Functionalized bis(thiosemicarbazonato) complexes of zinc and copper: synthetic platforms toward site-specific radiopharmaceuticals

Two new types of unsymmetrical bis(thiosemicarbazone) proligands and their neutral zinc(II) and copper(II) complexes have been synthesized. These bifunctional ligands both chelate the metal ions and provide pendent amino groups that can be readily functionalized with biologically active molecules. Functionalization has been demonstrated by the synthesis of three water-soluble glucose conjugates of the new zinc(II) bis(thiosemicarbazonato) complexes, and their copper(II) analogues have been prepared in aqueous solution via transmetalation. A range of techniques including NMR, electron paramagnetic resonance, cyclic voltammetry, high-performance liquid chromatography (HPLC), UV/vis, and fluorescence emission spectroscopy have been used to characterize the complexes. Four compounds, including two zinc(II) complexes, have been characterized by X-ray crystallography. The connectivity and conformation of the glucose conjugates have been assigned by NMR spectroscopy. Time-dependent density functional theory calculations have been used to assign the electronic transitions of the copper(II) bis(thiosemicarbazonato) chromophore. Two copper-64-radiolabeled complexes, including one glucose conjugate, have been prepared and characterized using radio-HPLC, and transmetalation is shown to be a viable method for radiolabeling compounds with copper radionuclides. Preliminary cell washout studies have been performed under normoxic conditions, and the uptake and intracellular distribution have been studied using confocal fluorescence microscopy.     

Characterization of 2-methylglyceric acid oligomers in secondary organic aerosol formed from the photooxidation of isoprene using trimethylsilylation and gas chromatography/ion trap mass spectrometry

In the present work, we have characterized in detail the chemical structures of secondary organic aerosol (SOA) components that were generated in a smog chamber and result from the photooxidation of isoprene under high-NO(x) conditions typical for a polluted atmosphere. Isoprene high-NO(x) SOA contains 2-methylglyceric acid (2-MG) and oligoester derivatives thereof. Trimethylsilylation, in combination with capillary gas chromatography (GC)/ion trap mass spectrometry (MS) and detailed interpretation of the MS data, allowed structural characterization the polar oxygenated compounds present in isoprene SOA up to 2-MG trimers. GC separation was achieved between 2-MG linear and branched dimers or trimers, as well as between the 2-MG linear dimer and isomeric mono-acetate derivatives thereof. The electron ionization (EI) spectra of the trimethylsilyl derivatives contain a wealth of structural information, including information about the molecular weight (MW), oligoester linkages, terminal carboxylic and hydroxymethyl groups, and esterification sites. Only part of this information can be achieved with a soft ionization technique such as electrospray (ESI) in combination with collision-induced dissociation (CID). The methane chemical ionization (CI) data were used to obtain supporting MW information. Interesting EI spectral differences were observed between the trimethylsilyl derivatives of 2-MG linear and branched dimers or trimers and between 2-MG linear dimer mono-acetate isomers.     

Engineering and analysis of surface interactions in a microfluidic herringbone micromixer

We developed a computational model and theoretical framework to investigate the geometrical optimization of particle-surface interactions in a herringbone micromixer. The enhancement of biomolecule- and particle-surface interactions in microfluidic devices through mixing and streamline disruption holds promise for a variety of applications. This analysis provides guidelines for optimizing the frequency and specific location of surface interactions based on the flow pattern and relative hydraulic resistance between a groove and the effective channel. The channel bottom, i.e., channel surface between grooves, was identified as the dominant location for surface contact. In addition, geometries that decrease the groove-to-channel hydraulic resistance improve contact with the channel top. Thus, herringbone mixers appear useful for a variety of surface-interaction applications, yet they have largely not been employed in an optimized fashion.     

Hybrid Supramolecular and Colloidal Hydrogels that Bridge Multiple Length Scales

Hybrid nanocomposites were constructed based on colloidal nanofibrillar hydrogels with interpenetrating supramolecular hydrogels, displaying enhanced rheological yield strain and a synergistic improvement in storage modulus. The supramolecular hydrogel consists of naphthyl‐functionalized hydroxyethyl cellulose and a cationic polystyrene derivative decorated with methylviologen moieties, physically cross‐linked with cucurbit[8]uril macrocyclic hosts. Fast exchange kinetics within the supramolecular system are enabled by reversible cross‐linking through the binding of the naphthyl and viologen guests. The colloidal hydrogel consists of nanofibrillated cellulose that combines a mechanically strong nanofiber skeleton with a lateral fibrillar diameter of a few nanometers. The two networks interact through hydroxyethyl cellulose adsorption to the nanofibrillated cellulose surfaces. This work shows methods to bridge the length scales of molecular and colloidal hybrid hydrogels, resulting in synergy between reinforcement and dynamics.     

