bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-Term Potentiation Alters the Modulator Pharmacology of AMPA-Type Glutamate Receptors
Authors: Lin Bin , Brücher Fernando A. , Colgin Laura Lee , Lynch Gary
Published: December 2017

Changes in the biophysical properties of AMPA-type glutamate receptors have been proposed to mediate the expression of long-term potentiation (LTP). The present study tested if, as predicted from this hypothesis, AMPA receptor modulators differentially affect potentiated versus control synaptic currents. Whole cell recordings were collected from CA1 pyramidal neurons in hippocampal slices from adult rats. Within-neuron comparisons were made of the excitatory postsynaptic currents (EPSCs) elicited by two separate groups of Schaffer-collateral/commissural synapses. LTP was induced by theta burst stimulation in one set of inputs; cyclothiazide (CTZ), a drug that acts on the desensitization kinetics of AMPA receptors, was infused 30 min later. The decay time constants of the potentiated EPSCs prior to drug infusion were slightly, but significantly, shorter than those of control EPSCs. CTZ slowed the decay of the EPSCs, as reported in prior studies, and did so to a significantly greater degree in the potentiated synapses. Additionally, infusion of CTZ resulted in significantly greater effects on amplitude in potentiated pathways as compared with control pathways. The interaction between LTP and CTZ was also obtained in a separate set of experiments in which GABA receptor antagonists were used to block inhibitory postsynaptic currents. Additionally, there was no significant change in paired-pulse facilitation in the presence of CTZ, indicating that presynaptic effects of the drug were negligible. These findings provide new evidence that LTP modifies AMPA receptor kinetics. Candidates for the changes responsible for the observed effects of LTP were evaluated using a model of AMPA receptor kinetics; a simple increase in the channel opening rate provided the most satisfactory match with the LTP data.
NMDA Receptor Activation Mediates Hydrogen Peroxide–Induced Pathophysiology in Rat Hippocampal Slices
Authors: Avshalumov Marat V. , Rice Margaret E.
Published: December 2017

Endogenous reactive oxygen species (ROS) can act as modulators of neuronal activity, including synaptic transmission. Inherent in this process, however, is the potential for oxidative damage if the balance between ROS production and regulation becomes disrupted. Here we report that inhibition of synaptic transmission in rat hippocampal slices by H2O2can be followed by electrical hyperexcitability when transmission returns during H2O2washout. As in previous studies, H2O2exposure (15 min) reversibly depressed the extracellular population spike (PS) evoked by Schaffer collateral stimulation. Recovery of PS amplitude, however, was typically accompanied by mild epileptiform activity. Inclusion of ascorbate (400 μM) during H2O2washout prevented this pathophysiology. No protection was seen with isoascorbate, which is a poor substrate for the stereoselective ascorbate transporter and thus remains primarily extracellular. Epileptiform activity was also prevented by the N-methyl-d-aspartate (NMDA) receptor antagonist, dl-2-amino-5-phosphonopentanoic acid (AP5) during H2O2washout. Once hyperexcitability was induced, however, AP5 did not reverse it. When present during H2O2exposure, AP5 did not alter PS depression by H2O2but did inhibit the recovery of PS amplitude seen during pulse-train stimulation (10 Hz, 5 s) in H2O2. Inhibition of glutamate uptake by l- trans-2,4-pyrrolidine dicarboxylate (PDC; 50 μM) during H2O2washout markedly enhanced epileptiform activity; coapplication of ascorbate with PDC prevented this. These data indicate that H2O2exposure can cause activation of normally silent NMDA receptors, possibly via inhibition of redox-sensitive glutamate uptake. When synaptic transmission returns during H2O2washout, enhanced NMDA receptor activity leads to ROS generation and consequent oxidative damage. These data reveal a pathological cycle that could contribute to progressive degeneration in neurological disorders that involve oxidative stress, including cerebral ischemia.
Group I mGluRs Increase Excitability of Hippocampal CA1 Pyramidal Neurons by a PLC-Independent Mechanism
Authors: Ireland David R. , Abraham Wickliffe C.
Published: December 2017

Previous studies have implicated phospholipase C (PLC)-linked Group I metabotropic glutamate receptors (mGluRs) in regulating the excitability of hippocampal CA1 pyramidal neurons. We used intracellular recordings from rat hippocampal slices and specific antagonists to examine in more detail the mGluR receptor subtypes and signal transduction mechanisms underlying this effect. Application of the Group I mGluR agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) suppressed slow- and medium-duration afterhyperpolarizations (s- and mAHP) and caused a consequent increase in cell excitability as well as a depolarization of the membrane and an increase in input resistance. Interestingly, with the exception of the suppression of the mAHP, these effects were persistent, and in the case of the sAHP lasting for more than 1 h of drug washout. Preincubation with the specific mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), reduced but did not completely prevent the effects of DHPG. However, preincubation with both MPEP and the mGluR1 antagonist LY367385 completely prevented the DHPG-induced changes. These results demonstrate that the DHPG-induced changes are mediated partly by mGluR5 and partly by mGluR1. Because Group I mGluRs are linked to PLC via G-protein activation, we also investigated pathways downstream of PLC activation, using chelerythrine and cyclopiazonic acid to block protein kinase C (PKC) and inositol 1,4,5-trisphosphate-(IP3)-activated Ca2+stores, respectively. Neither inhibitor affected the DHPG-induced suppression of the sAHP or the increase in excitability nor did an inhibitor of PLC itself, U-73122. Taken together, these results argue that in CA1 pyramidal cells in the adult rat, DHPG activates mGluRs of both the mGluR5 and mGluR1 subtypes, causing a long-lasting suppression of the sAHP and a consequent persistent increase in excitability via a PLC-, PKC-, and IP3-independent transduction pathway.
Manipulating Objects With Internal Degrees of Freedom: Evidence for Model-Based Control
Authors: Dingwell Jonathan B. , Mah Christopher D. , Mussa-Ivaldi Ferdinando A.
Published: December 2017

