An investigation of targeted inhibition of transcription factor activity with pyrrole imidazole polyamide (PA) in chronic myeloid leukemia (CML) blast crisis cells

Tyrosine kinase inhibitor (TKI) therapy is the standard treatment for chronic phase (CP)-chronic myeloid leukemia (CML), yet patients in blast crisis (BC) phase of CML are unlikely to respond to TKI therapy. The transcription factor E2F1 is a down-stream target of the tyrosine kinase BCR-ABL1 and is up-regulated in TKI-resistant leukemia stem cells (LSC). Pyrrole imidazole polyamides (PA) are minor groove binders which can be programmed to target DNA sequences in a gene-selective manner. This manuscript describes such an approach with a PA designed to down-regulate E2F1 controlled gene expression by targeting a DNA sequence within 100 base pairs (bp) upstream of the E2F1 consensus sequence. Human BC-CML KCL22 cells were assessed after treatment with PA, TKI or their combination. Our PA inhibited BC-CML cell expansion based on cell density analysis compared to an untreated control after a 48-hour time-course of PA treatment. However, no evidence of cell cycle arrest was observed among BC-CML cells treated with PA, with respect to their no drug control counterparts. Thus, this work demonstrates that PAs are effective in inhibiting E2F1 TF activity which results in a temporal reduction in BC-CML cell number. We envisage that PAs could be used in the future to map genes under E2F1 control in CML LSCs

Moment-closure approximations for discrete adaptive networks

Moment-closure approximations are an important tool in the analysis of the dynamics on both static and adaptive networks. Here, we provide a broad survey over different approximation schemes by applying each of them to the adaptive voter model. While already the simplest schemes provide reasonable qualitative results, even very complex and sophisticated approximations fail to capture the dynamics quantitatively. We then perform a detailed analysis that identifies the emergence of specific correlations as the reason for the failure of established approaches, before presenting a simple approximation scheme that works best in the parameter range where all other approaches fail. By combining a focused review of published results with new analysis and illustrations, we seek to build up an intuition regarding the situations when existing approaches work, when they fail, and how new approaches can be tailored to specific problems. © 2013 Elsevier B.V. All rights reserved

An organic semiconductor laser based on star-shaped truxene-core oligomers for refractive index sensing

The sensing capabilities of an all-organic semiconductor distributed feedback laser based on star-shaped truxene-core molecules are described. Two assays are presented as a proof-of-principle demonstration. In the first, concentration changes in the range of 5-60% (v/v) glycerol solution in water were measured with a bulk detection sensitivity of 21 nm per refractive index unit. Secondly, layer-by-layer adsorption of polyelectrolytes to the laser surface, up to a thickness of ≈45 nm, was measured. The experimental results from both assays are compared to, and shown to agree with, a theoretical model. Organic semiconductor lasers of this type have a number of attractions including ease of large-scale fabrication, incorporation into existing assay equipment and no rigid optical alignment constraints for excitation and collection of emission, which makes them well-suited to sensing applications. Therefore, it is expected that this technology will be useful in biosensing applications where label-free samples are investigated