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Background: The ELDERCARE-AF trial demonstrated that low-dose edoxaban prevented stroke or systemic embolism (SE) in very elderly Japanese patients with non-valvular atrial fibrillation (NVAF) in whom standard oral anticoagulant therapy was inappropriate because of high bleeding risk. The aim of this study was to elucidate the characteristics and outcomes of such patients in routine clinical practice. Methods and Results: Data were extracted from the Fushimi AF Registry for ELDERCARE-eligible NVAF patients aged ≥80 years, with a CHADS2 score ≥2 and ≥1 bleeding risk factors, as shown in the ELDERCARE-AF trial. ELDERCARE-eligible patients (n=549; 12.8% of the entire cohort, 52.9% of those aged ≥80 years and with CHADS2 score ≥2) were less often male, were older, had more comorbidity and higher risk scores than non-eligible patients from the entire cohort (n=3,734). The crude incidence (% per patient-year) of adverse events was significantly higher in ELDERCARE-eligible than non-eligible patients (stroke/SE, 4.8% vs. 2.0%; major bleeding, 3.6% vs. 1.9%; all-cause mortality, 15.5% vs. 3.9%; cardiovascular death, 2.7% vs. 0.6%; all log-rank P

Waste product deposition and light stress in the retinal pigment epithelium (RPE) are crucial factors in the pathogenesis of various retinal degenerative diseases, including age-related macular degeneration (AMD), a leading cause of vision loss in elderly individuals worldwide. Given that autophagy in the RPE suppresses waste accumulation, determining the molecular mechanism by which autophagy is compromised in degeneration is necessary. Using polarized human RPE sheets, we found that bis-retinoid N-retinyl-N-retinylidene ethanolamine (A2E), a major toxic fluorophore of lipofuscin, causes significant impairment of autophagy and the simultaneous upregulation of Rubicon, a negative regulator of autophagy. Importantly, this impairment was reversed in Rubicon-specific siRNA-treated RPE sheets. In a retinal functional analysis using electroretinograms (ERGs), mice with the RPE-specific deletion of Rubicon showed no significant differences from control cre-expressing mice but presented partially but significantly enhanced amplitudes compared with Atg7 knockout mice. We also found that an inflammatory reaction in the retina in response to chronic blue light irradiation was alleviated in mice with the RPE-specific deletion of Rubicon. In summary, we propose that upregulating basal autophagy by targeting Rubicon is beneficial for protecting the RPE from functional damage with ageing and the inflammatory reaction caused by light-induced cellular stress.

A matrix metalloproteinase 1 (MMP-1) inhibitor activity cliff was predicted using the SAR Matrix method. Compound 4 was predicted as a highly potent activity cliff partner and found to possess 60 times higher inhibitory activity against MMP-1 than the structurally related compound 3. Furthermore, pharmacophore fitting of synthesized compounds indicated that the correctly predicted activity cliff was caused by interactions between the trifluoromethyl group at para position in compound 4 and residue ARG214 of MMP-1.

Significance Autophagy (cellular self-eating) is essential for the health and survival of eukaryotic cells. Therapeutic autophagy induction is a major goal in the field. Rubicon inhibits autophagy and is a potential target for autophagy inducers. Rubicon is localized to its site of action in the cell by binding to the small GTPase Rab7. Here, we report a high-resolution structure of a large part of Rubicon, known as the Rubicon Homology (RH) domain. We show how the RH domain binds to Rab7 and show that the Rab7-binding residues of Rubicon are essential for Rubicon localization and autophagy inhibition. This provides a roadmap to block Rubicon localization and activity in order to upregulate autophagy., Rubicon is a potent negative regulator of autophagy and a potential target for autophagy-inducing therapeutics. Rubicon-mediated inhibition of autophagy requires the interaction of the C-terminal Rubicon homology (RH) domain of Rubicon with Rab7–GTP. Here we report the 2.8-Å crystal structure of the Rubicon RH domain in complex with Rab7–GTP. Our structure reveals a fold for the RH domain built around four zinc clusters. The switch regions of Rab7 insert into pockets on the surface of the RH domain in a mode that is distinct from those of other Rab–effector complexes. Rubicon residues at the dimer interface are required for Rubicon and Rab7 to colocalize in living cells. Mutation of Rubicon RH residues in the Rab7-binding site restores efficient autophagic flux in the presence of overexpressed Rubicon, validating the Rubicon RH domain as a promising therapeutic target.

Background In Japan, a new anti-tuberculous drug, delamanid, was recognized as the drug of choice to treat multi-drug resistant pulmonary tuberculosis in July 2014. Methods We treated 28 cases of multidrug-resistant tuberculosis (MDR-TB) and three cases of extensively drug-resistant tuberculosis (XDR-TB) with delamanid from July 2014 to June 2018 at our hospital. Results There were 21 men and 10 women, with the mean age of 48 and 37 years, respectively. We used an average of 4.4 sensitive anti-tuberculous drugs for the MDR-TB cases and 4.7 for the XDR-TB cases with delamanid. We used linezolid in 19 of 31 cases, although it has not been recognized as an anti-tuberculous drug in Japan. On electrocardiography, QTc prolongation of more than 450 ms was seen in two cases (6.4%), but they were asymptomatic, thus the treatment with delamanid could be continued. In 10 cases, surgical resection was performed. We completed the treatment in 20 cases and continued the treatment in seven cases; however, the treatment was discontinued in four cases because of side effects. In all cases, the sputum cultures were negative. Conclusions Delamanid is a relatively safe drug with few side effects. However, some patients could not continue it because of difficulty of use in combination, therefore delamanid should be prescribed considering the side effects of all therapies in the regimen.

A series of carborane-containing NAMPT inhibitors were designed and synthesized based on the structure of compounds 1 and the NAMPT inhibitory activity was evaluated using NAMPT Colorimetric Assay. Among the compounds synthesized, compounds 2b and 2c showed significant NAMPT inhibitory activity with IC50 values of 0.098 ± 0.008 and 0.057 ± 0.001 µM, respectively. Docking simulation of compound 2 toward NAMPT using the crystal structure of the FK866-NAMPT complex (PDB code: 2GVJ ) with replacing the boron atom type by the C3 atom type of carboranes predicted that the NAMPT inhibitory activity of 2c was improved by the hydrogen bond formation between the carborane amide and H191 of NAMPT. Although dicarborane compounds 38, 50, 51, and 55 were synthesize aiming to two hydrophobic pockets present in the binding pocket of NAMPT, their inhibitory activity was moderate.

The present study identified the active radical species in acidic sodium chlorite and investigated the feasibility of quantifying these species with the diethylphenylenediamine (DPD) method. Electron spin resonance (ESR) spectroscopy was used to identify the active species generated in solutions containing sodium chlorite (NaClO2). The ESR signal was directly observed in an acidified sodium chlorite (ASC) aqueous solution at room temperature. This ESR signal was very long-lived, indicating that the radical was thermodynamically stable. The ESR parameters of this signal did not coincide with previously reported values of the chlorine radical (Cl●) or chlorine dioxide radical (O = Cl●-O and O = Cl-O●). We refer to this signal as being from the chloroperoxyl radical (Cl-O-O●). Quantum chemical calculations revealed that the optimal structure of the chloroperoxyl radical is much more thermodynamically stable than that of the chlorine dioxide radical. The UV-visible spectrum of the chloroperoxyl radical showed maximum absorbance at 354 nm. This absorbance had a linear relationship with the chloroperoxyl radical ESR signal intensity. Quantifying the free chlorine concentration by the DPD method also revealed a linear relationship with the maximum absorbance at 354 nm, which in turn showed a linear relationship with the chloroperoxyl radical ESR signal intensity. These linear relationships suggest that the DPD method can quantify chloroperoxyl radicals, which this study considers to be the active species in ASC aqueous solution.

