Kinetics and mechanism of the pyridinolysis of diaryl carbonates

The reactions of 4‐methylphenyl and 4‐chlorophenyl 4‐nitrophenyl carbonates ( 1 and 2 , respectively), phenyl, 4‐methylphenyl, 4‐chlorophenyl, and 4‐nitrophenyl 2,4‐dinitrophenyl carbonates ( 3 , 4 , 5 , and 6 , respectively), and bis(2,4‐dinitrophenyl) carbonate ( 7 ) with a series of pyridines are studied kinetically at 25.0 °C in 44 wt% ethanol–water and an ionic strength of 0.2 M (KCl). The reactions are followed spectrophotometrically and under excess amine pseudo‐first‐order rate coefficients (k_obs) are found. For all these reactions, plots of k_obs versus free amine concentration at constant pH are linear, the slope (k_N) being independent of pH. The Brønsted‐type plots (log k_N vs. pK_a of the conjugate acids of the pyridines) are all biphasic (linear portions at high and low pK_a and a curvature in between). These plots are in accordance with a stepwise mechanism, through a zwitterionic tetrahedral intermediate (T^±), and a change in the rate‐determining step from formation of T^± to its breakdown to products, as the pyridine basicity decreases. Also studied are the effects of the leaving, non‐leaving, and electrophilic groups of the substrate, and of the amine nature, on the value (value at the center of curvature of the Brønsted‐type plots). Copyright © 2008 John Wiley & Sons, Ltd.     

Synthesis and Biological Activity of a Cytostatic Inhibitor of MLLr Leukemia Targeting the DOT1L Protein

Histone methyltransferase DOT1L catalyzes mono-, di- and trimethylation of histone 3 at lysine residue 79 (H3K79) and hypermethylation of H3K79 has been linked to the development of acute leukemias characterized by the MLL (mixed-lineage leukemia) rearrangements (MLLr cells). The inhibition of H3K79 methylation inhibits MLLr cells proliferation, and an inhibitor specific for DOT1L, pinometostat, was in clinical trials (Phase Ib/II). However, the compound showed poor pharmacological properties. Thus, there is a need to find new potent inhibitors of DOT1L for the treatment of rearranged leukemias. Here we present the design, synthesis, and biological evaluation of a small molecule that inhibits in the nM level the enzymatic activity of hDOT1L, H3K79 methylation in MLLr cells with comparable potency to pinometostat, associated with improved metabolic stability and a characteristic cytostatic effect.     

Scrutiny of 13C-phenylalanine breath test reproducibility

We evaluated the reproducibility of the ¹³C-phenylalanine breath test (¹³C-PheBT). On three separate days, 21 healthy volunteers (11 F and 10 M) underwent ¹³C-PheBT with 100 mg l-[1-¹³C]phenylalanine taken orally. Short-term reproducibility was evaluated with paired examinations taken 3 days apart; paired examinations separated by 23 days (median) served for the medium-term reproducibility assessment. Expiratory air was sampled at 19 points throughout 3?h. Determined limited reproducibility of the ¹³C-PheBT must be taken into consideration while interpreting the results of this diagnostic tool. The results of this study imply the following conclusions: (i) From among the three parameters examined, the cumulative ¹³C recovery area under the curve (AUC) offers much better reproducibility than the maximum momentary ¹³C recovery in the expiratory air (D_max) or the time to reach the maximum momentary ¹³C recovery (T_max) (ii) Collection of the breath air samples for 2?h results in a much better reproducibility of AUC, than for 1?h only; (iii) Reproducibility of ¹³C-PheBT is affected neither by the duration of the time gap between repeated tests nor by gender; (iv) Comparison with data obtained formerly reveals that reproducibility of the ¹³C-PheBT is worse than either that of of the ¹³C-methacetin (¹³C-MBT) or the ¹³C-alpha-ketoisocaproic acic (¹³C-KICA-BT) breath tests. This finding will have to be taken into consideration while interpreting the results of this diagnostic tool.     

Passive mode locking of Yb:KLuW using a single-walled carbon nanotube saturable absorber

Mode locking of an Yb-doped bulk laser in the 1 microm spectral range using a single-walled carbon nanotube saturable absorber (SWCNT-SA) is demonstrated for the first time, to our knowledge. Passive mode locking of an Yb:KLuW laser resulted in nearly transform-limited pulses as short as 115 fs at 1048 nm. In addition, the nonlinear response of the SWCNT-SA was measured, yielding a modulation depth of 0.25% and a relaxation time of 750 fs.     

