Gene Expression Profiles Predict Emergence of Psychiatric Adverse Events in HIV/HCV-Coinfected Patients on Interferon-Based HCV Therapy

The efficacy of pegylated IFN-α and ribavirin (pegIFN/RBV) in the treatment of Hepatitis C infection is limited by psychiatric adverse effects (IFN-PE). Our study examined the ability of differential gene expression patterns prior to therapy to predict emergent IFN-PE among 28 HIV/HCV co-infected patients treated with pegIFN-α2b/RBV

Differential modes of DNA binding by mismatch uracil DNA glycosylase from Escherichia coli: implications for abasic lesion processing and enzyme communication in the base excision repair pathway

Mismatch uracil DNA glycosylase (Mug) from Escherichia coli is an initiating enzyme in the base-excision repair pathway. As with other DNA glycosylases, the abasic product is potentially more harmful than the initial lesion. Since Mug is known to bind its product tightly, inhibiting enzyme turnover, understanding how Mug binds DNA is of significance when considering how Mug interacts with downstream enzymes in the base-excision repair pathway. We have demonstrated differential binding modes of Mug between its substrate and abasic DNA product using both band shift and fluorescence anisotropy assays. Mug binds its product cooperatively, and a stoichiometric analysis of DNA binding, catalytic activity and salt-dependence indicates that dimer formation is of functional significance in both catalytic activity and product binding. This is the first report of cooperativity in the uracil DNA glycosylase superfamily of enzymes, and forms the basis of product inhibition in Mug. It therefore provides a new perspective on abasic site protection and the findings are discussed in the context of downstream lesion processing and enzyme communication in the base excision repair pathway

TELLS (Testing for Essential Learning and Literacy Skills): The impact and implications of a state-mandated remedial program

As a reaction to A Nation at Risk (1983) and other task force reports of the 1980s, which exposed serious flaws in American public schooling, many states adopted reform proposals to improve elementary and secondary education. Pennsylvania\u27s state leadership responded with a state-mandated program, TELLS (Testing for Essential Learning and Literacy Skills), a combined standardized testing and remedial education program designed to identify students weak in the areas of mathematics and reading, and to improve instruction to remediate those weaknesses. This case study focuses on the impact of the TELLS program on the professional staff, school board, students, and parents in Northern Area, a small rural school district in Pennsylvania. The broader purpose of the study is to identify a range of issues and effects that arise, and must be considered, when state-mandated reforms move to the local level. Data for the study were derived from qualitative methods such as interviews, classroom observations, field notes, and state-level and local school district documents. Analysis of the data, coupled with a review of educational reform literature, supports five major conclusions concerning state-mandated reforms, and TELLS in particular. First, one best system reform mandates tend to ignore the idiosyncratic needs of rural school districts. Second, the Berman-McLaughlin (1978) model, developed for federally sponsored educational reforms, has utility in explaining TELLS implementation, and the model may be applicable to state-level reforms in general. Third, rural school districts, such as Northern Area tend to lack sufficient personnel and financial resources necessary to successfully implement state-mandated reforms. Fourth, when reform efforts call for more of the same educational practices, e.g., standardized testing and remedial programs, they often fail the very children they are designed to help because these efforts tend to label children as slow, then track them into lower level remedial classes, thereby eroding their self-esteem. Fifth, with newly elected political leaders, reform initiatives change dramatically. The study concludes with a set of recommendations for improving the implementation process of state-mandated reform efforts

Apparent Directional Scanning for DNA Repair

Recently it was observed that the DNA repair protein human O6-alkylguanine-DNA alkyltransferase repairs lesions at the 5′ ends of 70-nucleotide single-stranded DNA roughly threefold more frequently than lesions at the 3′ ends. Here, we introduce a coarse-grained model to show how a local asymmetry in binding kinetics (rather than thermodynamics) together with irreversible alkyl transfer can give rise to this apparent bias in sequence scanning. Exploration of the parameter space provides quantitative relationships that can be used to validate the proposed mechanism by gel-based assays