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Abstract: Composites based on an elastomer, natural rubber (NR), and pristine multiwalled carbon nanotubes (MWCNTs) were prepared using a two-roll mill mixer. The high shear stress produced a homogeneous dispersion of CNTs in the NR matrix. Using an atomic force microscopy nanomechanical mapping technique, the structure and nanoscale mechanical properties of the resulting composites were investigated in term of CNT loading. Topography, elastic modulus, and adhesive energy distribution maps of the materials were obtained at the same point and at the same time in a single scan. Such maps were used to identify and characterize the CNT, NR, and mechanical interfacial regions formed around the CNTs. The mechanical interfacial regions together with the CNTs divide the elastomer matrix into small “cells”. We claim that the cellular structure is produced in the CNTs/NR composites. [ABSTRACT FROM AUTHOR]

Abstract: Nanocomposite based on an elastomer, natural rubber (NR), and pristine multi-walled carbon nanotubes (MWCNT) was prepared using a two-roll mill mixer. The high shearing stress induced homogeneous dispersion of 5 phr. MWCNTs in NR matrix. A procedure based on combination of Johnson–Kendall–Robert (JKR) contact mechanics and “two-point method” together with AFM force measurements, was successfully used to visualize nanomechanical mapping on the resulting nanocomposites. Topography, elastic modulus, and adhesive energy distribution maps were obtained at the same point and at the same time in a single scan. Such maps were successfully used to identify and characterize CNTs and NR regions in nanocomposites. The intermediate modulus region formed around CNTs was investigated on the quantitative evaluation in real space and demonstrated the existence of interaction between CNTs and NR matrix. [Copyright &y& Elsevier]

Abstract: A new side electron emission device (SEED) was fabricated with carbon nanofiber/aluminum (CNF/Al) composites prepared by the elastomer precursor method. In the SEED, a cross-sectional side face of the CNF/Al composite plate was perpendicularly placed onto an anode surface by inserting an insulating spacer. Above a certain threshold voltage in a vacuum, field electrons were obtained from the side face of the composite emitter. With increasing content of CNFs in the composite, the threshold voltage decreased and emission currents increased. The current of ~8μA was kept stable up to 93h under a continuous application of 1kV. This improved stability as compared to a conventional field emission device was attributed to a reduced damage of CNFs in the SEED structure. [Copyright &y& Elsevier]

Abstract: Following the discovery of JTK-109 (1) as a potent inhibitor of hepatitis C virus NS5B RNA-dependent RNA polymerase, [(a) Hirashima, S.; Suzuki, T.; Ishida, T.; Noji, S.; Yata, S.; Ando, I.; Komatsu, M.; Ikeda, S.; Hashimoto, H. J. Med. Chem. 2006, 49, 4721. (b) Hashimoto, H.; Mizutani, K.; Yoshida, A. Int. Patent Appl. WO 01/47883, 2001.] further studies toward the improvement of the cellular potency have been performed. A greater than 40-fold improvement was achieved through replacing the biphenyl moiety with a 2-morpholinophenyl group and the benzimidazole ring with the tetracyclic scaffold to afford compound 7 with an excellent replicon potency (EC50 =7.6nM). [Copyright &y& Elsevier]

In addition to urocortin (Ucn I), Ucn II and Ucn III were identified as endogenous ligands for corticotropin-releasing factor type 2 receptor (CRF2 receptor). CRF2 receptor is abundantly located in central hypothalamic ventromedial nucleus (VMH) and in peripheral cardiovascular system. In this mini-review, we focused on the roles of these urocortins and CRF2 receptor in the hypothalamus and the cardiovascular system.Ucn II mRNA was increased in the parvocellular part or the magnocellular part of the hypothalamic paraventricular nucleus (PVN) following immobilization stress or 3 days of water deprivation, respectively. Therefore, it is thought that Ucn II may modulate CRF and vasopressin synthesis in the PVN in a paracrine or autocrine fashion through PVN CRF2 receptor.The early and later phases of Ucn I-mediated feeding suppression may be CRF1 and CRF2 receptor-mediated events, respectively. Ucn II decreases food intake at a later phase, beyond 4h post injection. A large dose of corticosterone increased plasma leptin and insulin levels as well as the levels of CRF2 receptor mRNA. Adrenalectomy, starvation, and immobilization each lowered plasma leptin and insulin levels and were associated with decrements in CRF2 receptor mRNA levels in the VMH. Peripheral injection of leptin increased VMH CRF2 receptor mRNA, as can induce reductions of food intake and body weight, indicating that circulating leptin is involved in the regulation of VMH CRF2 receptor mRNA expression. Therefore, it is also plausible that VMH CRF2 receptor transduces the anorexogenic effects of leptin as well as those of urocortins.The systemic administration of Ucn II decreases mean arterial pressure (arterial vascular tone) and causes tachycardia via vascular CRF2 receptor in rats, similar to the effects of Ucn I. Thus, CRF2 receptor seems to mediate cardioprotective effects of urocortins. [Copyright &y& Elsevier]

