Direct observation of the protonation state of an imino sugar glycosidase inhibitor upon binding

Glycosidases are some of the most ubiquitous enzyme in nature. Their biological significance, coupled to their enormous catalytic prowess derived from tight binding of the transition state, is reflected in their importance as therapeutic targets. Many glycosidase inhibitors are known. Imino sugars are often potent inhibitors, yet many facets of their mode of action, such as their degree, if any, of transition-state "mimicry" and their protonation state when bound to the target glycosidase remain unclear. Atomic resolution analysis of the endoglucanase, Cel5A, in complex with a cellobio-derived isofagomine in conjunction with the pH dependence of Ki and kcat/KM reveals that this compound binds as a protonated sugar. Surprisingly, both the enzymatic nucleophile and the acid/base are unprotonated in the complex.     

Infrared (1.2-1.6 microm) luminescence in Cr4+:Yb3Al5O12 single crystal with 940 nm diode pumping

Infrared (1.2-1.6 microm) luminescence in a ytterbium aluminium garnet (YbAG) crystal, doped with Cr (0.05at.%) ions, was investigated under CW laser diode pumping (lambda=940 nm). The Cr4+ emission band was observed with its peak at 1.34 microm and measured to be about 1.3 times with respect to Yb3+ IR luminescence (lambda=1.03 microm). We demonstrate that for the excitation wavelength of 940 nm Yb3+ ions act as sensitizers of the 3B2(3T2)-3B1(3A2) emission of Cr4+ ions. This crystal is promising as a high-efficient system for tunable laser (1.2-1.6 microm) output.     

Preparation of diverse BODIPY diesters

The synthesis and properties of a variety of substituted BODIPY diesters is presented. We find that certain substitution patterns afford appreciable yields of the target compounds and that electronic effects result in predicable differential fluorescent behavior. Challenges to further water solubilize these dyes and/or provide new points of attachment for biological tagging remain, these strategies are discussed.     

Theoretical optimization of Irinotecan-based anticancer strategies in the case of drug-induced efflux

The anticancer drug Irinotecan (CPT11) is known to trigger the induction of ATP-Binding Cassette (ABC) transporters, responsible for the efflux of the drug and its metabolites outside of the cells. The drug-modulated overexpression of those transporters prevents its accumulation in the intracellular medium, therefore decreasing its efficacy. A critical clinical concern lies in the design of CPT11-based therapeutic strategies which eradicate a maximum number of cancer cells despite their ability to become resistant. In order to address this issue, we supplemented an existing mathematical model of CPT11 molecular pharmacokinetics–pharmacodynamics (PK–PD) with a new model of CPT11-induced overexpression of ABC transporters. We then theoretically optimized exposure to CPT11 given as a single agent or combined either with ABC transporter inhibitors, or with inhibitors of nuclear factors whose activation is responsible for transporter overexpression. We firstly considered a cancer cell population endowed with the ability of inducing their transporters. For any drug combination, we concluded that the highest concentration of CPT11 should be administered in order to kill a maximum number of cancer cells, despite the triggering of resistance. We then considered a population of healthy cells which were assumed to be identical to cancer cells except that they were not able to become resistant. Optimal schemes were defined as the ones which maximized DNA damage in cancer cells under the constraint of DNA damage in healthy cells not exceeding a tolerability threshold. The optimal therapeutic strategy consisted in combining CPT11 with ABC transporter inhibitors as it achieved a complete reversal of resistance by means of the lowest concentrations of CPT11.     

Synthesis and characterization of doped apatite-type lanthanum silicates for SOFC applications

A series of iron- and/or aluminium-doped apatite-type lanthanum silicates (ATLS) La_9.83Si_{6 ‐ x ‐ y}Al_xFe_yO_26 ± δ (x = 0, 0.25, 0.75, and 1.5, y = 0, 0.25, 0.75, and 1.5) were synthesized using the mechanochemical activation (MA), solid state reaction (SSR), Pechini (Pe) and sol-gel (SG) methods. The total conductivity of the prepared materials was measured under air in the temperature range 600-850 °C using 4-probe AC impedance spectroscopy. Its dependence on composition, synthesis method, sintering conditions and powder particle size was investigated. It was found that for electrolytes of the same composition, those prepared via mechanochemical activation exhibited the highest total specific conductivity, which was improved with increasing Al- and decreasing Fe-content. The highest conductivity value at 700 °C, equal to 2.04 × 10^− 2 S cm^− 1, was observed for the La_9.83Si₅Al_0.75Fe_0.25O_26 ± δ electrolyte. La_9.83Si_4.5Fe_1.5O_26 ± δ electrolyte samples synthesized using the Pechini method exhibited higher conductivity when sintered conventionally than when spark-plasma sintering (SPS) was used.     

Die Trennung der Bernsteins?ure von Weinstein- und Milchs?ure

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