bluuebunny/crossref_metadata_2025 huggingface dataset:
Extracellular purine metabolism and signaling of CD73-derived adenosine in murine Treg and Teff cells
Authors: Romio Michael , Reinbeck Benjamin , Bongardt Sabine , Hüls Sandra , Burghoff Sandra , Schrader Jürgen
Published: May 2011

CD73-derived adenosine acts as potent inhibitor of inflammation, and regulatory T cells (Treg) have been shown to express CD73 as a novel marker. This study explored the role of endogenously formed adenosine in modulating NF-κB activity and cytokine/chemokine release from murine Treg and effector T cells (Teff) including key enzymes/purinergic receptors of extracellular ATP catabolism. Stimulating murine splenocytes and CD4+ T cells with anti-CD3/anti-CD28 significantly upregulated activated NF-κB in CD73−/− T cells (wild type: 4.36 ± 0.21; CD73−/−: 6.58 ± 0.75; n = 4; P = 0.029). This was associated with an augmented release of proinflammatory cytokines IL-2, TNF-α, and IFN-γ. Similar changes were observed with the CD73 inhibitor APCP (50 μM) on NF-κB and IFN-γ in wild-type CD4+ T-cells. Treatment of stimulated CD4+ T-cells with adenosine (25 μM) potently reduced IFN-γ release which is mediated by adenosine A2a receptors (A2aR). AMP (50 μM) also reduced cytokine release which was not inhibited by APCP. In Teff, A2aR activation (CGS21680) potently inhibited the release of IL-1, IL-2, IL-3, IL-4, IL-12, IL-13, IFN-γ, TNF-α, granulocyte-macrophage colony-stimulating factor (GM-CSF), CCL3, and CCL4. However, in Treg, CGS21680 did not alter cytokine/chemokine release. In summary, CD73-derived adenosine tonically inhibits active NF-κB in CD4+ T-cells, thereby modulating the release of a broad spectrum of proinflammatory cytokines and chemokines. Downregulation of P2X7 and upregulation of CD73 in Treg after antigenic stimulation may be an important mechanism to maintain the ability of Treg to generate immunosuppressive adenosine.
Differential modulation of the molecular dynamics of the type IIa and IIc sodium phosphate cotransporters by parathyroid hormone
Authors: Lanzano Luca , Lei Tim , Okamura Kayo , Giral Hector , Caldas Yupanqui , Masihzadeh Omid , Gratton Enrico , Levi Moshe , Blaine Judith
Published: May 2011

The kidney is a key regulator of phosphate homeostasis. There are two predominant renal sodium phosphate cotransporters, NaPi2a and NaPi2c. Both are regulated by parathyroid hormone (PTH), which decreases the abundance of the NaPi cotransporters in the apical membrane of renal proximal tubule cells. The time course of PTH-induced removal of the two cotransporters from the apical membrane, however, is markedly different for NaPi2a compared with NaPi2c. In animals and in cell culture, PTH treatment results in almost complete removal of NaPi2a from the brush border (BB) within 1 h whereas for NaPi2c this process in not complete until 4 to 8 h after PTH treatment. The reason for this is poorly understood. We have previously shown that the unconventional myosin motor myosin VI is required for PTH-induced removal of NaPi2a from the proximal tubule BB. Here we demonstrate that myosin VI is also necessary for PTH-induced removal of NaPi2c from the apical membrane. In addition, we show that, while at baseline the two cotransporters have similar diffusion coefficients within the membrane, after PTH addition the diffusion coefficient for NaPi2a initially exceeds that for NaPi2c. Thus NaPi2c appears to remain “tethered” in the apical membrane for longer periods of time after PTH treatment, accounting, at least in part, for the difference in response times to PTH of NaPi2a versus NaPi2c.
Constitutive ERK activity induces downregulation of tristetraprolin, a major protein controlling interleukin8/CXCL8 mRNA stability in melanoma cells
Authors: Bourcier Christine , Griseri Paola , Grépin Renaud , Bertolotto Corinne , Mazure Nathalie , Pagès Gilles
Published: May 2011

Most melanoma cells are characterized by the V600E mutation in B-Raf kinase. This mutation leads to increased expression of interleukin (CXCL8), which plays a key role in cell growth and angiogenesis. Thus CXCL8 appears to be an interesting therapeutic target. Hence, we performed vaccination of mice with GST-CXCL8, which results in a reduced incidence of syngenic B16 melanoma cell xenograft tumors. We next addressed the molecular mechanisms responsible for aberrant CXCL8 expression in melanoma. The CXCL8 mRNA contains multiples AU-rich sequences (AREs) that modulate mRNA stability through the binding of tristetraprolin (TTP). Melanoma cell lines express very low TTP levels. We therefore hypothesized that the very low endogenous levels of TTP present in different melanoma cell lines might be responsible for the relative stability of CXCL8 mRNAs. We show that TTP is actively degraded by the proteasome and that extracellular-regulated kinase inhibition results in TTP accumulation. Conditional expression of TTP in A375 melanoma cells leads to CXCL8 mRNA destabilization via its 3′ untranslated regions (3′-UTR), and TTP overexpression reduces its production. In contrast, downregulation of TTP by short hairpin RNA results in upregulation of CXCL8 mRNA. Maintaining high TTP levels in melanoma cells decreases cell proliferation and autophagy and induces apoptosis. Sorafenib, a therapeutic agent targeting Raf kinases, decreases CXCL8 expression in melanoma cells through reexpression of TTP. We conclude that loss of TTP represents a key event in the establishment of melanomas through constitutive expression of CXCL8, which constitutes a potent therapeutic target.
Effect of the α2δ ligand, pregabalin, on colonic sensory and motor functions in healthy adults
Authors: Iturrino Johanna , Camilleri Michael , Busciglio Irene , Burton Duane , Zinsmeister Alan R.
Published: May 2011

