bluuebunny/crossref_metadata_2025 huggingface dataset:
Regulation of cardiac volume-sensitive chloride channel by focal adhesion kinase and Src kinase
Authors: Walsh Kenneth B. , Zhang Jining
Published: July 2005

The volume-sensitive chloride current ( ICl,swell) is found in the mammalian myocardium and is activated by osmotic swelling. The goal of this study was to examine the importance of the tyrosine kinases focal adhesion kinase (FAK) and Src kinase in cardiac ICl,swellregulation. Neonatal rat ventricular myocytes were cultured on collagen membranes and infected with adenovirus expressing β-galactosidase (AdLacZ), FAK, or FAK-related nonkinase. FAK-related nonkinase (FRNK) is an endogenous cardiac protein, which functions as an inhibitor of FAK. Whole cell patch-clamp recordings demonstrated that osmotic swelling was associated with the activation of an outward rectifying current in uninfected and AdLacZ-infected cells. Consistent with the properties of ICl,swell, this current displayed a reversal potential close to the equilibrium potential for Cl−; was inhibited by the Cl−channel blockers 4,4′-dinitrostilbene-2,2′-disulfonic acid, 5-nitro-2-(3-phenylpropylamino)-benzoic acid, and tamoxifen; and was eliminated in hypertonic solution. In addition to activating ICl,swell, hypotonic swelling enhanced the tyrosine phosphorylation of multiple cardiac proteins including those in the range of 68–70 and 120–130 kDa. Pretreatment of the cells with the drug 4-amino-5-(4-chlorophenyl)-7-( t-butyl)pyrazolo[3,4-d]pyrimidine, an inhibitor of FAK and Src, diminished swelling-induced phosphorylation of these proteins but paradoxically increased ICl,swell. Furthermore, overexpression of FRNK but not FAK caused a twofold augmentation in ICl,swelland increased the rate of current activation. Thus the tyrosine kinases FAK and Src contribute to the regulation of ICl,swell.
β-Catenin regulates differentiation of respiratory epithelial cells in vivo
Authors: Mucenski Michael L. , Nation Jennifer M. , Thitoff Angela R. , Besnard Valérie , Xu Yan , Wert Susan E. , Harada Naomoto , Taketo Makoto M. , Stahlman Mildred T. , Whitsett Jeffrey A.
Published: July 2005

An activated form of β-catenin [CatnbΔ(ex3)] was expressed in respiratory epithelial cells of the developing lung. Although morphogenesis was not altered at birth, air space enlargement and epithelial cell dysplasia were observed in the early postnatal period and persisted into adulthood. The CatnbΔ(ex3)protein caused squamous, cuboidal, and goblet cell dysplasia in intrapulmonary conducting airways. Atypical epithelial cells that stained for surfactant pro protein C (pro-SP-C) and had morphological characteristics of alveolar type II cells were observed in bronchioles of the transgenic mice. CatnbΔ(ex3)inhibited expression of Foxa2 and caused goblet cell hyperplasia associated with increased staining for mucins and the MUC5A/C protein. In vitro, both wild type and activated β-catenin negatively regulated the expression of the Foxa2 promoter. CatnbΔ(ex3)also caused pulmonary tumors in adult mice. Activation of β-catenin caused ectopic differentiation of alveolar type II-like cells in conducting airways, goblet cell hyperplasia, and air space enlargement, demonstrating a critical role for the Wnt/β-catenin signal transduction pathway in the differentiation of the respiratory epithelium in the postnatal lung.
Microvascular rarefaction and decreased angiogenesis in rats with fetal programming of hypertension associated with exposure to a low-protein diet in utero
Authors: Pladys P. , Sennlaub F. , Brault S. , Checchin D. , Lahaie I. , Lê N. L. O. , Bibeau K. , Cambonie G. , Abran D. , Brochu M. , Thibault G. , Hardy P. , Chemtob S. , Nuyt A. M.
Published: July 2005

In hypertension, increased peripheral vascular resistance results from vascular dysfunction with or without structural changes (vessel wall remodeling and/or microvascular rarefaction). Humans with lower birth weight exhibit evidence of vascular dysfunction. The current studies were undertaken to investigate whether in utero programming of hypertension is associated with in vivo altered response and/or abnormal vascular structure. Offspring of Wistar dams fed a normal (CTRL) or low (LP)-protein diet during gestation were studied. Mean arterial blood pressure response to ANG II was significantly increased, and depressor response to sodium nitroprusside (SNP) infusions significantly decreased in male LP adult offspring relative to CTRL. No arterial remodeling was observed in male LP compared with CTRL offspring. Capillary and arteriolar density was significantly decreased in striated muscles from LP offspring at 7 and 28 days of life but was not different in late fetal life [ day 21 of gestation (E21)]. Angiogenic potential of aortic rings from LP newborn (day of birth, P0) was significantly decreased. Striated muscle expressions (Western blots) of ANG II AT1 receptor subtype, endothelial nitric oxide synthase, angiopoietin 1 and 2, Tie 2 receptor, vascular endothelial growth factor and receptor, and platelet-derived growth factor C at E21 and P7 were unaltered by antenatal diet exposure. In conclusion, blood pressure responses to ANG II and SNP are altered, and microvascular structural changes prevail in this model of fetal programming of hypertension. The capillary rarefaction is absent in the fetus and appears in the neonatal period, in association with decreased angiogenic potential. The study suggests that intrauterine protein restriction increases susceptibility to postnatal factors resulting in microvascular rarefaction, which could represent a primary event in the genesis of hypertension.
Lactate is a critical “sensed” variable in caudal hindbrain monitoring of CNS metabolic stasis
Authors: Patil Gopal D. , Briski Karen P.
Published: July 2005

