Search

Dothideomycetesis the largest class of kingdom Fungi and comprises an incredible diversity of lifestyles, many of which have evolved multiple times. Plant pathogens represent a major ecological niche of the class Dothideomycetesand they are known to infect most major food crops and feedstocks for biomass and biofuel production. Studying the ecology and evolution of Dothideomyceteshas significant implications for our fundamental understanding of fungal evolution, their adaptation to stress and host specificity, and practical implications with regard to the effects of climate change and on the food, feed, and livestock elements of the agro-economy. In this study, we present the first large-scale, whole-genome comparison of 101 Dothideomycetesintroducing 55 newly sequenced species. The availability of whole-genome data produced a high-confidence phylogeny leading to reclassification of 25 organisms, provided a clearer picture of the relationships among the various families, and indicated that pathogenicity evolved multiple times within this class. We also identified gene family expansions and contractions across the Dothideomycetesphylogeny linked to ecological niches providing insights into genome evolution and adaptation across this group. Using machine-learning methods we classified fungi into lifestyle classes with >95 % accuracy and identified a small number of gene families that positively correlated with these distinctions. This can become a valuable tool for genome-based prediction of species lifestyle, especially for rarely seen and poorly studied species.

During inflammation lymphatic vessels (LVs) are enlarged and their density is increased to facilitate the migration of activated immune cells and antigens. However, after antigen clearance, the expanded LVs shrink to maintain homeostasis. Here we show that interleukin (IL)-17A, secreted from T helper type 17 (TH17) cells, is a negative regulator of lymphangiogenesis during the resolution phase of TH17-mediated immune responses. Moreover, IL-17A suppresses the expression of major lymphatic markers in lymphatic endothelial cells and decreases in vitroLV formation. To investigate the role of IL-17A in vivo, we utilized a cholera toxin-mediated inflammation model and identified inflammation and resolution phases based on the numbers of recruited immune cells. IL-17A, markedly produced by TH17 cells even after the peak of inflammation, was found to participate in the negative regulation of LV formation. Moreover, blockade of IL-17A resulted in not only increased density of LVs in tissues but also their enhanced function. Taken together, these findings improve the current understanding of the relationship between LVs and inflammatory cytokines in pathologic conditions.

During inflammation lymphatic vessels (LVs) are enlarged and their density is increased to facilitate the migration of activated immune cells and antigens. However, after antigen clearance, the expanded LVs shrink to maintain homeostasis. Here we show that interleukin (IL)-17A, secreted from T helper type 17 (TH17) cells, is a negative regulator of lymphangiogenesis during the resolution phase of TH17-mediated immune responses. Moreover, IL-17A suppresses the expression of major lymphatic markers in lymphatic endothelial cells and decreases in vitroLV formation. To investigate the role of IL-17A in vivo, we utilized a cholera toxin-mediated inflammation model and identified inflammation and resolution phases based on the numbers of recruited immune cells. IL-17A, markedly produced by TH17 cells even after the peak of inflammation, was found to participate in the negative regulation of LV formation. Moreover, blockade of IL-17A resulted in not only increased density of LVs in tissues but also their enhanced function. Taken together, these findings improve the current understanding of the relationship between LVs and inflammatory cytokines in pathologic conditions.

The genetics behind the progression of myelodysplasia to secondary acute myeloid leukemia (sAML) is poorly understood. In this study, we profiled somatic mutations and their dynamics using next generation sequencing on serial samples from a total of 124 patients, consisting of a 31 patient discovery cohort and 93 patients from two validation cohorts. Whole-exome analysis on the discovery cohort revealed that 29 of 31 patients carry mutations related to at least one of eight commonly mutated pathways in AML. Mutations in genes related to DNA methylation and splicing machinery were found in T-cell samples, which expand at the initial diagnosis of the myelodysplasia, suggesting their importance as early disease events. On the other hand, somatic variants associated with signaling pathways arise or their allelic burdens expand significantly during progression. Our results indicate a strong association between mutations in activated signaling pathways and sAML progression. Overall, we demonstrate that distinct categories of genetic lesions play roles at different stages of sAML in a generally fixed order.

Genetic association studies on the pharmacokinetics of tacrolimus have reported conflicting results, except for the role of the CYP3A5*3polymorphism. The objective of this study was to identify genetic variants affecting the pharmacokinetics of tacrolimus using the DMETTMPlus microarray in 42 healthy males. Aside from CYP3A5*3,the rs3814055 polymorphism in the NR1I2gene was associated with the tacrolimus pharmacokinetics based on false discovery rate-corrected multiple tests and the least absolute shrinkage and selection operator analysis. The area under the concentration-time curve to the last quantifiable time point (AUClast) was 3.42 times greater in subjects with homozygous mutations in both genes (CYP3A5*3/*3and NR1I2T/T) than in wild-type subjects. The two variants explained the 54% variability in the tacrolimus AUClast. An in vitroluciferase reporter assay indicated that downregulation of PXR expression is the likely molecular mechanism responsible for the increased exposure to tacrolimus in subjects carrying the rs3814055 C>T variant.