A side electron emission device was made of a carbon nanofiber/elastomer composite sheet. Instead of a conventional field emission configuration, electron emitters consisting of cross-sectional sides of the composite sheet were put in position perpendicular to the phosphor/anode surface by inserting an insulating spacer. Light emission of 4200 cd/m2 at 1 kV was achieved by intense electron emission from the cross section since the carbon nanofibers preferentially orient parallel to the sheet plane and stick out of the cross section. This simple device structure enabled us to fabricate a flexible, transparent field emission device. [ABSTRACT FROM AUTHOR]

Field-emission characteristics of a carbon nanotube (CNT)/elastomer composite have been investigated. We performed theoretical calculations of the field distribution in a field emission device structure with the side-electron configuration of the composite sheet. According to the calculation results, the electric field is found to be concentrated at the edge of the composite sheet which leads to an enhancement of the local electric field at the CNT tips protruding from the composite. Furthermore, we calculated the trajectories of emitted electrons. From the obtained results, bright luminescence over 37000 cd/m2 from green phosphor was obtained by optimizing the electrode structure. [ABSTRACT FROM AUTHOR]

The article mentions that Cysteinyl leukotrienes (cysLTs), such as LTC4, LTD4, and LTE4, can augment the accumulation of eosinophils in the tissues of asthmatic airways.

Background Eosinophilic esophagitis (EoE) is related to allergic diseases such as bronchial asthma (BA), atopic dermatitis, and allergic rhinitis. The aim of this study was to examine the eosinophil infiltration in the upper gastrointestinal (GI) tract in patients with BA using esophagogastroduodenoscopy. Methods Patients with BA who had upper GI tract symptoms were enrolled. Patients who received systemically administered steroids were excluded. Eosinophil infiltrations in the esophagus, stomach, and duodenum were examined with regard to the endoscopic findings and pathological findings of biopsy specimens (UMIN000010132). Results Ninety patients were enrolled from October in 2012 to September in 2014. Thirty-six were male, 54 were female, and the mean age was 57.5 years. Eighty-one (90%) used inhaled corticosteroids. Fourteen patients (15.6%) had reflux esophagitis, 8 of whom had grade A and 6 had grade B. No patient with EoE was observed. One female patient who had marked eosinophil infiltration in the esophagus, stomach, and duodenum was diagnosed as having eosinophilic gastroenteritis, but endoscopy showed only mucosal edema in the antrum. Another female patient who had marked eosinophil infiltration in the esophagus, stomach, and duodenum was diagnosed as having eosinophilic granulomatosis with polyangiitis, and endoscopy showed erosions in the antrum and the duodenum. Three patients had eosinophil infiltration in the stomach, but none of them had severe symptoms. Conclusions Patients with asthma who had upper gastrointestinal symptoms rarely had eosinophilic gastrointestinal disorders. Biopsy specimens are of high importance in the diagnosis of eosinophilic gastrointestinal disorders even if there is no remarkable endoscopic finding. [ABSTRACT FROM AUTHOR]

