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Objective Point-of-care (POC) devices allow for prothrombin time/international normalized ratio (PT/INR) testing in whole blood (WB) and timely administration of plasma or prothrombin complex concentrate during cardiopulmonary bypass surgery. This study evaluated the sensitivities of a new POC PT test, a dry-hematology method with heparin neutralization technology (DRIHEMATO PT-S [DRI PT-S]; A&T Corporation, Kanagawa, Japan), and compared it with other POC tests currently available. Design Prospective, observational study. Setting University hospital, single center. Participants Healthy volunteers and warfarin-treated and cardiac surgical patients. Measurement and Main Results In WB samples obtained from 6 healthy volunteers, PT-INR results of DRI PT-S were not affected by an in vitro addition of heparin <6.0 U/mL. In warfarin-treated samples (n = 88, PT/INR 0.98-3.87), PT-INR with DRI PT-S showed acceptable correlation with the laboratory method ( r 2 = 0.85, p < 0.001). In blood samples obtained from cardiac surgical patients (n = 72), heparin prolonged the PT/INR with the laboratory assay, dry-hematology method with non heparin neutralization technology (DRI PT), Coaguchek XS (Roche Diagnostics, Basel, Switzerland), and Hemochron Jr. (Accriva Diagnostics, Edison, NJ), but DRI PT-S was not affected by heparin anticoagulation. In nonheparinized samples, different methods between DRI PT-S and the laboratory method yielded acceptable correlations ( r 2 = 0.76, p < 0.0001). There was a moderate correlation between factor levels and the PT-INR with DRI PT-S (factor [F]II: r 2 = 0.63, FVII: r 2 = 0.47, FX: r 2 = 0.67; p < 0.0001). Conclusions This study demonstrated that PT/INR can be accurately assessed using the dry-hematology method in WB under therapeutic heparin levels. Currently available other POC PT/INR tests are affected by heparin, and thus they are not recommended for coagulation monitoring during cardiopulmonary bypass. [ABSTRACT FROM AUTHOR]

We developed a concise protocol for the synthesis of ellipticine quinone from the appropriate 3-iodoindole-2-carbaldehydes in four steps. The key step is the construction of carbazole-1,4-quinone through tandem Ring-Closing Metathesis (RCM) and dehydrogenation under oxygen atmosphere. Therefore, the ellipticine quinone analogs possessing substitution at the 8- and/or 9-positions were synthesized using this method. In total, 14 compounds were evaluated for antiproliferative activity against HCT-116 and HL-60 cell lines; 9-nitroellipticine quinone was found to have superior activity compared to calothrixin B. [ABSTRACT FROM AUTHOR]

We report a convenient synthesis of carbazole-1,4-quinone alkaloid koeniginequinones A and B using a tandem ring-closing metathesis with the dehydrogenation reaction sequence under an O 2 atmosphere as an important step. Using this method, carbazole-1,4-quinones substituted at the 5-, 6-, 7-, and/or 8-positions have been synthesized. Moreover, 24 compounds, including koeniginequinones A and B, have been evaluated for their antiproliferative activity against HCT-116 and HL-60 cells, and the 6-nitro analog exhibited the most potent activity against both tumor cell types. [ABSTRACT FROM AUTHOR]

In this study, we achieved the total synthesis of carbazole alkaloid mukoenine A through a seven-step sequence involving the construction of a carbazole framework using the electrocyclization of a 6π-electron system including an allene intermediate as the key step. Subsequently, the synthesis of pyrano[3,2- a ]carbazole alkaloid girinimbine was achieved by the construction of the pyran ring via selenoetherification of the o-allylic phenol moiety of mukoenine A. [Display omitted] • The total synthesis of mukoenine A has been accomplished via a seven-step sequence. • Girinimbine was synthesized by the construction of the pyran ring via mukoenine A. • The carbazole framework was constructed by the allene-mediated electrocyclization. [ABSTRACT FROM AUTHOR]

Abstract: A novel one-pot synthesis of carbazole-1,4-quinone by consecutive Pd-catalyzed cyclocarbonylation, desilylation, and oxidation reactions is described. We propose a possible mechanism of the cyclocarbonylation reaction between 3-iodo-2-propenylindole and CO (1 atm) in the presence of a tributyl(vinyl)tin and Pd-catalyst and the resulting acylpalladium species was directly coupled with a terminal alkene to produce the carbazole-1,4-quinone. To our knowledge, this is the first example of this type of reaction. A new formal total synthesis of a carbazole-1,4-quinone alkaloid, murrayaquinone A was established using this reaction. [Copyright &y& Elsevier]