Pregabalin, an α2δ ligand, is used clinically to treat somatic pain. A prior study suggested that pregabalin reduces distension-induced pain while increasing rectal compliance. We aimed to quantify effects of pregabalin on colonic sensory and motor functions and assess relationships between sensory effects and colonic compliance. We conducted a randomized, double-blind, placebo-controlled, parallel-group study of a single oral administration of 75 or 200 mg of pregabalin in 62 healthy adults (aged 18–75 yr). Subjects underwent left colon intubation. We assessed “stress-arousal symptoms”, compliance, sensation thresholds, sensation ratings averaged over four levels of distension, fasting and postprandial colonic tone, and phasic motility index (MI). Analysis of covariance (adjusted for age, sex, body mass index, and corresponding predrug response) and proportional hazard models were used. There were no clinically important differences among treatment groups for demographics, predrug compliance, tone, MI, and sensation. Treatment was associated with reduced energy and increased drowsiness but no change in tension or relaxation. Sensation ratings averaged over the four distension levels were lower for gas sensation [overall effect P = 0.14, P = 0.05 (pregabalin 200 mg vs. placebo)] and for pain sensation [overall effect P = 0.12, P = 0.04 (pregabalin 200 mg vs. placebo)]. The magnitude of the effect of 200 mg of pregabalin relative to placebo is on average a 25% reduction of both gas and pain sensation ratings. Pregabalin did not significantly affect colonic compliance, sensation thresholds, colonic fasting tone, and MI. Thus 200 mg of pregabalin reduces gas and pain sensation and should be tested in patients with colonic pain.
Visualizing ocular lens fluid dynamics using MRI: manipulation of steady state water content and water fluxes
Authors: Vaghefi Ehsan , Pontre Beau P. , Jacobs Marc D. , Donaldson Paul J.
Published: May 2011

Studies using various MRI techniques have shown that a water-protein concentration gradient exists in the ocular lens. Because this concentration is higher in the core relative to the lens periphery, a gradient in refractive index is established in the lens. To investigate how the water-protein concentration profile is maintained, bovine lenses were incubated in different solutions, and changes in water-protein concentration ratio monitored using proton density weighted (PD-weighted) imaging in the absence and presence of heavy water (D2O). Lenses incubated in artificial aqueous humor (AAH) maintained the steady state water-protein concentration gradient, but incubating lenses in high extracellular potassium (KCl-AAH) or low temperature (Low T-AAH) caused a collapse of the gradient due to a rise in water content in the core of the lens. To visualize water fluxes, lenses were incubated in D2O, which acts as a contrast agent. Incubation in KCl-AAH and low T-AAH dramatically slowed the movement of D2O into the core but did not affect the movement of D2O into the outer cortex. D2O seemed to preferentially enter the lens cortex at the anterior and posterior poles before moving circumferentially toward the equatorial regions. This directionality of D2O influx into the lens cortex was abolished by incubating lenses in high KCl-AAH or low T-AAH, and resulted in homogenous influx of D2O into the outer cortex. Taken together, our results show that the water-protein concentration ratio is actively maintained in the core of the lens and that water fluxes preferentially enter the lens at the poles.
Ventilatory effects of substance P-saporin lesions in the nucleus tractus solitarii of chronically hypoxic rats
Authors: Wilkinson Katherine A. , Fu Zhenxing , Powell Frank L.
Published: May 2011

During ventilatory acclimatization to hypoxia (VAH), time-dependent increases in ventilation lower Pco2 levels, and this persists on return to normoxia. We hypothesized that plasticity in the caudal nucleus tractus solitarii (NTS) contributes to VAH, as the NTS receives the first synapse from the carotid body chemoreceptor afferents and also contains CO2-sensitive neurons. We lesioned cells in the caudal NTS containing the neurokinin-1 receptor by microinjecting the neurotoxin saporin conjugated to substance P and measured ventilatory responses in awake, unrestrained rats 18 days later. Lesions did not affect hypoxic or hypercapnic ventilatory responses in normoxic control rats, in contrast to published reports for similar lesions in other central chemosensitive areas. Also, lesions did not affect the hypercapnic ventilatory response in chronically hypoxic rats (inspired Po2 = 90 Torr for 7 days). These results suggest functional differences between central chemoreceptor sites. However, lesions significantly increased ventilation in normoxia or acute hypoxia in chronically hypoxic rats. Hence, chronic hypoxia increases an inhibitory effect of neurokinin-1 receptor neurons in the NTS on ventilatory drive, indicating that these neurons contribute to plasticity during chronic hypoxia, although such plasticity does not explain VAH.
Cold tolerance, cold-induced hyperphagia, and nonshivering thermogenesis are normal in α1-AMPK−/−mice
Authors: Bauwens Jake D. , Schmuck Eric G. , Lindholm Christopher R. , Ertel Rebecca L. , Mulligan Jacob D. , Hovis Ian , Viollet Benoit , Saupe Kurt W.
Published: May 2011

