bluuebunny/crossref_metadata_2025 huggingface dataset:
Afferent signaling drives oxytocinergic preautonomic neurons and mediates training-induced plasticity
Authors: Cavalleri Marina T. , Burgi Katia , Cruz Josiane C. , Jordão Maria T. , Ceroni Alexandre , Michelini Lisete C.
Published: July 2011

We showed previously that oxytocinergic (OTergic) projections from the hypothalamic paraventricular nucleus (PVN) to the dorsal brain stem mediate training-induced heart rate (HR) adjustments and that beneficial effects of training are blocked by sinoaortic denervation (SAD; Exp Physiol 94: 630–640; 1103–1113, 2009). We sought now to determine the combined effect of training and SAD on PVN OTergic neurons in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. Rats underwent SAD or sham surgery and were trained (55% of maximal capacity) or kept sedentary for 3 mo. After hemodynamic measurements were taken at rest, rats were deeply anesthetized. Fresh brains were frozen and sliced to isolate the PVN; samples were processed for OT expression (real-time PCR) and fixed brains were processed for OT immunofluorescence. In sham rats, training improved treadmill performance and increased the gain of baroreflex control of HR. Training reduced resting HR (−8%) in both groups, with a fall in blood pressure (−10%) only in SHR rats. These changes were accompanied by marked increases in PVN OT mRNA expression (3.9- and 2.2-fold in WKY and SHR rats, respectively) and peptide density in PVN OTergic neurons (2.6-fold in both groups), with significant correlations between OT content and training-induced resting bradycardia. SAD abolished PVN OT mRNA expression and markedly reduced PVN OT density in WKY and SHR. Training had no effect on HR, PVN OT mRNA, or OT content following SAD. The chronic absence of inputs from baroreceptors and chemoreceptors uncovers the pivotal role of afferent signaling in driving both the plasticity and activity of PVN OTergic neurons, as well as the beneficial effects of training on cardiovascular control.
Role of the α-adrenergic system in femoral vascular reactivity in neonatal llamas and sheep: a comparative study between highland and lowland species
Authors: Moraga Fernando A. , Reyes Roberto V. , Herrera Emilio A. , Riquelme Raquel A. , Ebensperger Germán , Pulgar Víctor M. , Parer Julian T. , Giussani Dino A. , Llanos Aníbal J.
Published: July 2011

Using an integrative approach at the whole animal, isolated vessels, and molecular levels, we tested the hypothesis that the llama, a species that undergoes pregnancy under the influence of the chronic hypoxia of high altitude, delivers offspring with an increased α-adrenergic peripheral vascular reactivity compared with neonates from lowland species. We studied the femoral vascular response to acute hypoxia in vivo, the reactivity of femoral vessels ex vivo, and the expression of femoral α1-adrenergic receptor subtypes using RT-PCR in vitro. The increase in femoral resistance during hypoxia was 3.6 times greater in newborn llamas than newborn sheep ( P < 0.05). The sensitivity of the contractile response to noradrenaline (pD2 = 5.18 ± 0.06 vs. 4.84 ± 0.05, P < 0.05) and the maximal response (Rmax = 101.3 ± 1.4 vs. 52.4 ± 1.4% K+max, P < 0.05) and sensitivity (pD2 = 5.47 ± 0.03 vs. 4.57 ± 0.05, P < 0.05) to phenylephrine were higher in femoral vessels from newborn llamas than newborn sheep. Competitive inhibition with prazosin of noradrenaline-induced contraction followed by Schild analysis showed higher affinity in the llama than the sheep (pA2 = 10.08 ± 0.093 vs. 8.98 ± 0.263, respectively, P < 0.05), consistent with greater α1B-adrenergic receptor transcript expression observed in small femoral arteries from neonatal llama. The llama newborn demonstrates significantly greater α-adrenergic peripheral vascular reactivity compared with neonates from lowland species that could be partially explained by preferential expression of α1B-adrenergic receptor subtype.
Patterning of somatosympathetic reflexes reveals nonuniform organization of presympathetic drive from C1 and non-C1 RVLM neurons
Authors: Burke Peter G. R. , Neale Jemima , Korim Willian S. , McMullan Simon , Goodchild Ann K.
Published: July 2011

To determine the organization of presympathetic vasomotor drive by phenotypic populations of rostral ventrolateral medulla (RVLM) neurons, we examined the somatosympathetic reflex (SSR) evoked in four sympathetic nerves together with selective lesions of RVLM presympathetic neurons. Urethane-anesthetized (1.3 g/kg ip), paralyzed, vagotomized and artificially ventilated Sprague-Dawley rats ( n = 41) were used. First, we determined the afferent inputs activated by sciatic nerve (SN) stimulation at graded stimulus intensities (50 sweeps at 0.5–1 Hz, 1–80 V). Second, we recorded sympathetic nerve responses (cervical, renal, splanchnic, and lumbar) to intensities of SN stimulation that activated A-fiber afferents (low) or both A- and C-fiber afferents (high). Third, with low-intensity SN stimulation, we examined the cervical SSR following RVLM microinjection of somatostatin, and we determined the splanchnic SSR in rats in which presympathetic C1 neurons were lesioned following intraspinal injections of anti-dopamine-β-hydroxylase-saporin (anti-DβH-SAP). Low-intensity SN stimulation activated A-fiber afferents and evoked biphasic responses in the renal, splanchnic, and lumbar nerves and a single peak in the cervical nerve. Depletion of presympathetic C1 neurons (59 ± 4% tyrosine hydroxylase immunoreactivity profiles lesioned) eliminated peak 2 of the splanchnic SSR and attenuated peak 1, suggesting that only RVLM neurons with fast axonal conduction were spared. RVLM injections of somatostatin abolished the single early peak of cervical SSR confirming that RVLM neurons with fast axonal conduction were inhibited by somatostatin. It is concluded that unmyelinated RVLM presympathetic neurons, presumed to be all C1, innervate splanchnic, renal, and lumbar but not cervical sympathetic outflows, whereas myelinated C1 and non-C1 RVLM neurons innervate all sympathetic outflows examined. These findings suggest that multiple levels of neural control of vasomotor tone exist; myelinated populations may set baseline tone, while unmyelinated neurons may be recruited to provide actions at specific vascular beds in response to distinct stressors.
The PGC-1α-related coactivator promotes mitochondrial and myogenic adaptations in C2C12 myotubes
Authors: Philp Andrew , Belew Micah Y. , Evans Ashleigh , Pham Don , Sivia Itwinder , Chen Ai , Schenk Simon , Baar Keith
Published: July 2011

