bluuebunny/crossref_metadata_2025 huggingface dataset:
A SYSTEMS BIOLOGY APPROACH TO THE STUDY OF CISPLATIN DRUG RESISTANCE IN OVARIAN CANCERS
Authors: CHEN JAKE Y. , YAN ZHONG , SHEN CHANGYU , FITZPATRICK DAWN P. G. , WANG MU
Published: June 2007

Cisplatin-induced drug resistance is known to involve a complex set of cellular changes whose molecular mechanism details remain unclear. In this study, we developed a systems biology approach to examine proteomics- and network-level changes between cisplatin-resistant and cisplatin-sensitive cell lines. This approach involves experimental investigation of differential proteomics profiles and computational study of activated enriched proteins, protein interactions, and protein interaction networks. Our experimental platform is based on a Label-free liquid Chromatography/mass spectrometry proteomics platform. Our computational methods start with an initial list of 119 differentially expressed proteins. We expanded these proteins into a cisplatin-resistant activated sub-network using a database of human protein-protein interactions. An examination of network topology features revealed the activated responses in the network are closely coupled. By examining sub-network proteins using gene ontology categories, we found significant enrichment of proton-transporting ATPase and ATP synthase complexes activities in cisplatin-resistant cells in the form of cooperative down-regulations. Using two-dimensional visualization matrixes, we further found significant cascading of endogenous, abiotic, and stress-related signals. Using a visual representation of activated protein categorical sub-networks, we showed that molecular regulation of cell differentiation and development caused by responses to proteome-wide stress as a key signature to the acquired drug resistance.
ENVIRONMENTAL PERCEPTION OF MOBILE ROBOT BASED ON MULTI-SENSORS' DATA FUSION
Authors: GUO LANSHEN , ZHANG MINGLU , SUN LIXIN
Published: June 2007

We have built up a system to apperceive unknown environment based on multi-sensors' data fusion, which enabled the self-determinative mobile robot recognize timely the type of obstacles around it in the course of travel, and the mobile robot would be provided with more intelligent operations. Firstly, the paper introduced the theory of environmental perception for mobile robot and the configuration of the multi-sensors' data fusion technology. Secondly, combining with the characteristics of neural network (NN) and aiming at the shortages of the former solving projects, it was brought forward that the MLP (Multi-layer perceptron) based on the improved back propagation (BP) arithmetic and four mature items of fusion rules, which were applied to apperceive the real surroundings. Thirdly, the paper presents a kind of structure of multi-sensor information data fusion. Two sub-networks for barrier recognition are separately built and incorporated with each other to form a high-powered recognition system by parallel connection.
ADAPTIVE KERNEL DISCRIMINANT ANALYSIS AND ITS APPLICATIONS ON PATTERN RECOGNITION
Authors: LI JUN-BAO , PAN JENG-SHYANG
Published: June 2007

In pattern recognition, feature extraction techniques are widely employed to reduce the dimensionality of data and to enhance the discriminatory information. In this paper, we present an extension of KFD method based on the data-dependent kernel, called the adaptive kernel discriminant analysis (AKDA), for feature extraction and pattern classification. AKDA is more adaptive to the input data than KDA owing to the optimization of projection from input space to feature space with the data-dependent kernel, which enhances the performance of KDA. Experimental results on ORL, Yale and MNIST database show that the proposed AKDA gives the higher performance than KDA.
THE BOND STRENGTH MEASUREMENT OF SILICON-SILICON BONDING WAFERS BASED ON CRACK OPENING METHOD
Authors: CHEN LIGUO , CHEN TAO , SUN LINING
Published: June 2007

A measurement system based on crack-opening method has been developed to measure the fracture toughness of silicon direct bonding wafers. The theory of crack-opening method was introduced and amended according to the shape of the specimen. The parameters and function required in the measurement of bond energy were mentioned, and the selection principle of thickness of the razor was given. A new experimental device based on IR vision and image processing in the measurement was developed. Finally, a contrast experiment was carried out successfully and the error of the method was analyzed which validated the feasibility and the localization of the method.
Functional characterization of voltage-gated K+ channels in mouse pulmonary artery smooth muscle cells
Authors: Ko Eun A. , Burg Elyssa D. , Platoshyn Oleksandr , Msefya Joseph , Firth Amy L. , Yuan Jason X.-J.
Published: June 2007

Mice are useful animal models to study pathogenic mechanisms involved in pulmonary vascular disease. Altered expression and function of voltage-gated K+ (KV) channels in pulmonary artery smooth muscle cells (PASMCs) have been implicated in the development of pulmonary arterial hypertension. KV currents ( IK(V)) in mouse PASMCs have not been comprehensively characterized. The main focus of this study was to determine the biophysical and pharmacological properties of IK(V) in freshly dissociated mouse PASMCs with the patch-clamp technique. Three distinct whole cell IK(V) were identified based on the kinetics of activation and inactivation: rapidly activating and noninactivating currents (in 58% of the cells tested), rapidly activating and slowly inactivating currents (23%), and slowly activating and noninactivating currents (17%). Of the cells that demonstrated the rapidly activating noninactivating current, 69% showed IK(V) inhibition with 4-aminopyridine (4-AP), while 31% were unaffected. Whole cell IK(V) were very sensitive to tetraethylammonium (TEA), as 1 mM TEA decreased the current amplitude by 32% while it took 10 mM 4-AP to decrease IK(V) by a similar amount (37%). Contribution of Ca2+-activated K+ (KCa) channels to whole cell IK(V) was minimal, as neither pharmacological inhibition with charybdotoxin or iberiotoxin nor perfusion with Ca2+-free solution had an effect on the whole cell IK(V). Steady-state activation and inactivation curves revealed a window K+ current between −40 and −10 mV with a peak at −31.5 mV. Single-channel recordings revealed large-, intermediate-, and small-amplitude currents, with an averaged slope conductance of 119.4 ± 2.7, 79.8 ± 2.8, 46.0 ± 2.2, and 23.6 ± 0.6 pS, respectively. These studies provide detailed electrophysiological and pharmacological profiles of the native KV currents in mouse PASMCs.
Adenine nucleotide-creatine-phosphate module in myocardial metabolic system explains fast phase of dynamic regulation of oxidative phosphorylation
Authors: van Beek Johannes H. G. M.
Published: June 2007

