Sascha Ott

Finding optimal models for small gene networks.

Finding gene networks from microarray data has been one focus of research in recent years. Given search spaces of super-exponential size, researchers have been applying heuristic approaches like greedy algorithms or simulated annealing to infer such networks. However, the accuracy of heuristics is uncertain, which--in combination with the high measurement noise of microarrays--makes it very difficult to draw conclusions from networks estimated by heuristics. We present a method that finds optimal Bayesian networks of considerable size and show first results of the application to yeast data. Having removed the uncertainty due to the heuristic methods, it becomes possible to evaluate the power of different statistical models to find biologically accurate networks.

Nodal cis-regulatory elements reveal epiblast and primitive endoderm heterogeneity in the peri-implantation mouse embryo.

Nodal, a secreted factor known for its conserved functions in cell-fate specification and the establishment of embryonic axes, is also required in mammals to maintain the pluripotency of the epiblast, the tissue that gives rise to all fetal lineages. Although Nodal is expressed as early as E3.5 in the mouse embryo, its regulation and functions at pre- and peri-implantation stages are currently unknown. Sensitive reporter transgenes for two Nodal cis-regulatory regions, the PEE and the ASE, exhibit specific expression profiles before implantation. Mutant and inhibitor studies find them respectively regulated by Wnt/β-catenin signaling and Activin/Nodal signaling, and provide evidence for localized and heterogeneous activities of these pathways in the inner cell mass, the epiblast and the primitive endoderm. These studies also show that Nodal and its prime effector, FoxH1, are not essential to preimplantation Activin/Nodal signaling. Finally, a strong upregulation of the ASE reporter in implanting blastocysts correlates with a downregulation of the pluripotency factor Nanog in the maturing epiblast. This study uncovers conservation in the mouse blastocyst of Wnt/β-catenin and Activin/Nodal-dependent activities known to govern Nodal expression and the establishment of polarity in the blastula of other deuterostomes. Our results indicate that these pathways act early on to initiate distinct cell-specification processes in the ICM derivatives. Our data also suggest that the activity of the Activin/Nodal pathway is dampened by interactions with the molecular machinery of pluripotency until just before implantation, possibly delaying cell-fate decisions in the mouse embryo.

A comparative study of S/MAR prediction tools

BackgroundS/MARs are regions of the DNA that are attached to the nuclear matrix. These regions are known to affect substantially the expression of genes. The computer prediction of S/MARs is a highly significant task which could contribute to our understanding of chromatin organisation in eukaryotic cells, the number and distribution of boundary elements, and the understanding of gene regulation in eukaryotic cells. However, while a number of S/MAR predictors have been proposed, their accuracy has so far not come under scrutiny.ResultsWe have selected S/MARs with sufficient experimental evidence and used these to evaluate existing methods of S/MAR prediction. Our main results are: 1.) all existing methods have little predictive power, 2.) a simple rule based on AT-percentage is generally competitive with other methods, 3.) in practice, the different methods will usually identify different sub-sequences as S/MARs, 4.) more research on the H-Rule would be valuable.ConclusionA new insight is needed to design a method which will predict S/MARs well. Our data, including the control data, has been deposited as additional material and this may help later researchers test new predictors.

Intrasplicing--analysis of long intron sequences.

We propose a new model for the splicing of long introns, which we call intrasplicing. The basic idea of this model is that the splicing of long introns may be facilitated by the splicing of inner parts of the intron prior to the splicing of the long intron itself. Since long introns have up to about 100,000 bases, this model seems to be a likely explanation of their splicing. To investigate the possibility of this model, we develop a new computational method for the analysis of DNA sequences with respect to splicing. We analyze the genomic sequence of four species with our method and derive several results indicating that intrasplicing may be an appropriate model for the splicing of at least part of the long intron sequences.

On the Complexity of Deriving Position Specific Score Matrices from Examples

PSSMs (Position-Specific Score Matrices) have been applied to various problems in Bioinformatics. We study the following problem: given positive examples (sequences) and negative examples (sequences), finda PSSM which correctly discriminates between positive and negative examples. We prove that this problem is solvedin polynomial time if the size of a PSSM is bounded by a constant. On the other hand, we prove that this problem is NP-hard if the size is not bounded. We also prove similar results on deriving a mixture of PSSMs.

Acetylene-substituted pyrazino[2,3-f][1,10]phenanthrolines and their Ru(II) complexes: syntheses, electronic properties and an exploration of their suitability as building blocks for metal-coordinated dehydroannulenes

Aryl- and silyl-terminated 6,7-dialkynylpyrazino[2,3-f][1,10]phenanthrolines (pyzphen) have been prepared by the condensation of [1,10]phenanthroline-5,6-diamine with appropriately functionalised dialkynyl-1,2-diones. These new ligands were used as chelators in the formation of the corresponding [Ru(bpy)2(pyzphen)]·2PF6 and [Ru(phen)2(pyzphen)]·2PF6 complexes. The terminally free diethynyl [Ru(bpy)2(pyzphen)] complex, obtained by protodesilylation of a silyl-protected precursor, was shown to be amenable to oxidative acetylene hetero-coupling reactions with arylacetylenes and allowed the preparation of the corresponding butadiynyl-substituted derivatives. Homo-coupling reactions of the terminally free diethynyl [Ru(bpy)2(pyzphen)] complex to produce cyclic dehydroannulene-arrays were successful, but furnished an inseparable mixture of compounds of at least two different ring sizes. The photophysical and electrochemical properties of both the free ligands and their Ru(II)-complexes are clearly modified by the presence of the alkynyl substituents. In comparison with non-acetylenic model compounds it was established that acetylene substitution induces bathochromically shifted electronic absorptions and emissions to various degrees in ligands and complexes, leads to increased luminescence lifetimes and quantum yields of the ruthenium pyzphen complexes, and renders the acetylenic ligands and their complexes more susceptible to electrochemical reduction.

On the complexity of deriving position specific score matrices from positive and negative sequences

Position-specific score matrices (PSSMs) have been applied to various problems in computational molecular biology. In this paper, we study the following problem: given positive examples (sequences) and negative examples (sequences), find a PSSM which correctly discriminates between positive and negative examples. We prove that this problem is solved in polynomial time if the size of a PSSM is bounded by a constant. On the other hand, we prove that this problem is NP-hard if the size is not bounded. We also prove hardness results for deriving multiple PSSMs and related problems.

A (bpy)~2Ru-coordinated dehydro[12]annulene with exotopically fused diimine binding sites

Synthesis and electronic properties of a dinuclear (bpy)(2)Ru(II) polypyridyl complex are described in which the bridging ligand consists of two dipyridophenazines fused to a formally antiaromatic dehydro[12]annulene and where the electronic and electrochemical properties of the complex are markedly influenced by the cyclic all-carbon core.

Inferring a Union of Halfspaces from Examples

We consider the following problem which is motivated by applications in Bioinformatics: given positive and negative points in d- dimensions, find a minimum cardinality set of halfspaces whose union covers all positive points and no negative points. We prove that approximation of this problem is at least as hard as approximation of graph coloring. On the other hand, we show that the two-dimensional case of the problem can be solved in polynomial time. Other related results are shown, too.