Comparison of structure fingerprint and molecular interaction field based methods in explaining biological similarity of small molecules in cell-based screens

In this work, we calculated the pair wise chemical similarity for a subset of small molecules screened against the NCI60 cancer cell line panel. Four different compound similarity calculation methods were used: Brutus, GRIND, Daylight and UNITY. The chemical similarity scores of each method were related to the biological similarity data set. The same was done also for combinations of methods. In the end, we had an estimate of biological similarity for a given chemical similarity score or combinations thereof. The data from above was used to identify chemical similarity ranges where combining two or more methods (data fusion) led to synergy. The results were also applied in ligand-based virtual screening using the DUD data set. In respect to their ability to enrich biologically similar compound pairs, the ranking of the four methods in descending performance is UNITY, Daylight, Brutus and GRIND. Combining methods resulted always in positive synergy within a restricted range of chemical similarity scores. We observed no negative synergy. We also noted that combining three or four methods had only limited added advantage compared to combining just two. In the virtual screening, using the estimated biological similarity for ranking compounds produced more consistent results than using the methods in isolation.     

Origin of the failure of classical nucleation theory: incorrect description of the smallest clusters

We carry out molecular Monte Carlo simulations of clusters in an imperfect vapor. We show that down to very small cluster sizes, classical nucleation theory built on the liquid drop model can be used very accurately to describe the work required to add a monomer to the cluster. However, the error made in modeling the smallest of clusters as liquid drops results in an erroneous absolute value for the cluster work of formation throughout the size range. We calculate factors needed to correct the cluster formation work given by the liquid drop model. The corrected work of formation results in nucleation rates in good agreement with recent nucleation experiments on argon and water.     

Improving the mechanical properties of CNF films by NMMO partial dissolution with hot calender activation

Reinforcing of cellulose nanofibril (CNF) films by partial dissolution with N-methylmorpholine-N-oxide (NMMO) was investigated. The method investigated is composed of impregnation of CNF film with liquid solution of NMMO followed by dry heat activation. The heat activation of the impregnated film was carried out using a heated calendering nip, which enabled simultaneous heating and compression. The partial dissolution of cellulose by NMMO caused a significant increase in the transparency of CNF film due to the decrease of film porosity and increased surface smoothness. The dry strength of the reinforced film was increased from 122 up to 195 MPa. Furthermore, the wet strength of the reinforced film was up to 70% greater than the dry strength of pure CNF film. The changes in the fibrillar structure were investigated with topographical imaging (SEM and AFM) and spectroscopically using NMR and FTIR. No significant changes in the fibril structure or cellulose morphology were observed. Moreover, the treated film resisted significant water pressure, highlighting CNF film’s permanent water resistance. The partial dissolution process with NMMO was also capable of reinforcing a CNF composite film with macro scale structural elements (lyocell short-cut fibres). The strategy investigated is a robust and fast method to improve the mechanical properties of fibrillary cellulose films, allowing them utilization in applications where improved water resistance and fully cellulosic character are required properties.     

Local Semicircle Law for Random Regular Graphs

We consider random d‐regular graphs on N vertices, with degree d at least (log N)⁴. We prove that the Green's function of the adjacency matrix and the Stieltjes transform of its empirical spectral measure are well approximated by Wigner's semicircle law, down to the optimal scale given by the typical eigenvalue spacing (up to a logarithmic correction). Aside from well‐known consequences for the local eigenvalue distribution, this result implies the complete (isotropic) delocalization of all eigenvectors and a probabilistic version of quantum unique ergodicity.© 2017 Wiley Periodicals, Inc.     

LC-MS/MS profiling for detection of endogenous steroids and prostaglandins in tissue samples

Roles of steroid hormones, and compounds that can influence their levels in cells, are of increasing interest in e.g. cancer research, partly because resistance to hormone therapies often complicates treatment. To elucidate the processes involved, the hormones and related compounds need to be accurately measured. Reversed-phase liquid chromatography with dynamic multiple reaction monitoring mass spectrometric detection in electrospray mode is capable of providing such measurements. Therefore, LC-MS/MS was developed for sensitive, selective analysis of 11 steroid hormones, cholesterol and two prostaglandins. The effects of the tissue matrix, and solid-phase extraction (SPE) sample clean-up, on the LC-MS/MS signals of the hormones were also investigated. The results show that the developed LC-MS/MS method, following SPE clean-up to reduce matrix interference, can detect selected steroids in extracts of mouse tissues. The method provides linear measurements of the steroids at concentrations up to few ng/μL, and limits of detection in the range 0.03-0.2 pg/μL (for some compounds lower than those of previously reported methods).     

