligands B(a)P and TCDD abrogate E2-induced BRCA-1 promoter activity. The repressive effects of TCDD are paralleled by increased recruitment of the liganded AhR and HDAC1, reduced occupancy by p300, SRC-1, and diminished acetylation of H4 at the BRCA-1 promoter region flanking the XREs. We propose that the ligand status of the AhR modulates activation of the BRCA-1 promoter by estrogen. (Cancer Res 2006; 66(4): 2224-32)