Background: High mobility group box 1 (HMGB1)-receptor for advanced glycation endo-products (RAGE) axis serves as a key player in linking inflammation and carcinogenesis. Recently, papaverine was revealed to suppress the HMGB1-RAGE inflammatory signaling pathway and cancer cell proliferation. Therefore, a dual suppressor targeting this axis is expected to become a new type of therapeutic agent to treat cancer. Methods: Papaverine 3D pharmacophore mimetic compounds were selected by the LigandScout software from our in-house, anti-cancer chemical library and assessed for their anti-inflammatory activities by a HMGB1-RAGE-mediated interleukin-6 production assay using macrophage-like RAW264.7 cells. Molecular-biological analyses, such as Western blotting, were performed to clarify the mechanism of action. Results: A unique 6-methoxy-3-hydroxy-styrylchromone was found to possess potent anti-inflammatory and anti-cancer activities via the suppression of the HMGB1-RAGE-extracellular signal-regulated kinase 1/2 signaling pathway. Furthermore, the 3D pharmacophore-activity relationship analyses revealed that the hydroxyl group at the C4′ position of the benzene ring in a 3-styryl moiety was significant in its dual suppressive effects. Conclusions: These findings indicated that this compound may provide a valuable scaffold for the development of a new type of anti-cancer drug possessing anti-inflammatory activity and as a tool for understanding the link between inflammation and carcinogenesis.

Amyloid β (Aβ) aggregation inhibitor activity cliff involving a curcumin structure was predicted using the SAR Matrix method on the basis of 697 known Aβ inhibitors from ChEMBL (data set 2487). Among the compounds predicted, compound B was found to possess approximately 100 times higher inhibitory activity toward Aβ aggregation than curcumin. TEM images indicate that compound B induced the shortening of Aβ fibrils and increased the generation of Aβ oligomers in a concentration dependent manner. Furthermore, compound K, in which the methyl ester of compound B was replaced by the tert-butyl ester, possessed low cytotoxicity on N2A cells and attenuated Aβ-induced cytotoxicity, indicating that compound K would have an ability for preventing neurotoxicity caused by Aβ aggregation.

Discoidin domain receptor 1 (DDR1) inhibitors with a desired pharmacophore were designed using deep generative models (DGMs). DDR1 is a receptor tyrosine kinase activated by matrix collagens and implicated in diseases such as cancer, fibrosis and hypoxia. Herein we describe the synthesis and inhibitory activity of compounds generated from DGMs. Three compounds were found to have sub‐micromolar inhibitory activity. The most potent of which, compound 3 (N‐(4‐chloro‐3‐((pyridin‐3‐yloxy)methyl)phenyl)‐3‐(trifluoromethyl)benzamide), had an IC50 value of 92.5 nM. Furthermore, these compounds were predicted to interact with DDR1, which have a desired pharmacophore derived from a known DDR1 inhibitor. The results of synthesis and experiments indicated that our de novo design strategy is practical for hit identification and scaffold hopping., Helpful for scaffold hopping: DDR1 inhibitors were designed using a deep generative model that generates chemical structures with the desired pharmacophore. In structure sampling, about 10,000 generated structures from the agent network have pharmacophore scores greater than 0.8. After filtering the structures, nine compounds were synthesized and their inhibitory activities were evaluated against DDR1. The results of this study show that our de novo design strategy is practical for hit identification and scaffold hopping.

Introduction: Hyperlipidemia is a well-established risk factor for cardiovascular disease. However, low cholesterol is also reported to be associated with poor outcome in chronic disease, which is called “cholesterol paradox”, and the impact of cholesterol level on the incidence of stroke or systemic embolism (SE) in atrial fibrillation (AF) remains unclear. Methods: The Fushimi AF Registry is a community-based prospective survey of the AF patients in Fushimi-ku, Kyoto, Japan. We obtained baseline total cholesterol level (TC) in 3,051 patients, and examined the relationship between TC and incidence of stroke/SE. Results: TC was inversely correlated with age and positively correlated with body weight. Patients with lower TC were more likely to be male, and had more diabetes, coronary artery disease, heart failure, prior stroke/SE, chronic kidney disease, and anemia. CHA 2 DS 2 -VASc score was inversely correlated with TC. Prescription of statin was higher in patients with lower TC, but that of oral anti-coagulants was not associated with TC. During the median follow-up of 1,476 days, stroke/SE occurred in 277 (9.1%) patients. After adjustment for the components of CHA 2 DS 2 -VASc score, body weight, and prescription of oral anti-coagulants and statins, TC had significant inverse association with the incidence of stroke/SE (hazard ratio (HR), 0.94; 95% confidence interval (CI) 0.91-0.98 for 10-mg/dl increase) (Table). TC was significantly associated with ischemic stroke/SE (HR, 0.95; 95% CI 0.91-0.99 for 10-mg/dl increase), but was not associated with intracranial bleeding (HR, 0.95; 95% CI 0.88-1.02 for 10-mg/dl increase). When we divided the patients into the elderly (≥75 years) and the young, low TC was a predictor for stroke/SE in the elderly (HR, 0.94; 95% CI 0.90-0.99 for 10-mg/dl increase), but was not in the young (HR, 0.95; 95% CI 0.90-1.01 for 10-mg/dl increase). Conclusions: Low TC might be an independent predictor for stroke/SE in elderly patients with AF.

Glyoxalase I (GLO I) is a known therapeutic target in cancer. Even though TLSC702, a GLO I inhibitor that we discovered, induces apoptosis in tumor cells, exceptionally higher doses are required compared with those needed to inhibit GLO I activity in vitro. In this work, structure-activity optimization studies were conducted on four sections of the TLSC702 molecule to determine the partial structural features necessary for the inhibition of GLO I. Herein, we found that the carboxy group in TLSC702 was critical for binding with the divalent zinc at the active site of GLO I. In contrast, the side chain substituents in the meta- and para- positions of the benzene ring had little influence on the in vitro inhibition of GLO I. The CLogP values of the TLSC702 derivatives showed a positive correlation with the antiproliferative effects on NCI-H522 cells. Thus, two derivatives of TLSC702, which displayed either high or low lipophilicity due to the types of substituents at the phenyl position, were selected. Even though both derivatives showed comparable inhibitory effects as that of their parent compound, the derivative with the high CLogP value was distinctly more antiproliferative than TLSC702. In contrast, the derivative with the low CLogP value did not decrease cell viability in NCI-H522 and HL-60 cells. These findings suggested that structural improvements, such as the addition of hydrophobic moieties to the phenyl group, enhanced the ability of TLSC702 to induce apoptosis by increasing cell membrane permeability.