We investigated whether serum deprivation induces islet amyloid polypeptide (IAPP) oligomer accumulation and/or a proinflammatory response and, if so, whether the addition of interleukin (IL)‐1 receptor antagonist to the culture medium can relieve the proinflammatory response during serum‐deprived culture of nonhuman primate (NHP) islets. After culture in medium with and without Ana under serum‐deprived culture conditions, IAPPoligomer/amyloid accumulation, in vitroviability, islet function, cytokine secretion, and posttransplantation outcome in streptozotocin‐induced diabetic nude mice were determined in islets isolated from heterozygote human IAPPtransgenic (hIAPP+/−) mice and/or NHPislets. Serum deprivation induced accumulation of IAPPoligomer, but not amyloid, in NHPislets. Anakinra (Ana) protected islets from the serum deprivation–induced impairment of in vitroviability and glucose‐stimulated insulin secretion and attenuated serum deprivation–induced caspase‐1 activation, transcription, and secretion of IL‐1β, IL‐6, and tumor necrosis factor‐α in hIAPP+/−mice and NHPislets. Supplementation of medium with Ana during serum‐deprived culture also improved posttransplantation in vivooutcomes of NHPislets. In conclusion, serum deprivation induced accumulation of IAPPoligomers and proinflammatory responses in cultured isolated islets. Supplementation of the culture medium with Ana attenuated the functional impairment and proinflammatory responses induced by serum deprivation in ex vivoculture of NHPislets. Serum deprivation induces accumulation of islet amyloid polypeptide oligomers and proinflammatory responses in cultured isolated islets, and supplementing the culture medium with anakinra attenuates the functional impairment and proinflammatory responses induced by serum deprivation in ex vivoculture of nonhuman primate islets.

The JAK2V617F mutation is found in most patients with a myeloproliferative neoplasm (MPN). This gain-of-function mutation dysregulates cytokine signaling and is associated with increased accumulation of DNA damage, a process likely to drive disease evolution. JAK2V617F inhibits NHE-1 upregulation in response to DNA damage and consequently represses Bcl-xL deamidation and apoptosis, thus giving rise to inappropriate cell survival. However, the mechanism whereby NHE-1 expression is inhibited by JAK2V617F is unknown. In this study, we demonstrate that the accumulation of reactive oxygen species (ROS) in cells expressing JAK2V617F compromises the NHE-1/Bcl-xL deamidation pathway by repressing NHE-1 upregulation in response to DNA damage. In JAK2V617F-positive cells, increased ROS levels results from aberrant PI3K signaling, which decreases nuclear localization of FOXO3A and decreases catalase expression. Furthermore, when compared with autologous control erythroblasts, clonally derived JAK2V617F-positive erythroblasts from MPN patients displayed increased ROS levels and reduced nuclear FOXO3A. However, in hematopoietic stem cells (HSCs), FOXO3A is largely localized within the nuclei despite the presence of JAK2V617F mutation, suggesting that JAK2-FOXO signaling has a different effect on progenitors compared with stem cells. Inactivation of FOXO proteins and elevation of intracellular ROS are characteristics common to many cancers, and hence these findings are likely to be of relevance beyond the MPN field.

Cellular senescence is considered as an important tumor-suppressive mechanism. Here, we demonstrated that heparan sulfate (HS) prevents cellular senescence by fine-tuning of the fibroblast growth factor receptor (FGFR) signaling pathway. We found that depletion of 3′-phosphoadenosine 5′-phosphosulfate synthetase 2 (PAPSS2), a synthetic enzyme of the sulfur donor PAPS, led to premature cell senescence in various cancer cells and in a xenograft tumor mouse model. Sodium chlorate, a metabolic inhibitor of HS sulfation also induced a cellular senescence phenotype. p53 and p21 accumulation was essential for PAPSS2-mediated cellular senescence. Such senescence phenotypes were closely correlated with cell surface HS levels in both cancer cells and human diploid fibroblasts. The determination of the activation of receptors such as FGFR1, Met, and insulin growth factor 1 receptor β indicated that the augmented FGFR1/AKT signaling was specifically involved in premature senescence in a HS-dependent manner. Thus, blockade of either FGFR1 or AKT prohibited p53 and p21 accumulation and cell fate switched from cellular senescence to apoptosis. In particular, desulfation at the 2-O position in the HS chain contributed to the premature senescence via the augmented FGFR1 signaling. Taken together, we reveal, for the first time, that the proper status of HS is essential for the prevention of cellular senescence. These observations allowed us to hypothesize that the FGF/FGFR signaling system could initiate novel tumor defenses through regulating premature senescence.

