Molecular Mechanisms of Itch Sensations

Itch is a sensation which causes scratching response to protect skin against external harmful reagents. Acute itch arises in short time period after insect bites or allergen contact. Chronic itch happens in various skin diseases such as atopic dermatitis: AD) and psoriasis. Chronic itch usually continues for over six weeks and is resistant to commonly used anti-histamine drugs. While pain has caught an early attention due to its severity, the molecular mechanism of itch has not been studied in detail. Itch and pain share common features because they are transmitted by similar neuronal circuits. However, itch is a distinct somatosensation and has opposite characteristics to pain. Itch elicits scratching but pain causes withdrawal reflex. Interestingly, minor pain induced by scratching reduces itch and suppression of pain by opioid analgesics such as morphine elicits itch as a side effect. Despite recent advances, our understanding about itch sensory mechanisms is still primitive. Gastrin-releasing peptide receptor: GRPR) was identified as the first itch-specific receptor in the spinal cord. GRPR cell ablation by bombesin-saporin abolished general scratching responses to pruritogens. Because GRPR mutant mice still have remained itch responses, it is possible that additional itch mediators are present in the spinal GRPR neurons. Differential screening and pharmacological or small interfering RNA: siRNA) approach identified four histamine-independent: Atp2a1, Pld3, Pacsin3 and Itpr3), three histamine-dependent: S100a8, CALR and DSP) and one both-dependent: TRPV4) itch genes. Atp2a1 and Itpr3 were selected for further characterization. Atp2a1 and Itpr3 are involved in GRPR downstream Ca2+ signaling pathway for histamine-independent itch. GRPR is also expressed in peripheral tissues such as dorsal root ganglia: DRG) and skin in addition to the spinal cord. Gastrin-releasing peptide: GRP) intradermal: i.d.) injection induces dose-dependent scratching responses that are abolished in GRPR mutant mice. Peripheral: intraperitoneal: i.p.) and i.d.) application of GRPR antagonists inhibits chloroquine: CQ), GRP and allergic contact dermatitis: ACD)-induced scratching responses in mice. It is interesting to find peripheral GRPR functions for itch sensation because it will provide an alternative therapeutic route for itch by targeting peripheral GRPR activities rather than spinal cord GRPR. This also can circumvent potential side effects in central nervous system: CNS) by intrathecal: i.t.) injections. TRPV4 was identified as a crucial itch mediator in DRG for both histamine-dependent and -independent itch by siRNA screening. TRPV4 is co-expressed with multiple pruritic genes such as GRP, transient receptor potential vanilloid 1: TRPV1), mas-related G-protein coupled receptor A3: MrgprA3) and histamine receptor 1: H1R). TRPV4-/- mice showed reduced scratching responses in CQ and histamine-induced pruritic models. siRNA i.t. injection efficiently reduced TRPV4 expression in DRG and decreased both types of itch consistently. i.t. application of endogenous TRPV4 agonist, 5, 6-epoxyeicosatrienoic acid: 5, 6-EET), caused scratching responses that were significantly attenuated in TRPV4-/- mice. Interestingly, TRPV4-/- mice had reduced scratching responses in ACD mice model without affecting on skin inflammation. TRPV4 expression was up-regulated in ACD mice DRG suggesting that an increased TRPV4 activity may be responsible for the aggravated chronic itch. Ca2+ imaging with DRG culture further confirmed that TRPV4 activation is functionally involved in itch sensory transmission in peripheral neurons. TRPV4 in DRG will be a good candidate for treatment of ACD-related chronic itch. Characterization of GRPR-mediated itch mechanisms and identification of novel itch-specific genes will provide basic understanding about itch sensory mechanism and pioneering work for future itch studies such as identifying potential itch therapeutic targets

Modeling of HVDC System to Improve Estimation of Transient DC Current and Voltages for AC Line-to-Ground FaultAn Actual Case Study in Korea

A new modeling method for high voltage direct current (HVDC) systems and associated controllers is presented for the power system simulator for engineering (PSS/E) simulation environment. The aim is to improve the estimation of the transient DC voltage and current in the event of an AC line-to-ground fault. The proposed method consists primary of three interconnected modules for (a) equation conversion; (b) control-mode selection; and (c) DC-line modeling. Simulation case studies were carried out using PSS/E and a power systems computer aided design/electromagnetic transients including DC (PSCAD/EMTDC) model of the Jeju-Haenam HVDC system in Korea. The simulation results are compared with actual operational data and the PSCAD/EMTDC simulation results for an HVDC system during single-phase and three-phase line-to-ground faults, respectively. These comparisons show that the proposed PSS/E modeling method results in the improved estimation of the dynamic variation in the DC voltage and current in the event of an AC network fault, with significant gains in computational efficiency, making it suitable for real-time analysis of HVDC systems.111Ysciescopu

Analysis of a PML method applied to computation to resonances in open systems and acoustic scattering problems

We consider computation of resonances in open systems and acoustic scattering problems. These problems are posed on an unbounded domain and domain truncation is required for the numerical computation. In this paper, a perfectly matched layer (PML) technique is proposed for computation of solutions to the unbounded domain problems. For resonance problems, resonance functions are characterized as improper eigenfunction (non-zero solutions of the eigenvalue problem which are not square integrable) of the Helmholtz equation on an unbounded domain. We shall see that the application of the spherical PML converts the resonance problem to a standard eigenvalue problem on the infinite domain. Then, the goal will be to approximate the eigenvalues first by replacing the infinite domain by a finite computational domain with a convenient boundary condition and second by applying finite elements to the truncated problem. As approximation of eigenvalues of problems on a bounded domain is classical [12], we will focus on the convergence of eigenvalues of the (continuous) PML truncated problem to those of the infinite PML problem. Also, it will be shown that the domain truncation does not produce spurious eigenvalues provided that the size of computational domain is sufficiently large. The spherical PML technique has been successfully applied for approximation of scattered waves [13]. We develop an analysis for the case of a Cartesian PML application to the acoustic scattering problem, i.e., solvability of infinite and truncated Cartesian PML scattering problems and convergence of the truncated Cartesian PML problem to the solution of the original solution in the physical region as the size of computational domain increases

