bluuebunny/crossref_metadata_2025 huggingface dataset:
NEUTRAL EVOLUTION AND MUTATION RATES OF SEQUENTIAL DYNAMICAL SYSTEMS
Authors: MORTVEIT H. S. , REIDYS C. M.
Published: February 2005

In this paper we study the evolution of sequential dynamical systems [Formula: see text] as a result of the erroneous replication of the SDS words. An [Formula: see text] consists of (a) a finite, labeled graph Y in which each vertex has a state, (b) a vertex labeled sequence of functions (Fvi,Y), and (c) a word w, i.e. a sequence (w1,…,wk), where each wi is a Y-vertex. The function Fwi,Y updates the state of vertex wi as a function of the states of wi and its Y-neighbors and leaves the states of all other vertices fixed. The [Formula: see text] over the word w and Y is the composed map: [Formula: see text]. The word w represents the genotype of the [Formula: see text] in a natural way. We will randomly flip consecutive letters of w with independent probability q and study the resulting evolution of the [Formula: see text]. We introduce combinatorial properties of [Formula: see text] which allow us to construct a new distance measure [Formula: see text] for words. We show that [Formula: see text] captures the similarity of corresponding [Formula: see text]. We will use the distance measure [Formula: see text] to study neutrality and mutation rates in the evolution of words. We analyze the structure of neutral networks of words and the transition of word populations between them. Furthermore, we prove the existence of a critical mutation rate beyond which a population of words becomes essentially randomly distributed, and the existence of an optimal mutation rate at which a population maximizes its mutant offspring.
Simulated microgravity using the Random Positioning Machine inhibits differentiation and alters gene expression profiles of 2T3 preosteoblasts
Authors: Pardo Steven J. , Patel Mamta J. , Sykes Michelle C. , Platt Manu O. , Boyd Nolan L. , Sorescu George P. , Xu Min , van Loon Jack J. W. A. , Wang May D. , Jo Hanjoong
Published: February 2005

Exposure to microgravity causes bone loss in humans, and the underlying mechanism is thought to be at least partially due to a decrease in bone formation by osteoblasts. In the present study, we examined the hypothesis that microgravity changes osteoblast gene expression profiles, resulting in bone loss. For this study, we developed an in vitro system that simulates microgravity using the Random Positioning Machine (RPM) to study the effects of microgravity on 2T3 preosteoblast cells grown in gas-permeable culture disks. Exposure of 2T3 cells to simulated microgravity using the RPM for up to 9 days significantly inhibited alkaline phosphatase activity, recapitulating a bone loss response that occurs in real microgravity conditions without altering cell proliferation and shape. Next, we performed DNA microarray analysis to determine the gene expression profile of 2T3 cells exposed to 3 days of simulated microgravity. Among 10,000 genes examined using the microarray, 88 were downregulated and 52 were upregulated significantly more than twofold using simulated microgravity compared with the static 1-g condition. We then verified the microarray data for some of the genes relevant in bone biology using real-time PCR assays and immunoblotting. We confirmed that microgravity downregulated levels of alkaline phosphatase, runt-related transcription factor 2, osteomodulin, and parathyroid hormone receptor 1 mRNA; upregulated cathepsin K mRNA; and did not significantly affect bone morphogenic protein 4 and cystatin C protein levels. The identification of gravisensitive genes provides useful insight that may lead to further hypotheses regarding their roles in not only microgravity-induced bone loss but also the general patient population with similar pathological conditions, such as osteoporosis.
Caveolin-3 knockout mice show increased adiposity and whole body insulin resistance, with ligand-induced insulin receptor instability in skeletal muscle
Authors: Capozza Franco , Combs Terry P. , Cohen Alex W. , Cho You-Ree , Park So-Young , Schubert William , Williams Terence M. , Brasaemle Dawn L. , Jelicks Linda A. , Scherer Philipp E. , Kim Jason K. , Lisanti Michael P.
Published: February 2005

Caveolin-3 (Cav-3) is expressed predominantly in skeletal muscle fibers, where it drives caveolae formation at the muscle cell's plasma membrane. In vitro studies have suggested that Cav-3 may play a positive role in insulin signaling and energy metabolism. We directly address the in vivo metabolic consequences of genetic ablation of Cav-3 in mice as it relates to insulin action, glucose metabolism, and lipid homeostasis. At age 2 mo, Cav-3 null mice are significantly larger than wild-type mice, and display significant postprandial hyperinsulinemia, whole body insulin resistance, and whole body glucose intolerance. Studies using hyperinsulinemic-euglycemic clamps revealed that Cav-3 null mice exhibited 20% and 40% decreases in insulin-stimulated whole body glucose uptake and whole body glycogen synthesis, respectively. Whole body insulin resistance was mostly attributed to 20% and 40% decreases in insulin-stimulated glucose uptake and glucose metabolic flux in the skeletal muscle of Cav-3 null mice. In addition, insulin-mediated suppression of hepatic glucose production was significantly reduced in Cav-3 null mice, indicating hepatic insulin resistance. Insulin-stimulated glucose uptake in white adipose tissue, which does not express Cav-3, was decreased by ∼70% in Cav-3 null mice, suggestive of an insulin-resistant state for this tissue. During fasting, Cav-3 null mice possess normal insulin receptor protein levels in their skeletal muscle. However, after 15 min of acute insulin stimulation, Cav-3 null mice show dramatically reduced levels of the insulin receptor protein, compared with wild-type mice treated identically. These results suggest that Cav-3 normally functions to increase the stability of the insulin receptor at the plasma membrane, preventing its rapid degradation, i.e., by blocking or slowing ligand-induced receptor downregulation. Thus our results demonstrate the importance of Cav-3 in regulating whole body glucose homeostasis in vivo and its possible role in the development of insulin resistance. These findings may have clinical implications for the early diagnosis and treatment of caveolinopathies.
Na+ influx triggers bleb formation on inner hair cells
Authors: Shi Xiaorui , Gillespie Peter G. , Nuttall Alfred L.
Published: February 2005

