Classification tree models for the prediction of blood-brain barrier passage of drugs

The use of classification trees for modeling and predicting the passage of molecules through the blood-brain barrier was evaluated. The models were built and evaluated using a data set of 147 molecules extracted from the literature. In the first step, single classification trees were built and evaluated for their predictive abilities. In the second step, attempts were made to improve the predictive abilities using a set of 150 classification trees in a boosting approach. Two boosting algorithms, discrete and real adaptive boosting, were used and compared. High-predictive classification trees were obtained for the data set used, and the models could be improved with boosting. In the context of this research, discrete adaptive boosting gives slightly better results than real adaptive boosting.     

Chiral separation strategy in polar organic solvent chromatography and performance comparison with normal-phase liquid and supercritical-fluid chromatography

A strategy, including a rapid screening and several optimisation steps, for the separation of chiral molecules of pharmaceutical interest by polar organic solvent chromatography (POSC), using four polysaccharide-based stationary phases, is proposed and compared with previously reported strategies in normal-phase (NPLC) and supercritical fluid chromatography (SFC). In a first part of this paper, different examples demonstrate the effectiveness of the POSC strategy for fast method development. Optimisation is based on the use of experimental design to map the experimental domain in an efficient way. In the second part, the best screening results, obtained after performance of earlier defined chromatographic screening strategies in NPLC and SFC, are compared to those obtained in POSC. The three techniques show complementary separation results and allowed baseline separation of 23 of 25 compounds. POSC is found to be a very interesting separation mode compared to NPLC, because of the many fast (< 10 min) baseline separations obtained.     

On Entropic Reduction of Fluctuations

We point out that there is no general relation between ground state degeneracy and finite-temperature fluctuations for tilted interfaces.     

Strongly Correlated Alignment of Fluorinated 5,11‐Bis(triethylgermylethynyl)anthradithiophene Crystallites in Solution‐Processed Field‐Effect Transistors

The crystallinity of an organic semiconductor film determines the efficiency of charge transport in electronic devices. This report presents a micro‐to‐nanoscale investigation on the crystal growth of fluorinated 5,11‐bis(triethylgermylethynyl)anthradithiophene (diF‐TEG‐ADT) and its implication for the electrical behavior of organic field‐effect transistors (OFETs). diF‐TEG‐ADT exhibits remarkable self‐assembly through spin‐cast preparation, with highly aligned edge‐on stacking creating a fast hole‐conducting channel for OFETs.     

Robust calibrations on reduced sample sets for API content prediction in tablets: Definition of a cost-effective NIR model development strategy

Owing to spectral variations from other sources than the component of interest, large investments in the NIR model development may be required to obtain satisfactory and robust prediction performance. To make the NIR model development for routine active pharmaceutical ingredient (API) prediction in tablets more cost-effective, alternative modelling strategies were proposed. They used a massive amount of prior spectral information on intra- and inter-batch variation and the pure component spectra to define a clutter, i.e., the detrimental spectral information. This was subsequently used for artificial data augmentation and/or orthogonal projections. The model performance improved statistically significantly, with a 34–40% reduction in RMSEP while needing fewer model latent variables, by applying the following procedure before PLS regression: (1) augmentation of the calibration spectra with the spectral shapes from the clutter, and (2) net analyte pre-processing (NAP). The improved prediction performance was not compromised when reducing the variability in the calibration set, making exhaustive calibration unnecessary. Strong water content variations in the tablets caused frequency shifts of the API absorption signals that could not be included in the clutter. Updating the model for this kind of variation demonstrated that the completeness of the clutter is critical for the performance of these models and that the model will only be more robust for spectral variation that is not co-linear with the one from the property of interest.     

Selective Introduction of Sulfhydryl Groups into Recombinant Proteins for Study of Protein–Protein Interactions

In the present work, we proposed to create special sorbents for the study of protein–protein interactions, based on the fixation of cysteine-inserted beta-casein mutants with thiol-Sepharose resin. As a model system, we used bovine beta-casein, which belongs to the family of intrinsically unstructured proteins. Insertion of distal cysteines into the unfolded protein was not found to significantly change beta-casein properties. An amphiphilic beta-casein molecule has one hydrophilic domain and one hydrophobic domain placed on the N- and C-terminus, thus enabling one to exploit its capacity to engage in different types of intermolecular interactions. Two different casein-Sepharose sorbents incorporating either C-4 or C-208 beta-casein mutants bound to thiol-Sepharose were produced, exposing the hydrophobic domain in the case of the C-4 and the hydrophilic domain in the case of the C-208 mutant, respectively. The results obtained using the proposed sorbents with native beta-casein, another partially unfolded protein prion, and an oligomeric globular glyceraldehyde-3-phosphate dehydrogenase were found to be consistent with the data obtained by ELISA on free protein–protein complexes. Thus, Sepharose modified with various proteins is suitable for isolation of proteins interacting with the chromatographic phase bound partners from multicomponent systems such as milk. The obtained results allow the proposing of a fast and convenient method to be used for isolation of proteins, determination of protein-interacting partners, and the study of multi-protein complexes.