Computational models of a large metabolic system can be assembled from modules that represent a biological function emerging from interaction of a small subset of molecules. A “skeleton model” is tested here for a module that regulates the first phase of dynamic adaptation of oxidative phosphorylation (OxPhos) to demand in heart muscle cells. The model contains only diffusion, mitochondrial outer membrane (MOM) permeation, and two isoforms of creatine kinase (CK), in cytosol and mitochondrial intermembrane space (IMS), respectively. The communication with two neighboring modules occurs via stimulation of mitochondrial ATP production by ADP and Pi from the IMS and via time-varying cytosolic ATP hydrolysis during contraction. Assuming normal cytosolic diffusion and high MOM permeability for ADP, the response time of OxPhos ( tmito; generalized time constant) to steps in cardiac pacing rate is predicted to be 2.4 s. In contrast, with low MOM permeability, tmito is predicted to be 15 s. An optimized MOM permeability of 21 μm/s gives tmito = 3.7 s, in agreement with experiments on rabbit heart with blocked glycolytic ATP synthesis. The model correctly predicts a lower tmito if CK activity is reduced by 98%. Among others, the following predictions result from the model analysis: 1) CK activity buffers large ADP oscillations; 2) ATP production is pulsatile in beating heart, although it adapts slowly to demand with “time constant” ∼14 heartbeats; 3) if the muscle isoform of CK is overexpressed, OxPhos reacts slower to changing workload; and 4) if mitochondrial CK is overexpressed, OxPhos reacts faster.
Brain-derived neurotrophic factor in the hypothalamic paraventricular nucleus reduces energy intake
Authors: Wang ChuanFeng , Bomberg Eric , Billington Charles , Levine Allen , Kotz Catherine M.
Published: June 2007

Recent studies show that brain-derived neurotrophic factor (BDNF) decreases feeding and body weight after peripheral and ventricular administration. BDNF mRNA and protein, and its receptor tyrosine kinase B (TrkB) are widely distributed in the hypothalamus and other brain regions. However, there are few reports on specific brain sites of actions for BDNF. We evaluated the effect of BDNF in the hypothalamic paraventricular nucleus (PVN) on feeding. BDNF injected unilaterally or bilaterally into the PVN of food-deprived and nondeprived rats significantly decreased feeding and body weight gain within the 0- to 24-h and 24- to 48-h postinjection intervals. Effective doses producing inhibition of feeding behavior did not establish a conditioned taste aversion. PVN BDNF significantly decreased PVN neuropeptide Y (NPY)-induced feeding at 1, 2, and 4 h following injection. BDNF administration in the PVN abolished food-restriction-induced NPY gene expression in the hypothalamic arcuate nucleus. In conclusion, BDNF in the PVN significantly decreases food intake and body weight gain, suggesting that the PVN is an important site of action for BDNF in its effects on energy metabolism. Furthermore, BDNF appears to interact with NPY in its anorectic actions, although a direct effect on NPY remains to be established.
Exercise training increases branched-chain oxoacid dehydrogenase kinase content in human skeletal muscle
Authors: Howarth Krista R. , Burgomaster Kirsten A. , Phillips Stuart M. , Gibala Martin J.
Published: June 2007

The branched-chain oxoacid dehydrogenase complex (BCOAD) is rate determining for the oxidation of branched-chain amino acids (BCAAs) in skeletal muscle. Exercise training blunts the acute exercise-induced activation of BCOAD (BCOADa) in human skeletal muscle (McKenzie S, Phillips SM, Carter SL, Lowther S, Gibala MJ, Tarnopolsky MA. Am J Physiol Endocrinol Metab 278: E580–E587, 2000); however, the mechanism is unknown. We hypothesized that training would increase the muscle protein content of BCOAD kinase, the enzyme responsible for inactivation of BCOAD by phosphorylation. Twenty subjects [23 ± 1 yr; peak oxygen uptake (V̇o2peak) = 41 ± 2 ml·kg−1·min−1] performed 6 wk of either high-intensity interval or continuous moderate-intensity training on a cycle ergometer ( n = 10/group). Before and after training, subjects performed 60 min of cycling at 65% of pretraining V̇o2peak, and needle biopsy samples (vastus lateralis) were obtained before and immediately after exercise. The effect of training was demonstrated by an increased V̇o2peak, increased citrate synthase maximal activity, and reduced muscle glycogenolysis during exercise, with no difference between groups (main effects, P < 0.05). BCOADa was lower after training (main effect, P < 0.05), and this was associated with a ∼30% increase in BCOAD kinase protein content (main effect, P < 0.05). We conclude that the increased protein content of BCOAD kinase may be involved in the mechanism for reduced BCOADa after exercise training in human skeletal muscle. These data also highlight differences in models used to study the regulation of skeletal muscle BCAA metabolism, since exercise training was previously reported to increase BCOADa during exercise and decrease BCOAD kinase content in rats (Fujii H, Shimomura Y, Murakami T, Nakai N, Sato T, Suzuki M, Harris RA. Biochem Mol Biol Int 44: 1211–1216, 1998).
Nephrogenesis and the renal renin-angiotensin system in fetal sheep: effects of intrauterine growth restriction during late gestation
Authors: Zohdi Vladislava , Moritz Karen M. , Bubb Kristen J. , Cock Megan L. , Wreford Nigel , Harding Richard , Black M. Jane
Published: June 2007

