New in vitro multiple cardiac ion channel screening system for preclinical Torsades de Pointes risk prediction under the Comprehensive in vitro Proarrhythmia Assay concepta.

Cardiotoxicity, particularly drug-induced Torsades de Pointes (TdP), is a concern in drug safety assessment. The recent establishment of human induced pluripotent stem cell-derived cardiomyocytes (human iPSC-CMs) has become an attractive human-based platform for predicting cardiotoxicity. Moreover, electrophysiological assessment of multiple cardiac ion channel blocks is emerging as an important parameter to recapitulate proarrhythmic cardiotoxicity. Therefore, we aimed to establish a novel in vitro multiple cardiac ion channel screening-based method using human iPSC-CMs to predict the drug-induced arrhythmogenic risk. To explain the cellular mechanisms underlying the cardiotoxicity of three representative TdP high- (sotalol), intermediate- (chlorpromazine), and low-risk (mexiletine) drugs, and their effects on the cardiac action potential (AP) waveform and voltage-gated ion channels were explored using human iPSC-CMs. In a proof-of-principle experiment, we investigated the effects of cardioactive channel inhibitors on the electrophysiological profile of human iPSC-CMs before evaluating the cardiotoxicity of these drugs. In human iPSC-CMs, sotalol prolonged the AP duration and reduced the total amplitude (TA) via selective inhibition of IKr and INa currents, which are associated with an increased risk of ventricular tachycardia TdP. In contrast, chlorpromazine did not affect the TA; however, it slightly increased AP duration via balanced inhibition of IKr and ICa currents. Moreover, mexiletine did not affect the TA, yet slightly reduced the AP duration via dominant inhibition of ICa currents, which are associated with a decreased risk of ventricular tachycardia TdP. Based on these results, we suggest that human iPSC-CMs can be extended to other preclinical protocols and can supplement drug safety assessments.

Alternative splicing in shaping the molecular landscape of the cochlea.

The cochlea is a complex organ comprising diverse cell types with highly specialized morphology and function. Until now, the molecular underpinnings of its specializations have mostly been studied from a transcriptional perspective, but accumulating evidence points to post-transcriptional regulation as a major source of molecular diversity. Alternative splicing is one of the most prevalent and well-characterized post-transcriptional regulatory mechanisms. Many molecules important for hearing, such as cadherin 23 or harmonin, undergo alternative splicing to produce functionally distinct isoforms. Some isoforms are expressed specifically in the cochlea, while some show differential expression across the various cochlear cell types and anatomical regions. Clinical phenotypes that arise from mutations affecting specific splice variants testify to the functional relevance of these isoforms. All these clues point to an essential role for alternative splicing in shaping the unique molecular landscape of the cochlea. Although the regulatory mechanisms controlling alternative splicing in the cochlea are poorly characterized, there are animal models with defective splicing regulators that demonstrate the importance of RNA-binding proteins in maintaining cochlear function and cell survival. Recent technological breakthroughs offer exciting prospects for overcoming some of the long-standing hurdles that have complicated the analysis of alternative splicing in the cochlea. Efforts toward this end will help clarify how the remarkable diversity of the cochlear transcriptome is both established and maintained.

Follistatin regulates the specification of the apical cochlea responsible for low-frequency hearing in mammals.

The cochlea's ability to discriminate sound frequencies is facilitated by a special topography along its longitudinal axis known as tonotopy. Auditory hair cells located at the base of the cochlea respond to high-frequency sounds, whereas hair cells at the apex respond to lower frequencies. Gradual changes in morphological and physiological features along the length of the cochlea determine each region's frequency selectivity, but it remains unclear how tonotopy is established during cochlear development. Recently, sonic hedgehog (SHH) was proposed to initiate the establishment of tonotopy by conferring regional identity to the primordial cochlea. Here, using mouse genetics, we provide in vivo evidence that regional identity in the embryonic cochlea acts as a framework upon which tonotopy-specific properties essential for frequency selectivity in the mature cochlea develop. We found that follistatin (FST) is required for the maintenance of apical cochlear identity, but dispensable for its initial induction. In a fate-mapping analysis, we found that FST promotes expansion of apical cochlear cells, contributing to the formation of the apical cochlear domain. SHH, in contrast, is required both for the induction and maintenance of apical identity. In the absence of FST or SHH, mice produce a short cochlea lacking its apical domain. This results in the loss of apex-specific anatomical and molecular properties and low-frequency-specific hearing loss.

