Modulation of NF-κB-dependent gene transcription using programmable DNA minor groove binders

Nuclear factor κB (NF-κB) is a transcription factor that regulates various aspects of immune response, cell death, and differentiation as well as cancer. In this study we introduce the Py-Im polyamide 1 that binds preferentially to the sequences 5′-WGGWWW-3′ and 5′GGGWWW-3′. The compound is capable of binding to κB sites and reducing the expression of various NF-κB–driven genes including IL6 and IL8 by qRT-PCR. Chromatin immunoprecipitation experiments demonstrate a reduction of p65 occupancy within the proximal promoters of those genes. Genome-wide expression analysis by RNA-seq compares the DNA-binding polyamide with the well-characterized NF-κB inhibitor PS1145, identifies overlaps and differences in affected gene groups, and shows that both affect comparable numbers of TNF-α–inducible genes. Inhibition of NF-κB DNA binding via direct displacement of the transcription factor is a potential alternative to the existing antagonists

Cops, Teachers, and the Art of the Impossible: Explaining the lack of diffusion of impossible job innovations

In their now classic Impossible Jobs in Public Management, Hargrove and Glidewell (1990) argue that public agencies with limited legitimacy, high conflict, low professional authority, and weak agency myths have essentially impossible jobs. Leaders of such agencies can do little more than cope, which is also a theme of James Q. Wilson (1989), among others. Yet in the years since publication of Impossible Jobs, one such position, that of police commissioner has proven possible. Over a sustained 17-year period, the New York City Police Department has achieved dramatic reductions in crime with relatively few political repercussions, as described by Kelling and Sousa (2001). A second impossible job discussed by Wilson and also by Frederick Hess (1999), city school superintendent, has also proven possible, with Houston and Edmonton having considerable academic success educating disadvantaged children. In addition, Atlanta and Pittsburgh enjoyed significant success in elementary schooling, though the gains were short-lived for reasons we will describe. More recently, under Michelle Rhee, Washington D.C. schools have made the most dramatic gains among city school systems. These successes in urban crime control and public schooling have not been widely copied. Accordingly, we argue that the real conundrum of impossible jobs is why agency leaders fail to copy successful innovations. Building on the work of Teodoro (2009), we will discuss how the relative illegitimacy of clients and inflexibility of personnel systems combine with the professional norms, job mobility and progressive ambition of agency leaders to limit the diffusion of innovations in law enforcement and schooling. We will conclude with ideas about how to overcome these barriers

DNA minor groove binders as therapeutic agents

This article describes the current state-of-the-art in the development of small- and medium-sized molecules that interact with double-stranded DNA (dsDNA) by minor groove binding. The supramolecular structure of dsDNA is described and how this informs the development of minor groove binding agents. The structure and biological activity of biologically derived, bioinspired, and synthetic minor groove binders (MGBs) are then evaluated. The therapeutic applications of MGBs as antiinfectives and anticancer agents are presented