Comparison of the Plasma Metabolome Profiles Between the Internal Thoracic Artery and Ascending Aorta in Patients Undergoing Coronary Artery Bypass Graft Surgery Using Gas Chromatography Time-of-Flight Mass Spectrometry.

BackgroundThe left internal thoracic artery (LITA) has been used as the first conduit of choice in coronary artery bypass grafting (CABG) because of excellent long-term patency and outcomes. However, no studies have examined substances other than nitric oxide that could be beneficial for the bypass conduit, native coronary artery or ischemic myocardium. This study was conducted to evaluate differences in metabolic profiles between the LITA and ascending aorta using gas chromatography-time of flight-mass spectrometry (GC-TOF-MS).MethodsTwenty patients who underwent CABG using the LITA were prospectively enrolled. Plasma samples were collected simultaneously from the LITA and ascending aorta. GC-TOF-MS based untargeted metabolomic analyses were performed and a 2-step volcano plot analysis was used to identify distinguishable markers from two plasma metabolome profiles. Semi-quantitative and quantitative analyses were performed using GC-TOF-MS and enzyme-linked immunosorbent assay, respectively, after selecting target metabolites based on the metabolite set enrichment analysis.ResultsInitial volcano plot analysis demonstrated 5 possible markers among 851 peaks detected. The final analysis demonstrated that the L-cysteine peak was significantly higher in the LITA than in the ascending aorta (fold change = 1.86). The concentrations of intermediate metabolites such as L-cysteine, L-methionine and L-cystine in the 'cysteine and methionine metabolism pathway' were significantly higher in the LITA than in the ascending aorta (2.0-, 1.4- and 1.2-fold, respectively). Quantitative analysis showed that the concentration of hydrogen sulfide (H₂S) was significantly higher in the LITA.ConclusionThe plasma metabolome profiles of the LITA and ascending aorta were different, particularly higher plasma concentrations of L-cysteine and H₂S in the LITA

Metal-organic framework based on hinged cube tessellation as transformable mechanical metamaterial

Mechanical metamaterials exhibit unusual properties, such as negative Poisson???s ratio, which are difficult to achieve in conventional materials. Rational design of mechanical metamaterials at the microscale is becoming popular partly because of the advance in three-dimensional printing technologies. However, incorporating movable building blocks inside solids, thereby enabling us to manipulate mechanical movement at the molecular scale, has been a difficult task. Here, we report a metal-organic framework, self-assembled from a porphyrin linker and a new type of Zn-based secondary building unit, serving as a joint in a hinged cube tessellation. Detailed structural analysis and theoretical calculation show that this material is a mechanical metamaterial exhibiting auxetic behavior. This work demonstrates that the topology of the framework and flexible hinges inside the structure are intimately related to the mechanical properties of the material, providing a guideline for the rational design of mechanically responsive metal-organic frameworks

Vav1 inhibits RANKL-induced osteoclast differentiation and bone resorption

Vav1 is a Rho/Rac guanine nucleotide exchange factor primarily expressed in hematopoietic cells. In this study, we investigated the potential role of Vav1 in osteoclast (OC) differentiation by comparing the ability of bone marrow mononuclear cells (BMMCs) obtained from Vav1-deficient (Vav1−/−) and wild-type (WT) mice to differentiate into mature OCs upon stimulation with macrophage colony stimulating factor and receptor activator of nuclear kappa B ligand in vitro. Our results suggested that Vav1 deficiency promoted the differentiation of BMMCs into OCs, as indicated by the increased expression of tartrate-resistant acid phosphatase, cathepsin K, and calcitonin receptor. Therefore, Vav1 may play a negative role in OC differentiation. This hypothesis was supported by the observation of more OCs in the femurs of Vav1−/− mice than in WT mice. Furthermore, the bone status of Vav1−/− mice was analyzed in situ and the femurs of Vav1−/− mice appeared abnormal, with poor bone density and fewer number of trabeculae. In addition, Vav1-deficient OCs showed stronger adhesion to vitronectin, an αvβ3 integrin ligand important in bone resorption. Thus, Vav1 may inhibit OC differentiation and protect against bone resorption