Large blebs form rapidly on apical membranes of sensory inner hair cells (IHCs) when the organ of Corti is freshly isolated from adult guinea pigs. Bleb formation had two distinguishable phases. Initially, we identified small particles labeled with fluorescent annexin V; these rapidly coalesced into larger aggregates. After particle aggregation, a single membrane bleb emerged from cuticular plate at the vestigial kinocilium location, eventually reaching ∼10 μm maximum spherical diameter; blebs this size often detached from IHCs. Development of blebs was associated with elevated concentration of intracellular Na+; blocking Na+ influx through mechanotransduction and ATP channels in the apical pole of IHCs or by replacement of Na+ with N-methyl-d-glucamine prevented Na+ loading and bleb formation. Depletion of intracellular ATP, blocking cAMP synthesis, inhibition of vesicular transport with brefeldin A, or inhibition of phosphatidylinositol 3-kinase with 2-(4-morpholinyl)-8-phenyl-1(4 H)-benzopyran-4-one (LY-294002) significantly reduced bleb formation in the presence of a Na+ load. Neither the mechanism of blebbing nor the size growth of the IHC blebs was associated with cellular apoptosis or necrosis. Bleb formation was not significantly reduced by disassembling microtubules or decreasing intracellular hydrostatic pressure. Moreover, no polymerized actin was observed in the lumen of blebs. We conclude that IHC bleb formation differs from classic blebbing mechanisms and that IHC blebs arise from imbalance of endocytosis and exocytosis in the apical plasma membrane, linked to Na+ loading that occurs in vitro.
Polarized trafficking of E-cadherin is regulated by Rac1 and Cdc42 in Madin-Darby canine kidney cells
Authors: Wang Bo , Wylie Fiona G. , Teasdale Rohan D. , Stow Jennifer L.
Published: February 2005

E-cadherin is a major cell-cell adhesion protein of epithelia that is trafficked to the basolateral cell surface in a polarized fashion. The exact post-Golgi route and regulation of E-cadherin transport have not been fully described. The Rho GTPases Cdc42 and Rac1 have been implicated in many cell functions, including the exocytic trafficking of other proteins in polarized epithelial cells. These Rho family proteins are also associated with the cadherin-catenin complexes at the cell surface. We have used functional mutants of Rac1 and Cdc42 and inactivating toxins to demonstrate specific roles for both Cdc42 and Rac1 in the post-Golgi transport of E-cadherin. Dominant-negative mutants of Cdc42 and Rac1 accumulate E-cadherin at a distinct post-Golgi step. This accumulation occurs before p120 ctn interacts with E-cadherin, because p120 ctn localization was not affected by the Cdc42 or Rac1 mutants. Moreover, the GTPase mutants had no effect on the trafficking of a targeting mutant of E-cadherin, consistent with the selective involvement of Cdc42 and Rac1 in basolateral trafficking. These results provide a new example of Rho GTPase regulation of basolateral trafficking and demonstrate novel roles for Cdc42 and Rac1 in the post-Golgi transport of E-cadherin.
Knockdown of occludin expression leads to diverse phenotypic alterations in epithelial cells
Authors: Yu Alan S. L. , McCarthy Karin M. , Francis Stacy A. , McCormack Joanne M. , Lai Jean , Rogers Rick A. , Lynch Robert D. , Schneeberger Eveline E.
Published: February 2005

The function of occludin (Occ) in the tight junction is undefined. To gain insight into its role in epithelial cell biology, occludin levels in Madin-Darby canine kidney II cells were suppressed by stably expressing short interfering RNA. Suppression of occludin was associated with a decrease in claudins-1 and -7 and an increase in claudins-3 and -4. Claudin-2 levels were unaffected. The tight junction “fence” function was not impaired in suppressed Occ (Occ−) clones, as determined by BODIPY-sphingomyelin diffusion in the membrane. The most striking changes were those related to control of the cytoskeleton and the “gate” function of tight junctions. A reduced ability of Occ− clones to extrude apoptotic cells from the monolayers suggested that neighbors of apoptotic cells either failed to sense their presence or were unable to coordinate cytoskeletal activity necessary for their extrusion. To further test the extent to which actin cytoskeletal activity depends on the presence of occludin, Occ− and Occ+ monolayers were depleted of cholesterol. Previous studies showed that cholesterol depletion is associated with reorganization of the actin cytoskeleton and a fall in transepithelial electrical resistance. In contrast to control Occ (Occ+) cells, transepithelial electrical resistance did not fall significantly in cholesterol-depleted Occ− monolayers and they failed to generate Rho-GTP, one of the signaling molecules involved in regulating the actin cytoskeleton. While steady-state transepithelial electrical resistance was similar in all clones, tight junction permeability to mono- and divalent inorganic cations was increased in Occ− monolayers. In addition, there was a disproportionately large increase in permeability to monovalent organic cations, up to 6.96 Å in diameter. Chloride permeability was unaffected and there was little change in mannitol flux. The data suggest that occludin transduces external (apoptotic cells) and intramembrane (rapid cholesterol depletion) signals via a Rho signaling pathway that, in turn, elicits reorganization of the actin cytoskeleton. Impaired signaling in the absence of occludin may also alter the dynamic behavior of tight junction strands, as reflected by an increase in permeability to large organic cations; the permeability of ion pores formed of claudins, however, is less affected.
ATR/TEM8 is highly expressed in epithelial cells lining Bacillus anthracis’ three sites of entry: implications for the pathogenesis of anthrax infection
Authors: Bonuccelli Gloria , Sotgia Federica , Frank Philippe G. , Williams Terence M. , de Almeida Cecilia J. , Tanowitz Herbert B. , Scherer Philipp E. , Hotchkiss Kylie A. , Terman Bruce I. , Rollman Brent , Alileche Abdelkrim , Brojatsch Jürgen , Lisanti Michael P.
Published: February 2005

