Neuronal Blocker Research Articles

Antihypertensive Drugs for the Prevention of Atrial Fibrillation: A Drug Target Mendelian Randomization Study.

We investigated the potential impact of antihypertensive drugs for atrial fibrillation (AF) prevention through a drug target Mendelian randomization study to avoid the potential limitations of clinical studies. Validated published single-nucleotide polymorphisms (SNPs) that mimic the action of 12 antihypertensive drug classes, including alpha-adrenoceptor blockers, adrenergic neuron blockers, angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers, beta-adrenoceptor blockers, centrally acting antihypertensive drugs, calcium channel blockers, loop diuretics, potassium-sparing diuretics and mineralocorticoid receptor antagonists, renin inhibitors, thiazides and related diuretic agents, and vasodilators were used. We estimated, via their corresponding gene and protein targets, the downstream effect of these drug classes to prevent AF via systolic blood pressure using 2-sample Mendelian randomization analyses. The SNPs were extracted from 2 European genome-wide association studies for the drug classes (n=317 754; n=757 601) and 1 European genome-wide association study for AF (n=1 030 836). Drug target Mendelian randomization analyses supported the significant preventive causal effects of lowering systolic blood pressure per 10 mm Hg via alpha-adrenoceptor blockers (n=11 SNPs; odds ratio [OR], 0.34 [95% CI, 0.21-0.56]; P=2.74×10-05), beta-adrenoceptor blockers (n=17 SNPs; OR, 0.52 [95% CI, 0.35-0.78]; P=1.62×10-03), calcium channel blockers (n=49 SNPs; OR, 0.50 [95% CI, 0.36-0.70]; P=4.51×10-05), vasodilators (n=19 SNPs; OR, 0.53 [95% CI, 0.34-0.84]; P=7.03×10-03), and all 12 antihypertensive drug classes combined (n=158 SNPs; OR, 0.64 [95% CI, 0.54-0.77]; P=8.50×10-07) on AF risk. Our results indicated that lowering systolic blood pressure via protein targets of various antihypertensive drugs seems promising for AF prevention. Our findings inform future clinical trials and have implications for repurposing antihypertensive drugs for AF prevention.

Role of Phenylethanolamine-N-methyltransferase on Nicotine-Induced Vasodilation in Rat Cerebral Arteries.

The sympathetic-parasympathetic (or axo-axonal) interaction mechanism mediated that neurogenic relaxation, which was dependent on norepinephrine (NE) releases from sympathetic nerve terminal and acts on β2-adrenoceptor of parasympathetic nerve terminal, has been reported. As NE is a weak β2-adrenoceptor agonist, there is a possibility that synaptic NE is converted to epinephrine by phenylethanolamine-N-methyltransferase (PNMT) and then acts on the β2-adrenoceptors to induce neurogenic vasodilation. Blood vessel myography technique was used to measure relaxation and contraction responses of isolated basilar arterial rings of rats. Nicotine-induced relaxation was sensitive to propranolol, guanethidine (an adrenergic neuronal blocker), and Nω-nitro-l-arginine. Nicotine- and exogenous NE-induced vasorelaxation was partially inhibited by LY-78335 (a PNMT inhibitor), and transmural nerve stimulation depolarized the nitrergic nerve terminal directly and was not inhibited by LY-78335; it then induced the release of nitric oxide (NO). Epinephrine-induced vasorelaxation was not affected by LY-78335. However, these vasorelaxations were completely inhibited by atenolol (a β1-adrenoceptor antagonist) combined with ICI-118,551 (a β2-adrenoceptor antagonist). These results suggest that NE may be methylated by PNMT to form epinephrine and cause the release of NO and vasodilation. These results provide further evidence supporting the physiological significance of the axo-axonal interaction mechanism in regulating brainstem vascular tone.

Repurposing antihypertensive drugs for pain disorders: a drug-target mendelian randomization study.