Rewarding and Reinforcing Effects of 25H-NBOMe in Rodents.

The drug 25H-NBOMe is a new psychoactive substance (NPS). The use of these substances is likely to pose a threat to public health because they elicit effects similar to those of known psychoactive substances with similar chemical structures. However, data regarding the abuse potential of 25H-NBOMe are lacking. Here, we evaluated the abuse liability of 25H-NBOMe in rodents. The rewarding and reinforcing effects were evaluated through conditioned place preference (CPP) and self-administration (SA) tests after administration of 25H-NBOMe. To investigate the effects of 25H-NBOMe on the central nervous system, we determined the changes in dopamine levels by in vivo microdialysis. In the locomotor activity test, 25H-NBOme significantly increased locomotor activity in mice. In the place conditioning test, the 25H-NBOMe (0.1 and 0.5 mg/kg) groups showed a significantly increase in CPP in mice. In the SA test, the 25H-NBOMe (0.01 mg/kg) administered group showed a significant increased number of infusions and active lever presses. In microdialysis, the 25H-NBOMe (10 mg/kg) administered group was significantly increased in rats.

Current sensorless position-tracking control with angular acceleration error observers for hybrid-type stepping motors.

This paper exhibits an advanced observer-based position-tracking controller for hybrid-type stepping motors with consideration of parameter and load uncertainties. As the main contribution, a current sensorless observer-based pole-zero cancellation speed controller is devised for the outer loop position-tracking controller including the convergence rate boosting mechanism. The features of this study are summarized as follows; first, the pole-zero cancellation angular acceleration error observer for the inner loop speed controller, second, the pole-zero cancellation speed control forcing the order of the controlled speed error dynamics to be 1, and, third, the outer loop position control incorporating the first-order target tracking system with its convergence rate booster. The resultant effectiveness is verified on a 10-W stepping motor control system.

The Influence of Tyrosol-Enriched Rhodiola sachalinensis Extracts Bioconverted by the Mycelium of Bovista plumbe on Scopolamine-Induced Cognitive, Behavioral, and Physiological Responses in Mice.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by cognitive deficits, which are accompanied by memory loss and cognitive disruption. Rhodiola sachalinensis (RSE) is a medicinal plant that has been used in northeastern Asia for various pharmacological activities. We attempted to carry out the bioconversion of RSE (Bio-RSE) using the mycelium of Bovista plumbe to obtain tyrosol-enriched Bio-RSE. The objective of this study was to investigate the effects of Bio-RSE on the activation of the cholinergic system and the inhibition of oxidative stress in mice with scopolamine (Sco)-induced memory impairment. Sco (1 mg/kg body weight, i.p.) impaired the mice's performance on the Y-maze test, passive avoidance test, and water maze test. However, the number of abnormal behaviors was reduced in the groups supplemented with Bio-RSE. Bio-RSE treatment improved working memory and avoidance times against electronic shock, increased step-through latency, and reduced the time to reach the escape zone in the water maze test. Bio-RSE dramatically improved the cholinergic system by decreasing acetylcholinesterase activity and regulated oxidative stress by increasing antioxidant enzymes (superoxide dismutase (SOD) and catalase (CAT)). The reduction in nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling in the brain tissue due to scopolamine was restored by the administration of Bio-RSE. Bio-RSE also significantly decreased amyloid-beta 1-42 (Aß1-42) and amyloid precursor protein (APP) expression. Moreover, the increased malondialdehyde (MDA) level and low total antioxidant capacity in Sco-treated mouse brains were reversed by Bio-RSE, and an increase in Nrf2 and HO-1 was also observed. In conclusion, Bio-RSE protected against Sco-induced cognitive impairment by activating Nrf2/HO-1 signaling and may be developed as a potential beneficial material for AD.

Signal Detection of Adverse Events Following Pneumococcal Vaccines from the Korea Adverse Event Reporting System Database, 2005-2016.