The transcriptional coactivator PGC-1α is a potent regulator of skeletal muscle metabolism. Less is known about the structurally similar PGC-1α-related coactivator (PRC) that is enriched in myoblasts and adult skeletal muscle. The present study was designed to determine the effect of PRC on the metabolic profile of C2C12 myotubes. Overexpression of full-length PRC increased PRC gene expression by 2.7 ± 0.3-fold and protein content by 108 ± 5.3%. This modest elevation in PRC resulted in an increased rate of myoblast proliferation (61.5 ± 2.7%) and resulted in myotubes characterized by increased MyoD (18.2 ± 0.52%) and myosin heavy chain (15.4 ± 3.13%) protein. PRC overexpressing myotubes showed increases in mRNA for some—COX4 (2.6 ± 0.18-fold), ATP5B (2.7 ± 0.34-fold) cytochrome c (5.1 ± 0.68-fold)—but not all, MTCO1 (0.61 ± 0.18-fold) and HAD (0.98 ± 0.36-fold) mitochondrial genes, as well as a significant increase in cytochrome– c (28.7 ± 7.02%) protein content. The enzyme activity of the electron transport chain (ETC) complex IV (3.7 ± 0.01-fold) and citrate synthase (2.1 ± 0.14-fold) was increased by PRC, as was the mtDNA:nucDNA ratio (11 ± 0.3%). PRC increased cellular respiration (142%), basal (197%) and insulin-stimulated (253%) glucose uptake, as well as palmitate uptake (28.6 ± 3.31%) and oxidation (31.1 ± 2.17%). Associated with these changes in function, PRC overexpression increased GLUT4 mRNA (4.5 ± 0.22-fold) and protein (13.8 ± 2.08%) and CPT1 protein (28.9 ± 4.23%). Electrical stimulation of C2C12 myotubes resulted in a transient increase in PRC mRNA that was smaller (2.1 ± 0.3-fold vs. 4.4 ± 0.23-fold) and occurred earlier (3 h vs. 6 h) than PGC-1α. Collectively, our data show that PRC promotes skeletal muscle myogenesis and metabolism in vitro, thus identifying PRC as a functional skeletal muscle coactivator capable of regulating mitochondrial substrate utilization and respiration.
Atherosclerotic lesion progression is attenuated by reconstitution with bone marrow from macrophage-specific cholesteryl ester hydrolase transgenic mice
Authors: Bie Jinghua , Zhao Bin , Ghosh Shobha
Published: July 2011

Accumulation of cholesteryl ester (CE)-enriched macrophage foam cells is central to the development of atherosclerotic lesions. Intracellular CE hydrolysis is the rate-limiting step in the removal of free cholesterol from macrophage foam cells. Enhancing this process by transgenic overexpression of CE hydrolase (CEH) resulted in a significant decrease in diet-induced atherosclerosis in LDL receptor-deficient (LDLR−/−) mice. However, for development of this step as an antiatherosclerotic target it is imperative to demonstrate that increase in CE hydrolysis after initiation of lesion formation will also attenuate further lesion progression. The objective of the present study was to directly address this issue using an animal model. LDLR−/− mice were fed a high-fat high-cholesterol diet (Western Diet) for 8 wk to initiate lesion formation and were then divided into three groups. Group 1 mice were killed to determine baseline lesion development. Mice in groups 2 and 3 were irradiated and transplanted with either LDLR−/− or LDLR−/−CEH transgenic bone marrow and maintained on Western Diet. Atherosclerotic lesion progression was assessed after 12 wk. While a more than fourfold increase in total lesions (compared to group 1) was seen in group 2 receiving LDLR−/− marrow, a significantly lower increase (<2-fold) was noted in mice reconstituted with CEH transgenic marrow ( group 3). Lesions in group 3 mice were also more cellular with smaller necrotic cores. Lesion progression is associated with a switch in macrophage phenotype from anti-inflammatory M2 to proinflammatory M1 phenotype and is consistent with reduced lesion progression. Aortas from group 3 mice contained a significantly higher percentage of macrophages in M2 phenotype (Ly6Clo). These data demonstrate for the first time that enhancing macrophage CE hydrolysis even after lesion initiation can still attenuate further lesion progression and also switches the phenotype of lesion-associated macrophages to anti-inflammatory M2 phenotype establishing intracellular CE hydrolysis as an anti-atherosclerotic as well as anti-inflammatory target.
Hypotension in the chronically hypoxic chicken embryo is related to the β-adrenergic response of chorioallantoic and femoral arteries and not to bradycardia
Authors: Lindgren Isa , Crossley Dane , Villamor Eduardo , Altimiras Jordi
Published: July 2011

