Polynomial algorithms for the Maximal Pairing Problem: efficient phylogenetic targeting on arbitrary trees

Background: The Maximal Pairing Problem (MPP) is the prototype of a class of combinatorial optimization problems that are of considerable interest in bioinformatics: Given an arbitrary phylogenetic tree T and weights ωxy for the paths between any two pairs of leaves (x, y), what is the collection of edge-disjoint paths between pairs of leaves that maximizes the total weight? Special cases of the MPP for binary trees and equal weights have been described previously; algorithms to solve the general MPP are still missing, however. Results: We describe a relatively simple dynamic programming algorithm for the special case of binary trees. We then show that the general case of multifurcating trees can be treated by interleaving solutions to certain auxiliary Maximum Weighted Matching problems with an extension of this dynamic programming approach, resulting in an overall polynomial-time solution of complexity (n^4 log n) w.r.t. the number n of leaves. The source code of a C implementation can be obtained under the GNU Public License from http://www.bioinf.uni-leipzig.de/Software/Targeting. For binary trees, we furthermore discuss several constrained variants of the MPP as well as a partition function approach to the probabilistic version of the MPP. Conclusions: The algorithms introduced here make it possible to solve the MPP also for large trees with high-degree vertices. This has practical relevance in the field of comparative phylogenetics and, for example, in the context of phylogenetic targeting, i.e., data collection with resource limitations.Human Evolutionary Biolog

RNA secondary structure prediction from multi-aligned sequences

It has been well accepted that the RNA secondary structures of most functional non-coding RNAs (ncRNAs) are closely related to their functions and are conserved during evolution. Hence, prediction of conserved secondary structures from evolutionarily related sequences is one important task in RNA bioinformatics; the methods are useful not only to further functional analyses of ncRNAs but also to improve the accuracy of secondary structure predictions and to find novel functional RNAs from the genome. In this review, I focus on common secondary structure prediction from a given aligned RNA sequence, in which one secondary structure whose length is equal to that of the input alignment is predicted. I systematically review and classify existing tools and algorithms for the problem, by utilizing the information employed in the tools and by adopting a unified viewpoint based on maximum expected gain (MEG) estimators. I believe that this classification will allow a deeper understanding of each tool and provide users with useful information for selecting tools for common secondary structure predictions.Comment: A preprint of an invited review manuscript that will be published in a chapter of the book `Methods in Molecular Biology'. Note that this version of the manuscript may differ from the published versio

Use of tamoxifen and raloxifene for breast cancer chemoprevention in 2010

PURPOSE: Two selective estrogen receptor modulators (SERMs), tamoxifen and raloxifene, have been shown in randomized clinical trials to reduce the risk of developing primary invasive breast cancer (IBC) in high-risk women. In 1998, the U.S. Food and Drug Administration (FDA) used these studies as a basis for approving tamoxifen for primary breast chemoprevention in both premenopausal and postmenopausal women at high risk. In 2007, the FDA approved raloxifene for primary breast cancer chemoprevention for postmenopausal women. METHODS: Data from the year 2010 National Health Interview Survey (NHIS) were analyzed to estimate the prevalence of tamoxifen and raloxifene use for chemoprevention of primary breast cancers among U.S. women. RESULTS: Prevalence of use of chemopreventive agents for primary tumors was 20,598 (95% CI, 518–114,864) for U.S. women aged 35 to 79 for tamoxifen. Prevalence was 96,890 (95% CI, 41,277–192,391) for U.S. women aged 50 to79 for raloxifene. CONCLUSION: Use of tamoxifen and raloxifene for prevention of primary breast cancers continues to be low. In 2010, women reporting medication use for breast cancer chemoprevention were primarily using the more recently FDA-approved drug raloxifene. Multiple possible explanations for the low use exist, including lack of awareness and/or concern about side effects among primary care physicians and patients

Identification and analysis of miRNAs in human breast cancer and teratoma samples using deep sequencing

<p>Abstract</p> <p>Background</p> <p>MiRNAs play important roles in cellular control and in various disease states such as cancers, where they may serve as markers or possibly even therapeutics. Identifying the whole repertoire of miRNAs and understanding their expression patterns is therefore an important goal.</p> <p>Methods</p> <p>Here we describe the analysis of 454 pyrosequencing of small RNA from four different tissues: Breast cancer, normal adjacent breast, and two teratoma cell lines. We developed a pipeline for identifying new miRNAs, emphasizing extracting and retaining as much data as possible from even noisy sequencing data. We investigated differential expression of miRNAs in the breast cancer and normal adjacent breast samples, and systematically examined the mature sequence end variability of miRNA compared to non-miRNA loci.</p> <p>Results</p> <p>We identified five novel miRNAs, as well as two putative alternative precursors for known miRNAs. Several miRNAs were differentially expressed between the breast cancer and normal breast samples. The end variability was shown to be significantly different between miRNA and non-miRNA loci.</p> <p>Conclusion</p> <p>Pyrosequencing of small RNAs, together with a computational pipeline, can be used to identify miRNAs in tumor and other tissues. Measures of miRNA end variability may in the future be incorporated into the discovery pipeline as a discriminatory feature. Breast cancer samples show a distinct miRNA expression profile compared to normal adjacent breast.</p

In vitro and in vivo delivery of a sustained release nanocarrier-based formulation of an MRTF/SRF inhibitor in conjunctival fibrosis