Liposomes-entrapped chondroitin sulphate: ultrastructural characterization and in vitro biocompatibility

The purpose of this study was ultrastructural characterization of liposomes-entrapped chondroitin sulphate and to prove their in vitro biocompatibility in a human dermal fibroblast culture system, in order to use liposome-entrapped chondroitin sulphate in the treatment of inflammatory disorders. Chondroitin sulphate entrapped in liposomes appears as electron-dense particles in ultra-thin section. Comparative studies using chondroitin sulphate, empty liposomes and liposome-chondroitin sulphate systems were performed in order to evaluate their effect on growth and morphology of fibroblasts after 48 h of culture. Light microscopy indicated that chondroitin sulphate, empty liposomes and liposome-chondroitin sulphate systems do not induce appreciable cytotoxic effects, and cells maintain normal morphology when compared to control fibroblasts.     

Radiative energy loss in a finite dynamical QCD medium

The radiative energy loss of a quark jet traversing a finite size QCD medium with dynamical constituents is calculated to first order in opacity. Although finite size corrections reduce the energy loss relative to an infinite dynamical QCD medium, under realistic conditions it remains significantly larger than in a static medium. Quantitative predictions of jet suppression in relativistic heavy ion collisions must therefore account for the dynamics of the medium's constituents. Finite size effects are shown to induce a nonlinear path length dependence of the energy loss. Our results suggest a simple general mapping between energy loss expressions for static and dynamical QCD media.     

Computation of Saturation Dependence of Effective Diffusion Coefficient in Unsaturated Argillite Micro-fracture by Lattice Boltzmann Method

Getting access to the effective diffusion coefficient is a key point to provide realistic predictions of migration of radionuclides from radioactive waste repository in deep argillaceous geological formations. In the present work, the effective diffusion coefficient was computed inside an argillite micro-fracture as a function of its saturation level. The micrometric fracture geometry was extracted from the X-ray \(\mu \)-tomography image (\(0.7\,\upmu \mathrm{m}\) voxel resolution) of an Opalinus clay sample. It was collected in the host rock excavated damaged zone surrounding a borehole in the Mont Terri laboratory. The computations were performed using two two-relaxation-time lattice Boltzmann models. The first one, a phase separation model, was used to extract the connected liquid phase inside the fracture for given saturations. The second, a diffusion model, was used to compute non-reactive tracer diffusion in the connected liquid phase of the fracture and to calculate the effective diffusion coefficient for the associated saturations. The dependence of the effective diffusion coefficient on saturation was found to be quasi-linear and to qualitatively match the Maxwell expression for saturations lower than 0.8.     

Simulation and optimization of 2.6–2.8 μm GaSb-based VCSELs

We present the simulation results of threshold operation of mid-infrared GaSb-based vertical-cavity surface-emitting lasers (VCSELs) obtained with the use of comprehensive fully self-consistent optical-electrical-thermal-recombination numerical model. The results show that by a proper design of VCSEL structure and composition of the active region it is theoretically possible to achieve room-temperature (RT) threshold operation for wavelength of 2.8 μm which is about 0.2 μm longer than those reported so far in the literature for III-V VCSELs with type-I quantum wells. Calculated values of the RT threshold current were equal to 2.5 and 4.0 mA for tunnel-junction diameters of 2 and 4 μm, respectively.     

A Uniform Benchmark for Testing SsrA-Derived Degrons in the Escherichia coli ClpXP Degradation Pathway

The ssrA degron is commonly used in fusion proteins to control protein stability in bacteria or as an interaction module. These applications often rely on the modular activities of the ssrA tag in binding to the SspB adaptor and in engaging the ClpXP protease. However, a comparison of these activities for a substantial standard set of degron variants has not been conducted previously, which may hinder the development of new variants optimized exclusively for one application. Here, we strive to establish a benchmark that will facilitate the comparison of ssrA variants under uniform conditions. In our workflow, we included methods for expression and purification of ClpX, ClpP, SspB and eGFP-degrons, assays of ClpX ATPase activity, of eGFP-degron binding to SspB and for measuring eGFP-degron degradation in vitro and in vivo. Using uniform, precise and sensitive methods under the same conditions on a range of eGFP-degrons allowed us to determine subtle differences in their properties that can affect their potential applications. Our findings can serve as a reference and a resource for developing targeted protein degradation approaches.