Recent studies indicate that a substantial amount of metabolically active brown adipose tissue (BAT) exists in adult humans. Given the unique ability of BAT to convert calories to heat, there is intense interest in understanding the regulation of BAT metabolism in hopes that its manipulation might be an effective way of expending excess calories. Because of the established role of AMP-activated protein kinase (AMPK) as a “metabolic master switch” and its extremely high levels of activity in BAT, it was hypothesized that AMPK might play a central role in regulating BAT metabolism. To test this hypothesis, whole body α1-AMPK−/−(knockout) and wild-type mice were studied 1) under control (room temperature) conditions, 2) during chronic cold exposure (14 days at 4°C), and 3) during acute nonshivering thermogenesis (injection of a β3-adrenergic agonist). Under control conditions, loss of α1-AMPK resulted in downregulation of two important prothermogenic genes in BAT, thyrotropin-releasing hormone (−9.2-fold) and ciliary neurotrophic factor (−8.7-fold). Additionally, it caused significant upregulation of α2-AMPK activity in BAT, white adipose tissue, and liver, but not cardiac or skeletal muscle. During acute nonshivering thermogenesis and chronic cold exposure, body temperature was indistinguishable in the α1-AMPK−/−and wild-type mice. Similarly, the degree of cold-induced hyperphagia was identical in the two groups. We conclude that α1-AMPK does not play an obligatory role in these processes and that adaptations to chronic loss of α1-AMPK are able to compensate for its loss via several mechanisms.
Age exacerbates chronic catecholamine-induced impairments in contractile reserve in the rat
Authors: Liles John T. , Ida Kevin K. , Joly Kristin M. , Chapo Joseph , Plato Craig F.
Published: May 2011

Contractile reserve decreases with advancing age and chronic isoproterenol (ISO) administration is a well-characterized model of cardiac hypertrophy known to impair cardiovascular function. This study evaluated whether nonsenescent, mature adult rats are more susceptible to detrimental effects of chronic ISO administration than younger adult rats. Rats received daily injections of ISO (0.1 mg/kg sc) or vehicle for 3 wk. ISO induced a greater impairment in contractile reserve [maximum of left ventricular pressure development (Δ+dP/d tmax)] in mature adult ISO-treated (MA-ISO) than in young adult ISO-treated rats (YA-ISO) in response to infusions of mechanistically distinct inotropes (digoxin, milrinone; 20–200 μl·kg−1·min−1), while basal and agonist-induced changes in heart rate and systolic arterial pressure (SAP) were not different across groups. ISO decreased expression of the calcium handling protein, sarco(endo)plasmic reticulum Ca2+-ATPase-2a, in MA-ISO compared with YA, YA-ISO, and MA rats. Chronic ISO also induced greater increases in cardiac hypertrophy [left ventricular (LV) index: 33 ± 3 vs. 22 ± 5%] and caspase-3 activity (34 vs. 5%) in MA-ISO relative to YA-ISO rats. Moreover, β-myosin heavy chain (β-MHC) and atrial natriuretic factor (ANF) mRNA expression was significantly elevated in MA-ISO. These results demonstrate that adult rats develop greater impairments in systolic performance than younger rats when exposed to chronic catecholamine excess. Reduced contractile reserve may result from calcium dysregulation, increased caspase-3 activity, or increased β-MHC and ANF expression. Although several studies report age-related declines in systolic performance in older and senescent animals, the present study demonstrates that catecholamine excess induces reductions in systolic performance significantly earlier in life.
Effect of intra-amniotic lipopolysaccharide on nephron number in preterm fetal sheep
Authors: Galinsky Robert , Moss Timothy J. M. , Gubhaju Lina , Hooper Stuart B. , Black M. Jane , Polglase Graeme R.
Published: May 2011

Chorioamnionitis is an antecedent of preterm birth. We aimed to determine the effect of experimental chorioamnionitis in fetal sheep during late gestation on 1) nephron number, 2) renal corpuscle volume, and 3) renal inflammation. We hypothesized that exposure to chorioamnionitis would lead to inflammation in fetal kidneys and adversely impact on the development of nephrons, leading to a reduction in nephron number. At ∼121 days of gestation (term ∼147 days), pregnant ewes bearing twin or singleton fetuses received a single intra-amniotic injection of lipopolysaccharide ( n = 6; 3 singletons, 3 twins); controls were either untreated or received an intra-amniotic injection of saline ( n = 8; 4 singletons, 4 twins). One twin was used from each twin-bearing ewe. At ∼128 days of gestation, fetuses were delivered via Caesarean section. Kidneys were collected and stereologically analyzed to determine nephron number and renal corpuscle volume. Renal inflammation was assessed using immunohistochemistry. Experimental chorioamnionitis did not affect body weight or relative kidney weight. There was a significant reduction in nephron number but no change in renal corpuscle volume in LPS-exposed fetuses relative to controls. On average, nephron number was significantly reduced by 23 and 18% in singleton and twin LPS-exposed fetuses, respectively. The degree of renal inflammation did not differ between groups. Importantly, this study demonstrates that exposure to experimental chorioamnionitis adversely impacts on nephron number in the developing fetus.
Both high and low maternal salt intake in pregnancy alter kidney development in the offspring
Authors: Koleganova Nadezda , Piecha Grzegorz , Ritz Eberhard , Becker Luis Eduardo , Müller Annett , Weckbach Monika , Nyengaard Jens Randel , Schirmacher Peter , Gross-Weissmann Marie-Luise
Published: May 2011