Addressing the rising prevalence of pain disorders and limitations of current analgesics, our study explores repurposing antihypertensive drugs for pain management, inspired by the link between hypertension and pain. We leverage a drug-target Mendelian Randomization (MR) approach to explore their dual benefits and establish causal connections. A comprehensive compilation of antihypertensive drug classes was undertaken through British National Formulary, with their target genes identified using the DrugBank database. Relevant single nucleotide polymorphisms (SNPs) associated with these targets were selected from published genomic studies on systolic blood pressure (SBP) as genetic instruments. These SNPs were validated through MR against acute coronary artery disease (CAD) to ensure genes not linked to CAD were excluded from acting as proxies for antihypertensive drugs. An MR analysis of 29 pain-related outcomes was conducted using the FinnGen R10 database employing the selected and validated genetic instruments. We utilized the Inverse Variance Weighted (IVW) method for primary analysis, applying Bonferroni correction to control type I error. IVW's multiplicative random effects (MRE) addressed heterogeneity, and MR-PRESSO managed pleiotropy, ensuring accurate causal inference. Our analysis differentiates strong and suggestive evidence in linking antihypertensive drugs to pain disorder risks. Strong evidence was found for adrenergic neuron blockers increasing migraine without aura risk, loop diuretics reducing panniculitis, and vasodilator antihypertensives lowering limb pain risk. Suggestive evidence suggests alpha-adrenoceptor blockers might increase migraine risk, while beta-adrenoceptor blockers could lower radiculopathy risk. Adrenergic neuron blockers also show a potential protective effect against coxarthrosis (hip osteoarthritis) and increased femgenpain risk (pain and other conditions related to female genital organs and menstrual cycle). Additionally, suggestive links were found between vasodilator antihypertensives and reduced radiculopathy risk, and both alpha-adrenoceptor blockers and renin inhibitors possibly decreasing dorsalgianas risk (unspecified dorsalgia). These findings highlight the intricate effects of antihypertensive drugs on pain disorders, underlining the need for further research. The findings indicate that antihypertensive medications may exert varied effects on pain management, suggesting a repurposing potential for treating specific pain disorders. The results advocate for further research to confirm these associations and to explore underlying mechanisms, to optimize pain management practices.

A Novel Implementation Methodology for Error Correction Codes on a Neuromorphic Architecture

The Internet of Things infrastructure connects a massive number of edge devices with an increasing demand for intelligent sensing and inferencing capability. Such data-sensitive functions necessitate energy-efficient and programmable implementations of Error Correction Codes (ECC) and decoders. The algorithmic flow of ECCs with concurrent accumulation and comparison types of operations are innately exploitable by neuromorphic architectures for energy efficient execution–an area that is relatively unexplored outside of machine learning applications. For the first time, we propose a methodology to map the hard-decision class of decoder algorithms on a neuromorphic architecture. We present the implementation of the Gallager B (GaB) decoding algorithm on a TrueNorth-inspired architecture that is emulated on the Xilinx Zynq ZCU102 MPSoC. Over this reference implementation, we propose architectural modifications at the neuron block level that result in a reduction of energy consumption by 31% with a negligible increase in resource usage while achieving the same error correction performance.

The Acute Effects and Mechanism of Ketamine on Nicotine-Induced Neurogenic Relaxation of the Corpus Cavernosum in Mice.

The present study aimed to investigate the acute effects and the mechanism of ketamine on nicotine-induced relaxation of the corpus cavernosum (CC) in mice. This study measured the intra-cavernosal pressure (ICP) of male C57BL/6 mice and the CC muscle activities using an organ bath wire myograph. Various drugs were used to investigate the mechanism of ketamine on nicotine-induced relaxation. Direct ketamine injection into the major pelvic ganglion (MPG) inhibited MPG-induced increases in ICP. D-serine/L-glutamate-induced relaxation of the CC was inhibited by MK-801 (N-methyl-D-aspartate (NMDA) receptor inhibitor), and nicotine-induced relaxation was enhanced by D-serine/L-glutamate. NMDA had no effect on CC relaxation. Nicotine-induced relaxation of the CC was suppressed by mecamylamine (a non-selective nicotinic acetylcholine receptor antagonist), lidocaine, guanethidine (an adrenergic neuronal blocker), Nw-nitro-L-arginine (a non-selective nitric oxide synthase inhibitor), MK-801, and ketamine. This relaxation was almost completely inhibited in CC strips pretreated with 6-hydroxydopamine (a neurotoxic synthetic organic compound). Ketamine inhibited cavernosal nerve neurotransmission via direct action on the ganglion and impaired nicotine-induced CC relaxation. The relaxation of the CC was dependent on the interaction of the sympathetic and parasympathetic nerves, which may be mediated by the NMDA receptor.