Prolonged fetal hypoxia leads to growth restriction and can cause detrimental prenatal and postnatal alterations. The embryonic chicken is a valuable model to study the effects of prenatal hypoxia, but little is known about its long-term effects on cardiovascular regulation. We hypothesized that chicken embryos incubated under chronic hypoxia would be hypotensive due to bradycardia and βAR-mediated relaxation of the systemic and/or the chorioallantoic (CA) arteries. We investigated heart rate, blood pressure, and plasma catecholamine levels in 19-day chicken embryos (total incubation 21 days) incubated from day 0 in normoxia or hypoxia (14–15% O2). Additionally, we studied α-adrenoceptor (αAR)-mediated contraction, relaxation to the β-adrenoceptor (βAR) agonist isoproterenol, and relaxation to the adenylate cyclase activator forskolin in systemic (femoral) and CA arteries (by wire myography). Arterial pressure showed a trend toward hypotension in embryos incubated under chronic hypoxic conditions compared with the controls (mean arterial pressure 3.19 ± 0.18 vs. 2.59 ± 0.13 kPa, normoxia vs. hypoxia, respectively. P = 0.056), without an accompanied bradycardia and elevation in plasma norepinephrine and lactate levels. All vessels relaxed in response to βAR stimulation with isoproterenol, but the CA arteries completely lacked an αAR response. Furthermore, hypoxia increased the sensitivity of femoral arteries (but not CA arteries) to isoproterenol. Hypoxia also increased the responsiveness of femoral arteries to forskolin. In conclusion, we suggest that hypotension in chronic hypoxic chicken embryos is the consequence of elevated levels of circulating catecholamines acting in vascular beds with exclusive (CA arteries) or exacerbated (femoral arteries) βAR-mediated relaxation, and not a consequence of bradycardia.
Cellular and molecular basis of increased ammoniagenesis in potassium deprivation
Authors: Abu Hossain Shaikh , Chaudhry Farrukh A. , Zahedi Kamyar , Siddiqui Faraaz , Amlal Hassane
Published: July 2011

Hypokalemia is associated with increased ammoniagenesis and stimulation of net acid excretion by the kidney in both humans and experimental animals. The molecular mechanisms underlying these effects remain unknown. Toward this end, rats were placed in metabolic cages and fed a control or K+-deficient diet (KD) for up to 6 days. Rats subjected to KD showed normal acid-base status and serum electrolytes composition. Interestingly, urinary NH4+excretion increased significantly and correlated with a parallel decrease in urine K+excretion in KD vs. control animals. Molecular studies showed a specific upregulation of the glutamine transporter SN1, which correlated with the upregulation of glutaminase (GA), glutamate dehydrogenase (GDH), and phosphoenolpyruvate carboxykinase. These effects occurred as early as day 2 of KD. Rats subjected to a combined KD and 280 mM NH4Cl loading (to induce metabolic acidosis) for 2 days showed an additive increase in NH4+excretion along with an additive increment in the expression levels of ammoniagenic enzymes GA and GDH compared with KD or NH4Cl loading alone. The incubation of cultured proximal tubule cells NRK 52E or LLC-PK1in low-K+medium did not affect NH4+production and did not alter the expression of SN1, GA, or GDH in NRK cells. These results demonstrate that K+deprivation stimulates ammoniagenesis through a coordinated upregulation of glutamine transporter SN1 and ammoniagenesis enzymes. This effect is developed before the onset of hypokalemia. The signaling pathway mediating these events is likely independent of KD-induced intracellular acidosis. Finally, the correlation between increased NH4+production and decreased K+excretion indicate that NH4+synthesis and transport likely play an important role in renal K+conservation during hypokalemia.
Combining angiotensin II blockade and renin receptor inhibition results in enhanced antifibrotic effect in experimental nephritis
Authors: Zhang Jiandong , Gu Chunyan , Noble Nancy A. , Border Wayne A. , Huang Yufeng
Published: July 2011

The limited antifibrotic effect of therapeutic angiotensin blockade, the fact that angiotensin blockade dramatically elevates renin levels, and recent evidence that renin has an angiotensin-independent, receptor-mediated profibrotic action led us to hypothesize that combining renin receptor inhibition and ANG II blockade would increase the antifibrotic effect of angiotensin blockade alone. Using cultured nephritic glomeruli from rats with anti-Thy-1-induced glomerulonephritis, the maximally effective dose of enalaprilate was determined to be 10−4M, which reduced mRNAs for transforming growth factor (TGF)-β1, fibronectin (FN), and plasminogen activator inhibitor-1 (PAI-1) by 49, 65, and 56% and production of TGF-β1 and FN proteins by 60 and 49%, respectively. Disease alone caused 6.8-fold increases in ANG II levels that were reduced 64% with enalaprilate. In contrast, two- and threefold disease-induced increases in renin mRNA and activity were further increased 2- and 3.7-fold with 10−4M enalaprilate treatment. Depressing the renin receptor by 80% with small interfering (si) RNA alone reduced fibrotic markers in a manner remarkably similar to enalaprilate alone but had no effect on glomerular renin expression. Enalaprilate and siRNA combination therapy further reduced disease markers. Notably, elevated TGF-β1 and FN production was reduced by 73 and 81%, respectively. These results support the notion of a receptor-mediated profibrotic action of renin, suggest that the limited effectiveness of ANG II blockade may be due, at least in part, to the elevated renin they induce, and support our hypothesis that adding renin receptor inhibitor to ANG II blockade in patients may have therapeutic potential.
Role of AUF1 and HuR in the pH-responsive stabilization of phosphoenolpyruvate carboxykinase mRNA in LLC-PK1-F+cells
Authors: Mufti Judy , Hajarnis Sachin , Shepardson Kelly , Gummadi Lakshmi , Taylor Lynn , Curthoys Norman P.
Published: July 2011