Most types of cancers are made up of heterogeneous mixtures of genetically distinct subclones. In particular, acute myeloid leukemia (AML) has been shown to undergo substantial clonal evolution over the course of the disease. AML tends to harbor fewer mutations than solid tumors, making it challenging to infer clonal structure. Here, we present a 9-year, whole-exome sequencing study of a single case at 12 time points, from the initial diagnosis until a fourth relapse, including 6 remission samples in between. To the best of our knowledge, it covers the longest time span of any data set of its kind. We used these time series data to track the hierarchy and order of variant acquisition, and subsequently analyzed the evolution of somatic variants to infer clonal structure. From this, we postulate the development and extinction of subclones, as well as their anticorrelated expansion via varying drug responses. In particular, we show that new subclones started appearing after the first complete remission. The presence and absence of different subclones during remission and relapses implies differing drug responses among subclones. Our study shows that time series analysis contrasting remission and relapse periods provides a much more comprehensive view of clonal structure and evolution.

Cellulose-calcium silicate (CCS) nanocomposites were fabricated through an environment-friendly process from waste wood, glass, and clam shells. Effect of heat-treatment on synthesis of CCS nanocomposites was investigated in terms of the precursor ratio and firing temperature. The optimization of cellulose, silicon, and calcium ratio resulted in the low temperature synthesis and also reducing input energy and the production of toxic by-products. The synthesized CCS nanocomposites were examined for its versatility, especially regarding its ability to replace plastics. The resulting biodegradable material has the potential for use in a variety of applications, including reducing CO2emissions.

In the present study, we carried out a flux cored arc welding using a super duplex stainless steel as a filler metal and analysed the cause of cracking that occurred at the aging treatment for 30 min at 850°C. The stress concentration effect by the notch of the welding bead affected the hot cracking susceptibility, and the impact value of weldment was remarkably decreased due to the precipitation of secondary phases. In addition, the precipitation of sof the adjacent area to the crack was measured to be higher by ~12 wt- than the non-adjacent area to the crack. As a result of analysis of fracture plane, it was embrittled by segregation of impurities or inclusions, which acted as a starting point of the crack, and the crack grew according to the widely distributed sphase.

Selected topics of Plasma-Surface Interaction (PSI) activities in KSTAR are briefly introduced. SOL parameter measurements, particle balance and fuel retention, in-vessel dust research, and finally tungsten R & D are discussed. Some quantitative numbers from the initial phase of the operation are given for comparison with that of other machines.

The electrochemical performance of an anode material for a solid oxide fuel cell (SOFC) depends highly on microstructure in addition to composition. In this study, a NiO–yttria‐stabilised zirconia (NiO–YSZ) composite with a highly dispersed microstructure and large pore volume/surface area has been synthesised by ultrasonic spray pyrolysis (USP) and its electrochemical characteristics has been investigated. For comparison, the electrochemical performance of a conventional NiO–YSZ is also evaluated. The power density of the zirconia electrolyte‐supported SOFC with the synthesised anode is ∼392 mW cm–2at 900 °C and that of the SOFC with the conventional NiO–YSZ anode is ∼315 mW cm–2. The improvement is ∼24%. This result demonstrates that the synthesised NiO–YSZ is a potential alternative anode material for SOFCs fabricated with a zirconia solid electrolyte.

To explore the neuroanatomic basis of amnestic mild cognitive impairment (aMCI) in patients with Parkinson disease (PD; aMCI-PD) and without PD (aMCI-PD−).

TiO2from the incineration of dye wastewater flocculated sludge using TiCl4coagulant was produced. Optimal catalyst amount and Pt-loading on TiO2were studied for the production of H2by photocatalytic reforming of methanol (6% vol.). On the other hand, BTSE (biologically treated sewage effluent) was flocculated using TiCl4 and produced sludge was incinerated to generate TiO2. TiO2was loaded with optimum Pt and added to the supernatant in a photocatalytic reactor to test the efficiency of using remaining organics as a “sacrificial reagent” for photocatalytic hydrogen production. Dissolved organic carbon (DOC) and molecular weight distribution (MWD) were measured for nanofiltration (NF) and TiCl4flocculation followed by photocatalysis. TiO2(from the incineration of BTSE flocculated sludge using TiCl4) was produced and loaded with 0.5% Pt. Results showed that the optimum concentration of TiO2(from dye wastewater) for H2production was 0.3 g/L, while the optimum amount of Pt was 0.5%. DOC and MWD removal was similar for the flocculation of BTSE followed by photocatalytic reaction and the NF process. Remaining organic compounds after flocculation could not be used as sacrificial reagent to induce H2production. Further investigations on studying the UV intensity and/or identifying organic/inorganic scavengers to inhibit H2production are underway.