A Review of Current Situation of Ultrasound Guided Nerve Block in Anesthesiologists’ Skill Training

In recent years, ultrasound-guided neuronal block had gradually become an indispensable skill for anesthesiologists in clinical work. Its visualization in operation makes the puncture more accuracy and anesthesia more effect, which effectively reduced the occurrence of related complications. However, it is not easy to master the ultrasound-guided neuronal block skill. Since the complexity of the knowledge system of ultrasound-guided nerve block, it makes the learning process cost more and learning period longer. So that the related teaching and training are facing great challenges. With the continuous innovation of teaching and training concepts and methods, a large number of teaching and training methods related to nerve block ultrasound-guided neuronal block had emerged, but there was still lacking a standardized, scientific and systematic teaching and training system in this field of medical education. Our review systematically summarized the current situation of ultrasound-guided nerve block training and reported the emergence of new forms and new methods in each link of teaching and training. We aimed to provide a sufficient and powerful reference for the reform and optimization of teaching system in this field.

In Situ Effects of Doxycycline on Neuromuscular Junction in Mice.

The antibacterial mechanism of doxycycline is known, but its effects on the nerve-muscle system are still not unclear. The aim of the study was to combine molecular targets of the neuromuscular machinery using the in situ neuronal blocker effect of doxycycline, a semisynthetic second-generation tetracycline derivative, on mice neuromuscular preparations. The effects of doxycycline were assessed on presynaptic, synaptic cleft, and postsynaptic neurotransmission, along with the muscle fiber, using the traditional myographic technique. Precisely, the effects of doxycycline were categorized into "all" or "nothing" effects depending on the concentration of doxycycline used; "all" was obtained with 4 μM doxycycline, and "nothing" was obtained with 1-3 μM doxycycline. The rationale of this study was to apply known pharmacological tools against the blocker effect of 4 μM doxycycline, such as F55-6 (Casearia sylvestris), CaCl2 (or Ca2+), atropine, neostigmine, polyethylene glycol (PEG 400), and d-Tubocurarine. The evaluation of cholinesterase enzyme activity and the diaphragm muscle histology were performed, and protocols on the neuromuscular preparation submitted to indirect or direct stimuli were complementary. Doxycycline does not affect cholinesterase activity nor causes damage to skeletal muscle diaphragm; it acts on ryanodine receptor, sarcolemmal membrane, and neuronal sodium channel with a postjunctional consequence due to the decreased availability of muscle nicotinic acetylcholine receptors. In conclusion, in addition to the neuronal blocker effect of doxycycline, we showed that doxycycline acts on multiple targets. It is antagonized by F55-6, a neuronal Na+-channel agonist, and Ca2+, but not by neostigmine.

Cortistatin Inhibits Intestinal Ion Secretion via Activating the Somatostatin‐2 Receptor in the Submucosal Neurons of the Mouse Colon