Anthrax is a disease caused by infection with spores from the bacteria Bacillus anthracis. These spores enter the body, where they germinate into bacteria and secrete a tripartite toxin that causes local edema and, in systemic infections, death. Recent studies identified the cellular receptor for anthrax toxin (ATR), a type I membrane protein. ATR is one of the splice variants of the tumor endothelial marker 8 (TEM8) gene. ATR and TEM8 are identical throughout their extracellular and transmembrane sequence, and both proteins function as receptors for the toxin. ATR/TEM8 function and expression have been associated with development of the vascular system and with tumor angiogenesis. TEM8 is selectively upregulated in endothelial cells during blood vessel formation and tumorigenesis. However, selective expression of TEM8 in endothelial cells contradicts the presumably ubiquitous expression of the receptor. To resolve this controversial issue, we evaluated the distribution of ATR/TEM8 in a variety of tissues. For this purpose, we generated and characterized a novel anti-ATR/TEM8 polyclonal antibody. Here, we show that this novel antibody recognizes all three ATR/TEM8 isoforms, which are widely and differentially expressed in various tissue types. We found that ATR/TEM8 expression is not only associated with tumor endothelial cells, as previously described. Indeed, ATR/TEM8 is highly and selectively expressed in the epithelial cells lining those organs that constitute the anthrax toxin's sites of entry, i.e., the lung, the skin, and the intestine. In fact, we show that ATR/TEM8 is highly expressed in the respiratory epithelium of the bronchi of the lung and is particularly abundant in the ciliated epithelial cells coating the bronchi. Furthermore, immunostaining of skin biopsies revealed that ATR/TEM8 is highly expressed in the keratinocytes of the epidermis. Finally, we show that the epithelial cells lining the small intestine strongly express ATR/TEM8 isoforms. This is the first demonstration that the ATR/TEM8 protein is highly expressed in epithelial cells, which represent the primary location for bacterial invasion. These results suggest that the ATR/TEM8 expression pattern that we describe here is highly relevant for understanding the pathogenesis of anthrax infection.
Role of nitric oxide mechanisms in gastric emptying of, and the blood pressure and glycemic responses to, oral glucose in healthy older subjects
Authors: Gentilcore Diana , Visvanathan Renuka , Russo Antonietta , Chaikomin Reawika , Stevens Julie E. , Wishart Judith M. , Tonkin Anne , Horowitz Michael , Jones Karen L.
Published: February 2005

The primary aims of this study were to evaluate the effects of the nitric oxide (NO) synthase inhibitor NG-nitro-l-arginine methyl ester (l-NAME) on gastric emptying (GE) of, and the blood pressure (BP), glycemic, insulin, and incretin responses to, oral glucose in older subjects. Eight healthy subjects (4 males and 4 females, aged 70.9 ± 1.3 yr) were studied on two separate days, in double-blind, randomized order. Subjects received an intravenous infusion of either l-NAME (180 μg·kg−1·h−1) or saline (0.9%) at a rate of 3 ml/min for 150 min. Thirty minutes after the commencement of the infusion (0 min), subjects consumed a 300-ml drink containing 50 g glucose labeled with 20 MBq 99mTc-sulfur colloid, while sitting in front of a gamma camera. GE, BP (systolic and diastolic), heart rate (HR), blood glucose, plasma insulin, and incretin hormones, glucose-dependant insulinotropic-polypeptide (GIP), and glucagon-like peptide-1 (GLP-1), were measured. l-NAME had no effect on GE, GIP, and GLP-1. Between −30 and 0 min l-NAME had no effect on BP or HR. After the drink (0–60 min), systolic and diastolic BP fell ( P < 0.05) and HR increased ( P < 0.01) during saline; these effects were attenuated ( P < 0.001) by l-NAME. Blood glucose levels between 90 and 150 min were higher ( P < 0.001) and plasma insulin were between 15 and 150 min less ( P < 0.001) after l-NAME. The fall in BP, increase in HR, and stimulation of insulin secretion by oral glucose in older subjects were mediated by NO mechanisms by an effect unrelated to GE or changes in incretin hormones.
Mechanisms through which bradykinin promotes glomerular injury in diabetes
Authors: Tan Yan , Wang Bing , Keum Joo-Seob , Jaffa Ayad A.
Published: February 2005