PURPOSE: We aimed to analyze the surveillance reports of adverse events (AEs) due to different types of pneumococcal vaccines, in addition to detecting and validating signals of pneumococcal vaccines by comparing AEs with labels. MATERIALS AND METHODS: We analyzed the percentages of AEs according to vaccine type [pneumococcal polysaccharide vaccines (PPSVs) and pneumococcal conjugate vaccines (PCVs)] in children and adults using data from the Korea Adverse Event Reporting System (KAERS) database from 2005 to 2016. A signal was defined as an AE that met all three indices of data mining: proportional reporting ratio (PRR), reporting odds ratio (ROR), and information component (IC). We validated the detected signals by calculating sensitivity, specificity, as well as positive and negative predictive values of the signals against label information. RESULTS: Of the 39933 AE reports on vaccination, 5718 (7.0%) were related to pneumococcal vaccine. The most frequent AE after vaccination with PPSV was fever (23.9%) in children and injection-site reaction in adults. The most frequent AE after vaccination with PCV in children was pharyngitis (26.2%). In total, 13 AEs met all three indices for signal detection. Among these, hypotension, apathy, sepsis, and increased serum glutamic oxaloacetic transaminase level were not listed on vaccine labels. In validation analysis, PRR and ROR performed slightly better than IC for adults who were vaccinated with PPSVs. CONCLUSION: Overall, 13 new signals of PPSVs, including four signals not listed on the labels, were detected. Further research based on additional AE reports is required to confirm the validity of these signals for children.

Gamma Irradiated Rhodiola sachalinensis Extract Ameliorates Testosterone-Induced Benign Prostatic Hyperplasia by Downregulating 5-Alpha Reductase and Restoring Testosterone in Rats.

The effect of Rhodiola sachalinensis Boriss extract irradiated with 50 kGy gamma rays (HKC) on benign prostatic hyperplasia (BPH) was investigated. Seven-week-old male SD rats received a subcutaneous injection of 20 mg/kg of testosterone propionate (TP) to induce BPH. Then, the testosterone only group received testosterone, the testosterone + finasteride group received testosterone and finasteride (5 mg/kg), the testosterone + HKC group received testosterone and HKC extract (500 mg/kg). Prostate weight and the dihydrotestosterone (DHT) levels in serum or prostate tissue were determined. The mRNA expressions of 5-alpha reductase (AR) in prostate tissue were also measured. Compared to the control group, prostate weight was significantly improved in the TP group and decreased in the HKC and finasteride-treated groups. Furthermore, the mRNA expression of 5-AR in the prostate was significantly reduced in the HKC and finasteride-treated groups. Similarly, the expression levels of α-smooth muscle actin (α-SMA) and cytokeratin, which are associated with prostatic enlargement in the HKC and finasteride groups, were much lower than in the TP group. HKC treatment showed similar efficacy to finasteride treatment on rats with testosterone-induced BPH. HKC may be explored as a potential new drug for BPH treatment.

Efficient micro-cavity top emission OLED with optimized Mg:Ag ratio cathode.

Micro-cavity top-emitting organic light emitting diodes (TEOLEDs) are now receiving prominence as a technology for the active matrix display applications. The semi-transparent metal cathode plays the crucial role in realizing TEOLEDs structure. Here, we report the optimization results on Mg:Ag ratio as the semitransparent cathode deposited by vacuum thermal evaporation. The optimized Mg:Ag cathode with 1:10 ratio (wt %) shows a sheet resistance value as low as 5.2 Ω/□, an average transmittance of 49.7%, reflectance of 41.4%, and absorbance of 8.9% over the visible spectral region (400~700 nm). The fabricated red TEOLEDs device implemented using LiF (1nm)/Mg:Ag (1:10) cathode shows the voltage value of 4.17 V at a current density of 10.00 mA/cm2, and current efficiencies variation from 55.3 to 50.1 cd/A over the brightness range 2,000 - 12,000 cd/m2. The electroluminescence (EL) spectrum displays the light emission at 608 nm wavelength with a half width of 29.5 nm. The narrow half-width of red light emission is attributed to the micro-cavity effects due to the semitransparent cathode.