Abstract: A simple and novel method to synthesize iron and aluminium-doped titanium dioxide (TiO2) was investigated. Titanium tetrachloride (TiCl4) was used as a coagulant to remove organic matter from wastewater. The settled floc (sludge) was dewatered and incinerated at 600°C after TiCl4 flocculation. The resultant by-product from the waste sludge was valuable TiO2. TiCl4 coagulant was added with FeCl3 and Al2(SO4)3 coagulants to dope iron and aluminium on TiO2 in a flocculation process. The effect of iron and aluminium on TiO2 was investigated in terms of scanning electron microscopy/energy dispersive X-ray (SEM/EDX), X-ray diffraction (XRD), optical absorbance and photocatalytic activity. The majority of Fe/TiO2 and Al/TiO2 particles were found to be less than 1μm size formed by 0.1μm agglomerates using SEM analysis. Fe/TiO2 included Ti, O, C, P and Fe elements and Al/TiO2 consisted of Ti, O, C, P and Al elements as confirmed by EDX results. Remaining organic carbon from the settled organic matter was the source of C atom in TiO2 whereas the P atom in TiO2 came from phosphorus nutrient present in wastewater. The majority of acetaldehyde with Fe/TiO2 and Al/TiO2 was significantly removed under UV irradiation within 60min. However, at higher iron concentration, acetaldehyde removal decreased by almost 50%. Under visible light irradiation, the photo-decomposition of acetaldehyde using the Fe/TiO2 and Al/TiO2 was marginal. [Copyright &y& Elsevier]

Migraine carries an increased risk for cardiovascular and cerebrovascular diseases that cannot be explained by traditional cardiovascular risk factors. The circulating endothelial progenitor cell (EPC) number is a surrogate biologic marker of vascular function, and diminished EPC counts are associated with higher cardiovascular risk. We investigated whether abnormalities in EPC levels and functions are present in migraine patients.

InN 1D materials were successfully grown by metal-organic vapor phase epitaxy (MOVPE) and non-catalytic, template-free hydride metal-organic vapor phase epitaxy (H-MOVPE) on Si, GaN, and c-Al2O3 substrates. Dislocation-free, high-quality InN nanorods with [00.1] growth axis were formed via an apparent vapor-solid (VS) growth mechanism by H-MOVPE. On a contrary when conventional MOVPE was employed InN nanowires were grown via vapor-liquid-solid (VLS) mechanism. The controlled growth of self-seeded III-Nitride nanostructured materials has been demonstrated.

Ciglitizone, a class of thiazolidinediones, acts as a potent activator of the adipose differentiation program in established preadipose cell lines. Thiazolidinediones have also been investigated in diabetic patients and have been reported to act as peroxisome proliferator-activated receptor-γ ligands. Intramuscular adipogenesis or marbling through transdifferentiation of satellite cells in cattle was successfully conducted earlier. In this report, the effects of ciglitizone on the differentiation pathway of porcine myogenic satellite cells was investigated. Semitendinosus muscle was aseptically taken from 10-d-old piglets under general anesthesia, and porcine satellite cells were obtained and grown to near confluence. Postconfluent cells (d 0) were further cultured in differentiation medium containing an adipogenic mixture plus ciglitizone (10 μM) for 48 h. From d 2 onward, the cells were cultured only in the presence of ciglitizone until d 10. Controls were cultured in differentiation medium only. Exposure of porcine satellite cells to the adipogenic mixture plus ciglitizone generated lipid droplets on d 2, and subsequently, exposure of cells to ciglitizone alone helped in cytoplasmic lipid filling, providing them with the acquisition of adipocyte morphology. An increase (P< 0.05) in the fusion (structures containing 2 to 3 nuclei) of satellite cells was observed, and myosin heavy chain appeared with greater intensity (immunohistochemistry) in the control group from d 2 onward. Adipocyte-specific transcriptional factors (i.e., CCAAT/enhancer binding protein-α and peroxisome proliferator-activated receptor-γ) were predominant during transdifferentiation and were observed with immuhistochemistry, Western blot (~47.2 and ~60.4 kDa, respectively), and real-time PCR. Ciglitizone appeared to convert the differentiation pathway of satellite cells into that of adipoblasts.