Previous studies have shown that intrauterine growth restriction (IUGR) can impair nephrogenesis, but uncertainties remain about the importance of the gestational timing of the insult and the effects on the renal renin-angiotensin system (RAS). We therefore hypothesized that induction of IUGR during late gestation alters the RAS, and this is associated with a decrease in nephron endowment. Our aims were to determine the effects of IUGR induced during the later stages of nephrogenesis on 1) nephron number; 2) mRNA expression of angiotensin AT1 and AT2 receptors, angiotensinogen, and renin genes in the kidney; and 3) the size of maculae densae. IUGR was induced in fetal sheep ( n = 7) by umbilical-placental embolization from 110 to 130 days of the ∼147-day gestation; saline-infused fetuses served as controls ( n = 7). Samples of cortex from the left kidney were frozen, and the right kidney was perfusion fixed. Total kidney volume, nephron number, renal corpuscle volume, total maculae densae volume, and the volume of macula densa per glomerulus were stereologically estimated. mRNA expression of AT1 and AT2 receptors, angiotensinogen, and renin in the renal cortex was determined. In IUGR fetuses at 130 days, body and kidney weights were significantly reduced and nephron number was reduced by 24%. There was no difference in renin, angiotensinogen, or AT1 and AT2 receptor mRNA expression levels in the IUGR kidneys compared with controls. We conclude that fetal growth restriction late in nephrogenesis can lead to a marked reduction in nephron endowment but does not affect renal corpuscle or macula densa size, or renal RAS gene expression.
Protein restriction in lactation confers nephroprotective effects in the male rat and is associated with increased antioxidant expression
Authors: Tarry-Adkins Jane L. , Joles Jaap A. , Chen Jian-Hua , Martin-Gronert Malgorzata S. , van der Giezen Dionne M. , Goldschmeding Roel , Hales C. Nicholas , Ozanne Susan E.
Published: June 2007

Telomere shortening has been implicated in the aging process and various age-associated disorders, including renal disease. Moreover, oxidative stress has been identified as an initiator of accelerated telomere shortening. We have shown previously that maternal protein restriction during lactation leads to reduced renal telomere shortening, reduced albuminuria, and increased longevity in rats. Here we address the hypothesis that maternal protein restriction during lactation is nephroprotective and associated with increased expression of antioxidative enzymes and decreased age-dependent renal telomere shortening. Newborn rats were suckled by a dam fed either a control (20% protein) or low-protein (8% protein) diet. All animals were weaned onto standard chow. Offspring that had been suckled by protein-restricted mothers had reduced albuminuria, N-acetyl-glucosaminidase, and urinary aldosterone excretion. These animals also did not show significant age-dependent renal telomere shortening and hence had significantly longer telomeres at 12 mo of age. This lack of renal telomere shortening was associated with increased levels of the antioxidant enzymes manganese superoxide dismutase, glutathione peroxidase, and glutathione reductase. These findings suggest that beneficial effects of slow growth during lactation are associated with increased antioxidant capacity and prevention of age-dependent telomere shortening in the kidney.
Contribution of AMPA/kainate receptors in the rostral ventrolateral medulla to the hypotensive and sympathoinhibitory effects of clonidine
Authors: Wang Wei-Zhong , Wang Li-Gang , Gao Lie , Wang Wei
Published: June 2007

The depressor and sympathoinhibitory effect of the imidazoline drug clonidine is reported to be associated with functional states of the central glutamate receptors. The rostral ventrolateral medulla (RVLM) has been recognized as a specific target area for mediating the central depressor mechanism of clonidine. The objective of this study was to determine the role of the glutamate receptor subtype α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor within the RVLM in clonidine-induced depressor and sympathoinhibitory action in anesthetized normotensive rats. Unilateral microinjection of 200 pmol of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a potent AMPA/kainate receptor antagonist, into the RVLM completely abolished the pressor action evoked by AMPA (5 pmol) without affecting the pressor action of N-methyl-d-aspartate (20 pmol). Pretreatment with intra-RVLM injection of CNQX (20 and 200 pmol) dose dependently attenuated the reduction in blood pressure (BP), heart rate (HR), and renal sympathetic nerve activity (RSNA) elicited by intra-RVLM clonidine (5 nmol) or intravenous clonidine (10 μg/kg), while 2 pmol of CNQX did not alter clonidine-induced cardiovascular action. Furthermore, the decreases in BP, HR, and RSNA evoked by intravenous clonidine (10 μg/kg) or intra-RVLM clonidine (5 nmol) were reversed when CNQX (20 and 200 pmol) was subsequently injected into the RVLM. In conclusion, these data show that blockade of AMPA/kainate receptors in the RVLM significantly antagonizes decreases in BP, HR, and sympathetic activity induced by clonidine, suggesting that the AMPA/kainate receptors within the RVLM contribute to the depressor and sympathoinhibitory effect of clonidine.
The GLP-1 agonist exendin-4 reduces food intake in nonhuman primates through changes in meal size
Authors: Scott Karen A. , Moran Timothy H.
Published: June 2007