Background: Symptoms of rhinitis and asthma can be exacerbated during Japanese cedar pollen (JCP)-scattering season, even in subjects who are not sensitized to JCP, suggesting that innate immune responses may contribute to this process. We previously reported that house dust mite directly activates the effector functions of eosinophils. Similar mechanisms may play roles in the JCP-related aggravation of allergic diseases., Objective: To investigate whether JCP or Cry j 1, a major allergen of JCP, can modify the effector functions of eosinophils., Methods: Eosinophils isolated from the peripheral blood of healthy donors were stimulated with either JCP or Cry j 1, and their adhesion to human intercellular adhesion molecule-1 was measured using eosinophil peroxidase assays. The generation of eosinophil superoxide anion (O 2 - ) was measured based on the superoxide dismutase-inhibitable reduction of cytochrome C. Concentrations of eosinophil-derived neurotoxin in the cell media were measured by enzyme-linked immunosorbent assay as a marker of degranulation., Results: Both JCP and Cry j 1 directly induced eosinophil adhesiveness, generation of O 2 - , and release of eosinophil-derived neurotoxin. Both anti-αM and anti-β2 integrin antibodies blocked all of these eosinophil functions induced by JCP and Cry j 1. Similarly, PAR-2 antagonists also partially suppressed all of these effector functions induced by JCP and Cry j 1., Conclusion: JCP and Cry j 1 directly activate the functions of eosinophils, and both αMβ2 integrin and partly PAR-2 are contributed to this activation. Therefore, JCP-induced eosinophil activation may play a role in the aggravation of allergic airway diseases in nonsensitized patients as well as in JCP-sensitized patients., Competing Interests: Conflict of interest: MN received fees for speaking from Torii Pharmaceutical Co., Ltd. The rest of the authors declare no conflicts of interest., (Copyright © 2021. Asia Pacific Association of Allergy, Asthma and Clinical Immunology.)

Reverse osmosis membranes of aromatic polyamide (PA) reinforced with a crystalline cellulose nanofiber (CNF) were synthesized and their desalination performance was studied. Comparison with plain PA membranes shows that the addition of CNF reduced the matrix mobility resulting in a molecularly stiffer membrane because of the attractive forces between the surface of the CNFs and the PA matrix. Fourier transform-infrared spectroscopy and X-ray photoelectron spectroscopy results showed complex formation between the carboxy groups of the CNF surface and the m- phenylenediamine monomer in the CNF-PA composite. Molecular dynamics simulations showed that the CNF-PA had higher hydrophilicity which was key for the higher water permeability of the synthesized nanocomposite membrane. The CNF-PA reverse osmosis nanocomposite membranes also showed enhanced antifouling performance and improved chlorine resistance. Therefore, CNF shows great potential as a nanoreinforcing material towards the preparation of nanocomposite aromatic PA membranes with longer operation lifetime due to its antifouling and chlorine resistance properties.

Background: Even in subjects who are not sensitized to house dust mite (HDM), allergic symptoms can be clinically aggravated by exposure to dust. We previously reported that Dermatophagoides farinae ( Df ), an important HDM, or Der f 1, a major allergen of Df , induced the effector functions of eosinophils, which may be an important mechanism for HDM-induced symptoms in nonsensitized patients. In a clinical setting, β2-adrenergic agonists, such as salbutamol and formoterol, are used for the treatment of asthma attacks or exacerbation to release the airway obstruction. Several reports have suggested that some β2-adrenergic agonists have an anti-inflammatory capacity., Objective: In this study, we investigated whether β2-adrenergic agonist could modify the Df - or Der f 1-induced activation of eosinophils., Methods: Blood eosinophils obtained from healthy donors were preincubated with either formoterol (1 μM), salbutamol (1 μM), or buffer control and then stimulated with Df extract (1 μg/mL) or Der f 1 (100 pg/mL). Eosinophil adhesion to intercellular adhesion molecule (ICAM)-1 was measured using eosinophil peroxidase assays. Generation of superoxide anion (O 2 - ) was examined based on the superoxide dismutase-inhibitable reduction of cytochrome C. Eosinophil-derived neurotoxin (EDN) concentrations in cell media were measured by enzyme-linked immunosorbent assay., Results: Formoterol, but not salbutamol, suppressed the Df - or Der f 1-induced eosinophil adhesion to ICAM-1. Furthermore, formoterol, but not salbutamol, suppressed Df -induced O 2 - generation or EDN release. Neither formoterol nor salbutamol suppressed spontaneous eosinophil adhesion, O 2 - generation, or EDN release., Conclusion: These findings suggested that formoterol, but not salbutamol, suppressed Df - or Der f 1-induced eosinophil activation when used at the same concentration. Therefore, formoterol could potentially be used for the treatment of bronchial asthma via both bronchodilation and anti-inflammatory effect., Competing Interests: Conflict of Interest: KN received honoraria from AstraZeneca. KOD is employee of Torii Pharmaceutical Co., Ltd. MN received honoraria from AstraZeneca and KYORIN Pharmaceutical Co., Ltd. The other authors have no conflicts of interest., (Copyright © 2020. Asia Pacific Association of Allergy, Asthma and Clinical Immunology.)

