BRCA1 Functions as a Differential Modulator of Chemotherapy-induced Apoptosis

We have evaluated the role played by BRCA1 in mediating the phenotypic response to a range of chemotherapeutic agents commonly used in cancer treatment. Here we provide evidence that BRCA1 functions as a differential mediator of chemotherapy-induced apoptosis. Specifically, we demonstrate that BRCA1 mediates sensitivity to apoptosis induced by antimicrotubule agents but conversely induces resistance to DNA-damaging agents. These data are supported by a variety of experimental models including cells with inducible expression of BRCA1, siRNA-mediated inactivation of endogenous BRCA1, and reconstitution of BRCA1-deficient cells with wild-type BRCA1. Most notably we demonstrate that BRCA1 induces a 10–1000-fold increase in resistance to a range of DNA-damaging agents, in particular those that give rise to double-strand breaks such as etoposide or bleomycin. In contrast, BRCA1 induces a >1000-fold increase in sensitivity to the spindle poisons, paclitaxel and vinorelbine. Fluorescence-activated cell sorter analysis demonstrated that BRCA1 mediates G2/M arrest in response to both antimicrotubule and DNA-damaging agents. However, poly(ADP-ribose) polymerase and caspase-3 cleavage assays indicate that the differential effect mediated by BRCA1 in response to these agents occurs through the inhibition or induction of apoptosis. Therefore, our data suggest that BRCA1 acts as a differential modulator of apoptosis depending on the nature of the cellular insult.

Monitoring electrical resistance of concretes containing alternative cementitious materials to assess their resistance to chloride penetration

This is an invited contribution in a special issue of the Journal of Cement and Concrete Composites

Analysis and Synthesis of pHEMT Class-E Amplifiers with Shunt Inductor including ON-State Active-Device Resistance Effects

In this theoretical paper, the analysis of the effect that ON-state active-device resistance has on the performance of a Class-E tuned power amplifier using a shunt inductor topology is presented. The work is focused on the relatively unexplored area of design facilitation of Class-E tuned amplifiers where intrinsically low-output-capacitance monolithic microwave integrated circuit switching devices such as pseudomorphic high electron mobility transistors are used. In the paper, the switching voltage and current waveforms in the presence of ON-resistance are analyzed in order to provide insight into circuit properties such as RF output power, drain efficiency, and power-output capability. For a given amplifier specification, a design procedure is illustrated whereby it is possible to compute optimal circuit component values which account for prescribed switch resistance loss. Furthermore, insight into how ON-resistance affects transistor selection in terms of peak switch voltage and current requirements is described. Finally, a design example is given in order to validate the theoretical analysis against numerical simulation.