New analogues of vardenafil and sildenafil illegally added to dietary supplements were detected by high-performance liquid chromatography (HPLC) analysis with a photodiode array detector (PDA). These compounds were isolated and their structures elucidated by mass spectrometry (MS), infrared (IR) spectroscopy, one- and two-dimensional nuclear magnetic resonance (NMR). One of the new analogues given the trivial name pseudovardenafil (compound 1) was structurally elucidated and shown to be 1-[[3-(1,4-dihydro-5-methyl-4-oxo-7-propylimidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxyphenyl]sulfonyl]-piperidine. It was a vardenafil analogue isolated from a dietary supplement capsule. Compared with vardenafil, the piperidine ring was substituted for the ethylpiperazine group. The second new analogue, trivially named hydroxyhongdenafil (compound 2), was separated from bulk powder used as a raw material for a dietary supplement. The piperazine and phenyl groups were connected through an acetyl group instead of a sulfonyl group, and hydroxyethylpiperazine was substituted for the methylpiperazine of sildenafil. It was structurally elucidated as 5-[2-ethoxy-5-[[4-(2-hydroxyethyl)-1-piperazinyl]acetyl]phenyl]-1,4-dihydro-1-methyl-3-propyl-7H-pyrazolo[4,3-d]pyrimidin-7-one.

A compact frequency multiplier waveguide module is built by placing a planar microstrip section between two rectangular waveguides. The size of the microstrip section is minimized by eliminating all harmonic band-rejection filters. Special feed locations for the input waveguide-to-microstrip transition patches provide the second-harmonic rejection at the input, and a balanced circuit configuration formed with a pair of transistors produces the pump signal cancellation at the output. The measurements on a fully-assembled waveguide module showed a peak frequency conversion gain of-2.3 dB at 16.7 GHz with the associated output power level of 6 dBm.

Opuntia humifusaRaf. (O. humifusaRaf.) is a member of the Cactaceae family. To determine the antioxidative and anti‐inflammatory effects of this herb, various solvent fractions (methanol, hexane, chloroform, ethyl acetate, butanol, and water) prepared from the leaves of cacti were tested using DPPH (2,2‐diphenyl‐l‐picrylhydrazyl radical) and xanthine oxidase assays, and nitric oxide (NO)‐producing macrophage cells. We found that O. humifusaRaf. displayed potent antioxidative and anti‐inflammatory activity. Thus, all solvent fractions, except for the water layer, showed potent scavenging effects. The scavenging effect of the ethyl acetate fraction was higher than that of the other fractions, with IC50 values of 3.6 and 48.2 μg mL−1. According to activity‐guided fractionation, one of the active radical scavenging principles in the ethyl acetate fraction was found to be quercetin. In contrast, only two fractions (chloroform and ethyl acetate) significantly suppressed nitric oxide production from the lipopolysaccharide (LPS)‐activated RAW264.7 cells. In addition, chloroform and ethyl acetate fractions significantly blocked the expression of inducible nitric oxide synthetase (iNOS) and interleukin‐6 (IL‐6) from the RAW264.7 cells stimulated by LPS. Moreover, ethyl acetate fractions significantly blocked the expression of IL‐1β from the RAW264.7 cells stimulated by LPS. Therefore, the results suggested that O. humifusaRaf. may modulate radical‐induced toxicity via both direct scavenging activity and the inhibition of reactive species generation, and the modulation of the expression of inflammatory cytokines. Finally, O. humifusaRaf. may be useful as a functional food or drug against reactive species‐mediated disease.

Opuntia humifusaRaf. (O. humifusaRaf.) is a member of the Cactaceae family. To determine the antioxidative and anti-inflammatory effects of this herb, various solvent fractions (methanol, hexane, chloroform, ethyl acetate, butanol, and water) prepared from the leaves of cacti were tested using DPPH (2,2-diphenyl-l-picrylhydrazyl radical) and xanthine oxidase assays, and nitric oxide (NO)-producing macrophage cells. We found that O. humifusaRaf. displayed potent antioxidative and anti-inflammatory activity. Thus, all solvent fractions, except for the water layer, showed potent scavenging effects. The scavenging effect of the ethyl acetate fraction was higher than that of the other fractions, with IC50 values of 3.6 and 48.2 μg mL−1. According to activity-guided fractionation, one of the active radical scavenging principles in the ethyl acetate fraction was found to be quercetin. In contrast, only two fractions (chloroform and ethyl acetate) significantly suppressed nitric oxide production from the lipopolysaccharide (LPS)-activated RAW264.7 cells. In addition, chloroform and ethyl acetate fractions significantly blocked the expression of inducible nitric oxide synthetase (iNOS) and interleukin-6 (IL-6) from the RAW264.7 cells stimulated by LPS. Moreover, ethyl acetate fractions significantly blocked the expression of IL-1β from the RAW264.7 cells stimulated by LPS. Therefore, the results suggested that O. humifusaRaf. may modulate radical-induced toxicity via both direct scavenging activity and the inhibition of reactive species generation, and the modulation of the expression of inflammatory cytokines. Finally, O. humifusaRaf. may be useful as a functional food or drug against reactive species-mediated disease.

