Impaired phosphorylation and mis-localization of Bub1 and BubR1 are responsible for the defective mitotic checkpoint function in Brca2-mutant thymic lymphomas

Breast cancer susceptibility gene, BRCA2, is a tumor suppressor and individuals who inherit one defected copy of BRCA2 allele experience early onset breast cancer or ovarian cancer accompanied by the loss of the wild type allele. Mouse model for Brca2 mutation shows growth retardation and paradoxical occurrence of thymic lymphomas. Thymic lymphomas from Brca2-mutant mice harbor mutations in p53, Bub1, and BubR1, which function as mitotic checkpoint proteins. Therefore, interplay between Brca2 and mitotic checkpoint has been suggested in the maintenance of genetic fidelity, although it has not been assessed whether the unique mutations in Bub1 and BubR1 found in Brca2-mutant mice are responsible for the abolishment of mitotic checkpoint function. This report demonstrates that Bub1 and BubR1 mutant proteins from Brca2-/- thymic lymphomas have defects in the phosphorylation and kinetochore localization after spindle damage. Thus, the mutations of Bub1 and BubR1 found in Brca2- mutant mice indeed are responsible for the chromosome instability in Brca2-mutated tumors.     

Indo study of some cyclic carbenes

INDO calculations, with geometry optimization, have been performed on the cyclic carbenes cyclopropenylidene (I) cyclopropylidene (II), and cyclopentadienylidene (III). It is found that all three systems have a singlet ground state and, due to aromaticity, the triplet-singlet energy separations for I and III are particularly large. In addition, for each system, the electronic structure and its influences on geometry and reactivity are discussed.     

Thermosonimetry of the phase II/III transition of hexachloroethane

A thermosonimetric study has shown that the Phase II/III polymorphic transition of hexachloroethane emits acoustic signals. This solid-solid phase transition is known to occur by a nucleation-growth process during which a nucleus of the new phase, once formed, grows at the expense of the mother phase to form a complete crystal without fracture. Acoustic emissions from a conditioned multi-crystal sample have been used to study the transition. Acoustic activity correlated well with dilatometric measurements. Frequency analysis on waveforms of many hundreds of individual acoustic emissions revealed marked differences between individual signals. Principal-components analysis on 24 signal features revealed a single dispersed cluster with a highly non-uniform distribution of signals. These experiments provided highly reproducible average power spectra. Time-resolved acoustic power spectra were also generated. These additional types of information cannot be obtained by other techniques.     

Molecular characteristics of the inhibition of human neutrophil elastase by nonsteroidal antiinflammatory drugs

Nonsteroidal antiinflammatory drugs(NSAIDs) are known as clinically effective agents for treatment of inflammatory diseases. Inhibition of cyclooxygenase has been thought to be a major facet of the pharmacological mechanism of NSAIDs. However, it is difficult to ascribe the antiinflammatory effects of NSAIDs solely to the inhibition of prostaglandin synthesis. Human neutrophil elastase (HNElastase; HNE, EC 3.4.21.37) has been known as a causative factor in inflammatory diseases. To investigate the specific relationship between HNElastase inhibition and specificity of molecular structure of several NSAIDs, HNElastase was purified by Ultrogel AcA54 gel filtration, CM-Sephadex ion exchange, and HPLC (with TSK 250 column) chromatography. HNElastase was inhibited by aspirin and salicylate in a competitive manner and by naproxen, ketoprofen, phenylbutazone, and oxyphenbutazone in a partial competative manner, but not by ibuprofen and tolmetin. HNElastase-phenylbutazone-complex showed strong Raman shifts at 200, 440, 1124, 1194, 1384, 1506, and 1768 cm(-1). The Raman bands 1194, 1384, and 1768 cm(-1) may represent evidences of the conformational change at -N=N-phi radical, pyrazol ring, and -C=O radical of the elastase-drug complex, respectively. Phenylbutazone might be bound to HNElastase by ionic and hydrophobic interaction, and masked the active site. Inhibition of HNElastase could be another mechanism of action of NSAIDs besides cyclooxygenase inhibition in the treatment of inflammatory diseases. Different inhibition characteristics of HNE-lastase by NSAIDs such as aspirin, phenylbutazone-like drugs and ineffective drugs could be important points for drawing the criteria for appropriate drugs in clinical application.     

Evaluation of Poisson solvation models using a hybrid explicit/implicit solvent method

Implicit solvent methods have become popular tools in the field of protein dynamics simulations, yet evaluation of their validity has been primarily limited to comparisons with experimental and theoretical data for small molecules. In this paper, we use a recently developed hybrid explicit/implicit solvent methodology to evaluate the accuracy of several Poisson-based implicit solvent models. Specifically, we focus on the calculation of electrostatic solvation free energies of various fixed conformations for two proteins. We show that, among various dielectric boundary definitions, the Lee-Richards molecular surface has the best agreement with hybrid solvent results. Furthermore, certain modifications of the molecular surface Poisson protocol provide varied results. For instance, simple modifications of atomic radii on charged residues generally improve absolute errors but do not significantly reduce relative errors among conformations. On the other hand, using a water-probe radius of 1.0 A, as opposed to the standard value of 1.4 A, to generate the molecular surface, moderately improves both absolute and relative results.     

Total internal reflection-based biochip utilizing a polymer-filled cavity with a micromirror sidewall

A total internal reflection (TIR)-based biochip utilizing a polymer-filled cavity with a micromirror sidewall has been designed and fabricated. The implementation of the micromirror sidewall cavity facilitates precise alignment of the excitation light beam into the system. The incident angle of illumination can be easily modified by selecting polymers of different indices of refraction while optical losses are minimized. The design enables the hybrid, vertical integration of a laser diode and a CCD camera, resulting in a compact optical system. Brownian motion of fluorescent microspheres and real-time photobleaching of rhodamine 6G molecules is demonstrated. The proposed TIR-based chip simplifies current TIR optical configurations and could potentially be used as an optical-microfluidic platform for an integrated lab-on-a-chip microsystem.     

Bond Prices Under Information Asymmetry and a Short Rate with Instantaneous Feedback

Methodology and Computing in Applied Probability - We study an information asymmetry problem in a bond market. Especially we derive bond price dynamics of traders with different levels of...