First-principles prediction of the pK(a)s of anti-inflammatory oxicams

The gas- and aqueous-phase acidities of a series of oxicams have been computed by combining M05-2X/6-311+G(3df,2p) gas-phase free energies with solvation free energies from the CPCM-UAKS, COSMO-RS, and SMD solvent models. To facilitate accurate gas-phase calculations, a benchmarking study was further carried out to assess the performance of various density functional theory methods against the high-level composite method G3MP2(+). Oxicams are typically diprotic acids, and several tautomers are possible in each protonation state. The direct thermodynamic cycle and the proton exchange scheme have been employed to compute the microscopic pK(a)s on both solution- and gas-phase equilibrium conformers, and these were combined to yield the macroscopic pK(a) values. Using the direct cycle of pK(a) calculation, the CPCM-UAKS model delivered reasonably accurate results with MAD ~ 1, whereas the SMD and COSMO-RS models' performance was less satisfactory with MAD ~ 3. Comparison with experiment also indicates that direct cycle calculations based on solution conformers generally deliver better accuracy. The proton exchange cycle affords further improvement for all solvent models through systematic error cancellation and therefore provides better reliability for the pK(a) prediction of compounds of these types. The latter approach has been applied to predict the pK(a)s of several recently synthesized oxicam derivatives.     

Determination of anthelmintic drug residues in milk using ultra high performance liquid chromatography–tandem mass spectrometry with rapid polarity switching

A new UHPLC–MS/MS (ultra high performance liquid chromatography coupled to tandem mass spectrometry) method was developed and validated to detect 38 anthelmintic drug residues, consisting of benzimidazoles, avermectins and flukicides. A modified QuEChERS-type extraction method was developed with an added concentration step to detect most of the analytes at <1 μg kg⁻¹ levels in milk. Anthelmintic residues were extracted into acetonitrile using magnesium sulphate and sodium chloride to induce liquid–liquid partitioning followed by dispersive solid phase extraction for cleanup. The extract was concentrated into dimethyl sulphoxide, which was used as a keeper to ensure analytes remain in solution. Using rapid polarity switching in electrospray ionisation, a single injection was capable of detecting both positively and negatively charged ions in a 13 min run time. The method was validated at two levels: the unapproved use level and at the maximum residue level (MRL) according to Commission Decision (CD) 2002/657/EC criteria. The decision limit (CCα) of the method was in the range of 0.14–1.9 and 11–123 μg kg⁻¹ for drugs validated at unapproved and MRL levels, respectively. The performance of the method was successfully verified for benzimidazoles and levamisole by participating in a proficiency study.     

Objective and subjective evaluations of the multi-channel auralization technique as applied to solo instruments

Auralizations are commonly used today by architectural acousticians as a tool to model acoustically sensitive spaces. This paper presents investigations employing an auralization methodology known as multi-channel auralizations, to determine the benefits of using an increasing number of channels in such auralizations. First an objective evaluation was conducted to examine how acoustic parameters, such as reverberation time, vary when using “quadrant” (one fourth of a spherical source) or “thirteenth” sources to create the binaural room impulse responses. Large differences in the values were found between the different sections of the sphere, on the order of several just noticeable differences. Two subjective studies were then pursued, first to determine if auralizations made with an increasing number of channels sound more realistic and have an increased perceived source size, using solo musical instruments of varying directivity indices as the sources. Overall, subjects perceived the auralizations made with an increasing number of channels as more realistic, whereas results for perceived source size are less clear. The second subjective study assessed the ease with which subjects could identify the source orientation from the auralizations as a function of number of channels. Results indicate that more channels made it easier for subjects to differentiate between source orientations.     

Underwound DNA under tension: structure, elasticity, and sequence-dependent behaviors

DNA melting under torsion plays an important role in a wide variety of cellular processes. In the present Letter, we have investigated DNA melting at the single-molecule level using an angular optical trap. By directly measuring force, extension, torque, and angle of DNA, we determined the structural and elastic parameters of torsionally melted DNA. Our data reveal that under moderate forces, the melted DNA assumes a left-handed structure as opposed to an open bubble conformation and is highly torsionally compliant. We have also discovered that at low forces melted DNA properties are highly dependent on DNA sequence. These results provide a more comprehensive picture of the global DNA force-torque phase diagram.     

Modulation of amyloid-β aggregation by metal complexes with a dual binding mode and their delivery across the blood–brain barrier using focused ultrasound

One of the key hallmarks of Alzheimer''s disease is the aggregation of the amyloid-β peptide to form fibrils. Consequently, there has been great interest in studying molecules that can disrupt amyloid-β aggregation. While a handful of molecules have been shown to inhibit amyloid-β aggregation in vitro, there remains a lack of in vivo data reported due to their inability to cross the blood–brain barrier. Here, we investigate a series of new metal complexes for their ability to inhibit amyloid-β aggregation in vitro. We demonstrate that octahedral cobalt complexes with polyaromatic ligands have high inhibitory activity thanks to their dual binding mode involving π–π stacking and metal coordination to amyloid-β (confirmed via a range of spectroscopic and biophysical techniques). In addition to their high activity, these complexes are not cytotoxic to human neuroblastoma cells. Finally, we report for the first time that these metal complexes can be safely delivered across the blood–brain barrier to specific locations in the brains of mice using focused ultrasound.