Analysis and Countermeasures for Sideband of Gear Mesh Frequency(GMF) Induced by Shaft Fretting Corrosion in a Gearbox

Case StudyCS deals with trouble shooting and solving a chronic fretting corrosion damage b/w a gear and shaft (shrink fit). The damage on the geared shaft always accompanied by an increase in the amplitude and frequency side bands at the gear mesh frequency (GMF). The troubleshooting process and analysis revealed that the distance between the two gears is a critical design parameter for preventing fretting corrosion

Modeling and Analysis of an LCC HVDC System Using DC Voltage Control to Improve Transient Response and Short-Term Power Transfer Capability

A new control method for a line-commutated converter-based (LCC) high-voltage direct-current (HVDC) system is presented and compared to a conventional strategy. In the proposed method, both the DC voltage and current of an LCC HVDC system are regulated to increase the short-term operating margin of DC power transfer and improve transient responses to DC power references. In particular, an increased operating margin of DC power transfer is achieved via the DC voltage regulation method. To verify the effectiveness of the proposed method, a state space model of an LCC HVDC system is developed considering DC voltage and current references as input variables and analyzed for various values of the DC line inductance and converter controller gains. The state space model can be used for time-efficient analyses of the dynamic characteristics of an LCC HVDC system. Simulation case studies are performed using MATLAB, where the state space model of the Jeju-Haenam HVDC system is implemented as a test case and compared to its comprehensive PSCAD model. The case study results suggest that the proposed method increases the short-term operating margin and speeds up the transient response of the HVDC system. Therefore, it will effectively improve real-time grid frequency regulation.11sciescopu

Analysis and Countermeasures for Sideband of Gear Mesh Frequency(GMF) Induced by Shaft Fretting Corrosion in a Gearbox

Case StudyCS deals with trouble shooting and solving a chronic fretting corrosion damage b/w a gear and shaft (shrink fit). The damage on the geared shaft always accompanied by an increase in the amplitude and frequency side bands at the gear mesh frequency (GMF). The troubleshooting process and analysis revealed that the distance between the two gears is a critical design parameter for preventing fretting corrosion

Design and development of pH-responsive polyurethane membranes for intravaginal release of nanomedicines

The final publication is available at Elsevier via https://doi.org/10.1016/j.actbio.2018.10.003� 2018. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/The objective of this study was to develop and characterize a novel intravaginal membrane platform for pH-triggered release of nanoparticles (NPs), which is essential for efficient intravaginal delivery of certain effective but acid-labile therapeutic agents for sexually transmitted infections, such as small interfering RNA (siRNA). A pH-responsive polyurethane (PU) was electrospun into a porous nanofibrous membrane. The diameters of the fibers, as well as the thickness and pore sizes of the membrane under dry and wet conditions (pH 4.5 and 7.0), were determined from scanning electron microscopy (SEM) micrographs. pH-dependent zeta-potential (_) of the membrane was evaluated using a SurPASS electrokinetic analyzer. Visiblex� color-dyed polystyrene NPs (PSNs, 200_nm, COOH) and CCR5 siRNA-encapsulated solid lipid NPs (SLNs) were used for in vitro NP release studies in a vaginal fluid simulant (VFS) at pH 4.5 (normal physiological vaginal pH) and 7.0 (vaginal pH neutralization by semen). During 24_h of incubation in VFS, close-to-zero PSNs (2_�_1%) and 28_�_4% SLNs were released through the PU membrane at pH 4.5, whereas the release of PSNs and SLNs significantly increased to 60_�_6% and 59_�_8% at pH 7.0, respectively. The pH-responsive release of NPs hinged on the electrostatic interaction between the pH-responsive membrane and the anionic NPs, and the change in pH-responsive morphology of the membrane. In vitro biocompatibility studies of the membrane showed no significant cytotoxicity to VK2/E6E7 human epithelial cells and Sup-T1 human T-cells and no significant changes in the expression of pro-inflammatory cytokines (IL-6, IL-8, and IL-1_). Overall, the porous pH-responsive PU membrane demonstrated its potential in serving as a �window� membrane in reservoir-type intravaginal rings (IVRs) for pH-responsive intravaginal release of NPs. Statement of Significance Stimuli-responsive intravaginal nanoparticle release is achieved for the first time through a new electrospun pH-responsive polyurethane (PU) semi-permeable membrane, which can serve as a �window� membrane in the reservoir-type IVR for the prevention of human immunodeficiency virus (HIV) transmission. Almost no release of nanoparticles was observed at normal pH in the female genital tract (in vaginal fluid simulant [VFS], at pH 4.5); however, a continuous release of NPs was observed at elevated pH in the female genital tract (in VFS, at pH 7.0). This pH-responsive intravaginal release can reduce side effect and drug resistance by avoiding unnecessary exposure. The PU semi-permeable membrane demonstrated potential use as biomaterials for �smart� intravaginal nanoparticle release and has great potential to protect women from HIV.Natural Sciences and Engineering Research Council of Canada [grant RGPIN/04922-2014]Natural Sciences and Engineering Research Council of Canada [grant RGPIN/2015-06008