Background and Aim: IgG4-related pleural effusion is rare and difficult to distinguish from tuberculous pleurisy because of its some similar findings including the high adenosine deaminase (ADA) in pleural effusion. Therefore, we aimed to demonstrate features of IgG4-related pleural effusion compared with tuberculous pleurisy. Methods: We retrospectively performed a chart review of hospitalized adult patients with IgG4-related pleural effusion and tuberculous pleurisy. The period of the study was from January 2017 to May 2019. Furthermore, we collected reports of IgG4-related pleural effusion using resources from PubMed and the Japan Medical Abstracts Society, and considered these reports and patients of our hospital together. We compared IgG4-related pleural effusion to tuberculous pleurisy. Results: We enrolled 19 patients with IgG4-related pleural effusion and 40 patients with tuberculous pleurisy. In laboratory findings of pleural effusion, patients with IgG4-related pleural effusion showed higher total protein (TP) and lower lactate dehydrogenase (LDH) and ADA than those with tuberculous pleurisy. We developed a prediction score which included TP ≥5.2 mg/dL, LDH ≤250 U/L, and ADA ≤60 U/L in laboratory findings of pleural effusion. The area under the curve of the score was 0.949 (95% confidence level: 0.905-0.993). Each variable was assigned a value of 1 point. When the cut-off value was 2 points, sensitivity and specificity were 87.5% and 100%. Conclusion: The study demonstrated that laboratory findings of pleural effusion could differentiate between IgG4-related pleural effusion and tuberculous pleurisy.

The systemic decline in autophagic activity with age impairs homeostasis in several tissues, leading to age-related diseases. A mechanistic understanding of adipocyte dysfunction with age could help to prevent age-related metabolic disorders, but the role of autophagy in aged adipocytes remains unclear. Here we show that, in contrast to other tissues, aged adipocytes upregulate autophagy due to a decline in the levels of Rubicon, a negative regulator of autophagy. Rubicon knockout in adipocytes causes fat atrophy and hepatic lipid accumulation due to reductions in the expression of adipogenic genes, which can be recovered by activation of PPARγ. SRC-1 and TIF2, coactivators of PPARγ, are degraded by autophagy in a manner that depends on their binding to GABARAP family proteins, and are significantly downregulated in Rubicon-ablated or aged adipocytes. Hence, we propose that age-dependent decline in adipose Rubicon exacerbates metabolic disorders by promoting excess autophagic degradation of SRC-1 and TIF2., Autophagic activity declines with age in several tissues and is linked to aging-associated functional decline and pathologies. Here the authors show that Rubicon, a negative regulator of autophagy, decreases in adipocytes with age, and its loss leads to adipocyte dysfunction via excess autophagic degradation of SRC-1 and TIF2.

Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) is an attractive therapeutic strategy for targeting cancer metabolism. So far, many potent NAMPT inhibitors have been developed and shown to bind to two unique tunnel-shaped cavities existing adjacent to each active site of a NAMPT homodimer. However, cytotoxicities and resistances to NAMPT inhibitors have become apparent. Therefore, there remains an urgent need to develop effective and safe NAMPT inhibitors. Thus, we designed and synthesized two close structural analogues of NAMPT inhibitors, azaindole&ndash, piperidine (3a)- and azaindole&ndash, piperazine (3b)-motif compounds, which were modified from the well-known NAMPT inhibitor FK866 (1). Notably, 3a displayed considerably stronger enzyme inhibitory activity and cellular potency than did 3b and 1. The main reason for this phenomenon was revealed to be due to apparent electronic repulsion between the replaced nitrogen atom (N1) of piperazine in 3b and the N&delta, atom of His191 in NAMPT by our in silico binding mode analyses. Indeed, 3b had a lower binding affinity score than did 3a and 1, although these inhibitors took similar stable chair conformations in the tunnel region. Taken together, these observations indicate that the electrostatic enthalpy potential rather than entropy effects inside the tunnel cavity has a significant impact on the different binding affinity of 3a from that of 3b in the disparate enzymatic and cellular potencies. Thus, it is better to avoid or minimize interactions with His191 in designing further effective NAMPT inhibitors.

Manufacturing readiness of the world’s first highly reliable 650V GaN HEMT is demonstrated with high process capability (CpK >1.6) for leakage and on resistance. This reliable manufacturing process was developed in a Si-CMOS compatible 6-inch foundry and has been demonstrated with over five thousand wafers worth of data, and spread over four generations of technology nodes. The analysis covers multiple device products and packages collected during industrialization of a JEDEC qualified process over a four year period. Silicon manufacturing processes are employed including a gold-free metallurgy that avoids the use of evaporation/liftoff processes, traditional in compound semiconductors. GaN wafer breakage data from the AFSW Foundry based on four years of manufacturing is presented. Backside contamination acceptance testing results from our foundry is also presented in this paper. These data sets show the flexibility of Transphorm’s GaN Epi and power GaN HEMT process to be compatible to any Si Foundry making the solution scalable. Wide bandgap high frequency and high voltage GaN devices significantly reduce the system size and improve energy efficiency of power conversion in all areas of electricity conversion, ranging from PV inverters to electric vehicles making the above results significant and making GaN high volume production a reality.

Rubicon is a potent negative regulator of autophagy and a potential target for autophagy-inducing therapeutics. Rubicon-mediated inhibition of autophagy requires the interaction of the C-terminal Rubicon homology (RH) domain of Rubicon with Rab7-GTP. Here we report the 2.8 Å crystal structure of the Rubicon RH domain in complex with Rab7-GTP. Our structure reveals a novel fold for the RH domain built around four zinc clusters. The switch regions of Rab7 insert into pockets on the surface of the RH domain in a mode that is distinct from those of other Rab-effector complexes. Rubicon residues at the dimer interface are required for Rubicon and Rab7 to colocalize in living cells. Mutation of Rubicon RH residues in the Rab7 binding site restore efficient autophagic flux in the presence of overexpressed Rubicon, validating the Rubicon RH domain as a promising therapeutic target.

Methane/methanol conversion is one of the most important chemical reactions. Methane monooxygenases from methanotrophs are enzymes that catalyze methane/methanol conversion under mild conditions. Here we report the reconstitution of purified photosystem II (PSII) from Thermosynechococcus elongatus BP-1 into the membrane fraction containing particulate methane monooxygenase (pMMO) from Methylosinus trichosporium OB3b. Photoinduced hydroxylation of methane to methanol was successfully achieved by using the PSII-reconstituted membrane containing pMMO under light irradiation. This result indicates that the sequential redox chain from PSII through the quinone pool to pMMO can be constructed and that water can serve as the electron donor for methane hydroxylation under irradiation with light. pMMO in the membrane fraction produced hydrogen peroxide as a byproduct when an electron donor was added for methane hydroxylation, whereas under light irradiation conditions the PSII-reconstituted membrane containing pMMO did not generate hydrogen peroxide. Optimization of the electron-transfer rate can easily be achieved with this system by tuning the light intensity.