There is substantial evidence that humans possess an accurate and adaptable internal model of the dynamics of their arm that is utilized by the nervous system for controlling arm movements. However, it is not known if such model-based strategies are used for controlling dynamical systems outside the body. The need to predict events in the external world is not restricted to the execution of reaching movements or to the handling of rigid tools. Model-based control may also be critical for performing functional tasks with non-rigid objects such as stabilizing a cup of coffee. The present study investigated the strategies used by humans to control simple mass-spring objects. Subjects made straight line reaching movements to a target while interacting with a robotic manipulandum that simulated the dynamics of a one-dimensional mass on a spring. After learning, neither hand nor object kinematics returned to those of free reaching, suggesting that this task was not learned as a perturbation of free reaching. Although there are control strategies (such as slowing the movement of the hand) that would require little or no knowledge of object dynamics, subjects did not adopt these strategies. Instead, they tailored their motor commands to the particular object being manipulated. When object parameters were unexpectedly altered in a way that required no changes in kinematics to successfully complete the task, subjects nonetheless exhibited substantial kinematic deviations. These deviations were consistent with those predicted by a model of the arm-plus-object system driven by a low-impedance controller that incorporated an explicit inverse model of arm-plus-object dynamics. The observed behavior could not be reproduced by a controller that relied on modulating hand impedance alone with no inverse model. These results were therefore consistent with the hypothesis that subjects learn to control the kinematics of manipulated objects by forming an internal model that specified the forces to be exerted by the hand on the object to induce the desired motion of that object.
Interhemispheric Transmission of Visuomotor Information in Humans: fMRI Evidence
Authors: Tettamanti M. , Paulesu E. , Scifo P. , Maravita A. , Fazio F. , Perani D. , Marzi C. A.
Published: December 2017

Normal human subjects underwent functional magnetic resonance imaging (fMRI) while performing a simple visual manual reaction-time (RT) task with lateralized brief stimuli, the so-called Poffenberger's paradigm. This paradigm was employed to measure interhemispheric transmission (IT) time by subtracting mean RT for the uncrossed hemifield-hand conditions, that is, those conditions not requiring an IT, from the crossed hemifield-hand conditions, that is, those conditions requiring an IT to relay visual information from the hemisphere of entry to the hemisphere subserving the response. The obtained difference is widely believed to reflect callosal conduction time, but so far there is no direct physiological evidence in humans. The aim of our experiment was twofold: first, to test the hypothesis that IT of visuomotor information requires the corpus callosum and to identify the cortical areas specifically activated during IT. Second, we sought to discover whether IT occurs mainly at premotor or perceptual stages of information processing. We found significant activations in a number of frontal, parietal, and temporal cortical areas and in the genu of the corpus callosum. These activations were present only in the crossed conditions and therefore were specifically related to IT. No selective activation was present in the uncrossed conditions. The location of the activated callosal and cortical areas suggests that IT occurs mainly, but not exclusively, at premotor level. These results provide clear cut evidence in favor of the hypothesis that the crossed-uncrossed difference in the Poffenberger paradigm depends on IT rather than on a differential hemispheric activation.
Synaptic Inhibition of Pyramidal Cells Evoked by Different Interneuronal Subtypes in Layer V of Rat Visual Cortex
Authors: Xiang Zixiu , Huguenard John R. , Prince David A.
Published: December 2017

Properties of GABAA receptor-mediated unitary inhibitory postsynaptic currents (uIPSCs) in pyramidal (P) cells, evoked by fast spiking (FS) and low-threshold spike (LTS) subtypes of interneurons in layer V of rat visual cortex slices were examined using dual whole cell recordings. uIPSCs evoked by FS cells were larger and faster rising than those evoked by LTS cells, consistent with the known primary projections of FS and LTS cell axons to perisomatic and distal dendritic areas of layer V pyramidal cells, respectively, and the resulting electrotonic attenuation for LTS-P synaptic events. Unexpectedly, the decay time constants for LTS-P and FS-P uIPSCs were not significantly different. Modeling results were consistent with differences in the underlying GABAAreceptor–mediated conductance at LTS-P and FS-P synapses. Paired-pulse depression (PPD), present at both synapses, was associated with an increase in failure rate and a decrease in coefficient of variation, indicating that presynaptic mechanisms were involved. Furthermore, the second and first uIPSC amplitudes during PPD were not inversely correlated, suggesting that PPD at both synapses is independent of previous release and might not result from depletion of the releasable pool of synaptic vesicles. Short, 20-Hz trains of action potentials in presynaptic interneurons evoked trains of uIPSCs with exponentially decreasing amplitudes at both FS-P and LTS-P synapses. FS-P uIPSC amplitudes declined more slowly than those of LTS-P uIPSCs. Thus FS and LTS cells, with their differences in firing properties, synaptic connectivity with layer V P cells, and short-term synaptic dynamics, might play distinct roles in regulating the input-output relationship of the P cells.
A Ba2+-Sensitive K+ Current Contributes to the Resting Membrane Potential of Neurons in Rat Suprachiasmatic Nucleus
Authors: de Jeu Marcel , Geurtsen Alwin , Pennartz Cyriel
Published: December 2017

