TRESK channel contribution to nociceptive sensory neurons excitability: modulation by nerve injury

<p>Abstract</p> <p>Background</p> <p>Neuronal hyperexcitability is a crucial phenomenon underlying spontaneous and evoked pain. In invertebrate nociceptors, the S-type leak K⁺channel (analogous to TREK-1 in mammals) plays a critical role of in determining neuronal excitability following nerve injury. Few data are available on the role of leak K_2Pchannels after peripheral axotomy in mammals.</p> <p>Results</p> <p>Here we describe that rat sciatic nerve axotomy induces hyperexcitability of L4-L5 DRG sensory neurons and decreases TRESK (K2P18.1) expression, a channel with a major contribution to total leak current in DRGs. While the expression of other channels from the same family did not significantly change, injury markers ATF3 and Cacna2d1 were highly upregulated. Similarly, acute sensory neuron dissociation (<it>in vitro </it>axotomy) produced marked hyperexcitability and similar total background currents compared with neurons injured <it>in vivo</it>. In addition, the sanshool derivative IBA, which blocked TRESK currents in transfected HEK293 cells and DRGs, increased intracellular calcium in 49% of DRG neurons in culture. Most IBA-responding neurons (71%) also responded to the TRPV1 agonist capsaicin, indicating that they were nociceptors. Additional evidence of a biological role of TRESK channels was provided by behavioral evidence of pain (flinching and licking), in vivo electrophysiological evidence of C-nociceptor activation following IBA injection in the rat hindpaw, and increased sensitivity to painful pressure after TRESK knockdown in vivo.</p> <p>Conclusions</p> <p>In summary, our results clearly support an important role of TRESK channels in determining neuronal excitability in specific DRG neurons subpopulations, and show that axonal injury down-regulates TRESK channels, therefore contributing to neuronal hyperexcitability.</p

Characterization of intrinsic properties of cingulate pyramidal neurons in adult mice after nerve injury

The anterior cingulate cortex (ACC) is important for cognitive and sensory functions including memory and chronic pain. Glutamatergic excitatory synaptic transmission undergo long-term potentiation in ACC pyramidal cells after peripheral injury. Less information is available for the possible long-term changes in neuronal action potentials or intrinsic properties. In the present study, we characterized cingulate pyramidal cells in the layer II/III of the ACC in adult mice. We then examined possible long-term changes in intrinsic properties of the ACC pyramidal cells after peripheral nerve injury. In the control mice, we found that there are three major types of pyramidal cells according to their action potential firing pattern: (i) regular spiking (RS) cells (24.7%), intrinsic bursting (IB) cells (30.9%), and intermediate (IM) cells (44.4%). In a state of neuropathic pain, the population distribution (RS: 21.3%; IB: 31.2%; IM: 47.5%) and the single action potential properties of these three groups were indistinguishable from those in control mice. However, for repetitive action potentials, IM cells from neuropathic pain animals showed higher initial firing frequency with no change for the properties of RS and IB neurons from neuropathic pain mice. The present results provide the first evidence that, in addition to synaptic potentiation reported previously, peripheral nerve injury produces long-term plastic changes in the action potentials of cingulate pyramidal neurons in a cell type-specific manner

Rainwater harvesting systems reduce detergent use

Unidad de excelencia María de Maeztu MdM-2015-0552Purpose: Due to population growth, urban water demand is expected to increase significantly, as well as the environmental and economic costs required to supply it. Rainwater harvesting (RWH) systems can play a key role in helping cities meet part of their water demand as an alternative to conventional water abstraction and treatment. This paper presents an environmental and economic analysis of RWH systems providing households with water for laundry purposes in a life cycle thinking perspective. Conclusions: LCA and LCC present better results for high-density scenarios. Overall, avoided environmental and economic impacts from detergent reduction clearly surpass environmental impacts (in all categories except terrestrial acidification) and economic cost of the RWHsystem in most cases (except two scenarios). Another important finding is that 80%of the savings are achieved by minimizing detergent and fabric softener by using soft rainwater; and the remaining 20% comes from replacing the use of tap water