Toeplitz Operators on Bloch-type Spaces and Classes of Weighted Sobolev Distributions

We study Toeplitz operators between analytic Bloch-type spaces of the unit disk. We construct suitable classes of distributions that generate bounded Toeplitz operators between these spaces. The classes are naturally connected to the corresponding results in the reflexive Bergman space setting and previously known results on A ¹ and the Bloch space. We also study distributional symbols satisfying logarithmic BMO-condition. In addition, sufficient compactness criteria are provided.     

Structural principles of semiconducting Group 14 clathrate frameworks

We have performed a comprehensive theoretical investigation of the structural principles of semiconducting clathrate frameworks composed of the Group 14 elements carbon, silicon, germanium, and tin. We have investigated the basic clathrate frameworks, together with their polytypes, intergrowth clathrate frameworks, and extended frameworks based on larger icosahedral building blocks. Quantum chemical calculations with the PBE0 hybrid density functional method provided a clear overview of the structural trends and electronic properties among the various clathrate frameworks. In agreement with previous experimental and theoretical studies, the clathrate II framework proved to be the energetically most favorable, but novel hexagonal polytypes of clathrate II also proved to be energetically very favorable. In the case of silicon, several of the studied clathrate frameworks possess direct and wide band gaps. The band structure diagrams and simulated powder X-ray patterns of the studied frameworks are provided and systematic preliminary evaluation of guest-occupied frameworks is conducted to shed light on the characteristics of novel, experimentally feasible clathrate compositions.     

Comprehensive core-level study of the effects of isomerism, halogenation, and methylation on the tautomeric equilibrium of cytosine

Core-level X-ray photoemission and near-edge X-ray absorption fine structure spectra of 5-methylcytosine, 5-fluorocytosine, and isocytosine are presented and discussed with the aid of high-level ab initio calculations. The effects of the methylation, halogenation, and isomerization on the relative stabilities of cytosine tautomers are clearly identified spectroscopically. The hydroxy-oxo tautomeric forms of these molecules have been identified, and their quantitative populations at the experimental temperature are calculated and compared with the experimental results and with previous calculations. The calculated values of Gibbs free energy and Boltzmann population ratios are in good agreement with the experimental results characterizing tautomer equilibrium.     

Solutions to and Validation of Matrix-Diffusion Models

A model transport system is considered in which a pulse of tracer molecules is advected along a flow channel with porous walls. The advected tracer thus undergoes diffusion, matrix-diffusion, inside the walls, which affects the breakthrough curve of the tracer. Analytical solutions in the form of series expansions are derived for a number of situations which include a finite depth of the porous matrix, varying aperture of the flow channel, and longitudinal diffusion and Taylor dispersion of the tracer in the flow channel. Novel expansions for the Laplace transforms of the concentration in the channel facilitated closed-form expressions for the solutions. A rigorous result is also derived for the asymptotic form of the breakthrough curve for a finite depth of the porous matrix, which is very different from that for an infinite matrix. A specific experimental system was created for validation of matrix-diffusion modeling for a matrix of finite depth. A previously reported fracture-column experiment was also modeled. In both cases model solutions gave excellent fits to the measured breakthrough curves with very consistent values for the diffusion coefficients used as the fitting parameters. The matrix-diffusion modeling performed could thereby be validated.     

Quantum Diffusion and Delocalization for Band Matrices with General Distribution

We consider Hermitian and symmetric random band matrices H in d \geqslant 1{d \geqslant 1} dimensions. The matrix elements H _xy , indexed by x,y ? L ì \mathbbZ^d{x,y \in \Lambda \subset \mathbb{Z}^d}, are independent and their variances satisfy s_xy²:=\mathbbE |H_xy|² = W^-d f((x - y)/W){\sigma_{xy}^2:=\mathbb{E} |{H_{xy}}|^2 = W^{-d} f((x - y)/W)} for some probability density f. We assume that the law of each matrix element H _xy is symmetric and exhibits subexponential decay. We prove that the time evolution of a quantum particle subject to the Hamiltonian H is diffusive on time scales t << W^d/3{t\ll W^{d/3}} . We also show that the localization length of the eigenvectors of H is larger than a factor W^d/6{W^{d/6}} times the band width W. All results are uniform in the size |Λ| of the matrix. This extends our recent result (Erdős and Knowles in Commun. Math. Phys., 2011) to general band matrices. As another consequence of our proof we show that, for a larger class of random matrices satisfying ?_xs_xy²=1{\sum_x\sigma_{xy}^2=1} for all y, the largest eigenvalue of H is bounded with high probability by 2 + M^{-2/3 + e}{2 + M^{-2/3 + \varepsilon}} for any ${\varepsilon > 0}${\varepsilon > 0}, where M : = 1 / (max_x,ys_xy²){M := 1 / (\max_{x,y}\sigma_{xy}^2)} .