A Ba2+-sensitive K+ current was studied in neurons of the suprachiasmatic nucleus (SCN) using the whole cell patch-clamp technique in acutely prepared brain slices. This Ba2+-sensitive K+ current was found in approximately 90% of the SCN neurons and was uniformly distributed across the SCN. Current-clamp studies revealed that Ba2+ (500 μM) reversibly depolarized the membrane potential by 6.7 ± 1.3 mV ( n = 22) and concomitantly Ba2+ induced an increase in the spontaneous firing rate of 0.8 ± 0.2 Hz ( n = 12). The Ba2+-evoked depolarizations did not depend on firing activity or spike dependent synaptic transmission. No significant day/night difference in the hyperpolarizing contribution to the resting membrane potential of the present Ba2+-sensitive current was observed. Voltage-clamp experiments showed that Ba2+ (500 μM) reduced a fast-activating, voltage-dependent K+ current. This current was activated at levels below firing threshold and exhibited outward rectification. The Ba2+-sensitive K+ current was strongly reduced by tetraethylammonium (TEA; 20 and 60 mM) but was insensitive to 4-aminopyridine (4-AP; 5 mM) and quinine (100 μM). A component of Ba2+-sensitive K+ current remaining in the presence of TEA exhibited no clear voltage dependence and is less likely to contribute to the resting membrane potential. The voltage dependence, kinetics and pharmacological properties of the Ba2+- and TEA-sensitive K+ current make it unlikely that this current is a delayed rectifier, Ca2+-activated K+ current, ATP-sensitive K+ current, M-current or K+ inward rectifier. Our data are consistent with the Ba2+- and TEA-sensitive K+ current in SCN neurons being an outward rectifying K+ current of a novel identity or belonging to a known family of K+ channels with related properties. Regardless of its precise molecular identity, the current appears to exert a significant hyperpolarizing effect on the resting potential of SCN neurons.
Sensorimotor Integration in Human Postural Control
Authors: Peterka R. J.
Published: December 2017

It is generally accepted that human bipedal upright stance is achieved by feedback mechanisms that generate an appropriate corrective torque based on body-sway motion detected primarily by visual, vestibular, and proprioceptive sensory systems. Because orientation information from the various senses is not always available (eyes closed) or accurate (compliant support surface), the postural control system must somehow adjust to maintain stance in a wide variety of environmental conditions. This is the sensorimotor integration problem that we investigated by evoking anterior-posterior (AP) body sway using pseudorandom rotation of the visual surround and/or support surface (amplitudes 0.5–8°) in both normal subjects and subjects with severe bilateral vestibular loss (VL). AP rotation of body center-of-mass (COM) was measured in response to six conditions offering different combinations of available sensory information. Stimulus-response data were analyzed using spectral analysis to compute transfer functions and coherence functions over a frequency range from 0.017 to 2.23 Hz. Stimulus-response data were quite linear for any given condition and amplitude. However, overall behavior in normal subjects was nonlinear because gain decreased and phase functions sometimes changed with increasing stimulus amplitude. “Sensory channel reweighting” could account for this nonlinear behavior with subjects showing increasing reliance on vestibular cues as stimulus amplitudes increased. VL subjects could not perform this reweighting, and their stimulus-response behavior remained quite linear. Transfer function curve fits based on a simple feedback control model provided estimates of postural stiffness, damping, and feedback time delay. There were only small changes in these parameters with increasing visual stimulus amplitude. However, stiffness increased as much as 60% with increasing support surface amplitude. To maintain postural stability and avoid resonant behavior, an increase in stiffness should be accompanied by a corresponding increase in damping. Increased damping was achieved primarily by decreasing the apparent time delay of feedback control rather than by changing the damping coefficient (i.e., corrective torque related to body-sway velocity). In normal subjects, stiffness and damping were highly correlated with body mass and moment of inertia, with stiffness always about 1/3 larger than necessary to resist the destabilizing torque due to gravity. The stiffness parameter in some VL subjects was larger compared with normal subjects, suggesting that they may use increased stiffness to help compensate for their loss. Overall results show that the simple act of standing quietly depends on a remarkably complex sensorimotor control system.
Effects of Voluntary Blinks on Saccades, Vergence Eye Movements, and Saccade-Vergence Interactions in Humans
Authors: Rambold H. , Sprenger A. , Helmchen C.
Published: December 2017