Bicyclo[3,3,1]non-2-ene was used as a novel three-dimensional skeleton for the design and synthesis of hypoxia-inducible factor (HIF)-1 inhibitors. Among the compounds synthesized, compound 4b was found to be a potent inhibitor of HIF-1α protein accumulation under hypoxia and inhibited HIF-1α transcriptional activity in HeLa (human cervical carcinoma) cells (half maximal inhibitory concentration [IC50] = 3.0 μM). The inhibition of HIF-1α accumulation induced by compound 4b was attenuated by treating the cells with MG132, a proteasome inhibitor, in a concentration-dependent manner, indicating that the compound 4b induces oxygen-independent proteasomal degradation of HIF-1α.

c-Met is a receptor-type tyrosine kinase, which is involved in a wide range of cellular responses such as proliferation, motility, migration and invasion. It has been reported to be overexpressed in various cancers. However, the role of c-Met in breast cancer stem cells (CSCs) still remains unclear. We herein, show that c-Met expression is significantly elevated in Basal-like type of breast cancer in comparison with other subtypes. High expression of c-Met strongly correlated with the expression of two CSC markers, ALDH1A3 and CD133 in breast cancers. In addition, breast cancers at tumor stage III-IV expressing both c-Methigh and ALDH1A3high had poor prognosis. Furthermore, treatment with c-Met inhibitors (Crizotinib, Foretinib, PHA-665752 and Tivantinib) in MDA-MB157 cells with high c-Met protein expression resulted in significant suppression in cell viability, contrary to MDA-MB468 cells with low c-Met protein expression. These c-Met inhibitors also suppressed cell viability and tumor-sphere formation of ALDH1high breast cancer cells with high c-Met expression. These results suggest that c-Met in ALDH1 positive CSCs seems to play an important role in breast cancer repopulation. Therefore, we conclude that c-Met is a potential therapeutic target in ALDH1 positive breast CSCs.

1. Introduction With its proven ability to reduce size (form factor) and save energy (high efficiency) Gallium Nitride (GaN) is now no longer a nice to have, it is a must-have for power conversion. In applications ranging from sub 100 watt to multi kilowatt highly efficient power converters and inverters, GaN HEMTs high switching speed and low efficiency make it a natural choice of Silicon based devices reaching their physical limits of performance. Transphorm has already commercialized JEDEC qualified GaN HEMT power switches manufactured in an automotive grade 6 inch Si CMOS fab [1]. With this strong base and its ability to reduce size, weight and improve miles per gallon, GaN HEMTs are now increasingly being investigated for EV & HEV applications such as on board chargers and other auxiliary power conversion within the automobile under 10 kW. We will review the first ever Automotive (AEC Q101) Qualification for GaN and also discuss results for highly stressed robustness tests, FIT rates & lifetime testing. 2. GaN Products and Qualification Normally off GaN devices (Fig. 1) are achieve through integration of a low voltage Si-MOSFET input device with a high voltage depletion mode GaN device offering the best combination of input gate interface and the most robust high voltage GaN platform [2]. Electrical characteristics of the normally-off GaN power switch are summarized in Table 1 with a Low Rds(on), low gate charge (Qg) and low capacitance (Coss) that enable high efficiency, small form factor power systems. The Ron *Qg or Ron * Coss figure of merit is already better than mature Silicon Superjunction MOSFETs and achieved simultaneously with superior reliability performance. We have successfully passed (on multiple products and generations) the full suite of JEDEC qualification tests [3], as shown in Table 2. 3. Robustness, Long Term Reliability and Lifetime of High Voltage GaN To further establish confidence in long term reliability and operation in the field with low FIT rates, we have extended JEDEC qualification to 3-5x the stresses, for e.g. 5,000 hours of HTRB (5x JEDEC stress) with no degradation in resistance, threshold or leakage (Fig 3). Systematic high voltage off-stage (HVOS) acceleration at over 1100 volts was done to determine intrinsic lifetime (MTTF) of over 100 Million hours and 1% failure of more than 1M hours (Fig 5). Similarly through accelerated high temperature on-state testing of GaN, a high temperature MTTF of over 100 Million hours at 175C was determined. Recently, in March 2017, we completed the first ever successful AEC-Q101 standard qualification of GaN products [4]. These will be discussed in detail at the conference. 4. GaN Products and Qualification The comprehensive suite of data and results with a 3 year manufacturing history on over 3,000 wafers in a high volume commercial 6-inch Wafer fabrication facility unequivocally demonstrate that GaN power switches are now reliable and ready for a wide array of consumer & communication, industrial & renewable energy as well as automotive applications. The next milestones which are now happening include announcement of a variety of end system products (Titanium rated data server power supplies, PV Inverters, Telecom power supplies and Servo motor drives), paving the way for an exciting era in highest efficiency, highest reliability power conversion with GaN. 5. References P. Parikh, et. al., “Commercialization of 600V GaN HEMTs,” 2014 SSDM, Tsukuba, Sep., 2014. Power GaN Devices- Materials, Applications and Reliability, Edited by M. Meneghini et. al., Springer International Publishing, 2017. T. Kikkawa, et al. 600 V JEDEC-Qualified Highly Reliable GaN HEMTs on Si Substrates,” IEEE IEDM, San Francisco, Dec. 2014. APEC 2017, http://www.transphormusa.com/news/transphorm-announces-first-automotive-qualified-gan-fets/ Figure 1

Flutamide, a chemotherapeutic agent for prostate cancer, is known to enhance warfarin anticoagulation. However, not much is known about its pharmaceutical interaction. We herein report the case of a patient with an implanted pacemaker for atrial fibrillation with bradycardia who was on warfarin. This patient presented with deterioration of hematuria, gingival, ear, and subcutaneous bleeding. The prothrombin time-international normalized ratio was extremely elevated after starting flutamide to treat progression of prostate cancer. Fatal bleeding complications were able to be prevented by the immediate administration of prothrombin complex concentrate, but the effect of flutamide on warfarin was prolonged for about two more weeks after the withdrawal of flutamide.

This manuscript proves maturity of GaN-on-Si technology for the world’s first highly reliable 650V GaN HEMT [2],[3],[4],[5],[6],[7],[8] by demonstrating three years of manufacturing data of since ramp. This technology was initially developed in a pilot line in Transphorm Goleta, CA and then later ported into a Si-CMOS compatible 6-inch foundry at AFSW(Aizu Fujitsu Semiconductor Wafers Solution Ltd). Data set generated from over three thousand wafers worth of data spread over three generations of technology nodes covering multiple products and packages post qualification is presented Silicon manufacturing processes are employed including gold- free, and avoiding the use of evaporation/liftoff typical to compound semiconductors. Best practice of defect detection, failure analysis and process control methods from Si manufacturing industry have been employed to maintain and improve yield for this new technology. Probe yield and line yield for the GaN process now matches that of mature Si-CMOS process running in the same fabrication facility[1]. Wide bandgap high-speed and high- voltage GaN devices significantly reduce the system size and improve energy efficiency of power conversion in all areas of electricity conversion, ranging from PV inverters to electric vehicles. The results below demonstrates that GaN high volume production is now a reality.

RATIONALE Levels of pleural fluid adenosine deaminase (ADA), a useful marker for the diagnosis of tuberculous pleurisy, are elevated in some reports of immunoglobulin G4 (IgG4)-related pleural effusion. We describe a patient with IgG4-related pleural effusion who exhibited a high concentration of ADA. Furthermore, we reviewed the literature to compare patients with IgG4-related pleural effusion and tuberculous pleurisy. PATIENT CONCERNS A 75-year-old male patient had dyspnea for 1 month with a left pleural effusion that was exudative, lymphocyte dominant. The pleural fluid test results revealed a total protein (TP) concentration of 6.60 g/dl, a lactate dehydrogenase (LDH) level of 383 IU/dl, and an ADA concentration of 54.5 U/L. An interferon gamma release assay showed a negative result. DIAGNOSES Histological analysis of the thoracoscopic pleural biopsy revealed lymphoplasmacytic infiltration, with 80 IgG4-positive plasma cells/high-power field, and an IgG4/IgG ratio of approximately 40% to 50%. Other diseases were ruled out based on symptoms, negative autoimmune antigen results, and histopathologic findings. Thus, he was diagnosed with IgG4-related pleural effusion. INTERVENTIONS He received 15 mg of prednisolone as therapy. OUTCOMES His pleural effusion and symptoms improved gradually within several months, and prednisolone was tapered to 6 mg daily. LESSONS It is important to distinguish between IgG4-related pleural effusion and tuberculous pleurisy. Therefore, we compared 22 patients with IgG4-related pleural effusion from PubMed and the Japan Medical Abstracts Society to 40 patients with tuberculous pleurisy at Fukujuji Hospital from January 2017 to May 2019. According to thoracentesis findings, 14 of 18 patients with IgG4-related pleural effusion had high ADA more than 40 U/L. The pleural effusion of patients with IgG4-related pleural effusion showed higher TP levels (P