Onset of metabolic acidosis leads to a rapid and pronounced increase in expression of phosphoenolpyruvate carboxykinase (PEPCK) in rat renal proximal convoluted tubules. This adaptive response is modeled by treating a clonal line of porcine LLC-PK1-F+cells with an acidic medium (pH 6.9, 9 mM HCO3−). Measurement of the half-lives of PEPCK mRNA in cells treated with normal (pH 7.4, 26 mM HCO3−) and acidic medium established that the observed increase is due in part to stabilization of the PEPCK mRNA. The pH-responsive stabilization was reproduced in a Tet-responsive chimeric reporter mRNA containing the 3′-UTR of PEPCK mRNA. This response was lost by mutation of a highly conserved AU sequence that binds AUF1 and is the primary element that mediates the rapid turnover of PEPCK mRNA. However, siRNA knockdown of AUF1 had little effect on the basal levels and the pH-responsive increases in PEPCK mRNA and protein. Electrophoretic mobility shift assays established that purified recombinant HuR, another AU element binding protein, also binds with high affinity and specificity to multiple sites within the final 92-nucleotides of the 3′-UTR of the PEPCK mRNA, including the highly conserved AU-rich element. siRNA knockdown of HuR caused pronounced decreases in basal expression and the pH-responsive increases in PEPCK mRNA and protein. Therefore, basal expression and the pH-responsive stabilization of PEPCK mRNA in LLC-PK1-F+cells, and possibly in the renal proximal tubule, may require the remodeling of HuR and AUF1 binding to the elements that mediate the rapid turnover of PEPCK mRNA.
Villin and actin in the mouse kidney brush-border membrane bind to and are degraded by meprins, an interaction that contributes to injury in ischemia-reperfusion
Authors: Ongeri Elimelda Moige , Anyanwu Odinaka , Reeves W. Brian , Bond Judith S.
Published: July 2011

Meprins, metalloproteinases abundantly expressed in the brush-border membranes (BBMs) of rodent proximal kidney tubules, have been implicated in the pathology of renal injury induced by ischemia-reperfusion (IR). Disruption of the meprin β gene and actinonin, a meprin inhibitor, both decrease kidney injury resulting from IR. To date, the in vivo kidney substrates for meprins are unknown. The studies herein implicate villin and actin as meprin substrates. Villin and actin bind to the cytoplasmic tail of meprin β, and both meprin A and B are capable of degrading villin and actin present in kidney proteins as well as purified recombinant forms of these proteins. The products resulting from degradation of villin and actin were unique to each meprin isoform. The meprin B cleavage site in villin was Glu744-Val745. Recombinant forms of rat meprin B and homomeric mouse meprin A had Kmvalues for villin and actin of ∼1 μM (0.6–1.2 μM). The kcatvalues varied substantially (0.6–128 s−1), resulting in different efficiencies for cleavage, with meprin B having the highest kcat/ Kmvalues (128 M−1·s−1× 106). Following IR, meprins and villin redistributed from the BBM to the cytosol. A 37-kDa actin fragment was detected in protein fractions from wild-type, but not in comparable preparations from meprin knockout mice. The levels of the 37-kDa actin fragment were significantly higher in kidneys subjected to IR. The data establish that meprins interact with and cleave villin and actin, and these cytoskeletal proteins are substrates for meprins.
Changes in intervertebral disc morphology persist 5 mo after 21-day bed rest
Authors: Belavý Daniel L. , Bansmann P. Martin , Böhme Gisela , Frings-Meuthen Petra , Heer Martina , Rittweger Jörn , Zange Jochen , Felsenberg Dieter
Published: July 2011

As part of the nutrition-countermeasures (NUC) study in Cologne, Germany in 2010, seven healthy male subjects underwent 21 days of head-down tilt bed rest and returned 153 days later to undergo a second bout of 21-day bed rest. As part of this model, we aimed to examine the recovery of the lumbar intervertebral discs and muscle cross-sectional area (CSA) after bed rest using magnetic resonance imaging and conduct a pilot study on the effects of bed rest in lumbar muscle activation, as measured by signal intensity changes in T2-weighted images after a standardized isometric spinal extension loading task. The changes in intervertebral disc volume, anterior and posterior disc height, and intervertebral length seen after bed rest did not return to prebed-rest values 153 days later. While recovery of muscle CSA occurred after bed rest, increases ( P ≤ 0.016) in multifidus, psoas, and quadratus lumborum muscle CSA were seen 153 days after bed rest. A trend was seen for greater activation of the erector spinae and multifidus muscles in the standardized loading task after bed rest. Greater reductions of multifidus and psoas CSA muscle and greater increases in multifidus signal intensity with loading were associated with incidence of low back pain in the first 28 days after bed rest ( P ≤ 0.044). The current study contributes to our understanding of the recovery of the lumbar spine after 21-day bed rest, and the main finding was that a decrease in spinal extensor muscle CSA recovers within 5 mo after bed rest but that changes in the intervertebral discs persist.
Decreased hyperpolarization-activated currents in layer 5 pyramidal neurons enhances excitability in focal cortical dysplasia
Authors: Albertson Asher J. , Yang Jianming , Hablitz John J.
Published: July 2011

Focal cortical dysplasia is associated with the development of seizures in children and is present in up to 40% of intractable childhood epilepsies. Transcortical freeze lesions in newborn rats reproduce many of the anatomical and physiological characteristics of human cortical dysplasia. Rats with freeze lesions have increased seizure susceptibility and a region of hyperexcitable cortex adjacent to the lesion. Since alterations in hyperpolarization-activated nonspecific cation (HCN) channels are often associated with epilepsy, we used whole cell patch-clamp recording and voltage-sensitive dye imaging to examine alterations in HCN channels and inwardly rectifying hyperpolarization-activated currents ( Ih) in cortical dysplasia. (L5) pyramidal neurons in lesioned animals had hyperpolarized resting membrane potentials, increased input resistances and reduced voltage “sag” associated with Ihactivation. These differences became nonsignificant after application of the Ihblocker ZD7288. Temporal excitatory postsynaptic potential (EPSP) summation and intrinsic excitability were increased in neurons near the freeze lesion. Using voltage-sensitive dye imaging of neocortical slices, we found that inhibiting Ihwith ZD7288 increased the half-width of dye signals. The anticonvulsant lamotrigine produced a significant decrease in spread of activity. The ability of lamotrigine to decrease network activity was reduced in the hyperexcitable cortex near the freeze lesion. These results suggest that Ihserves to constrain network activity in addition to its role in regulating cellular excitability. Reduced Ihmay contribute to increased network excitability in cortical dysplasia.
A history of low back pain associates with altered electromyographic activation patterns in response to perturbations of standing balance
Authors: Jacobs Jesse V. , Henry Sharon M. , Jones Stephanie L. , Hitt Juvena R. , Bunn Janice Y.
Published: July 2011