Caudal hindbrain “sensing” of glucoprivation activates central neural mechanisms that enhance systemic glucose availability, but the critical molecular variable(s) linked to detection of local metabolic insufficiency remains unclear. Central neurons and glia are metabolically coupled via intercellular trafficking of the glycolytic product lactate as a substrate for neuronal oxidative respiration. Using complementary in vivo models for experimental manipulation of lactate availability within the caudal hindbrain, we investigated the hypothesis that lactate insufficiency may be monitored by local metabolically “sensitive” neurons as an indicator of central nervous system energy imbalance. The data show that caudal fourth ventricular (CV4) administration of the monocarboxylate transporter inhibitor α-cyano-4-hydroxycinnamate (4CIN) resulted in dose-dependent increases in blood glucose in euglycemic animals, whereas the degree and duration of hypoglycemia elicited by insulin administration were exacerbated by exogenous l-lactate delivery to the CV4. Immunocytochemical processing of the hindbrain for the inducible c- fos gene product Fos revealed that 4CIN enhanced Fos immunoreactivity in the dorsal vagal complex (DVC), e.g., the nucleus of the solitary tract and dorsal vagal motor nucleus, and adjacent area postrema, sites where cells characterized by unique sensitivity to diminished glucose and/or glycolytic intermediate/end product levels reside, and in the medial vestibular nucleus (MV), and that CV4 l-lactate infusion increased Fos labeling within the DVC and MV after insulin-induced hypoglycemia. Together, these results support the view that lactate is a critical monitored metabolic variable in caudal hindbrain detection of energy imbalance resulting from glucoprivation and that diminished uptake and/or oxidative catabolism of this fuel activates neural mechanisms that increase systemic glucose availability.
Lipopolysaccharide-induced fever in Pekin ducks is mediated by prostaglandins and nitric oxide and modulated by adrenocortical hormones
Authors: Gray David A. , Maloney Shane K. , Kamerman Peter R.
Published: July 2005

Information on avian fever is limited, and, in particular, very little is known about the mediators and modulators of the febrile response in birds. Therefore, in this study, the possible mediatory roles of nitric oxide (NO) and prostaglandins (PGs), together with a potential modulatory role for adrenocortical hormones in the generation of fever was investigated in conscious Pekin ducks. Their body temperatures were continuously measured by abdominally implanted temperature-sensitive data loggers. The febrile response induced by intramuscular injection of LPS at a dose of 100 μg/kg was compared with and without inhibition of NO production by N-nitro-l-arginine methyl ester (l-NAME), inhibition of PG synthesis (by diclofenac), and elevation of circulating concentrations of dexamethasone and corticosterone (by exogenous administration). LPS administration induced a marked, monophasic fever with a rise in temperature of more than 1°C after 3–4 h. In the presence of l-NAME, diclofenac, and adrenocorticoids at doses that had no effect upon normal body temperature in afebrile ducks, there was a significant inhibition of the LPS-induced fever. In addition, during the febrile response, the blood concentration of corticosterone was significantly elevated (from a basal level of 73.6 ± 9.8 ng/ml to a peak level of 132.6 ± 16.5 ng/ml). The results strongly suggest that the synthesis of both NO and PGs is a vital step in the generation of fever in birds and that the magnitude of the response is subject to modulation by adrenocorticoids.
Impact of glutamine supplementation on glucose homeostasis during and after exercise
Authors: Iwashita Soh , Williams Phillip , Jabbour Kareem , Ueda Takeo , Kobayashi Hisamine , Baier Shawn , Flakoll Paul J.
Published: July 2005

The interaction of glutamine availability and glucose homeostasis during and after exercise was investigated, measuring whole body glucose kinetics with [3-3H]glucose and net organ balances of glucose and amino acids (AA) during basal, exercise, and postexercise hyperinsulinemic-euglycemic clamp periods in six multicatheterized dogs. Dogs were studied twice in random treatment order: once with glutamine (12 μmol·kg−1·min−1; Gln) and once with saline (Con) infused intravenously during and after exercise. Plasma glucose fell by 7 mg/dl with exercise in Con ( P < 0.05), but it did not fall with Gln. Gln further stimulated whole body glucose production and utilization an additional 24% above a normal exercise response ( P < 0.05). Net hepatic uptake of glutamine and alanine was greater with Gln than Con during exercise ( P < 0.05). Net hepatic glucose output was increased sevenfold during exercise with Gln ( P < 0.05) but not with Con. Net hindlimb glucose uptake was increased similarly during exercise in both groups ( P < 0.05). During the postexercise hyperinsulinemic-euglycemic period, glucose production decreased to near zero with Con, but it did not decrease below basal levels with Gln. Gln increased glucose utilization by 16% compared with Con after exercise ( P < 0.05). Furthermore, net hindlimb glucose uptake in the postexercise period was increased approximately twofold vs. basal with Gln ( P < 0.05) but not with Con. Net hepatic uptake of glutamine during the postexercise period was threefold greater for Gln than Con ( P < 0.05). In conclusion, glutamine availability modulates glucose homeostasis during and after exercise, which may have implications for postexercise recovery.
GABAB-receptor-mediated suppression of sympathetic outflow from the spinal cord of neonatal rats
Authors: Cheng Yi-Wen , Ku Min-Chi , Ho Chiu-Ming , Chai Chok-Yung , Su Chun-Kuei
Published: July 2005

