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• Mesenchymal stem cell therapy is a promising option to treat pulmonary hypertension. • However, preclinical evidence on safety and efficacy remains insufficient. • Further preclinical data using a clinically-relevant model should be accumulated. Pulmonary arterial hypertension (PAH) is a disease characterized by progressive pulmonary vascular remodeling, resulting in right-sided heart failure and premature death. Current available therapies for PAH have limited efficacy, and new therapeutic strategies need to be developed. Mesenchymal stem/stromal cells (MSCs) may offer a novel therapeutic approach to PAH. Since the first report in 2006, a number of preclinical studies have demonstrated a potential therapeutic effect of this approach, with attenuated hemodynamic and histological progression of PAH, in animal models of PAH. However, there remain several issues that should be addressed for this approach to be clinically successful. With the aim to highlight such issues, this review clarifies existing knowledge on MSC therapy for PAH in preclinical studies, including types of PAH animal models used for MSC therapy, MSC sources, and administration protocol (route, cell dose, and timing of administration). This review thereafter summarizes thoroughly and discusses the mechanism underpinning MSC therapy for PAH. For clinical success of MSC therapy, insufficient evidence of safety (e.g. critical risk of pulmonary embolism) and therapeutic efficacy of MSCs on established PAH with severe vascular remodeling, as well as further optimization of the MSC administration protocol, are considered as remaining issues to be addressed. In terms of the efficacy, it is controversial whether angiogenic cytokines, which are considered as one of the therapeutic mechanisms of MSC, have beneficial effect for human PAH. To address these issues, further preclinical data using more clinically-relevant animal models of PAH, such as SU5416 model, should be accumulated, whereas most preclinical studies have been conducted using monocrotaline-induced PAH model. While MSC therapy has a great potential to become a novel therapy in PAH, continuing careful preclinical research is warranted for clinical success in PAH. [ABSTRACT FROM AUTHOR]

The development of molecular aggregation structures during stretching deformation and local structure mapping around a crack tip of a segmented polyurethane elastomer film were investigated by in situ simultaneous small-angle X-ray scattering (SAXS) and wide-angle X-ray diffraction (WAXD) and by micro-beam WAXD, respectively. Both the hard segment (HS) domain orientation and the strain-induced crystallization of poly(ε-caprolactone) chains were tracked by the WAXD pattern due to the high crystallinity of the symmetric non-bulky aliphatic HS structure. Strain-induced crystallization occurred locally at the vicinity of the crack tip, and the crystallinity immediately decayed in the exterior, whereas the HS domain orientation was observed throughout the stretched film. The mechanisms underlying crack arrest and the mechanical strength of polyurethane elastomer films are associated with the local strain-induced crystallization at the crack tip, the mechanical stability of the HS domains, and the avoidance of local stress concentration through the HS domain orientation. [ABSTRACT FROM AUTHOR]

Clopidogrel (Plavix ® , Sanofi-Aventis), the adenosine diphosphate P2Y 12 receptor antagonist, is reported to be effective in the prevention of cardiovascular events and is often used in combination with aspirin, particularly in high-risk patients. ASP6537 is a reversible cyclooxygenase (COX)-1 inhibitor that is under investigation as an anti-platelet agent. First, we investigated the reversibility of the antiplatelet effect of ASP6537 and its interaction with ibuprofen to compare the usability of ASP6537 with that of aspirin. We then evaluated the antithrombotic effect of ASP6537 in combination with clopidogrel using a FeCl 3 -induced thrombosis model in guinea pigs. ASP6537 exerted reversible antiplatelet activity, and no pharmacodynamic interaction with ibuprofen was noted. When administered as monotherapy, ASP6537 exerted a significant antithrombotic effect at ≥3 mg/kg, while aspirin inhibited thrombosis at 100 mg/kg. ASP6537 exerted significant additive effects in combination with clopidogrel, and the minimum antithrombotic dose was reduced by concomitant administration of clopidogrel. Our study showed that ASP6537 did not interact with ibuprofen and has clear additive effects in combination with clopidogrel. ASP6537 may therefore represent a promising antiplatelet agent for use in clinical settings in combination with clopidogrel. [ABSTRACT FROM AUTHOR]

Summary A surface marker that distinctly identifies cardiac progenitors (CPs) is essential for the robust isolation of these cells, circumventing the necessity of genetic modification. Here, we demonstrate that a Glycosylphosphatidylinositol-anchor containing neurotrophic factor receptor, Glial cell line-derived neurotrophic factor receptor alpha 2 ( Gfra2 ), specifically marks CPs. GFRA2 expression facilitates the isolation of CPs by fluorescence activated cell sorting from differentiating mouse and human pluripotent stem cells. Gfra2 mutants reveal an important role for GFRA2 in cardiomyocyte differentiation and development both in vitro and in vivo. Mechanistically, the cardiac GFRA2 signaling pathway is distinct from the canonical pathway dependent on the RET tyrosine kinase and its established ligands. Collectively, our findings establish a platform for investigating the biology of CPs as a foundation for future development of CP transplantation for treating heart failure. [ABSTRACT FROM AUTHOR]