Extracellular matrix (ECM) underlies a complicated multicellular architecture that is subjected to significant forces from mechanical environment. Although various components of the ECM have been enumerated, mechanisms that evolve the sophisticated ECM architecture remain to be addressed. Here we show that periostin, a matricellular protein, promotes incorporation of tenascin-C into the ECM and organizes a meshwork architecture of the ECM. We found that both periostin null mice and tenascin-C null mice exhibited a similar phenotype, confined tibial periostitis, which possibly corresponds to medial tibial stress syndrome in human sports injuries. Periostin possessed adjacent domains that bind to tenascin-C and the other ECM protein: fibronectin and type I collagen, respectively. These adjacent domains functioned as a bridge between tenascm-C and the ECM, which increased deposition of tenascin-C on the ECM. The deposition of hexabrachions of tenascin-C may stabilize bifurcations of the ECM fibrils, which is integrated into the extracellular meshwork architecture. This study suggests a role for periostin in adaptation of the ECM architecture in the mechanical environment. [ABSTRACT FROM AUTHOR]

Summary: Fibrous dysplasia is a benign bone disease caused by a mutation in the gene for the stimulatory guanine nucleotide-binding protein Gsα, leading to high cyclic adenosine monophosphate levels. Histologically, fibrous dysplasia is characterized by the production of fibrous tissue accompanied by the deposition of ectopic type I collagen and other bone-associated extracellular matrix proteins, as well as by irregular woven intramembranous bone onto which type I collagen-containing Sharpey fibers are often attached. Fibrous dysplasia is also characterized by high expression of c-Fos/c-Jun, known targets for cyclic adenosine monophosphate signaling. In this study, we examined the expression of the bone-related extracellular matrix protein, periostin, and its known receptor, integrin αvβ3 (CD51/61), in normal bones as well as in fibrous dysplasia. Immunohistochemistry and in situ hybridization studies revealed that periostin was expressed in the extracellular matrix during intramembranous but not endochondral ossification, as well as in the fibrous component of fibrous dysplasia; and all cells adjacent to periostin-positive regions expressed CD51/61. Importantly, periostin was abundantly localized to Sharpey fibers. To investigate the contribution of c-Fos, we examined transgenic mice overexpressing c-fos, which develop sclerotic lesions closely resembling those found in fibrous dysplasia. In all lesions, transformed osteoblasts expressed high levels of periostin, whereas normal osteoblasts did not. Our results show that periostin is a novel marker for intramembranous ossification, and is a good candidate as a diagnostic tool and/or a therapeutic target in fibrous dysplasia. Moreover, the Gsα–cyclic adenosine monophosphate–c-Fos pathway might represent one mechanism of periostin up-regulation in fibrous dysplasia, resulting in altered collagen fibrillogenesis characteristic of this disease. [Copyright &y& Elsevier]

Abstract: Zinc 31-hydroxy-131-oxo-chlorins possessing various perfluorooctyl groups in the 17-propionate were prepared by modifying naturally occurring chlorophyll-a. The synthetic compound having four perfluorooctyl groups readily self-assembled to form large J-aggregates, which were dissolved in fluorous phases with more ordered supramolecular structures than in a hydrocarbon solvent. [Copyright &y& Elsevier]

Abstract: A tandem ring-closing metathesis and dehydrogenation reaction under oxygen atmosphere was newly developed to the synthesis of carbazole-1,4-quinones. This new tandem reaction was applied to the synthesis of murrayaquinone A in four steps. [Copyright &y& Elsevier]

In this study, the total syntheses of 1,3,4-trisubstituted carbazole alkaloid clausamine E was accomplished via an eight-step sequence using construction of the 1,4-dioxygenated carbazole framework based on the cyclocarbonylation between 3-iodo-2-(prop-2-enyl)indole and CO (1 atm) in the presence of tributyl(vinyl)tin and a Pd catalyst. Image 1 • The total synthesis of clausamine E has been accomplished via an eight-step sequence. • Synthesis of 1,4-dioxygenated carbazoles by Pd-catalyzed cyclocarbonylation. • This method could be used as a versatile method to synthesize substituted carbazoles. [ABSTRACT FROM AUTHOR]

