Combining Modular Ligation and Supramolecular Self‐Assembly for the Construction of Star‐Shaped Macromolecules

A well‐defined random copolymer of styrene (S) and chloromethylstyrene (CMS) featuring lateral chlorine moieties with an alkyne terminal group is prepared (P(S‐co‐CMS), = 5500 Da, PDI = 1.13). The chloromethyl groups are converted into Hamilton wedge (HW) entities (P(S‐co‐HWS), = 6200 Da, PDI = 1.13). The P(S‐co‐HWS) polymer is subsequently ligated with tetrakis(4‐azidophenyl)methane to give HW‐functional star‐shaped macromolecules (P(S‐co‐HWS))₄, = 25 100 Da, PDI = 1.08). Supramolecular star‐shaped copolymers are then prepared via self‐assembly between the HW‐functionalized four‐arm star‐shaped macromolecules ( P(S‐co‐HW )) ₄ and cyanuric acid (CA) end‐functionalized PS (PS–CA, = 3700 Da, PDI = 1.04), CA end‐functionalized poly(methyl methacrylate) (PMMA–CA, = 8500 Da, PDI = 1.13) and CA end‐functionalized polyethylene glycol (PEG–CA, = 1700 Da, PDI = 1.05). The self‐assembly is monitored by ¹H NMR spectroscopy and light scattering analyses.     

Developing On-Site Trace Level Speciation of Lead,Cadmium and Zinc by Stripping Chronopotentiometry (SCP): Fast Screening and Quantification of Total Metal Concentrations

Electrochemical stripping techniques are interesting candidates for carrying out onsite speciation of environmentally relevant trace metals due to the existing low-cost portable instrumentation available and the low detection limits that can be achieved. In this work, we describe the initial analytical technique method development by quantifying the total metal concentrations using Stripping Chronopotentiometry (SCP). Carbon paste screen-printed electrodes were modified with thin films of mercury and used to quantify sub-nanomolar concentrations of lead and cadmium and sub-micromolar concentrations of zinc in river water. Low detection limits of 0.06 nM for Pb(II) and 0.04 nM for Cd(II) were obtained by the standard addition method using a SCP deposition time of 180 s. The SCP results obtained for Pb(II) and Cd(II) agreed with those of inductively coupled plasma mass spectrometry (ICP-MS). The coupling of SCP with screen-printed electrodes opens up excellent potential for the development of onsite speciation of trace metals. Due to the low analysis throughput obtained for the standard addition method, we also propose a new, more rapid screening Cd(II) internal standard methodology to significantly increase the number of samples that can be analyzed per day.     

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.     

Evaluating Optical Quality of a Bifocal Soft Contact Lens in Near Vision Using a Shack–Hartmann Wavefront Aberrometer

To assess optical characteristics of bifocal soft contact lenses (BCLs) in use, we measured wavefront aberrations of human eyes, of eyes with a monofocal soft contact lens (MCL), and of eyes with a BCL. Modulation transfer functions (MTFs), Strehl ratios, and simulated images for far and near vision were produced with the measured aberrations. High order aberrations of subject 1 were significantly smaller than those of subject 2 (t-test, P = 0.001). We found that wearing the BCL improved the optical quality of an eye in subject 1, expressed as the horizontal MTF from 2 to 48 cycles per degree (cpd) for near vision and the Strehl ratio (t-test, P = 0.009 for Strehl ratio). But we did not find the same effect in subject 2. This difference may be due to the difference in the aberrations of the eyes of the two subjects.     

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.     

