Characterization of α-gustducin

Aims/Introduction: Taste receptors, T1rs and T2rs, and the taste‐selective G‐protein, α‐gustducin, are expressed outside the taste‐sensing system, such as enteroendocrine L cells. Here, we examined whether α‐gustducin also affects nutrition sensing and insulin secretion by pancreatic β‐cells. Materials and Methods: The expression of α‐gustducin and taste receptors was evaluated in β‐cell lines, and in rat and mouse islets either by quantitative polymerase chain reaction or fluorescence immunostaining. The effects of α‐gustducin knockdown on insulin secretion and on cyclic adenosine monophosphate and intracellular Ca2+ levels in rat INS‐1 cells were estimated. Sucralose (taste receptor agonist)‐induced insulin secretion was investigated in INS‐1 cells with α‐gustducin suppression and in islets from mouse disease models. Results: The expression of Tas1r3 and α‐gustducin was confirmed in β‐cell lines and pancreatic islets. Basal levels of cyclic adenosine monophosphate, intracellular calcium and insulin secretion were significantly enhanced with α‐gustducin knockdown in INS‐1 cells. The expression of α‐gustducin was decreased in high‐fat diet‐fed mice and in diabetic db/db mice. Sucralose‐induced insulin secretion was not attenuated in INS‐1 cells with α‐gustducin knockdown or in mouse islets with decreased expression of α‐gustducin. Conclusions: α‐Gustducin is involved in the regulation of cyclic adenosine monophosphate, intracellular calcium levels and insulin secretion in pancreatic β‐cells in a manner independent of taste receptor signaling. α‐Gustducin might play a novel role in β‐cell physiology and the development of type 2 diabetes

Self-Turn-on-Free 5V Gate Driving for 1200V Scaled IGBT

Negative biasing of the gate voltage in a scaled insulated gate bipolar transistor (IGBT) during the off-state was modeled and found to be effective against self-turn-on failures. The required self-turn-on-free criteria were verified experimentally.31st IEEE International Symposium on Power Semiconductor Devices and ICs (ISPSD 2019), 19-23 May 2019, Shanghai, Chin

Inhibition of endothelin receptors in the treatment of pulmonary arterial hypertension: does selectivity matter?

Treatment options for pulmonary arterial hypertension (PAH) have considerably improved in the past few years. Endothelin (ET)-receptor antagonism has been established as a first-line option for the majority of PAH patients. Endothelin-receptor antagonists (ETRAs) comprise sulfonamide and non-sulfonamide agents with different affinities for ET-receptor subtypes (ETA and ETB), and the focus of development has shifted from drugs with less selectivity to those with high selectivity. There is ongoing debate as to whether selective or non-selective ET-receptor antagonism is more beneficial in the treatment of PAH. This paper reviews the current evidence from experimental and clinical studies obtained from a thorough literature search focusing on the three marketed drugs bosentan, sitaxentan, and ambrisentan. A clinically meaningful difference among the three approved ETRAs with respect to their ET-receptor selectivity could not be demonstrated to date. Therefore, in clinical practice, other features are likely to be of greater relevance when considering treatment, such as the potential for serious drug–drug interactions, convenience of dosing schedule, or rates of limiting side effects. These characteristics bear more relation to the chemical or pharmacological properties of the drugs than to receptor selectivity itself

Development of Perylene-Based Non-Fullerene Acceptors through Bay-Functionalization Strategy

Perylene has had a tremendous impact in the history of material research for the molecular semiconductors. Among numerous derivatives of this polyaromatic hydrocarbon, perylene diimide (PDI) represents a promising class of organic materials envisioned as non-fullerene acceptors (NFAs) for the practical organic photovoltaic (OPV) applications due to their enhanced photo- and thermal stability and remarkably high electron affinity, some of which realize band-like transport properties. The present review guides some of the representative achievements in the development of rationally designed PDI systems, highlighting synthetic methodologies based on bay-functionalization strategies for creating well-designed molecular nanostructures and structure-performance relationship of perylene-based small molecular acceptors (SMAs) for the photovoltaic outcomes

