Xelaglifam, a novel GPR40/FFAR1 agonist, exhibits enhanced ß-arrestin recruitment and sustained glycemic control for type 2 diabetes.

Xelaglifam, developed as a GPR40/FFAR1 agonist, induces glucose-dependent insulin secretion and reduces circulating glucose levels for Type 2 diabetes treatment. This study investigated the effects of Xelaglifam in comparison with Fasiglifam on the in vitro/in vivo anti-diabetic efficacy and selectivity, and the mechanistic basis. In vitro studies on downstream targets of Xelaglifam were performed in GPR40-expressing cells. Xelaglifam treatment exhibited dose-dependent effects, increasing inositol phosphate-1, Ca2+ mobilization, and ß-arrestin recruitment (EC50: 0.76 nM, 20 nM, 68 nM), supporting its role in Gq protein-dependent and G-protein-independent mechanisms. Despite a lack of change in the cAMP pathway, the Xelaglifam-treated group demonstrated increased insulin secretion compared to Fasiglifam in HIT-T15 ß cells under high glucose conditions. High doses of Xelaglifam (<30 mg/kg) did not induce hypoglycemia in Sprague-Dawley rats. In addition, Xelaglifam lowered glucose and increased insulin levels in diabetic rat models (GK, ZDF, OLETF). In GK rats, 1 mg/kg of Xelaglifam improved glucose tolerance (33.4 % and 15.6 % for the 1 and 5 h) after consecutive glucose challenges. Moreover, repeated dosing in ZDF and OLETF rats resulted in superior glucose tolerance (34 % and 35.1 % in ZDF and OLETF), reducing fasting hyperglycemia (18.3 % and 30 % in ZDF and OLETF) at lower doses; Xelaglifam demonstrated a longer-lasting effect with a greater effect on ß-cells including 3.8-fold enhanced insulin secretion. Co-treatment of Xelaglifam with SGLT-2 inhibitors showed additive or synergistic effects. Collectively, these results demonstrate the therapeutic efficacy and selectivity of Xelaglifam on GPR40, supportive of its potential for the treatment of Type 2 diabetes.

Experiences with an Extraperitoneal Transvesicoscopic Repair of a Vesicovaginal Fistula.

Purpose A vesicovaginal fistula (VVF) is a debilitating condition for women in terms of both its personal and social impacts. A reported transperitoneal laparoscopic approach to treatment has some limitations such as risk of intra-peritoneal organ injury and unnecessary bladder dissection. We here report on our experiences with an extraperitoneal transvesicoscopic approach to a VVF repair, which overcomes these drawbacks. Materials and Methods Seven VVF patients were treated using the transvesicoscopic approach. Under general anesthesia, patients were placed in the dorsal lithotomy position. The VVF orifice was obstructed via the vaginal canal using a Foley catheter. The bladder was then filled with normal saline under cystoscopic inspection, and a 5 mm trocar was inserted into it at the suprapubic area. The bladder wall was next fixed to the anterior abdominal wall. Thereafter, two 3 mm ports were punctured at the interspinous skin crease allowing the fistula margin to be cut and sutured in layers. Results Six of the study subjects in whom we attempted a transvesicoscopic repair of VVF had undergone a hysterectomy due to myoma and one had an intraabdominal abscess removal with Behcet's disease. One myoma patient who had a preexisting vesicoperitoneal fistula was converted to an open transabdominal VVF repair. The mean age of the 6 remaining patients was 46.0 ± 7.2 years (range, 35-57). The mean operation time was 273 ± 40.6 minutes (range, 223-323). There was no instances of significant pain or other immediate complications. Five patients showed no recurrence of the fistula during the follow-up period (8.7±5.1 months). Conclusion A transvesicoscopic approach is an effective modality for the repair of a VVF that is more minimally invasive and has a lower morbidity than a transabdominal procedure.

Venadaparib Is a Novel and Selective PARP Inhibitor with Improved Physicochemical Properties, Efficacy, and Safety.