Polyamide (PA) membranes comprise most of the reverse osmosis membranes currently used for desalination and water purification. However, their fouling mechanisms with natural organic matter (NOM) is still not completely understood. In this work, we studied three different types of PA membranes: a laboratory made PA, a commercial PA, and a multiwalled carbon nanotube (CNT-PA nanocomposite membrane during cross-flow measurements by NaCl solutions including NOM, humic acid (HA), or alginate, respectively). Molecular dynamic simulations were also used to understand the fouling process of NOM down to its molecular scale. Low molecular weight humic acid binds to the surface cavities on the PA structures that leads to irreversible adsorption induced by the high surface roughness. In addition, the larger alginate molecules show a different mechanism, due to their larger size and their ability to change shape from the globule type to the uncoiled state. Specifically, alginate molecules either bind through Ca 2+ bridges or they uncoil and spread on the surface. This work shows that carbon nanotubes can help to decrease roughness and polymer mobility on the surfaces of the membranes at the molecular scale, which represents a novel method to design antifouling membranes.

Background: Even in subjects who are not sensitized to house dust mite (HDM), allergic symptoms can be aggravated by exposure to dust, suggesting that innate immune responses may be involved in these processes. Since eosinophils express pattern recognition receptors, HDM may directly upregulate eosinophil functions through these re ceptors. The objective of this study was to examine whether Dermatophagoides farinae (Df), a representative HDM, or Der f 1, a major allergen of Df, modifies the effector functions of eosinophils., Methods: Eosinophils isolated from the blood of healthy donors or allergic patients were stimulated with Df extract or Der f 1, and their adhesion to recombinant human intercellular adhesion molecule (ICAM)-1 was measured using eosinophil peroxidase assays. Generation of the eosinophil superoxide anion (O2-) was examined based on the superoxide dismutase-inhibitable reduction of cytochrome C. Eosinophil-derived neurotoxin (EDN) concentrations in cell media were measured by ELISA as a marker of degranulation., Results: Df extract or Der f 1 directly induced eosinophil adhesion to ICAM-1, O2- generation, and EDN release. Anti-αM- or anti-β2-integrin antibodies or protease-activated receptor (PAR)-2 antagonists suppressed the eosinophil adhesion, O2- generation, and EDN release induced by Df extract or Der f 1. Eosinophils from allergic patients showed higher adhesion to ICAM-1 than those from healthy donors., Conclusions: These findings suggested that Df extract and Der f 1 directly activate eosinophil functions through αMβ2-integrin and PAR-2. Eosinophil activation by HDM may play roles in the aggravation of allergic symptoms, not only in HDM-sensitized patients, but also in nonsensitized patients., (© 2019 S. Karger AG, Basel.)

Background: Renal replacement therapy is vital for patients with chronic renal failure. Each type of renal replacement therapy has its own characteristics, and patients select it according on their living environment or conception of quality of life. Under the recent medical environment in Japan, economic burden of dialysis is another concern. For patients with chronic renal failure, the outcome of dialysis is vital. How to prevent or control side effects and complications is also important. One type of dialysis treatment is called peritoneal dialysis. Complications from long-term peritoneal dialysis include encapsulating peritoneal sclerosis (EPS), which can lead to life-threatening intestinal obstruction. Here, we hope to prevent the incidence of EPS through examining new possibilities in the pathogenesis during peritoneal dialysis and considering countermeasures., Summary: Membrane dialysis is a treatment methodology that makes use of the semipermeable function of body membranes. When the composition of the peritoneal dialysate is adjusted, it also removes waste products and adjusts water level. Chemical stimuli of peritoneal dialysate on peritonea can trigger inflammation and, when long-lasting, the latter is considered to cause EPS. For the body, chemical stimuli are invasive. Damaged body tissues have a capacity to repair themselves. The innate immune system is known to work in response to nonspecific stimulation, and so it is well conceivable that it is active in the abdominal cavity under peritoneal dialysis. Among many inflammatory cells involved in the innate immune system, we focus on the role of eosinophils to consider the possibility of unknown pathogenesis. Key Messages: Eosinophilic inflammation may cause EPS., (© 2018 S. Karger AG, Basel.)