Using a splanchnic nerve-spinal cord preparation in vitro that could spontaneously generate sympathetic nerve discharge (SND), we investigated the roles of intraspinal GABAB receptors in the regulation of SND. Despite an age-dependent difference in sensitivity, bath applications of baclofen (Bac; GABAB-receptor agonist) consistently reduced SND in a concentration-dependent manner. The drug specificity of Bac in activation of GABAB receptors was verified by application of its antagonist saclofen (Sac) or CGP-46381 (CGP). Sac or CGP alone did not change SND. However, in the presence of Sac or CGP, the effects of Bac on SND inhibition were reversibly attenuated. The splanchnic sympathetic preganglionic neuron (SPN) was recorded by blind whole cell, patch-clamp techniques. We examined Bac effects on electrical membrane properties of SPNs. Applications of Bac reduced excitatory synaptic events, induced membrane hyperpolarizations, and inhibited SPN firing. In the presence of 12 mM Mg2+ or 0.5 μM TTX to block Ca2+- or action potential-dependent synaptic transmissions, applications of Bac induced an outward baseline current that reversed at −29 ± 6 mV. Because the K+ equilibrium potential in our experimental conditions was −100 mV, the Bac-induced currents could not simply be attributed to an alteration of K+ conductance. On the other hand, applications of Bac to Cs+-loaded SPNs reduced Cd2+-sensitive and high-voltage-activated inward currents, indicating an inhibition of voltage-gated Ca2+ currents. Our results suggest that the activation of intraspinal GABAB receptors suppresses SND via a mixture of ion events that may link to a change in Ca2+ conductance.
Adrenergic receptors mediate stress-induced elevations in extracellular Hsp72
Authors: Johnson John D. , Campisi Jay , Sharkey Craig M. , Kennedy Sarah L. , Nickerson Molly , Fleshner Monika
Published: July 2005

Heat-shock protein concentrations in the blood increase after exposure to a variety of stressors, including trauma and psychological stress. Although the physiological function of extracellular heat shock protein remains controversial, there is evidence that extracellular heat shock protein 72 (Hsp72) can facilitate immunologic responses. The signal(s) that mediate(s) the in vivo elevation of extracellular Hsp72 in the blood after stressor exposure remain(s) unknown. Here we report that Hsp72 increases in the circulation via an α1-adrenergic receptor-mediated signaling pathway. Activation of α1-adrenoceptors results in a rapid increase in circulating Hsp72, and blockade of α1-adrenoceptors prevents the stress-induced rise in circulating Hsp72. Furthermore, our studies exclude a role for β-adrenoceptors, glucocorticoids, and ACTH in mediating stress-induced elevations in circulating extracellular Hsp72. Understanding the signals involved in elevating extracellular Hsp72 could facilitate the use of extracellular Hsp72 to bolster immunity and perhaps prevent exacerbation of inflammatory diseases during stress.
Nonthermoregulatory control of cutaneous vascular conductance and sweating during recovery from dynamic exercise in women
Authors: Journeay W. shane , Reardon Francis D. , McInnis Natalie H. , Kenny Glen P.
Published: July 2005

The purpose of the study was to examine the effect of 1) active (loadless pedaling), 2) passive (assisted pedaling), and 3) inactive (motionless) recovery modes on mean arterial pressure (MAP), cutaneous vascular conductance (CVC), and sweat rate during recovery after 15 min of dynamic exercise in women. It was hypothesized that an active recovery mode would be most effective in attenuating the fall in MAP, CVC, and sweating during exercise recovery. Ten female subjects performed 15 min of cycle ergometer exercise at 70% of their predetermined peak oxygen consumption followed by 20 min of 1) active, 2) passive, or 3) inactive recovery. Mean skin temperature (T̄sk), esophageal temperature (Tes), skin blood flow, sweating, cardiac output (CO), stroke volume (SV), heart rate (HR), total peripheral resistance (TPR), and MAP were recorded at baseline, end exercise, and 2, 5, 8, 12, 15, and 20 min postexercise. Cutaneous vascular conductance (CVC) was calculated as the ratio of laser-Doppler blood flow to MAP. In the active recovery mode, CVC, sweat rate, MAP, CO, and SV remained elevated over inactive values ( P < 0.05). The passive mode was equally as effective as the active mode in maintaining MAP. Sweat rate was different among all modes after 12 min of recovery ( P < 0.05). TPR during active recovery remained significantly lower than during recovery in the inactive mode ( P < 0.05). No differences in either Tes or T̄sk were observed among conditions. The results indicate that CVC can be modulated by central command and possibly cardiopulmonary baroreceptors in women. However, differences in sweat rate may be influenced by factors such as central command, mechanoreceptor stimulation, or cardiopulmonary baroreceptors.
Corticosterone Slowly Enhances Miniature Excitatory Postsynaptic Current Amplitude in Mice CA1 Hippocampal Cells
Authors: Karst Henk , Joëls Marian
Published: July 2005