Hydrogen effects on nanoindentation behavior of metallic glass ribbons

Recently, metallic glass (MG) membranes that are permeable to hydrogen have gained interest due to the increasing importance of hydrogen separation in a number of applications, e.g., hydrogen-powered fuel cells. An important issue in the context of MG membranes is the hydrogen-induced embrittlement and efforts to understand the role played by hydrogen in the mechanical properties, especially yielding and plastic deformation behavior, of MGs are being made. In this study, therefore, an attempt was made by performing nanoindentation tests with cube-corner and spherical indenter tips on a series of Ni–Nb–Zr amorphous alloy ribbons to investigate the hydrogen effects on nanohardness and pop-in behavior (Figure 1). Weight gain measurements after hydrogen charging and thermal desorption spectroscopy (TDS) studies (Figure 2) were utilized to identify how the total hydrogen is partitioned into mobile and immobile parts. These, in turn, indicate the significant role of hydrogen mobility in the amorphous structure on the mechanical properties. In high-Zr alloys containing immobile H, both hardness (H) and shear yielding stress (τmax) increase significantly; while in low-Zr alloys having only mobile hydrogen, decrease in hardness and τmax were noted (Figure 1). The changes in shear transformation zone (STZ) volume, estimated through cumulative analysis of τmax, caused by hydrogen absorption were also found to depend on hydrogen mobility such that immobile hydrogen reduces the STZ volume while mobile hydrogen increases it. *This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (No. 2013R1A1A2A10058551)

Dynamically simulating the interaction of midazolam and the CYP3A4 inhibitor itraconazole using individual coupled whole-body physiologically-based pharmacokinetic (WB-PBPK) models

BACKGROUND: Drug-drug interactions resulting from the inhibition of an enzymatic process can have serious implications for clinical drug therapy. Quantification of the drugs internal exposure increase upon administration with an inhibitor requires understanding to avoid the drug reaching toxic thresholds. In this study, we aim to predict the effect of the CYP3A4 inhibitors, itraconazole (ITZ) and its primary metabolite, hydroxyitraconazole (OH-ITZ) on the pharmacokinetics of the anesthetic, midazolam (MDZ) and its metabolites, 1' hydroxymidazolam (1OH-MDZ) and 1' hydroxymidazolam glucuronide (1OH-MDZ-Glu) using mechanistic whole body physiologically-based pharmacokinetic simulation models. The model is build on MDZ, 1OH-MDZ and 1OH-MDZ-Glu plasma concentration time data experimentally determined in 19 CYP3A5 genotyped adult male individuals, who received MDZ intravenously in a basal state. The model is then used to predict MDZ, 1OH-MDZ and 1OH-MDZ-Glu concentrations in an CYP3A-inhibited state following ITZ administration. RESULTS: For the basal state model, three linked WB-PBPK models (MDZ, 1OH-MDZ, 1OH-MDZ-Glu) for each individual were elimination optimized that resulted in MDZ and metabolite plasma concentration time curves that matched individual observed clinical data. In vivo K(m )and V(max )optimized values for MDZ hydroxylation were similar to literature based in vitro measures. With the addition of the ITZ/OH-ITZ model to each individual coupled MDZ + metabolite model, the plasma concentration time curves were predicted to greatly increase the exposure of MDZ as well as to both increase exposure and significantly alter the plasma concentration time curves of the MDZ metabolites in comparison to the basal state curves. As compared to the observed clinical data, the inhibited state curves were generally well described although the simulated concentrations tended to exceed the experimental data between approximately 6 to 12 hours following MDZ administration. This deviations appeared to be greater in the CYP3A5 *1/*1 and CYP3A5 *1/*3 group than in the CYP3A5 *3/*3 group and was potentially the result of assuming that ITZ/OH-ITZ inhibits both CYP3A4 and CYP3A5, whereas in vitro inhibition is due to CYP3A4. CONCLUSION: This study represents the first attempt to dynamically simulate metabolic enzymatic drug-drug interactions via coupled WB-PBPK models. The workflow described herein, basal state optimization followed by inhibition prediction, is novel and will provide a basis for the development of other inhibitor models that can be used to guide, interpret, and potentially replace clinical drug-drug interaction trials

Pharmacokinetics of Amitriptyline Demethylation;A Crossover Study with Single Doses of Amitriptyline and Nortriptyline