Background and AimsCortistatin (CST) is a somatostatin‐like neuropeptide that is found in both the central and peripheral nervous system. CST binds with high affinity to all somatostatin receptors and also has actions not shared by somatostatin. We previously found that CST is expressed by enteric neurons in the guinea pig ileum and acts as an inhibitory neurotransmitter in the submucosal plexus. The aim of the present study was to evaluate the effect of CST on neurogenic intestinal secretion.MethodsMucosal/submucosal flat‐sheet preparations from mouse proximal colon were mounted in Ussing flux chambers for measurement of short‐circuit current (Isc) as an indicator of mucosal secretion. Transmural electrical field stimulation (EFS) evoked characteristic biphasic increases in Isc, with an early rapidly rising phase followed by a sustained phase.ResultsApplication of CST‐14, CST‐17, or CST‐29 to the basolateral side of the mucosal/submucosal preparation decreased baseline Isc in a concentration‐dependent manner with an IC50 of 90.5 nM, 52.1 nM, or 102.9 nM, respectively. The somatostatin‐2 receptor (SSTR‐2) antagonist CYN 154806 (1 mM) significantly suppressed CST‐14 (100 nM), CST‐17 (100 nM), or CST‐29 (100 nM)‐evoked ΔIsc by 36.0 ± 8.2% (n=5; P < 0.05), 47.2 ± 11.2% (n=5; P < 0.01), or 51.7.0 ± 8.4% (n=5; P < 0.01), respectively. The neuronal blocker tetrodotoxin (300 nM) significantly reduced CST‐14 (100 nM), CST‐17 (100 nM), or CST‐29 (100 nM)‐evoked ΔIsc by 36.5 ± 2.7% (n=5; P < 0.01), 48.9 ± 11.2% (n=5; P < 0.01), or 49.5 ± 3.6% (n=5; P < 0.01), respectively. All of the CSTs (1 nM – 1 mM) also produced a concentration‐dependent reduction of the EFS‐evoked biphasic secretory responses. The effect of CSTs on the EFS‐evoked responses was antagonized by CYN 154806 (1 mM). Immunohistochemical staining with a CST‐17 polyclonal antibody revealed expression of CST‐17 immunoreactivity (IR) in mouse colonic submucosal neurons. CST‐17‐IR was localized in cholinergic secretomotor neurons but was absent from non‐cholinergic secretomotor neurons and calbindin‐IR neurons.ConclusionsThe results suggest that CST acts at SST‐2 receptors in the submucosal plexus to suppress secretomotor neuronal excitability and neurogenic intestinal secretion in the mouse colon.

MicroRNA-22 coordinates vascular and motor neuronal pathfinding via sema4 during zebrafish development.

A precise guiding signal is crucial to orchestrate directional migration and patterning of the complex vascular network and neural system. So far, limited studies have reported the discovery and functions of microRNAs (miRNAs) in guiding vascular and neural pathfinding. Currently, we showed that the deficiency of miRNA-22a, an endothelial-enriched miRNA, caused dramatic pathfinding defects both in intersegmental vessels (ISVs) and primary motor neurons (PMNs) in zebrafish embryos. Furthermore, we found the specific inhibition of miR-22a in endothelial cells (ECs) resulted in patterning defects of both ISVs and PMNs. Neuronal block of miR-22a mainly led to axonal defects of PMN. Sema4c was identified as a potential target of miR-22a through transcriptomic analysis and in silico analysis. Additionally, a luciferase assay and EGFP sensor assay confirmed the binding of miR-22a with 3'-UTR of sema4c. In addition, downregulation of sema4c in the miR-22a morphants significantly neutralized the aberrant patterning of vascular and neural networks. Then we demonstrated that endothelial miR-22a regulates PMNs axonal navigation. Our study revealed that miR-22a acted as a dual regulatory cue coordinating vascular and neuronal patterning, and expanded the repertoire of regulatory molecules, which might be of use therapeutically to guide vessels and nerves in the relevant diseases.

Hepatotoxicity Caused By Phenyramidol Hydrochloride: A Case Report

Introduction: Drug-induced liver injury is a common cause of liver dysfunction. Phenyramidol causes a neuronal blocking effect and is used as a moderately potent non-narcotic analgesic that can be accompanied by muscle relaxant activity. In this article, a clinically asymptomatic case of hepatotoxicity is described following the intake of phenyramidol HCl tablets in a suicide attempt.
 Case Report: A 52-year-old female patient was admitted to the emergency department 24 hours after allegedly attempting suicide by ingesting 16 tablets of 400 mg phenyramidol HCI. She displayed no clinical symptoms. An abdominal examination was normal. The results of her first blood test showed: ALT at 58 U/L and AST at 55 U/L. After 24 hours, ALT and AST were measured at 594 U/L and 820 U/L, respectively. The patient, whose liver function tests regressed following symptomatic treatment administered in the gastroenterology department, was discharged 5 days later.
 Conclusion: Drug toxicities can be difficult to diagnose but becomes easier if an agent can be identified that is suspected of causing liver injury. Accordingly, phenyramidol should be considered as a drug that causes hepatotoxicity.