We demonstrate efficient antifouling and low protein adhesion of multiwalled carbon nanotubes-polyamide nanocomposite (MWCNT-PA) reverse-osmosis (RO) membranes by combining experimental and theoretical studies using molecular dynamics (MD) simulations. Fluorescein isothiocyanate (FITC)-labeled bovine serum albumin (FITC-BSA) was used for the fouling studies. The fouling was observed in real time by using a crossflow system coupled to a fluorescence microscope. Notably, it was observed that BSA anchoring on the smooth MWCNT-PA membrane was considerably weaker than that of other commercial/laboratory-made plain PA membranes. The permeate flux reduction of the MWCNT-PA nanocomposite membranes by the addition of FITC-BSA was 15% of its original value, whereas those of laboratory-made plain PA and commercial membranes were much larger at 34%-50%. Computational MD simulations indicated that the presence of MWCNT in PA results in weaker interactions between the membrane surface and BSA molecule due to the formation of (i) a stiffer PA structure resulting in lower conformity of the molecular structure against BSA, (ii) a smoother surface morphology, and (iii) an increased hydrophilicity involving the formation of an interfacial water layer. These results are important for the design and development of promising antiorganic fouling RO membranes for water treatment.

In typical kinase inhibitor programs, a hinge binder showing best potency with preferential specificity is initially selected, followed by fine-tuning of the accompanying substituents on its core module. A shortcoming of this approach is that the exclusive focus on a single chemotype can endanger all the analogues in the series if a critical shortcoming is revealed. Thus, an early evaluation of structure-activity relationships (SARs) can mitigate unforeseen outcomes within a series of multiple compounds, although there have been very few examples to follow such a policy. PI4KIIIα is one of four mammalian phosphatidylinositol-4 kinases and has recently drawn significant attention as an emerging target for hepatitis C virus (HCV) treatment. In this letter, a novel "head-to-tail" approach to discover a diverse set of PI4KIIIα inhibitors is reported. We believe this method will generate distinct core scaffolds, a rational strategy to circumvent potential risks in general kinase programs.

In the airways of severe asthmatics, an increase of neutrophils and eosinophils is often observed despite high-dose corticosteroid therapy. We previously reported that interleukin-8-stimulated neutrophils induced trans-basement membrane migration (TBM) of eosinophils, suggesting the link between neutrophils and eosinophils. Concentrations of lipopolysaccharide (LPS) in the airway increase in severe asthma. As neutrophils express Toll-like receptor (TLR)4 and can release chemoattractants for eosinophils, we investigated whether LPS-stimulated neutrophils modify eosinophil TBM. Neutrophils and eosinophils were isolated from peripheral blood of healthy volunteers and severe asthmatics. Eosinophil TBM was examined using a modified Boyden's chamber technique. Eosinophils were added to the upper compartment, and neutrophils and LPS were added to the lower compartment. Migrated eosinophils were measured by eosinophil peroxidase assays. LPS-stimulated neutrophils induced eosinophil TBM (about 10-fold increase), although LPS or neutrophils alone did not. A leukotriene B 4 receptor antagonist, a platelet-activating factor receptor antagonist or an anti-TLR4 antibody decreased eosinophil TBM enhanced by LPS-stimulated neutrophils by almost half. Neutrophils from severe asthmatics induced eosinophil TBM and lower concentrations of LPS augmented neutrophil-induced eosinophil TBM. These results suggest that the combination of neutrophils and LPS leads eosinophils to accumulate in the airways, possibly involved the pathogenesis of severe asthma., Competing Interests: Conflicts of Interest: None declared.

Carbon nanotubes/polyamide (PA) nanocomposite thin films have become very attractive as reverse osmosis (RO) membranes. In this work, we used molecular dynamics to simulate the influence of single walled carbon nanotubes (SWCNTs) in the polyamide molecular structure as a model case of a carbon nanotubes/polyamide nanocomposite RO membrane. It was found that the addition of SWCNTs decreases the pore size of the composite membrane and increases the Na and Cl ion rejection. Analysis of the radial distribution function of water confined in the pores of the membranes shows that SWCNT+PA nanocomposite membranes also exhibit smaller clusters of water molecules within the membrane, thus suggesting a dense membrane structure (SWCNT+PA composite membranes were 3.9% denser than bare PA). The results provide new insights into the fabrication of novel membranes reinforced with tubular structures for enhanced desalination performance.