Abstract Background Sustained drug delivery is a large unmet clinical need in glaucoma. Here, we incorporated a Myocardin-Related Transcription Factor/Serum Response Factor inhibitor, CCG-222740, into slow release large unilamellar vesicles derived from the liposomes DOTMA (1,2-di-O-octadecenyl-3-trimethylammonium propane) and DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine), and tested their effects in vitro and in vivo. Results The vesicles were spherical particles of around 130 nm and were strongly cationic. A large amount of inhibitor could be incorporated into the vesicles. We showed that the nanocarrier CCG-222740 formulation gradually released the inhibitor over 14 days using high performance liquid chromatography. Nanocarrier CCG-222740 significantly decreased ACTA2 gene expression and was not cytotoxic in human conjunctival fibroblasts. In vivo, nanocarrier CCG-222740 doubled the bleb survival from 11.0 ± 0.6 days to 22.0 ± 1.3 days (p = 0.001), decreased conjunctival scarring and did not have any local or systemic adverse effects in a rabbit model of glaucoma filtration surgery. Conclusions Our study demonstrates proof-of-concept that a nanocarrier-based formulation efficiently achieves a sustained release of a Myocardin-Related Transcription Factor/Serum Response Factor inhibitor and prevents conjunctival fibrosis in an established rabbit model of glaucoma filtration surgery.https://deepblue.lib.umich.edu/bitstream/2027.42/146540/1/12951_2018_Article_425.pd

Analysis of conserved microRNAs in floral tissues of sexual and apomictic Boechera species

<p>Abstract</p> <p>Background</p> <p>Apomixis or asexual seed formation represents a potentially important agronomic trait whose introduction into crop plants could be an effective way to fix and perpetuate a desirable genotype through successive seed generations. However, the gene regulatory pathways underlying apomixis remain unknown. In particular, the potential function of microRNAs, which are known to play crucial roles in many aspects of plant growth and development, remains to be determined with regards to the switch from sexual to apomictic reproduction.</p> <p>Results</p> <p>Using bioinformatics and microarray validation procedures, 51 miRNA families conserved among angiosperms were identified in <it>Boechera</it>. Microarray assay confirmed 15 of the miRNA families that were identified by bioinformatics techniques. 30 cDNA sequences representing 26 miRNAs could fold back into stable pre-miRNAs. 19 of these pre-miRNAs had miRNAs with <it>Boechera</it>-specific nucleotide substitutions (NSs). Analysis of the Gibbs free energy (ΔG) of these pre-miRNA stem-loops with NSs showed that the <it>Boechera</it>-specific miRNA NSs significantly (p ≤ 0.05) enhance the stability of stem-loops. Furthermore, six transcription factors, the Squamosa promoter binding protein like SPL6, SPL11 and SPL15, Myb domain protein 120 (MYB120), RELATED TO AP2.7 DNA binding (RAP2.7, TOE1 RAP2.7) and TCP family transcription factor 10 (TCP10) were found to be expressed in sexual or apomictic ovules. However, only SPL11 showed differential expression with significant (p ≤ 0.05) up-regulation at the megaspore mother cell (MMC) stage of ovule development in apomictic genotypes.</p> <p>Conclusions</p> <p>This study constitutes the first extensive insight into the conservation and expression of microRNAs in <it>Boechera </it>sexual and apomictic species. The miR156/157 target squamosa promoter binding protein-like 11 (SPL11) was found differentially expressed with significant (p ≤ 0.05) up-regulation at the MMC stage of ovule development in apomictic genotypes. The results also demonstrate that nucleotide changes in mature miRNAs significantly (p ≤ 0.05) enhance the thermodynamic stability of pre-miRNA stem-loops.</p

NAViGaTing the Micronome – Using Multiple MicroRNA Prediction Databases to Identify Signalling Pathway-Associated MicroRNAs

MicroRNAs are a class of small RNAs known to regulate gene expression at the transcript level, the protein level, or both. Since microRNA binding is sequence-based but possibly structure-specific, work in this area has resulted in multiple databases storing predicted microRNA:target relationships computed using diverse algorithms. We integrate prediction databases, compare predictions to in vitro data, and use cross-database predictions to model the microRNA:transcript interactome--referred to as the micronome--to study microRNA involvement in well-known signalling pathways as well as associations with disease. We make this data freely available with a flexible user interface as our microRNA Data Integration Portal--mirDIP (http://ophid.utoronto.ca/mirDIP).mirDIP integrates prediction databases to elucidate accurate microRNA:target relationships. Using NAViGaTOR to produce interaction networks implicating microRNAs in literature-based, KEGG-based and Reactome-based pathways, we find these signalling pathway networks have significantly more microRNA involvement compared to chance (p<0.05), suggesting microRNAs co-target many genes in a given pathway. Further examination of the micronome shows two distinct classes of microRNAs; universe microRNAs, which are involved in many signalling pathways; and intra-pathway microRNAs, which target multiple genes within one signalling pathway. We find universe microRNAs to have more targets (p<0.0001), to be more studied (p<0.0002), and to have higher degree in the KEGG cancer pathway (p<0.0001), compared to intra-pathway microRNAs.Our pathway-based analysis of mirDIP data suggests microRNAs are involved in intra-pathway signalling. We identify two distinct classes of microRNAs, suggesting a hierarchical organization of microRNAs co-targeting genes both within and between pathways, and implying differential involvement of universe and intra-pathway microRNAs at the disease level