Methanotrophs have been used to convert methane to methanol at ambient temperature and pressure. In order to accumulate methanol using methanotrophs, methanol dehydrogenase (MDH) must be downregulated as it consumes methanol. Here, we describe a methanol production system wherein MDH expression is controlled by using methanotroph mutants. We used the MxaF knockout mutant of Methylosinus trichosporium OB3b. It could only grow with MDH (XoxF) which has a cerium ion in its active site and is only expressed by bacteria in media containing cerium ions. In the presence of 0 μM copper ion and 25 μM cerium ion, the mutant grew normally. Under conditions conducive to methanol production (10 μM copper ion and 0 μM cerium ion), cell growth was inhibited and methanol accumulated (2.6 μmol·mg−1 dry cell weight·h−1). The conversion efficiency of the accumulated methanol to the total amount of methane added to the reaction system was ~0.3%. The aforementioned conditions were repeatedly alternated by modulating the metal ion composition of the bacterial growth medium.

Accumulating evidence has suggested the fundamental functions of NAD+-poly(ADP-ribose) metabolism in cellular and physiological processes, including energy homeostasis, signal transduction, DNA transaction, genomic stability and cell death or survival. The NAD+ biosynthesis and poly(ADP-ribose) [(ADP-R)n] turnover are tightly controlled by several key enzymes, such as nicotinamide phosphoribosyltransferase (NmPRT), nicotinamide mononucleotide adenylyltransferases (NMNATs), poly(ADP-ribose) polymerase (PARP), poly(ADP-ribose) glycohydrolase (PARG) and ADP-ribose pyrophosphorylase (ADPRPPL). Many researches investigating the roles of these enzymes in cells have revealed the physiological and pathological importance, and thereby the therapeutical values. Among these enzymes, the polymer degrading enzyme PARG has not yet been intensively studied, because of the low cellular content, lack of cell-available PARG chemical inhibitors and PARG genetic models. So, the biological roles of (ADP-R)n catabolism by PARG are still being elucidated as compared to those of synthesis by PARP. However, recent studies delineate that PARG-dependent (ADP-R)n degradation is critical for many pathological conditions, and thus PARG is an important target for chemical therapeutics for several diseases. This review will present the recent progresses about the roles of NAD+-(ADP-R)n metabolism and the structures and functions of PARG, with a focus on its role in DNA repair and cell death by apoptosis in relation to central regulatory network, and the therapeutic potentials of PARG inhibitors in cancer chemotherapy.

Autophagy is a multistep membrane traffic pathway. In contrast to autophagosome formation, the mechanisms underlying autophagosome-lysosome fusion remain largely unknown. Here, we describe a novel autophagy regulator, inositol polyphosphate-5-phosphatase E (INPP5E), involved in autophagosome-lysosome fusion process. In neuronal cells, INPP5E knockdown strongly inhibited autophagy by impairing the fusion step. A fraction of INPP5E is localized to lysosomes, and its membrane anchoring and enzymatic activity are necessary for autophagy. INPP5E decreases lysosomal phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2), one of the substrates of the phosphatase, that counteracts cortactin-mediated actin filament stabilization on lysosomes. Lysosomes require actin filaments on their surface for fusing with autophagosomes. INPP5E is one of the genes responsible for Joubert syndrome, a rare brain abnormality, and mutations found in patients with this disease caused defects in autophagy. Taken together, our data reveal a novel role of phosphoinositide on lysosomes and an association between autophagy and neuronal disease.

Gallium Nitride (GaN) is now a popular choice for power conversion. High voltage (HV) GaN HEMTs (GaN FETs) in the range of 650–900 volts are emerging as the next standard for power conversion. This paper highlights key successes in efficient and compact converters/inverters ranging from high performance gaming/crypto-mining power supplies, titanium class server power, servo drives, PV inverters, and automotive OBCs, dc-dc converters, pole charges. The reasons for market success including unmatched quality & reliability, high volume GaN on Si manufacturing, robust performance in applications as well as challenges to achieve the full potential of GaN FETs are presented.

Hepatitis C virus (HCV) infection is known to induce autophagy, but the mechanism of autophagy induced by HCV remains controversial. Here, we investigated the characteristics of autophagy induced by HCV infection. First, to examine the involvement of autophagy-related gene (ATG) proteins in HCV-induced LC3 lipidation, we established ATG5, ATG13 or ATG14 knockout (KO) Huh7.5.1 cell lines and confirmed that the accumulation of lipidated LC3 was induced in an ATG13- and ATG14-independent manner. On the other hand, HCV infectivity was not influenced by deficiencies in these genes. We also confirmed that LC3-positive dots were co-localized with ubiquitinated aggregates, and deficiency of ATG5 or ATG14 enhanced the accumulation of ubiquitinated aggregates compared to that in the restored cells, suggesting that HCV infection induces ATG5- and ATG14-dependent selective autophagy. Moreover, LC3-positive ubiquitinated aggregates accumulated near the site of the replication complex. We further examined autophagy flux in cells replicating HCV RNA using bafilomycin or E64d, and found that the increase of LC3 lipidation by treatment with bafilomycin or E64d was impaired in HCV-replicating cells, suggesting that autophagy flux is inhibited by the progress of HCV infection. Our present study suggests that (1) HCV RNA replication induces selective autophagy and (2) the progress of HCV infection impairs autophagy flux.

Covalent modification of LC3 and GABARAP proteins to phosphatidylethanolamine in the double-membrane phagophore is a key event in the early phase of macroautophagy, but can also occur on single-membrane structures. In both cases this involves transfer of LC3/GABARAP from ATG3 to phosphatidylethanolamine at the target membrane. Here we have purified the full-length human ATG12-5–ATG16L1 complex and show its essential role in LC3B/GABARAP lipidation in vitro. We have identified two functionally distinct membrane-binding regions in ATG16L1. An N-terminal membrane-binding amphipathic helix is required for LC3B lipidation under all conditions tested. By contrast, the C-terminal membrane-binding region is dispensable for canonical autophagy but essential for VPS34-independent LC3B lipidation at perturbed endosomes. We further show that the ATG16L1 C-terminus can compensate for WIPI2 depletion to sustain lipidation during starvation. This C-terminal membrane-binding region is present only in the β-isoform of ATG16L1, showing that ATG16L1 isoforms mechanistically distinguish between different LC3B lipidation mechanisms under different cellular conditions.

