Discovery of Cell‐Permeable Inhibitors That Target the BRCT Domain of BRCA1 Protein by Using a Small‐Molecule Microarray

BRCTs are phosphoserine‐binding domains found in proteins involved in DNA repair, DNA damage response and cell cycle regulation. BRCA1 is a BRCT domain‐containing, tumor‐suppressing protein expressed in the cells of breast and other human tissues. Mutations in BRCA1 have been found in ca. 50 % of hereditary breast cancers. Cell‐permeable, small‐molecule BRCA1 inhibitors are promising anticancer agents, but are not available currently. Herein, with the assist of microarray‐based platforms, we have discovered the first cell‐permeable protein–protein interaction (PPI) inhibitors against BRCA1. By targeting the (BRCT)₂ domain, we showed compound 15 a and its prodrug 15 b inhibited BRCA1 activities in tumor cells, sensitized these cells to ionizing radiation‐induced apoptosis, and showed synergistic inhibitory effect when used in combination with Olaparib (a small‐molecule inhibitor of poly‐ADP‐ribose polymerase) and Etoposide (a small‐molecule inhibitor of topoisomerase II). Unlike previously reported peptide‐based PPI inhibitors of BRCA1, our compounds are small‐molecule‐like and could be directly administered to tumor cells, thus making them useful for future studies of BRCA1/PARP‐related pathways in DNA damage and repair response, and in cancer therapy.     

Global hysteresis in ferroelectrics with incommensurate phases

A review of the basic experimental results connected with the formation of long-living metastable states in the incommensurate phases of ferroelectric crystals and related phenomena is given. The interpretation and appropriate physical mechanisms underlying the global hysteresis phenomena associated with these states are considered.     

Fictitious domain methods for two‐phase flow energy balance computations in nuclear components

This paper is dedicated to the numerical simulation of nuclear components (cores and steam generators) by fictitious domain methods. The fictitious domain approach consists in immersing the physical domain under study in a Cartesian domain, called the fictitious domain, and in performing the numerical resolution on this fictitious domain. The calculation times are then efficiently reduced by the use of fast solvers. In counterpart, one has to handle with an immersed boundary, generally non‐aligned with the Cartesian mesh, which can be non‐trivial. The two fictitious domain methods compared here on industrial simulations and developed by Ramière et al. deal with an approximate immersed interface directly derived from the uniform Cartesian mesh. All the usual immersed boundary conditions (Dirichlet, Robin, Neumann), possibly mixed, are handled through a unique formulation of the fictitious problem. This kind of approximation leads to first‐order methods in space that exhibit a good ratio of the precision of the approximate solution over the CPU time, which is very important for industrial simulations. After a brief recall of the fictitious domain method with spread interface (Ramière et al., CMAME 2007) and the fictitious domain method with immersed jumps (Ramière et al., JCP 2008), we will focus on the numerical results provided by these methods applied to the energy balance equation in a steam generator. The advantages and drawbacks of each method will be pointed out. Generally speaking, the two methods confirm their very good efficiency in terms of precision, convergence, and calculation time in an industrial context. Copyright © 2011 John Wiley & Sons, Ltd.     

Magnetization switching modes in nanopillar spin valve under the external field

The current-induced magnetic switching is studied in Co/Cu/Co nanopillar with an in-plane magnetization traversed under the perpendicular-to-plane external field.Magnetization switching is found to take place when the current density exceeds a threshold.By analyzing precessional trajectories,evolutions of domain walls and magnetization switching times under the perpendicular magnetic field,there are two different magnetization switching modes:nucleation and domain wall motion reversal;uniform magnetization ...     

High Tc superconductors with different Cu2+/Cu3+ ratios in the Y–Ba–Cu–O system

Studies on different phases in the Y-Ba-Cu-O system have revealed that T_C around 90 K is obtainable with different Cu /Cu ratios provided the correct oxygen proportion is maintained.     

Krull property of generalized power series rings

Let D be an integral domain and let $(S,\le )$ be a torsion-free, ≤-cancellative, subtotally ordered monoid. We show that the generalized power series ring $?D^{S,\le }?$ is a Krull domain if and only if D is a Krull domain and S is a Krull monoid.     

Statistical inference for Vasicek-type model driven by Hermite processes

Let $Z$ denote a Hermite process of order $q\ge 1$ and self-similarity parameter $H\in (\frac{1}{2},1)$. This process is $H$-self-similar, has stationary increments and exhibits long-range dependence. When $q=1$, it corresponds to the fractional Brownian motion, whereas it is not Gaussian as soon as $q?2$. In this paper, we deal with a Vasicek-type model driven by $Z$, of the form $d{X}_t=a(b?X_t)dt+d{Z}_t$. Here, $a>0$ and $b\in \mathbb{R}$ are considered as unknown drift parameters. We provide estimators for $a$ and $b$ based on continuous-time observations. For all possible values of $H$ and $q$, we prove strong consistency and we analyze the asymptotic fluctuations.