New class of biodegradable polymers formed from reactions of an inorganic functional group

Although numerous small molecules have been synthesized with sulfenamide bonds (R(2)N-SR), this is the first report of the synthesis of polysulfenamides. These polymers are readily synthesized at room temperature using secondary diamines and dithiosuccinimides. The dithiosuccinimides were readily synthesized in one step by the reaction of dithiols such as HS(CH(2))(6)SH with N-chlorosuccinimide. The resulting dithiosuccinimides were either recrystallized or readily purified by chromatography on silica gel and required no special handling. The conversions of polymerization ranged from 95 to 98%, and the molecular weights of the polymer reached as high as 6,300 g mol(-1). The sulfenamide bond was very stable in organic solvents, and no degradation was observed under atmospheric conditions in C(6)D(6) for 30 days. In contrast, the sulfenamide bond readily decomposed in less than 12 h in D(2)O. Polysulfenamides were fabricated into micron-sized particles loaded with dye and endocytosed into JAWSII immature dendritic and HEK293 cells. Polysulfenamides represent a new class of polymers that are readily synthesized, stable in aprotic solvents, and readily degrade in water.     

Potential and limitations of ensemble docking

A major problem in structure-based virtual screening applications is the appropriate selection of a single or even multiple protein structures to be used in the virtual screening process. A priori it is unknown which protein structure(s) will perform best in a virtual screening experiment. We investigated the performance of ensemble docking, as a function of ensemble size, for eight targets of pharmaceutical interest. Starting from single protein structure docking results, for each ensemble size up to 500,000 combinations of protein structures were generated, and, for each ensemble, pose prediction and virtual screening results were derived. Comparison of single to multiple protein structure results suggests improvements when looking at the performance of the worst and the average over all single protein structures to the performance of the worst and average over all protein ensembles of size two or greater, respectively. We identified several key factors affecting ensemble docking performance, including the sampling accuracy of the docking algorithm, the choice of the scoring function, and the similarity of database ligands to the cocrystallized ligands of ligand-bound protein structures in an ensemble. Due to these factors, the prospective selection of optimum ensembles is a challenging task, shown by a reassessment of published ensemble selection protocols.     

The liquid-liquid diffusive extraction of hydrocarbons from a North Sea oil using a microfluidic format

Extraction of a GC-amenable hydrocarbon fraction from oil by liquid-liquid diffusion across a laminar interface can be performed in a microfluidic format. Analysis of figures of merit, determined using standard analytical techniques, show this method to be an effective new tool for rapidly processing small quantities of oil and petroleum for GC analysis. Methods based upon similar microsystems devices could find widespread use in a variety of fields, including those associated with organic geochemistry and oil exploration and production, where the manipulation of petroleum constituents (greater than C14) is necessary for analytical purposes.     

Inhibition of UVA-induced c-Jun N-terminal kinase activity results in caspase-dependent apoptosis in human keratinocytes

Inhibition of c-Jun N-terminal kinase (JNK) with the pharmacologic inhibitor SP600125 in UVA-irradiated HaCaT cells and human primary keratinocytes resulted in dramatic phenotypic changes indicative of cell death. These phenotypic changes correlated with caspase 8, 9 and 3 activations as well as cleavage of the caspase substrate polyADP-ribose polymerase (PARP). Morphologic analysis and analysis of sub-G0 DNA content confirmed apoptotic cell death in these keratinocytes after combination treatment. Addition of the general caspase inhibitor zVAD-fmk to combination-treated HaCaT cells was able to completely block caspase activation, PARP cleavage, the increase in sub-G0 DNA content and the classic morphologic features of apoptosis, indicating that this combination treatment resulted in caspase-dependent apoptotic cell death. zVAD-fmk treatment of primary keratinocytes was able to completely inhibit caspase activation and PARP cleavage, reduce morphologic apoptosis at lower concentrations of SP600125 and decrease the sub-G(0) DNA content detected after UVA + SP600125 treatment. However, cell death and a significant amount of debris was still detected after caspase inhibitor treatment, particularly with 125 nM SP600125. At subconfluent conditions and low passage, primary keratinocytes were more sensitive to UVA irradiation alone than HaCaT cells. In conclusion, we have observed that inhibition of UVA-induced JNK activity with the pharmacologic inhibitor SP600125 resulted in caspase-dependent apoptotic cell death in both the immortalized keratinocyte cell line HaCaT and primary keratinocytes. However, the increased sensitivity of primary keratinocytes to experimental stress may have also resulted in direct cellular injury and caspase-independent cell death.     