Palatal Fistula Repair : Methods and Results

Thirty-seven patients of the palatal fistula after primary palatoplasty were reviewed, with special reference to the methods used to repair, their results and the effect on speech. The operative procedures used include local mucoperiosteal flap, mucosal flap, tongue flap and free mucosal graft, which were selected according to size, location and local condition of the fistula. If possible, it is better to select the operative procedure that will disturb neither the maxillar development nor orthodontic treatment. As for speech, closure of the fistula seems to be an important trigger for the improvement in the intelligibility of the speech

Weight Tracking Method for OFDM Adaptive Array in Time Variant Fading Channel

(MMSE-AAA) is attractive. To get the space diversity gain, the distance between adjacent elements should be set to be more than several wavelengths. However, it is difficult to derive the optimal weights with a few training symbols because fading status is independent in each element. As a result, Bit Error Rate (BER) performance is deteriorated. In this paper, we propose a novel weight tracking method to achieve space diversity gain and fast convergence with a few pilot symbols. In the proposed method, before updating the weights, channel estimation is applied to track the multipath fading of the desired signals. By computer simulation, we show that the proposed system can improve BER performance compared to the conventional system without channel estimation, even if the Doppler frequency is high

Functional Interference of Sp1 and NF-κB through the Same DNA Binding Site

Gene activation by NF-κB/Rel transcription factors is modulated by synergistic or antagonistic interactions with other promoter-bound transcription factors. For example, Sp1 sites are often found in NF-κB-regulated genes, and Sp1 can activate certain promoters in synergism with NF-κB through nonoverlapping binding sites. Here we report that Sp1 acts directly through a subset of NF-κB binding sites. The DNA binding affinity of Sp1 to these NF-κB sites, as determined by their relative dissociation constants and their relative efficiencies as competitor DNAs or as binding site probes, is in the order of that for a consensus GC box Sp1 site. In contrast, NF-κB does not bind to a GC box Sp1 site. Sp1 can activate transcription through immunoglobulin kappa-chain enhancer or P-selectin promoter NF-κB sites. p50 homodimers replace Sp1 from the P-selectin promoter by binding site competition and thereby either inhibit basal Sp1-driven expression or, in concert with Bcl-3, stimulate expression. The interaction of Sp1 with NF-κB sites thus provides a means to keep an elevated basal expression of NF-κB-dependent genes in the absence of activated nuclear NF-κB/Rel

Clarithromycin overcomes stromal cell-mediated drug resistance against proteasome inhibitors in myeloma cells via autophagy flux blockage leading to high NOXA expression.

We previously reported that macrolide antibiotics, such as clarithromycin (CAM), blocked autophagy flux, and simultaneous proteasome and autophagy inhibition by bortezomib (BTZ) plus CAM resulted in enhanced apoptosis induction in multiple myeloma (MM) cells via increased endoplasmic reticulum (ER) stress loading. However, in actual therapeutic settings, cell adhesion-mediated drug resistance between bone marrow stromal cells (BMSC) and MM cells has been known to be a barrier to treatment. To investigate whether CAM could enhance BTZ-induced cytotoxicity in MM cells under direct cell adhesion with BMSC, we established a co-culture system of EGFP-labeled MM cells with BMSC. The cytotoxic effect of BTZ on MM cells was diminished by its interaction with BMSC; however, the attenuated cytotoxicity was recovered by the co-administration of CAM, which upregulates ER stress loading and NOXA expression. Knockout of NOXA in MM cells canceled the enhanced cell death by CAM, indicating that NOXA is a key molecule for cell death induction by the co-administration of CAM. Since NOXA is degraded by autophagy as well as proteasomes, blocking autophagy with CAM resulted in the sustained upregulation of NOXA in MM cells co-cultured with BMSC in the presence of BTZ. Our data suggest that BMSC-associated BTZ resistance is mediated by the attenuation of ER stress loading. However, the addition of CAM overcomes BMSC-associated resistance via upregulation of NOXA by concomitantly blocking autophagy-mediated NOXA degradation and transcriptional activation of NOXA by ER stress loading