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Showing papers by "Rob Knight published in 2006"


Journal ArticleDOI
TL;DR: Analysis of previously published sequences from the Columbia river, its estuary, and the adjacent coastal ocean using the UniFrac interface provided insights that were not apparent from the initial data analysis, which used other commonly employed techniques to compare the communities.
Abstract: Background: Moving beyond pairwise significance tests to compare many microbial communities simultaneously is critical for understanding large-scale trends in microbial ecology and community assembly. Techniques that allow microbial communities to be compared in a phylogenetic context are rapidly gaining acceptance, but the widespread application of these techniques has been hindered by the difficulty of performing the analyses. Results: We introduce UniFrac, a web application available at http://bmf.colorado.edu/unifrac, that allows several phylogenetic tests for differences among communities to be easily applied and interpreted. We demonstrate the use of UniFrac to cluster multiple environments, and to test which environments are significantly different. We show that analysis of previously published sequences from the Columbia river, its estuary, and the adjacent coastal ocean using the UniFrac interface provided insights that were not apparent from the initial data analysis, which used other commonly employed techniques to compare the communities. Conclusion: UniFrac provides easy access to powerful multivariate techniques for comparing microbial communities in a phylogenetic context. We thus expect that it will provide a completely new picture of many microbial interactions and processes in both environmental and medical contexts.

1,404 citations


Journal ArticleDOI
TL;DR: Fast-FIND is easy to implement, takes less than a second to search the entire Drosophila genome sequence for arbitrary patterns adjacent to sites of alternative polyadenylation, and is sufficiently fast to allow sensitivity analysis on the patterns.
Abstract: Many vital biological processes, including transcription and splicing, require a combination of short, degenerate sequence patterns, or motifs, adjacent to defined sequence features. Although these motifs occur frequently by chance, they only have biological meaning within a specific context. Identifying transcripts that contain meaningful combinations of patterns is thus an important problem, which existing tools address poorly. Here we present a new approach, Fast-FIND (Fast-F ully I ndexed N ucleotide D atabase), that uses a relational database to support rapid indexed searches for arbitrary combinations of patterns defined either by sequence or composition. Fast-FIND is easy to implement, takes less than a second to search the entire Drosophila genome sequence for arbitrary patterns adjacent to sites of alternative polyadenylation, and is sufficiently fast to allow sensitivity analysis on the patterns. We have applied this approach to identify transcripts that contain combinations of sequence motifs for RNA-binding proteins that may regulate alternative polyadenylation. Fast-FIND provides an efficient way to identify transcripts that are potentially regulated via alternative polyadenylation. We have used it to generate hypotheses about interactions between specific polyadenylation factors, which we will test experimentally.

387 citations



Book ChapterDOI
TL;DR: This chapter highlights recent genetic studies of craniofacial development in zebrafish that have revealed new tissue interactions and shows that the process of CNC development is highly conserved across the vertebrates.
Abstract: The skeletal derivatives of the cranial neural crest (CNC) are patterned through a combination of intrinsic differences between crest cells and extrinsic signals from adjacent tissues, including endoderm and ectoderm. In this chapter, we focus on how CNC cells positionally interpret these cues to generate such highly specialized structures as the jaw and ear ossicles. We highlight recent genetic studies of craniofacial development in zebrafish that have revealed new tissue interactions and show that the process of CNC development is highly conserved across the vertebrates.

131 citations


Journal ArticleDOI
01 Jan 2006-RNA
TL;DR: Analysis of ribosomal RNA sequences and structures from a wide range of species revealed unexpected universal compositional trends that may improve the accuracy of RNA secondary structure prediction, and suggest caution in interpreting differences in the rate of change of the GC content in different parts of the molecule as evidence of differential selection.
Abstract: We have encountered an unexpected property of rRNA secondary structures that may generalize to all RNAs. Analysis of 8892 ribosomal RNA sequences and structures from a wide range of species revealed unexpected universal compositional trends. First, different categories of rRNA secondary structure (stems, loops, bulges, and junctions) have distinct, characteristic base compositions. Second, the observed patterns of variation are similar among sequences from large and small rRNA subunits and all domains of life, despite extensive evolutionary divergence. Surprisingly, these differences do not seem to be related to selection for different compositions in different structural categories, but rather relate to the overall composition of the molecule: Randomized RNAs with no evolutionary history show the same structure-dependent compositional biases as rRNAs. These compositional trends may improve the accuracy of RNA secondary structure prediction, because they allow us to compare predicted structures against known compositional preferences. They also suggest caution in interpreting differences in the rate of change of the GC content in different parts of the molecule as evidence of differential selection.