Particle interactions in kaolinite suspensions and corresponding aggregate structures

The surface charge densities of the silica face surface and the alumina face surface of kaolinite particles, recently determined from surface force measurements using atomic force microscopy, show a distinct dependence on the pH of the system. The silica face was found to be negatively charged at pH>4, whereas the alumina face surface was found to be positively charged at pH<6, and negatively charged at pH>8. The surface charge densities of the silica face and the alumina face were utilized in this study to determine the interaction energies between different surfaces of kaolinite particles. Results indicate that the silica face-alumina face interaction is dominant for kaolinite particle aggregation at low pH. This face-face association increases the stacking of kaolinite layers, and thereby promotes the edge-face (edge-silica face and edge-alumina face) and face-face (silica face-alumina face) associations with increasing pH, and hence the maximum shear-yield stress at pH 5-5.5. With further increase in pH, the face-face and edge-face association decreases due to increasing surface charge density on the silica face and the edge surfaces, and decreasing surface charge density on the alumina face. At high pH, all kaolinite surfaces become negatively charged, kaolinite particles are dispersed, and the suspension is stabilized. The face-face association at low pH has been confirmed from cryo-SEM images of kaolinite aggregates taken from suspension which show that the particles are mostly organized in a face-face and edge-face manner. At higher pH conditions, the cryo-SEM images of the kaolinite aggregates reveal a lower degree of consolidation and the edge-edge association is evident.     

Anhydrous TEMPO-H: reactions of a good hydrogen atom donor with low-valent carbon centres

In this paper, we report a novel synthesis of anhydrous 1-hydroxy-2,2,6,6-tetramethyl-piperidine (TEMPO-H). An X-ray crystal structure and full characterization of the compound are included. Compared to hydrated TEMPO-H, its anhydrous form exhibits improved stability and a differing chemical reactivity. The reactions of anhydrous TEMPO-H with a variety of low-valent carbon centres are described. For example, anhydrous TEMPO-H was reacted with 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene (IMes), an unsaturated NHC. Crystals of [CHNC(6)H(2)(CH(3))(3)](2)C···HO(NC(5)H(6)(CH(3))(4)), IMes···TEMPO-H, were isolated and a crystal structure determined. The experimental structure is compared to the results of theoretical calculations on the hydrogen-bonded dimer. Anhydrous TEMPO-H was also reacted with the saturated NHC, 1,3-bis(2,6-diisopropylphenyl)imidazolidin-2-ylidene (SIPr), giving the product [CH(2)Ni-Pr(2)C(6)H(3)](2)CH···O(NC(5)H(6)(CH(3))(4)). In contrast, the reaction of hydrated TEMPO-H with 1,3-bis(2,6-diisopropylphenyl)imidazolidin-2-ylidene gave small amounts of the hydrolysis product, N-(2,6-diisopropylphenyl)-N-[2-(2,6-diisopropylphenylamino)ethyl]formamide. Finally, anhydrous TEMPO-H was reacted with (triphenylphosphoranylidene)ketene to generate Ph(3)PC(H)C(=O)O(NC(5)H(6)(CH(3))(4)). A full characterization of the product, including an X-ray crystal structure, is described.     

MSCALE: A General Utility for Multiscale Modeling

The combination of theoretical models of macromolecules that exist at different spatial and temporal scales has become increasingly important for addressing complex biochemical problems. This work describes the extension of concurrent multiscale approaches, introduces a general framework for carrying out calculations, and describes its implementation into the CHARMM macromolecular modeling package. This functionality, termed MSCALE, generalizes both the additive and subtractive multiscale scheme (e.g. QM/MM ONIOM-type), and extends its support to classical force fields, coarse grained modeling (e.g. ENM, GNM, etc.), and a mixture of them all. The MSCALE scheme is completely parallelized with each subsystem running as an independent, but connected calculation. One of the most attractive features of MSCALE is the relative ease of implementation using the standard MPI communication protocol. This allows external access to the framework and facilitates the combination of functionality previously isolated in separate programs. This new facility is fully integrated with free energy perturbation methods, Hessian based methods, and the use of periodicity and symmetry, which allows the calculation of accurate pressures. We demonstrate the utility of this new technique with four examples; (1) subtractive QM/MM and QM/QM calculations; (2) multi-force field alchemical free energy perturbation; (3) integration with the SANDER module of AMBER and the TINKER package to gain access to potentials not available in CHARMM; and (4) mixed resolution (i.e. coarse grain / all-atom) normal mode analysis. The potential of this new tool is clearly established and in conclusion an interesting mathematical problem is highlighted and future improvements are proposed.     