Background: The serum level of carcinoembryonic antigen (CEA) is a marker of malignant disease but can also be increased in benign diseases. Patients with allergic bronchopulmonary aspergillosis (ABPA) have bronchial asthma showing a wide variety of radiological findings. We measured serum CEA levels in patients with ABPA and evaluated the relationships of serum CEA levels with peripheral blood eosinophil counts, total blood levels of immunoglobin (Ig) E, and findings of computed tomography (CT) in ABPA., Methods: The subjects were 13 patients (6 men and 7 women aged 34 to 76 years) who had been treated for ABPA at our hospital. Serum levels of CEA, peripheral blood eosinophil counts, total blood IgE levels, and CT findings were examined before and after treatment with prednisolone., Results: Before the start of the treatment 7 of 13 patients had serum CEA levels higher than the upper limit of normal. The serum CEA level was not correlated with eosinophil counts or total IgE values. Serum CEA levels were examined after treatment in 9 patients and were found to have significantly decreased as pulmonary consolidation improved. Furthermore, serum CEA levels before treatment in patients with pulmonary consolidation were significantly higher than those in patients without consolidation., Conclusion: Serum CEA levels are elevated in some patients with ABPA; these elevations might be associated with consolidation in the lung. Elevated serum CEA levels decrease as the consolidation decreases after treatment. The elevation of serum CEA might be attributed to the presence of local inflammation in the lung.

JTK-853, a palm site-binding NS5B nonnucleoside polymerase inhibitor, shows antiviral activity in vitro and in hepatitis C virus (HCV)-infected patients. Here, we report the results of genotypic and phenotypic analyses of resistant variants in 24 HCV genotype 1-infected patients who received JTK-853 (800, 1,200, or 1,600 mg twice daily or 1,200 mg three times daily) in a 3-day monotherapy. Viral resistance in NS5B was investigated using HCV RNA isolated from serum specimens from the patients. At the end of treatment (EOT) with JTK-853, the amino acid substitutions M414T (methionine [M] in position 414 at baseline was replaced with threonine [T] at EOT), C445R (cysteine [C] in position 445 at baseline was replaced with arginine [R] at EOT), Y448C/H (tyrosine [Y] in position 448 at baseline was replaced with cysteine [C] or histidine [H] at EOT), and L466F (leucine [L] in position 466 at baseline was replaced with phenylalanine [F] at EOT), which are known to be typical resistant variants of nonnucleoside polymerase inhibitors, were observed in a clonal sequencing analysis. These substitutions were also selected by a treatment with JTK-853 in vitro, and the 50% effective concentration of JTK-853 in the M414T-, C445F-, Y448H-, and L466V-harboring replicons attenuated the susceptibility by 44-, 5-, 6-, and 21-fold, respectively, compared with that in the wild-type replicon (Con1). These findings suggest that amino acid substitutions of M414T, C445R, Y448C/H, and L466F are thought to be viral resistance mutations in HCV-infected patients receiving JTK-853 in a 3-day monotherapy.

JTK-853 is a novel piperazine derivative nonnucleoside inhibitor of hepatitis C virus (HCV) RNA-dependent RNA polymerase. JTK-853 showed potent inhibitory activity against genotype 1 HCV polymerase, with a 50% inhibitory concentration in the nanomolar range, and showed potent antiviral activity against the genotype 1b replicon, with a 50% effective concentration of 0.035 μM. The presence of human serum at up to 40% had little effect on the antiviral activity of JTK-853. Structure analysis of HCV polymerase with JTK-853 revealed that JTK-853 associates with the palm site and β-hairpin region of HCV polymerase, and JTK-853 showed decreased antiviral activity against HCV replicons bearing the resistance mutations C316Y, M414T, Y452H, and L466V in the palm site region of HCV polymerase. JTK-853 showed an additive combination effect with other DAAs (direct antiviral agents), such as nucleoside polymerase inhibitor, thumb pocket-binding nonnucleoside polymerase inhibitor, NS5A inhibitor, and protease inhibitor. Collectively, these data demonstrate that JTK-853 is a potent and novel nonnucleoside palm site-binding HCV polymerase inhibitor, suggesting JTK-853 as a potentially useful agent in combination with other DAAs for treatment of HCV infections.