Phthalic Anhydride-Mediated Direct Glycosylation of Anomeric Hydroxy Arabinofuranose: Synthesis of Repeating Oligoarabinofuranoside and Tetradecasaccharide Arabinan Motif of Mycobacterial Cell Wall.

An efficient direct phthalic anhydride-mediated one-pot glycosylation method employing anomeric hydroxy arabinofuranose as glycosyl donor and triflic anhydride as activating agent has been developed. This method afforded the desired di- and oligoarabinofuranosides in good yields even in gram scale glycosylation when t-butylphthalic anhydride was used. Moreover, our new method can be further extended to the syntheses of repeating oligoarabinofuranoside and tetradecasaccharide arabinan motif found in mycobacterial cell wall.

O-linked ß-N-acetylglucosaminidase inhibitor attenuates ß-amyloid plaque and rescues memory impairment.

Deposition of ß-amyloid (Aß) as senile plaques and disrupted glucose metabolism are two main characteristics of Alzheimer's disease (AD). It is unknown, however, how these two processes are related in AD. Here we examined the relationship between O-GlcNAcylation, which is a glucose level-dependent post-translational modification that adds O-linked ß-N-acetylglucosamine (O-GlcNAc) to proteins, and Aß production in a mouse model of AD carrying 5XFAD genes. We found that 1,2-dideoxy-2'-propyl-α-d-glucopyranoso-[2,1-D]-Δ2'-thiazoline (NButGT), a specific inhibitor of O-GlcNAcase, reduces Aß production by lowering γ-secretase activity both in vitro and in vivo. We also found that O-GlcNAcylation takes place at the S708 residue of nicastrin, which is a component of γ-secretase. Moreover, NButGT attenuated the accumulation of Aß, neuroinflammation, and memory impairment in the 5XFAD mice. This is the first study to show the relationship between Aß generation and O-GlcNAcylation in vivo. These results suggest that O-GlcNAcylation may be a suitable therapeutic target for the treatment of AD.

Changes in intraocular pressure after pharmacologic pupil dilation.

BACKGROUND: Intraocular pressure (IOP) may vary according to the change of ocular conditions. In this study, we want to assess the effect and mechanism of pupil dilation on IOP in normal subjects. METHODS: We prospectively evaluated 32 eyes of 32 patients (age; 61.7±8.2 years) with normal open angles under diurnal IOP. IOP was measured every two hours from 9 AM to 11 PM for one day to establish baseline values and was measured again for one day to assess the differences after dilation. To induce dilation, we administered 2.5% phenylephrine and 1% tropicamide every 5 minutes from 8:30 AM to 8:45 AM and for every two hours from 11 AM to 9 PM to keep the pupil dilated. Diurnal IOP, biometry, Visante OCT, and laser flare photometry were measured before and after dilation. RESULTS: We observed a significant increase in IOP after dilation, 1.85±2.01 mmHg (p=0.002). IOP elevation remained significant until about four hours after dilation. Thereafter, IOP decreased slowly and eventually reached pre-dilation level (p>0.05). Flare values decreased, and the anterior chamber angle became wider after mydriasis. CONCLUSIONS: Dilation of the pupil significantly and incidentally elevated IOP in normal subjects. Further related studies are warranted to characterize the mechanism of the increased IOP after dilation.

Protein O-GlcNAcylation regulates Drosophila growth through the insulin signaling pathway.

Modification of nuclear and cytosolic proteins by O-linked N-acetylglucosamine (O-GlcNAcylation) is ubiquitous in cells. The in vivo function of the protein O-GlcNAcylation, however, is not well understood. Here, we manipulated the cellular O-GlcNAcylation level in Drosophila and found that it promotes developmental growth by enhancing insulin signaling. This increase in growth is due mainly to cell growth and not to cell proliferation. Our data suggest that the increase in the insulin signaling activity is mediated, at least in part, through O-GlcNAcylation of Akt. These results indicate that O-GlcNAcylation is one of the crucial mechanisms involved in control of insulin signaling during Drosophila development.

Effect of electron-withdrawing protecting groups at remote positions of donors on glycosylation stereochemistry.