A single dose crossover pharmacokinetic study of amitriptyline and nortriptyline was done to find out the extent of first-pass metabolism to nortriptyline after amitripyline administration, and the contribution of nortriptyline during amitriptyline therapy. Six healthy male volunteers took part in this study and were given single doses (50 mg) of amitriptyline and nortriptyline at more than three-week intervals. Plasma concentrations of the drugs were measured up to 48 hours. Total area under the plasma concentration-time curve (AUe) of amitriptyline (744.6±258.4 ng/ml·hl was smaller than that of nortriptyline (l497.3±589.8 ng/ml'h), and the mean terminal half-life of amitriptyline (21.8±3.9 hr) was shorter than that of nortriptyline (36.8±5.9 h). The total area under the plasma concentration-time curve of nortriptyline produced by amitriptyline administration was 498.1 ±274.5 ng/ml·h, and the fraction produced by the first-pass of amitriptyline was 33.7 ± 10.5%. From this data, it can be estimated that the average nortriptyline concentration could be about 40% of the total tricyclic antidepressants present in the plasma of patients taking multiple amitriptyline therapy at steady state. About 34% of nortriptyline is produced by first- pass effect during gastrointestinal absorption of amitriptyline to systemic circulation resulting from N-demethylation of amitriptyline in the liver. Then, the rest of the nortriptyline is formed continuously at a rate proportional to the rate of amitriptyline elimination

Picture Quality and Sound Quality of OLED TVs

Unlike the past when cathode-ray tube (CRT) dominated display industry, many different types of flat panel displays (FPDs) are now leading the industry. Of these, organic light-emitting diode (OLED) display has recently become a next-generation display since this display is recognised as having advantages over other competing technologies in picture quality and form factor. With major attributes of picture quality considered, a series of evaluations based on objective measures was performed with an OLED TV compared to an LCD TV. OLED TV outperformed LCD TV 100 times in black, 20 times in colour contrast, 30% in dynamic range coverage, 50 times in local contrast and 20 times in viewing angle. In addition, sound quality of the OLED TV was assessed using both objective and subjective evaluation methods compared to conventional TV speakers since OLED panel speaker technology was recently commercialised. The OLED panel speaker showed better performance both in objective and subjective methods

Endogenous metabolic markers for predicting the activity of dihydropyrimidine dehydrogenase

Five-fluorouracil (5-FU) is a chemotherapeutic agent that is mainly metabolized by the rate-limiting enzyme dihydropyrimidine dehydrogenase (DPD). The DPD enzyme activity deficiency involves a wide range of severities. Previous studies have demonstrated the effect of a DPYD single nucleotide polymorphism on 5-FU efficacy and highlighted the importance of studying such genes for cancer treatment. Common polymorphisms of DPYD in European ancestry populations are less frequently present in Koreans. DPD is also responsible for the conversion of endogenous uracil (U) into dihydrouracil (DHU). We quantified U and DHU in plasma samples of healthy male Korean subjects, and samples were classified into two groups based on DHU/U ratio. The calculated DHU/U ratios ranged from 0.52 to 7.12, and the two groups were classified into the 10th percentile and 90th percentile for untargeted metabolomics analysis using liquid chromatography-quantitative time-of-flight-mass spectrometry. A total of 4440 compounds were detected and filtered out based on a coefficient of variation below 30%. Our results revealed that six metabolites differed significantly between the high activity group and low activity group (false discovery rate q-value \u3c 0.05). Uridine was significantly higher in the low DPD activity group and is a precursor of U involved in pyrimidine metabolism; therefore, we speculated that DPD deficiency can influence uridine levels in plasma. Furthermore, the cutoff values for detecting DPD deficient patients from previous studies were unsuitable for Koreans. Our metabolomics approach is the first study that reported the DHU/U ratio distribution in healthy Korean subjects and identified a new biomarker of DPD deficiency

Cordycepin inhibits human ovarian cancer by inducing autophagy and apoptosis through Dickkopf-related protein 1/β-catenin signaling

Cordycepin, the major active component from Cordyceps militaris, has been reported to significantly inhibit some types of cancer; however, its effects on ovarian cancer are still not well understood. In this study, we treated human ovarian cancer cells with different doses of cordycepin and found that it dose-dependently reduced ovarian cancer cell viability, based on Cell counting kit-8 reagent. Immunoblotting showed that cordycepin increased Dickkopf-related protein 1 (Dkk1) levels and inhibited β-catenin signaling. Atg7 knockdown in ovarian cancer cells significantly inhibited cordycepin-induced apoptosis, whereas β-catenin overexpression abolished the effects of cordycepin on cell death and proliferation. Furthermore, we found that Dkk1 overexpression by transfection downregulated the expression of c-Myc and cyclin D1. siRNA-mediated Dkk1 silencing downregulated the expression of Atg8, beclin, and LC3 and promoted β-catenin translocation from the cytoplasm into the nucleus. These results suggest that cordycepin inhibits ovarian cancer cell growth, possibly through coordinated autophagy and Dkk1/β-catenin signaling. Taken together, our findings provide new insights into the treatment of ovarian cancer using cordycepin