People with a history of low back pain (LBP) exhibit altered responses to postural perturbations, and the central neural control underlying these changes in postural responses remains unclear. To characterize more thoroughly the change in muscle activation patterns of people with LBP in response to a perturbation of standing balance, and to gain insight into the influence of early- vs. late-phase postural responses (differentiated by estimates of voluntary reaction times), this study evaluated the intermuscular patterns of electromyographic (EMG) activations from 24 people with and 21 people without a history of chronic, recurrent LBP in response to 12 directions of support surface translations. Two-factor general linear models examined differences between the 2 subject groups and 12 recorded muscles of the trunk and lower leg in the percentage of trials with bursts of EMG activation as well as the amplitudes of integrated EMG activation for each perturbation direction. The subjects with LBP exhibited 1) higher baseline EMG amplitudes of the erector spinae muscles before perturbation onset, 2) fewer early-phase activations at the internal oblique and gastrocnemius muscles, 3) fewer late-phase activations at the erector spinae, internal and external oblique, rectus abdominae, and tibialis anterior muscles, and 4) higher EMG amplitudes of the gastrocnemius muscle following the perturbation. The results indicate that a history of LBP associates with higher baseline muscle activation and that EMG responses are modulated from this activated state, rather than exhibiting acute burst activity from a quiescent state, perhaps to circumvent trunk displacements.
Inhibition to excitation ratio regulates visual system responses and behavior in vivo
Authors: Shen Wanhua , McKeown Caroline R. , Demas James A. , Cline Hollis T.
Published: July 2011

The balance of inhibitory to excitatory (I/E) synaptic inputs is thought to control information processing and behavioral output of the central nervous system. We sought to test the effects of the decreased or increased I/E ratio on visual circuit function and visually guided behavior in Xenopus tadpoles. We selectively decreased inhibitory synaptic transmission in optic tectal neurons by knocking down the γ2 subunit of the GABAAreceptors (GABAAR) using antisense morpholino oligonucleotides or by expressing a peptide corresponding to an intracellular loop of the γ2 subunit, called ICL, which interferes with anchoring GABAAR at synapses. Recordings of miniature inhibitory postsynaptic currents (mIPSCs) and miniature excitatory PSCs (mEPSCs) showed that these treatments decreased the frequency of mIPSCs compared with control tectal neurons without affecting mEPSC frequency, resulting in an ∼50% decrease in the ratio of I/E synaptic input. ICL expression and γ2-subunit knockdown also decreased the ratio of optic nerve-evoked synaptic I/E responses. We recorded visually evoked responses from optic tectal neurons, in which the synaptic I/E ratio was decreased. Decreasing the synaptic I/E ratio in tectal neurons increased the variance of first spike latency in response to full-field visual stimulation, increased recurrent activity in the tectal circuit, enlarged spatial receptive fields, and lengthened the temporal integration window. We used the benzodiazepine, diazepam (DZ), to increase inhibitory synaptic activity. DZ increased optic nerve-evoked inhibitory transmission but did not affect evoked excitatory currents, resulting in an increase in the I/E ratio of ∼30%. Increasing the I/E ratio with DZ decreased the variance of first spike latency, decreased spatial receptive field size, and lengthened temporal receptive fields. Sequential recordings of spikes and excitatory and inhibitory synaptic inputs to the same visual stimuli demonstrated that decreasing or increasing the I/E ratio disrupted input/output relations. We assessed the effect of an altered I/E ratio on a visually guided behavior that requires the optic tectum. Increasing and decreasing I/E in tectal neurons blocked the tectally mediated visual avoidance behavior. Because ICL expression, γ2-subunit knockdown, and DZ did not directly affect excitatory synaptic transmission, we interpret the results of our study as evidence that partially decreasing or increasing the ratio of I/E disrupts several measures of visual system information processing and visually guided behavior in an intact vertebrate.
Multiple T-type Ca2+ current subtypes in electrophysiologically characterized hamster dorsal horn neurons: possible role in spinal sensory integration
Authors: Ku Wen-hsin , Schneider Stephen P.
Published: July 2011

Whole cell patch-clamp recordings were used to investigate the contribution of transient, low-threshold calcium currents ( IT) to firing properties of hamster spinal dorsal horn neurons. IT was widely, though not uniformly, expressed by cells in Rexed's laminae I–IV and correlated with the pattern of action potential discharge evoked under current-clamp conditions: IT in neurons responding to constant membrane depolarization with one or two action potentials was nearly threefold larger than IT in cells responding to the same activation with continuous firing. IT was evoked by depolarizing voltage ramps exceeding 46 mV/s and increased with ramp slope (240–2,400 mV/s). Bath application of 200 μM Ni2+ depressed ramp-activated IT. Phasic firing recorded in current clamp could only be activated by membrane depolarizations exceeding ∼43–46 mV/s and was blocked by Ni2+ and mibefradil, suggesting IT as an underlying mechanism. Two components of IT, “fast” and “slow,” were isolated based on a difference in time constant of inactivation (12 ms and 177 ms, respectively). The amplitude of the fast subtype depended on the slope of membrane depolarization and was twice as great in burst-firing cells than in cells having a tonic discharge. Post hoc single-cell RT-PCR analyses suggested that the fast component is associated with the CaV3.1 channel subtype. IT may enhance responses of phasic-firing dorsal horn neurons to rapid membrane depolarizations and contribute to an ability to discriminate between afferent sensory inputs that encode high- and low-frequency stimulus information.
On a Difference Equation with Exponentially Decreasing Nonlinearity
Authors: Braverman E. , Saker S. H.
Published: July 2011

