Cooperativity as quantification and optimization paradigm for nuclear receptor modulators

Nuclear Receptors (NRs) are highly relevant drug targets, for which small molecule modulation goes beyond a simple ligand/receptor interaction. NR–ligands modulate Protein–Protein Interactions (PPIs) with coregulator proteins. Here we bring forward a cooperativity mechanism for small molecule modulation of NR PPIs, using the Peroxisome Proliferator Activated Receptor γ (PPARγ), which describes NR–ligands as allosteric molecular glues. The cooperativity framework uses a thermodynamic model based on three-body binding events, to dissect and quantify reciprocal effects of NR–coregulator binding (K^I_D) and NR–ligand binding (K^II_D), jointly recapitulated in the cooperativity factor (α) for each specific ternary ligand·NR·coregulator complex formation. These fundamental thermodynamic parameters allow for a conceptually new way of thinking about structure–activity-relationships for NR–ligands and can steer NR modulator discovery and optimization via a completely novel approach.

A cooperativity framework describes the formation of nuclear receptor ternary complexes and deconvolutes ligand and cofactor binding into intrinsic affinities and a cooperativity factor, providing a conceptually new understanding of NR modulation.     

Improved diffusion Monte Carlo propagators for bosonic systems using Itô calculus

The construction of importance sampled diffusion Monte Carlo (DMC) schemes accurate to second order in the time step is discussed. A central aspect in obtaining efficient second order schemes is the numerical solution of the stochastic differential equation (SDE) associated with the Fokker-Plank equation responsible for the importance sampling procedure. In this work, stochastic predictor-corrector schemes solving the SDE and consistent with It? calculus are used in DMC simulations of helium clusters. These schemes are numerically compared with alternative algorithms obtained by splitting the Fokker-Plank operator, an approach that we analyze using the analytical tools provided by Ito; calculus. The numerical results show that predictor-corrector methods are indeed accurate to second order in the time step and that they present a smaller time step bias and a better efficiency than second order split-operator derived schemes when computing ensemble averages for bosonic systems. The possible extension of the predictor-corrector methods to higher orders is also discussed.     

Determination of 90Sr and 210Pb in deer bone samples by liquid scintillation counting after ion-exchange procedures

This work describes a procedure for the isolation of ⁹⁰Sr and ²¹⁰Pb from deer bones by anion exchange methods and their sequential measurement by LSC. To prevent collection of Pb on the Sr·Spec^® resin we first separated Pb on a Dowex anion exchange column. Sr, which is not held back on the Dowex column, was then purified using Sr·Spec^® resin: first Ca and the Ra isotopes were eluted with 3 M HNO₃ and then Sr was eluted with distilled water. With this 2-steps procedure pure ²¹⁰Pb and ⁹⁰Sr spectra can be achieved. The chemical yield of both steps was determined by ICP-MS. Our ⁹⁰Sr results show satisfying agreement with data obtained by a shorter Sr·Spec^® method and also by the “classical” ⁹⁰Sr determination using fuming nitric acid. Also ²¹⁰Pb results were checked by re-measuring bone samples with already known ²¹⁰Pb activities. Further our method was verified on the reference sample IAEA-A-12.     

Laccase–polyazetidine prepolymer–MWCNT integrated system: Biochemical properties and application to analytical determinations in real samples

Bioelectrochemical properties of Trametes versicolor Laccase (TvL) and Trametes hirsuta Laccase (ThL) immobilized by using polyazetidine prepolymer (PAP) onto multi-walled carbon nanotubes (MWCNTs) screen printed electrode (SPE) surface, have been studied with several redox mediators by cyclic voltammetry (CV). The efficient entrapment of laccase in the PAP layer was confirmed by determination of both kinetic parameters (maximum current and Michaelis–Menten apparent constant) and analytical performances by chronoamperometry. The Laccase-modified MWCNTs electrode provides an effective biosensor for determination of polyphenols and catecholamines in real matrices; performances of the considered biosensors for real samples analysis are also compared and discussed.     

Immobilization of η-cyclopentadienyltris(dimethylamido)zirconium polymerization catalysts on a chlorosilane- and HMDS-modified mesoporous silica surface: a new concept for supporting metallocene amides towards heterogeneous single-site-catalysts

The modification of a mesoporous silica surface with Si(Ind)(CH₃)₂Cl and the immobilization of CpZr(NMe₂)₃ on this surface was studied via IR-spectroscopy. To reduce side reactions, the indenyl-modified silica was reacted with hexamethyldisilazane (HMDS) under IR-control before the CpZr(NMe₂)₃-immobilization. The role of the hydroxyl group protection with HMDS is discussed. The surface modifications have been repeated via Schlenk technique at the same conditions and the surface modifications were studied with ¹³C CP MAS–NMR, ¹H MAS–NMR, elemental-, SEM- and BET-analysis. The surface species of the resulting catalysts are discussed. The precatalysts have been treated with methylaluminoxane (MAO) (Al:Zr (mol:mol)=500:1) and the resulting Zr contents (leaching-effect) are discussed. All catalysts have been tested in ethylene and propylene polymerization.     

Determination of boron and hydrogen in materials for multicrystalline solar cell production with prompt gamma activation analysis

Journal of Radioanalytical and Nuclear Chemistry - For the optimization of the manufacturing process of multicrystalline silicon (mc-Si) for solar cells in order to reduce energy consumption and...     

Highly Emissive Self‐Trapped Excitons in Fully Inorganic Zero‐Dimensional Tin Halides

The spatial localization of charge carriers to promote the formation of bound excitons and concomitantly enhance radiative recombination has long been a goal for luminescent semiconductors. Zero‐dimensional materials structurally impose carrier localization and result in the formation of localized Frenkel excitons. Now the fully inorganic, perovskite‐derived zero‐dimensional Sn^II material Cs₄SnBr₆ is presented that exhibits room‐temperature broad‐band photoluminescence centered at 540 nm with a quantum yield (QY) of 15±5 %. A series of analogous compositions following the general formula Cs_4?xA_xSn(Br_1?yI_y)₆ (A=Rb, K; x≤1, y≤1) can be prepared. The emission of these materials ranges from 500 nm to 620 nm with the possibility to compositionally tune the Stokes shift and the self‐trapped exciton emission bands.     

Selective C(sp3)−H Aerobic Oxidation Enabled by Decatungstate Photocatalysis in Flow

A mild and selective C(sp³)?H aerobic oxidation enabled by decatungstate photocatalysis has been developed. The reaction can be significantly improved in a microflow reactor enabling the safe use of oxygen and enhanced irradiation of the reaction mixture. Our method allows for the oxidation of both activated and unactivated C?H bonds (30 examples). The ability to selectively oxidize natural scaffolds, such as (?)‐ambroxide, pregnenolone acetate, (+)‐sclareolide, and artemisinin, exemplifies the utility of this new method.     

Towards an efficient atomic frequency comb quantum memory

We present an efficient photon-echo experiment based on atomic frequency combs [Phys. Rev. A 79 (2009) 052329]. Echoes containing an energy of up to 35% of that of the input pulse are observed in a Pr³⁺-doped Y₂SiO₅ crystal. This material allows for the precise spectral holeburning needed to make a sharp and highly absorbing comb structure. We compare our results with a simple theoretical model with satisfactory agreement. Our results show that atomic frequency combs has the potential for high-efficiency storage of single photons as required in future long-distance communication based on quantum repeaters.