University of Utah

About: University of Utah is a education organization based out in Salt Lake City, Utah, United States. It is known for research contribution in the topics: Population & Medicine. The organization has 52894 authors who have published 124076 publications receiving 5265834 citations. The organization is also known as: The U & The University of Utah.

A structural basis for drug-induced long QT syndrome

Abstract: Mutations in the HERG K+ channel gene cause inherited long QT syndrome (LQT), a disorder of cardiac repolarization that predisposes affected individuals to lethal arrhythmias [Curran, M. E., Splawski, I., Timothy, K. W., Vincent, G. M., Green, E. D. & Keating, M. T. (1995) Cell 80, 795–804]. Acquired LQT is far more common and is most often caused by block of cardiac HERG K+ channels by commonly used medications [Roden, D. M., Lazzara, R., Rosen, M., Schwartz, P. J., Towbin, J. & Vincent, G. M. (1996) Circulation 94, 1996–2012]. It is unclear why so many structurally diverse compounds block HERG channels, but this undesirable side effect now is recognized as a major hurdle in the development of new and safe drugs. Here we use alanine-scanning mutagenesis to determine the structural basis for high-affinity drug block of HERG channels by MK-499, a methanesulfonanilide antiarrhythmic drug. The binding site, corroborated with homology modeling, is comprised of amino acids located on the S6 transmembrane domain (G648, Y652, and F656) and pore helix (T623 and V625) of the HERG channel subunit that face the cavity of the channel. Other compounds that are structurally unrelated to MK-499, but cause LQT, also were studied. The antihistamine terfenadine and a gastrointestinal prokinetic drug, cisapride, interact with Y652 and F656, but not with V625. The aromatic residues of the S6 domain that interact with these drugs (Y652 and F656) are unique to eag/erg K+ channels. Other voltage-gated K+ (Kv) channels have Ile and Val (Ile) in the equivalent positions. These findings suggest a possible structural explanation for how so many commonly used medications block HERG but not other Kv channels and should facilitate the rational design of drugs devoid of HERG channel binding activity.

Targeted chromosomal cleavage and mutagenesis in Drosophila using zinc-finger nucleases.

Abstract: Zinc-finger nucleases (ZFNs) are hybrids between a nonspecific DNA-cleavage domain and a DNA-binding domain composed of Cys(2)His(2) zinc fingers. Because zinc fingers can be manipulated to recognize a broad range of sequences, these enzymes have the potential to direct cleavage to arbitrarily chosen targets. We have tested this idea by designing a pair of ZFNs that recognize a unique site in the yellow (y) gene of Drosophila. When these nucleases were expressed in developing larvae, they led to somatic mutations specifically in the y gene. These somatic mosaics were observed in approximately one-half of the males expressing both nucleases. Germline y mutations were recovered from 5.7% of males, but from none of the females, tested. DNA sequences were determined and showed that all of the mutations were small deletions and/or insertions located precisely at the designed target. These are exactly the types of alterations expected from nonhomologous end joining (NHEJ) following double-strand cleavage of the target. This approach promises to permit generation of directed mutations in many types of cells and organisms.

Extracting information from textual documents in the electronic health record: a review of recent research.

Abstract: Objectives: We examine recent published research on the extraction of information from textual documents in the Electronic Health Record (EHR). Methods: Literature review of the research published after 1995, based on PubMed, conference proceedings, and the ACM Digital Library, as well as on relevant publications referenced in papers already included. Results: 174 publications were selected and are discussed in this review in terms of methods used, pre-processing of textual documents, contextual features detection and analysis, extraction of information in general, extraction of codes and of information for decision-support and enrichment of the EHR, information extraction for surveillance, research, automated terminology management, and data mining, and de-identification of clinical text. Conclusions: Performance of information extraction systems with clinical text has improved since the last systematic review in 1995, but they are still rarely applied outside of the laboratory they have been developed in. Competitive challenges for information extraction from clinical text, along with the availability of annotated clinical text corpora, and further improvements in system performance are important factors to stimulate advances in this field and to increase the acceptance and usage of these systems in concrete clinical and biomedical research contexts. Cli

Radio Tomographic Imaging with Wireless Networks

Abstract: Radio Tomographic Imaging (RTI) is an emerging technology for imaging the attenuation caused by physical objects in wireless networks. This paper presents a linear model for using received signal strength (RSS) measurements to obtain images of moving objects. Noise models are investigated based on real measurements of a deployed RTI system. Mean-squared error (MSE) bounds on image accuracy are derived, which are used to calculate the accuracy of an RTI system for a given node geometry. The ill-posedness of RTI is discussed, and Tikhonov regularization is used to derive an image estimator. Experimental results of an RTI experiment with 28 nodes deployed around a 441 square foot area are presented.