Probing ionophore selectivity in argon-tagged hydrated alkali metal ion-crown ether systems

Crown ethers are an important family of compounds that are closely related to naturally occurring ionophores. Thus, crown ethers are useful in modeling the size-selective behavior of ionophores. Using a combination of infrared predissociation spectroscopy and density functional theory calculations, we have investigated M(+)(18-crown-6 ether)(H(2)O)(1-4) Ar complexes, where M = Li, Na, K, Rb and Cs in the gas phase. The argon-tagging technique was used to lower the internal energies (effective temperatures ~100 K), yielding well-resolved spectra in the OH stretching region for systems containing up to three waters. Spectral changes were monitored as both the size of the ion and degree of hydration were varied. While there is not a particular spectroscopic signature of gas-phase selectivity reported in this work, the unique role that K(+) plays in the systems studied, as a "bridge" between the smaller and larger alkali metal ions, is consistent with the well-known special affinity for K(+) by 18-crown-6 ether in the aqueous phase.     

Effects of formalin preservation on stable carbon and nitrogen isotope signatures in Calanoid copepods: implications for the use of Continuous Plankton Recorder Survey samples in stable isotope analyses

Preserved and archived organic material offers huge potential for the conduct of retrospective and long-term historical ecosystem reconstructions using stable isotope analyses, but because of isotopic exchange with preservatives the obtained values require validation. The Continuous Plankton Recorder (CPR) Survey is the most extensive long-term monitoring program for plankton communities worldwide and has utilised ships of opportunity to collect samples since 1931. To keep the samples intact for subsequent analysis, they are collected and preserved in formalin; however, previous studies have found that this may alter stable carbon and nitrogen isotope ratios in zooplankton. A maximum ~0.9‰ increase of δ(15) N and a time dependent maximum ~1.0‰ decrease of δ(13) C were observed when the copepod, Calanus helgolandicus, was experimentally exposed to two formalin preservatives for 12 months. Applying specific correction factors to δ(15) N and δ(13) C values for similarly preserved Calanoid species collected by the CPR Survey within 12 months of analysis may be appropriate to enable their use in stable isotope studies. The isotope values of samples stored frozen did not differ significantly from those of controls. Although the impact of formalin preservation was relatively small in this and other studies of marine zooplankton, changes in isotope signatures are not consistent across taxa, especially for δ(15) N, indicating that species-specific studies may be required.     

Real-time assessment of cigarette smoke particle deposition in vitro

ABSTRACT: BACKGROUND: Recently there has been a rapid increase in approaches to assess the effects of cigarette smoke in vitro. Despite a range of gravimetric and chemical methods, there is a requirement to identify simpler and more reliable methods to quantify in vitro whole smoke dose, to support extrapolation and comparisons to human/in vivo dose. We have previously characterised an in vitro exposure system using a Borgwaldt RM20S smoking machine and a chamber exposing cellular cultures to whole smoke at the air-liquid interface. In this study we demonstrate the utility of a quartz crystal microbalance (QCM), using this exposure system, to assess real-time cigarette smoke particulate deposition during a 30 minute smoke exposure. Smoke was generated at various dilutions (1:5--1:400, smoke:air) using two cigarette products, 3R4F Kentucky reference and 1 mg commercially available cigarettes. The QCM, integrated into the chamber, assessed particulate deposition and data generated was compared to traditional chemical spectrofluorometric analysis. RESULTS: The QCM chamber was able to detect mass differences between the different products within the nanogram range. 3R4F reference cigarette smoke deposition ranged from 25.75 [PLUS-MINUS SIGN]2.30 mug/cm2 (1:5) to 0.22 [PLUS-MINUS SIGN]0.03 mug/cm2 (1:400). 1 mg cigarette smoke deposition was less and ranged from 1.42 [PLUS-MINUS SIGN]0.26 mug/cm2 (1:5), to 0.13 [PLUS-MINUS SIGN]0.02 mug/cm2 (1:100). Spectrofluorometric analysis demonstrated statistically significant correlation of particulate deposition with the QCM (p < 0.05), and regression R2 value were 97.4 %. The fitted equation for the linear model which describes the relationship is: QCM = [MINUS SIGN]0.6796 + 0.9744 chemical spectrofluorescence CONCLUSIONS: We suggest the QCM is a reliable, effective and simple tool that can be used to quantify smoke particulate deposition in real-time, in vitro and can be used to quantify other aerosols delivered to our chamber for assessment.