Specific cell-permeable inhibitor of proteasome trypsin-like sites selectively sensitizes myeloma cells to bortezomib and carfilzomib

Proteasomes degrade the majority of proteins in mammalian cells, are involved in the regulation of multiple physiological functions, and are established targets of anticancer drugs. The proteasome has three types of active sites. Chymotrypsin-like sites are the most important for protein breakdown and have long been considered the only suitable targets for antineoplastic drugs; however, our recent work demonstrated that inhibitors of caspase-like sites sensitize malignant cells to inhibitors of the chymotrypsin-like sites. Here, we describe the development of specific cell-permeable inhibitors and an activity-based probe of the trypsin-like sites. These compounds selectively sensitize multiple myeloma cells to inhibitors of the chymotrypsin-like sites, including antimyeloma agents bortezomib and carfilzomib. Thus, trypsin-like sites are cotargets for anticancers drugs. Together with inhibitors of chymotrypsin- and caspase-like sites developed earlier, we provide the scientific community with a complete set of tools to separately modulate proteasome active sites in living cells.     

Synthesis and Characterization of PS-PIB-PS Triblock Copolymers

Abstract

Poly(styrene-isobutylene-styrene) (PS-PIB-PS) block copolymers synthesized via living carbocationic polymerization using a di- or tricumyl chloride/TiCl₄/pyridine initiating system in 60/40 (v/v) hexane/methyl chloride cosolvents. The kinetics of formation of the PIB block at ? 80°C were found to be first order in isobutylene (IB) concentration, first order in the concentration of initiating sites, second order in TaiCl₄ concentration, and a negative fractional order with respect to the pyridine concentration. The rate of polymerization was found to decrease with increasing temperature, indicating an equilibrium between dormant, covalent and active, ionized chain ends, and chain-end concentration studies suggested that there was no contribution by free ions to the rate of propagation. Diagnosis of the livingness of the IB polymerization indicated that at high (≥90%) monomer conversion, β-proton elimination becomes important, causing the timing of addition of styrene to be critical. Addition of styrene at an IB reaction time significantly exceeding the time necessary for complete IB consumption resulted in contamination of the product with a substantial amount of homo-PS; conversely, addition at intermediate IB conversion resulted in slow copolymerization between IB and styrene and the formation of a tapered block copolymer. Addition of styrene at an IB conversion of about 90% resulted in well-defined block copolymers which displayed ordered, phase-separated morphologies consisting of cylinders of PS in a continuous phase of PIB. The block copolymers possessed properties consistent with those of physically crosslinked rubbers. Dynamic mechanical spectroscopy revealed two glass transitions with a broad rubbery plateau extending from about 0 to 100°C, and tensile strengths of up to 25 MPa and elongations to 1000% were observed for some samples.     

p‐Chloro‐, p‐bromo‐ and two polymorphs of p‐iodo­aceto­phenone

The title p‐haloaceto­phenones, C₈H₇XO (X = Cl, Br and I), have different packing modes. The chloro compound contains H⋯O and H⋯Cl contacts, but no Cl⋯O contacts. The bromo compound and one polymorph (A) of the iodo compound are isomorphous, with significant X⋯O contacts [Br⋯O = 3.320 (4) Å and I⋯O = 3.374 (5) Å]. In the other polymorph (B) of the iodo compound, the I⋯O distance is 3.082 (4) Å. Both polymorphs contain C—H⋯π contacts; these contacts are shorter in A than in B.     

A Magnetic Transport Middle Eastern Positron Beam

A magnetically guided slow positron beam is being constructed at Qatar University and is currently being optimised for regular operation. This is the first positron beam in the Middle East, as well as being the first Arabic positron beam. Novel features in the design include a purely magnetic in-line deflector, working in the solenoid guiding field, to eliminate un-moderated positrons and block the direct line of sight to the source. The impact of this all-magnetic transport on the Larmor radius and resultant beam characteristics are studied by SIMION simulations for both ideal and real life magnetic field variations. These results are discussed in light of the coupled effect arising from electrostatic beam extraction.     

Characterization of a-B5C:H prepared by PECVD of orthocarborane: Results of preliminary FTIR and nuclear reaction analysis studies

The electronic properties of a-Si:H vary with hydrogen passivation of dangling bond defects. It appears this effect is also operative in semiconducting amorphous hydrogenated boron carbide (a-B₅C:H). Therefore, the ability to quantify the amount of hydrogen will be key to development of the materials science of a-B₅C:H. The results of an initial investigation probing the ability to quickly correlate hydrogen concentration in a-B₅C:H films with infrared spectroscopy are reported. a-B₅C:H thin films were growth on Si (1 1 1) substrates by plasma-enhanced chemical vapor deposition (PECVD) using sublimed orthocarborane and argon as the precursor gas. Nuclear reaction analysis (NRA) was performed to quantify the atomic concentration of H in the a-B₅C:H films. While the observed vibronic structure does not show stretches due to terminal C–H or bridging B–H–B, analysis of the terminal B–H stretch at ～2570 cm^?1 gives a proportionality constant of A = 2 × 10²² cm^?2. We conclude that the methods previously developed for correlating H concentration to infrared data in a-Si:H are similarly viable for a-B₅C:H films.     

Investigation of the end-gas autoignition process in natural gas engines and evaluation of the methane number index

Engine knock and misfire are barriers to pathways leading to high-efficiency Spark-Ignited (SI) Natural Gas (NG) engines. The general tendency to knock is highly dependent on engine operating conditions and the fuel reactivity. The problem is further complicated by the wide range of chemical reactivity in pipeline quality NG, represented by the Methane Number (MN) (65< MN<95). Understanding the underlying phenomena responsible for engine knock can support the development of predictive tools capable of identifying knock onset/intensity as well as a fuel's propensity to knock, allowing engine manufacturers to expand the knock envelope and design more efficient/robust SI NG engines. Additionally, there is an opportunity for increased efficiency by controlling levels of end-gas autoignition if this can be predicted and controlled. This work focuses on the development of a novel methodology to understand/predict a fuel's propensity to knock. This methodology is based on the charge fraction undergoing autoignition, namely fractional end-gas autoignition (F-EGAI), and was developed based on first order laminar flame speeds and ignition delay analysis combined with a 0-D homogeneous batch reactor model. This methodology proved to be suitable to predict a fuel's propensity to knock, even under conditions when light knock was observed. The simple modeling approach was used to explain the results from a series of MN tests with multiple NG compositions exhibiting a wide range of reactivity compositions and providing insight on why fuels of very different chemical compositions can have the same MN. Lastly, a CFD model was developed was used to confirm the methodology capability and provide further insights in the physical and chemical phenomena behind end gas autoignition.     

Die elektrometrische Titration der Chroms?ure unter Anwendung von (a) der Wasserstoff-Elektrode und (b) der Sauerstoff-Elektrode

Ohne Zusammenfassung     

Potentiometrie

Ohne Zusammenfassung     

Ueber den Wassergehalt der Steinkohlen

Ohne Zusammenfassung