Corticosteroid hormones are released in high amounts after stress and bind to intracellular receptors in the brain, which in activated form function as transcription factors. We here tested the effect of a high dose of corticosterone on AMPA-receptor–mediated transmission in the CA1 hippocampal area, which is enriched in corticosteroid receptors. To focus on slow gene-mediated effects of the hormone, excitatory postsynaptic currents were measured at least 1 h after a brief application of 100 nM corticosterone to slices from adrenally intact adult mice. The amplitude but not frequency of miniature postsynaptic excitatory currents was found to be significantly enhanced. These effects were mimicked by 100 nM RU 28362, a selective agonist for intracellular glucocorticoid receptors. Evoked AMPA responses at the single cell were significantly enhanced when measured 2–4 h after application of 100 nM corticosterone, but not at earlier moments nor with a longer delay. In summary, the present results show that activation of hippocampal glucocorticoid receptors induces a slow enhancement of AMPA-receptor–mediated responses, at the single-cell level.
Enhancement of Asynchronous and Train-Evoked Exocytosis in Bovine Adrenal Chromaffin Cells Infected With a Replication Deficient Adenovirus
Authors: Thiagarajan Ramachandran , Wilhelm Jennifer , Tewolde Teclemichael , Li Yingjie , Rich Mark M. , Engisch Kathrin L.
Published: July 2005

Bovine adrenal chromaffin cells share many characteristics with neurons and are often used as a simple model system to study ion channels and neurotransmitter release. We infected bovine adrenal chromaffin cells with a replication deficient adenovirus that induces expression of the common reporters β-galactosidase and Green Fluorescent Protein via a bicistronic sequence. In perforated-patch recordings performed 48-h postinfection, peak calcium currents were reduced 32%, primarily due to loss of ω-conotoxin-GVIA-sensitive current. In contrast, sodium currents were increased 17%. Exocytosis, detected as an increase in membrane capacitance immediately after a single step depolarization, was reduced in proportion to the decrease in calcium influx. However, capacitance continued to increase for seconds after the depolarization. The amplitude of this poststimulus drift, or asynchronous exocytosis, was approximately three times that which occurred in a small fraction of control cells. Exocytosis evoked by repetitive stimulation with a train of brief depolarizations was increased 50%. Intracellular calcium levels measured during and after stimulation were lower, not higher, in adenovirus-infected cells. Electroporated cells showed reduced calcium currents but no enhancement of exocytosis. Cells infected with UV-irradiated virus showed reduced calcium currents and enhancement of exocytosis, but the changes were smaller than those caused by intact virus. Our results are consistent with the idea that adenovirus capsid and adenoviral DNA contribute to a Ca2+influx- and [Ca2+]i-independent enhancement of exocytosis in bovine chromaffin cells.
Cerebellar Disease Alters the Axis of the High-Acceleration Vestibuloocular Reflex
Authors: Walker Mark F. , Zee David S.
Published: July 2005

L. W. Schultheis and D. A. Robinson showed that the axis of the rotational vestibuloocular reflex (RVOR) cannot be altered by visual-vestibular mismatch (“cross-axis adaptation”) when the vestibulocerebellum is lesioned. This suggests that the cerebellum may calibrate the axis of eye velocity of the RVOR under natural conditions. Thus we asked whether patients with cerebellar disease have alterations in the RVOR axis and, if so, what might be the mechanism. We used three-axis scleral coils to record head and eye movements during yaw, pitch, and roll head impulses in 18 patients with cerebellar disease and in a comparison group of eight subjects without neurologic disease. We found distinct shifts of the eye-velocity axis in patients. The characteristic finding was a disconjugate upward eye velocity during yaw. Measured at 70 ms after the onset of head rotation, the median upward gaze velocity was 15% of yaw head velocity for patients and <1% for normal subjects ( P < 0.001). Upward eye velocity was greater in the contralateral (abducting) eye during yaw and in the ipsilateral eye during roll. Patients had a higher gain (eye speed/head speed) for downward than for upward pitch (median ratio of downward to upward gain: 1.3). In patients, upward gaze velocities during both yaw and roll correlated with the difference in anterior (AC) and posterior canal excitations, scaled by the respective pitch gains. Our findings support the hypothesis that upward eye velocity during yaw results from AC excitation, which must normally be suppressed by the intact cerebellum.
Serotonin 5-HT2Receptors Induce a Long-Lasting Facilitation of Spinal Reflexes Independent of Ionotropic Receptor Activity
Authors: Shay Barbara L. , Sawchuk Michael , Machacek David W. , Hochman Shawn
Published: July 2005