Macroautophagy is a major intracellular degradation system. We previously reported that overexpression of phosphatase-deficient MTMR3, a member of the myotubularin phosphatidylinositol (PI) 3-phosphatase family, leads to induction of autophagy. In this study, we found that MTMR3 interacted with mTORC1, an evolutionarily conserved serine/threonine kinase complex, which regulates cell growth and autophagy in response to environmental stimuli. Furthermore, overexpression of MTMR3 inhibited mTORC1 activity. The N-terminal half of MTMR3, including the PH-G and phosphatase domains, was necessary and sufficient for these effects. Phosphatase-deficient MTMR3 provided more robust suppression of mTORC1 activity than wild-type MTMR3. Furthermore, phosphatase-deficient full length MTMR3 and the phosphatase domain alone were localized to the Golgi. These results suggest a new regulatory mechanism of mTORC1 in association with PI3P.

Epstein-Barr virus-positive T-cell lymphoproliferative diseases (EBV-T-LPDs) are rare lymphomas with poor prognosis. Although chemotherapeutic strategies such as CHOP have been often selected, they have exhibited only limited efficacy. To clarify the mechanism of chemoresistance, we examined P-glycoprotein (P-gp) expression. P-gp acts as an energy-dependent efflux pump that excretes drugs from the cytoplasm, resulting in low-intracellular drug concentrations and poor sensitivity to chemotherapy. We examined P-gp expression in EBV-positive cells by immunohistochemistry staining in three patients of EBV-T-LPDs and the expression was detected in all patients. We also examined mdr1 mRNA expression by reverse-transcriptase polymerase-chain reaction (RT-PCR) in EBV-positive tumor cells from these patients and additional three patients. The expression was detected in all examined patients. In five EBV-T-LPDs patients, P-gp function was detected by Rhodamine-123 efflux assay in these cells. The efflux was inhibited by treatment with a P-gp inhibitor, cyclosporine A (CsA). We also examined and detected P-gp expression in EBV-positive T-cell lines SNT8 and SNT16 established from EBV-T-LPDs patients, by RT-PCR and western blotting. The function was also detected by Rhodamine-123 efflux in these cell lines. Inhibition and knock down of P-gp by CsA and siRNA, respectively, enhanced etoposide- and doxorubicin-induced cell death in the EBV-positive T-cell lines. Finally, we infected the T-cell line MOLT4 with EBV, and found that mdr1 mRNA expression and Rhodamine 123 efflux were upregulated after infection. These results indicated that enhanced P-gp expression contributed to the chemoresistance of EBV-T-LPDs.

N-3 fatty acids, including eicosapentaenoic acid (EPA), prevent ischemic stroke. The preventive effect has been attributed to an antithrombic effect induced by elevated EPA and reduced arachidonic acid (AA) levels. However, the relationship between intracranial hemorrhage and N-3 fatty acids has not yet been elucidated. In this cross-sectional study, we compared common clinical and lifestyle parameters between 70 patients with intracranial hemorrhages and 66 control subjects. The parameters included blood chemistry data, smoking, alcohol intake, fish consumption, and the incidences of underlying diseases. The comparisons were performed using the Mann-Whitney U test followed by multiple logistic regression analysis. Nonparametric tests revealed that the 70 patients with intracerebral hemorrhages exhibited significantly higher diastolic blood pressures and alcohol intakes and lower body mass indices, high-density lipoprotein (HDL) cholesterol levels, EPA concentrations, EPA/AA ratios, and vegetable consumption compared with the 66 control subjects. A multiple logistic regression analysis revealed that higher diastolic blood pressure and alcohol intake and lower body mass index, HDL cholesterol, EPA/AA ratio, and vegetable consumption were relative risk factors for intracerebral hemorrhage. High HDL cholesterol was a common risk factor in both of the sex-segregated subgroups and the

Group A Streptococcus (GAS) is deleterious pathogenic bacteria whose interaction with blood vessels leads to life-threatening bacteremia. Although xenophagy, a special form of autophagy, eliminates invading GAS in epithelial cells, we found that GAS could survive and multiply in endothelial cells. Endothelial cells were competent in starvation-induced autophagy, but failed to form double-membrane structures surrounding GAS, an essential step in xenophagy. This deficiency stemmed from reduced recruitment of ubiquitin and several core autophagy proteins in endothelial cells, as demonstrated by the fact that it could be rescued by exogenous coating of GAS with ubiquitin. The defect was associated with reduced NO-mediated ubiquitin signaling. Therefore, we propose that the lack of efficient clearance of GAS in endothelial cells is caused by their intrinsic inability to target GAS with ubiquitin to promote autophagosome biogenesis for xenophagy., Author summary Autophagy is an intracellular bulk degradation system to survive within starved condition, which is one of the most common threats limiting organism’s expansion. By the system, cells digest their own cytoplasmic compartments that are sequestered by double membrane structure called autophagosome. It is also utilized for selective targeting of unwanted materials inside the cells including invading bacteria. This system targeting bacteria is called xenophagy, and provides “non-specialists” with innate immune system. Xenophagy is well characterized in epithelial cells since they are primary targets for invading bacteria. However, even though bacterial penetration into blood vessel could cause severe symptoms, it remains unknown weather endothelial cells retain functional xenophagy fighting against them. In this report, we showed that endothelial cells fail to suppress group A Streptococcus (GAS) growth due to defect in xenophagy. It is due to endothelial cell’s defect in ubiquitination of GAS, which plays a key role in target recognition during selective autophagy. Because we confirmed that endothelial cells are proficient in canonical, non-selective autophagy, our findings illustrate intrinsic defect in xenophagy as unique but general character of endothelial cells, shedding light onto cell type specificity in selective autophagy.

So far, many inhibitors of tyrosinase have been discovered for cosmetic and clinical agents. However, the molecular mechanisms underlying the inhibition in the active site of tyrosinase have not been well understood. To explore this problem, we examined here the inhibitory effects of 4'-hydroxylation and methoxylation of phenylbenzoic acid (PBA) isomers, which have a unique scaffold to inhibit mushroom tyrosinase. The inhibitory effect of 3-PBA, which has the most potent inhibitory activity among the isomers, was slightly decreased by 4'-hydroxylation and further decreased by 4'-methoxylation against mushroom tyrosinase. Surprisingly, 4'-hydroxylation but not methoxylation of 2-PBA appeared inhibitory activity. On the other hand, both 4'-hydroxylation and methoxylation of 4-PBA increased the inhibitory activity against mushroom tyrosinase. In silico docking analyses using the crystallographic structure of mushroom tyrosinase indicated that the carboxylic acid or 4'-hydroxyl group of PBA derivatives could chelate with cupric ions in the active site of mushroom tyrosinase, and that the interactions of Asn260 and Phe264 in the active site with the adequate-angled biphenyl group are involved in the inhibitory activities of the modified PBAs, by parallel and T-shaped π-π interactions, respectively. Furthermore, Arg268 could fix the angle of the aromatic ring of Phe264, and Val248 is supposed to interact with the inhibitors as a hydrophobic manner. These results may enhance the structural insight into mushroom tyrosinase for the creation of novel tyrosinase inhibitors.