We establish a necessary and sufficient condition for global stability
of the nonlinear discrete red blood cells survival model and demonstrate that local asymptotic
stability implies global stability. Oscillation and solution bounds are investigated. We also show
that, for different values of the parameters, the solution exhibits some time‐varying dynamics, that is,
if the system is moved in a direction away from stability (by increasing the parameters), then
it undergoes a series of bifurcations that leads to increasingly long periodic cycles and finally to
deterministic chaos. We also study the chaotic behavior of the model with a constant positive
perturbation and prove that, for large enough values of one of the parameters, the perturbed system
is again stable.
Optimization of Molecularly Imprinted Polymer Method for Rapid Screening of 17β-Estradiol in Water by Fluorescence Quenching
Authors: Yang Yu , Lai Edward P. C.
Published: July 2011

A new method was optimized for rapid screening of 17β-estradiol (E2) in water under 10 min. Molecularly imprinted polymer (MIP) particles (325 ± 25 nm) were added in a water sample at pH 5.5 and 20∘C to form a suspension. Fluorescence emission from E2 nonspecifically bound onto the MIP particles was first quenched by large gold nanoparticles (43 ± 5 nm). The Stern-Volmer plot was linear, with dynamic quenching constants (Ksv) of 2.9 ×104 M-1. Fluorescence emission from E2 specifically bound inside the MIP particles was next quenched by small nitrite anions that easily penetrated the imprinted cavities. The Stern-Volmer plot became nonlinear, withKsv= 2.1 × 102 M-1and static quenching constant (V) below 1.0 M-1. The difference between these two emission intensities varied as the initial E2 concentration in water, generating a Scatchard calibration curve withR2>0.97from 0.1 to 10 ppb.
Utility of Quantitative 99mTc-MAA SPECT/CT for 90yttrium-Labelled Microsphere Treatment Planning: Calculating Vascularized Hepatic Volume and Dosimetric Approach
Authors: Garin Etienne , Rolland Yan , Lenoir Laurence , Pracht Marc , Mesbah Habiba , Porée Philippe , Laffont Sophie , Clement Bruno , Raoul Jean-Luc , Boucher Eveline
Published: July 2011

Objectives. The
aim of this study was to assess the
effectiveness of SPECT/CT for volume
measurements and to report a case illustrating
the major impact of SPECT/CT in calculating the
vascularized liver volume and dosimetry prior to
injecting radiolabelled yttrium-90 microspheres
(Therasphere). Materials and
Methods. This was a phantom study,
involving volume measurements carried out by two
operators using SPECT and SPECT/CT images. The
percentage of error for each method was
calculated, and interobserver reproducibility
was evaluated. A treatment using
Therasphere was planned in a patient
with three hepatic arteries, and the
quantitative analysis of SPECT/CT for this
patient is provided. Results.
SPECT/CT volume measurements proved to be
accurate (mean error <6% for volumes
≥16 cm3) and
reproductive (interobserver agreement = 0.9). In the case report, 99mTc-MAA SPECT/CT identified a large liver volume, not
previously identified with angiography, which was shown to be
vascularized after selective MAA injection into an arterial
branch, resulting in a large modification in the activity of
Therasphere used. Conclusions. MAA
SPECT/CT is accurate for vascularized liver volume measurements,
providing a valuable contribution to the therapeutic planning of
patients with complex hepatic vascularization.
Approximation of Fixed Points of Weak Bregman Relatively Nonexpansive Mappings in Banach Spaces
Authors: Chen Jiawei , Wan Zhongping , Yuan Liuyang , Zheng Yue
Published: July 2011

We introduce a concept of weak Bregman relatively nonexpansive mapping which is distinct from Bregman relatively nonexpansive mapping. By using projection techniques, we construct several modification of Mann type iterative algorithms with errors and Halpern‐type iterative algorithms with errors to find fixed points of weak Bregman relatively nonexpansive mappings and Bregman relatively nonexpansive mappings in Banach spaces. The strong convergence theorems for weak Bregman relatively nonexpansive mappings and Bregman relatively nonexpansive mappings are derived under some suitable assumptions. The main results in this paper develop, extend, and improve the corresponding results of Matsushita and Takahashi (2005) and Qin and Su (2007).
Evolution of Genome Size in Duckweeds (Lemnaceae)
Authors: Wang Wenqin , Kerstetter Randall A. , Michael Todd P.
Published: July 2011

To extensively estimate the DNA content and to provide a basic reference for duckweed genome sequence research, the nuclear DNA content for 115 different accessions of 23 duckweed species was measured by flow cytometry (FCM) stained with propidium iodide as DNA stain. The 1C-value of DNA content in duckweed family varied nearly thirteen-fold, ranging from 150 megabases (Mbp) in Spirodela polyrhiza to 1,881 Mbp in Wolffia arrhiza. There is a continuous increase of DNA content in Spirodela, Landoltia, Lemna, Wolffiella, and Wolffia that parallels a morphological reduction in size. There is a significant intraspecific variation in the genus Lemna. However, no such variation was found in other studied species with multiple accessions of genera Spirodela, Landoltia, Wolffiella, and Wolffia.
New Thermoelectric Sensor Adapted to Realize an Infrared Radiations Detector
Authors: Rahmoun Mohammed , Hachami Khalid , Touil Abdelwahad , Bellach Benaissa , Bailich Mohammed , Merdani Ammar
Published: July 2011