In humans, low glomerular numbers are related to hypertension, cardiovascular, and renal disease in adult life. The present study was designed 1) to explore whether above- or below-normal dietary salt intake during pregnancy influences nephron number and blood pressure in the offspring and 2) to identify potential mechanisms in kidney development modified by maternal sodium intake. Sprague-Dawley rats were fed low (0.07%)-, intermediate (0.51%)-, or high (3.0%)-sodium diets during pregnancy and lactation. The offspring were weaned at 4 wk and subsequently kept on a 0.51% sodium diet. The kidney structure was assessed at postnatal weeks 1 and 12 and the expression of proteins of interest at term and at week 1. Blood pressure was measured in male offspring by telemetry from postnatal month 2 to postnatal month 9. The numbers of glomeruli at weeks 1 and 12 were significantly lower and, in males, telemetrically measured mean arterial blood pressure after month 5 was higher in offspring of dams on a high- or low- compared with intermediate-sodium diet. A high-salt diet was paralleled by higher concentrations of marinobufagenin in the amniotic fluid and an increase in the expression of both sprouty-1 and glial cell-derived neutrophic factor in the offspring's kidney. The expression of FGF-10 was lower in offspring of dams on a low-sodium diet, and the expression of Pax-2 and FGF-2 was lower in offspring of dams on a high-sodium diet. Both excessively high and excessively low sodium intakes during pregnancy modify protein expression in offspring kidneys and reduce the final number of glomeruli, predisposing the risk of hypertension later in life.
Characterization of postsynaptic Ca2+signals at theDrosophilalarval NMJ
Authors: Desai Sunil A. , Lnenicka Gregory A.
Published: May 2011

Postsynaptic intracellular Ca2+concentration ([Ca2+]i) has been proposed to play an important role in both synaptic plasticity and synaptic homeostasis. In particular, postsynaptic Ca2+signals can alter synaptic efficacy by influencing transmitter release, receptor sensitivity, and protein synthesis. We examined the postsynaptic Ca2+transients at the Drosophila larval neuromuscular junction (NMJ) by injecting the muscle fibers with Ca2+indicators rhod-2 and Oregon Green BAPTA-1 (OGB-1) and then monitoring their increased fluorescence during synaptic activity. We observed discrete postsynaptic Ca2+transients along the NMJ during single action potentials (APs) and quantal Ca2+transients produced by spontaneous transmitter release. Most of the evoked Ca2+transients resulted from the release of one or two quanta of transmitter and occurred largely at synaptic boutons. The magnitude of the Ca2+signals was correlated with synaptic efficacy; the Is terminals, which produce larger excitatory postsynaptic potentials (EPSPs) and have a greater quantal size than Ib terminals, produced a larger Ca2+signal per terminal length and larger quantal Ca2+signals than the Ib terminals. During a train of APs, the postsynaptic Ca2+signal increased but remained localized to the postsynaptic membrane. In addition, we showed that the plasma membrane Ca2+-ATPase (PMCA) played a role in extruding Ca2+from the postsynaptic region of the muscle. Drosophila melanogaster has a single PMCA gene, predicted to give rise to various isoforms by alternative splicing. Using RT-PCR, we detected the expression of multiple transcripts in muscle and nervous tissues; the physiological significance of the same is yet to be determined.
Role of pH in a nitric oxide-dependent increase in cytosolic Cl−in retinal amacrine cells
Authors: McMains Emily , Gleason Evanna
Published: May 2011

Nitric oxide (NO) synthase-expressing neurons are found throughout the vertebrate retina. Previous work by our laboratory has shown that NO can transiently convert inhibitory GABAergic synapses onto cultured retinal amacrine cells into excitatory synapses by releasing Cl−from an internal store in the postsynaptic cell. The mechanism underlying this Cl−release is currently unknown. Because transport of Cl−across internal membranes can be coupled to proton flux, we asked whether protons could be involved in the NO-dependent release of internal Cl−. Using pH imaging and whole cell voltage-clamp recording, we addressed the relationship between cytosolic pH and cytosolic Cl−in cultured retinal amacrine cells. We found that NO reliably produces a transient decrease in cytosolic pH. A physiological link between cytosolic pH and cytosolic Cl−was established by demonstrating that shifting cytosolic pH in the absence of NO altered cytosolic Cl−concentrations. Strong buffering of cytosolic pH limited the ability of NO to increase cytosolic Cl−, suggesting that cytosolic acidification is involved in generating the NO-dependent elevation in cytosolic Cl−. Furthermore, disruption of internal proton gradients also reduced the effects of NO on cytosolic Cl−. Taken together, these results suggest a cytosolic environment where proton and Cl−fluxes are coupled in a dynamic and physiologically meaningful way.
Light exposure induces short- and long-term changes in the excitability of retinorecipient neurons in suprachiasmatic nucleus
Authors: LeSauter Joseph , Silver Rae , Cloues Robin , Witkovsky Paul
Published: May 2011

The suprachiasmatic nucleus (SCN) is the locus of a hypothalamic circadian clock that synchronizes physiological and behavioral responses to the daily light-dark cycle. The nucleus is composed of functionally and peptidergically diverse populations of cells for which distinct electrochemical properties are largely unstudied. SCN neurons containing gastrin-releasing peptide (GRP) receive direct retinal input via the retinohypothalamic tract. We targeted GRP neurons with a green fluorescent protein (GFP) marker for whole cell patch-clamping. In these neurons, we studied short (0.5–1.5 h)- and long-term (2–6 h) effects of a 1-h light pulse (LP) given 2 h after lights off [Zeitgeber time (ZT) 14:00–15:00] on membrane potential and spike firing. In brain slices taken from light-exposed animals, cells were depolarized, and spike firing rate increased between ZT 15:30 and 16:30. During a subsequent 4-h period beginning around ZT 17:00, GRP neurons from light-exposed animals were hyperpolarized by ∼15 mV. None of these effects was observed in GRP neurons from animals not exposed to light or in immediately adjacent non-GRP neurons whether or not exposed to light. Depolarization of GRP neurons was associated with a reduction in GABAA-dependent synaptic noise, whereas hyperpolarization was accompanied both by a loss of GABAAdrive and suppression of a TTX-resistant leakage current carried primarily by Na. This suggests that, in the SCN, exposure to light may induce a short-term increase in GRP neuron excitability mediated by retinal neurotransmitters and neuropeptides, followed by long-term membrane hyperpolarization resulting from suppression of a leakage current, possibly resulting from genomic signals.
Dipole source analyses of laser evoked potentials obtained from subdural grid recordings from primary somatic sensory cortex
Authors: Baumgärtner Ulf , Vogel Hagen , Ohara Shinji , Treede Rolf-Detlef , Lenz Fred
Published: May 2011

