Multidisciplinary Preclinical Investigations on Three Oxamniquine Analogues as New Drug Candidates for Schistosomiasis**

Schistosomiasis is a disease of poverty affecting millions of people. Praziquantel (PZQ), with its strengths and weaknesses, is the only treatment available. We previously reported findings on three lead compounds derived from oxamniquine (OXA), an old antischistosomal drug: ferrocene-containing (Fc-CH₂-OXA), ruthenocene-containing (Rc-CH₂-OXA) and benzene-containing (Ph-CH₂-OXA) OXA derivatives. These derivatives showed excellent in vitro activity against both Schistosoma mansoni larvae and adult worms and S. haematobium adult worms, and were also active in vivo against adult S. mansoni. Encouraged by these promising results, we conducted additional in-depth preclinical studies and report in this investigation on metabolic stability studies, in vivo studies on S. haematobium and juvenile S. mansoni, computational simulations, and formulation development. Molecular dynamics simulations supported the in vitro results on the target protein. Though all three compounds were poorly stable within an acidic environment, they were only slightly cleared in the in vitro liver model. This is likely the reason why the promising in vitro activity did not translate into in vivo activity on S. haematobium. This limitation could not be overcome by the formulation of lipid nanocapsules as a way to improve the in vivo activity. Further studies should focus on increasing the compound's bioavailability, to reach an active concentration in the microenvironment of the parasite.     

A model of students’ combinatorial thinking

Combinatorial topics have become increasingly prevalent in K-12 and undergraduate curricula, yet research on combinatorics education indicates that students face difficulties when solving counting problems. The research community has not yet addressed students’ ways of thinking at a level that facilitates deeper understanding of how students conceptualize counting problems. To this end, a model of students’ combinatorial thinking was empirically and theoretically developed; it represents a conceptual analysis of students’ thinking related to counting and has been refined through analyzing students’ counting activity. In this paper, the model is presented, and relationships between formulas/expressions, counting processes, and sets of outcomes are elaborated. Additionally, the usefulness and potential explanatory power of the model are demonstrated through examining data both from a study the author conducted, and from existing literature on combinatorics education.     

Photodissociation spectroscopy and dynamics of the CH2CFO radical

The photodissociation spectroscopy and dynamics resulting from excitation of the B (2)A(")<--X (2)A(") transition of CH(2)CFO have been examined using fast beam photofragment translational spectroscopy. The photofragment yield spectrum reveals vibrationally resolved structure between 29 870 and 38 800 cm(-1), extending approximately 6000 cm(-1) higher in energy than previously reported in a laser-induced fluorescence excitation spectrum. At all photon energies investigated, only the CH(2)F+CO and HCCO+HF fragment channels are observed. Both product channels yield photofragment translational energy distributions that are characteristic of a decay mechanism with a barrier to dissociation. Using the barrier impulsive model, it is shown that fragmentation to CH(2)F+CO products occurs on the ground state potential energy surface with the isomerization barrier between CH(2)CFO and CH(2)FCO governing the observed translational energy distributions.     

Photophysics of Acetophenone Interacting with DNA: Why the Road to Photosensitization is Open

Deoxyribonucleic acid photosensitization, i.e. the photoinduced electron‐ or energy‐transfer of chromophores interacting with DNA, is a crucial phenomenon that triggers important DNA lesions such as pyrimidine dimerization, even upon absorption of relatively low‐energy radiation. Oxidative lesions may also be produced via the photoinduced production of reactive oxygen species. Aromatic ketones, and acetophenone in particular, are well known for their sensitization effects. In this contribution we model the structural and dynamical properties of the acetophenone/DNA aggregates as well as their spectroscopic and photophysical properties using high‐level hybrid quantum mechanics/molecular mechanics methods. We show that the key steps of the photochemistry of acetophenone in gas phase are conserved in the macromolecular environment and thus an ultrafast singlet–triplet conversion of acetophenone is expected prior to the transfer to DNA.     

On Solving Quickest Time Problems in Time-Dependent, Dynamic Networks

In this paper, a pseudopolynomial time algorithm is presented for solving the integral time-dependent quickest flow problem (TDQFP) and its multiple source and sink counterparts: the time-dependent evacuation and quickest transshipment problems. A more widely known, though less general version, is the quickest flow problem (QFP). The QFP has historically been defined on a dynamic network, where time is divided into discrete units, flow moves through the network over time, travel times determine how long each unit of flow spends traversing an arc, and capacities restrict the rate of flow on an arc. The goal of the QFP is to determine the paths along which to send a given supply from a single source to a single sink such that the last unit of flow arrives at the sink in the minimum time. The main contribution of this paper is the time-dependent quickest flow (TDQFP) algorithm which solves the TDQFP, i.e. it solves the integral QFP, as defined above, on a time-dependent dynamic network, where the arc travel times, arc and node capacities, and supply at the source vary with time. Furthermore, this algorithm solves the time-dependent minimum time dynamic flow problem, whose objective is to determine the paths that lead to the minimum total time spent completing all shipments from source to sink. An optimal solution to the latter problem is guaranteed to be optimal for the TDQFP. By adding a small number of nodes and arcs to the existing network, we show how the algorithm can be used to solve both the time-dependent evacuation and the time-dependent quickest transshipment problems. This revised version was published online in August 2006 with corrections to the Cover Date.     