Here we review the equatorial ß-directing effects of electron-withdrawing protecting groups at remote positions of mannopyranosyl donors, mannuronate donors, rhamnopyranosyl donors, and 2,6-dideoxyglucopyranosyl donors. We discuss the equatorial α-directing effect of an electron-withdrawing group at the N-5 position of sialyl donors. The proposed mechanism and origin of some of the equatorial ß-directing effects are described. We also review the effects of potentially participating, electron-withdrawing protecting groups at remote positions of glycopyranosyl and glycofuranosyl donors on the glycosylation stereochemistries. Further, we present substantial evidence in favor of the remote participation by the electron-withdrawing protecting groups and also include reports that are opposed to remote participation.

Survival and prognostic analysis of adjacent segments after spinal fusion.

BACKGROUND: To examine the survival function and prognostic factors of the adjacent segments based on a second operation after thoracolumbar spinal fusion. METHODS: This retrospective study reviewed 3,188 patients (3,193 cases) who underwent a thoracolumbar spinal fusion at the author's hospital. Survival analysis was performed on the event of a second operation due to adjacent segment degeneration. The prognostic factors, such as the cause of the disease, surgical procedure, age, gender and number of fusion segments, were examined. Sagittal alignment and the location of the adjacent segment were measured in the second operation cases, and their association with the types of degeneration was investigated. RESULTS: One hundred seven patients, 112 cases (3.5%), underwent a second operation due to adjacent segment degeneration. The survival function was 97% and 94% at 5 and 10 years after surgery, respectively, showing a 0.6% linear reduction per year. The significant prognostic factors were old age, degenerative disease, multiple-level fusion and male. Among the second operation cases, the locations of the adjacent segments were the thoracolumbar junctional area and lumbosacral area in 11.6% and 88.4% of cases, respectively. Sagittal alignment was negative or neutral, positive and strongly positive in 47.3%, 38.9%, and 15.7%, respectively. Regarding the type of degeneration, spondylolisthesis or kyphosis, retrolisthesis, and neutral balance in the sagittal view was noted in 13.4%, 36.6%, and 50% of cases, respectively. There was a significant difference according to the location of the adjacent segment (p = 0.000) and sagittal alignment (p = 0.041). CONCLUSIONS: The survival function of the adjacent segments was 94% at 10 years, which had decreased linearly by 0.6% per a year. The likelihood of a second operation was high in those with old age, degenerative disease, multiple-level fusion and male. There was a tendency for the type of degeneration to be spondylolisthesis or kyphosis in cases of the thoracolumbar junctional area and strongly positive sagittal alignment, but retrolisthesis in cases of the lumbosacral area and neutral or positive sagittal alignment.

Electrochemical determination of carbohydrate-binding proteins using carbohydrate-stabilized gold nanoparticles and silver enhancement.

A highly sensitive electrochemical lectin biosensor has been developed for the first time using carbohydrate-stabilized gold nanoparticles and silver-enhancement technique. A target lectin protein, Concanavalin A (Con A), was specifically bound to the self-assembled monolayer of thiolated mannose on a gold electrode. Mannose-stabilized gold nanoparticles were added to form a sandwich-type complex with the Con A and were followed by silver-enhancement process to coat the mannose-stabilized gold nanoparticles with silver metal. The coated metallic silver was dissolved in an acidic solution and the resulting silver ions were detected by anodic stripping voltammetry. The present lectin biosensor gave a linear response (R(2)=0.999) for Con A concentration from 0.084 µg/mL to 50.0 µg/mL with a remarkable detection limit (S/N=3) of 0.070 µg/mL, which is much lower compared to those obtained with the reported microgravimetric and colorimetric detection methods.

Evaluation of anterior lenticonus in alport syndrome using tracey wavefront aberrometry and transmission electron microscopy.