Exendin-4 (Ex4), a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist, has been shown to reduce food intake and suppress gastric emptying in rodents and humans. In this study we investigated the effects of peripheral administration of Ex4 on food intake and meal patterns in adult male rhesus macaques. Rhesus macaques ( n = 4) that had been trained to lever press for food pellets were injected intramuscularly 15 min before the start of their 6-h daily feeding period. Ex4 was given at doses of 0.10, 0.32, 0.56, 1.0, and 3.0 μg/kg. Ex4 suppressed food intake in a dose-dependent manner, with the 3.0 μg/kg dose completely preventing feeding during the 6-h period and the 0.10 μg/kg dose suppressing intake by 17%. Doses of 0.32, 0.56, 1.0, and 3.0 μg/kg caused significant reductions in cumulative intake at all six hourly time points. Ex4 inhibited food intake through a specific effect on meal size. Meal size was significantly reduced in a dose-dependent manner with significant reductions at the 0.32 and 1.0 μg/kg doses ( P < 0.05). Day 2 and 3intakes returned to baseline levels with no compensation for Ex4-induced feeding suppression. Administration of doses of 0.32 and 0.56 μg/kg Ex4 over 5 consecutive days led to sustained reductions in intake with no evidence of compensation. Again, these reductions were due to specific effects on meal size. These results demonstrate that activation of GLP-1 pathways has potent effects on the controls of meal size and overall food intake in a nonhuman primate model.
Greater uterine artery blood flow during pregnancy in multigenerational (Andean) than shorter-term (European) high-altitude residents
Authors: Wilson Megan J. , Lopez Miriam , Vargas Marco , Julian Colleen , Tellez Wilma , Rodriguez Armando , Bigham Abigail , Armaza J. Fernando , Niermeyer Susan , Shriver Mark , Vargas Enrique , Moore Lorna G.
Published: June 2007

Multigenerational (Andean) compared with shorter-term (European) high-altitude residents exhibit less hypoxia-associated reductions in birth weight. Because differences in arterial O2content are not responsible, we asked whether greater pregnancy-associated increases in uterine artery (UA) blood flow and O2delivery were involved. Serial studies were conducted in 42 Andean and 26 European residents of La Paz, Bolivia (3600 m) at weeks 20, 30, 36 of pregnancy and 4 mo postpartum using Doppler ultrasound. There were no differences postpartum but Andean vs. European women had greater UA diameter (0.65 ± 0.01 vs. 0.56 ± 0.01 cm), cross-sectional area (33.1 ± 0.97 vs. 24.7 ± 1.18 mm2), and blood flow at week 36 (743 ± 87 vs. 474 ± 36 ml/min) (all P < 0.05) and thus 1.6-fold greater uteroplacental O2delivery near term (126.82 ± 18.47 vs. 80.33 ± 8.69 ml O2·ml blood−1·min−1, P < 0.05). Andeans had greater common iliac (CI) flow and lower external iliac relative to CI flow (0.52 ± 0.11 vs. 0.95 ± 0.14, P < 0.05) than Europeans at week 36. After adjusting for gestational age, maternal height, and parity, Andean babies weighed 209 g more than the Europeans. Greater UA cross-sectional area at week 30 related positively to birth weight in Andeans ( r = +0.39) but negatively in Europeans ( r = −0.37) (both P < 0.01). We concluded that a greater pregnancy-associated increase in UA diameter raised UA blood flow and uteroplacental O2delivery in the Andeans and contributed to their ability to maintain normal fetal growth under conditions of high-altitude hypoxia. These data implicate the involvement of genetic factors in protecting multigenerational populations from hypoxia-associated reductions in fetal growth, but future studies are required for confirmation and identification of the specific genes involved.
Interleukin-6 stimulates α-MG uptake in renal proximal tubule cells: involvement of STAT3, PI3K/Akt, MAPKs, and NF-κB
Authors: Lee Yu Jin , Heo Jung Sun , Suh Han Na , Lee Min Young , Han Ho Jae
Published: June 2007

Recent studies have shown that interleukin 6 (IL-6) acts on the cellular proliferation-activating transduction signals during cellular regeneration. Therefore, this study examined the effect of IL-6 on the activation of Na+/glucose cotransporters (SGLTs) and its related signaling pathways in primary cultured renal proximal tubule cells (PTCs). IL-6 increased the level of α-methyl-d-[14C]glucopyranoside (α-MG) uptake in time- and dose-dependent manners. IL-6 also increased SGLT1 plus SGLT2 mRNA and protein expression level. The IL-6 receptors (IL-6Rα and gp130) were expressed in PTCs. In addition, genistein and herbimycin A completely blocked the IL-6-induced increases in α-MG uptake and the protein expression level of SGLTs. On the other hand, IL-6 increased the level of 5-(and-6)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate-sensitive cellular reactive oxygen species (ROS), and IL-6-induced increases in α-MG uptake and the protein expression level of SGLTs were blocked by ascorbic acid or taurine (antioxidants). IL-6 also increased the phosphorylation of signal transducer and activator of transcription-3 (STAT3), phosphoinositide-3 kinase (PI3K)/Akt, and mitogen-activated protein kinases (MAPKs) in a time-dependent manner. A pretreatment with STAT3 inhibitor LY 294002, an Akt inhibitor, or MAPK inhibitors significantly blocked the IL-6-induced increase in α-MG uptake. In addition, IL-6 increased the level of nuclear factor-κB (NF-κB) phosphorylation. A pretreatment with SN50 or BAY 11-7082 also blocked the IL-6-induced increase in α-MG uptake. In conclusion, IL-6 increases the SGLT activity through ROS, and its action in renal PTCs is associated with the STAT3, PI3K/Akt, MAPKs, and NF-κB signaling pathways.
Characterization of Na+/H+exchanger NHE8 in cultured renal epithelial cells
Authors: Zhang Jianning , Bobulescu Ion Alexandru , Goyal Sunita , Aronson Peter S. , Baum Michel G. , Moe Orson W.
Published: June 2007

