Compound set enrichment: a novel approach to analysis of primary HTS data

The main goal of high-throughput screening (HTS) is to identify active chemical series rather than just individual active compounds. In light of this goal, a new method (called compound set enrichment) to identify active chemical series from primary screening data is proposed. The method employs the scaffold tree compound classification in conjunction with the Kolmogorov-Smirnov statistic to assess the overall activity of a compound scaffold. The application of this method to seven PubChem data sets (containing between 9389 and 263679 molecules) is presented, and the ability of this method to identify compound classes with only weakly active compounds (potentially latent hits) is demonstrated. The analysis presented here shows how methods based on an activity cutoff can distort activity information, leading to the incorrect activity assignment of compound series. These results suggest that this method might have utility in the rational selection of active classes of compounds (and not just individual active compounds) for followup and validation.     

Observation of highly flexible residues in amyloid fibrils of the HET-s prion

We report the observation of undetected (until now) residues of the prion protein fragment HET-s(218-289) which give rise to well-resolved (13)C, (15)N, and (1)H NMR resonances under high-resolution magic-angle spinning (HRMAS) conditions. The observed signals belong to large polymeric units as shown by measuring the lateral diffusion constants. The amino acids identified in the spectra are compatible with their localization in the segments of the protein which could not be detected in earlier solid-state NMR experiments. The observed chemical shifts indicate that these residues are in a random-coil conformation. Complementary experiments which detect only dynamic or static residues, respectively, strongly suggest that they belong to different parts of the same molecule.     

A steady-state system in non-equilibrium thermodynamics including thermal and electrical effects

The steady-state equations for a charged gas or fluid consisting of several components, exposed to an electric field, are considered. These equations form a system of strongly coupled, quasilinear elliptic equations which in some situations can be derived from the Boltzmann equation. The model uses the duality between the thermodynamic fluxes and the thermodynamic forces. Physically motivated mixed Dirichlet–Neumann boundary conditions are prescribed. The existence of generalized solutions is proven. The key of the proof is a transformation of the problem by using the entropic variables, or electro-chemical potentials, which symmetrize the equations. The uniqueness of weak solutions is shown under the assumption that the boundary data are not far from the thermal equilibrium. A general uniqueness result cannot be expected for physical reasons. © 1998 B. G. Teubner Stuttgart—John Wiley & Sons, Ltd.     

Poly[(methylene oxide) oligo(ethylene oxide)] vs. poly(ethylene oxide) as hosts for neodymium compounds

In view of the residual crystallinity in PEO found to limit the solubility of some Nd³⁺-compounds, amorphous PEO (aPEO) was synthesized for exploration as an alternative host. Complexation, solubility limit, morphology, and response to moisture absorption in the doped systems were investigated using FTIR, DSC, TGA, and WAXD techniques. Representing a perturbation to the structural regularity present in PEO, aPEO was found to present lower solubilities for dopants (Nd(act)₃ and Nd(acac)₃, both characterized by a weak Nd³⁺–ether oxygen interaction. On the other hand, no difference in solubility was observed for dopant Nd(NO₃)₃, characterized by a strong Nd³⁺–ether oxygen interaction. Laser interferometry was employed to assess film homogeneity of the Nd(NO₃)₃-doped systems across a 20-mm diameter, and the measured peak-to-valley distortion values were observed to be encouraging for practical applications. © 1994 John Wiley & Sons, Inc.     

Electroweak corrections to monojet production at the Tevatron and the LHC

The first LHC results seem to disfavor, from the point of view of naturalness, any constrained MSSM realization with universal conditions at the SUSY-breaking scale. A more motivated scenario is given by split-family SUSY, in which the first two generations of squarks are heavy, compatible with a U(2)³ flavor symmetry. We consider this flavor symmetry to be broken at a very high scale and study the consequences at low energies through its RGE evolution. Initial conditions compatible with a split scenario are found, and the preservation of correlations from minimal U(2)³ breaking are checked. The various chiral operators in ΔF=2 processes are analyzed, and we show that, due to LHC gluino bounds, the (LL)(RR) operators cannot always be neglected. Finally, we also study a possible extension of the U(2)³ model compatible with the lepton sector.