Discovery of DNA dyes Hoechst 34580 and 33342 as good candidates for inhibiting amyloid beta formation: in silico and in vitro study

Combining Lipinski’s rule with the docking and steered molecular dynamics simulations and using the PubChem data base of about 1.4 million compounds, we have obtained DNA dyes Hoechst 34580 and Hoechst 33342 as top-leads for the Alzheimer’s disease. The binding properties of these ligands to amyloid beta (Aβ) fibril were thoroughly studied by in silico and in vitro experiments. Hoechst 34580 and Hoechst 33342 prefer to locate near hydrophobic regions with binding affinity mainly governed by the van der Waals interaction. By the Thioflavin T assay, it was found that the inhibition constant IC50 ≈ 0.86 and 0.68 μM for Hoechst 34580 and Hoechst 33342, respectively. This result qualitatively agrees with the binding free energy estimated using the molecular mechanic-Poisson Boltzmann surface area method and all-atom simulations with the AMBER-f99SB-ILDN force field and water model TIP3P. In addition, DNA dyes have the high capability to cross the blood brain barrier. Thus, both in silico and in vitro experiments have shown that Hoechst 34580 and 33342 are good candidates for treating the Alzheimer’s disease by inhibiting Aβ formation.     

Modular curves and bases for the spaces of cuspidal modular forms

Let Γ⊂SL ₂(ℝ) be a Fuchsian group of the first kind. For a character χ of Γ→ℂ^× of finite order, we define the usual space S _m (Γ,χ) of cuspidal modular forms of weight m≥0. For each ξ in the upper half–plane and m≥3, we construct cuspidal modular forms Δ _k,m,ξ,χ ∈S _m (Γ,χ) (k≥0) which represent the linear functionals f?\fracd^kfdz^k|_z=xf\mapsto\frac{d^{k}f}{dz^{k}}|_{z=\xi} in terms of the Petersson inner product. We write their Fourier expansion and use it to write an expression for the Ramanujan Δ-function. Also, with the aid of the geometry of the Riemann surface attached to Γ, for each non-elliptic point ξ and integer m≥3, we construct a basis of S _m (Γ,χ) out of the modular forms Δ _k,m,ξ ,χ (k≥0). For Γ=Γ ₀(N), we use this to write a matrix realization of the usual Hecke operators T _p for S _m (N,χ).     

Catalytic Water Oxidation by Ruthenium(II) Quaterpyridine (qpy) Complexes: Evidence for Ruthenium(III) qpy‐N,N′′′‐dioxide as the Real Catalysts

Polypyridyl and related ligands have been widely used for the development of water oxidation catalysts. Supposedly these ligands are oxidation‐resistant and can stabilize high‐oxidation‐state intermediates. In this work a series of ruthenium(II) complexes [Ru(qpy)(L)₂]²⁺ (qpy=2,2′:6′,2′′:6′′,2′′′‐quaterpyridine; L=substituted pyridine) have been synthesized and found to catalyze Ce^IV‐driven water oxidation, with turnover numbers of up to 2100. However, these ruthenium complexes are found to function only as precatalysts; first, they have to be oxidized to the qpy‐N,N′′′‐dioxide (ONNO) complexes [Ru(ONNO)(L)₂]³⁺ which are the real catalysts for water oxidation.     

Rapid discovery of inhibitors of <Emphasis Type="Italic">Toxoplasma gondii</Emphasis> using hybrid structure-based computational approach

Toxoplasma (T.) gondii, the causative agent of toxoplasmosis, is a ubiquitous opportunistic pathogen that infects individuals worldwide, and is a leading cause of severe congenital neurologic and ocular disease in humans. No vaccine to protect humans is available, and hypersensitivity and toxicity limit the use of the few available medicines. Therefore, safer and more effective medicines to treat toxoplasmosis are urgently needed. Using the Hybrid Structure Based (HSB) method, we have previously identified small molecule inhibitors of P. falciparum that seem to target a novel protein–protein interaction between the Myosin tail interacting protein and myosin light chain. This pathway has been hypothesized to be involved in invasion of host erythrocytes by the parasite and is broadly conserved among the apicomplexans. Guided by similar computational drug design approaches, we investigated this series of small molecules as potential inhibitors of T. gondii. Compound C3-21, identified as the most active inhibitor in this series, exhibited an IC₅₀ value ~500 nM against T. gondii. Among the 16 structural analogs of C3-21 tested thus far, nine additional compounds were identified with IC₅₀ values <10.0 μM. In vitro assays have revealed that C3-21 markedly limits intracellular growth of T. gondii tachyzoites, but has no effect on host cell human foreskin fibroblasts (HFF) at concentrations more than a log greater than the concentration that inhibits the parasites.     

Formal approaches to rule-based systems in medicine: The case of CADIAG-2

There is no established formal framework for expert systems based on weighted IF–THEN rules. We discuss three mathematical models that have been recently proposed by the authors for CADIAG-2—a well-known system of this kind. The three frameworks are based on fuzzy logics, probability theory and possibilistic logic, respectively. CADIAG-2 is used here as a case study to evaluate these frameworks. We point out their use, advantages and disadvantages. In addition, the described models provide insight into various aspects of CADIAG-2.     

On degrees and birationality of the maps $$X_0(N)\rightarrow \mathbb P^2$$ X 0 ( N ) → P 2 constructed via modular forms

Monatshefte für Mathematik - In this paper we prove a formula which relates the degree of a curve which is the image of a mapping $$z\longmapsto (f(z): g(z): h(z))$$ constructed out of three...     

Measurement of glutathione in human brain at 3T using an improved double quantum filter in vivo

A single voxel proton NMR double quantum filter (DQF) for measurement of glutathione (GSH) in human brain at 3T is reported. Yield enhancement for the CH₂ resonances of the cysteine moiety at 2.95 ppm has been achieved by means of dual encoding. After the preparation of double quantum and zero quantum coherences (DQC and ZQC) at equal magnitude, the first DQC encoding was followed by interchange of DQC and ZQC, and another DQC encoding. The multi-quantum coherences were fully utilized to generate a GSH target signal at 2.95 ppm. The optimal echo time and the editing efficiency were obtained with numerical analysis of the filtering performance and phantom measurements. The dual-DQC encoding method provided GSH yield greater by a factor of 2.1 than single-DQC encoding for identical slice-selective RF pulses in phantom tests. Using the phantom relaxation times and the ratio of edited GSH to N-acetylaspartate (NAA) 2.0-ppm peak areas, the concentration of GSH in the medial parietal cortex of the healthy human brain in vivo was estimated to be 1.0 ± 0.3 mM (mean ± SD, n = 7), with reference to NAA at 10 mM.