Biomedical subjects

L Ridgway Scott

Publications and source records attributed to L Ridgway Scott.

5 recordsLinked to original sources

PubMed2005

Linear independence of pairwise comparisons of DNA microarray data.

MOTIVATION: For DNA microarrays, the gain in certainty by performing multiple experimental repeats is offset by the high cost of each experiment. In a typical experiment, two independent measurements (that is, data from two separate arrays) are combined to yield a single comparative index per gene. Thus, although one uses 2n arrays and performs 2n independent measurements, one obtains only n comparative measurements. We addressed the question: how many of the potential n2 comparisons derivable from such data are actually independent, and what effect do these additional comparisons have on the false positive rate. RESULTS: We show there are precisely 2n - 1 independent comparisons available from among the n2 possibilities. Applying these additional n - 1 independent comparisons to experimental and simulated data reduced the false positive rate by as much as 10-fold, with excellent agreement between experimental and theoretical false positive rates.

Algorithms↗

PubMed2003

Adherence of packing defects in soluble proteins.

For protein structure to prevail in water, its backbone hydrogen bonds must be shielded from water attack, requiring a cluster of "wrapping" nonpolar groups. Thus, underwrapped regions are adhesive, as exogenous removal of surrounding water becomes thermodynamically favorable. Here we measure the average adhesive force exerted by an underwrapped hydrogen bond on a test hydrophobe and thus define a new interactivity constant.

Apoproteins↗

PubMed2003

Structural defects and the diagnosis of amyloidogenic propensity.

Disease-related amyloidogenic propensity has been unexpectedly found in proteins driven to adopt a monomeric uncomplexed state at high concentrations under near-physiological conditions. This situation occasionally arises in new health treatments, such as kidney dialysis. Assuming that under such conditions a partial retention of native structure takes place, this work identifies a structural characteristic indicating amyloidogenic propensity: a high density of backbone hydrogen bonds exposed to water attack in monomeric structure. On this basis, we propose a diagnostic tool based on the identification of hydrogen bonds with a paucity of intramolecular dehydration or "wrapping." We use this predictor to identify potentially pathogenic mutations that foster amyloidogenic propensity in human prions. Such mutations either enhance the intramolecular dehydration of beta-sheet hydrogen bonds, thus stabilizing the nucleus for rearrangement into the scrapie fold, or contribute to the destabilization of the cellular form by introducing additional underwrapped hydrogen bonds. Our predictions are consistent with known disease-related mutations and lead to a cogent explanation of the pathogenic nature of specific mutations affecting the cellular prion protein structural wrapping. On the other hand, a different wrapping of a very similar fold, mouse doppel, induces a dramatically different level of amyloidogenic propensity, suggesting that the packing within the fold, and not the fold itself, contains the signal for aggregation.

Amyloid↗

PubMed2002

Correct identification of genes from serial analysis of gene expression tag sequences.

SAGE (serial analysis of gene expression) is a remarkable technique for genome-wide analysis of gene expression. It is crucial to understand the extent to which SAGE can accurately indicate a gene or expressed sequence tag (EST) with a single tag. We analyzed the effect of the size of SAGE tag on gene identification. Our observation indicates that SAGE tags are in general not long enough to achieve the degree of uniqueness of identification originally envisaged. Our observations also indicate that the limitation of using SAGE tag to identify a gene can be overcome by converting SAGE tags into longer 3' EST sequences with the generation of longer cDNA fragments from SAGE tages for gene identification (GLGI) method.

Expressed Sequence Tags↗

PubMed2002

Computational Analysis of Gene Identification with SAGE.

SAGE is one of the few techniques capable of uniformly probing gene expression at a genome level irrespective of mRNA abundance and without a priori knowledge of the transcripts present. However, individual SAGE tags can match many sequences in the reference database, complicating gene identification. We perform a baseline evaluation of gene identification with SAGE using UniGene Human as the reference database by analyzing 1) the distributions of tags for various length tag sets formed for UniGene Human and 2) the tag-to-sequence mapping using a SAGE tag set consisting of 37,522 tags derived from human myeloid cells. The extensive multiplicity of the dbEST component of UniGene significantly detracts from gains that might be expected by extending tags within the scope of the SAGE protocol. In order to achieve reasonable sequence specificity for gene identification with the content of the commonly used UniGene sequence collection, tags on the order of hundreds of bases in length are required. One way to produce tags of such lengths is with GLGI, which extends SAGE tags to the 3' end of cDNA. We show that the longer sequences produced by GLGI relieve significantly the multiple match condition. In the myeloid sample, we also found a correlation between multiple match severity and high copy number. We extrapolate these findings, providing insights into the use of UniGene Human as a reference for gene identification.

Animals↗