Poly(ADP-ribose) glycohydrolase (PARG) plays an essential role in poly(ADP-ribose) (PAR) turnover, and thereby regulating DNA transactions, such as DNA repair, replication, transcription and recombination. Here, we examined the inhibitory activities of 6-hydroxy-3H-xanthene-3-one (HXO) derivatives and analyzed their binding modes in the active site of PARG by in silico docking study. Among the derivatives, Rose Bengal was found to be the most potent inhibitor of PARG and its halogen groups were revealed to cooperatively potentiate the inhibitory activity. Importantly, the binding mode of Rose Bengal occupied the active site of PARG revealed the presence of unique "Sandwich" residues of Asn869 and Tyr792, which enable the inhibitor to bind tightly with the active pocket. This sandwich interaction could stabilize the π-π interactions of HXO scaffold with Phe902 and Tyr795. In addition, to increase the binding affinity, the iodine and chlorine atoms of this inhibitor could contribute to the inducing of favorable disorders, which promote an entropy boost on the active site of PARG for structural plasticity, and making the stable configuration of HXO scaffold in the active site, respectively, as judged by the analysis of binding free energy. These results provide new insights into the active site of PARG and an additional opportunity for designing selective PARG inhibitors.

Tyrosinase inhibitors have become increasingly critical agents in cosmetic, agricultural, and medicinal products. Although a large number of tyrosinase inhibitors have been reported, almost all the inhibitors were unfortunately evaluated by using commercial available mushroom tyrosinase. Here, we examined the inhibitory effects of three isomers of thujaplicin (α, β, and γ) on human tyrosinase and analyzed their binding modes using homology model and docking studies. As the results, γ-thujaplicin was found to strongly inhibit human tyrosinase with the IC50 of 1.15 μM, extremely superior to a well-known tyrosinase inhibitor kojic acid (IC50 = 571.17 μM). MM-GB/SA binding free energy decomposition analyses suggested that the potent inhibitory activity of γ-thujaplicin may be due to the interactions with His367, Ile368, and Val377 (hot spot amino acid residues) in human tyrosinase. Furthermore, the binding mode of α-thujaplicin indicated that Val377 and Ser380 may cause van der Waals clashes with the isopropyl group of α-thujaplicin. These results provide a novel structural insight into the hot spot of human tyrosinase for the specific binding of γ-thujaplicin and a way to optimize not only thujaplicins but also other lead compounds as specific inhibitors for human tyrosinase in a rational manner.

Passion fruit seed extract (PFSE), a product rich in stilbenes such as piceatannol and scirpusin B, has various physiological effects. It is unclear whether PFSE and its stilbene derivatives inhibit cancer cell proliferation via human glyoxalase I (GLO I), the rate-limiting enzyme for detoxification of methylglyoxal. We examined the anticancer effects of PFSE in two types of human cancer cell lines with different GLO I expression levels, NCI–H522 cells (highly-expressed GLO I) and HCT116 cells (lowly-expressed GLO I). PFSE and its stilbenes inhibited GLO I activity. In addition, PFSE and its stilbenes supressed the cancer cell proliferation of NCI–H522 cells more than HCT116 cells. These observations suggest that PFSE can provide a novel anticancer strategy for prevention and treatment., Highlights • Piceatannol, and scirpusin B inhibited GLO I activity. • Passion fruit seed extract suppressed proliferation and colony formation of NCI–H522 cells. • Passion fruit seed extract and piceatannol could exert anticancer activity via GLO I inhibition.

Water-soluble chitosan derivative-based nanoparticles (carboxymethyl chitosan-chitooligosaccharide nanoparticles (CMC-COS NP) and sulphated chitosan-chitooligosaccharide nanoparticles (SC-COS NP)) were prepared by the formation of polyelectrolyte complexes. SC-COS NP and CMC-COS NP both induced the proliferation of mouse fibroblasts, whereas they elicited dose-dependent inhibitory effects on the proliferation of both HeLa and mouse B16 melanoma cells. Injection of SC-COS NP and CMC-COS NP modulated serum Th cytokines and stimulated the proliferation of splenic lymphocytes (CD4+ and CD8+ T cells, CD19+ B cells and NK cells) in mice, indicating the ability of these particles to regulate both humoral and cell-mediated immune responses. These properties demonstrated their promising potential for application as biomedical materials.

Granulated concrete samples obtained from the upper surface of deteriorated RC (reinforced concrete) slabs under the surface asphalt layer of a road were examined by microscopic technique and chemical analyses. The muddy components in the granulated concrete were composed of fine-granulated cement pastes and externally invasive clays and asphalt. Deicing salts were thought to be involved in the granulation of concrete, because calcium hydroxide had completely disappeared from the cement pastes although carbonation was not observed. The granulation was considered to be triggered by cracks caused by re-bar corrosion or an alkali-silica reaction. It was estimated that the progress of granulation was due to a complex mechanism of physical action by repetition loads and chemical action by deicing salts.

Background NEJ002 study, comparing gefitinib with carboplatin (CBDCA) and paclitaxel (PTX; Taxol) as the first-line treatment for advanced non-small cell lung cancer (NSCLC) harboring an epidermal growth factor receptor (EGFR) mutation, previously reported superiority of gefitinib over CBDCA/PTX on progression-free survival (PFS). Subsequent analysis was carried out mainly regarding overall survival (OS). Materials and methods For all 228 patients in NEJ002, survival data were updated in December, 2010. Detailed information regarding subsequent chemotherapy after the protocol treatment was also assessed retrospectively and the impact of some key drugs on OS was evaluated. Results The median survival time (MST) was 27.7 months for the gefitinib group, and was 26.6 months for the CBDCA/PTX group (HR, 0.887; P = 0.483). The OS of patients who received platinum throughout their treatment (n = 186) was not statistically different from that of patients who never received platinum (n = 40). The MST of patients treated with gefitinib, platinum, and pemetrexed (PEM) or docetaxel (DOC, Taxotere; n = 76) was around 3 years. Conclusions No significant difference in OS was observed between gefitinib and CBDCA/PTX in the NEJ002 study, probably due to a high crossover use of gefitinib in the CBDCA/PTX group. Considering the many benefits and the risk of missing an opportunity to use the most effective agent for EGFR-mutated NSCLC, the first-line gefitinib is strongly recommended.

Human glyoxalase I (GLO I), a rate-limiting enzyme for detoxification of methylglyoxal (MG), a by-product of glycolysis, is known to be a potential therapeutic target for cancer. Here, we searched new scaffolds from natural compounds for designing novel GLO I inhibitors and found trans-stilbene scaffold. We examined the inhibitory abilities to human GLO I of commercially available trans-stilbene compounds. Among them, piceatannol was found to have the most potent inhibitory activity against human GLO I. Piceatannol could inhibit the proliferation of human lung cancer NCI-H522 cells, which are dependent on GLO I for survival, in a dose- and time-dependent manner. In addition, piceatannol more significantly inhibited the proliferation of NCI-H522 cells than that of NCI-H460 cells, which are less dependent on GLO I. Importantly, overexpression of GLO I in NCI-H522 cells resulted in less sensitive to the antiproliferative activity of piceatannol. Taken together, this is the first report demonstrating that piceatannol inhibits GLO I activity and the GLO I-dependent proliferation of cancer cells. Furthermore, we determined a pharmacophore for novel inhibitors of human GLO I by computational simulation analyses of the binding mode of piceatannol to the enzyme hot spot in the active site. We suggest that piceatannol is a possible lead compound for the development of novel GLO I inhibitory anticancer drugs.