     

Diastereoselective Hydrogen‐Transfer Reactions: An Experimental and DFT Study

Radical reductions of halogenated precursors bearing a heterocycle exo (α) to the carbon‐centered radical proceed with enhanced anti‐selectivity, a phenomenon that we termed “exocyclic effect”. New experimental data and DFT calculations at the BHandHLYP/TZVP level demonstrate that the origin of the exocyclic effect is linked to the strain energy required for a radical intermediate to reach its reactive conformation at the transition state (ΔE^≠_strain). Furthermore, radical reductions of constrained THP systems indicate that high 2,3‐anti inductions are reached only when the radical chain occupies an equatorial orientation. Hydride deliveries to different acyclic substrates and calculations also suggest that the higher anti‐selectivities obtained with borinate intermediates are not related to the formation of a complex mimicking an exocycle. From a broader standpoint, this study reveals important conformational factors for reactions taking place at a center vicinal to a heterocycle or an α‐alkoxy group.     

Mukaiyama aldolisation reactions of α,β-epoxyaldehydes in aqueous media

The Mukaiyama aldolisation reaction in aqueous media of cis and trans α,β-epoxyaldehydes with tert-butyldimethylsilyl ketene acetal in the presence of Lewis's acids was studied. Sc(OTf)₃ gave the best results in terms of selectivity. The same reaction of cis and trans α,β-epoxyaldehydes with the enoxysilane of ethyl pyruvate resulted in epoxy substituted ulosonic derivatives issued from a double sequential condensation of the pyruvate on the epoxy derivatives.     

Microwave-assisted extraction of phenolic antioxidants from potato peels

A response surface method was used to optimize the microwave-assisted extraction parameters such as extraction time (t) (min), solvent (methanol) concentration (S) (v/v) and microwave power level (MP) for extraction of antioxidants from potato peels. Max. total phenolics content of 3.94 mg g?1 dry weight (dw) was obtained at S of 67.33%, t of 15 min and a MP of 14.67%. For ascorbic acid (1.44 mg g?1 dw), caffeic acid (1.33 mg g?1 dw), ferulic acid (0.50 mg g?1 dw) max contents were obtained at S of 100%, t of 15 min, and MP of 10%, while the max chlorogenic acid content (1.35 mg g?1 dw) was obtained at S of 100%, t of 5 min, and MP of 10%. The radical scavenging activity of the extract was evaluated by using the DPPH assay and optimum antioxidant activity was obtained at S of 100%, t of 5 min, and MP of 10%.     

Inelastic interaction of nearly equal solitons for the quartic gKdV equation

This paper describes the interaction of two solitons with nearly equal speeds for the quartic (gKdV) equation

$\partial_tu+\partial_x(\partial_x^2u+u^4)=0,\quad t,x\in \mathbb{R}.$

(0.1)

We call soliton a solution of (0.1) of the form u(t,x)=Q _c (x?ct?y ₀), where c>0, y ₀∈? and \(Q_{c}''+Q_{c}^{4}=cQ_{c}\). Since (0.1) is not an integrable model, the general question of the collision of two given solitons \(Q_{c_{1}}(x-c_{1}t)\), \(Q_{c_{2}}(x-c_{2}t)\) with c ₁≠c ₂ is an open problem.

We focus on the special case where the two solitons have nearly equal speeds: let U(t) be the solution of (0.1) satisfying

$\lim_{t\to-\infty}\|{U}(t)-Q_{c_1^-}(.-c_1^-t)-Q_{c_2^-}(.-c_2^-t)\|_{H^1}=0,$

for \(\mu_{0}=(c_{2}^{-}-c_{1}^{-})/(c_{1}^{-}+c_{2}^{-})>0\) small. By constructing an approximate solution of (0.1), we prove that, for all time t∈?,

$\begin{array}{l}\displaystyle{U}(t)={Q}_{c_1(t)}(x-y_1(t))+{Q}_{c_2(t)}(x-y_2(t))+{w}(t)\\[6pt]\displaystyle\quad\mbox{where }\|w(t)\|_{H^1}\leq|\ln\mu_0|\mu_0^2,\end{array}$

with y ₁(t)?y ₂(t)>2|ln?μ ₀|+C, for some C∈?. These estimates mean that the two solitons are preserved by the interaction and that for all time they are separated by a large distance, as in the case of the integrable KdV equation in this regime.

However, unlike in the integrable case, we prove that the collision is not perfectly elastic, in the following sense, for some C>0,

$\lim_{t\to+\infty}c_1(t)>c_2^-\biggl(1+\frac{\mu_0^5}{C}\biggr),\quad \lim_{t\to+\infty}c_2(t)

and \({w}(t)\not\to0\) in H ¹ as t→+∞.