NHE8 is expressed in the apical membrane of the proximal tubule and is predicted to be a Na+/H+exchanger on the basis of its primary amino acid sequence. Functional characterization of native NHE8 in mammalian cells has not been possible to date. We screened a number of polarized renal cell lines for the plasma membrane Na+/H+exchangers (NHE1, 2, 3, 4, and 8) and found only NHE1 and NHE8 transcripts in NRK cells by RT-PCR. NHE8 protein is expressed in the apical membrane of NRK cells as demonstrated by immunoblots, confocal fluorescent immunocytochemistry, and immunoelectron microscopy. NHE1, on the other hand, is expressed primarily in the basolateral membrane. Bilateral perfusion of NRK cells grown on permeable supports shows Na+/H+exchange activity on both the apical and basolateral membranes. NHE8-specific small interfering RNA knocks down NHE8 protein expression but does not affect NHE1 protein levels. Knockdown of NHE8 protein is accompanied by a commensurate reduction in apical NHE activity, without altered basolateral NHE activity. Conversely, transfection of NHE1-specific small interfering RNA knocks down NHE1 protein expression without affecting NHE8 protein levels and reduces basolateral NHE activity without affecting apical NHE activity. NHE8 is the only apical membrane Na+/H+exchanger in NRK cells. NHE8 activity is Na+dependent, displaying a cooperative sigmoidal relationship, and is highly sensitive to 5-( N-ethyl- n-isopropyl)-amiloride (EIPA). NRK cells provide a useful system where NHE8 can be studied in its native environment.
Relationship between circadian blood pressure variation and circadian protein excretion in CKD
Authors: Agarwal Rajiv
Published: June 2007

Circadian blood pressure changes are blunted in patients with chronic kidney disease (CKD). Proteinuria is the most important correlate of hypertension in CKD. However, little is known about the influence of circadian blood pressure changes and variation in protein excretion rate. Furthermore, the impact of blood pressure components, e.g., mean arterial pressure and pulse pressure, on proteinuria has not been evaluated. To analyze the relationship of circadian changes in blood pressure on urinary protein excretion patterns, glomerular filtration rate was measured with iothalamate clearance and 24-h ambulatory blood pressure with SpaceLabs 90207 monitor in 22 patients with CKD. It was found that hourly protein excretion rates were 31% higher during the night. Excretion results of sodium, potassium, chloride, urea, and creatinine were also between 30 and 40% higher at night. Systolic, mean arterial, and pulse pressures but not diastolic pressure were related to daytime protein excretion rate. At night, the relationship of systolic, diastolic, and mean arterial pressures was significantly lower and essentially flat with respect to protein excretion rate, but the relationship of pulse pressure and proteinuria was not different from that seen during the day. Circadian variation in blood pressure did not impact circadian sodium excretion rate. In conclusion, these data suggest that patients with CKD have patterns of proteinuria that share different relationships with blood pressure components depending on the awake-sleep state. Pulse pressure is related to proteinuria independent of the awake-sleep state. Reducing mean arterial pressure during the day and pulse pressure during the day or night may be effective antiproteinuric strategies.
Do skeletal muscle phenotypic characteristics of Xhosa and Caucasian endurance runners differ when matched for training and racing distances?
Authors: Kohn Tertius A. , Essén-Gustavsson Birgitta , Myburgh Kathryn H.
Published: June 2007

Although East African black athletes dominate endurance running events, it is unknown whether black and white endurance runners with similar racing ability, matched for training, may differ in their skeletal muscle biochemical phenotype. Thirteen Xhosa (XR) and 13 Caucasian (CR) endurance runners were recruited and matched for 10-km performance, average preferred racing distance (PRDA), and training volume. Submaximal and maximal exercise tests were done, and vastus lateralis muscle biopsies were taken. XR were significantly lighter and shorter than CR athletes but had similar maximum oxygen consumption corrected for body weight and peak treadmill speed (PTS). XR had lower plasma lactate concentrations at 80% PTS ( P < 0.05) compared with CR. Also, XR had more type IIA (42.4 ± 9.2 vs. 31.3 ± 11.5%, P < 0.05) and less type I fibers (47.8 ± 10.9 vs. 63.1 ± 13.2%, P < 0.05), although oxidative enzyme activities did not differ. Furthermore, XR compared with CR had higher lactate dehydrogenase (LDH) activity in homogenate muscle samples (383 ± 99 vs. 229 ± 85 μmol·min−1·g dry weight−1, P < 0.05) and in both type IIa ( P < 0.05) and type I ( P = 0.05) single-fiber pools. A marked difference ( P < 0.05) in the composition of LDH isoform content was found between the two groups with XR having higher levels of LDH5-4 isoforms (skeletal muscle isozymes; LDH-M) than CR, which was not accounted for by fiber-type differences alone. These results confirm differences in muscle phenotype and physiological characteristics, particularly associated with high-intensity running.
Cholecystokinin B-Type Receptors Mediate a G-Protein-Dependent Depolarizing Action of Sulphated Cholecystokinin Ocatapeptide (CCK-8s) on Rodent Neonatal Spinal Ventral Horn Neurons
Authors: Oz Murat , Yang Keun-Hang , Shippenberg Toni S. , Renaud Leo P. , O'Donovan Michael J.
Published: June 2007