Monodispersive size-controlled gold nanoplates were synthesized with high purity from the reduction of hydrogen tetrachloroaurate by reduced amount of sodium citrate, which kinetically controls the reaction pathway, in the presence of poly(vinyl pyrrolidone) (PVP). With the insufficient addition of the reductant, the molar ratio of sodium citrate and PVP relative to hydrogen tetrachloroaurate played an important role in determining the geometric shape and size of the product. These nanoplates were single crystals with planar width of 80−500 nm and thickness of 10−40 nm, exhibiting strong surface plasmon absorption in the near-infrared (NIR) region of 700−2000 nm. The gold nanoplates were used as the synthetically provided nanoblocks to fabricate single-crystalline nanocomponents, such as a nanoscaled gear or a nanoscaled letter.

The pharmacokinetic interaction between clozapine, an atypical antipsychotic with metabolic complications, including weight gain, and green tea consumption has not been evaluated, although green tea is responsible for beneficial effects, including weight reduction, and is widely consumed in the world. Commercial green tea extract (175 mg kg−1) or saline was administered orally for 4 days before the oral administration of clozapine (20 mg kg−1) to rats. Plasma concentrations of clozapine were measured up to 5 h after clozapine administration, and then hepatic CYP1A2 expression and activity were determined. There was no significant difference in the elimination half‐life of clozapine between the green tea extract and saline groups. However, the time to reach peak concentration (Tmax) was significantly increased by green tea extract. The mean total area under the plasma concentration‐time curve (AUC0‐∞) and maximal peak plasma concentration (Cmax) of clozapine in the green tea extract group were significantly lower than those of controls. Green tea extract induced a ∼2‐fold increase in hepatic CYP1A2 levels, while the activity increased slightly (by 10% of control). Because of this reduction in AUC and Tmaxof clozapine by green tea extract pretreatment, we suggest that both the rate and amount of absorption of clozapine may be reduced by green tea extract, although the hepatic elimination phase may not be significantly altered. Therefore, the clinical implications of the effects of green tea on the bioavailability of clozapine in patients should be further evaluated.

The pharmacokinetic interaction between clozapine, an atypical antipsychotic with metabolic complications, including weight gain, and green tea consumption has not been evaluated, although green tea is responsible for beneficial effects, including weight reduction, and is widely consumed in the world. Commercial green tea extract (175 mg kg−1) or saline was administered orally for 4 days before the oral administration of clozapine (20 mg kg−1) to rats. Plasma concentrations of clozapine were measured up to 5 h after clozapine administration, and then hepatic CYP1A2 expression and activity were determined. There was no significant difference in the elimination half-life of clozapine between the green tea extract and saline groups. However, the time to reach peak concentration (Tmax) was significantly increased by green tea extract. The mean total area under the plasma concentration-time curve (AUC0-∞) and maximal peak plasma concentration (Cmax) of clozapine in the green tea extract group were significantly lower than those of controls. Green tea extract induced a ∼2-fold increase in hepatic CYP1A2 levels, while the activity increased slightly (by 10% of control). Because of this reduction in AUC and Tmaxof clozapine by green tea extract pretreatment, we suggest that both the rate and amount of absorption of clozapine may be reduced by green tea extract, although the hepatic elimination phase may not be significantly altered. Therefore, the clinical implications of the effects of green tea on the bioavailability of clozapine in patients should be further evaluated.

Abstract A compact beam-steering lens design appropriate for millimeter-wave and submillimeter-wave applications is experimentally verified with an X-band test model. The lens achieves coupling to plane-wave beams through arrays of patch antennas placed on its two outer surfaces. The isolation between input and output antennas is accomplished by inserting a metal ground plane in the middle of the lens. The two closest patch antennas on the front and the backside are connected together with microstrip circuits that include switched-line phased shifters and interconnecting vias through the lens substrate. Three different X-band 100-element plane-wave microstrip lenses that use passive delay lines instead of actual phase-shifters were fabricated to successfully demonstrate the beam-steering angles of 20 and 40 degrees. From a separate waveguide measurement on the unit-cell element only, the insertion loss of the lens was estimated to be approximately 3.5 dB with bandwidth of 2% at 10 GHz.

