A generic approach to the impurity profiling of drugs using standardised and independent capillary zone electrophoresis methods coupled to electrospray ionisation mass spectrometry

Three standardised, capillary zone electrophoresis-electrospray ionisation mass spectrometry (CZE-ESI-MS) methods were developed for the analysis of six drug candidates and their respective process-related impurities comprising a total of 22 analytes with a range of functional groups and lipophilicities. The selected background electrolyte conditions were found to be: 60/40 v/v 10 mM ammonium formate pH 3.5/organic, 60/40 v/v 10 mM ammonium acetate pH 7.0/organic and 10 mM piperidine, pH 10.5, where the organic solvent is 50/50 v/v methanol/acetonitrile. The coaxial sheath flow consisted of either 0.1% v/v formic acid in 50/50 v/v methanol/water, or 10 mM ammonium acetate in 50/50 v/v methanol/water, depending on the mixture being analysed. Factor analysis and informational theory were used to quantify the orthogonality of the methods and predict their complementarities. The three selected CZE-ESI-MS methods allowed the identification of 21 out of 22 of all the drug candidates and their process-related impurities and provided orthogonality with four established high-performance liquid chromatography-mass spectrometry (HPLC-MS) methods. These methodologies therefore form the basis of a generic approach to impurity profiling of pharmaceutical drug candidates and can be applied with little or no analytical method development, thereby offering significant resource and time savings.     

Imaging the In Vivo Degradation of Tissue Engineering Implants by Use of Supramolecular Radiopaque Biomaterials

For in situ tissue engineering (TE) applications it is important that implant degradation proceeds in concord with neo‐tissue formation to avoid graft failure. It will therefore be valuable to have an imaging contrast agent (CA) available that can report on the degrading implant. For this purpose, a biodegradable radiopaque biomaterial is presented, modularly composed of a bisurea chain‐extended polycaprolactone (PCL2000‐U4U) elastomer and a novel iodinated bisurea‐modified CA additive (I‐U4U). Supramolecular hydrogen bonding interactions between the components ensure their intimate mixing. Porous implant TE‐grafts are prepared by simply electrospinning a solution containing PCL2000‐U4U and I‐U4U. Rats receive an aortic interposition graft, either composed of only PCL2000‐U4U (control) or of PCL2000‐U4U and I‐U4U (test). The grafts are explanted for analysis at three time points over a 1‐month period. Computed tomography imaging of the test group implants prior to explantation shows a decrease in iodide volume and density over time. Explant analysis also indicates scaffold degradation. (Immuno)histochemistry shows comparable cellular contents and a similar neo‐tissue formation process for test and control group, demonstrating that the CA does not have apparent adverse effects. A supramolecular approach to create solid radiopaque biomaterials can therefore be used to noninvasively monitor the biodegradation of synthetic implants.     

Development of ion-conducting polymer electrolytes for use in high-energy lithium rechargeable batteries

Polymers based on poly(thylene oxide) (PEO) are a very promising new type of stable electrolytes for lithium rechargeable batteries. Their relatively low ionic conductivities can be more than compensated by the very small electrolyte thicknesses that can be used. Specific energies of 100 Wh/kg at sustained specific powers of 70 W/kg, have been obtained at Hydro-Québec with 100 μm of PEO electrolyte at 100°C. In an electric vehicle, this would give a driving range of over 300 km at 80 km/h, more than three times as much as lead-acid batteries. PEO-related polymers have been developed for lower temperature applications such as computers or portable appliances. Advantages over competitive Ni-Cd batteries are higher energy densities and absence of self-discharge, with expected shell lifes of 10 years. Laboratory prototypes (3600 cm², 10 Wh) demonstrate the absence of scale-up effects and excellent cycling capability (over 300 charge-discharge cycles).     

Amiloride-sensitive channels in type I fungiform taste cells in mouse

Background  

Taste buds are the sensory organs of taste perception. Three types of taste cells have been described. Type I cells have voltage-gated outward currents, but lack voltage-gated inward currents. These cells have been presumed to play only a support role in the taste bud. Type II cells have voltage-gated Na⁺ and K⁺ current, and the receptors and transduction machinery for bitter, sweet, and umami taste stimuli. Type III cells have voltage-gated Na⁺, K⁺, and Ca²⁺ currents, and make prominent synapses with afferent nerve fibers. Na⁺ salt transduction in part involves amiloride-sensitive epithelial sodium channels (ENaCs). In rodents, these channels are located in taste cells of fungiform papillae on the anterior part of the tongue innervated by the chorda tympani nerve. However, the taste cell type that expresses ENaCs is not known. This study used whole cell recordings of single fungiform taste cells of transgenic mice expressing GFP in Type II taste cells to identify the taste cells responding to amiloride. We also used immunocytochemistry to further define and compare cell types in fungiform and circumvallate taste buds of these mice.     

Evidence for a role of glutamate as an efferent transmitter in taste buds

Background  

Glutamate has been proposed as a transmitter in the peripheral taste system in addition to its well-documented role as an umami taste stimulus. Evidence for a role as a transmitter includes the presence of ionotropic glutamate receptors in nerve fibers and taste cells, as well as the expression of the glutamate transporter GLAST in Type I taste cells. However, the source and targets of glutamate in lingual tissue are unclear. In the present study, we used molecular, physiological and immunohistochemical methods to investigate the origin of glutamate as well as the targeted receptors in taste buds.     

Progress in solid core photonic bandgap fibers

We investigate both experimentally and numerically confinement and bend losses in solid-core photonic bandgap fibers. We proposed two designs, based on the addition of air regions in the cladding, allowing these losses to be reduced significantly while keeping the optical properties of bandgap fibers. We also present and discuss numerical results on the impact of transversal defects on the fiber confinement loss in the case of a realistic low loss fiber.     

Log-robust portfolio management with parameter ambiguity

We present a robust optimization approach to portfolio management under uncertainty when randomness is modeled using uncertainty sets for the continuously compounded rates of return, which empirical research argues are the true drivers of uncertainty, but the parameters needed to define the uncertainty sets, such as the drift and standard deviation, are not known precisely. Instead, a finite set of scenarios is available for the input data, obtained either using different time horizons or assumptions in the estimation process. Our objective is to maximize the worst-case portfolio value (over a set of allowable deviations of the uncertain parameters from their nominal values, using the worst-case nominal values among the possible scenarios) at the end of the time horizon in a one-period setting. Short sales are not allowed. We consider both the independent and correlated assets models. For the independent assets case, we derive a convex reformulation, albeit involving functions with singular Hessians. Because this slows computation times, we also provide lower and upper linear approximation problems and devise an algorithm that gives the decision maker a solution within a desired tolerance from optimality. For the correlated assets case, we suggest a tractable heuristic that uses insights derived in the independent assets case.