The molecular aggregation structure evolution during uniaxial stretching deformation and the uniaxial tensile mechanical properties for an environmentally benign and biodegradable segmented poly(urethane-urea) (SPUU) elastomer based on an α-amino acid lysine-based diisocyanate (LDI) was investigated. The performance was compared with a conventional SPUU elastomer consisting of a symmetric aliphatic short chain diisocyanate (1,4-butane diisocyanate). Both SPUUs contain a 1,4-butanediamine chain extender and poly(ε-caprolactone) soft segments. The evolution of molecular aggregation structure during stretching was monitored using in-situ simultaneous small-angle X-ray scattering and wide-angle X-ray diffraction. The LDI-based SPUU film contains weakly aggregated, disordered hard segment domains that readily dissociate upon mechanical deformation. The permanent deformation through fragmentation of the hard segment domains and strain-induced crystallization are associated with the low strength and large hysteresis loss of the LDI-based SPUU. [ABSTRACT FROM AUTHOR]

The yeast strain, Cryptococcus flavus GB-1, isolated from rice husks as a candidate producer of a biodegradable plastic (BP)-degrading enzyme. The genomic DNA sequence encoding the BP-degrading enzyme of GB-1 was determined. The enzyme was named CfCLE because the deduced amino acid sequence (239 amino acids) was found to be 93% identical to that of CLE of Cryptococcus sp. S-2 (accession No. BAK82405.1 ). The strain GB-1 forms a clear zone (halo) around its colonies on emulsified polybutylene succinate- co -adipate (PBSA) agar plates containing soybean oil but not on plates containing glucose. A UV-induced mutant from this strain, designated as GB-1-DMC1, formed halos on emulsified PBSA plates containing glucose and showed 1.53 U/ml of PBSA-degrading activity in liquid culture with glucose, which was more than 2.5-fold higher than that of the parent strain GB-1 (0.58 U/ml). Moreover, using xylose as a carbon source enhanced the PBSA-degrading activity of both strains. Xylose fed-batch cultivation of GB-1 and GB-1-DMC1 using a 5-l jar fermentor for 72 h produced 12.1 and 21.2 U/ml of CfCLE, respectively. Purified CfCLE has a molecular mass of 22 kDa, and its optimal pH and temperature for enzyme activity is 7.8 and 45 °C, respectively. CfCLE degraded various BP cast films. [ABSTRACT FROM AUTHOR]

Abstract: The conductivity and elastic modulus of (CeO2)1− x (YO1.5) x for x values of 0.10, 0.15, 0.20, 0.30, and 0.40 were investigated by experiments and molecular dynamics simulations. The calculated conductivity exhibited a maximum value at approximately 15 mol% Y2O3; this trend agreed with that of the experimental results. In order to clarify the reason for the occurrence of the maximum conductivity, the paths for the transfer of oxygen vacancies were counted. The numerical result revealed that as the content of Y2O3 dopant increases, the number of paths for the transfer of oxygen vacancies decreases, whereas the number of oxygen vacancies for conductivity increases. Thus, the trade-off between the increase in the number of vacancy sites and the decrease in the vacancy transfer was considered to be the reason for the maximum conductivity occurring at the Y2O3 dopant content of approximately 15 mol%. The calculated elastic modulus also exhibited a minimum value at approximately 20 mol% Y2O3, which also agreed with the experimental results. It was shown that the Y–O–Y bonding energy increased with the increasing content of Y2O3 dopant. Thus, the trade-off between the increase in the number of vacancy sites and that in the Y–O–Y bonding energy was considered to be the reason for the minimum elastic modulus occurring at the Y2O3 dopant content of approximately 20 mol%. [Copyright &y& Elsevier]

Abstract: The initiation of stress corrosion cracking in fcc Fe–Cr–Ni ternary alloys was studied by means of quantum chemical molecular dynamics at 288°C. This study showed that the iron and chromium atoms segregate faster than nickel atoms at the surfaces. The atomic model showed that nickel enrichment occurred at the inner oxide layer. The binding energy helps reduce the mobility of the nickel atoms. The surface morphology showed that Fe, Cr, and O accumulate on the very top surface while Fe, Cr, Ni, and O bonding takes place beneath this revealing the formation of an outer and inner oxide film. The diffusion of oxygen and hydrogen into the surface increases when it is under strain. The deeply diffused hydrogen becomes negatively charged by taking electron from metal atoms. Consequently, the process weakens the metallic bonds following with the result that oxygen can diffuse easily into the surface. It seems that hydrogen effectively functions as an oxygen carrier. This kind of reaction process can take place in the molecular domain of a crack tip and thus play a vital role in initiating the SCC process. [Copyright &y& Elsevier]