In diabetes, mesangial cell proliferation and extracellular matrix expansion are critical components in the development of glomerulosclerosis. We reported that diabetes alters the activity of the kallikrein-kinin system and that these alterations contribute to the development of diabetic nephropathy. The present study examined the influence of streptozotocin-induced diabetes on the renal expression of bradykinin (BK) B2receptors (B2KR), connective tissue growth factor (CTGF), transforming growth factor-β (TGF-β), and TGF-β type II receptor (TGF-βRII) and assessed the signaling mechanisms through which B2KR activation may promote glomerular injury. Eight weeks after the induction of diabetes, renal mRNA levels of B2KR, CTGF, and TGF-β as well as protein levels of CTGF and TGF-βRII were measured in control (C), diabetic (D), and insulin-treated diabetic (D+I) rats. Renal B2KR and TGF-β mRNA levels expressed relative to β-actin mRNA levels and CTGF and TGF-βRII protein levels were significantly increased in D and D+I rats compared with C rats ( P < 0.03, n = 5). To assess the contribution of B2KR activation on modulating the expression of CTGF, TGF-βRII, and collagen I, mesangial cells (MC) were treated with BK (10−8M) for 24 h and CTGF and TGF-βRII protein levels were measured by Western blots and collagen I mRNA levels were measured by RT-PCR. A two- to threefold increase in CTGF and TGF-βRII protein levels was observed in response to BK stimulation ( P < 0.001, n = 6). In addition, a marked increase in collagen I mRNA levels was observed in response to BK stimulation. Treatment of MC with BK (10−8M) for 5 min significantly increased the tyrosine phosphorylation of p60src kinase and of p42/p44 MAPK ( P < 0.05, n = 4). Inhibition of src kinase by PP1 (10 μM) inhibited the increase in p42/p44 MAPK activation in response to BK. Finally, to determine whether BK stimulates CTGF, TGF-βRII, and collagen I expression via activation of MAPK pathways, MC were pretreated with an inhibitor of p42/p44 MAPK (PD-98059) for 45 min, followed by BK (10−8M) stimulation for 24 h. Selective inhibition of p42/p44 MAPK significantly inhibited the BK-induced increase in CTGF, TGF-βRII, and collagen I levels. These findings are the first to demonstrate that BK regulates the expression of CTGF, TGF-βRII, and collagen I in MC and provide a mechanistic pathway through which B2KR activation may contribute to the development of diabetic nephropathy.
A mathematical model of ventilation response to inhaled carbon monoxide
Authors: Stuhmiller James H. , Stuhmiller Louise M.
Published: February 2005

A comprehensive mathematical model, describing the respiration, circulation, oxygen metabolism, and ventilatory control, is assembled for the purpose of predicting acute ventilation changes from exposure to carbon monoxide in both humans and animals. This Dynamic Physiological Model is based on previously published work, reformulated, extended, and combined into a single model. Model parameters are determined from literature values, fitted to experimental data, or allometrically scaled between species. The model predictions are compared with ventilation-time history data collected in goats exposed to carbon monoxide, with quantitatively good agreement. The model reaffirms the role of brain hypoxia on hyperventilation during carbon monoxide exposures. Improvement in the estimation of total ventilation, through a more complete knowledge of ventilation control mechanisms and validated by animal data, will increase the accuracy of inhalation toxicology estimates.
Velocity and attenuation of sound in the isolated fetal lung as it is expanded with air
Authors: Berger Philip J. , Skuza Elizabeth M. , Ramsden C. Andrew , Wilkinson Malcolm H.
Published: February 2005

We measured the velocity and attenuation of audible sound in the isolated lung of the near-term fetal sheep to test the hypothesis that the acoustic properties of the lung provide a measure of the volume of gas it contains. We introduced pseudorandom noise (bandwidth 70 Hz–7 kHz) to one side of the lung and recorded the noise transmitted to the surface immediately opposite, starting with the lung containing only fetal lung liquid and making measurements after stepwise inflation with air until a leak developed. The velocity of sound in the lung fell rapidly from 187 ± 28.2 to 87 ± 3.7 m/s as lung density fell from 0.93 ± 0.01 to 0.75 ± 0.01 g/ml (lung density = lung weight/gas volume plus lung tissue volume). For technical reasons, no estimate of velocity could be made before the first air injection. Thereafter, as lung density fell to 0.35 ± 0.01 g/ml, there was a further decline in velocity to 69.6 ± 4.6 m/s. High-frequency sound was attenuated as lung density decreased from 1.0 to 0.5 g/ml, with little change thereafter down to a density of 0.35 ± 0.01 g/ml. We conclude that both the velocity of audible sound through the lung and the degree to which high-frequency sound is attenuated in the lung provide information on the degree of inflation of the isolated fetal lung, particularly at high lung densities. If studies of sound transmission through the lung in the intact organism were to confirm these findings, the acoustic properties of the lung could provide a means for monitoring lung aeration during mechanical ventilation of newborn infants.
Effects of Structured Nontarget Stimuli on Saccadic Latency
Authors: White Brian J. , Gegenfurtner Karl R. , Kerzel Dirk
Published: February 2005