107 citations


Journal ArticleDOI
TL;DR: Considering the ease of oral administration, higher response rate, longer time to progression and overall survival benefit, the combination of lenalidomide-dexamethasone may very well represent the treatment of choice for early refractory or relapsing multiple myeloma.
Abstract: 7521 Background: Lenalidomide is a novel, orally administered, immunomodulatory drug (IMiD) that has single-agent activity against MM and additive effects when combined with dexamethasone (Dex). Me...

81 citations


Journal ArticleDOI
TL;DR: The current study findings suggest that the administration of erythropoietic agents should be minimized in MM pts receiving Len/Dex, providing a longer median time to progression (TTP), higher response rates, and higher CR rates.
Abstract: 7506 Background: Lenalidomide (Len) is a novel, orally administered, immunomodulatory drug (IMiD) that has single-agent activity against multiple myeloma (MM) and additive effects when combined wit...

31 citations


Journal ArticleDOI
TL;DR: A new class of methods based on the changes in nucleotide substitution rates that occur when a gene is transferred to a new organism, which will be widely useful in detecting HGT events linked to the evolution of important bacterial traits, such as antibiotic resistance and pathogenicity.
Abstract: Horizontal gene transfer (HGT) has allowed bacteria to evolve many new capabilities. Because transferred genes perform many medically important functions, such as conferring antibiotic resistance, improved detection of horizontally transferred genes from sequence data would be an important advance. Existing sequence-based methods for detecting HGT focus on changes in nucleotide composition or on differences between gene and genome phylogenies; these methods have high error rates. First, we introduce a new class of methods for detecting HGT based on the changes in nucleotide substitution rates that occur when a gene is transferred to a new organism. Our new methods discriminate simulated HGT events with an error rate up to 10 times lower than does GC content. Use of models that are not time-reversible is crucial for detecting HGT. Second, we show that using combinations of multiple predictors of HGT offers substantial improvements over using any single predictor, yielding as much as a factor of 18 improvement in performance (a maximum reduction in error rate from 38% to about 3%). Multiple predictors were combined by using the random forests machine learning algorithm to identify optimal classifiers that separate HGT from non-HGT trees. The new class of HGT-detection methods introduced here combines advantages of phylogenetic and compositional HGT-detection techniques. These new techniques offer order-of-magnitude improvements over compositional methods because they are better able to discriminate HGT from non-HGT trees under a wide range of simulated conditions. We also found that combining multiple measures of HGT is essential for detecting a wide range of HGT events. These novel indicators of horizontal transfer will be widely useful in detecting HGT events linked to the evolution of important bacterial traits, such as antibiotic resistance and pathogenicity.

28 citations


Journal ArticleDOI
TL;DR: Multivariate analysis indicates that Lenalidomide in combination with dexamethasone is more effective than dexamETHasone-placebo regardless of prior thalidomides in relapsed/refractory multiple myeloma.
Abstract: 7522 Background: Lenalidomide (len), an analog of thalidomide (thal) is a novel, oral immunomodulatory agent that is effective against multiple myeloma (MM). Two randomized, Phase III trials (MM009...

22 citations


Journal ArticleDOI
TL;DR: Thal/Dex is significantly superior to dexamethasone alone as first-line therapy for multiple myeloma as well as placebo/Dex, crossing the upper boundary for superiority.
Abstract: 7517 Background: Thalidomide plus dexamethasone (Thal/Dex) yields superior response rates versus dexamethasone (Dex) but its impact as primary therapy for multiple myeloma (MM) is unknown. Methods:...

20 citations


Journal ArticleDOI
TL;DR: DivergentSet addresses the important but so far neglected bioinformatics task of choosing a representative set of sequences from a larger collection and it is found that using a phylogenetic tree to guide the construction of divergent sets of sequences can be up to 2 orders of magnitude faster than the naive method of using a full distance matrix.

Journal ArticleDOI
TL;DR: Len/Dex provided higher response rates and improved TTP compared with Dex at first relapse and beyond and these data support the use of Len/Dex for pts as 2nd-line therapy for relapsed MM.
Abstract: 7600 Background: High-dose Dex remains a standard therapy for relapsed or refractory MM. Lenalidomide is a novel, oral, immunomodulatory drug (IMiD) that has activity against MM with additive effects when combined with Dex. At the interim analysis of MM-009/010, Len/Dex achieved a significant benefit over Dex, providing a longer median TTP, higher response rates, and higher CR rates. Aim: This prospective subgroup analysis was performed to determine the potential benefit of starting Len/Dex at first relapse by analyzing outcomes versus Dex among patients (pts) who had received only 1 versus >1 prior line of therapy. Methods: Pts who had received 1–3 prior treatments and were not refractory to Dex were randomized to either oral lenalidomide (25 mg daily for 3 weeks every 4 weeks) plus Dex (40 mg on Days 1–4, 9–12, 17–20 every 4 weeks for 4 months, then 40 mg on Days 1–4 every cycle thereafter) or placebo plus Dex. The EBMT criteria were used for response. Randomization was stratified at entry by number of ...