Blinks are known to change the kinematic properties of horizontal saccades, probably by influencing the saccadic premotor circuit. The neuronal basis of this effect could be explained by changes in the activity of omnipause neurons in the nucleus raphe interpositus or in the saccade-related burst neurons of the superior colliculus. Omnipause neurons cease discharge during both saccades and vergence movements. Because eyelid blinks can influence both sets of neurons, we hypothesized that blinks would influence the kinematic parameters of saccades in all directions, vergence, and saccade-vergence interactions. To test this hypothesis, we investigated binocular eye and lid movements in five normal healthy subjects with the magnetic search coil technique. The subjects performed conjugate horizontal and vertical saccades from gaze straight ahead to targets at 20° up, down, right, or left while either attempting not to blink or voluntarily blinking. While following the same blink instruction, subjects made horizontal vergence eye movements of 7° and combined saccade-vergence movements with a version amplitude of 20°. The movements were performed back and forth from two targets simultaneously presented nearby (38 cm) and more distant (145 cm). Small vertical saccades accompanied most vergence movements. These results show that blinks change the kinematics (saccade duration, peak velocity, peak acceleration, peak deceleration) of not only horizontal but also of vertical saccades, of horizontal vergence eye movements, and of combined saccade-vergence eye movements. Peak velocity, acceleration, and deceleration of eye movements were decreased on the average by 30%, and their duration increased by 43% on the average when they were accompanied by blinks. The blink effect was time dependent with respect to saccade and vergence onset: the greatest effect occurred 100 ms prior to saccade onset, whereas there was no effect when the blink started after saccade onset. The effects of blinks on saccades and vergence, which are tightly coupled to latency, support the hypothesis that blinks cause profound spatiotemporal perturbations of the eye movements by interfering with the normal saccade/vergence premotor circuits. However, the measured effect may to a certain degree but not exclusively be explained by mechanical interference.
Mutability of Bifunctional Thigh Muscle Activity in Pedaling due to Contralateral Leg Force Generation
Authors: Kautz S. A. , Brown D. A. , Van der Loos H.F.M. , Zajac F. E.
Published: December 2017

Locomotion requires uninterrupted transitions between limb extension and flexion. The role of contralateral sensorimotor signals in executing smooth transitions is little understood even though their participation is crucial to bipedal walking. However, elucidating neural interlimb coordinating mechanisms in human walking is difficult because changes to contralateral sensorimotor activity also affect the ipsilateral mechanics. Pedaling, conversely, is ideal for studying bilateral coordination because ipsilateral mechanics can be independently controlled. In pedaling, the anterior and posterior bifunctional thigh muscles develop needed anterior and posterior crank forces, respectively, to dominate the flexion-to-extension and extension-to-flexion transitions. We hypothesized that contralateral sensorimotor activity substantially contributes to the appropriate activation of these bifunctional muscles during the limb transitions. Bilateral pedal forces and surface electromyograms (EMGs) from four thigh muscles were collected from 15 subjects who pedaled with their right leg against a right-crank servomotor, which emulated the mechanical load experienced in conventional two-legged coupled-crank pedaling. In one pedaling session, the contralateral (left) leg pseudo-pedaled (i.e., EMG activity and pedal forces were pedaling-like, but pedal force was not allowed to affect crank rotation). In other sessions, the mechanically decoupled contralateral leg was first relaxed and then produced rhythmic isometric force trajectories during either leg flexion or one of the two limb transitions of the pedaling leg. With contralateral force production in the extension-to-flexion transition (predominantly by the hamstrings), rectus femoris activity and work output increased in the pedaling leg during its flexion-to-extension transition, which occurs simultaneously with contralateral extension-to-flexion in conventional pedaling. Similarly, with contralateral force production in the other transition (i.e., flexion-to-extension; predominantly by rectus femoris), hamstrings activity and work output increased in the pedaling leg during its extension-to-flexion transition. Therefore rhythmic isometric force generation in the contralateral leg supported the ongoing bifunctional muscle activity and resulting work output in the pedaling leg. The results suggest that neural interlimb coordinating mechanisms fine-tune bifunctional muscle activity in rhythmic lower-limb tasks to ensure limb flexion/extension transitions are executed successfully.
Two Types of Nicotinic Receptors Mediate an Excitation of Neocortical Layer I Interneurons
Authors: Christophe Elodie , Roebuck Aline , Staiger Jochen F. , Lavery Daniel J. , Charpak Serge , Audinat Etienne
Published: December 2017

Nicotinic acetylcholine receptors are widely expressed in the neocortex but their functional roles remain largely unknown. Here we investigated the effect of nicotinic receptor activation on interneurons of layer I, which contains a high density of cholinergic fiber terminals. Ninety-seven of 101 neurons recorded in whole cell configuration in rat acute slices were excited by local pressure application of nicotinic agonists, acetylcholine (500 μM), 1,1-dimethyl-4-phenyl-piperazinium (500 μM) or choline (10 mM). Biocytin labeling confirmed that our sample included different morphological types of layer I interneurons. The responses to nicotinic agonists persisted in presence of glutamate and muscarinic receptor antagonists and on further addition of Cd2+ or tetrodotoxin, indicating that they were mediated by direct activation of postsynaptic nicotinic receptors. The kinetics of the currents and their sensitivity to nicotinic receptor antagonists, methyllycaconitine (1–10 nM) or dihydro-β-erythroidine (500 nM), suggested that early and late components of the responses were mediated by α7 and non-α7 types of receptors. Both components had inwardly rectifying I-V curves, which differed when intracellular spermine was omitted. Single-cell RT-PCR experiments identified α4, α7, and β2 as the predominantly expressed mRNAs, suggesting that the receptors consisted of α7 homomers and α4β2 heteromers. Finally, selective excitation of layer I interneurons through activation of their nicotinic receptors resulted in a tetrodotoxin-sensitive increase of inhibitory synaptic currents recorded in nonpyramidal cells but not in pyramidal cells of layer II/III. These results suggest that acetylcholine released in layer I may induce a disinhibition of the cortical network through activation of nicotinic receptors expressed by layer I interneurons.
Calcium-Dependent Regulation of Cholinergic Cell Phenotype in the Hypothalamus In Vitro
Authors: Belousov Andrei B. , Hunt Nicole D. , Raju Ryan P. , Denisova Janna V.
Published: December 2017