The present paper deals with the design and the realization of a new thermoelectric sensor (Seebeck), sensitive to the infrared radiations emitted by different sources. The function mechanism utilizes radiative absorption phenomena, heat transfer, and thermoelectric effects. The sensor includes two printed circuits, the first is a planar thermoelectric circuit constituted of many plated differential thermocouples, and the second is constituted of a resistive constantan track and placed at the top of the first circuit so that the constantan track is placed on the top of the even thermocouple junctions. The constantan track, covered with a resin of great absorptivity, collects the infra-red radiations and generates temperature gradients between the junction points of the first circuit. Then the resulting temperature differences between the junction points are directly converted into a proportional Seebeck voltage. As an application, the sensor is adapted in order to realize a device for detecting infrared radiations, and the results are very encouraging.
Aspergillus fumigatusin Poultry
Authors: Arné Pascal , Thierry Simon , Wang Dongying , Deville Manjula , Le Loc'h Guillaume , Desoutter Anaïs , Féménia Françoise , Nieguitsila Adélaïde , Huang Weiyi , Chermette René , Guillot Jacques
Published: July 2011

Aspergillus fumigatusremains a major respiratory pathogen in birds. In poultry, infection byA. fumigatusmay induce significant economic losses particularly in turkey production.A. fumigatusdevelops and sporulates easily in poor quality bedding or contaminated feedstuffs in indoor farm environments. Inadequate ventilation and dusty conditions increase the risk of bird exposure to aerosolized spores. Acute cases are seen in young animals following inhalation of spores, causing high morbidity and mortality. The chronic form affects older birds and looks more sporadic. The respiratory tract is the primary site ofA. fumigatusdevelopment leading to severe respiratory distress and associated granulomatous airsacculitis and pneumonia. Treatments for infected poultry are nonexistent; therefore, prevention is the only way to protect poultry. Development of avian models of aspergillosis may improve our understanding of its pathogenesis, which remains poorly understood.
Representing Images' Meanings by Associative Values with Given Lexicons Considering the Semantic Tolerance Relation
Authors: Dai Ying
Published: July 2011

An approach of representing meanings of images based on associative values with lexicons is proposed. For this, the semantic tolerance relation model (STRM) that reflects the tolerance degree between defined lexicons is generated, and two factors of semantic relevance (SR) and visual similarity (VS) are involved in generating associative values. Furthermore, the algorithm of calculating associative values using pixel-based bidirectional associative memories (BAMs) in combination with the STRM, which is easy in implementation, is depicted. The experiment results of multilexicons-based retrieval by individuals show the effectiveness and efficiency of our proposed method in finding the expected images and the improvement in retrieving accuracy because of incorporating SR with VS in representing meanings of images.
Piperidine-Substituted Perylene Sensitizer for Dye-Sensitized Solar Cells
Authors: Otsuki Joe , Takaguchi Yusho , Takahashi Daichi , Kalimuthu Palanisamy , Singh Surya Prakash , Islam Ashraful , Han Liyuan
Published: July 2011

We have prepared a novel piperidine-donor-substituted perylene sensitizer, PK0002, and studied the photovoltaic performance in dye-sensitized solar cells (DSSCs). Physical properties and photovoltaic performance of this new perylene derivative PK0002 are reported and compared with those of unsubstituted perylene sensitizer, PK0003. PK0002, when anchored to nanocrystalline TiO2 films, achieves very efficient sensitization across the whole visible range extending up to 800 nm. The incident photon-to-current conversion efficiency (IPCE) spectrum was consistent with the absorption spectrum and resulted in a high short-circuit photocurrent density (Jsc) of 8.8 mA cm-2. PK0002 showed higher IPCE values than PK0003 in the 520–800 nm region. Under standard AM 1.5 irradiation (100 mW cm-2) and using an electrolyte consisting of 0.6 M dimethylpropyl-imidazolium iodide, 0.05 M I2, 0.1 M LiI, and 0.5 M tert-butylpyridine in acetonitrile, a solar cell containing sensitizer PK0002 yielded a short-circuit photocurrent density of 7.7 mA cm-2, an open-circuit photovoltage of 0.57 V, and a fill factor of 0.70, corresponding to an overall conversion efficiency of 3.1%.
Self-Assemblies of Single-Walled Carbon Nanotubes through Tunable Tethering of Pyrenes by Dextrin for Rapidly Chiral Sensing
Authors: Wei Wei-Li , Chen Qiushui , Li Haifang , Lin Jin-Ming
Published: July 2011

Pyrene-modified dextrin (Py-Dex) was synthesized via the Schiff base reaction between reducing end of dextrins and 1-aminopyrene, and then self-assemblies of single-walled carbon nanotubes (SWNTs) were fabricated through the tunable tethering of pyrene to SWNTs by dextrin chains. The Py-Dex-SWNTs assemblies were found to be significantly water-soluble because of the synergistic effect of dextrin chains and pyrene moieties. Py-Dex and Py-Dex-SWNTs were adequately characterized by NMR, UV-vis, fluorescence spectroscopy, Raman spectroscopy, matrix-assisted laser desorption/ionization-time of flight mass spectroscopy, and transmission electron microscopy. The tethering effect of dextrin toward pyrene moieties was clearly revealed and was found to be tunable by adjusting the length of dextrin chains. The fluorescence of pyrene moieties was sufficiently quenched by SWNTs with the support of dextrin chains. Furthermore, the Py-Dex-SWNTs assemblies were used for chiral selective sensing by introducing cyclodextrins as chiral binding sites. The rapid chiral sensing was successfully tested for different enantiomers.
Oviposition and Embryotoxicity ofIndigofera suffruticosaon Early Development ofAedes aegypti(Diptera: Culicidae)
Authors: Vieira Jeymesson Raphael Cardoso , Leite Roberta Maria Pereira , Lima Izabela Rangel , Navarro Daniela do Amaral Ferraz , Bianco Everson Miguel , Leite Sônia Pereira
Published: July 2011

