Sterol 14alpha-demethylase as a potential target for antitrypanosomal therapy: enzyme inhibition and parasite cell growth

Sterol 14alpha-demethylases (CYP51) serve as primary targets for antifungal drugs, and specific inhibition of CYP51s in protozoan parasites Trypanosoma brucei (TB) and Trypanosoma cruzi (TC) might provide an effective treatment strategy for human trypanosomiases. Primary inhibitor selection is based initially on the cytochrome P450 spectral response to ligand binding. Ligands that demonstrate strongest binding parameters were examined as inhibitors of reconstituted TB and TC CYP51 activity in vitro. Direct correlation between potency of the compounds as CYP51 inhibitors and their antiparasitic effect in TB and TC cells implies essential requirements for endogenous sterol production in both trypanosomes and suggests a lead structure with a defined region most promising for further modifications. The approach developed here can be used for further large-scale search for new CYP51 inhibitors.     

Combined molecular and supramolecular bottom-up nanoengineering for enhanced nonlinear optical response: experiments, modeling, and approaching the fundamental limit

The authors study the combination of two independent strategies that enhance the hyperpolarizability of ionic organic chromophores. The first molecular-level strategy is the extension of the conjugation path in the active chromophore. The second supramolecular-level strategy is the bottom-up nanoengineering of an inclusion complex of the chromophore in an amylose helix by self-assembly. The authors study a series of five (dimethylamino)stilbazolium-type chromophores with increasing conjugation length between the (dimethylamino)phenyl donor ring and the pyridinium acceptor ring in conjunction with four amylose helices of differing molecular weights. The first hyperpolarizabilities of the self-assembled inclusion complexes, as determined with frequency-resolved femtosecond hyper-Rayleigh scattering at 800 and 1300 nm, are compared with experimental values for the free chromophores in solution and with theoretical values. While the experimental values for the hyperpolarizability in solution are lower than the theoretically predicted values, an enhancement upon inclusion is observed, with the longest chromophore in the best amylose helix showing an enhancement by one order of magnitude. Molecular modeling of the inclusion of the chromophore suggests that the coplanarity of the two rings is more important than all-trans configuration in the conjugation path. The fundamental limit analysis indicates that the inclusion inside the amylose helix results in an optimal excited-level energy spacing that is responsible for breaching the apparent limit.     

Broadband 10 Gb/s operation of graphene electro‐absorption modulator on silicon

High performance integrated optical modulators are highly desired for future optical interconnects. The ultra‐high bandwidth and broadband operation potentially offered by graphene based electro‐absorption modulators has attracted a lot of attention in the photonics community recently. In this work, we theoretically evaluate the true potential of such modulators and illustrate this with experimental results for a silicon integrated graphene optical electro‐absorption modulator capable of broadband 10 Gb/s modulation speed. The measured results agree very well with theoretical predictions. A low insertion loss of 3.8 dB at 1580 nm and a low drive voltage of 2.5 V combined with broadband and athermal operation were obtained for a 50 μm‐length hybrid graphene‐Si device. The peak modulation efficiency of the device is 1.5 dB/V. This robust device is challenging best‐in‐class Si (Ge) modulators for future chip‐level optical interconnects.     

Stress relaxation as a microstructural probe for immiscible polymer blends

Relaxation has been investigated in immiscible blends that consist of slightly viscoelastic components. Both the shear and normal stresses have been measured after cessation of steady shear flow as well as after transient shear histories. The latter can generate a fibrillar structure which can relax by either retraction or break-up via end-pinching or Rayleigh instabilities. Each of these three relaxation mechanisms is reflected in the shape of the stress curves, from which also the corresponding structural time scales can be deduced. The experimental results have been used to evaluate the Doi-Ohta and Lee-Park models for immiscible blends. The scaling relations by Doi-Ohta are confirmed by the experimental results, but none of the existing models can correctly predict the complex relaxation behaviour observed for a highly deformed droplet phase. In the present study an alternative approach has been proposed. The stress relaxation due to fibril break-up via Rayleigh instabilities has been predicted successfully by combining physical models for the structural changes with the basic approach of the Doi-Ohta model.     

Asymmetric synthesis of chiral tectons with tetrapodal symmetry: fourfold asymmetric reactions

The diastereoselective fourfold addition to Ellman-type imines furnished after deprotection the tetrapodal amines in excellent yields. The unprecedented asymmetric fourfold addition of hydride and alkylzinc reagents to tetrapodal ketones and aldehydes, respectively, is achieved by employing CBS-reduction or [2.2]paracyclophane-based ketimine ligands with good to excellent global enantiomeric ratios.     

Antimicrobial equipment of poly(isoprene) applying thiol‐ene chemistry

The functionalization of anionically polymerized isoprene with cysteamine applying the thiol‐ene reaction is reported. Antimicrobial activity is implemented by quaternization of the amino functionality by either alkylation or by protonation. The resulting polymers were tested against Gram‐positive as well as Gram‐negative bacteria strains according to the Japanese Industrial Standard Z2801:2000 protocol, partly revealing excellent biocidal performance. Thermal stability up to 200°C allows extrusion processing of the functionalized poly(isoprene)s. The best performing polymer, that is, bearing butylated ammonium‐groups, was compounded with the commodity material poly(propylene). The compound bearing 5 wt % of the biocidal polymer exhibited satisfactory biocidal properties. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Penalised spline support vector classifiers: computational issues

We study computational issues for support vector classification with penalised spline kernels. We show that, compared with traditional kernels, computational times can be drastically reduced in large problems making such problems feasible for sample sizes as large as ~10⁶. The optimisation technology known as interior point methods plays a central role. Penalised spline kernels are also shown to allow simple incorporation of low-dimensional structure such as additivity. This can aid both interpretability and performance.