Reports of cholecystokinin (CCK) binding and expression of CCK receptors in neonatal rodent spinal cord suggest that CCK may influence neuronal excitability. In patch-clamp recordings from 19/21 ventral horn motoneurons in neonatal (PN 5–12 days) rat spinal cord slices, we noted a slowly rising and prolonged membrane depolarization induced by bath-applied sulfated CCK octapeptide (CCK-8s; 1 μM), blockable by the CCKBreceptor antagonist L-365,260 (1 μM). Responses to nonsulfated CCK-8 or CCK-4 were significantly weaker. Under voltage clamp ( VH−65 mV), 22/24 motoneurons displayed a CCK-8s-induced tetrodotoxin-resistant inward current [peak: −136 ± 28 pA] with a similar time course, mediated via reduction in a potassium conductance. In 29/31 unidentified neurons, CCK-8s induced a significantly smaller inward current (peak: −42.8 ± 5.6 pA), and I-V plots revealed either membrane conductance decrease with net inward current reversal at 101.3 ± 4.4 mV ( n = 16), membrane conductance increase with net current reversing at 36.1 ± 3.8 mV ( n = 4), or parallel shift ( n = 9). Intracellular GTP-γ-S significantly prolonged the effect of CCK-8s ( n = 6), whereas GDP-β-S significantly reduced the CCK-8s response ( n = 6). Peak inward currents were significantly reduced after 5-min perfusion with N-ethylmaleimide. In isolated neonatal mouse spinal cord preparations, CCK-8s (30–300 nM) increased the amplitude and discharge of spontaneous depolarizations recorded from lumbosacral ventral roots. These observations imply functional postsynaptic G-protein-coupled CCKBreceptors are prevalent in neonatal rodent spinal cord.
Increased Thalamocortical Synaptic Response and Decreased Layer IV Innervation in GAP-43 Knockout Mice
Authors: Albright Michael J. , Weston Matthew C. , Inan Melis , Rosenmund Christian , Crair Michael C.
Published: June 2007

The growth-associated protein, GAP-43, is an axonally localized neuronal protein with high expression in the developing brain and in regenerating neurites. Mice that lack GAP-43 (GAP-43−/−) fail to form a whisker-related barrel map. In this study, we use GAP-43−/−mice to examine GAP-43 synaptic function in the context of thalamocortical synapse development and cortical barrel map formation. Examination of thalamocortical synaptic currents in an acute brain slice preparation and in autaptic thalamic neurons reveals that GAP-43−/−synapses have larger α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate receptor (AMPAR)-mediated currents than controls despite similar AMPAR function and normal probability of vesicular release. Interestingly, GAP-43−/−synapses are less sensitive to blockade by a competitive glutamate receptor antagonist, suggesting higher levels of neurotransmitter in the cleft during synaptic transmission. Field excitatory postsynaptic potentials (EPSPs) from GAP-43−/−thalamocortical synapses reveal a reduced fiber response, and anatomical analysis shows reduced thalamic innervation of barrel cortex in GAP-43−/−mice. Despite this fact synaptic responses in the field EPSPs are similar in GAP-43−/−mice and wild-type littermate controls, and the ratio of AMPAR-mediated to N-methyl-d-aspartate receptor (NMDAR)-mediated currents (AMPAR:NMDAR ratio) is larger than normal. This suggests that GAP-43−/−mice form fewer thalamocortical synapses in layer IV because of decreased anatomical innervation of the cortex, but the remaining contacts are individually stronger possibly due to increased neurotransmitter concentration in the synaptic cleft. Together, these results indicate that in addition to its well known role in axonal pathfinding GAP-43 plays a functional role in regulating neurotransmitter release.
Role of the Primate Superior Colliculus in the Control of Head Movements
Authors: Walton Mark M. G. , Bechara Bernard , Gandhi Neeraj J.
Published: June 2007

One important behavioral role for head movements is to assist in the redirection of gaze. However, primates also frequently make head movements that do not involve changes in the line of sight. Virtually nothing is known about the neural basis of these head-only movements. In the present study, single-unit extracellular activity was recorded from the superior colliculus while monkeys performed behavioral tasks that permit the temporal dissociation of gaze shifts and head movements. We sought to determine whether superior colliculus contains neurons that modulate their activity in association with head movements in the absence of gaze shifts and whether classic gaze-related burst neurons also discharge for head-only movements. For 26% of the neurons in our sample, significant changes in average firing rate could be attributed to head-only movements. Most of these increased their firing rate immediately prior to the onset of a head movement and continued to discharge at elevated frequency until the offset of the movement. Others discharged at a tonic rate when the head was stable and decreased their activity, or paused, during head movements. For many putative head cells, average firing rate was found to be predictive of head displacement. Some neurons exhibited significant changes in activity associated with gaze, eye-only, and head-only movements, although none of the gaze-related burst neurons significantly modulated its activity in association with head-only movements. These results suggest the possibility that the superior colliculus plays a role in the control of head movements independent of gaze shifts.
Differential Distribution of Kir4.1 in Spinal Cord Astrocytes Suggests Regional Differences in K+ Homeostasis
Authors: Olsen M. L. , Campbell S. L. , Sontheimer H.
Published: June 2007

