Gastrin-releasing peptide (GRP) functions as a neurotransmitter for non-histaminergic itch, but its site of action (sensory neurons vs spinal cord) remains controversial. To determine the role of GRP in sensory neurons, we generated a floxed Grp mouse line. We found that conditional knockout of Grp in sensory neurons results in attenuated non-histaminergic itch, without impairing histamine-induced itch. Using a Grp-Cre knock-in mouse line, we show that the upper epidermis of the skin is exclusively innervated by GRP fibers, whose activation via optogeneics and chemogenetics in the skin evokes itch-but not pain-related scratching or wiping behaviors. In contrast, intersectional genetic ablation of spinal Grp neurons does not affect itch nor pain transmission, demonstrating that spinal Grp neurons are dispensable for itch transmission. These data indicate that GRP is a neuropeptide in sensory neurons for nonhistaminergic itch, and GRP sensory neurons are dedicated to itch transmission.

SUMMARYChronic itch or pruritus is a debilitating disorder that is refractory to conventional anti-histamine treatment. Kappa opioid receptor (KOR) agonists have been used to treat chronic itch, but the underlying mechanism remains elusive. Here, we find that KOR and gastrin-releasing peptide receptor (GRPR) overlap in the spinal cord, and KOR activation attenuated GRPR-mediated histamine-independent acute and chronic itch in mice. Notably, canonical KOR-mediated Gαi signaling is not required for desensitizing GRPR function. In vivo and in vitro studies suggest that KOR activation results in the translocation of Ca2+-independent protein kinase C (PKC)δ from the cytosol to the plasma membrane, which in turn phosphorylates and inhibits GRPR activity. A blockade of phospholipase C (PLC) in HEK293 cells prevented KOR-agonist-induced PKCδ translocation and GRPR phosphorylation, suggesting a role of PLC signaling in KOR-mediated GRPR desensitization. These data suggest that a KOR-PLC-PKCδ-GRPR signaling pathway in the spinal cord may underlie KOR-agonists-induced anti-pruritus therapies.

Highly scaled FinFET SRAM cells, of area down to 0.128μm 2 , were fabricated using high-κ dielectric and a single metal gate to demonstrate cell size scalability and to investigate V t variability for the 32 nm node and beyond. A single-sided ion implantation (I/I) scheme was proposed to reduce V t variation of Fin-FETs in a SRAM cell, where resist shadowing is a great issue. In the 0.187μm 2 cell, at V d = 0.6 V, a static noise margin (SNM) of 95 mV was obtained and stable read/write operations were verified from N-curve measurements. σV t of transistors in 0.187μm 2 cells was measured with and without channel doping and the result was summarized in the Pelgrom plot. With the 22 nm node design rule, FinFET SRAM cell layouts were compared against planar-FET SRAM cell layouts. An un-doped FinFET SRAM cell was simulated to have significant advantage in read/write margin over a planar-FET SRAM cell, which would have higher σV t mainly caused by heavy doping into the channel region.

The aim of this study was to detect IL36RN variant types and frequency in Han patients with generalized pustular psoriasis (GPP) in Sichuan region of China, reveal the difference of variant frequency between GPP alone and GPP + PV (psoriasis vulgaris), and preliminarily clarify the pathogenesis of GPP in this region.Genomic DNA was extracted and subjected to polymerase chain reaction (PCR) for the amplification of the entire encoding and splice sites of the IL36RN gene followed by bidirectional sequencing. Differences in frequencies of IL36RN variants between groups were analyzed by SPSS Statistics 17.0 software. Meanwhile, the IL36RN variant frequency between GPP alone and GPP + PV was compared.The total IL36RN variant frequency was 60.47% in Han GPP patients from Sichuan region of China. Three variant types (c.115 + 6T > C, c.140A > G, c.227C > T) were identified, among which c.115 + 6T > C exhibited the highest frequency (55.81%). All the 3 variants’ frequency of GPP alone group had statistical significance when compared with PV patients and normal controls (P < .05). The IL36RN variant frequency of GPP alone group was statistically higher than that of GPP + PV group (79.17% vs 36.84%, P < .05).IL36RN may be the major disease-causing gene in GPP patients in Han population in Sichuan region of China. c.115 + 6T > C is a possible hot-spot mutation within the IL36RN gene. In contrast to GPP + PV, IL36RN mutations possibly play a more important role in the development of GPP alone.