High-performance sealants using rubber composites containing multiwalled carbon nanotubes (MWNTs) were developed in order to probe and excavate oil in deeper wells. However, the stress-strain behavior and the reinforcing mechanism of highly concentrated MWNT/rubber composites subjected to large deformation remain largely unexplored. Here we report on the complete stress-strain relationships of MWNT/rubber composites under uniaxial tension before rupture, with a suggestion of a novel reinforcement effect of high concentration of MWNTs. A theoretical model is developed to understand the reinforcing mechanism and estimate the mechanical properties of MWNT/rubber composites under large deformation. We have demonstrated that persistence length and reorientation of MWNTs during stretch have a significant impact on mechanical properties, such as the modulus of the rubber composite. These results provide guidelines for developing MWNT-reinforced composites to achieve desired nonlinear and extreme mechanical performance for a wide range of applications.

Interfacial shear strengths or static frictions between carbon nanotubes (CNT) in contact at different cross angles are studied by using atomic mechanics. It is shown that the axial interfacial shear strengths between parallel CNTs in commensurate are two orders of magnitude greater than those in incommensurate. This strong chiral dependence is not surprising and is similar to that of the friction between two graphite basal planes. In contrast, we find that the interfacial shear strengths of crossly contacted CNT pairs are much less dependent upon chirality. The estimated values of interfacial shear strengths, ranging from 0.05 to 0.35 GPa, agree very well with experimentally measured results available in the literature. These results may thus be used as a basis for explaining the observed tension strengths of CNT bundles and films that are mainly bonded by van der Waals interactions and the mechanical behaviors of composite materials with highly concentrated CNTs.

Adiponectin (AdN), an adipokine derived from the adipose tissue, has an insulin-sensitizing effect, and plasma AdN is shown to be decreased in obesity and/or insulin resistant state. To clarify whether changes in AdN are also responsible for the development of glucocorticoid-induced insulin resistance, we examined AdN concentration in plasma and AdN expression in the adipose tissue, using corticotropin-releasing hormone (CRH) transgenic mouse (CRH-Tg), an animal model of Cushing syndrome. We found, unexpectedly, that plasma AdN levels in CRHTg were significantly higher than those in wild-type littermates (wild-type: 19.7+/-2.5, CRH-Tg: 32.4+/-3.1 microg/mL, p<0.01). On the other hand, AdN mRNA and protein levels were significantly decreased in the adipose tissue of CRH-Tg. Bilateral adrenalectomy in CRH-Tg eliminated both their Cushing's phenotype and their increase in plasma AdN levels (wild-type/sham: 9.4+/-0.5, CRH-Tg/sham: 15.7+/-2.0, CRH-Tg/ADX: 8.5+/-0.4 microg/mL). These results strongly suggest that AdN is not a major factor responsible for the development of insulin resistance in Cushing syndrome. Our data also suggest that glucocorticoid increases plasma AdN levels but decreases AdN expression in adipocytes, the latter being explained possibly by the decrease in AdN metabolism in the Cushing state.

We report a new series of hepatitis C virus NS5B RNA polymerase inhibitors containing a conformationally constrained tetracyclic scaffold. SAR studies led to the identification of 6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indoles (19 and 20) bearing a basic pendent group with high biochemical and cellular potencies. These compounds displayed a very small shift in cellular potency when the replicon assay was performed in the presence of human serum albumin.

Interleukin (IL)-12 is a key factor in cell-mediated immunity that drives the development of Th1 cells and stimulates T lymphocytes and natural killer cells to produce interferon (INF)-gamma. The IL-12B gene, which encodes the p40 subunit of IL-12, is located at chromosome 5q31-33 and a linkage finding for autoimmune thyroid disease (AITD) on 5q31-33 in a Japanese population has been reported. It is also reported that the A/C polymorphism in the 3' untranslated region (UTR) of the IL-12B gene (1188A/C) is associated with IL12B mRNA expression levels. We attempted to determine whether genetic polymorphisms of the IL-12B gene are associated with AITD. One hundred three patients with Hashimoto's thyroiditis, 90 patients with Graves' disease, and 123 healthy control subjects were recruited. We detected the 1188A/C polymorphism using a PCR-RFLP method and the A/T polymorphism in intron 4 of the IL-12B gene using a cycle sequencing method. These IL-12B gene polymorphisms showed strong linkage disequilibrium, and their genotype and allele frequencies in the patients did not differ from those in the control subjects. Our results suggest that IL-12B gene polymorphisms were unlikely to have an effect on the development of Hashimoto's thyroiditis or Graves' disease in Japanese patients.