PUBLICATIONS

Names of UBM student authors are underlined.

Simulation of the Human Intracranial Arterial Tree

Leopold Grinberg1, Tomer Anor2, Elizabeth Cheever1, Joseph R. Madsen2 and George Em Karniadakis1

1Division of Applied Mathematics, Brown University, Providence, RI, USA

2Children’s Hospital, Harvard Medical School, Boston MA, USA

Phil. Trans. Roy. Soc. (London) Series A – in press, 2009

Abstract: High-resolution unsteady 3D flow simulations in large intracranial arterial networks of a healthy subject and a patient with hydrocephalus have been performed. The large size of the computational domains requires the use of thousands of computer processors and solution of the flow equations with about one billion degrees of freedom. We have developed and implemented a two-level domain decomposition method, and a new type of outflow boundary condition to control flow rates at tens of terminal vessels of the arterial network. In the paper we demonstrate the flow patterns in the normal and abnormal intracranial arterial networks using patient-specific data.

A RNA Binding Map Uncovers Sequence and Secondary Structure Determinants of PTB Binding

Reid D.1,5, Chang B.1,5, Thompson W.2,5, Kovoor A.3 and Fairbrother W.G.1,4,6

1MCB Department, Brown University, Providence, Rhode Island 02912, USA

2Department of Applied Math, Brown University, Providence, Rhode Island 02912, USA

3Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island 02881, USA

4Center for Computational Molecular Biology, Brown University, Providence, Rhode Island 02912, USA

5These authors contributed equally to this work.

6Address all correspondence to fairbrother@brown.edu

POLS-Biology – under review, 2009

Abstract: Location studies and RNA maps have revolutionized our understanding of the global function of splicing factors and started to elucidate the architecture of complexes that define splice site selection. The chance of precipitating any particular splicing factor binding site is biased by level of gene expression. For the many splicing factors that interact with both pre-mRNA and mRNA, the IP output is further biased towards the thousand fold more abundant mRNA. This bias affects motif finding and our ability to create RNA maps and makes distinction between RNPs formed on exonic mRNA or pre-mRNA impossible. We have developed a novel approach to surveying protein pre-RNA interactions that circumvent this problem. We applied this approach to a splicing factor that has proved somewhat refractile to Chip and SELEX based analysis, PTB, and report multiple binding motifs consistent with the semi-independent multi RRM modes of binding proposed in the literature. The output was used to map PTB binding showing enrichment at the polypyrimidine tract upstream of the 3'ss and an avoidance of binding exonic sequence. We also find a strong preference for PTB binding unpaired RNA, mostly because high affinity PTB targets like CU repeats have nearest neighbor thermodynamic terms that are less favorable to forming double stranded structures than other dinucleotide combinations. We note that other examples of these intrinsically unstructured motifs (Poly A, U, CU or AG repeats) are prominent functional elements bound by single stranded RNA binding proteins (PAB, U2AF65, SR proteins) thus suggesting an evolutionary scenario where single stranded binding proteins have evolved to bind intrinsically unstructured RNA.