A 5.28-mm² 4.5-pJ/SOP Energy-Efficient Spiking Neural Network Hardware With Reconfigurable High Processing Speed Neuron Core and Congestion-Aware Router

In recent years, fast computation, low power, and small footprint are the key motivations for building SNN hardware. The unique features of SNN hardware have not been fully exploited, where the computation speed and energy efficiency of the SNN hardware can be improved according to the sparse spiking and non-uniform traffic of SNN. In this paper, we propose a 5.28-mm <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$^{2}~4096$ </tex-math></inline-formula> -neuron 1M-synapse energy-efficient digital SNN hardware that can achieve ultra-low energy per synaptic operation of 4.5 pJ. The proposed neuron computing unit is implemented in pipeline architecture to achieve high synaptic processing speed. The proposed spike processing unit can significantly increase the processing speed of the neuron core by <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$1.9\times $ </tex-math></inline-formula> and <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$9.4\times $ </tex-math></inline-formula> when the spike injection rate is 50% and 10%, respectively. Besides, the increase in the processing speed of the neuron core leads to a reduction in energy consumption of up to 81.5%. An event-driven clock gating circuit that can reduce the power consumption of the proposed neuron block by more than 70% is proposed in this paper. This paper proposes a supervised STDP+ algorithm for SNN training, and the classification accuracy of the MNIST digits is 89.6% with 73.6% weight sparsity of the output layer.

Computational drug repurposing of bethanidine for SENP1 inhibition in cardiovascular diseases treatment

AimsBethanidine (BW467C60) is a newly presented strong adrenergic neuron blocking factor which has a hypotensive operation in man. SENPs are essential for maintaining a balance between SUMOylation and deSUMOylation which can be disturbed by changing the expression of (sentrin-specific proteases) SENPs. SENP1 is the most studied isoform of SENPs. Hypertrophic stimuli can increase SENP1 expression using calcium/calcineurin-NFAT3 signaling in heart. Moreover, SENP1 expression may positively relate to the expression of mitochondrial genes of the heart, and can cause the heart and mitochondrial dysfunction. Materials and methodsIn order to inhibit SENP1 using Bethanidine, molecular docking and molecular dynamics (MD) simulation of SENP1 with Bethanidine were performed. Molecular docking showed that Bethanidine can inhibit SENP1. Key findings: MD Simulation showed that Bethanidine constitutes a stable complex with SENP1 as was evident from RMSD, RMSF, H-bond and DSSP plots. Free binding energy and the interaction patterns were obtained from molecular docking, and MD trajectory exhibited Bethanidine can be a potential drug candidate for SENP1 inhibition. Significance: This study supplies enough evidences that Bethanidine is a potential inhibitor of SENP1 and can be applied for the treatment of cardiovascular diseases.

An adaptive threshold neuron for recurrent spiking neural networks with nanodevice hardware implementation

We propose a Double EXponential Adaptive Threshold (DEXAT) neuron model that improves the performance of neuromorphic Recurrent Spiking Neural Networks (RSNNs) by providing faster convergence, higher accuracy and a flexible long short-term memory. We present a hardware efficient methodology to realize the DEXAT neurons using tightly coupled circuit-device interactions and experimentally demonstrate the DEXAT neuron block using oxide based non-filamentary resistive switching devices. Using experimentally extracted parameters we simulate a full RSNN that achieves a classification accuracy of 96.1% on SMNIST dataset and 91% on Google Speech Commands (GSC) dataset. We also demonstrate full end-to-end real-time inference for speech recognition using real fabricated resistive memory circuit based DEXAT neurons. Finally, we investigate the impact of nanodevice variability and endurance illustrating the robustness of DEXAT based RSNNs.