Objective: AKR-501 (YM477) is an orally active thrombopoietin (TPO) receptor agonist that mimics the biological effect of TPO in vitro and in vivo. Here, we report that AKR-501 in combination with TPO has additive effect on megakaryocytopoiesis. Materials and Methods: Granulocyte colony-stimulating factor–mobilized human peripheral blood CD34+ cells were cultured with AKR-501, TPO, or a combination of the two in serum-free liquid culture system. The numbers of hematopoietic progenitor cells, megakaryocytic progenitor cells, and megakaryocytes were measured using flow cytometry. Further, the effect of AKR-501 on TPO binding to TPO receptor was examined. Results: Both AKR-501 and TPO alone increased the number of megakaryocytes, and the maximum activities of AKR-501 and TPO were similar. Interestingly, in the presence of TPO concentrations producing maximal stimulation, the addition of AKR-501 increased the number of megakaryocytes to about 200% of that generated with TPO only. In the time course experiment, the combination of AKR-501 and TPO augmented the numbers of hematopoietic progenitor cells and colony-forming unit in culture in the early stages. Thus, the combination of AKR-501 and TPO enhanced not only the differentiation into megakaryocytes, but also the expansion of human hematopoietic progenitor cells. Further, AKR-501 did not inhibit TPO binding to the TPO receptor. This result indicated the possibility that AKR-501 and TPO may act simultaneously on the TPO receptor, and this could be responsible for their additive effect of on megakaryocytopoiesis. Conclusions: This study suggests that AKR-501 would be useful for the treatment of thrombocytopenia even at high plasma levels of endogenous TPO following chemotherapy. [Copyright &y& Elsevier]

Abstract: Quantum chemical molecular dynamics simulation was applied to study the oxidation of bare Fe (111) and Fe–Cr (111) surfaces with strain in high temperature water. Simulation results implied the surface morphologies differ from Fe to Fe–Cr because of strong bond between oxygen and chromium atoms. Oxygen atoms were trapped around chromium atoms at Fe–Cr surface, whereas oxygen penetrated into the lattice of Fe bare surface. As a result, the oxygen diffusivity into the Fe–Cr crystal surface reduced. It indicated that the preferential oxidation of chromium would take place on Fe–Cr clean surface at the beginning of the oxidation process. Diffusion of hydrogen and oxygen significantly increased when strain applied to the defective surface. Hydrogen atoms being in the lattice of metal possessed the highly negative charge which indicated the surface oxidized by this negative charge H. Negative charged oxygen atoms make bond with the metallic atom which breakage ultimate metal–metal bond. These bond breakages indicated the formation of oxide layer on the surface and play a key role in subsequent localized corrosion nucleation like stress corrosion cracking. [Copyright &y& Elsevier]

Abstract: Glycoside-hydrolase-family 9 (GHF9) cellulases are known to be widely distributed in metazoa. These enzymes have been appreciably well investigated in protostome invertebrates such as arthropods, nematodes, and mollusks but have not been characterized in deuterostome invertebrates such as sea squirts and sea urchins. In the present study, we isolated the cellulase from the Japanese purple sea urchin Strongylocentrotus nudus and determined its enzymatic properties and primary structure. The sea urchin enzyme was extracted from the acetone-dried powder of digestive tract of S. nudus and purified by conventional chromatographies. The purified enzyme, which we named SnEG54, showed a molecular mass of 54kDa on SDS–PAGE and exhibited high hydrolytic activity toward carboxymethyl cellulose with an optimum temperature and pH at 35°C and 6.5, respectively. SnEG54 degraded cellulose polymer and cellooligosaccharides larger than cellotriose producing cellotriose and cellobiose but not these small cellooligosaccharides. From a cDNA library of the digestive tract we cloned 1822-bp cDNA encoding the amino-acid sequence of 444 residues of SnEG54. This sequence showed 50–57% identity with the sequences of GHF9 cellulases from abalone, sea squirt, and termite. The amino-acid residues crucial for the catalytic action of GHF9 cellulases are completely conserved in the SnEG54 sequence. An 8-kbp structural gene fragment encoding SnEG54 was amplified by PCR from chromosomal DNA of S. nudus. The positions of five introns are consistent with those in other animal GHF9 cellulase genes. Thus, we confirmed that the sea urchin produces an active GHF9 cellulase closely related to other animal cellulases. [Copyright &y& Elsevier]