It has been suggested that the remote distractor effect is the result of nontarget stimulation of a central region representing a collicular fixation zone near the time of target onset. The distributed network of the cells responsible for this effect is believed to extend over a large area, responding to distractors ≤10 deg in the periphery. Several studies also implicate the superior colliculus as the substrate behind an inhibited saccadic response arising from a display change. We investigated this further by using a patch of pink noise of various sizes as a nontarget stimulus. We show that the onset of a small patch (2.3 × 2.3 deg) of centrally displayed pink noise can produce a significant increase in saccadic latency to a simultaneously presented peripheral Gabor target. In contrast, a large patch (36 × 36 deg) of pink noise did not increase latency despite the fact that it also stimulated the region representing the fixation zone. Furthermore, only the large patch of noise facilitated latency when presented before target onset. We also examined the effect of patch sizes between these two extremes and found a steady decrease in latency as patch size increased. This confirms that nontarget stimulation of the region representing the fixation zone near the time of target onset is not in itself sufficient to produce the increase in latency typically found with remote distractors. The results are consistent with the idea that only a spatially confined object leads to a discharge of collicular fixation neurons.
Roles of Inhibition in Creating Complex Auditory Responses in the Inferior Colliculus: Facilitated Combination-Sensitive Neurons
Authors: Nataraj Kiran , Wenstrup Jeffrey J.
Published: February 2005

We studied roles of inhibition on temporally sensitive facilitation in combination-sensitive neurons from the mustached bat's inferior colliculus (IC). In these integrative neurons, excitatory responses to best frequency (BF) tones are enhanced by much lower frequency signals presented in a specific temporal relationship. Most facilitated neurons (76%) showed inhibition at delays earlier than or later than the delays causing facilitation. The timing of inhibition at earlier delays was closely related to the best delay of facilitation, but the inhibition had little influence on the duration or strength of the facilitatory interaction. Local iontophoretic application of antagonists to receptors for glycine (strychnine, STRY) and γ-aminobutyric acid (GABA) (bicuculline, BIC) showed that STRY abolished facilitation in 96% of tested units, but BIC eliminated facilitation in only 28%. This suggests that facilitatory interactions are created in IC and reveals a differential role for these neurotransmitters. The facilitation may be created by coincidence of a postinhibitory rebound excitation activated by the low-frequency signal with the BF-evoked excitation. Unlike facilitation, inhibition at earlier delays was not eliminated by application of antagonists, suggesting an origin in lower brain stem nuclei. However, inhibition at delays later than facilitation, like facilitation itself, appears to originate within IC and to be more dependent on glycinergic than GABAergic mechanisms. Facilitatory and inhibitory interactions displayed by these combination-sensitive neurons encode information within sonar echoes and social vocalizations. The results indicate that these complex response properties arise through a series of neural interactions in the auditory brain stem and midbrain.
Overexpression of Inducible Nitric Oxide Synthase in Rostral Ventrolateral Medulla Causes Hypertension and Sympathoexcitation via an Increase in Oxidative Stress
Authors: Kimura Yoshikuni , Hirooka Yoshitaka , Sagara Yoji , Ito Koji , Kishi Takuya , Shimokawa Hiroaki , Takeshita Akira , Sunagawa Kenji
Published: February 2005

The present study examined the role of inducible nitric oxide synthase (iNOS) in the rostral ventrolateral medulla (RVLM) of the brain stem, where the vasomotor center is located, in the control of blood pressure and sympathetic nerve activity. Adenovirus vectors encoding iNOS (AdiNOS) or β-galactosidase (Adβgal) were transfected into the RVLM in Wistar-Kyoto (WKY) rats. Blood pressure and heart rate were monitored using a radiotelemetry system. iNOS expression in the RVLM was confirmed by immunohistochemical staining or Western blot analysis. Mean arterial pressure significantly increased from day 6 to day 11 after AdiNOS transfection, but did not change after Adβgal transfection. Urinary norepinephrine excretion was significantly higher in AdiNOS-transfected rats than in Adβgal-transfected rats. Microinjection of aminoguanidine or
S
-methylisothiourea, iNOS inhibitors, or tempol, an antioxidant, significantly attenuated the pressor response evoked by iNOS gene transfer. The levels of thiobarbituric acid-reactive substances, a marker of oxidative stress, were significantly greater in AdiNOS-transfected rats than in Adβgal-transfected rats. Dihydroethidium fluorescence in the RVLM was increased in AdiNOS-transfected rats. In addition, nitrotyrosine-positive cells were observed in the RVLM only in AdiNOS-transfected rats. Intracisternal infusion of tempol significantly attenuated the pressor response and the increase in the levels of thiobarbituric acid–reactive substances induced by AdiNOS transfection. These results suggest that overexpression of iNOS in the RVLM increases blood pressure via activation of the sympathetic nervous system, which is mediated by an increase in oxidative stress.
Modification of PI3K- and MAPK-Dependent Chemotaxis in Aortic Vascular Smooth Muscle Cells by Protein Kinase C
βII
Authors: Campbell Malcolm , Trimble Elisabeth R.
Published: February 2005

