Tom Eck

HIV-1 reverse transcriptase (RT) undergoes a series of conformational changes during viral replication and is a central target for antiretroviral therapy. The intrinsic flexibility of RT can provide novel allosteric sites for inhibition. Crystals of RT that diffract X-rays to better than 2 Å resolution facilitated the probing of RT for new druggable sites using fragment screening by X-ray crystallography. A total of 775 fragments were grouped into 143 cocktails, which were soaked into crystals… Show more

HIV-1 reverse transcriptase (RT) undergoes a series of conformational changes during viral replication and is a central target for antiretroviral therapy. The intrinsic flexibility of RT can provide novel allosteric sites for inhibition. Crystals of RT that diffract X-rays to better than 2 Å resolution facilitated the probing of RT for new druggable sites using fragment screening by X-ray crystallography. A total of 775 fragments were grouped into 143 cocktails, which were soaked into crystals of RT in complex with the non-nucleoside drug rilpivirine (TMC278). Seven new sites were discovered, including the Incoming Nucleotide Binding, Knuckles, NNRTI Adjacent, and 399 sites, located in the polymerase region of RT, and the 428, RNase H Primer Grip Adjacent, and 507 sites, located in the RNase H region. Three of these sites (Knuckles, NNRTI Adjacent, and Incoming Nucleotide Binding) are inhibitory and provide opportunities for discovery of new anti-AIDS drugs. Show less

Clonal expansion of premalignant lesions is an important step in the progression to cancer. This process is commonly considered to be a consequence of sustaining a proliferative mutation. Here, we investigate whether the growth trajectory of clones can be better described by a model in which clone growth does not depend on a proliferative advantage. We developed a simple computer model of clonal expansion in an epithelium in which mutant clones can only colonize space left unoccupied by the… Show more

Clonal expansion of premalignant lesions is an important step in the progression to cancer. This process is commonly considered to be a consequence of sustaining a proliferative mutation. Here, we investigate whether the growth trajectory of clones can be better described by a model in which clone growth does not depend on a proliferative advantage. We developed a simple computer model of clonal expansion in an epithelium in which mutant clones can only colonize space left unoccupied by the death of adjacent normal stem cells. In this model, competition for space occurs along the frontier between mutant and normal territories, and both the shapes and the growth rates of lesions are governed by the differences between mutant and normal cells' replication or apoptosis rates. The behavior of this model of clonal expansion along a mutant clone's frontier, when apoptosis of both normal and mutant cells is included, matches the growth of UVB-induced p53-mutant clones in mouse dorsal epidermis better than a standard exponential growth model that does not include tissue architecture. The model predicts precancer cell mutation and death rates that agree with biological observations. These results support the hypothesis that clonal expansion of premalignant lesions can be driven by agents, such as ionizing or nonionizing radiation, that cause cell killing but do not directly stimulate cell replication. Show less

Regions of gain and loss of genomic DNA occur in many cancers and can drive the genesis and progression of disease. These copy number aberrations (CNAs) can be detected at high resolution by using microarray-based techniques. However, robust statistical approaches are needed to identify nonrandom gains and losses across multiple experiments/samples. We have developed a method called Significance Testing for Aberrant Copy number (STAC) to address this need.

Germline mutations in BRCA1 and BRCA2 account for 20-40% of large multiple case breast cancer families. However, breast cancer susceptibility in the majority of other families (termed BRCAX families) is not due to BRCA1 and BRCA2 mutations. Here we applied array-based Comparative Genomic Hybridization (aCGH) to characterize copy number alterations in 44 breast cancers from the 38 BRCAX families currently included in an international collaborative linkage analysis.

The adaptive-resonance-theory (ART) architectures comprise a family of neural networks that efficiently self-organize stable recognition codes in response to arbitrary sequences of input patterns. This paper focuses on the ART 2 network architecture that is designed for the processing of both binary- and analog-valued patterns. The problems encountered in implementing the primary ART 2 architecture as originally presented by Gail Carpenter and Stephen Grossberg are discussed. An enhanced ART 2… Show more

The adaptive-resonance-theory (ART) architectures comprise a family of neural networks that efficiently self-organize stable recognition codes in response to arbitrary sequences of input patterns. This paper focuses on the ART 2 network architecture that is designed for the processing of both binary- and analog-valued patterns. The problems encountered in implementing the primary ART 2 architecture as originally presented by Gail Carpenter and Stephen Grossberg are discussed. An enhanced ART 2 architecture that receives its input from a functional-link preprocessor is proposed. Experimental results that demonstrate this architecture's superior performance over the previous ART 2 architecture are provided. Finally, a text-free speaker recognition system that employs the enhanced ART 2 architecture as its classifier is described. Show less