Glutamate is a major fast excitatory neurotransmitter in the CNS including the hypothalamus. Our previous experiments in hypothalamic neuronal cultures showed that a long-term decrease in glutamate excitation upregulates ACh excitatory transmission. Data suggested that in the absence of glutamate activity in the hypothalamus in vitro, ACh becomes the major excitatory neurotransmitter and supports the excitation/inhibition balance. Here, using neuronal cultures, fura-2 Ca2+ digital imaging, and immunocytochemistry, we studied the mechanisms of regulation of cholinergic properties in hypothalamic neurons. No ACh-dependent activity and a low number (0.5%) of cholinergic neurons were detected in control hypothalamic cultures. A chronic (2 wk) inactivation of N-methyl-d-aspartate (NMDA) ionotropic glutamate receptors, L-type voltage-gated Ca2+ channels, calmodulin, Ca2+/calmodulin-dependent protein kinases II/IV (CaMK II/IV), or protein kinase C (PKC) increased the number of cholinergic neurons (to 15–24%) and induced ACh activity (in 40–60% of cells). Additionally, ACh activity and an increased number of cholinergic neurons were detected in hypothalamic cultures 2 wk after a short-term (30 min) pretreatment with bis-( o-aminophenoxy)- N,N,N′,N′-tetraacetic acid tetrakis(acetoxy-methyl) ester (BAPTA AM; 2.5 μM), a membrane permeable Ca2+-chelating agent that blocks cytoplasmic Ca2+ fluctuations. An increase in the number of cholinergic neurons following a chronic NMDA receptor blockade was likely due to the induction of cholinergic phenotypic properties in postmitotic noncholinergic neurons, as determined using 5-bromo-2′-deoxyuridine (BrdU) labeling. In contrast, a chronic inactivation of non-NMDA glutamate receptors or cGMP-dependent protein kinase had little effect on the expression of ACh properties. The data suggest that Ca2+, at normal intracellular concentrations, tonically suppresses the development of cholinergic properties in hypothalamic neurons. However, a decrease in Ca2+ influx into cells (through NMDA receptors or L-type Ca2+ channels), inactivation of intracellular Ca2+ fluctuations, or downregulation of Ca2+-dependent signal transduction pathways (CaMK II/IV and PKC) remove the tonic inhibition and trigger the development of cholinergic phenotype in some hypothalamic neurons. An increase in excitatory ACh transmission may represent a novel form of neuronal plasticity that regulates the activity and excitability of neurons during a decrease in glutamate excitation. This type of plasticity has apparent region-specific character and is not expressed in the cortex in vitro; neither increase in ACh activity nor change in the number of cholinergic neurons were detected in cortical cultures under all experimental conditions.
Acute Topical Application of Tumor Necrosis Factor α Evokes Protein Kinase A-Dependent Responses in Rat Sensory Neurons
Authors: Zhang Jun-Ming , Li Huiqing , Liu Baogang , Brull Sorin J.
Published: December 2017

Local perfusion of the dorsal root ganglion (DRG) with tumor necrosis factor α (TNF-α) in rats induces cutaneous hypersensitivity to mechanical stimuli. Thus we investigated the cellular mechanisms of TNF-α-induced mechanical hyperalgesia. The L4and L5 DRGs with the sciatic nerves attached were excised from rats for in vitro dorsal root microfilament recording. After baseline recording for 15 min, TNF-α (0.001, 0.01, 0.1, or 1 ng/ml) was applied to the DRG for 15 min, followed by washout for at least 30 min. Alternatively, H-89 or Rp-cAMPS, two specific cAMP-dependent protein kinase (PKA) inhibitors, was added to the perfusion solution for 15 min prior to TNF-α application. TNF-α (1 ng/ml) induced neuronal discharges in 67% (14/21) of C fibers and 27% (4/15) of Aβ fibers when applied topically to the DRG. Acute TNF-α application not only evoked discharges in silent fibers, but also enhanced ongoing activity of spontaneously active fibers and increased neuronal sensitivity to electrical stimulation of the peripheral nerves. H-89 (10 μM) and Rp-cAMPS (100 μM) each completely blocked the TNF-α-evoked response in most C and Aβ fibers tested but did not affect fiber conductivity. Our results demonstrates that exogenous inflammatory cytokines such as TNF-α can elicit a PKA-dependent response in sensory neurons and thus strongly suggest that endogenous TNF-α may contribute to the development of certain pathological pain states.
Saccade Target Selection in the Superior Colliculus During a Visual Search Task
Authors: McPeek Robert M. , Keller Edward L.
Published: December 2017