Manufacturing readiness of the world's first highly reliable 650V GaN HEMT is demonstrated with high process capability (CpK>1.6) for leakage and on resistance. This technology was developed in a Si-CMOS compatible 6-inch foundry and has been demonstrated with over one thousand wafers worth of data spread over two generations of technology nodes covering multiple products and packages collected during ramp up post qualification. Silicon manufacturing processes are employed including gold-free processes that avoid the use of evaporation/liftoff typical to compound semiconductors. Probe yield and Line yield for the GaN process now matches mature Si-CMOS process running in the same fabrication facility. Extended qualification results beyond JEDEC standard are also shown for GaN products for the first time. Products in cascode configuration were tested. Wide bandgap high speed and high voltage GaN devices significantly reduce the system size and improve energy efficiency of power conversion in all areas of electricity conversion, ranging from PV inverters to electric vehicles making the above results significant and making GaN high volume production a reality.

Tyrosinase is known as the key enzyme for melanin biosynthesis, which is effective in preventing skin injury by ultra violet (UV). In past decades, tyrosinase has been well studied in the field of cosmetics, medicine, agriculture and environmental sciences, and a lot of tyrosinase inhibitors have been developed for their needs. Here, we searched for new types of tyrosinase inhibitors and found phenylbenzoic acid (PBA) as a unique scaffold. Among three isomers of PBA, 3-phenylbenzoic acid (3-PBA) was revealed to be the most potent inhibitor against mushroom tyrosinase (IC50=6.97μM, monophenolase activity; IC50=36.3μM, diphenolase activity). The kinetic studies suggested that the apparent inhibition modes for the monophenolase and diphenolase activities were noncompetitive and mixed type inhibition, respectively. Analyses by in silico docking studies using the crystallographic structure of mushroom tyrosinase indicated that the carboxylic acid group of the 3-PBA could adequately bind to two cupric ions in the tyrosinase. To prove this hypothesis, we examined the effect of modification of the carboxylic acid group of the 3-PBA on its inhibitory activity. As expected, the esterification abrogated the inhibitory activity. These observations suggest that 3-PBA is a useful lead compound for the generation of novel tyrosinase inhibitors and provides a new insight into the molecular basis of tyrosinase catalytic mechanisms.

D-Glucosamine hydrochloride (GlcN∙HCl) is an endogenous amino monosaccharide synthesized from glucose that is useful in the treatment of joint diseases in both humans and animals. The aim of this study was to examine amino acid metabolism in dogs after oral administration of GlcN∙HCl. Accelerated fumarate respiration and elevated plasma levels of lactic acid and alanine were observed after administration. These results suggest that oral administration of GlcN∙HCl induces anaerobic respiration and starvation in cells, and we hypothesize that these conditions promote cartilage regeneration. Further studies are required to evaluate the expression of transforming growth factor-beta (TGF-β).

To preserve consistency among developed emission scenarios, the scenarios used in climate modeling, and the climate scenarios available for impact research, the pattern scaling technique is useful technique. The basic assumption of pattern scaling is that the spatial response pattern per 1 K increase in the global mean surface air temperature (SAT) (scaling pattern) is the same among emission scenarios, but this assumption requires further validation. We therefore investigated the dependence of the scaling pattern of the annual mean SAT on GHGs emission scenarios of representative concentration pathways (RCP) and the causes of that dependence using the Model for Interdisciplinary research on Climate 5 developed by Japanese research community. In particular, we focused on the relationships of the dependency with effects of aerosols and Atlantic meridional overturning circulation. We found significant dependencies of the scaling pattern on emission scenarios at middle and high latitudes of the Northern Hemisphere, with differences of >15 % over parts of East Asia, North America, and Europe. Impact researchers should take into account those dependencies that seriously affect their research. The mid-latitude dependence is caused by differences in sulfate aerosol emissions per 1 K increase in the global mean SAT, and the high-latitude dependence is mainly caused by nonlinear responses of sea ice and ocean heat transport to global warming. Long-term trends in land-use and land-cover changes did not significantly affect the scaling pattern of annual mean SAT, but they might have an effect at different timescales.

We examined the effects of oral glucosamine hydrochloride (GlcN), N-acetyl-d-glucosamine (GlcNAc) and d-glucose (Glc) administration on plasma total free amino acid (PFAA) concentrations in dogs. The PFAA concentrations increased in the control group and the GlcNAc group at one hour after feeding, and each amino acid concentration increased. On the other hand, in the GlcN group and the Glc group PFAA concentrations decreased at one hour after feeding. A significant decrease in amino acid concentration was observed for glutamate, glycine and alanine. Our results suggest the existence of differences in PFAA dynamics after oral administration of GlcN and GlcNAc in dogs.

Nowadays, chitin and chitosan are applied in many medical and pharmaceutical products. However little is known about the metabolism of chitin and chitosan in vivo. In the human body, lysozyme will degrade chitin and chitosan into chito-oligosaccharides. 13C labeled chitosan is an essential prerequisite for the further study of the fate of chito-oligosaccharides in vivo. To fulfill this requirement, chitosans were extracted from mycelia of fungi, Absidia coerulea ATCC 14076 and Gongronella butleri USDB 0201 and ATCC 42618 grown in solid substrate fermentation (SSF) and submerged fermentation (SMF) to select the best fungus and fermentation method for the production of 13C labeled chitosan. Based on the production yield of chitosan, the SSF method is the best method for the production of fungal chitosan when compared with SMF methods (i.e., fed-batch fermentation and batch fermentation). However synthesis of 13C labeled chitosan in cell wall of G. butleri grown in SSF medium coated with 1-13C-glucose was not observed. Alternatively, fungus A. coerulea was grown in SMF medium containing 2-13C-glucose. The successful synthesis of 13C labeled glucosamine from 2-13C-glucose was observed in mycelia of A. coerulea grown in SMF medium containing 2-13C-glucose in a yield of about 13 g/100 g mycelia.

When Salmonella invade mammalian epithelial cells, some populations are surrounded by the autophagy protein LC3. We found that LC3 was recruited in proximity to Salmonella independently of both Atg9L1 and FIP200, which are required for formation of autophagosomes. The dynamics of the ULK1 complex and Atg9L1 were dependent on one another., Salmonella develops into resident bacteria in epithelial cells, and the autophagic machinery (Atg) is thought to play an important role in this process. In this paper, we show that an autophagosome-like double-membrane structure surrounds the Salmonella still residing within the Salmonella-containing vacuole (SCV). This double membrane is defective in Atg9L1- and FAK family-interacting protein of 200 kDa (FIP200)-deficient cells. Atg9L1 and FIP200 are important for autophagy-specific recruitment of the phosphatidylinositol 3-kinase (PI3K) complex. However, in the absence of Atg9L1, FIP200, and the PI3K complex, LC3 and its E3-like enzyme, the Atg16L complex, are still recruited to Salmonella. We propose that the LC3 system is recruited through a mechanism that is independent of isolation membrane generation.

Henry's law constants and infinite dilution activity coefficients of propane, propene, butane, 2-methylpropane, 1-butene, 2-methylpropene, trans-2-butene, cis-2-butene, 1,3-butadiene, dimethyl ether, chloroethane, and 1,1-difluoroethane in 2-methyl-3-buten-2-ol and 3-methyl-3-buten-1-ol in the temperature range of (250 to 330) K were measured by a gas stripping method, and partial molar excess enthalpies were calculated from the activity coefficients. The estimated uncertainties are about 2 % for the Henry's law constants and 3 % for the infinite dilution activity coefficients. In general the Henry's law constants followed the order of increasing Henry's law constant with decreases in the normal boiling point temperature of the liquefied gas except for 1,3-butadiene, and the partial molar excess enthalpies of gases followed the order of increasing partial molar excess enthalpy with decreases of the polarity of the gases except for chloroethane and 1,1-difluoroethane.