Inhibitors of histone deacetylases (HDACs) have been shown to induce differentiation and/or apoptosis of human tumor cells. Novel 3-(4-substituted-phenyl)-N-hydroxy-2-propenamides have been prepared as a new class of HDAC inhibitors and evaluated for their antiproliferative activity and HDAC inhibitory activity. Incorporation of a 1,4-phenylene carboxamide linker, shown by 5, and a 4-(dimethylamino)phenyl or 4-(pyrrolidin-1-yl)phenyl group as a cap substructure generated highly potent hydroxamic acid-based HDAC inhibitors 5a and 5b.

A series of 45 phenethylamine derivatives were synthesized and evaluated for their inhibitory activity against pig kidney aldose reductase (ALR2, EC 1.1.1.21). Their IC50 values ranged from 400 μM to 24 μM. The binding modes of compounds at the active site of ALR2 were examined using flexible docking. The results indicated that phenethylamine derivatives nicely fit into the active pocket of ALR2 by forming various hydrogen bonding and hydrophobic interactions. 3D-QSAR analysis was also conducted using FlexX-docked alignment of the compounds. The best prediction was obtained by CoMSIA combined with hydrophobic and hydrogen bond donor/acceptor field (q² = 0.557, r² = 0.934). A new derivative, 4-oxo-4-(4-hydroxyindole)butanoic acid, was designed, taking into account the CoMSIA field and the binding mode derived by FlexX docking. This rationally designed compound exhibits an ALR2 inhibition with an IC50 value of 7.4 μM, which compares favorably to that of a well-known ALR2 inhibitor, tolrestat (IC50 = 16 μM) and represents a potency approximately 240-fold higher than that of an original phenethylamine lead compound, YUA001.

Inhibitors of histone deacetylases (HDACs) have been shown to induce differentiation and/or apoptosis of human tumor cells. Novel 3-(4-substituted-phenyl)-N-hydroxy-2-propenamides have been prepared as a new class of HDAC inhibitors and evaluated for their antiproliferative activity and HDAC inhibitory activity. Incorporation of a 1,4-phenylene carboxamide linker, shown by 5, and a 4-(dimethylamino)phenyl or 4-(pyrrolidin-1-yl)phenyl group as a cap substructure generated highly potent hydroxamic acid-based HDAC inhibitors 5a and 5b.

A series of 45 phenethylamine derivatives were synthesized and evaluated for their inhibitory activity against pig kidney aldose reductase (ALR2, EC 1.1.1.21). Their IC50 values ranged from 400 μM to 24 μM. The binding modes of compounds at the active site of ALR2 were examined using flexible docking. The results indicated that phenethylamine derivatives nicely fit into the active pocket of ALR2 by forming various hydrogen bonding and hydrophobic interactions. 3D-QSAR analysis was also conducted using FlexX-docked alignment of the compounds. The best prediction was obtained by CoMSIA combined with hydrophobic and hydrogen bond donor/acceptor field (q² = 0.557, r² = 0.934). A new derivative, 4-oxo-4-(4-hydroxyindole)butanoic acid, was designed, taking into account the CoMSIA field and the binding mode derived by FlexX docking. This rationally designed compound exhibits an ALR2 inhibition with an IC50 value of 7.4 μM, which compares favorably to that of a well-known ALR2 inhibitor, tolrestat (IC50 = 16 μM) and represents a potency approximately 240-fold higher than that of an original phenethylamine lead compound, YUA001.

Chiral ferrocenyl imidazolium salts were obtained from optically pure ferrocenyl alcohols or acetates by substitution with retention of configurations. Their rhodium and iridium complexes were synthesized and applied to asymmetric hydrogenations. The benzimidazolylidene−iridium complex showed up to 52.6% ee in the transfer hydrogenation of 4‘-methylacetophenone.

Two new triterpenoid saponins (1 and 2) were isolated from the stem bark of Cussonia bancoensis together with the known stigmasterol, ursolic acid, 23-hydroxyursolic acid (3), and 3β-hydroxylup-20(29)-en-28-oic acid. On the basis of their spectroscopic data and on chemical transformations, the structures of the new saponins have been established as 3-O-(α-l-arabinopyranosyl)-23-hydroxyursolic acid (1) and 3-O-(β-d-glucopyranosyl)-23-hydroxyursolic acid (2). In a nitric oxide (NO)-production bioassay, compound 3 exhibited significant NO inhibitory activity, while compounds 1 and 2 were less potent than 3.

Cryopreserved patellar tendon allografts are often recommended for reconstruction of anterior cruciate ligaments (ACLs) because living donor fibroblasts are thought to promote repair. Animal studies, however, indicate that ligaments regenerate from recipient rather than donor cells. If applicable to man, these observations suggest that allograft cell viability is unimportant. We therefore used short tandem repeat analysis with polymerase chain reaction (PCR) amplification to determine the source of cells in nine human ACLs reconstructed with cryopreserved patellar tendon allografts. PCR amplification of donor and recipient DNA obtained before operation and DNA from the graft obtained two to ten months after transplantation revealed the genotype of cells and showed only recipient cells in the graft area. Rather than preserve the viability of donor cells, a technique is required which will facilitate the introduction of recipient cells into patellar tendon allografts.

