Synthesis and in vitro and in vivo Antifungal Activity of the Hydroxy Metabolites of Saperconazole

Herein we describe the scalable diastereoselective and enantioselective syntheses of eight enantiomers of hydroxy metabolites of saperconazole. The in vitro antifungal activity of the eight stereoisomers (compounds 1 – 8 ) was compared against a broad panel of Candida spp. (n=93), Aspergillus spp. (n=10), Cryptococcus spp. (n=19), and dermatophytes (n=27). The four 2S isomers 1 – 4 of the new agent were generally slightly more active than the four 2R isomers 5 – 8 . All eight isomers were tested in a model of experimental A. fumigatus infection in guinea pigs by intravenous inoculation of the fungal conidia. Treatment doses were 1.25 mg kg^?1 and 2.5 mg kg^?1 per day. Infection severity was measured in terms of mean survival time (MST) after infection and mean tissue burdens in brain, liver, spleen, and kidney at postmortem examination. Among the eight isomers, the 2S diastereomers 1 – 4 showed a generally higher level of activity than the 2R diastereomers 5 – 8 , revealing compounds 1 and 4 as the most potent overall in eradicating tissue burden and MST. Compared with reference compounds itraconazole and saperconazole, the hydroxy isomers 1 – 8 are less potent inhibitors of the growth of A. fumigatus in vitro and of ergosterol biosynthesis in both A. fumigatus and C. albicans.     

Synthesis,Microstructure, and Mechanical Properties of Ti3Sn(1−x)AlxC2 MAX Phase Solid Solutions

Ti₃Sn_(1−x)Al_xC₂ MAX phase solid solutions are successfully synthesized from different reactant mixtures. Rietveld refinement allows to carefully characterize their structures and the ocathedra and trigonal prims distortion parameters as a function of the Al content. Mechanical properties of solid solutions are studied from nanoindentation experiments and dynamic resonant method. It is shown that solid solution hardening is not operative in this system. Elastic modulus is found to increase from Ti₃SnC₂ to Ti₃AlC₂, and such a result is discussed in terms of Ti–A bond stiffness.     

Bio-Sourced Poly l-Lactide-Flax Composites with Close to Maximum Stiffness at Low Fiber Content through Two-Stage Annealing

Poly l -Lactide (PLLA) composites with short flax fibers (from 0 to 10 wt/wt%) with close to maximum theoretical stiffness are prepared by melt-compounding and injection-molding followed by a two-step isothermal crystallization protocol that fully separates the nucleation and growth stages (Tammann). The use of fast chip scanning calorimetry for thermal characterization avoids the complicating issues of crystal reorganization during the cooling and heating steps between the isothermal stages. Flax fibers are very efficient and selective nucleating agents of PLLA favoring the ordered α form. The resulting morphology exhibits trans-crystallization on the fibers surface, predominantly at fiber defects, with a clear reduction of crystal size and a very strong fiber matrix cohesion. Efficient nucleation further leads to a large reduction of the overall crystallization time. Avrami analysis evidences a reduction of crystal growth dimensionality, consistent with both optical and scanning electron microscopy. The high modulus of the composites is unambiguously related to the strong orientation of the fibers in the tensile direction, to their high aspect ratio and to the excellent matrix-fibers cohesion. On the other hand, the tensile strength and hardness appear isotropic within experimental uncertainty and are unfavorably influenced by the presence of the fibers and by the two-stage annealing.     

Cultivation of Head and Neck Squamous Cell Carcinoma Cells with Wound Fluid Leads to Cisplatin Resistance via Epithelial-Mesenchymal Transition Induction