Because real-world scenes typically contain many different potential objects of interest, selecting one goal from many is clearly a fundamental problem faced by the saccadic system. We recorded from visual, movement, and visuo-movement (VM) neurons in the superior colliculus (SC) of monkeys performing a reaction-time visual-search task requiring them to make saccades to an odd-colored target presented with distractors. First, we compared the responses of SC neurons in search with their responses when a single target was presented without distractors (single-stimulus task). Consistent with earlier reports, initial visual activity was smaller in search than in the single-stimulus task, while movement-related activity in the two tasks was comparable. Further experiments showed that much of the reduction in the initial visual response during search was due to lateral inhibition, although a top-down task-related component was also evident. Although the initial visual activity did not discriminate the target from the distractors, some neurons showed a biphasic pattern of visual activity. In VM burst neurons, the second phase of this activity was significantly larger when the target, rather than a distractor, was in the response field. We traced the time course of target/distractor discrimination using receiver operating characteristic (ROC) analysis and found that VM burst neurons, VM prelude neurons, and pure movement neurons discriminated the target from distractors before saccade onset but that phasic and tonic pure visual neurons did not. We also examined the relationship between target/distractor discrimination time and saccade latency. Discrimination in VM burst neurons having a biphasic pattern of visual activity and in many VM prelude neurons occurred after a consistent delay that did not depend on saccade latency, suggesting that these neurons are involved in target selection as well as movement initiation. In contrast, VM burst neurons lacking a biphasic pattern of visual activity, pure movement neurons, and a subset of VM prelude neurons discriminated the target at a time that was well correlated with saccade latency, suggesting that this latter group of neurons is involved in triggering movement execution but not in target selection. Thus a mix of signals likely related to target selection and movement initiation co-exists in different groups of SC neurons. This suggests that certain types of SC neurons participate in the target selection process and that the SC as a whole represents a gateway for target selection signals to be converted into a saccadic command.
A Method for Multidisciplinary System Analysis Based on Minimal Feedback Variables
Authors: Yin Qian , Wu Yizhong , Wang Boxing
Published: December 2017

As modern engineering design usually involves dependence of one discipline on another, multidisciplinary system analysis (MDSA) plays an important role in the multidisciplinary simulation and design optimization on coupled systems. The paper proposes an MDSA method based on minimal feedback variables (MDSA_MF) to enhance the solving efficiency. There are two phases in the method. In phase 1, design structural matrix (DSM) is introduced to represent a coupled system, and each off‐diagonal element is denoted by a coupling variable set; then an optimal sequence model is built to obtain a reordered DSM with minimal number of feedback variables. In phase 2, the feedback in the reordered DSM is broken, so that the coupled system is transformed into one directed acyclic graph; then, regarding the inputs depending on the broken feedback as independent variables, a least‐squares problem is constructed to minimize the residuals of these independents and corresponding outputs to zero, which means the multidisciplinary consistence is achieved. Besides, the MDSA_MF method is implemented in a multidisciplinary platform called FlowComputer. Several examples of coupled systems are modeled and solved in the platform using several MDSA methods. The results demonstrate that the proposed method could enhance the solving efficiency of coupled systems.
Trichomonas vaginalis Induces SiHa Cell Apoptosis by NF-κB Inactivation via Reactive Oxygen Species
Authors: Quan Juan-Hua , Kang Byung-Hun , Yang Jung-Bo , Rhee Yun-Ee , Noh Heung-Tae , Choi In-Wook , Cha Guang-Ho , Yuk Jae-Min , Lee Young-Ha
Published: December 2017

Trichomonas vaginalis induces apoptosis in host cells through various mechanisms; however, little is known about the relationship between apoptosis, reactive oxygen species (ROS), and NF-κB signaling pathways in the cervical mucosal epithelium. Here, we evaluated apoptotic events, ROS production, and NF-κB activity in T. vaginalis-treated cervical mucosal epithelial SiHa cells, with or without specific inhibitors, using fluorescence microscopy, DNA fragmentation assays, subcellular fractionation, western blotting, and luciferase reporter assay. SiHa cells treated with live T. vaginalis at a multiplicity of infection of 5 (MOI 5) for 4 h produced intracellular and mitochondrial ROS in a parasite-load-dependent manner. Incubation with T. vaginalis caused DNA fragmentation, cleavage of caspase 3 and PARP, and release of cytochrome c into the cytoplasm. T. vaginalis-treated SiHa cells showed transient early NF-κB p65 nuclear translocation, which dramatically dropped at 4 h after treatment. Suppression of NF-κB activity was dependent on parasite burden. However, treatment with the ROS scavenger, N-acetyl-C-cysteine (NAC), reversed the effect of T. vaginalis on apoptosis and NF-κB inactivation in SiHa cells. Taken together, T. vaginalis induces apoptosis in human cervical mucosal epithelial cells by parasite-dose-dependent ROS production through an NF-κB-regulated, mitochondria-mediated pathway.
Localized Subcutaneous Insulin-Derived Amyloidosis Excised after Evaluation Using Ultrasonography in a Patient with Type 2 Diabetes Mellitus
Authors: Hagiwara Seiya , Taneda Shinji , Fukumoto Takaya , Hagiwara Kazuya , Kikuchi Minoru , Kimura Tetsunori , Nakayama Hidetaka , Manda Naoki
Published: December 2017