Neuronal activity in the spinal cord results in extracellular potassium accumulation that is significantly higher in the dorsal horn than in the ventral horn. This is suggestive of differences in K+ clearance, widely thought to involve diffusional K+ uptake by astrocytes. We previously identified the inward rectifying K+ channel Kir4.1 as the major K+ conductance in spinal cord astrocytes in situ and hence hypothesized that different expression levels of Kir4.1 may account for the observed differences in potassium dynamics in spinal cord. Our results with immunohistochemical staining demonstrated highest Kir4.1 channel expression in the ventral horn and very low levels of Kir4.1 in the apex of the dorsal horn. Western blots from tissue of these two regions similarly confirmed much lower levels of Kir4.1 in the apex of the dorsal horn. Whole cell patch-clamp recordings from astrocytes in rat spinal cord slices also showed a difference in inwardly rectifying currents in these two regions. However, no statistical difference in either fast-inactivating (Ka) or delayed rectifying potassium currents (Kd) was observed, suggesting these differences were specific to Kir currents. Importantly, when astrocytes in each region were challenged with high [K+]o, astrocytes from the dorsal horn showed significantly smaller (60%) K+ uptake currents than astrocytes from the ventral horn. Taken together, these data support the conclusion that regional differences in astrocytic expression of Kir4.1 channels result in marked changes in potassium clearance rates in these two regions of the spinal cord.
Reference Frames for Reach Planning in Macaque Dorsal Premotor Cortex
Authors: Batista Aaron P. , Santhanam Gopal , Yu Byron M. , Ryu Stephen I. , Afshar Afsheen , Shenoy Krishna V.
Published: June 2007

When a human or animal reaches out to grasp an object, the brain rapidly computes a pattern of muscular contractions that can acquire the target. This computation involves a reference frame transformation because the target's position is initially available only in a visual reference frame, yet the required control signal is a set of commands to the musculature. One of the core brain areas involved in visually guided reaching is the dorsal aspect of the premotor cortex (PMd). Using chronically implanted electrode arrays in two Rhesus monkeys, we studied the contributions of PMd to the reference frame transformation for reaching. PMd neurons are influenced by the locations of reach targets relative to both the arm and the eyes. Some neurons encode reach goals using limb-centered reference frames, whereas others employ eye-centered reference fames. Some cells encode reach goals in a reference frame best described by the combined position of the eyes and hand. In addition to neurons like these where a reference frame could be identified, PMd also contains cells that are influenced by both the eye- and limb-centered locations of reach goals but for which a distinct reference frame could not be determined. We propose two interpretations for these neurons. First, they may encode reach goals using a reference frame we did not investigate, such as intrinsic reference frames. Second, they may not be adequately characterized by any reference frame.
Regulation of Burst Dynamics Improves Differential Encoding of Stimulus Frequency by Spike Train Segregation
Authors: Mehaffey W. Hamish , Fernandez Fernando R. , Maler Leonard , Turner Ray W.
Published: June 2007

Distinguishing between different signals conveyed in a single sensory modality presents a significant problem for sensory processing. The weakly electric fish Apteronotus leptorhynchus use electrosensory information to encode both low-frequency signals associated with environmental and prey signals and high-frequency communication signals between conspecifics. We identify a mechanism whereby the GABABcomponent of a feedback pathway to the electrosensory lobe is recruited to regulate the intrinsic burst dynamics and coding properties of pyramidal cells for these behaviorally relevant input signals. Through recordings in an in vitro slice preparation and a reduced model of pyramidal cells, we show that recruitment of dendritic GABABcurrents can shift the timing of a backpropagating spike and its influence on an intrinsic burst mechanism. This regulation of burst firing alters the coding properties of pyramidal cells by improving the correlation of burst and tonic spikes with respect to low- or high-frequency components of complex stimuli. GABABmodulation of spike backpropagation thus improves the segregation of burst and tonic spikes evoked by simulated sensory input, allowing pyramidal cells to parcel the spike train into coding streams for the low- and high-frequency components. As the feedback pathway is predicted to be activated in circumstances where environmental and communication stimuli coexist, these data reveal a novel means by which inhibitory input can regulate spike backpropagation to improve signal segregation.
Serotonin Modulates Dendritic Calcium Influx in Commissural Interneurons in the Mouse Spinal Locomotor Network
Authors: Díaz-Ríos Manuel , Dombeck Daniel A. , Webb Watt W. , Harris-Warrick Ronald M.
Published: June 2007

Commissural interneurons (CINs) help to coordinate left–right alternating bursting activity during fictive locomotion in the neonatal mouse spinal cord. Serotonin (5-HT) plays an active role in the induction of fictive locomotion in the isolated spinal cord, but the cellular targets and mechanisms of its actions are relatively unknown. We investigated the possible role of serotonin in modifying dendritic calcium currents, using a combination of two-photon microscopy and patch-clamp recordings, in identified CINs in the upper lumbar region. Dendritic calcium responses to applied somatic voltage-clamp steps were measured using fluorescent calcium indicator imaging. Serotonin evoked significant reductions in voltage-dependent dendritic calcium influx in about 40% of the dendritic sites studied, with no detectable effect in the remaining sites. We also detected differential effects of serotonin in different dendritic sites of the same neuron; serotonin could decrease voltage-sensitive calcium influx at one site, with no effect at a nearby site. Voltage-clamp studies confirmed that serotonin reduces the voltage-dependent calcium current in CINs. Current-clamp experiments showed that the serotonin-evoked decreases in dendritic calcium influx were coupled with increases in neuronal excitability; we discuss possible mechanisms by which these two seemingly opposing results can be reconciled. This research demonstrates that dendritic calcium currents are targets of serotonin modulation in a group of spinal interneurons that are components of the mouse locomotor network.
Effects of Anandamide and Noxious Heat on Intracellular Calcium Concentration in Nociceptive DRG Neurons of Rats
Authors: Fischbach Tilo , Greffrath Wolfgang , Nawrath Hermann , Treede Rolf-Detlef
Published: June 2007