Efficient DNA Binding and Condensation Using Low Molecular Weight,Low Charge Density Cationic Polymer Amphiphiles

A new class of biodegradable cationic macromolecules for DNA binding and condensation was developed by end‐group‐functionalization of poly(trimethylene carbonate). A series of one‐ and two‐armed structures was synthesized and their interaction with DNA was evaluated. To aid data interpretation, a non‐linear modeling method was applied to show efficient DNA binding that was intimately related to cationic charge density and macromolecular architecture. One‐armed, low charge density structures were consistently found to bind to DNA at lower charge ratios than their two‐armed, high charge density counterparts. This suggests that polymer backbone structure and characteristics are important considerations in the development of efficient cationic polymer systems for DNA condensation and delivery.

     

Vector magnetometer studies of the easy magnetisation direction in epitaxially grown DyFe2 film

A vector vibrating sample magnetometer has been used to determine the direction of easy magnetisation in a thin film of DyFe₂. The 4000 Å thick film, with a [1 1 0] growth direction, was prepared using molecular beam epitaxy. The results show that the direction of easy magnetisation is temperature dependent. At 4 K this direction corresponds to the [0 0 1] type axes. But at 290  the easy axis is close to a direction, but pointing out of the plane of the film at angle of (14±3)°. On the basis of the vector magnetometer results at 290 K we find two easy magnetisation axes close to or (and opposite directions). Finally, it is shown that DyFe₂ films are unique in that the remanent magnetisation can be manipulated to point either in or out of the plane of the film.     

ISOLATION OF MUTANTS OF THE FUNGUS Cercospora nicotianae ALTERED IN THEIR RESPONSE TO SINGLET-OXYGEN-GENERATING PHOTOSENSITIZERS

Fungi in the genus Cercospora produce a singlet-oxygen-generating photosensitizing toxin cercosporin, which plays an important role in the ability of these fungi to parasitize plants. Previous studies demonstrated that resistance to cercosporin was associated with the ability of the fungus to reduce and detoxify cercosporin transiently. In order to characterize the mechanism of cercosporin resistance further, two types of mutants were isolated. One set of mutants was selected directly for sensitivity to cercosporin. Six cercosporin-sensitive mutants were isolated. Five of the mutants were totally inhibited by cercosporin as well as by five other photosensitizers, methylene blue, toluidine blue, eosin Y, rose bengal and hematoporphyrin. These five mutants were also deficient in cercosporin-reducing ability. The sixth cercosporin-sensitive mutant was only partially inhibited by cercosporin. This mutant was unaltered in cercosporin-reducing ability and in its response to the other photosensitizers. In order to test hypotheses concerning the mechanism of cercosporin reduction, a second set of mutants was selected for general deficiency in cell surface-reducing capability by screening for the inability to reduce two tetrazolium dyes (p-tolyltetrazolium red and 2,3,5-triphenyltetrazolium chloride) of similar redox potential to cercosporin. Dye-reduction-deficient mutants were unaltered in their resistance to cercosporin and in cercosporin-reducing ability. We conclude that cercosporin resistance of these fungi is strongly correlated with the ability to reduce cercosporin. However, cercosporin-reducing ability is separable from the general ability to reduce external electron acceptors.     

Synthesis of the first poly(diaminosulfide)s and an investigation of their applications as drug delivery vehicles

This paper reports the first examples of poly(diaminosulfide)s that were synthesized by the reaction of a sulfur transfer reagent and several secondary diamines. The diaminosulfide group has the general structure of R(2)N-S-NR(2) and, although it has been used in the synthesis of small molecules, it has never been utilized in the synthesis of macromolecules until this report. A series of poly(diaminosulfide)s were synthesized at elevated temperatures, and the molecular weights of the polymers were as high as 12,400 g mol(-1) with conversions for the polymerization reaction up to 99%. The rate constants for the transamination reactions that lead to the polymers were measured in several solvents to provide an understanding the reaction conditions necessary to polymerize the monomers. The degradation of diaminosulfides were studied in D(2)O, C(6)D(6), CD(3)OD, CDCl(3), and DMSO-d(6)/D(2)O to demonstrate that they were very stable in organic solvents but degraded within hours under aqueous conditions. These results clearly demonstrated that diaminosulfides are very stable in organic solvents under ambient conditions. Poly(diaminosulfide)s have sufficient stabilities to be useful for many applications. The ability of these polymers to function as drug delivery vehicles were studied by the fabrication of nanoparticles of a water-insoluble poly(diaminosulfide) with a dye. The microparticles were readily absorbed into human embryonic 293 cells and possessed no measureable toxicity towards these same cells.     

Enhancement of chi((2)) cascading processes in one-dimensional photonic bandgap structures

We theoretically analyze the nonlinear phase shifts induced by cascaded chi((2)):chi((2)) processes in one-dimensional photonic bandgap structures. We find that the enhancement of the density of modes near the band edge, coupled with a suitable choice of relative phase mismatch, leads to a remarkable new effect: The relative phase shift of the fundamental field on transmission can be of the order of pi over a distance of 7mum , with input intensities of the order of only 10 MW/cm(2).