The cortical potentials evoked by cutaneous application of a laser stimulus (laser evoked potentials, LEP) often include potentials in the primary somatic sensory cortex (S1), which may be located within the subdivisions of S1 including Brodmann areas 3A, 3B, 1, and 2. The precise location of the LEP generator may clarify the pattern of activation of human S1 by painful stimuli. We now test the hypothesis that the generators of the LEP are located in human Brodmann area 1 or 3A within S1. Local field potential (LFP) source analysis of the LEP was obtained from subdural grids over sensorimotor cortex in two patients undergoing epilepsy surgery. The relationship of LEP dipoles was compared with dipoles for somatic sensory potentials evoked by median nerve stimulation (SEP) and recorded in area 3B (see Baumgärtner U, Vogel H, Ohara S, Treede RD, Lenz FA. J Neurophysiol 104: 3029–3041, 2010). Both patients had an early radial dipole in S1. The LEP dipole was located medial, anterior, and deep to the SEP dipole, which suggests a nociceptive dipole in area 3A. One patient had a later tangential dipole with positivity posterior, which is opposite to the orientation of the SEP dipole in area 3B. The reversal of orientations between modalities is consistent with the cortical surface negative orientation resulting from superficial termination of thalamocortical neurons that receive inputs from the spinothalamic tract. Therefore, the present results suggest that the LEP may result in a radial dipole consistent with a generator in area 3A and a putative later tangential generator in area 3B.
Cues to move increase information in superior colliculus tuning curves
Authors: Li Xiaobing , Basso Michele A.
Published: May 2011

Shifts in the location of spatial attention produce increases in the gain and sensitivity of neuronal responses to sensory stimuli. Cues to shift the line of sight have the same effect on sensory responses in a motor area involved in the control of eye movements, the superior colliculus. Evidence has shown that shifts of gaze and shifts of attention are linked, suggesting there may be similar underlying mechanisms. Here, we report on a novel way in which cues to move the eyes (top-down signals) can influence sensory responses of neurons by altering the variability of their discharge rate. We measured the spatial tuning of superior colliculus neuronal activity in trials with cues to either make or withhold saccadic eye movements. We found that tuning curve widths both increased and decreased, but that the information conveyed by the neuronal discharge about the stimulus increased with a cue to make a saccade. The increase in information resulted partly from a decrease in trial-to-trial variability of neuronal discharges for stimuli located at the flanks of the tuning curves rather than from increases in the discharge rate for stimuli located at the peak of the tuning curves. This result is consistent with theoretical work and provides a novel way for cognitive signals to influence sensory responses within motor regions of the brain.
Questioning the depolarizing effects of GABA during early brain development
Authors: Khakhalin Arseny S.
Published: May 2011

During early brain development, γ-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the adult brain, has been thought to be an important source of excitatory neurotransmission. This view, however, was recently challenged by a series of studies that claim that the excitatory effect of GABA is due to non-physiological in vitro experimental conditions. In this article, we aim to summarize results that support and challenge the traditional point of view, and indicate some strong and weak points of both positions.
Sensory versus motor loci for integration of multiple motion signals in smooth pursuit eye movements and human motion perception
Authors: Niu Yu-Qiong , Lisberger Stephen G.
Published: May 2011

We have investigated how visual motion signals are integrated for smooth pursuit eye movements by measuring the initiation of pursuit in monkeys for pairs of moving stimuli of the same or differing luminance. The initiation of pursuit for pairs of stimuli of the same luminance could be accounted for as a vector average of the responses to the two stimuli singly. When stimuli comprised two superimposed patches of moving dot textures, the brighter stimulus suppressed the inputs from the dimmer stimulus, so that the initiation of pursuit became winner-take-all when the luminance ratio of the two stimuli was 8 or greater. The dominance of the brighter stimulus could be not attributed to either the latency difference or the ratio of the eye accelerations for the bright and dim stimuli presented singly. When stimuli comprised either spot targets or two patches of dots moving across separate locations in the visual field, the brighter stimulus had a much weaker suppressive influence; the initiation of pursuit could be accounted for by nearly equal vector averaging of the responses to the two stimuli singly. The suppressive effects of the brighter stimulus also appeared in human perceptual judgments, but again only for superimposed stimuli. We conclude that one locus of the interaction of two moving visual stimuli is shared by perception and action and resides in local inhibitory connections in the visual cortex. A second locus resides deeper in sensory-motor processing and may be more closely related to action selection than to stimulus selection.
Opioid receptor modulation of GABAergic and serotonergic spinally projecting neurons of the rostral ventromedial medulla in mice
Authors: Pedersen Nigel P. , Vaughan Christopher W. , Christie MacDonald J.
Published: May 2011