PARP inhibitors have been approved by the FDA for use in the treatment of patients with ovarian, breast, pancreatic, and prostate cancers. PARP inhibitors show diverse suppressive effects on PARP family members and PARP-DNA trapping potency. These properties are associated with distinct safety/efficacy profiles. Here, we report the nonclinical characteristics of venadaparib (also known as IDX-1197 or NOV140101), a novel potent PARP inhibitor. The physiochemical properties of venadaparib were analyzed. Furthermore, the efficacy of venadaparib against PARP enzymes, PAR formation, and PARP trapping activities, and growth inhibition of cell lines with BRCA mutations were evaluated. Ex vivo and in vivo models were also established to study pharmacokinetics/pharmacodynamics, efficacy, and toxicity. Venadaparib specifically inhibits PARP-1 and -2 enzymes. Oral administration of venadaparib HCl at doses above 12.5 mg/kg significantly reduced tumor growth in the OV_065 patient-derived xenograft model. Intratumoral PARP inhibition remained at over 90% until 24 hours after dosing. Venadaparib had wider safety margins than olaparib. Notably, venadaparib showed favorable physicochemical properties and superior anticancer effects in homologous recombination-deficient in vitro and in vivo models with improved safety profiles. Our results suggest the possibility of venadaparib as a next-generation PARP inhibitor. On the basis of these findings, phase Ib/IIa studies on the efficacy and safety of venadaparib have been initiated.

Profiling Cannabinoid Contents and Expression Levels of Corresponding Biosynthetic Genes in Commercial Cannabis (Cannabis sativa L.) Cultivars.

Cannabis (Cannabis sativa L.) is widely cultivated and studied for its psychoactive and medicinal properties. As the major cannabinoids are present in acidic forms in Cannabis plants, non-enzymatic processes, such as decarboxylation, are crucial for their conversion to neutral active cannabinoid forms. Herein, we detected the levels of cannabidivarin (CBDV), cannabidiol (CBD), cannabichromene (CBC), and Δ9-tetrahydrocannabinol (Δ9-THC) in the leaves and vegetative shoots of five commercial Cannabis cultivars using a combination of relatively simple extraction, decarboxylation, and high-performance liquid chromatography analyses. The CBDV, CBC, and Δ9-THC levels were 6.3-114.9, 34.4-187.2, and 57.6-407.4 µg/g, respectively, and the CBD levels were the highest, ranging between 1.2-8.9 µg/g in leaf and vegetative shoot tissues of Cannabis cultivars. Additionally, correlations were observed between cannabinoid accumulation and transcription levels of genes encoding key enzymes for cannabinoid biosynthesis, including CsCBGAS, CsCBDAS, CsCBCAS, and CsTHCAS. These data suggest that the high accumulation of cannabinoids, such as CBC, Δ9-THC, and CBD, might be derived from the transcriptional regulation of CsCBGAS and CsCBDAS in Cannabis plants.

Barrier-assisted vapor phase CVD of large-area MoS2 monolayers with high spatial homogeneity.

Atomically thin molybdenum disulphide (MoS2) is a direct band gap semiconductor with negatively charged trions and stable excitons in striking contrast to the wonder material graphene. While large-area growth of MoS2 can be readily achieved by gas-phase chemical vapor deposition (CVD), growth of continuous MoS2 atomic layers with good homogeneity is indeed one of the major challenges in vapor-phase CVD involving all-solid precursors. In this study, we demonstrate the growth of large-area continuous single crystal MoS2 monolayers on c-plane sapphire by carefully positioning the substrate using a facile staircase-like barrier. The barrier offered great control in mitigating the secondary and intermediate phases as well as second layer nucleation, and eventually a continuous monolayer with high surface homogeneity is realized. Both micro-Raman and high-resolution transmission electron microscopy (HRTEM) results confirmed the high structural quality of the grown MoS2 layers. Using low temperature photoluminescence spectroscopy, additional pieces of information are provided for the strong band-edge emission in the light of vacancy compensation and formation of Mo-O bonding. The monolayer MoS2 transferred to SiO2/Si exhibited a room temperature field-effect mobility of ∼1.2 cm2 V-1 s-1 in a back-gated two-terminal configuration.

Difference in Cognitive Function by First Onset Age of Alcohol Induced Blackout and Its Duration.

OBJECTIVE: Alcohol-induced blackout (blackout) is a typical early symptom of cognitive impairment caused by drinking. However, the first onset age of blackout or the duration after onset of blackout has not been directly compared in previous studies. The purpose of this study was to investigate the differences in cognitive function to the first start age of blackouts and their duration. METHODS: Thirty-one male subjects were included in this study. Their age at the first blackout and the duration after the onset of blackout were investigated. Neuropsychological tests were conducted to determine their attention, memory, and executive function. Subjects were divided into three groups according to their age of the first onset blackout (group O1, < 20 years; group O2, 21-39 years; and group O3, > 40 years). Subjects were also divided into three groups by duration after the onset of blackout (P1, < 10 years; P2, 10-29 years; and P3, > 30 years). We then examined differences in neurocognitive function among these groups. RESULTS: O1 tended to have a lower memory score than O2 (F = 3.28, p = 0.053). Significant differences were observed in attention and executive function between groups P1 and P3 (Digit Span_backward: F = 6.07, p < 0.05; visual span_forward: F = 4.19, p < 0.05; executive intelligence quotient: F = 3.55, p < 0.05). CONCLUSION: Greater memory impairment was detected in subjects having an earlier age of the first blackout. The longer the duration after the onset of blackout, the more impaired their attention and executive function skills.