BACKGROUND AND OBJECTIVE: To evaluate the efficacy of Tracey wavefront aberrometry (Tracey Technologies, Houston, TX) and transmission electron microscopy for the detection of anterior lenticonus in Alport syndrome. PATIENTS AND METHODS: Tracey wavefront aberrometry was used to treat a patient with bilateral anterior lenticonus who had a history of Alport syndrome. For transmission electron microscopic examination, anterior lens capsules were obtained during clear lens phacoemulsification and intraocular lens implantation. RESULTS: Spherical aberrations were the predominant higher-order aberrations in the internal optics of both eyes. The Tracey wavefront aberrometer showed that most of the irregular astigmatism originated from the lenticular portion. Transmission electron microscopy of the specimens showed anterior lens capsules with decreased thickness and multiple dehiscences. CONCLUSION: Tracey wavefront aberrometry and transmission electron microscopy are effective tools for evaluation of anterior lenticonus in Alport syndrome.

Beta-directing effect of electron-withdrawing groups at O-3, O-4, and O-6 positions and alpha-directing effect by remote participation of 3-O-acyl and 6-O-acetyl groups of donors in mannopyranosylations.

Mannosylations of various acceptors with donors possessing an electron-withdrawing o-trifluoromethylbenzenesulfonyl, benzylsulfonyl, p-nitrobenzoyl, benzoyl, or acetyl group at O-3, O-4, or O-6 positions were found to be beta-selective except when donors had 3-O-acyl and 6-O-acetyl groups, which afforded alpha-mannosides as major products. The alpha-directing effect of 3-O-acyl and 6-O-acetyl groups was attributed to their remote participation, and the isolation of a stable bicyclic trichlorooxazine ring resulting from the intramolecular trapping of the anomeric oxocarbenium ion by 3-O-trichloroacetimidoyl group provided evidence for this remote participation. The triflate anion, counteranion of the mannosyl oxocarbenium ion, was essential for the beta-selectivity, and covalent alpha-mannosyl triflates with an electron-withdrawing group at O-3, O-4, or O-6 were detected by low-temperature NMR. The strongly electron-withdrawing sulfonyl groups, which exhibited a higher beta-directing effect in the mannosylation, made the alpha-mannosyl triflates more stable than the weakly electron-withdrawing acyl groups. We therefore proposed the mechanism for the beta-mannosylation and the origin of the beta-directing effect: the electron-withdrawing groups would stabilize the alpha-mannosyl triflate intermediate, and the subsequent reaction of the alpha-triflate (or its contact ion pair) with the acceptor would afford the beta-mannoside. The beta-selective mannosylation of a sterically demanding acceptor was achieved by employing a donor possessing two strongly electron-withdrawing benzylsulfonyl groups at O-4 and O-6 positions.

The surgical treatment for spinal intradural extramedullary tumors.

BACKGROUND: We wanted to investigate the results of surgical treatment and analyze the factors that have an influence on the neurologic symptoms and prognosis of spinal intradural extramedullary (IDEM) tumors. METHODS: The spinal IDEM tumor patients (11 cases) who had been treated by surgical excision and who were followed up more than 1 year were retrospectively analyzed. Pain was evaluated by the visual analogue scale (VAS) and the neurologic function was assessed by Nurick's grade. The pathological diagnosis, the preoperative symptom duration, the tumor location on the sagittal and axial planes and the percentage of tumor occupying the intradural space were investigated. In addition, all these factors were analyzed in relation to the degree of the preoperative symptoms and the prognosis. On the last follow-up, the MRI was checked to evaluate whether or not the tumor had recurred. RESULTS: The most common diagnosis was schwannomas (73%), followed by meningiomas (18%). The percentage of tumor occupying the intradural space was 82.9 +/- 9.4%. The VAS score was reduced in all cases from 8.0 +/- 1.2 to 1.2 +/- 0.8 (p = 0.003) and the Nurick's grade was improved in all cases from 3.0 +/- 1.3 to 1.0 +/- 0.0 (p = 0.005). The preoperative symptoms were correlated with only the percentage of tumor occupying the intradural space (VAS; r(2) = 0.75, p = 0.010, Nurick's grade; r(2) = 0.69, p = 0.019). One case of schwannoma recurred. CONCLUSIONS: The degree of neurologic symptoms was correlated with the percentage of tumor occupying the intradural space. All the tumors were able to be excised through the posterior approach. The postoperative neurologic recovery was excellent in all the cases regardless of any condition. Therefore, aggressive surgical excision is recommended even for cases with a long duration of symptoms or a severe neurologic deficit.