Electric properties of the water molecule in 1A1, 1B1, and 3B1 electronic states: Refined CASSCF and CASPT2 calculations

Summary The dipole moments and dipole polarizabilities of the ¹A₁, ¹B₁, and ³B₁ electronic states of the water molecule have been calculated by using the CASSCF approach followed by the evaluation of the dynamic electron correlation contribution by the second-order perturbation scheme CASPT2. All calculations have been carried out in a specifically extended ANO basis set which accounts for the Rydberg character of the two excited states. In order to estimate the correctness and accuracy of the present data a scan over a variety of different active spaces for the CASSCF wave function has been made. The present results are superior to earlier CASSCF calculations, although their qualitative features remain essentially the same. The dipole moments in ¹B₁ and ³B₁ states are predicted to be about 0.49 a.u. and 0.33 a.u., respectively, and have the opposite orientation with respect to the ground state dipole moment. The dipole polarizability tensors of the excited states are characterized by high anisotropy and are dominated by the in-plane component perpendicular to the symmetry axis. All their components are found to be about an order of magnitude larger than those of the ground state polarizability tensor. The excitation energy dependence on the choice of the active orbital space in the CASSCF reference function is also considered and the analysis of the present data concludes in the concept of what is called the mutually compatible active spaces for the two states involved in excitation. All CASPT2 results are in good agreement with the results of recent calculations carried out in the framework of the open-shell coupled cluster formalism. This agreement confirms the high efficiency of the CASSCF/CASPT2 approach to the treatment of the electron correlation effects.     

Odorant Receptor 7D4 Activation Dynamics

Deciphering how an odorant activates an odorant receptor (OR) and how changes in specific OR residues affect its responsiveness are central to understanding our sense of smell. A joint approach combining site‐directed mutagenesis and functional assays with computational modeling has been used to explore the signaling mechanics of OR7D4. In this OR, a genetic polymorphism affects our perception of androstenone. Molecular simulations totaling 0.12 ms predicted that, similarly to observations for other G‐protein‐coupled receptors with known experimental structures, an activation pathway connects the ligand and the G‐protein binding site. The 3D model activation mechanism correlates with in vitro data and notably predicts that the OR7D4 WM variant is not activated. Upon activation, an OR‐specific sequence motif is the convergence point of the mechanism. Our study suggests that robust homology modeling can serve as a powerful tool to capture OR dynamics related to smell perception.     

Generation of polymerosomes from double-emulsions

Diblock copolymers are known to spontaneously organize into polymer vesicles. Typically, this is achieved through the techniques of film rehydration or electroformation. We present a new method for generating polymer vesicles from double emulsions. We generate precision water-in-oil-in-water double emulsions from the breakup of concentric fluid streams; the hydrophobic fluid is a volatile mixture of organic solvent that contains dissolved diblock copolymers. We collect the double emulsions and slowly evaporate the organic solvent, which ultimately directs the self-assembly of the dissolved diblock copolymers into vesicular structures. Independent control over all three fluid streams enables precision assembly of polymer vesicles and provides for highly efficient encapsulation of active ingredients within the polymerosomes. We also use double emulsions with several internal drops to form new polymerosome structures.     

Synthesis and 1H NMR structural analysis of 11‐aryl/heteroarylnaphtha[2,1‐b]furans: X‐ray crystal structure of 11‐(4′‐pyridyl)naphtho[2,1 ‐b]furan

Synthesis of biaryl type systems, 11‐aryl/heteroarylnaphtho[2,1‐b]furans 8‐11 has been described with a view to studying the conformational orientation of C‐11 aryl/heteroaryl groups. Synthesis of 8‐11 was accomplished by a two‐step sequence involving O‐alkylation of 2‐naphthol with appropriate halo‐ketones 2‐4 , followed by cyclization of the resulting naphthoxy‐ketones 5‐7 with methanesulphonic acid. The structures of 8‐11 are based on detailed 2D NMR spectral analysis. The H8 in these compounds is not subject to significant anisotropic upfield shielding effects. The slightly upfield chemical shift of H8 in molecules 9‐11 , relative to 8 has been correlated with the electron density at C17 and C8 positions. While molecular modeling indicated dihedral angle (φ) between the C11 aryl/heteroaryl groups and the naphthofuran plane to be in the range of 70–60° in 8‐10 , a single X‐ray crystal structural analysis of 11‐(4′‐pyridyl)naphtho[2,1‐b]furan 10 indicated (φ) of 64.36°. In view of significant deviations from the orthogonal oreintation, the absence of any significant anisotropic shielding in 8‐11 is not entirely unexpected.