A 62-year-old man with type 2 diabetes mellitus, who had been on insulin therapy for the past 20 years, was found to have subcutaneous mass formation in the abdomen during a workup of worsened glycemic control. Because of suspected amyloid deposition, he was advised to avoid injections to the mass, which led to improvement of glycemic control. However, he strongly requested mass excision and was hospitalized. After evaluation using ultrasonography and computed tomography, a total mass excision was performed, and a diagnosis of insulin-derived amyloidosis was made. Comparison of the ultrasonographic and histopathological findings demonstrated that the location of the amyloid deposition nearly corresponded to the hypoechoic region. This case highlights that ultrasonography, which is a noninvasive imaging modality, can be useful for detection of insulin-derived amyloidosis.
Defining the Optimal Time of Adaptive Replanning in Prostate Cancer Patients with Weight Change during Volumetric Arc Radiotherapy: A Dosimetric and Mathematical Analysis Using the Gamma Index
Authors: Choi Hoon Sik , Jo Guang Sub , Chae Jong Pyo , Lee Sang Bong , Kim Chul Hang , Jeong Bae Kwon , Jeong Hojin , Lee Yun Hee , Ha In Bong , Kang Ki Mun , Song Jin Ho
Published: December 2017

We evaluated the changes in the dose distribution of radiation during volumetric arc radiotherapy (VMAT), to determine the right time for adaptive replanning in prostate cancer patients with progressive weight (WT) changes. Five prostate cancer patients treated with VMAT were selected for dosimetric analysis. On the original computed tomography images, nine artificial body contours were created to reflect progressive WT changes. Combined with three different photon energies (6, 10, and 15-MV), 27 comparable virtual VMAT plans were created per patient. The dosimetric analysis included evaluation of target coverage (D95%,Dmax), conformity index, homogeneity index, and organs at risk doses. The dose differences among the plans were determined using the gamma index analysis and were compared with the dosimetric analysis. Mean D95% became lower than 98% when body contour expanded by 2.0 cm or more and Dmax became higher than 107% when body contour contracted by 1.5 cm or more in 10-MV plans. This cut-off values correlated well with gamma index analysis results. Adaptive replanning should, therefore, be considered if the depth of body contour becomes 1.5 cm smaller (WT loss) or 2.0 cm larger (WT gain) in patients treated by VMAT with 10-MV photons.
Increased Abundance of Plasmacytoid Dendritic Cells and Interferon-Alpha Induces Plasma Cell Differentiation in Patients of IgA Nephropathy
Authors: Zheng Nuoyan , Wang Bing , Fan Jinjin , Luo Ning , Kong Qingyu , Ye Hongjian , Zhang Jiqin , Ming Hongyan , Yu Xueqing
Published: December 2017

The roles of pDC and IFN-αhave not been well defined in IgA nephropathy (IgAN). In this study, we investigated the abundance of pDCs and IFN-αin IgAN patients and the response of peripheral blood mononuclear cells (PBMCs) after stimulation of the pDC-preferred TLR9 ligand CpG2216. The effects of IFN-αon plasma cell differentiation and leukocyte migration were also investigated. Here, we found that the percentages of pDCs were increased in PBMCs of IgAN patients, than in those of healthy controls. Plasma levels of IFN-αproteins and abundance of plasma cells were higher in IgAN patients than in healthy donors. Plasma IFN-αlevels were positively associated with proteinuria, renal IgM deposition, and renal tubular atrophy/interstitial fibrosis grade in IgAN patients. Ex vivo activation of TLR9 on pDCs resulted in increased IFN-αproduction and enhanced plasma cell differentiation in IgAN patients as compared with healthy donors. IFN-αtreatment led to increased plasma cell differentiationin vitro. IFN-αalso significantly promoted expression of chemokines IP-10 and MCP-1 in human mesangial cells, which subsequently facilitated the transendothelial migration of human CD4+and CD14+cells. In conclusion, pDC and its secreted cytokine IFN-αmay play important roles in pathological changes of IgA nephropathy.
The “Invisible Hand” of Economic Markets Can Be Visualized through the Synergy Created by Division of Labor
Authors: Jaffé Klaus
Published: December 2017

Inspired by Adam Smith and Friedrich Hayek, economists promoting free markets postulate the existence of invisible forces that drive economic growth. Simulations with Sociodynamica allowed the emergence of market forces in virtual economies, showing that the synergistic working of division of labor in complex settings favors a stable state where all actors benefit (win-win interaction). By visualizing the detailed dynamics underlying this phenomenon in a simple virtual economy, the elements underpinning the synergistic effect on economic output produced by the division of labor between agents could be dissected. These are heterogeneity or spatial or temporal heterogeneous environment and/or agents; complementary activities of agents, with divergent optimization options; and synchrony. Markets help synchronize agent’s actions. The larger the contact horizon between participants of the market is, the more efficient the market forces act. These features allow for social processes that increase the information available and increase simultaneously the capacity of producing useful economic work, that is, synergy. This insight, although trivial if viewed a posteriori, improves our understanding of the source and nature of synergies in real economic markets and might render economic and natural sciences more consilient.
The Solubility of Tugarinovite (MoO2) in H2O at Elevated Temperatures and Pressures
Authors: Saha Pritam , Anderson Alan J. , Lee Thomas , Klemm Matthias
Published: December 2017