• The enantioselective total synthesis of (+)-asiaticumine A has been accomplished. • The construction of phenanthridine framework by MW-assisted electrocyclization. • The synthesis of 1,2-dihydroxyethyl moiety by Sharpless asymmetric dihydroxylation. • Its absolute configuration was determined to be S by Mosher's method. In this study, the first asymmetric enantioselective total syntheses of (+)-asiaticumine A (2) and its enantiomer were accomplished through a seven-step sequence using the bond formation between the C4a and N5 positions of the phenanthridine framework based on the microwave-assisted electrocyclization of cyclohexenylbenzaldoxime methyl ether as an aza 6π-hexatriene system followed by the Sharpless asymmetric dihydroxylation as the key step. In addition, the absolute configuration of natural (+)- 2 was determined to be S by Mosher's method. [ABSTRACT FROM AUTHOR]

Hepatitis E is a global public health problem. Ribavirin (RBV) and pegylated interferon alpha are currently administered to cure hepatitis E. Recently, in combination with RBV, sofosbuvir (SOF), an anti-hepatitis C virus nucleotide analog, is also given to patients with chronic hepatitis E. However, this combinatorial therapy sometimes fails to achieve a sustained virological response. In this study, we used 27 antiviral compounds, including 15 nucleos(t)ide analogs, for in vitro screening against a genotype 3 HEV strain containing a Gaussia luciferase reporter. RBV, SOF, 2′- C -methyladenosine, 2′- C -methylcytidine (2CMC), 2′- C -methylguanosine (2CMG), and two 4′-azido nucleoside analogs (R-1479 and RO-9187) suppressed replication of the reporter genome, while only RBV, SOF, 2CMC and 2CMG inhibited the growth of genotype 3 HEV in cultured cells. Although 2CMG and RBV (2CMG/RBV) exhibited a synergistic effect while SOF/RBV and 2CMC/RBV showed antagonistic effects on the reporter assay, these three nucleos(t)ide analogs acted additively with RBV in inhibiting HEV growth in cultured cells. Furthermore, SOF and 2CMG, with four interferons (IFN-α2b, IFN-λ1, IFN-λ2 and IFN-λ3), inhibited HEV growth efficiently and cleared HEV in cultured cells. These results suggest that, in combination with RBV or interferons, SOF and 2CMG would be promising bases for developing anti-HEV nucleos(t)ide analogs. • We tested inhibitory effects of 27 compounds on replication of an HEV reporter genome and growth of HEV in cultured cells. • 2′- C -methylguanosine (2CMG), 2′- C -methylcytidine (2CMC) and sofosbuvir (SOF) robustly suppressed HEV growth in cultured cells. • Ribavirin (RBV) with 2CMG suppressed replication of the reporter genome synergistically but antagonistically with 2CMC or SOF. • RBV with SOF, 2CMG, or 2CMC inhibited HEV growth additively and cleared HEV in cultured cells. • SOF or 2CMG with interferon-α2b, -λ1, -λ2, or -λ3 inhibited HEV growth additively and cleared HEV in cultured cells. [ABSTRACT FROM AUTHOR]

Liquid cell electron microscopy is a useful technique for the observation of chemical, biological, and mechanical processes in liquids at nanometer-scale resolution. This study investigated the generation and growth of nanobubbles using the Fresnel fringe method, which enabled us to determine the location of bubble interface; the nanobubbles were induced in the 600-nm-thick water sample in the cell, by the electron beam. Nucleation occurred first at the solid–liquid interface in the upstream side of electron beam, and this was followed by second-group nucleation at the downstream-side interface; all of the stable nucleations occurred on the solid surfaces. The size of the nucleated bubbles at the moment they became visible depended on the magnification used in the electron microscope, and a higher-energy density in the electron beam induced larger bubbles. The underlying mechanism was also considered in this study. [ABSTRACT FROM AUTHOR]