Tuning of size and shape of Au–Pt nanocatalysts for direct methanol fuel cells

In this article, we report the precise control of the size, shape, and surface morphology of Au–Pt nanocatalysts (cubes, blocks, octahedrons, and dogbones) synthesized via a seed-mediated approach. Gold “seeds” of different aspect ratios (1–4.2), grown by a silver-assisted approach, were used as templates for high-yield production of novel Au–Pt nanocatalysts at a low temperature (40 °C). Characterization by electron microscopy (SEM, TEM, HRTEM), energy dispersive X-ray analysis, UV–Vis spectroscopy, zeta-potential (surface charge), atomic force microscopy, X-ray photoelectron spectroscopy, and inductively coupled plasma mass spectrometry were used to better understand their physico-chemical properties, preferred reactivities and underlying nanoparticle growth mechanism. A rotating disk electrode was employed to evaluate the Au–Pt nanocatalysts electrochemical performance in the oxygen reduction reaction (ORR) and the methanol oxidation reaction of direct methanol fuel cells. The results indicate the Au–Pt dogbones are partially and in some cases completely unaffected by methanol poisoning during the evaluation of the ORR. The ORR performance of the octahedron particles in the absence of MeOH is superior to that of the Au–Pt dogbones and Pt-black; however, its performance is affected by the presence of MeOH.     

Design and enhanced gene silencing activity of spherical 2′-fluoroarabinose nucleic acids (FANA-SNAs)

Drug delivery vectors for nucleic acid therapeutics (NATs) face significant barriers for translation into the clinic. Spherical nucleic acids (SNAs) – nanoparticles with an exterior shell made up of DNA strands and a hydrophobic interior – have recently shown great potential as vehicles to improve the biodistribution and efficacy of NATs. To date, SNA design has not taken advantage of the powerful chemical modifications available to NATs. Here, we modify SNAs with 2′-deoxy-2′-fluoro-d-arabinonucleic acid (FANA-SNA), and show increased stability, enhanced gene silencing potency and unaided uptake (gymnosis) as compared to free FANA. By varying the spacer region between the nucleic acid strand and the attached hydrophobic polymer, we show that a cleavable DNA based spacer is essential for maximum activity. This design feature will be important when implementing functionalized nucleic acids into nanostructures for gene silencing. The modularity of the FANA-SNA was demonstrated by silencing two different targets. Transfection-free delivery was superior for the modified SNA compared to the free FANA oligonucleotide.

Optimizing FANA modified spherical nucleic acids (FANA-SNAs) for highly efficient delivery of nucleic acid therapeutics.     

Ab initio intermolecular energies between Li+ and H2 near the van der waals minimum: comparison between a perturbative procedure and an SCF supermolecule treatment

The electrostatic, exchange, polarization, and dispersion energies are computed without using the multipole expansion. It is seen that the overlap between the orbitals of the interacting molecules must be taken into account to describe qualitatively the first order term. The neglect of overlap in the polarization term overestimates the attractive energy around the van der Waals minimum. An interpretation of the polarization phenomena in terms of molecular orbitals is proposed. The results are compared with SCF calculations and the use of small basis sets is considered.     

Prediction of Migration Times of Organic Ions in Capillary Zone Electrophoresis

The electrophoretic mobility ratio (R value) of any two ions is constant and independent of the capillary type and electrophoretic conditions if their electrical charges and hydration radii are constant. The use of strong acid salts and quaternary ammonium salts is therefore proposed for the determination of R values. Such analytes are called markers. The following determinations can be carried out: (i) the determination of the migration time corresponding to the electroosmotic flow (EOF) in any capillary under any electrophoretic condition by measuring the migration times of two markers in the condition studied (useful when the EOF is weak); (ii) the determination of the migration time of an analyte in any capillary by knowing the migration time of the markers in the capillary studied. If the pH is changed and the ionization of the analyte is pH dependent, the resulting migration time for the analyte can be calculated. The constancy of the mobility ratios of seven markers was checked experimentally at eight different pH values (between pH 3 and 10), at three temperatures, and for two buffer concentrations. The predicted and experimental migration times were also compared in two different types of capillaries.     

The Caenorhabditis elegans DEG-3/DES-2 Channel Is a Betaine-Gated Receptor Insensitive to Monepantel

Natural plant compounds, such as betaine, are described to have nematocidal properties. Betaine also acts as a neurotransmitter in the free-living model nematode Caenorhabditis elegans, where it is required for normal motility. Worm motility is mediated by nicotinic acetylcholine receptors (nAChRs), including subunits from the nematode-specific DEG-3 group. Not all types of nAChRs in this group are associated with motility, and one of these is the DEG-3/DES-2 channel from C. elegans, which is involved in nociception and possibly chemotaxis. Interestingly, the activity of DEG-3/DES-2 channel from the parasitic nematode of ruminants, Haemonchus contortus, is modulated by monepantel and its sulfone metabolite, which belong to the amino-acetonitrile derivative anthelmintic drug class. Here, our aim was to advance the pharmacological knowledge of the DEG-3/DES-2 channel from C. elegans by functionally expressing the DEG-3/DES-2 channel in Xenopus laevis oocytes and using two-electrode voltage-clamp electrophysiology. We found that the DEG-3/DES-2 channel was more sensitive to betaine than ACh and choline, but insensitive to monepantel and monepantel sulfone when used as direct agonists and as allosteric modulators in co-application with betaine. These findings provide important insight into the pharmacology of DEG-3/DES-2 from C. elegans and highlight the pharmacological differences between non-parasitic and parasitic nematode species.