Dorsal root-evoked stimulation of sensory afferents in the hemisected in vitro rat spinal cord produces reflex output, recorded on the ventral roots. Transient spinal 5-HT2Creceptor activation induces a long-lasting facilitation of these reflexes (LLFR) by largely unknown mechanisms. Two Sprague–Dawley substrains were used to characterize network properties involved in this serotonin (5-HT) receptor–mediated reflex plasticity. Serotonin more easily produced LLFR in one substrain and a long-lasting depression of reflexes (LLDR) in the other. Interestingly, LLFR and LLDR were bidirectionally interconvertible using 5-HT2A/2Cand 5-HT1Areceptor agonists, respectively, regardless of substrain. LLFR was predominantly Aβ afferent fiber mediated, consistent with prominent 5-HT2Creceptor expression in the Aβ fiber projection territories (deeper spinal laminae). Reflex facilitation involved an unmasking of polysynaptic pathways and an increased receptive field size. LLFR emerged even when reflexes were evoked three to five times/h, indicating an activity independent induction. Both the NMDA and AMPA/kainate receptor–mediated components of the reflex could be facilitated, and facilitation was dependent on 5-HT receptor activation alone, not on coincident reflex activation in the presence of 5-HT. Selective blockade of GABAAand/or glycine receptors also did not prevent reflex amplification and so are not required for LLFR. Indeed, a more robust response was seen after blockade of spinal inhibition, indicating that inhibitory processes serve to limit reflex amplification. Overall we demonstrate that the serotonergic system has the capacity to induce long-lasting bidirectional changes in reflex strength in a manner that is nonassociative and independent of evoked activity or activation of ionotropic excitatory and inhibitory receptors.
Activation of Nicotinic Acetylcholine Receptors Increases the Frequency of Spontaneous GABAergic IPSCs in Rat Basolateral Amygdala Neurons
Authors: Zhu Ping Jun , Stewart Randall R. , McIntosh J. Michael , Weight Forrest F.
Published: July 2005

The basolateral amygdala (BLA) is a critical component of the amygdaloid circuit, which is thought to be involved in fear conditioned responses. Using whole cell patch-clamp recording, we found that activation of nicotinic acetylcholine receptors (nAChRs) leads to an action potential-dependent increase in the frequency of spontaneous GABAergic currents in principal neurons in the BLA. These spontaneous GABAergic currents were abolished by a low-Ca2+/high-Mg2+bathing solution, suggesting that they are spontaneous inhibitory postsynaptic currents (sIPSCs). Blockade of ionotropic glutamate receptors did not prevent this increased frequency of sIPSCs nor did blockade of α7nAChRs. Among the nAChR agonists tested, cystisine was more effective at increasing the frequency of the sIPSCs than nicotine or 1,1-dimethyl-4-phenyl piperazinium iodide, consistent with a major contribution of β4nAChR subunits. The nicotinic antagonist, dihydro-β-erythroidine, was less effective than d-tubocurarine in blocking the increased sIPSC frequency induced by ACh, suggesting that α4-containing nAChR subunits do not play a major role in the ACh-induced increased sIPSC frequency. Although α2/3/4/7and β2/4nAChR subunits were found in the BLA by RT-PCR, the agonist and antagonist profiles suggest that the ACh-induced increase in sIPSC frequency involves predominantly α3β4-containing nAChR subunits. Consistent with this, α-conotoxin-AuIB, a nAChR antagonist selective for the α3β4subunit combination, inhibited the ACh-induced increase in the frequency of sIPSCs. The observations suggest that nicotinic activation increases the frequency of sIPSCs in the BLA by acting mainly on α3β4-containing nicotinic receptors on GABAergic neurons and may play an important role in the modulation of synaptic transmission in the amygdala.
Differential activation of stress-response signaling in load-induced cardiac hypertrophy and failure
Authors: Rothermel Beverly A. , Berenji Kambeez , Tannous Paul , Kutschke William , Dey Asim , Nolan Bridgid , Yoo Ki-Dong , Demetroulis Elaine , Gimbel Michael , Cabuay Barry , Karimi Mohsen , Hill Joseph A.
Published: July 2005

Hypertrophic growth of the myocardium occurs in most forms of heart failure and may contribute to the pathogenesis of the failure state. Little is known about the regulatory mechanisms governing the often-coexisting phenotypes of hypertrophy, systolic failure, and diastolic stiffness that characterize clinical disease. We hypothesized that intracellular signaling pathways are differentially activated by graded degrees of hemodynamic stress. To test this, we developed models of graded pressure stress in mice and used them to directly compare compensated hypertrophy and pressure-overload heart failure. Surgical interventions were designed to be similar, on either side of a threshold separating compensated from decompensated responses. Our findings revealed two dramatically different hypertrophic phenotypes with only modest differences in the activation of relevant intracellular signaling pathways. Furthermore, we uncovered a functional requirement of calcineurin signaling in each model such that calcineurin suppression blunted hypertrophic growth. Remarkably, in each case, suppression of calcineurin signaling was not associated with clinical deterioration or increased mortality. Profiles of stress-response signaling and Ca2+ handling differ between the steady-state, maintenance phases of load-induced cardiac hypertrophy and failure. This information may be useful in identifying novel targets of therapy in chronic disease.
Cross-species analysis of the mammalian β-defensin gene family: presence of syntenic gene clusters and preferential expression in the male reproductive tract
Authors: Patil Amar A. , Cai Yibin , Sang Yongming , Blecha Frank , Zhang Guolong
Published: July 2005