The effect of the high order structure of an isotactic polypropylene (PP) composite on the resistivity of composites containing magnetically aligned Ni particles was studied. Only a small amount of particles needed to be added for the composite material to become conducting after heating while in a magnetic field. The Ni columns formed on applying the field were distorted by the formation of large PP spherulites. Changes to the crystallization process due to the addition of a nucleating agent gave rise to changes in the columnar structure, resulting in large changes in the resistivity of the composite material. Controlling the high order structure of the polymer matrix including its morphology is very important in order to be able to control the magnetically aligned Ni structure. [ABSTRACT FROM AUTHOR]

Abstract: This study investigated partial nitrification treatment of methane fermentation digester liquor effluent from magnesium ammonium phosphate precipitation process in a swim-bed reactor. The reactor was operated at a temperature of 35 °C and pH between 7.5 and 7.8. Partial nitrification was achieved at the onset of the experiments even though conventional activated sludge was used as seed sludge. The maximum nitrite production rate was 1.0 kg NO2-N/m3/d at a nitrogen loading rate of 2.0 kg-N/m3/d. The average effluent NO2-N/NH4-N ratio and the effluent NO3-N concentration were 1.04±0.34 and 5.7 mg/l, respectively, during the stable experiment periods. After 150 days of operation, the sludge volume index value decreased to 15 ml/g and the mean particle size of suspended sludge increased by approximately 3 times from 80 to 260 μm. Comparison of mineral analysis between the seed sludge and the partial nitrification sludge demonstrated that the mineral content of the latter increased approximately three-fold in comparison to that of the former. High Ca concentration was considered to be closely related to dense floc formation and superior settleability of the sludge. Both DGGE and DNA clone analysis verified that there were significant microbiological differences between the samples taken at different time periods. Nitrosomonas was confirmed to be the predominant species after stable partial nitrification performance was obtained. The overall results of this study validated our previous results that swim-bed reactor technology could be successfully used as a pre-treatment technology for anammox treatment. [Copyright &y& Elsevier]

Abstract: Effect of high salt concentration on the anammox treatment was investigated to establish an acclimation strategy under high salt concentration conditions. An anammox fixed-bed reactor with non-woven biomass carrier was used and the salt concentration was gradually increased from 2.5 g L−1 to 33 g L−1. The anammox reactor demonstrated stable nitrogen removal rate (NRR) of 1.7 kg-N m−3 d−1 for 65 days under a salt concentration of 30 g L−1. However, the NRR sharply declined at a salt concentration of greater than 30 g L−1. The bacterial community was examined by 16S rRNA gene analysis and DGGE after the acclimation of the anammox sludge to high salt conditions. Although the salt concentration was almost sea level, the freshwater anammox bacteria, KU2, were detected. In addition, the unidentified bacteria which perhaps belong to candidate division OP10 and Lysobacter sp. were found to coexist with anammox bacteria at a salt concentration of 30 g L−1. [Copyright &y& Elsevier]

Abstract: Endotoxemia has been reported as a mechanism for the fatal sequela after heatstroke. Subsequent disseminated fungal infection in a heatstroke patient has been also described. Beta-d-glucan, a constituent of the fungal cell wall, is an early diagnostic measure for fungal infection. In a heatstroke case, we examined for the first time levels of serum beta-d-glucan and endotoxin. A 34-year-old man with a body temperature of 43.5°C was admitted in a state of shock. Prior to the development of disseminated intravascular coagulopathy (DIC), a remarkable elevation of serum beta-d-glucan level to 116pg/mL (normal level<6.0pg/mL) was revealed on the first day of admission. However, serum endotoxin was not detected when using a method that excluded beta-d-glucan contamination from endotoxin measurement (normal level<1.0pg/mL). This change of beta-d-glucan level was accompanied by a depressed neutrophil function, especially in phagocytosis of 34% (normal range 70–90%) but not in bacterocidal function (81% versus a normal range of 70–100%). After intensive care including continuous hemodiafiltration, the patient regained consciousness but remained ataxic due to cerebellar infarction, which might have resulted from DIC, and subsequent bilateral fungal oculitis were revealed 45 days after admission. This case report demonstrates the elevation of serum beta-d-glucan but normal endotoxin levels after heatstroke, which may prompt further study to re-examine the serum levels of endotoxin in such catastrophic insults. [Copyright &y& Elsevier]