Hyperglycemia increases expression of platelet-derived growth factor (PDGF)-β receptor and potentiates chemotaxis to PDGF-BB in human aortic vascular smooth muscle cells (VSMCs) via PI3K and ERK/MAPK signaling pathways. The purpose of this study was to determine whether increased activation of protein kinase C (PKC) isoforms had a modulatory effect on the PI3K and ERK/MAPK pathways, control of cell adhesiveness, and movement. All known PKC isoforms were assessed but only PKC
α
and PKC
βII
levels were increased in 25 mmol/L glucose. However, only PKC
βII
inhibition affected (decreased) PI3K pathway and MAPK pathway activities and inhibited PDGF-β receptor upregulation in raised glucose, and specific MAPK inhibition was required to completely block the effect of glucose. In raised glucose conditions, activity of the ERK/MAPK pathway, PI3K pathway, and PKC
βII
were all sensitive to aldose reductase inhibition. Chemotaxis to PDGF-BB (360 pmol/L), absent in 5 mmol/L glucose, was present in raised glucose and could be blocked by PKC
βII
inhibition. Formation of lamellipodia was dependent on PI3K activation and filopodia on MAPK activation; both lamellipodia and filopodia were eliminated when PKC
βII
was inhibited. FAK phosphorylation and cell adhesion were reduced by PI3K inhibition, and although MAPK inhibition prevented chemotaxis, it did not affect FAK phosphorylation or cell adhesiveness. In conclusion, chemotaxis to PDGF-BB in 25 mmol/L glucose is PKC
βII
-dependent and requires activation of both the PI3K and MAPK pathways. Changes in cell adhesion and migration speed are mediated mainly through the PI3K pathway.
Akt Mediates the Cross-Talk Between β-Adrenergic and Insulin Receptors in Neonatal Cardiomyocytes
Authors: Morisco Carmine , Condorelli Gerolama , Trimarco Valentina , Bellis Alessandro , Marrone Chiara , Condorelli Gianluigi , Sadoshima Junichi , Trimarco Bruno
Published: February 2005

Upregulation of the sympathetic nervous system plays a key role in the pathogenesis of insulin resistance. Although the heart is a target organ of insulin, few studies have examined the mechanisms by which β-adrenergic stimulation affects insulin sensitivity in cardiac muscle. In this study, we explored the molecular mechanisms involved in the regulation of the cross-talk between β adrenergic and insulin receptors in neonatal rat cardiomyocytes and in transgenic mice with cardiac overexpression of a constitutively active mutant of Akt (E40K Tg). The results of this study show that β-adrenergic receptor stimulation has a biphasic effect on insulin-stimulated glucose uptake. Short-term stimulation induces an additive effect on insulin-induced glucose uptake, and this effect is mediated by phosphorylation of Akt in threonine 308 through PKA/Ca
2+
-dependent and PI3K-independent pathway, whereas insulin-evoked threonine phosphorylation of Akt is exclusively PI3K-dependent. On the other hand, long-term stimulation of β-adrenergic receptors inhibits both insulin-stimulated glucose uptake and insulin-induced autophosphorylation of the insulin receptor, and at the same time promotes threonine phosphorylation of the insulin receptor. This is mediated by serine 473 phosphorylation of Akt through PKA/Ca
2+
and PI3K-dependent pathways. Under basal conditions, E40K Tg mice show increased levels of threonine phosphorylation of the β subunit of the insulin receptor and blunted tyrosine autophosphorylation of the β-subunit of the insulin receptor after insulin stimulation. These results indicate that, in cardiomyocytes, β-adrenergic receptor stimulation impairs insulin signaling transduction machinery through an Akt-dependent pathway, suggesting that Akt is critically involved in the regulation of insulin sensitivity.
Calcitonin Gene-Related Peptide In Vivo Positive Inotropy Is Attributable to Regional Sympatho-Stimulation and Is Blunted in Congestive Heart Failure
Authors: Katori Tatsuo , Hoover Donald B. , Ardell Jeffrey L. , Helm Robert H. , Belardi Diego F. , Tocchetti Carlo G. , Forfia Paul R. , Kass David A. , Paolocci Nazareno
Published: February 2005

Calcitonin gene-related peptide (CGRP) is a nonadrenergic/noncholinergic (NANC) peptide with vasodilatative/inotropic action that may benefit the failing heart. However, precise mechanisms for its in vivo inotropic action remain unclear. To assess this, dogs with normal or failing (sustained tachypacing) hearts were instrumented for pressure–dimension analysis. In control hearts, CGRP (20 pmol/kg per minute) enhanced cardiac contractility (eg, +33±4.2% in end-systolic elastance) and lowered afterload (−14.2±2% in systemic resistance, both
P
<0.001). The inotropic response was markedly blunted by heart failure (+6.5±2%;
P
<0.001 versus control), whereas arterial dilation remained unaltered (−19.3±5%). CGRP-positive inotropy was not attributable to reflex activation because similar changes were observed in the presence of a ganglionic blocker. However, it was fully prevented by the β-receptor antagonist (timolol), identifying a dominant role of sympatho-stimulatory signaling. In control hearts, myocardial interstitial norepinephrine assessed by microdialysis almost doubled in response to CGRP infusion, whereas systemic plasma levels were unchanged. In addition, CGRP receptors were not observed in ventricular myocardium but were prominent in coronary arteries and the stellate ganglia. Ventricular myocytes isolated from normal and failing hearts displayed no inotropic response to CGRP, further supporting indirect sympatho-stimulation as the primary in vivo mechanism. In contrast, the peripheral vasodilatative capacity of CGRP was similar in femoral vascular rings from normal and failing hearts in dogs. Thus, CGRP-mediated positive inotropy is load-independent but indirect and attributable to myocardial sympathetic activation rather than receptor-coupled stimulation in canine hearts. This mechanism is suppressed in heart failure, so that afterload reduction accounts for CGRP-enhanced function in this setting.
Phibun Songkhram And Thai Nationalism in the Fascist Era
Authors: Reynolds Bruce
Published: February 2005