Locoregional recurrence is a major reason for therapy failure after surgical resection of head and neck squamous cell carcinoma (HNSCC). The physiological process of postoperative wound healing could potentially support the proliferation of remaining tumor cells. The aim of this study was to evaluate the influence of wound fluid (WF) on the cell cycle distribution and a potential induction of epithelial-mesenchymal transition (EMT). To verify this hypothesis, we incubated FaDu and HLaC78 cells with postoperative WF from patients after neck dissection. Cell viability in dependence of WF concentration and cisplatin was measured by flow cytometry. Cell cycle analysis was performed by flow cytometry and EMT-marker expression by rtPCR. WF showed high concentrations of interleukin (IL)-6, IL-8, IL-10, CCL2, MCP-1, EGF, angiogenin, and leptin. The cultivation of tumor cells with WF resulted in a significant increase in cell proliferation without affecting the cell cycle. In addition, there was a significant enhancement of the mesenchymal markers Snail 2 and vimentin, while the expression of the epithelial marker E-cadherin was significantly decreased. After cisplatin treatment, tumor cells incubated with WF showed a significantly higher resistance compared with the control group. The effect of cisplatin-resistance was dependent on the WF concentration. In summary, proinflammatory cytokines are predominantly found in WF. Furthermore, the results suggest that EMT can be induced by WF, which could be a possible mechanism for cisplatin resistance.     

Skeletal Ryanodine Receptors Are Involved in Impaired Myogenic Differentiation in Duchenne Muscular Dystrophy Patients

Duchenne muscular dystrophy (DMD) is characterized by progressive muscle wasting following repeated muscle damage and inadequate regeneration. Impaired myogenesis and differentiation play a major role in DMD as well as intracellular calcium (Ca²⁺) mishandling. Ca²⁺ release from the sarcoplasmic reticulum is mostly mediated by the type 1 ryanodine receptor (RYR1) that is required for skeletal muscle differentiation in animals. The study objective was to determine whether altered RYR1-mediated Ca²⁺ release contributes to myogenic differentiation impairment in DMD patients. The comparison of primary cultured myoblasts from six boys with DMD and five healthy controls highlighted delayed myoblast differentiation in DMD. Silencing RYR1 expression using specific si-RNA in a healthy control induced a similar delayed differentiation. In DMD myotubes, resting intracellular Ca²⁺ concentration was increased, but RYR1-mediated Ca²⁺ release was not changed compared with control myotubes. Incubation with the RYR-calstabin interaction stabilizer S107 decreased resting Ca²⁺ concentration in DMD myotubes to control values and improved calstabin1 binding to the RYR1 complex. S107 also improved myogenic differentiation in DMD. Furthermore, intracellular Ca²⁺ concentration was correlated with endomysial fibrosis, which is the only myopathologic parameter associated with poor motor outcome in patients with DMD. This suggested a potential relationship between RYR1 dysfunction and motor impairment. Our study highlights RYR1-mediated Ca²⁺ leakage in human DMD myotubes and its key role in myogenic differentiation impairment. RYR1 stabilization may be an interesting adjunctive therapeutic strategy in DMD.     

Thermodynamic investigation of the solid and liquid Au---Sb alloys

The heat content of solid and liquid AuSb₂ compound was measured from 298 K to T (375–963 K) on heating (drop method) with the help of a Tian-Calvet calorimeter. The heat capacity of the liquid compound as well as its enthalpy of fusion were deduced. The enthalpy of the liquid decreases strongly when temperature increases between the melting point and 831 K.

The enthalpy of formation of the Au---Sb melts was also determined by direct reaction calorimetry at 916 K with respect to concentration. The enthalpy of mixing is weakly negative in the whole range of concentration (_min^f = −3·47 kJ/mol at x_Au = 0·775) in agreement with the results of Béja at 923 K. disagree with the much more negative earlier data of Kameda et al. and of Hino et al. by emf and vapor pressure measurements.

Finally, the liquid/Au(cr) phase boundary determined at 916 K from the break in the h^f (x_Au) curve agrees well with the phase diagram calculated by Okamoto and Massalski but not with their experimental results.     