Excitability of Aβ sensory neurons is altered in an animal model of peripheral neuropathy

<p>Abstract</p> <p>Background</p> <p>Causes of neuropathic pain following nerve injury remain unclear, limiting the development of mechanism-based therapeutic approaches. Animal models have provided some directions, but little is known about the specific sensory neurons that undergo changes in such a way as to induce and maintain activation of sensory pain pathways. Our previous studies implicated changes in the Aβ, normally non-nociceptive neurons in activating spinal nociceptive neurons in a cuff-induced animal model of neuropathic pain and the present study was directed specifically at determining any change in excitability of these neurons. Thus, the present study aimed at recording intracellularly from Aβ-fiber dorsal root ganglion (DRG) neurons and determining excitability of the peripheral receptive field, of the cell body and of the dorsal roots.</p> <p>Methods</p> <p>A peripheral neuropathy was induced in Sprague Dawley rats by inserting two thin polyethylene cuffs around the right sciatic nerve. All animals were confirmed to exhibit tactile hypersensitivity to von Frey filaments three weeks later, before the acute electrophysiological experiments. Under stable intracellular recording conditions neurons were classified functionally on the basis of their response to natural activation of their peripheral receptive field. In addition, conduction velocity of the dorsal roots, configuration of the action potential and rate of adaptation to stimulation were also criteria for classification. Excitability was measured as the threshold to activation of the peripheral receptive field, the response to intracellular injection of depolarizing current into the soma and the response to electrical stimulation of the dorsal roots.</p> <p>Results</p> <p>In control animals mechanical thresholds of all neurons were within normal ranges. Aβ DRG neurons in neuropathic rats demonstrated a mean mechanical threshold to receptive field stimulation that were significantly lower than in control rats, a prolonged discharge following this stimulation, a decreased activation threshold and a greater response to depolarizing current injection into the soma, as well as a longer refractory interval and delayed response to paired pulse electrical stimulation of the dorsal roots.</p> <p>Conclusions</p> <p>The present study has demonstrated changes in functionally classified Aβ low threshold and high threshold DRG neurons in a nerve intact animal model of peripheral neuropathy that demonstrates nociceptive responses to normally innocuous cutaneous stimuli, much the same as is observed in humans with neuropathic pain. We demonstrate further that the peripheral receptive fields of these neurons are more excitable, as are the somata. However, the dorsal roots exhibit a decrease in excitability. Thus, if these neurons participate in neuropathic pain this differential change in excitability may have implications in the peripheral drive that induces central sensitization, at least in animal models of peripheral neuropathic pain, and Aβ sensory neurons may thus contribute to allodynia and spontaneous pain following peripheral nerve injury in humans.</p

SAQC: SNP Array Quality Control

<p>Abstract</p> <p>Background</p> <p>Genome-wide single-nucleotide polymorphism (SNP) arrays containing hundreds of thousands of SNPs from the human genome have proven useful for studying important human genome questions. Data quality of SNP arrays plays a key role in the accuracy and precision of downstream data analyses. However, good indices for assessing data quality of SNP arrays have not yet been developed.</p> <p>Results</p> <p>We developed new quality indices to measure the quality of SNP arrays and/or DNA samples and investigated their statistical properties. The indices quantify a departure of estimated individual-level allele frequencies (AFs) from expected frequencies via standardized distances. The proposed quality indices followed lognormal distributions in several large genomic studies that we empirically evaluated. AF reference data and quality index reference data for different SNP array platforms were established based on samples from various reference populations. Furthermore, a confidence interval method based on the underlying empirical distributions of quality indices was developed to identify poor-quality SNP arrays and/or DNA samples. Analyses of authentic biological data and simulated data show that this new method is sensitive and specific for the detection of poor-quality SNP arrays and/or DNA samples.</p> <p>Conclusions</p> <p>This study introduces new quality indices, establishes references for AFs and quality indices, and develops a detection method for poor-quality SNP arrays and/or DNA samples. We have developed a new computer program that utilizes these methods called SNP Array Quality Control (SAQC). SAQC software is written in R and R-GUI and was developed as a user-friendly tool for the visualization and evaluation of data quality of genome-wide SNP arrays. The program is available online (<url>http://www.stat.sinica.edu.tw/hsinchou/genetics/quality/SAQC.htm</url>).</p