Mammalian β-defensins are an important family of innate host defense peptides with pleiotropic activities. As a first step to study the evolutionary relationship and biological role of the β-defensin family, we identified their complete repertoires in the human, chimpanzee, mouse, rat, and dog following systemic, genome-wide computational searches. Although most β-defensin genes are composed of two exons separated by an intron of variable length, some contain an additional one or two exons encoding an internal pro-sequence, a segment of carboxy-terminal mature sequences or untranslated regions. Alternatively, spliced isoforms have also been found with several β-defensins. Furthermore, all β-defensin genes are densely clustered in four to five syntenic chromosomal regions, with each cluster spanning <1.2 Mb across the five species. Phylogenetic analysis indicated that, although the majority of β-defensins are evolutionarily conserved across species, subgroups of gene lineages exist that are specific in certain species, implying that some β-defensins originated after divergence of these mammals from each other, while most others arose before the last common ancestor of mammals. Surprisingly, RT-PCR revealed that all but one rat β-defensin transcript are preferentially expressed in the male reproductive tract, particularly in epididymis and testis, except that Defb4, a human β-defensin-2 ortholog, is more restricted to the respiratory and upper gastrointestinal tracts. Moreover, most β-defensins expressed in the reproductive tract are developmentally regulated, with enhanced expression during sexual maturation. Existence of such a vast array of β-defensins in the male reproductive tract suggests that these genes may play a dual role in both fertility and host defense.
Global transcriptional characterization of SP and MP cells from the myogenic C2C12 cell line: effect of FGF6
Authors: Decraene Charles , Benchaouir Rachid , Dillies Marie-Agnes , Israeli David , Bortoli Sylvie , Rochon Christelle , Rameau Philippe , Pitaval Amandine , Roux Diana Tronik-Le , Danos Olivier , Gidrol Xavier , Garcia Luis , Piétu Geneviève
Published: July 2005

With the use of Hoechst staining techniques, we have previously shown that the C2C12 myogenic cell line contains a side population (SP) that is largely increased in the presence of fibroblast growth factor 6 (FGF6). Here, we compared transcriptional profiles from SP and main population (MP) cells from either C2C12 or FGF6-expressing C2C12. Expression profiles of SPs show that these cells are less differentiated than MPs and display some similarities to stem cells. Moreover, principal component analysis made it possible to distinguish specific contributions of either FGF6 or differentiation effects on gene expression profiles. This demonstrated that FGF6-expanded SPs were similar to parental C2C12-derived SPs. Conversely, FGF6-treated MPs differed from parental MPs and were more related to SP cells. These results show that FGF6 pushed committed myogenic cells toward a more immature phenotype resulting in the accumulation of cells with a SP phenotype. We propose that FGF6 conditioning could provide a way to expand the pool of immature cells by myoblast dedifferentiation.
Gene expression profiling of the left ventricles in a rat model of intrinsic aerobic running capacity
Authors: Lee Soon Jin , Ways Justin A. , Barbato John C. , Essig David , Pettee Krista , DeRaedt Sarah J. , Yang Siming , Weaver David A. , Koch Lauren G. , Cicila George T.
Published: July 2005

Our previous work found DA rats superior for intrinsic aerobic running capacity (ARC) and several cardiac function indexes compared with Copenhagen (COP) rats, and identified ARC quantitative trait loci (QTLs) on rat chromosomes 16 (RNO16) and 3 (RNO3). The purpose of this study was to use these inbred rat strains as a genetic substrate for differential cardiac gene expression to identify candidate genes for the observed ARC QTLs. RNA expression was examined globally in left ventricles of 15-wk-old DA, F1(COP × DA), and COP rats using microarrays to identify candidate genes for ARC QTLs. We identified 199 differentially expressed probe sets and determined their chromosomal locations. Six differentially expressed genes and expressed sequence tags (ESTs) mapped near ARC QTL regions, including PDZ and LIM domain 3 ( Pdlim3). Differential expression of these genes/ESTs was confirmed by quantitative RT-PCR. The Ingenuity Pathways program identified 13 biological networks containing 50 (of the 199) differentially expressed probe sets and 85 additional genes. Four of these eighty-five genes mapped near ARC QTL-containing regions, including insulin receptor substrate 2 ( Irs2) and acyl-CoA sythetase long-chain family member 1 ( Acsl1). Most (148/199) differentially expressed probe sets showed left ventricular expression patterns consistent with the alleles exerting additive effects, i.e., F1(COP × DA) rat RNA expression was intermediate between DA and COP rats. This study identified several potential ARC QTL candidate genes and molecular networks, one of them related to energy expenditure involving Pik3r1 mRNA expression that may, in part, explain the observed strain differences in ARC and cardiac performance.
Bone Morphogenetic Proteins in Vascular Calcification
Authors: Hruska Keith A. , Mathew Suresh , Saab Georges
Published: July 2005

Vascular calcification is a common problem among the elderly and those with chronic kidney disease (CKD) and diabetes. The process of tunica media vascular calcification in CKD appears to involve a phenotypic change in the vascular smooth muscle cell (VSMC) resulting in cell-mediated mineralization of the extracellular matrix. The bone morphogenetic proteins (BMPs) are important regulators in orthotopic bone formation, and their localization at sites of vascular calcification raises the question of their role. In this review, we will discuss the actions of the BMPs in vascular calcification. Although the role of BMP-2 in vascular calcification is not proven, it has been the most studied member of the BMP family in this disease process. The role of BMP-2 may be through inducing osteoblastic differentiation of VSMCs through induction of
MSX-2
, or by inducing apoptosis of VSMCs, a process thought critical in the initiation of vascular calcification. Additionally, BMP-2 may be related to loss of regulation of the matrix Gla protein. A second BMP, BMP-7, less studied than BMP-2 may have opposing actions in vascular calcification. In postnatal life, BMP-7 is expressed primarily in the kidney, and expression is diminished by renal injury. BMP-7 is an important regulator of skeletal remodeling and the VSMC phenotype. BMP-7 restores skeletal anabolic balance in animal models of CKD with disordered skeletal modeling, also reducing serum phosphate in the process. BMP-7 also reverses vascular calcification in CKD, and reduction in vascular calcification is due, in part, to reduced serum phosphate, an important inducer of VSMC-mediated vascular mineralization and in part to direct actions on the VSMC.
The Retrieval of Ice-Cloud Properties from Cloud Radar and Lidar Synergy
Authors: Tinel Claire , Testud Jacques , Pelon Jacques , Hogan Robin J. , Protat Alain , Delanoë Julien , Bouniol Dominique
Published: July 2005