Abstract Neutrophils are recruited to infection sites and kill bacteria by phagocytosis and reactive oxygen species (ROS) production. It has been reported that vacuoles are present in neutrophils that produce ROS and are present in large numbers in blood smears of patients with bacterial infections. The leukocyte differentiation function on the Sysmex automated hematology analyzer classifies leukocytes by flow cytometry. Particularly, side-scattered light is known to reflect the quantity of organelles. This study investigated the possibility of detecting vacuoles or invagination of cell membrane in neutrophils producing ROS using a hematology analyzer. Whole blood and polymorphonuclear (PMN) cell fractions were activated with phorbol myristate acetate (PMA) or formylmethionylleucylphenylalanine (fMLP) and analyzed using the Sysmex XE-2100 automated hematology analyzer. PMN fractions were morphologically analyzed with a confocal laser scanning microscope (CLSM), electron microscope (EM), and general-purpose conventional flow cytometer. In the white blood cell differentiation scattergram obtained in this analysis, a new cluster separate from the original neutrophil cluster appeared in the eosinophil area in an area of higher side-scattering (SSC) intensity. Flow cytometry analysis of the PMN fractions revealed that the cells in this new cluster were CD16b- and APF-positive, indicating that the cells were activated neutrophils that produced ROS. CLSM and EM findings revealed that ROS production occurred in the cytoplasm and that the activated neutrophils contained some vacuole-like structures of vacuoles or invagination of cell membrane. Vacuole-like S structures were found within the cytoplasm of neutrophils producing ROS. These neutrophils were detected as an independent cluster in the eosinophil area with higher SSC intensity than that shown by neutrophils in the traditional cluster on the white blood cell differentiation scattergram, likely because the vacuole-like structures increased the SSC intensity. Highlights • Neutrophils produce vacuoles in their cytoplasm during ROS production. • Vacuoles increase the side-scattering light intensity of neutrophils in flow cytometry. • Neutrophils producing ROS are detectable using a hematology analyzer. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is recalcitrant to treatment as it is highly metastatic and rapidly progressive. While observing the behavior of human pancreatic BxPC-3 cells using an optical assay device called TAXIScan, we found that several synthetic pyrazole and pyrimidine derivatives inhibited cell migration. One such compound, 14–100 , inhibited metastasis of fluorescence-labeled BxPC-3 cells, which were transplanted into the pancreas of nude mice as a subcutaneously grown cancer fragment. Surprisingly, despite its low cytotoxicity, the compound also showed an inhibitory effect on cancer cell proliferation in vivo, suggesting that the compound alters cancer cell characteristics needed to grow in situ. Single-cell RNA-sequencing revealed changes in gene expression associated with metastasis, angiogenesis, inflammation, and epithelial-mesenchymal transition. These data suggest that the compound 14–100 could be a good drug candidate against pancreatic cancer. [Display omitted] • Synthesized pyrazole compound 14–100 inhibits pancreatic cancer cell growth in vivo. • Angiogenic ability and HSP70 expression is altered by 14–100. • Expression of CXCL8 was downregulated in the 14–100 treated cancer cells. • 14–100 has lower toxicity compared to the approved drug for pancreatic cancer. [ABSTRACT FROM AUTHOR]

As a solid-state membrane with only one-atom thickness, nano-porous graphene has attracted intense attention in many critical applications. Here, the key challenge is to suspend a single-layer graphene (SLG) and drill nanopores with precise dimensions. Here, we report a simple and reliable route for making suspended fluorinated SLG with size-tunable nanopores. Our method consists of two steps: 1. a free-standing SLG ribbon was created between two gold pads after deep dry etching of silicon substrate by xenon difluoride. The SLG was fluorinated by 5–13%. Superior to the normal wet etching method, the dry etching process is much simpler and results in less hole-defect and edge deformation. A large area fluorinated SLG can be suspended due to the sufficient etch depth. 2. a focused ion beam was introduced to drill nanopores in graphene with an initial diameter around 20 nm. Followed by an electron beam induced carbon deposition, the diameter of nanopore was gradually decreased to sub-10 nm. By changing the deposition time, the size of nanopore can be precisely controlled. High-cost transmission electron microscope is no longer needed. Our method provides a simple and effective way for preparing free-standing fluorinated SLG ribbon suitable for single-molecule detection. [ABSTRACT FROM AUTHOR]