We report a series of non-toxic cobalt(iii) complexes which inhibit Aβ peptide aggregation in vitro; these complexes can be safely delivered across the blood–brain barrier in mice using focused ultrasound.     

Effect of electrostatic spray on human pulmonary epithelial cells

Aerosolization techniques for delivery of gene therapies to the lungs decrease activity of these treatments. The low transfection is attributed to loss in molecular integrity. Electrosprays can aerosolize DNA without structural loss. Electrospray affects on human pulmonary cells are unknown. This study is to assess toxicity, inflammatory response, and transfection of DNA mixtures delivered via electrospray to human pulmonary cells. EpiAirway? cells are cultured on air–liquid interfaces and simulate in vivo. All conditions examined (except PEI/DNA 10:1) showed no toxic or inflammation response. Transfection was not observed. In vitro results indicate that electrosprays have potential for administering DNA therapeutics pulmonarily.     

Efficient tetrahydropyranyl and tetrahydrofuranyl protection/deprotection of alcohols and phenols with Al(OTf)3 as catalyst

A simple and efficient method for the conversion of alcohols and phenols into their corresponding THP and THF ethers at room temperature has been developed using 1 mol % aluminium triflate as catalyst. The deprotection reaction in the presence of methanol using Al(OTf)₃ was equally successful and could be performed at ambient temperature in high yields.     

Quantification of deuterated bisphenol A in serum,tissues, and excreta from adult Sprague‐Dawley rats using liquid chromatography with tandem mass spectrometry

Bisphenol A (BPA) is an important industrial chemical used in the manufacture of polycarbonate plastic products, epoxy resin‐based food can liners, and paper products. The presence of BPA in urine of >90% of Americans aged 6–60 suggests ubiquitous and frequent exposure and is problematic because of the potential for endocrine disruption. The ubiquity of environmental BPA in common laboratory supplies used for sample collection, storage, and analysis greatly increases the likelihood of false positive determinations, particularly at trace levels. The current study validated using liquid chromatography/tandem mass spectrometry (LC/MS/MS) in conjunction with deuterated BPA as the dosing material to circumvent contamination for high sensitivity quantifications in rat serum, tissues, urine, and feces. The methods described provided measurements of both estrogen receptor‐active aglycone and metabolically deactivated conjugated forms of BPA, a distinction that is critical to assessing toxicological potential. The adequacy of the described methodology was substantiated by its utility in analyzing samples from rats treated orally with a 100 µg/kg body weight dose of d6‐BPA. These results emphasize the challenges inherent in measuring BPA in biological samples and how employing stable isotope labeled dosing can facilitate pharmacokinetic studies needed to understand BPA metabolism and disposition. Such studies conducted in experimental animal models, in conjunction with properly validated human biomonitoring data, will be the basis for PBPK modeling of BPA in environmentally exposed humans. Published in 2010 by John Wiley & Sons, Ltd.     

Effect of temperature and solvent on polymer tacticity in the free‐radical polymerization of styrene and methyl methacrylate

The effect of temperature and solvent on polymer tacticity in free‐radical polymerization of styrene and methyl methacrylate was studied by ¹³C and ¹H NMR, respectively. Polystyrene shows a mild syndiotactic tendency (P_m = 0.36 ± 0.02) that is independent of temperature over a wide range (?10 to 120 °C), while poly(methyl methacrylate) shows a stronger syndiotactic tendency (P_m = 0.17 ± 0.01 at 30 °C) that decreases as temperature is increased (P_m = 0.22 ± 0.02 at 80 °C). None of the polymerization solvents studied (bulk, THF, DMF, DMSO, acetonitrile, and acetone) had a significant effect on polymer tacticity in either system. The triad fractions of both polymers showed deviations from the Bernoulli model, implying that the antepenultimate unit affects the propagation reaction. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013 , 51, 3351–3358     

Extension Theorems for Spaces Arising from Approximation by Translates of a Basic Function

We establish extension theorems for functions in spaces which arise naturally in studying interpolation by radial basic functions. These spaces are akin in some way to the non-integer-valued Sobolev spaces, although they are considerably more general. Such extensions allow us to establish local error estimates in a way which we make precise in the introductory section of our paper. There are many other applications of these fundamental results, including improved L_p error estimates for interpolation by shifts of a single basic function, but these applications have been left to a later paper.