Gastrodin Inhibits Allodynia and Hyperalgesia in Painful Diabetic Neuropathy Rats by Decreasing Excitability of Nociceptive Primary Sensory Neurons

Painful diabetic neuropathy (PDN) is a common complication of diabetes mellitus and adversely affects the patients’ quality of life. Evidence has accumulated that PDN is associated with hyperexcitability of peripheral nociceptive primary sensory neurons. However, the precise cellular mechanism underlying PDN remains elusive. This may result in the lacking of effective therapies for the treatment of PDN. The phenolic glucoside, gastrodin, which is a main constituent of the Chinese herbal medicine Gastrodia elata Blume, has been widely used as an anticonvulsant, sedative, and analgesic since ancient times. However, the cellular mechanisms underlying its analgesic actions are not well understood. By utilizing a combination of behavioral surveys and electrophysiological recordings, the present study investigated the role of gastrodin in an experimental rat model of STZ-induced PDN and to further explore the underlying cellular mechanisms. Intraperitoneal administration of gastrodin effectively attenuated both the mechanical allodynia and thermal hyperalgesia induced by STZ injection. Whole-cell patch clamp recordings were obtained from nociceptive, capsaicin-sensitive small diameter neurons of the intact dorsal root ganglion (DRG). Recordings from diabetic rats revealed that the abnormal hyperexcitability of neurons was greatly abolished by application of GAS. To determine which currents were involved in the antinociceptive action of gastrodin, we examined the effects of gastrodin on transient sodium currents (INaT) and potassium currents in diabetic small DRG neurons. Diabetes caused a prominent enhancement of INaT and a decrease of potassium currents, especially slowly inactivating potassium currents (IAS); these effects were completely reversed by GAS in a dose-dependent manner. Furthermore, changes in activation and inactivation kinetics of INaT and total potassium current as well as IAS currents induced by STZ were normalized by GAS. This study provides a clear cellular basis for the peripheral analgesic action of gastrodin for the treatment of chronic pain, including PDN

Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an

Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis

Search for heavy resonances decaying to two Higgs bosons in final states containing four b quarks

A search is presented for narrow heavy resonances X decaying into pairs of Higgs bosons (H) in proton-proton collisions collected by the CMS experiment at the LHC at root s = 8 TeV. The data correspond to an integrated luminosity of 19.7 fb(-1). The search considers HH resonances with masses between 1 and 3 TeV, having final states of two b quark pairs. Each Higgs boson is produced with large momentum, and the hadronization products of the pair of b quarks can usually be reconstructed as single large jets. The background from multijet and t (t) over bar events is significantly reduced by applying requirements related to the flavor of the jet, its mass, and its substructure. The signal would be identified as a peak on top of the dijet invariant mass spectrum of the remaining background events. No evidence is observed for such a signal. Upper limits obtained at 95 confidence level for the product of the production cross section and branching fraction sigma(gg -> X) B(X -> HH -> b (b) over barb (b) over bar) range from 10 to 1.5 fb for the mass of X from 1.15 to 2.0 TeV, significantly extending previous searches. For a warped extra dimension theory with amass scale Lambda(R) = 1 TeV, the data exclude radion scalar masses between 1.15 and 1.55 TeV

Search for supersymmetry in events with one lepton and multiple jets in proton-proton collisions at root s=13 TeV

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