The rostral ventromedial medulla (RVM) is an important site of opioid actions and forms part of an analgesic pathway that projects to the spinal cord. The neuronal mechanisms by which opioids act within this brain region remain unclear, particularly in relation to the neurotransmitters GABA and serotonin. In the present study, we examined serotonergic and GABAergic immunoreactivity, identified using immunohistochemistry for tryptophan hydroxylase (TPH) and glutamate decarboxylase (GAD), in combination with in vitro whole cell patch clamping to investigate the role of opioids on the mouse RVM with identified projections to the spinal cord. Tyr-d-Ala-Gly- N-Me-Phe-Gly-ol enkephalin (DAMGO) produced μ-opioid receptor-mediated outward currents in virtually all TPH-immunoreactive projecting neurons and GAD-immunoreactive nonprojecting neurons (87% and 86%). The other groups of RVM neurons displayed mixed responsiveness to DAMGO (40–68%). Deltorphin II and U-69593 produced δ- and κ-opioid receptor-mediated outward currents in smaller subpopulations of RVM neurons, with many of the δ-opioid responders forming a subpopulation of μ-opioid-sensitive GABAergic nonprojecting neurons. These findings are consistent with prior electrophysiological and anatomic studies in the rat RVM and indicate that both serotonergic and GABAergic RVM neurons mediate the actions of μ-opioids. Specifically, μ-opioids have a direct postsynaptic inhibitory influence over both GABAergic and serotonergic neurons, including those that project to the dorsal spinal cord.
Transforming Growth Factor-Beta Signaling in the Neural Stem Cell Niche: A Therapeutic Target for Huntington's Disease
Authors: Kandasamy Mahesh , Reilmann Ralf , Winkler Jürgen , Bogdahn Ulrich , Aigner Ludwig
Published: May 2011

The neural stem cell niches possess the regenerative capacity to generate new functional neurons in the adult brain, suggesting the possibility of endogenous neuronal replacement after injury or disease. Huntington disease (HD) is a neurodegenerative disease and characterized by neuronal loss in the basal ganglia, leading to motor, cognitive, and psychological disabilities. Apparently, in order to make use of the neural stem cell niche as a therapeutic concept for repair strategies in HD, it is important to understand the cellular and molecular composition of the neural stem cell niche under such neurodegenerative conditions. This paper mainly discusses the current knowledge on the regulation of the hippocampal neural stem cell niche in the adult brain and by which mechanism it might be compromised in the case of HD.
Gas Discharge Visualization: An Imaging and Modeling Tool for Medical Biometrics
Authors: Kostyuk Nataliya , Cole Phyadragren , Meghanathan Natarajan , Isokpehi Raphael D. , Cohly Hari H. P.
Published: May 2011

The need for automated identification of a disease makes the issue of medical biometrics very current in our society. Not all biometric tools available provide real-time feedback. We introduce gas discharge visualization (GDV) technique as one of the biometric tools that have the potential to identify deviations from the normal functional state at early stages and in real time. GDV is a nonintrusive technique to capture the physiological and psychoemotional status of a person and the functional status of different organs and organ systems through the electrophotonic emissions of fingertips placed on the surface of an impulse analyzer. This paper first introduces biometrics and its different types and then specifically focuses on medical biometrics and the potential applications of GDV in medical biometrics. We also present our previous experience with GDV in the research regarding autism and the potential use of GDV in combination with computer science for the potential development of biological pattern/biomarker for different kinds of health abnormalities including cancer and mental diseases.
Prevalence of Malnutrition in Orally and Tube-Fed Elderly Nursing Home Residents in Germany and Its Relation to Health Complaints and Dietary Intake
Authors: Volkert Dorothee , Pauly Lioba , Stehle Peter , Sieber Cornel C.
Published: May 2011

Objective. To investigate the prevalence of malnutrition in orally and tube-fed nursing home (NH) residents in Germany and its relation to common health complaints and dietary intake.Methods. In 350 NH residents, subjects' characteristics, Mini Nutritional Assessment (MNA), and several health problems were inquired with the nursing staff using standardised interviews. In a subset of 122 residents, dietary intake was assessed by 3-day weighing records.Results. 7.7% of the participants were tube fed. 24.1% of orally nourished and 57.7% of tube-fed residents were malnourished (MNA < 17 p.). Malnutrition was significantly related to nausea/vomiting, constipation, pressure ulcers, dehydration, infections, antibiotic use, and hospitalisation. Mean daily energy intake was 1535 ± 413 kcal and mean protein intake was 54.2 ± 0.9 g/d irrespective of the nutritional state.Conclusion. In Germany, malnutrition is widespread among NH residents and is related to common health problems. The MNA rather reflects health condition than currently reduced dietary intake.
Existence of Oscillatory Solutions of Singular Nonlinear Differential Equations
Authors: Rachůnková Irena , Rachůnek Lukáš , Tomeček Jan
Published: May 2011

Asymptotic properties of solutions of the singular differential equation are described. Here, f is Lipschitz continuous on ℝ and has at least two zeros 0 and L > 0. The function p is continuous on [0, ∞) and has a positive continuous derivative on (0, ∞) and p(0) = 0. Further conditions for f and p under which the equation has oscillatory solutions converging to 0 are given.
Prognostic and Risk Factors in Patients with Locally Advanced Cutaneous Squamous Cell Carcinoma of the Trunk and Extremities
Authors: Vinicius de Lima Vazquez , Scapulatempo Cristovam , Perpetuo Natalia Martins , Mohamed Faheez , de Carvalho Teóclito Sachetto , de Oliveira Antônio Talvane Torres , Segalla José Getúlio Martins , Carvalho André Lopes
Published: May 2011