During the late 1930s a political style, generally called 'fascist,' aimed at mobilising nations in the pursuit of expansionist aims had a profound impact around the world. Based on the apparent success of Germany, Italy, and Japan and the impending victory of Francisco Franco's forces in the Spanish Civil War, by early 1939 many observers saw fascism as the wave of the future. Among the Asian political leaders strongly influenced by the success of the fascist states was Phibun Songkhram, the military strongman of Thailand, the lone independent nation in Southeast Asia. Phibun and his adviser Wichit Wathakan promoted a jingoistic version of Thai nationalism, sought to militarise the nation, and adopted an aggressive policy towards neighbouring French Indochina in the wake of France's defeat in June 1940. In the short term these actions gave momentum to Phibun's efforts to consolidate his power and his plans to transform Thai society. Phibun's involvement with Japan and the arrival of Japanese troops in Thailand in December 1941, however, would lead to his temporary political eclipse in 1944 and modification of the more extreme elements of his program.
Japanese Geopolitics And the Mongol Lands, 1915–1945
Authors: Narangoa Li
Published: February 2005

The northernmost border of Japan's informal empire were the Mongol lands and Manchuria. For nearly a century this region lay on the borders between an expanding Russia and a retreating China and was a major area for Japanese ambitions on the Asian mainland. Japan's interest in the Mongol lands (including Manchuria) was spurred by general strategic, economic and ideological factors, and was justified by an academic discourse on geopolitics. Geo-political socialisation was carried out in respective areas and Mongol nationalism was drawn into these affairs. This paper examines the reasons for Japan's interest in these areas, and the arguments used to justify this expansionism.
Japan's Southward Advance and Colonial Taiwan
Authors: Kenichi Goto
Published: February 2005

In the mid 1930s, as southward advancement thought was on the rise in Japan, there was a rapidly emerging sense shared by the Taiwan Colonial Government, the military authorities, and Japanese residents in Taiwan that colonised Taiwan should play a more positive role in Japan's southward advance. This paper examines the background of the emergence of this advocacy of southward advance in Taiwan during the 1930s and its development during the ten years preceding the Japanese defeat in the Pacific War. In this examination, I draw attention not only to the predilections of the Taiwan Colonial Government, the Taiwan Army, and Japanese residents but also to the mechanism through which the colonised Taiwanese were integrated into the southward advance, and finally I compare the relationships of those three actors and the southern region (nanpo).
'The Modern Barbarian': Nguyen Van Vinh and the Complexity Of Colonial Modernity in Vietnam
Authors: Goscha Christopher
Published: February 2005

This article studies the life and socio-cultural works of Nguyen Van Vinh in order to understand better the complexity of 'colonial modernity' in Vietnam. Vinh saw in an alliance with colonial France the chance to modernise Vietnam in Western ways. Thanks to his translations and his essays on Vietnamese society and culture, he helped open the way to a larger cultural revolution in the 1930s. It was a way of dealing with the humiliation of colonial domination and a way of putting Vietnam back on a civilisational par with the rest of the 'modern' world. At the same time, Nguyen Van Vinh served as a powerful propaganda tool for the colonial state in its attempts to cut off Vietnam from her Asian context and ally her closely with colonial France through the Vietnamese language. Indeed, Nguyen Van Vinh provides a revealing example of the colonial origins of the Francophonie policy in Vietnam that began long before French decolonisation.
Georges Pierre Des Clozets, Robert Boyle, the Alchemical Patriarch of Antioch, And the Reunion of Christendom: Further New Sources
Authors: Principe Lawrence
Published: February 2005

In 1677, Georges Pierre des Clozets visited Robert Boyle and told him that he had been approved for membership in the Asterism, a secret international society of alchemical masters, headed by Pierre's patron Georges du Mesnillet, the Patriarch of Antioch. Extensive correspondence followed, replete with gifts and bizarre claims, until Pierre vanished in August 1678. This paper links several new documents—articles in the Mercure galant and the Gazette de France and a manuscript account by another convinced admirer of Pierre—to my previous study of him, particularly in regard to Pierre's claim to be working with the Patriarch to reunite Eastern and Western Churches. Dating from before and after Boyle's involvement, these sources add fresh details about Pierre and his other contacts, and show the consistency of Pierre's stories and the credibility he fashioned as he travelled around Europe convincing people of his claims alchemical and otherwise.
Combining Future Search and Open Space to Address Special Situations
Authors: Lent Richard M. , McCormick Marie T. , Pearce Donna Skubis
Published: February 2005

Open Space and Future Search can be combined as related steps in a process of helping a community decide on its future. Doing so creates newways to address difficult situations that neither method may be able to handle as well on its own. Two specific case studies following a similar combination design are presented showing the complementary nature of both methods when used together. Some conclusions are offered on when to consider this combined approach.
The Dangers of Success
Authors: Weber Susanne Maria
Published: February 2005

Based on the theoretical approach of Rogers’s diffusion of innovations model, the article examines the spread of large group interventions (LGIs) in German-speaking countries (Austria, Switzerland, and Germany) from 1999 to 2002. From this perspective, organization development consultants are the agents for diffusion of this new knowledge. An empirical study carried out in 1999 shows their status as innovators and early birds in the spread and diffusion of LGIs. A second study, carried out in 2000-2002 as a yearly trend survey, shows the tendencies of application and spread and the quantitative diffusion of LGIs in German-speaking countries thus far. They are successful in diffusion, but this success also carries its dangers: They might lose their clear shape and transformational power. They are hence to be analyzed with regard both to the risks of their success story and the promising myth of a fundamentally transforming experience.
Large Group Interventions
Authors: Mirvis Philip H.
Published: February 2005