Clouds are an important component of the earth’s climate system. A better description of their microphysical properties is needed to improve radiative transfer calculations. In the framework of the Earth, Clouds, Aerosols, and Radiation Explorer (EarthCARE) mission preparation, the radar–lidar (RALI) airborne system, developed at L’Institut Pierre Simon Laplace (France), can be used as an airborne demonstrator. This paper presents an original method that combines cloud radar (94–95 GHz) and lidar data to derive the radiative and microphysical properties of clouds. It combines the apparent backscatter reflectivity from the radar and the apparent backscatter coefficient from the lidar. The principle of this algorithm relies on the use of a relationship between the extinction coefficient and the radar specific attenuation, derived from airborne microphysical data and Mie scattering calculations. To solve radar and lidar equations in the cloud region where signals can be obtained from both instruments, the extinction coefficients at some reference range z0 must be known. Because the algorithms are stable for inversion performed from range z0 toward the emitter, z0 is chosen at the farther cloud boundary as observed by the lidar. Then, making an assumption of a relationship between extinction coefficient and backscattering coefficient, the whole extinction coefficient, the apparent reflectivity, cloud physical parameters, the effective radius, and ice water content profiles are derived. This algorithm is applied to a blind test for downward-looking instruments where the original profiles are derived from in situ measurements. It is also applied to real lidar and radar data, obtained during the 1998 Cloud Lidar and Radar Experiment (CLARE’98) field project when a prototype airborne RALI system was flown pointing at nadir. The results from the synergetic algorithm agree reasonably well with the in situ measurements.
Evaluation of Microphysical Retrievals from Polarimetric Radar with Wind Profiler Data
Authors: May Peter T. , Keenan Thomas D.
Published: July 2005

Polarimetric radar data have been used to produce microphysical classifications. This kind of analysis is run in a real-time mode from several research radars, including the C-band polarimetric (C-Pol) radar in Darwin, Australia. However, these classifications have had very little systematic evaluation with independent data. Using surface data is often difficult because of sampling issues, particularly for hail. The approach taken here is to use a combination of 50- and 920-MHz wind profiler estimates of rain and hail to provide validation data for the radar pixels over the profiler. The profilers also observe signals associated with lightning, and some comparisons are made between lightning occurrence and the radar measurements of graupel. The retrievals of hail–rain mixtures are remarkably robust; there are some issues regarding other microphysical classes, however, including difficulties in detecting melting snow layers in stratiform rain. These difficulties are largely due to the resampling of the radar volume data onto a grid and to poor separation of the snow classes.
Late Payment and Credit Management in the Small Firm Sector: Some Empirical Evidence
Authors: Peel Michael J. , Wilson Nicholas , Howorth Carole
Published: July 2005

MICHAEL J. PEEL IS W1TH CARDIFF Business School, Wales, AL.Professor Nicholas Wilson is with ILeeds University Business School, England, and Carole Howorth is with Nottingham University Business School, England. Based on the results of a qtuestionnlaire survey, this paper provides some new evidence relating to late payment and credit and working capital m-ianiagenment practices of a sample of 211 small businesses operating in the United Kingdom manufacturing sector. Small firnms are often suppliers of trade credit, despite the difficulties that this often causes them, and there is little empirical evidence on the credit granting decisions of smiall firnms. Theory suggests that firms facing a higher cost of institutional credit (i.e. small firms) are less likely to offer trade credit. Empirical evidence suggests that not only do small firms provide trade credit to their customers but they often finid themselves providing extended trade credit (i.e. are paid after the due dlate( late). It is clear that exten-dedI tu ade ((re(lit plays anl important signallinig' rol(e t'0o smaller- firms wishing to gaini sales anlt establish reputationi. This paper examtillIc. the extent of late payntient 1or stniall suippliers and the cit-t-ent pt acti(es ill tr-ade credit managenmenit. The kex restilts indicate that thei-e was large suppor t amiong respondenits for the cut rrent I JK legislation giving small firms the statuittot J right to initerest orn late payments, xvitlt such legislation being rated tlhe illost popular measuire to reduce late pax'lntelltt and also the highest rated factot- associated wtih improving busilless performance. Inproved credit attd financial management was, however, rated of relatively low import in this respect. In total, 59.5 pet cenit, of respondents stated that late paimet-tt posed an important or very iml1portall-it problem to their- businesses, wvitih 43. 1 pct l cent Oiving a similar resp)ttsi ts c espC of bad debts. 89 per cent indicated that they paid their own suppliers late to a greater or lesser extent. The amount of working capital management undertaken was found to be related to the severity of the problem for individual firms (i.e. necessity was driving action). Responses from the sample firms were found to differ significantly with respect to firm size; larger small firms had a worse late payment problem and consequently had to do more in the way of 'back-end' credit management (i.e. collection, analysis of late payment and debtor days). However, there was barely any support for credit management training among this sub-group. The smaller (micro) firms had a lesser late payment problem and subsequently did less 'back-end' credit management but were more concerned with various aspects of institutional finance. It was posited that the problems faced by small firms are at least partly associated with business size and with the life cycle of the firm.
Gender and Small Business Management: The Case of Norway in the 1990s
Authors: Spilling Olav R. , Berg Nina Gunnerud
Published: July 2005