55 patients with advanced cutaneous squamous cell carcinoma (CSCC) of the trunk and extremities were studied.A Tissue Microarraywas constructed using immunohistochemistry to quantify expression of the HER family, E-cadherins, and podoplanin. Clinical and histopathological factors related to lymph node metastasis and prognosis were also established. Primary tumor positivity was 25.5% for EGFR, 87.3% for HER-3, and 48.1% for HER-4. Metastases were positive for EGFR in 41.7%, for HER-3 in 83.3%, and HER-4 in 43.5%. HER-2 was negative in all samples. Membrane E-cadherin and cytoplasmic E-cadherin were positive in 47.3% and 30.2% of primary tumors and 45.5% and 27.3% of metastases, respectively. Podoplanin was positive in 41.8% of primary tumors and 41.7% of metastases. Intratumoral lymphocytic infiltrate was associated with lymph node metastasis. Patients with T3 tumors had better cancer-specific survival (CSS) than those with T4 tumors; patients with no lymph node involvement had better CSS than patients with N1 tumors. Undifferentiated tumors and hyperexpression of podoplanin were negative prognostic indicators on multivariate analysis.
The Mammary Gland Microenvironment Directs Progenitor Cell FateIn Vivo
Authors: Bussard Karen M. , Smith Gilbert H.
Published: May 2011

The mammary gland is a unique organ that continually undergoes postnatal developmental changes. In mice, the mammary gland is formed via signals from terminal end buds, which direct ductal growth and elongation. Intriguingly, it is likely that the entire cellular repertoire of the mammary gland is formed from a single antecedent cell. Furthermore, in order to produce progeny of varied lineages (e.g., luminal and myoepithelial cells), signals from the local tissue microenvironment influence mammary stem/progenitor cell fate. Data have shown that cells from the mammary gland microenvironment reprogram adult somatic cells from other organs (testes, nerve) into cells that produce milk and express mammary epithelial cell proteins. Similar results were found for human tumorigenic epithelial carcinoma cells. Presently, it is unclear how the deterministic power of the mammary gland microenvironment controls epithelial cell fate. Regardless, signals generated by the microenvironment have a profound influence on progenitor cell differentiationin vivo.
A Moment Problem for Discrete Nonpositive Measures on a Finite Interval
Authors: Kalmykov M. U. , Sidorov S. P.
Published: May 2011

We will estimate the upper and the lower bounds of the integral , where μ runs over all discrete measures, positive on some cones of
generalized convex functions, and satisfying certain moment conditions with respect
to a given Chebyshev system. Then we apply these estimations to find the error of
optimal shape‐preserving interpolation.
Existence and Uniqueness Theorem for Stochastic Differential Equations with Self‐Exciting Switching
Authors: Hu Guixin , Wang Ke
Published: May 2011

We introduce a new kind of equation, stochastic differential equations with self‐exciting switching. Firstly, we give some preliminaries for this kind of equation, and then, we get the main results of our paper; that is, we gave the sufficient condition which can guarantee the existence and uniqueness of the solution.
The Marine Safety Simulation based Electronic Chart Display and Information System
Authors: Zhang Xin Yu , Yin Yong , YiCheng Jin , Sun XiaoFeng , HongXiang Ren
Published: May 2011

Navigation safety has a huge impact on the world economy and our everyday lives. One navigation safety simulation model in ECDIS based on international standard format (S‐57) is put forward, which is mainly involved in route plan and route monitoring. The universal kriging interpolation is used in the route planning and to compute the water depth of any place in the sea bottom. The man‐machine conversation method is taken to amend planned route to obtain autodeciding of feasibility according to ECDIS information, and the route monitoring algorithm is improved by enhancing its precision caused by screen coordinate conversion. The DCQA (distance close quarters situation of approach) model and TCQA (time close quarters situation of approach) model are adopted to judge if the close quarters situation or the risk of collision between own ship and target ship is emerging. All these methods are proven to be reliable through the navigation simulator made by Dalian Maritime University which is certified by DNV to class A.
A Study of the Quench Sensitivity of 6061-T6 and 6069-T6 Aluminum Alloys
Authors: Kassner M. E. , Geantil P. , Li X.
Published: May 2011

The purpose of this study is to investigate the quench sensitivity of the mechanical properties of 6061 and 6069 aluminum alloys. The relationship between mechanical properties and quench delay time at various temperatures between 200–500°C was determined. It was concluded that the 6069-T6 was somewhat more quench sensitive than 6061, which may be consistent with the composition difference. This study also provides increased data on the quench sensitivity of the traditional alloy, 6061-T6.
Protein Expression of Mesenchymal Stem Cells after Transfection of pcDNA3.1−‐hVEGF165 by Ultrasound‐Targeted Microbubble Destruction
Authors: Pu Zhaoxia , You Xiangdong , Xu Qiyuan , Gao Feng , Xie Xiaojie , Zhang Hong , Jian′an Wang
Published: May 2011

Ultrasound‐targeted microbubble destruction (UTMD) has been proposed as a new technique for organ‐specific gene transfer and drug delivery. This study was performed to investigate the effect of UTMD on marrow mesenchymal stem cells (MSCs) transfected with pcDNA3.1−‐hVEGF165.pcDNA3.1−‐hVEGF165 were transfected into the third passage of MSCs, with or without UTMD under different ultrasound conditions. Protein expression was quantified by hVEGF165‐ELISA kit after transfection for 24, 48, and 72 hours. UTMD‐mediated transfection of MSCs yielded a significant protein expression. UTMD of mechanic index (MI) 0.6 for 90 seconds led to the highest level of protein expression.
Gum Arabic as a Cause of Occupational Allergy
Authors: Viinanen Arja , Salokannel Maija , Lammintausta Kaija
Published: May 2011