(Invited) A Low-Power Neuron Circuit Using a Positive Feedback Device for Spiking Neural Networks

For more efficient computation, researches on neuromorphic systems suitable for neural networks have been conducted [1]. To replace conventional neuron circuits for integrate-and-fire (IF) function in neuromorphic systems, neuron devices with high density and low power consumption per spike have been studied [2, 3]. In the previous work, an n-type positive feedback (PF) device with steep switching characteristic was proposed for hardware-based neural networks [4]. In this paper, a p-type PF device with a charge storage layer is reported as neurons, which integrates signals using positive program bias (V PGM). Fig. 1 shows a top view of a p-type PF device and an energy band diagram of the PF operation. Doping concentration and length of n-/p-channels are 1×1018 cm-3 and 1 μm, respectively. Fin width (W) and height (H) of PF device is 35 nm and 100 nm, respectively. Thickness of gate dielectric (SiO2/Si3N4/SiO2) for the charge storage layer is 2/4.2/9 nm. As a gate bias (V G2) decreases, a hole-injection barrier decreases, and holes easily flow from anode to p-channel region. As more holes are injected to p-channel region, electron injection barrier decreases, and electrons easily flow from cathode to n-channel region. By positive feedback like this, an anode current (I A) abruptly flows from anode to cathode as shown in the Fig. 1 (c). As a V PGM pulse is applied to G1, a turn-on voltage (V on) is shifted slightly toward the positive voltage. After 15 V PGM pulses are applied, V on shifts from -0.3 V to 0.03 V as indicated by the diamond symbols in Fig. 1 (c). The change of V on by the number of pulses (V PGM) mimics the IF operation of neurons. Fig. 2 shows the symbol of the PF device and the repeated measurement for IF operation of the PF device as a parameter of V G1. IF and reset operations were measured by applying pulses of V G1 and V reset (-7 V) to G1. Reliable IF function with the repeated measurement is obtained in the PF device. As V G1 increases from 5.8 V to 6.2 V, the firing rate of the PF device increases due to the increase in electrons trapped in the charge storage layer (Si3N4). Fig. 3 (a) shows a conventional neuron circuit for the IF function in SNNs [5]. When the membrane voltage (V mem) exceeds the threshold of M2, M2 is turned on and the neuron is fired. However, even if the membrane voltage is less than the threshold voltage of M2, the subthreshold current continues to flow, resulting in a leakage path through M3 and M2, which takes up a large part of the standby power in neuron block. Hence, replacing M2 with a PF device with steep switching characteristics can effectively block this leakage path. Consequently, it can significantly reduce power consumption [4]. A 400–128–10 sized MLP network was simulated in the circuit level. A full network is composed of NOR flash synaptic array [6], current mirror, and IF block. The power consumed by each block is shown in Fig. 3 (b). MNIST data sets were presented over 8 time steps with each duration of 1 ms. IF block consumes 177.2 mW, which is about 28.3% of the total power consumption, and most of the power is consumed by the leakage or generation of output spikes. Networks that use only few spikes [7] have a higher rate of power consumption by the leakage than creating spikes. In addition, to accurately calculate the negative weight sum using the capacitor (C mem), it is necessary to set the initial membrane voltage to a positive value, which further increases power consumption by the leakage. By replacing M2 with a PF device, it is possible to construct a novel neuron by significantly reducing unnecessary power consumption in the conventional neurons.Reference[1] S. Yu, Proc. IEEE 106, 2 (2018)[2] J. Luo et al., IEDM Tech. Dig. 122 (2019)[3] S. Dutta et al., Sci. Rep. 7 (2017)[4] K. Choi et al., Front. Neurosci. 12, 704 (2018).[5] W. Kang et al., Int. Jt. Conf. Neural. Netw. 1 (2019).[6] C, Kim et al., IEEE Trans. Electron Devices 65, 5 (2018).[7] S. Kheradpisheh et al., Int. J. Neural. Syst. (2020). Figure 1

Hydrogen Protons Modulate Perivascular Axo-axonal Interactions in the Middle Cerebral Artery of Rats.