There is a long literature and rich lore about the process of organization change and its engagement in large group intervention. This article takes a fresh look at this process through the lens of theater. It draws from a case study covering 5 years in a food business in Holland where a series of memorable events served to launch, guide, and punctuate a corporate transformation. The author, who contributed to some of these events, goes “behind the scenes” to illustrate how the performing arts can energize and deepen largescale change. Aseries of questions for practitioners aims to stimulate thinking about their own use of dramaturgy. The article concludes with brief consideration of the implications of change as theater for theory and practice.
Transorganization Development for Network Building
Authors: Clarke Nicholas
Published: February 2005

Transorganization development (TOD) is a four-stage model for improving collaboration in networks based on early research into successful collaborations together with input from an organization development (OD) practitioner base. However, this intervention has received surprisingly minimal empirical attention regarding its effectiveness, nor indeed any further conceptual development. This article provides some insights into the effectiveness of this intervention by analyzing the effects of the second stage of the model, the convention stage, which is a form of search conference. The intervention was found to facilitate problem solving and enabled a consensus to be reached to establish a new network planning structure. However, through integrating social network analysis with planned organizational change, itwas found that the most important outcomes of the intervention were its predominantly political effects.
Graphic Facilitation and Large-Scale Interventions
Authors: Tyler Carlotta , Valek Lynne , Rowland Regina
Published: February 2005

This article describes an international, multicultural, interfaith event sponsored by the Council for a Parliament of the World’s Religions (CPWR) that integrated graphic facilitation as a design component to support deep dialogue and encourage constructive action by participants representing a considerable diversity of cultures, languages, and traditions of faith. The abundance of graphic professionals (10) was a unique feature of the event staffing. The event was a minilaboratory for insights into the effective application of graphics in a global large system initiative. Graphic work moved beyond recording “call out” statements from participants to more nuanced, reflective, and participatory representations of large and small group dynamics. Graphic facilitators applied seven distinct forms of graphic utilization with facilitators and participants. The addition of graphic facilitation to the more traditional methods of facilitationwas found to contribute significantly to participant engagement and sustainability.
The World Café in Singapore
Authors: Tan Samantha , Brown Juanita
Published: February 2005

The World Café is a simple yet powerful conversational process that helps people engage in constructive dialogue, build personal relationships, foster collaborative learning, and discover newpossibilities for action. Café dialogues enable large groups, often hundreds of people, to think together creatively as part of a single, connected conversation. It has been used by tens of thousands of people on six continents in business, government, health, education, nongovernmental organization (NGO), and community settings. This article describes the range and spread of the World Café in Singapore as part of that nation’s effort to create a national learning culture and to transition from a top-down to a more open and inclusive society. In a multiracial and multireligious setting involving diverse national objectives and multiple levels of the hierarchy, the World Café is making a unique contribution to this young nation’s future.
Large Group Scenario Planning
Authors: Steil Gilbert , Gibbons-Carr Michele
Published: February 2005

All organizations and communities are strongly influenced by factors and events that lie outside their boundaries. A shared understanding of these environmental influences—in the past and the present—has been an important aspect of popular large group interventions. Traditional scenario planning has long been a way of confronting uncertainty and complexity about the future of environmental influences. Large group scenario planning is an adaptation of traditional scenario planning. Meeting for 2 or 3 days, a critical mass of an organization or a community can use scenarios of the future environment to move beyond their natural tendency to think of the future as an extrapolation of the past. Ageneral method is described, and the use of large group scenario planning by the Boston University School of Dental Medicine is presented.
Faster, Shorter, Cheaper May Be Simple; It’s Never Easy
Authors: Weisbord Marvin , Janoff Sandra
Published: February 2005

This article describes an experimental alternative to months-long systems redesigns. In one meeting, the global furniture retailer, IKEA, applying the principle of “whole system in the room,” created a new structure and process for product design, manufacture, and distribution, decentralizing an agglomeration of “silos” that no longer served. Some 52 stakeholders examined the existing system, developed a new design, created a strategic plan and formed task forces led by key executives to implement it. In 18 hours, the plan was developed and signed off on by the company president and key people from all affected functions, with active support from several customers. Was this idiosyncratic to IKEA or repeatable anywhere? The authors hypothesize that oneway to change a system in real time is for those with critical stakes in it to share what they knowunder conditions that enable action without asking permission from anyone not present.
Surviving Childhood Cancer: Parents’ Perceptions of Their Child’s Health
Authors: Svavarsdottir Erla Kolbrun
Published: February 2005

The improving prognosis for children with cancer refocuses attention to long-term outcomes. The purpose of this study was to assess whether changes in mothers’ and fathers’ perception of caregiving demands and well-being over a 1-year time period predicted parents’ perception of their child’s health at 12 months and to evaluate if these variables predicted change in health perceptions over a period of 1 year. Twenty Icelandic families of children younger than 18 years with cancer participated in the study. The change in general well-being over the year significantly predicted parents’ perception of their child’s health at 12 months; for the mothers, the change in well-being also predicted the changes in their perception of their child’s health over the 1-year period. These findings suggest the importance of incorporating long-term health-related outcomes and measures to improve well-being among family members in future research and clinical practice, when caring for children and families surviving childhood cancer.