OLAV R. SPILLING IS WITH THE CENTRE FOR Industrial Development and Entrepreneurship, Norwegian School of Management, Sandvika, and Nina Gunnerud Berg is with the Norwegian University of Science and Technology, Trondheim, Norway. The first is based on the Population Census, 1990 and provides representative data on self-employment and (self-reported) management positions in private as well as public businesses in the whole population. The second data set, from 1995, links data on all registered firm managers and board chairmen to data on firms recorded in the Central Register of Firms and Establishments. It provides comprehensive data on the share of male and female managers in various industries and size groups of companies. As far as self-employment is concerned, the data reveal a share of female self-employed of 25 per cent, which is comparable with the situation in other European countries, but below shares reported from the United States. However, the data reveal that self-employment has different meanings to men and women as female self-employment generally means to be in an economically more marginal position than is the situation for self-employed men. The data on business managers (top executives) reveal very small shares for women compared with men. Women managers are mainly in smaller firms, and even among these the share is rather small with, on average, about 16 per cent; for board chairmen the percentage is even smaller with about 10 per cent. The larger the firms, the smaller is the share of female managers, and they are virtually absent in the larger firms. When summarising the data, it turns out that businesses with female managers account for about 7 per cent of total private sector employment, and about 5 per cent of total turnover. Furthermore, the data reveal that to the extent women go into business as managers, they do so in sectors where women traditionally have a strong position in the labour market but even among these sectors very few have a majority of female managers. The general conclusion of this paper is that current research based on data on self-employment tends to give a too optimistic picture of the role of women in business. the vast majority of businesses managed by women are very small, and taking into account the 'weight' of their businesses, the role of women in business is still rather marginal.
High-tech Potential? An Exploratory Study of Very Small Firms' Usage of the Internet
Authors: Dandridge Tom , Levenburg Nancy M.
Published: July 2005

NANCY M. LEVENBURG AND THOMAS C. Dandridge are both with the Seidman School of Business, Grand Valley State University, Michigan, USA. Research on small business owners' use of the Internet has treated all firms with fewer than 25 employees as a common homogenous group and compared these with larger firms. This study looks in detail at Internet use by 195 US firms with fewer than 25 employees, finding marked differences in frequency and type of use among firms by size gradation. A general profile emerges since more frequent and more sophisticated use of the Internet exists by firms with four or more full-time equivalent (FTE) employees, and firms with intentions for growth in the next six months, including sales change, employment change and export plans. Given these new insights, suggestions for further research are offered.
What is Small Business Policy in the UK for? Evaluation and Assessing Small Business Policies
Authors: Curran James
Published: July 2005

PROFESSORJAMES CURRAN IS EMERITUS professor at Kingston University, England, and was formerly director of its Small Business Research Centre. Since 1980 the United Kingdom small business population has increased greatly. Small businesses have also acquired a key role in UK economic policies paralleled by a huge development in support structures to promote them. Despite broad rhetorical claims that policies and support help develop a strong enterprise culture and promote UK economic prosperity, the precise outcomes of these policies have been difficult to pin down. As policies developed over the twenty years, the evaluation of their achievements has also proved difficult because of methodological problems. This paper examines the problems of evaluating small business policies and support and draws out some key implications for their future in the UK It concludes that even allowing for the problems of evaluation, one of the best and clearest supported findings is of poor take-up of the support offered. In other words, although small businesses have become much more important in the UK economy, it is unlikely that this has been due to state intervention. Because of the well-entrenched unanimity on the value of small business support in the UK, little attention has been given to whether the support represents good value for public money. Small and medium-sized businesses now account for well over half of business turnover and jobs in the UK. Not only can there be doubts about whether the policies and support are cost effective but more importantly, the question can be asked whether such policies are needed at all any more.
Knowledge, Context and Learning in the Small Business
Authors: Dalley Jeff , Hamilton Bob
Published: July 2005

JEFF DALLEY HAS BEEN OWNER-MANAGER OF several small businesses and is currently associated with a boutique winery near Christchurch, New Zealand. Bob Hamilton is Professor of Management at the University of Canterbury, Christchurch, New Zealand. The first objective of this paper is to elaborate what is meant by small business 'context' It then seeks to demonstrate how the constructs of 'knowledge', 'context', and 'learning' operate as key determinants of the effectiveness of small business education and training. The supply of education and training to potential business founders and those already running their own businesses is itself a worldwide growth industry. This is happening even though much of what is provided is known to be ineffective and there is evidence that those on the receiving end are resistant to education and training. One criticism of the current situation is that the offerings are essentially supply-determined and lack any appreciation of the special context within which a small business exists. If this context is neglected or, worse, contradicted by the suppliers, then no effective learning will occur. Only disappointment and increased suspicion will result