As an endogenous agonist at the cannabinoid receptor CB1 and the capsaicin-receptor TRPV1, anandamide may exert both anti- and pronociceptive actions. Therefore we studied the effects of anandamide and other activators of both receptors on changes in free cytosolic calcium ([Ca2+]i) in acutely dissociated small dorsal root ganglion neurons (diameter: ≤30 μm). Anandamide (10 μM) increased [Ca2+]iin 76% of the neurons. The EC50was 7.41 μM, the Hill slope was 2.15 ± 0.43 (mean ± SE). This increase was blocked by the competitive TRPV1-antagonist capsazepine (10 μM) and in Ca2+-free extracellular solution. Neither exclusion of voltage-gated sodium channels nor additional blockade of voltage-gated calcium channels of the L-, N-, and/or T-type, significantly reduced the anandamide-induced [Ca2+]iincrease or capsaicin-induced [Ca2+]itransients (0.2 μM). The CB1-agonist HU210 (10 μM) inhibited the anandamide-induced rise in [Ca2+]i. Conversely, the CB1-antagonist AM251 (3 μM) induced a leftward shift of the concentration-response relationship by ∼4 μM ( P < 0.001; Hill slope, 2.17 ± 0.75). Intracellular calcium transients in response to noxious heat (47°C for 10 s) were highly correlated with the anandamide-induced [Ca2+]iincreases ( r = 0.84, P < 0.001). Heat-induced [Ca2+]itransients were facilitated by preincubation with subthreshold concentrations of anandamide (3 μM), an effect that was further enhanced by 3 μM AM251. Although anandamide acts on both TRPV1 and CB1 receptors in the same nociceptive DRG neurons, its pronociceptive effects dominate. Anandamide triggers an influx of calcium through TRPV1 but no intracellular store depletion. It facilitates the heat responsiveness of TRPV1 in a calcium-independent manner. These effects of anandamide differ from those of the classical exogenous TRPV1-agonist capsaicin and suggest a primarily modulatory mode of action of anandamide.
Temporal and Frequency Characteristics of Cartwheel Cells in the Dorsal Cochlear Nucleus of the Awake Mouse
Authors: Portfors Christine V. , Roberts Patrick D.
Published: June 2007

The dorsal cochlear nucleus (DCN) is an initial site of central auditory processing and also the first site of multisensory convergence in the auditory pathway. The auditory nerve imparts a tonotopic frequency organization on the responses of principal cells in the DCN. Cartwheel cells modify the responses of principal cells, but they do not receive direct auditory nerve input. This study shows that cartwheel cells respond well to tonal stimuli in the awake mouse and they have a well-defined characteristic frequency that corresponds to the tonotopic organization of the DCN. The auditory responses of cartwheel cells exhibit complex spectrotemporal responses to tones, with excitation and inhibition modulating the firing patterns in both frequency and time after onset of the stimulus. Temporal responses to best-frequency tones are highly variable between cartwheel cells, but a simple model is used to unify this variability as differences in the timing of synaptic currents. Cartwheel cell responses to two-tone stimuli show that interactions from different frequencies affect the output of cartwheel cells. The results suggest that at this primary auditory structure, processing of sound at one frequency can be modified by sounds of different frequency. These complex frequency and temporal interactions in cartwheel cells suggest that these neurons play an active role in basic sound processing.
Power in Voxel-based Lesion-Symptom Mapping
Authors: Kimberg Daniel Y. , Coslett H. Branch , Schwartz Myrna F.
Published: June 2007

Lesion analysis in brain-injured populations complements what can be learned from functional neuroimaging. Voxel-based approaches to mapping lesion-behavior correlations in brain-injured populations are increasingly popular, and have the potential to leverage image analysis methods drawn from functional magnetic resonance imaging. However, power is a major concern for these studies, and is likely to vary regionally due to the distribution of lesion locations. Here, we outline general considerations for voxel-based methods, characterize the use of a nonparametric permutation test adapted from functional neuroimaging, and present methods for regional power analysis in lesion studies.
Event-related Potentials Reveal Age Differences in the Encoding and Recognition of Scenes
Authors: Gutchess Angela H. , Ieuji Yoko , Federmeier Kara D.
Published: June 2007

The present study used event-related potentials (ERPs) to investigate how the encoding and recognition of complex scenes change with normal aging. Although functional magnetic resonance imaging (fMRI) studies have identified more drastic age impairments at encoding than at recognition, ERP studies accumulate more evidence for age differences at retrieval. However, stimulus type and paradigm differences across the two literatures have made direct comparisons difficult. Here, we collected young and elderly adults' encoding- and recognition-phase ERPs using the same materials and paradigm as a previous fMRI study [Gutchess, A. H., Welsh, R. C., Hedden, T., Bangert, A., Minear, M., Liu, L., et al. Aging and the neural correlates of successful picture encoding: Frontal activations compensate for decreased medial temporal activity. Journal of Cognitive Neuroscience, 17, 84–96, 2005]. Twenty young and 20 elderly adults incidentally encoded and then recognized photographs of outdoor scenes. During encoding, young adults showed a frontocentral subsequent memory effect, with high-confidence hits exhibiting greater positivity than misses. Elderly adults showed a similar subsequent memory effect, which, however, did not differ as a function of confidence. During recognition, young adults elicited a widespread old/new effect, and high-confidence hits were distinct from both low-confidence hits and false alarms. Elderly adults elicited a smaller and later old/new effect, which was unaffected by confidence, and hits and false alarms were indistinguishable in the waveforms. Consistent with prior ERP work, these results point to important age-related changes in recognition-phase brain activity, even when behavioral measures of memory and confidence pattern similarly across groups. We speculate that memory processes with different time signatures contribute to the apparent differences across encoding and retrieval stages, and across methods.