Recycling waste nutrient solution originating from the plant factory with the cultivation of newly isolated Acutodesmus species.

Plant factories have been developed to replace traditional agriculture, aiming to solve future problems of food availability. However, the nutrient solution in a plant factory is discharged after a single batch of plant cultivation, giving rise to large amounts of waste nutrient solution. Microalgae can be used to treat a wide variety of wastewater and effectively remove excessive nutrients from wastewater. Therefore, the incorporation of microalgal cultivation into a plant factory to treat waste nutrients would be a reasonable approach facilitating removal of waste nutrients with concomitant production of algal biomass. In this study, we isolated novel microalgal species suitable for the growth in waste nutrients from a plant factory and subsequently an underwater LED photobioreactor was constructed being incorporated into the plant factory system. Finally, treated waste nutrient solution was recycled back into the plant factory and successfully used for the cultivation of plant of butterhead lettuce (Lactuca sativa L.).

Effect of Climatic Parameters on Acute Urinary Retention Incidence.

OBJECTIVES: We investigated the effect of daily climatic parameters on spontaneous acute urinary retention (sAUR) and evaluated the risk factors for refractory/recurrent AUR. METHODS: A total of 4194 patients older than 40 years were diagnosed with AUR in the emergency department at Gangnam Severance Hospital, Seoul, from January 2007 to May 2016. To evaluate climatic parameters at sAUR onset, we included individuals living in the area around the hospital. We excluded patients with fever, who did not return to the hospital after the AUR episode or with AUR occurring within 2 weeks following admission for surgery or chemotherapy. RESULTS: Among 818 patients living in the two districts around the hospital, winter and October had the highest seasonal and monthly rates of sAUR development, respectively, and sAUR incidence increased with age. Daily temperature range and mean wind speed were significant risk factors for sAUR development. Several daily climatic parameters had seasonal effects on sAUR incidence. Over a mean follow-up of 0.98 years, 122 patients (14.9%) developed refractory/recurrent AUR. Transitional zone index (TZI; HR = 1.03; P = 0.002) and prostate-specific antigen (PSA) at the time of sAUR (HR = 1.01; P = 0.030) were significant predictors of refractory/recurrent AUR. Benign prostate hyperplasia medication and transurethral prostatectomy after sAUR were not risk factors for refractory/recurrent AUR. CONCLUSIONS: Cold temperature provoked sAUR in patients with higher age and International Prostate Symptom Score. Patients with higher TZI and PSA level at the time of sAUR had a greater risk of developing refractory/recurrent AUR.

Carbon-nanotube-assisted nanoepitaxy of Si-doped GaN for improved performance of InGaN/GaN light-emitting diodes.

Using single-walled carbon nanotubes (SWCNTs) as nanomasks on an undoped GaN template, a significant biaxial stress relaxation was achieved in the subsequently-grown Si-doped n-GaN layer. Enhanced near band edge (NBE) emission intensity, similar free carrier concentrations, and the reduced peak width of the asymmetric (102) crystallographic plane all confirmed the suppression of threading dislocations due to the nanoepitaxial growth process. Temperature-dependent photoluminescence (PL) revealed improved internal quantum efficiency (IQE) of InGaN/GaN multi-quantum wells (MQWs) grown on this n-GaN layer. Furthermore, enhanced light output power and a remarkable reduction in efficiency droop were observed for the blue light-emitting diodes (LEDs), especially at higher injection currents. Our results emphasize the strong potential for SWCNTs as nanomasks in the heteroepitaxy of GaN-based devices without the exploitation of complicated lithography or etching processes.

Tubeless percutaneous nephrolithotomy with non-absorbable hemostatic sealant (Quikclot®) versus nephrostomy tube placement: a propensity score-matched analysis.