Previous studies have demonstrated that nicotine can induce relaxation of the middle cerebral artery (MCA). However, whether this relaxation is associated with the activity of sensory calcitonin gene-related peptide (CGRP) nerves and whether this is modulated by hydrogen protons (H), facilitating the release of CGRP from sensory CGRPergic nerve terminals in the MCA, remains unclear. In this study, we examined the role of H in the modulation of neurogenic vasomotor responses in the rat-isolated endothelium-denuded MCA. Wire myography was used to measure vasoreactivity and indicated that nicotine-induced relaxation was sensitive to tetrodotoxin and lidocaine and drastically reduced levels of guanethidine (an adrenergic neuronal blocker), N-nitro-L-arginine (L-NNA), CGRP8-37, vasoactive intestinal polypeptide (VIP)6-28, capsaicin, capsazepine (a transient receptor potential vanilloid-1 inhibitor), and tetraethylammonium. However, this nicotine-induced relaxation was not sensitive to propranolol. Lowering the pH of the buffer solution with HCl caused pH-dependent vasorelaxation and deceased intracellular pH in the MCA rings, which was sensitive to L-NNA, CGRP8-37, VIP6-28, capsazepine, 4-aminopyridine (a voltage-gated potassium channel antagonist), and paxilline (a large conductance Ca-activated K channel antagonist). However, HCl-induced relaxation was not inhibited by glibenclamide (an ATP-sensitive K channel blocker). These results suggested that electrical and chemical activation of cerebral perivascular adrenergic nerves led to the release of H, which then facilitated the release of NO, VIP, and CGRP, resulting in vasorelaxation. Lowering the pH of the buffer solution caused potassium channels of vascular smooth muscle cells and perivascular nerves to open. In conclusion, our results demonstrated that H may act as a modulator on MCA perivascular nerves and/or smooth muscles.

The Altered Signaling on EFS-Induced Colon Contractility in Diabetic Rats.

Diabetes mellitus affects the colonic motility developing gastrointestinal symptoms, such as constipation. The aim of the study was to examine the role of intracellular signaling pathways contributing to colonic dysmotility in diabetes mellitus. To generate diabetes mellitus, the rats were injected by a single high dose of streptozotocin (65 mg/kg) intraperitoneally. The proximal colons from both normal and diabetic rats were contracted by applying an electrical field stimulation with pulse voltage of 40 V in amplitude and pulse duration of 1 ms at frequencies of 1, 2, 4, and 6 Hz. The muscle strips from both normal rats and rats with diabetes mellitus were pretreated with different antagonists and inhibitors. Rats with diabetes mellitus had lower motility than the control group. There were significant differences in the percentage of inhibition of contraction between normal rats and rats with diabetes mellitus after the incubation of tetrodotoxin (neuronal blocker), atropine (muscarinic receptor antagonist), prazosin (α1 adrenergic receptor antagonist), DPCPX (adenosine A1 receptor antagonist), verapamil (L-type Ca2+ channel blocker), U73122 (PLC inhibitor), ML-9 (MLCK inhibitor), udenafil (PDE5 inhibitor), and methylene blue (guanylate cyclase inhibitor). The protein expression of p-MLC and PDE5 were decreased in the diabetic group compared to the normal group. These results showed that the reduced colonic contractility resulted from the impaired neuronal conduction and decreased muscarinic receptor sensitivity, which resulted in decreased phosphorylation of MLC via MLCK, and cGMP activity through PDE5.

Low Power, CMOS-MoS2 Memtransistor based Neuromorphic Hybrid Architecture for Wake-Up Systems

Neuromorphic architectures have become essential building blocks for next-generation computational systems, where intelligence is embedded directly onto low power, small area, and computationally efficient hardware devices. In such devices, realization of neural algorithms requires storage of weights in digital memories, which is a bottleneck in terms of power and area. We hereby propose a biologically inspired low power, hybrid architectural framework for wake-up systems. This architecture utilizes our novel high-performance, ultra-low power molybdenum disulphide (MoS2) based two-dimensional synaptic memtransistor as an analogue memory. Furthermore, it exploits random device mismatches to implement the population coding scheme. Power consumption per CMOS neuron block was found to be 3 nw in the 65 nm process technology, while the energy consumption per cycle was 0.3 pJ for potentiation and 20 pJ for depression cycles of the synaptic device. The proposed framework was demonstrated for classification and regression tasks, using both off-chip and simplified on-chip sign-based learning techniques.