The solubility of tugarinovite (MoO2) in pure water was investigated at temperatures between 400 and 800°C and at pressures ranging between 95 and 480 MPa by using in situ synchrotron X-ray fluorescence (SXRF) to separately analyze high temperature aqueous solutions in a hydrothermal diamond anvil cell (HDAC). The concentration of molybdenum in the fluid at 400 and 500°C was below detection; however, at temperatures between 600 and 800°C, the solubility of tugarinovite increased with increasing temperature by two orders of magnitude. The molybdenum concentration at 600°C and 800°C is 44 ppm and 658 ppm, respectively. The results complement the data of Kudrin (1985) and provide the first measurement of MoO2 solubility at pressure and temperature conditions comparable to intrusion-related Mo deposit formation. The data are also relevant to the study of water chemistry and corrosion product transport in supercritical-water-cooled reactors, where Mo-bearing steel alloys interact with aqueous solutions at temperatures greater than 600°C. The application of in situ SXRF to solubility measurements of sparingly soluble minerals is recommended because it circumvents analytical uncertainties inherent in determinations obtained by quenching and weight loss measurements.
Synthesis, Spectroscopic, and Thermal Investigations of Metal Complexes with Mefenamic Acid
Authors: Kafarska Karolina , Gacki Michał , Wolf Wojciech M.
Published: December 2017

The novel metal complexes with empirical formulae M(mef)2·nH2O (where M = Mn(II), Co(II), Ni(II), Cu(II), Zn(II), and Cd(II); mef is the mefenamic ligand) were synthesized and characterized by elemental analysis, molar conductance, FTIR-spectroscopy, and thermal decomposition techniques. All IR spectra revealed absorption bands related to the asymmetric (νas) and symmetric (νs) vibrations of carboxylate group. The Nakamoto criteria clearly indicate that this group is bonded in a bidentate chelate mode. The thermal behavior of complexes was studied by TGA methods under non-isothermal condition in air. Upon heating, all compounds decompose progressively to metal oxides, which are the final products of pyrolysis. Cu(II), Zn(II), and Cd(II) complexes were also characterized by the coupled TG-FTIR technique, which finally proved the path and gaseous products of thermal decomposition. Additionally, the coupled TG-MS system was used to determine the principal volatile products of thermolysis and fragmentation processes of Mn(mef)2·3H2O and Co(mef)2·2H2O.
A Stochastic Programming Approach for Resilient Hub Location in Power Projection Network considering Random Hub Failures
Authors: Zhang Xu-Tao , Bi Hai-Ling , Wang Yun
Published: December 2017

Hubs are critical facilities in the power projection network. Due to the uncertainty factors such as terrorism threats, severe weather, and natural disasters, hub facilities may be disrupted randomly, which could lead to excessive cost or loss in practice. One of the most effective ways to withstand and reduce the impact of disruptions is designing more resilient networks. In this paper, a stochastic programming model is employed for the hub location problem in the presence of random hub failures. A heuristic algorithm based on Monte Carlo method and tabu search is put forward to solve the model. The proposed approach is more general if there are numbers of hubs that would fail even with different failure probability. Compared with the benchmark model, the model which takes the factor of stochastic failure of hubs into account can give a more resilient power projection network.
Parameter Estimation of a Reliability Model of Demand‐Caused and Standby‐Related Failures of Safety Components Exposed to Degradation by Demand Stress and Ageing That Undergo Imperfect Maintenance
Authors: Martorell S. , Martorell P. , Sánchez A. I. , Mullor R. , Martón I.
Published: December 2017

One can find many reliability, availability, and maintainability (RAM) models proposed in the literature. However, such models become more complex day after day, as there is an attempt to capture equipment performance in a more realistic way, such as, explicitly addressing the effect of component ageing and degradation, surveillance activities, and corrective and preventive maintenance policies. Then, there is a need to fit the best model to real data by estimating the model parameters using an appropriate tool. This problem is not easy to solve in some cases since the number of parameters is large and the available data is scarce. This paper considers two main failure models commonly adopted to represent the probability of failure on demand (PFD) of safety equipment: (1) by demand‐caused and (2) standby‐related failures. It proposes a maximum likelihood estimation (MLE) approach for parameter estimation of a reliability model of demand‐caused and standby‐related failures of safety components exposed to degradation by demand stress and ageing that undergo imperfect maintenance. The case study considers real failure, test, and maintenance data for a typical motor‐operated valve in a nuclear power plant. The results of the parameters estimation and the adoption of the best model are discussed.
A Direct Correlation between Viscosity and Liquid Structure in Cu-Sn Alloys
Authors: Zhao Yan , Hou Xiaoxia
Published: December 2017

The viscosity and liquid structure of Cu100-xSnx (x=10, 20, 30, 40, at.%) melts were investigated. Temperature dependence of viscosity η and correlation length D all shows an exponential decay function (Arrhenius-type equation), which is similar to our former studied Cu-Ag alloys. The correlation between viscosity and liquid structure had been studied. A simple relation between viscosity and correlation length D was found. The ratio of D and η shows a linear relationship with temperature, which is different from our former studied results in Cu-Ag alloys. Among the four Cu-Sn alloys, Cu80Sn20 and Cu70Sn30 alloys have higher activation energy for viscous flow (Ea,V), activation energy for structural evolution (Ea,D), and the slope (γ) of the linear relationship of D/η with temperature due to the Cu3Sn clusters formation.