The effects of nonisobaric and isobaric steps on a two-bed O2 pressure swing adsorption (PSA) packed with zeolite 5A were investigated. In addition, the operating conditions in the O2 PSA were studied to supply the various O2 concentrations to the oxygen aerator efficiently. Because the velocity variation along the bed and the related Mass Transfer Zone (MTZ) shape at the isobaric and nonisobaric steps were affected by the diffusion rate, the concentration-dependent rate parameter in a modified linear driving force (LDF) model was evaluated from the Darken equation related to the loading ratio correlation isotherm model. The LDF coefficients had a significant effect on the prediction of the O2 purity and recovery at the low flow rate region. However, the higher the feed flow rate, the lower the LDF parameter effect. It was also noted that the effects of each step time in the isobaric and nonisobaric steps on the PSA performance were subtle in the O2 purity and recovery except for the blowdown step. Also, there was the optimum step time to maximize the O2 purity and recovery in the adsorption and pressurization steps, while the increase of O2 purity and recovery with the pressurization equalization step time showed asymptotic curvature. The idle time at the pressurization step had a negative effect on the PSA performance, while the short idle time at the pressure equalization step led to improved product purity. However, it was negligible for the effect of the idle time at the blowdown step on the PSA performance. The successive variation between high and low P/F ratios caused the continuous variation of O2 purity and recovery to nearly the same extent as the results under each constant P/F ratio condition. Therefore, to save the operating cost of the oxygen aerator system, the desired oxygen concentration for the aerator can be supplied simply by controlling the feed rate or purge rate.

betaPix (PAK-interacting exchange factor) is a recently identified guanine nucleotide exchange factor for Rho family small G protein Cdc42/Rac. The protein interacts with p21-activated protein kinase (PAK) through its SH3 domain. We examined the effect of betaPix on MAP kinase signaling and cytoskeletal rearrangement in NIH3T3 fibroblast cells. Overexpression of betaPix enhanced the activation of p38 in the absence of other stimuli and also induced translocation of p38 to the nucleus. This betaPix-induced p38 activation was blocked by coexpression of dominant-negative Cdc42/Rac or kinase-inactive PAK, indicating that the effect of betaPix on p38 is exerted through the Cdc42/Rac-PAK pathway and requires PAK kinase activity. The essential role of betaPix in growth factor-stimulated p38 activation was evidenced by the blocking of platelet-derived growth factor-induced p38 activation in the cells expressing betaPix SH3m (W43K) and betaPix DHm (L238R,L239R). In addition, SB203580, a p38 inhibitor, and kinase-inactive p38 (T180A,Y182F) blocked membrane ruffling induced by betaPix, suggesting that p38 might be involved in mediating betaPix-induced membrane ruffling. The results in this study suggest that betaPix might have a role in nuclear signaling, as well as in actin cytoskeleton regulation, and that some part of these cellular functions is possibly mediated by p38 MAP kinase.

ABSTRACTSoluble mediators such as interleukin-1ß, tumor necrosis factor alpha (TNF-a), and inducible nitric oxide synthase (iNOS) produced from activated macrophages play an important role in the destruction of pancreatic ß cells in mice infected with a low dose of the D variant of encephalomyocarditis (EMC-D) virus. The tyrosine kinase signaling pathway was shown to be involved in EMC-D virus-induced activation of macrophages. This investigation was initiated to determine whether the Src family of kinases plays a role in the activation of macrophages, subsequently resulting in the destruction of ß cells, in mice infected with a low dose of EMC-D virus. We examined the activation of p59/p56Hck, p55Fgr, and p56/p53Lynin macrophages from DBA/2 mice infected with the virus. We found that p59/p56Hckshowed a marked increase in both autophosphorylation and kinase activity at 48 h after infection, whereas p55Fgrand p56/p53Lyndid not. The p59/p56Hckactivity was closely correlated with the tyrosine phosphorylation level of Vav. Treatment of EMC-D virus-infected mice with the Src kinase inhibitor, PP2, resulted in the inhibition of p59/p56Hckactivity and almost complete inhibition of the production of TNF-a and iNOS in macrophages and the subsequent prevention of diabetes in mice. On the basis of these observations, we conclude that the Src kinase, p59/p56Hck, plays an important role in the activation of macrophages and the subsequent production of TNF-a and nitric oxide, leading to the destruction of pancreatic ß cells, which results in the development of diabetes in mice infected with a low dose of EMC-D virus.