Aqueous extract ofIndigofera suffruticosaleaves obtained by infusion was used to evaluate the oviposition, its effect on development of eggs and larvae, and morphological changes in larvae ofAedes aegypti. The bioassays were carried out with aqueous extract in different concentrations on eggs, larvae, and female mosquitoes, and the morphological changes were observed in midgut of larvae. The extract showed repellent activity onA. aegyptimosquitoes, reducing significantly the egg laying by females with control substrate (343 (185–406)) compared with the treated substrate (88 (13–210)). No eclosion ofA. aegyptieggs at different concentrations studied was observed. The controleclodedin 35%. At concentration of 250 μg/mL, 93.3% of larvae remained in the second instar of development and at concentrations of 500, 750, and 1000 μg/mL the inhibitory effect was lower with percentages of 20%, 53.3%, and 46.6%, respectively. Morphological changes like disruption on the peritrophic envelope (PE), discontinued underlying epithelium, increased gut lumen, and segments with hypertrophic aspects were observed in anterior region of medium midgut of larvae ofA. aegypti. The results showed repellent activity, specific embryotoxicity, and general growth retardation inA. aegyptiby medium containing aqueous extract ofI. suffruticosaleaves.
Biological Roles of the Delta Family Notch Ligand Dll4 in Tumor and Endothelial Cells in Ovarian Cancer
Authors: Hu Wei , Lu Chunhua , Dong Han Hee , Huang Jie , Shen De-yu , Stone Rebecca L. , Nick Alpa M. , Shahzad Mian M.K. , Mora Edna , Jennings Nicholas B. , Lee Sun Joo , Roh Ju-Won , Matsuo Koji , Nishimura Masato , Goodman Blake W. , Jaffe Robert B. , Langley Robert R. , Deavers Michael T. , Lopez-Berestein Gabriel , Coleman Robert L. , Sood Anil K.
Published: July 2011

Emerging evidence suggests that the Notch/Delta-like ligand 4 (Dll4) pathway may offer important new targets for antiangiogenesis approaches. In this study, we investigated the clinical and biological significance of Dll4 in ovarian cancer. Dll4 was overexpressed in 72% of tumors examined in which it was an independent predictor of poor survival. Patients with tumors responding to anti-VEGF therapy had lower levels of Dll4 than patients with stable or progressive disease. Under hypoxic conditions, VEGF increased Dll4 expression in the tumor vasculature. Immobilized Dll4 also downregulated VEGFR2 expression in endothelial cells directly through methylation of the VEGFR2 promoter. RNAi-mediated silencing of Dll4 in ovarian tumor cells and tumor-associated endothelial cells inhibited cell growth and angiogenesis, accompanied by induction of hypoxia in the tumor microenvironment. Combining Dll4-targeted siRNA with bevacizumab resulted in greater inhibition of tumor growth, compared with control or treatment with bevacizumab alone. Together, our findings establish that Dll4 plays a functionally important role in both the tumor and endothelial compartments of ovarian cancer and that targeting Dll4 in combination with anti-VEGF treatment might improve outcomes of ovarian cancer treatment. Cancer Res; 71(18); 6030–9. ©2011 AACR.
Phase I Study of PARP Inhibitor ABT-888 in Combination with Topotecan in Adults with Refractory Solid Tumors and Lymphomas
Authors: Kummar Shivaani , Chen Alice , Ji Jiuping , Zhang Yiping , Reid Joel M. , Ames Matthew , Jia Lee , Weil Marcie , Speranza Giovanna , Murgo Anthony J. , Kinders Robert , Wang Lihua , Parchment Ralph E. , Carter John , Stotler Howard , Rubinstein Larry , Hollingshead Melinda , Melillo Giovanni , Pommier Yves , Bonner William , Tomaszewski Joseph E. , Doroshow James H.
Published: July 2011

A phase I trial of ABT-888 (veliparib), a PARP inhibitor, in combination with topotecan, a topoisomerase I–targeted agent, was carried out to determine maximum tolerated dose (MTD), safety, pharmacokinetics, and pharmacodynamics of the combination in patients with refractory solid tumors and lymphomas. Varying schedules and doses of intravenous topotecan in combination with ABT-888 (10 mg) administered orally twice a day (BID) were evaluated. Plasma and urine pharmacokinetics were assessed and levels of poly(ADP-ribose) (PAR) and the DNA damage marker γH2AX were measured in tumor and peripheral blood mononuclear cells (PBMC). Twenty-four patients were enrolled. Significant myelosuppression limited the ability to coadminister ABT-888 with standard doses of topotecan, necessitating dose reductions. Preclinical studies using athymic mice carrying human tumor xenografts also informed schedule changes. The MTD was established as topotecan 0.6 mg/m2/d and ABT-888 10 mg BID on days one to five of 21-day cycles. Topotecan did not alter the pharmacokinetics of ABT-888. A more than 75% reduction in PAR levels was observed in 3 paired tumor biopsy samples; a greater than 50% reduction was observed in PBMCs from 19 of 23 patients with measurable levels. Increases in γH2AX response in circulating tumor cells (CTC) and PBMCs were observed in patients receiving ABT-888 with topotecan. We show a mechanistic interaction of a PARP inhibitor, ABT-888, with a topoisomerase I inhibitor, topotecan, in PBMCs, tumor, and CTCs. Results of this trial reveal that PARP inhibition can modulate the capacity to repair topoisomerase I–mediated DNA damage in the clinic. Cancer Res; 71(17); 5626–34. ©2011 AACR.