Background. Gum arabic is a potential sensitizer in food industry. Methods. We examined 11 candy factory workers referred to examinations due to respiratory and skin symptoms paying attention to exposure and sensitization to gum arabic. Skin tests, pulmonary function tests, and respiratory provocation tests were carried out as indicated by the symptoms and findings. Results. Occupational asthma, caused by gum arabic was diagnosed in 4/11 candy factory workers and two of them had also occupational contact urticaria and one had occupational rhinitis. One of them had oral symptoms associated with ingestion of products containing gum arabic. Conclusions. Airborne exposure to gum arabic may cause sensitization leading to allergic rhinitis, asthma, and urticaria.
A New Ultra Fast Conduction Mechanism in Insulating Polymer Nanocomposites
Authors: Xu M. , Montanari G. C. , Fabiani D. , Dissado L. A. , Krivda A.
Published: May 2011

A brand new phenomenon, namely, electrical conduction via soliton-like ultra fast space charge pulses, recently identified in unfilled cross-linked polyethylene, is shown for the first time to occur in insulating polymer nanocomposites and its characteristics correlated with the electromechanical properties of nanostructured materials. These charge pulses are observed to cross the insulation under low electrical field in epoxy-based nanocomposites containing nanosilica particles with relative weights of 1%, 5%, 10%, and 20% at speeds orders of magnitude higher than those expected for carriers in insulating polymers. The characteristics of mobility, magnitude and repetition rate for both positive and negative charge pulses are studied in relation to nanofiller concentration. The results show that the ultra fast charge pulses (packets) are affected significantly by the concentration of nanoparticles. An explanation is presented in terms of a new conduction mechanism where the mechanical properties of the polymer and movement of polymer chains play an important role in the injection and transport of charge in the form of pulses. Here, the charge transport is not controlled by traps. Instead, it is driven by the contribution of polarization and the resultant electromechanical compression, which is substantially affected by the introduction of nanoparticles into the base polymer.
CCI-779 Inhibits Cell-Cycle G2–M Progression and Invasion of Castration-Resistant Prostate Cancer via Attenuation of UBE2C Transcription and mRNA Stability
Authors: Wang Hongyan , Zhang Chunpeng , Rorick Anna , Wu Dayong , Chiu Ming , Thomas-Ahner Jennifer , Chen Zhong , Chen Hongyan , Clinton Steven K. , Chan Kenneth K. , Wang Qianben
Published: May 2011

The cell-cycle G2–M phase gene UBE2C is overexpressed in various solid tumors including castration-resistant prostate cancer (CRPC). Our recent studies found UBE2C to be a CRPC-specific androgen receptor (AR) target gene that is necessary for CRPC growth, providing a potential novel target for therapeutic intervention. In this study, we showed that the G1–S cell-cycle inhibitor-779 (CCI-779), an mTOR inhibitor, inhibited UBE2C mRNA and protein expression in AR-positive CRPC cell models abl and C4-2B. Treatment with CCI-779 significantly decreased abl cell proliferation in vitro and in vivo through inhibition of cell-cycle progression of both G2–M and G1–S phases. In addition, exposure of abl and C4-2B cells to CCI-779 also decreased UBE2C-dependent cell invasion. The molecular mechanisms for CCI-779 inhibition of UBE2C gene expression involved a decreased binding of AR coactivators SRC1, SRC3, p300, and MED1 to the UBE2C enhancers, leading to a reduction in RNA polymerase II loading to the UBE2C promoter, and attenuation of UBE2C mRNA stability. Our data suggest that, in addition to its ability to block cell-cycle G1 to S-phase transition, CCI-779 causes a cell-cycle G2–M accumulation and an inhibition of cell invasion through a novel UBE2C-dependent mechanism, which contributes to antitumor activities of CCI-779 in UBE2C overexpressed AR-positive CRPC. Cancer Res; 71(14); 4866–76. ©2011 AACR.
Stem Cell Quiescence
Authors: Li Ling , Bhatia Ravi
Published: May 2011

Adult stem cells are maintained in a quiescent state but are able to exit quiescence and rapidly expand and differentiate in response to stress. The quiescent state appears to be necessary for preserving the self-renewal of stem cells and is a critical factor in the resistance of cancer stem cells (CSCs) to chemotherapy and targeted therapies. Limited knowledge about quiescence mechanisms has prevented significant advances in targeting of drug-resistant quiescent CSCs populations in the clinic. Thus, an improved understanding of the molecular mechanisms of quiescence in adult stem cells is critical for the development of molecularly targeted therapies against quiescent CSCs in different cancers. Recent studies have provided a better understanding of the intrinsic and extrinsic regulatory mechanisms that control stem cell quiescence. It is now appreciated that the p53 gene plays a critical role in regulating stem cell quiescence. Other intrinsic regulatory mechanisms include the FoxO, HIF-1α, and NFATc1 transcription factors and signaling through ATM and mTOR. Extrinsic microenvironmental regulatory mechanisms include angiopoietin-1, TGF-β, bone morphogenic protein, thrombopoietin, N-cadherin, and integrin adhesion receptors; Wnt/β-catenin signaling; and osteopontin. In this article, we review current advances in understanding normal stem cell quiescence, their significance for CSC quiescence and drug resistance, and the potential clinical applications of these findings. Clin Cancer Res; 17(15); 4936–41. ©2011 AACR.