The purpose of this study was to determine the efficacy and safety of tubeless percutaneous nephrolithotomy (PNL) using a non-absorbable hemostatic sealant (Quikclot(®)) as an adjunct compared to nephrostomy tube placement in patients exhibiting significant parenchymal bleeding following PNL. We identified 113 PNL cases performed between May 2011 and October 2014. For patients with insignificant parenchymal bleeding following stone removal, defined as a clear visualization of the surgical field at full irrigation of the nephroscope, tubeless PNL was performed. For patients with significant parenchymal bleeding, we introduced the tubeless Quikclot(®) technique as of September 2013 and have performed it ever since. Formerly, nephrostomy placement PNL was performed. In this study, 40 Quikclot(®) applied PNL cases were matched with an equal number of nephrostomy placement cases by propensity scoring based on body mass index, stone size, and Guy's stone score. The mean postoperative drop in hematocrit was comparative between the Quikclot(®) group and the nephrostomy group on both postoperative days 1 (p = 0.459) and 2 (p = 0.325). Quikclot(®) application was associated with lower VAS scores throughout the postoperative period, lower cumulative analgesic requirement (p = 0.025), and with shorter hospitalization (p = 0.002). Complication rates were comparable with no need for blood transfusions in any patients. Tubeless Quikclot(®) PNL was safe and provided effective hemostasis of significant parenchymal bleeding. By avoiding nephrostomy placement, we were able to reduce postoperative pain, analgesic requirements, and hospitalization. Application of Quikclot(®) may be considered prior to nephrostomy placement in patients with significant parenchymal bleeding.

Carrier localization in In-rich InGaN/GaN multiple quantum wells for green light-emitting diodes.

Carrier localization phenomena in indium-rich InGaN/GaN multiple quantum wells (MQWs) grown on sapphire and GaN substrates were investigated. Temperature-dependent photoluminescence (PL) spectroscopy, ultraviolet near-field scanning optical microscopy (NSOM), and confocal time-resolved PL (TRPL) spectroscopy were employed to verify the correlation between carrier localization and crystal quality. From the spatially resolved PL measurements, we observed that the distribution and shape of luminescent clusters, which were known as an outcome of the carrier localization, are strongly affected by the crystalline quality. Spectroscopic analysis of the NSOM signal shows that carrier localization of MQWs with low crystalline quality is different from that of MQWs with high crystalline quality. This interrelation between carrier localization and crystal quality is well supported by confocal TRPL results.

Fabrication and characteristics of GaN-based light-emitting diodes with a reduced graphene oxide current-spreading layer.

A reduced graphene oxide (GO) layer was produced on undoped and n-type GaN, and its effect on the current- and heat-spreading properties of GaN-based light-emitting diodes (LEDs) was studied. The reduced GO inserted between metal electrode and GaN semiconductor acted as a conducting layer and enhanced lateral current flow in the device. Especially, introduction of the reduced GO layer on the n-type GaN improved the electrical performance of the device, relative to that of conventional LEDs, due to a decrease in the series resistance of the device. The enhanced current-spreading was further of benefit, giving the device a higher light output power and a lower junction temperature at high injection currents. These results therefore indicate that reduced GO can be a suitable current and heat-spreading layer for GaN-based LEDs.

Size dependence of silica nanospheres embedded in 385 nm ultraviolet light-emitting diodes on a far-field emission pattern.

We demonstrate that the use of silica nanospheres (SNs) with sizes close to the emission wavelength of light-emitting diodes (LEDs) can enhance the light output power and manipulate the far-field emission pattern. Near-ultraviolet (NUV)-LEDs grown on a patterned sapphire substrate embedded with 300 nm SNs show a three times higher light output power than that without SNs, when measured through the top side. For far-field emission measurements, the LEDs embedded with 300 nm SNs show the significant increase of front emission due to the improved crystal quality of epitaxial films as well as the increase of Mie scattering effect of SNs. These experimental results indicate the important role of the size of embedded SNs in enhancing the light output power for NUV-LEDs.

Direct observation of CD4 T cell morphologies and their cross-sectional traction force derivation on quartz nanopillar substrates using focused ion beam technique.

Direct observations of the primary mouse CD4 T cell morphologies, e.g., cell adhesion and cell spreading by culturing CD4 T cells in a short period of incubation (e.g., 20 min) on streptavidin-functionalized quartz nanopillar arrays (QNPA) using a high-content scanning electron microscopy method were reported. Furthermore, we first demonstrated cross-sectional cell traction force distribution of surface-bound CD4 T cells on QNPA substrates by culturing the cells on top of the QNPA and further analysis in deflection of underlying QNPA via focused ion beam-assisted technique.

Air-ring microstructure arrays for enhanced light extraction from a face-up light-emitting diode.

In this Letter, a light-emitting diode (LED) with prism-shaped-air-ring microstructures (PSAMs) formed on flat sapphire substrate is demonstrated as an alternative design to face-up LEDs on patterned sapphire substrate (PSS) for enhanced light extraction efficiency. In this LED design, the emitted photons can be deflected to the top of the chip for its effective extraction, contrary to the PSS-LED wherein photons are guided to sapphire and get absorbed by packaging materials. The PSAM-LED showed an enhancement in the radiometric power as high as 10% with a low far-field angle of 129° over that of a PSS-LED under an injection current of 20 mA.