Thermoresponsive properties of poly(7-methacryloyloxycoumarin) ( P1a ) and its derivatives as homopolymers containing a photoreactive coumarin unit were systematically investigated. P1a showed a lower critical solution temperature (LCST)-type phase separation in dichloromethane, chloroform, and 1,1,2-trichloroethane. The temperature producing a 50% transmittance ( T c ) of 0.1 wt% P1a in distilled chloroform was 26 °C, while the T c value decreased to 21 °C in deuterated chloroform i.e., the deuterium isotope effect. The T c values in chloroform were adjustable from 28 to 57 °C by the introduction of the ethyleneoxy spacer and the substitution of α-methyl group by hydrogen. While the polymers containing 4-substituted coumarins were soluble in chloroform and dichloromethane from 0 °C to their boiling points. In the distilled chloroform solution, the coumarin units in P1a underwent a [2 + 2] cycloaddition and the transmittance at 500 nm decreased from 98% to 29% at 25 °C by a 180-s photoirradiation (326 mJ/cm 2 , emission band at 365 nm). [ABSTRACT FROM AUTHOR]

The O 4 -benzo[ c ]phenanthridine alkaloids exhibit potent antiproliferative activity against cancer cells, which is derived from their ability to inhibit of topoisomerase I and II. It has been reported that in the alkaloids a cationic quaternary ammonium atom, which results in resonance effects between ring A and B, is necessary for increased antiproliferative activity. These findings indicate the role of their substituents at ring A on inhibition of tumor cell proliferation. In the present study, we systematically assessed the cytotoxic activities of naturally occurring alkaloids and their derivatives containing various ring A substituents against two tumor cell lines, HCT-116 colon tumor cells and HL-60 promyelocytic leukemia cells. Among the cationic iminium alkaloids, which displayed more potent activity than the corresponding neutral derivatives, and the 7,8-oxygenated benzo[ c ]phenanthridine alkaloids, chelerythrine and NK109, exhibited stronger antiproliferative activity than the 8,9- and 9,10-oxygenated alkaloids. The activity of cationic iminium alkaloids could be correlated with the bond lengths of their ring A substituents and the electrostatic potentials of their ammonium molecules by DFT calculation. [ABSTRACT FROM AUTHOR]

Abstract: In this study, a swim-bed reactor was used for partial nitrification treatment of magnesium ammonium phosphate precipitation process treated effluent of methane fermentation digester liquor. Even without temperature, DO, and pH control, the maximum nitrite production rate of 2.66kg NO2–N/m3/d was achieved under a nitrogen loading rate of 5.45kgN/m3/d at 18°C and a nitrite production rate of 0.22kg NO2–N/m3/d was still attained at a nitrogen loading rate of 0.48kgN/m3/d even the operational temperature decreased to 8°C. The average effluent NO2–N/(NO2 +NO3–N) ratio reached 95.4% during the entire experimental period. The mean particle size of suspended sludge increased from 260 to 450μm and the microscopic observation confirmed the formation of dense-flocs. The results indicated that there were two regimes for ammonium oxidation, one at 20–30°C and the other at 10–20°C. Scanning electron microscopic observation and FISH analysis demonstrated that ammonium-oxidizing bacteria were the dominant microorganisms and were considered to be responsible for the satisfactory partial nitrification performance. [Copyright &y& Elsevier]

Abstract: Underground brine waste containing high concentrations of ammonium and with a salinity of 3% is usually generated during the production of methane gas and iodine in the gas field of Chiba Prefecture, Japan. In this study, one swim-bed reactor, packed with a novel acrylic fiber biomass carrier (Biofringe), was applied to the partial nitritation treatment of this kind of underground brine waste. A stable nitrite production rate of 1.6 kg NO2-N m−3 d−1 was obtained under a nitrogen loading rate of 3.0 kg-N m−3 d−1, at a pH of 7.5 and a temperature of 25 °C. Nitrate production was negligible and the effluent NO2-N/NO x -N ratio was above 98% due to the successful inhibition of nitrite-oxidizing bacterial activity. Free ammonia was considered to be the main factor for inhibiting the activity of nitrite-oxidizing bacteria. A microbial community shift was demonstrated by 16S rRNA analysis, and it was shown that the ammonium-oxidizing bacteria became the predominant species after successful nitrite accumulation was observed. [Copyright &y& Elsevier]