Minimization of Copper Losses in Copper Smelting Slag During Electric Furnace Treatment

In the quest to achieve the highest metal recovery during the smelting of copper concentrates, this study has evaluated the minimum level of soluble copper in iron-silicate slags. The experimental work was performed under slag-cleaning conditions for different levels of Fe in the matte and for a range of Fe/SiO₂ ratios in the slag. All experiments were carried out under conditions where three phases were present (copper?Cmatte?Cslag), which is the condition typically prevailing in many slag-cleaning electric furnaces. The %Fe in the electric furnace matte was varied between 0.5?wt.% and 11?wt.%, and two different Fe/SiO₂ ratios in the slag were used (targeted values were 1.4 and 1.6). All experiments were performed at 1200°C. From thermodynamic considerations, from industrial experience, and from the results obtained in this study, the minimum soluble copper content in the electric furnace slag is expected to be near 0.55?wt.% Cu. This level does not account for a portion of the copper present as mechanically entrained matte/metal droplets. Taking this into account, the current authors believe an overall copper level in discard slag between 0.7?wt.% and 0.8?wt.% can be obtained with optimal operating conditions. For these conditions, the copper losses in the slag are roughly 75% as dissolved copper and 25% as entrained matte and copper. Such conditions include operating the electric furnace at metallic copper saturation, maintaining the %Fe in the electric furnace matte between 6?wt.% and 9?wt.%, not exceeding a slag temperature of 1250°C, and controlling the Fe/SiO₂ ratio in the smelting furnace slag at ??1.5. In addition, magnetite reduction needs to be performed efficiently during the slag-cleaning cycle so as to maintain a total magnetite content of ??7?wt.% in the discard slag. The authors further consider that under exceptionally well-controlled conditions, a copper content in electric furnace discard slag between 0.55?wt.% and 0.7?wt.% can be obtained, by minimizing entrained matte and copper solubility in the discard slag.     

Frequency Dependence of the Soil Electromagnetic Properties Derived from Ground-Penetrating Radar Signal Inversion

The accuracy at which the subsurface electromagnetic properties can be identified from full wave inversion of ground penetrating radar (GPR) signals relies on the appropriateness of the model describing their frequency dependence. In this paper, we focus on the characterization of the frequency dependence of the dielectric permittivity and electric conductivity of a sandy soil subject to different water contents from inversion of GPR measurements. Based on previous studies of Lambot et al. the methodology relies on an ultrawide band (UWB) stepped-frequency continuous-wave (SFCW) radar combined with an off-ground monostatic transverse electromagnetic (TEM) horn antenna. Forward modeling of the radar signal is based on linear system transfer functions for describing the antenna, and on the exact solution of Maxwells equations for wave propagation in a horizontally multilayered medium representing the subsurface. Model inversion, formulated by the classical least-squares problem, is carried out iteratively using advanced global optimization techniques. The frequency dependence of the electromagnetic properties of the sandy soil is characterized by performing inversions of the radar signal in different and subsequent limited frequency bands, in which the electromagnetic parameters are assumed to be constant. We observed that over the entire frequency band considered in this study (1–3 GHz), the dielectric permittivity of the sand remains constant with frequency, whatever the water content is. In contrast, the electric conductivity increases significantly from 1GHz to 3 GHz, and this effect increases with water content. The frequency dependence of the electric conductivity may be adequately described using a simple linear relationship. This approach is advantageous since it limits the number of parameters to be optimized in the inverse modeling procedure.     

Design and function of novel superplasticizers for more durable high performance concrete (superplast project)

In this article we shall describe our quest and ultimate success in furthering our understanding of the action of superplasticizers on the rheology of cement and concrete. By specifically producing superplasticizers with varied architectures, we have been able to show the important structural features of the macromolecules that lead to a successful superplasticizer or water reducing agent. Both polycarboxylate and lignosulfonate polymers have been investigated. Using both non-reactive model MgO powders, three different types of cement blends, the adsorption behaviour and the effect on the rheological properties of these two important superplasticizer families have been used to further develop a conceptual model for superplasticizer — cement behaviour. This paper will deal mainly with the conceptual model, the materials and methods used to asses the polymer adsorption behaviour and rheological properties of the systems studied. We shall briefly describe the adsorption of the polymers onto the different surfaces and their influence on surface charge and rheology and the influence of the various ionic species found in cement pore solutions that may influence polymer-cement affinity. The key factors are shown to be the effective adsorbed polymer thickness and the induced surface charge which can be influenced by the polymer architecture, the pore solution composition and the initial particle surface charge.