Improved heat dissipation in gallium nitride light-emitting diodes with embedded graphene oxide pattern.

The future of solid-state lighting relies on how the performance parameters will be improved further for developing high-brightness light-emitting diodes. Eventually, heat removal is becoming a crucial issue because the requirement of high brightness necessitates high-operating current densities that would trigger more joule heating. Here we demonstrate that the embedded graphene oxide in a gallium nitride light-emitting diode alleviates the self-heating issues by virtue of its heat-spreading ability and reducing the thermal boundary resistance. The fabrication process involves the generation of scalable graphene oxide microscale patterns on a sapphire substrate, followed by its thermal reduction and epitaxial lateral overgrowth of gallium nitride in a metal-organic chemical vapour deposition system under one-step process. The device with embedded graphene oxide outperforms its conventional counterpart by emitting bright light with relatively low-junction temperature and thermal resistance. This facile strategy may enable integration of large-scale graphene into practical devices for effective heat removal.

Impact of interlayer processing conditions on the performance of GaN light-emitting diode with specific NiOx/graphene electrode.

This paper reports on the evaluation of the impact of introducing interlayers and postmetallization annealing on the graphene/p-GaN ohmic contact formation and performance of associated devices. Current-voltage characteristics of the graphene/p-GaN contacts with ultrathin Au, Ni, and NiO(x) interlayers were studied using transmission line model with circular contact geometry. Direct graphene/p-GaN interface was identified to be highly rectifying and postmetallization annealing improved the contact characteristics as a result of improved adhesion between the graphene and the p-GaN. Ohmic contact formation was realized when interlayer is introduced between the graphene and p-GaN followed by postmetallization annealing. Temperature-dependent I-V measurements revealed that the current transport was modified from thermionic field emission for the direct graphene/p-GaN contact to tunneling for the graphene/metal/p-GaN contacts. The tunneling mechanism results from the interfacial reactions that occur between the metal and p-GaN during the postmetallization annealing. InGaN/GaN light-emitting diodes with NiO(x)/graphene current spreading electrode offered a forward voltage of 3.16 V comparable to that of its Ni/Au counterpart, but ended up with relatively low light output power. X-ray photoelectron spectroscopy provided evidence for the occurrence of phase transformation in the graphene-encased NiO(x) during the postmetallization annealing. The observed low light output is therefore correlated to the phase change induced transmittance loss in the NiO(x)/graphene electrode. These findings provide new insights into the behavior of different interlayers under processing conditions that will be useful for the future development of opto-electronic devices with graphene-based electrodes.

High performance of InGaN light-emitting diodes by air-gap/GaN distributed Bragg reflectors.

The effect of air-gap/GaN DBR structure, fabricated by selective lateral wet-etching, on InGaN light-emitting diodes (LEDs) is investigated. The air-gap/GaN DBR structures in LED acts as a light reflector, and thereby improve the light output power due to the redirection of light into escape cones on both front and back sides of the LED. At an injection current of 20 mA, the enhancement in the radiometric power as high as 1.91 times as compared to a conventional LED having no DBR structure and a far-field angle as low as 128.2° are realized with air-gap/GaN DBR structures.

Improving the optical performance of InGaN light-emitting diodes by altering light reflection and refraction with triangular air prism arrays.

The effect of triangular air prism (TAP) arrays with different distance-to-width (d/w) ratios on the enhancement of light extraction efficiency (LEE) of InGaN light-emitting diodes (LEDs) is investigated. The TAP arrays embedded at the sapphire/GaN interface act as light reflectors and refractors, and thereby improve the light output power due to the redirection of light into escape cones on both the front and back sides of the LED. Enhancement in radiometric power as high as 117% and far-field angle as low as 129° are realized with a compact arrangement of TAP arrays compared with that of a conventional LED made without TAP arrays under an injection current of 20 mA.

Enhanced light output power of near UV light emitting diodes with graphene / indium tin oxide nanodot nodes for transparent and current spreading electrode.

We report GaN-based near ultraviolet (UV) light emitting diode (LED) that combines indium tin oxide (ITO) nanodot nodes with two-dimensional graphene film as a UV-transparent current spreading electrode (TCSE) to give rise to excellent UV emission efficiency. The light output power of 380 nm emitting UV-LEDs with graphene film on ITO nanodot nodes as TCSE was enhanced remarkably compared to conventional TCSE. The increase of the light output power is attributed to high UV transmittance of graphene, effective current spreading and injection, and texturing effect by ITO nanodots.