Identification of pheasant ghrelin and motilin and their actions on contractility of the isolated gastrointestinal tract

Motilin and ghrelin were identified in the pheasant by molecular cloning, and the actions of both peptides on the contractility of gastrointestinal (GI) strips were examined in vitro. Molecular cloning indicated that the deduced amino acid sequences of the pheasant motilin and ghrelin were a 22-amino acid peptide, FVPFFTQSDIQKMQEKERIKGQ, and a 26-amino acid peptide, GSSFLSPAYKNIQQQKDTRKPTGRLH, respectively. In in vitro studies using pheasant GI strips, chicken motilin caused contraction of the proventriculus and small intestine, whereas the crop and colon were insensitive. Human motilin, but not erythromycin, caused contraction of small intestine. Chicken motilin-induced contractions in the proventriculus and ileum were not inhibited by a mammalian motilin receptor antagonist, GM109. Neither atropine (a cholinergic receptor antagonist) nor tetrodotoxin (a neuron blocker) inhibited the responses of chicken motilin in the ileum but both drugs decreased the responses to motilin in the proventriculus, suggesting that the contractile mechanisms of motilin in the proventriculus was neurogenic, different from that of the small intestine (myogenic). On the other hand, chicken and quail ghrelin did not cause contraction in any regions of pheasant GI tract. Since interaction of ghrelin and motilin has been reported in the house musk shrew, interaction of two peptides was examined. The chicken motilin-induced contractions were not modified by ghrelin, and ghrelin also did not cause any contraction under the presence of motilin, suggesting the absence of interaction in both peptides. In conclusion, both the motilin system and ghrelin system are present in the pheasant. Regulation of GI motility by motilin might be common in avian species. However, absence of ghrelin actions in any GI regions suggests the avian species-related difference in regulation of GI contractility by ghrelin.

Modeling and Simulation of Asynchrony in Neuromorphic Computing

Neuromorphic computing is a non-von Neumann architecture which is also referred to as artificial neural network and that allows electronic system to function in the same manner as that of the human brain. In this paper we have developed neural core architecture analogous to that of the human brain. Each neural core has its own computational element neuron, memory to store information and local clock generator for synchronous functioning of neuron along with asynchronous input-output port and its port controller. The neuron model used here is a tailor-made of IBM TrueNorth’s neuron block. Our design methodology includes both synchronous and asynchronous circuit in order to build an event-driven neural network core. We have first simulated our design using Neuroph studio in order to calculate the weights and bias value and then used these weights for hardware implementation. With that we have successfully demonstrated the working of neural core using XOR application. It was designed in VHDL language and simulated in Xilinx ISE software.

Roles of α-Adrenoceptors and Sympathetic Nerve in Acute Herpetic Pain Induced by Herpes Simplex Virus Inoculation in Mice

Percutaneous inoculation with herpes simplex virus type-1 brings about herpes zoster-like skin lesions, tactile allodynia, and mechanical hyperalgesia in mice. This study was conducted to determine whether the sympathetic nervous system and α-adrenoceptors would be involved in these pain-related responses and whether the α2-adrenoceptor agonist clonidine would suppress these responses. The adrenergic neuron blocker guanethidine and the non-selective α-adrenoceptor antagonist phentolamine did not affect the pain-related responses, although these agents suppressed the pain-related responses induced by partial ligation of the sciatic nerve. The pain-related responses induced by herpetic inoculation was suppressed by intraperitoneal and intrathecal injections, but not by intraplantar and intracerebroventricular injections, of clonidine. The suppressive effect of an intraperitoneal injection of clonidine (0.1 mg/kg) was antagonized by intrathecal injections of phentolamine and the α2-adrenoceptor antagonist yohimbine, but not the a1-adrenoceptor antagonist prazosin. The results suggest that sympathetic nerves and α-adrenoceptors are not involved in the pain-related responses induced by herpetic infection. Clonidine suppresses the responses probably through the action on α2-adrenoceptors in the dorsal horn.