A general framework for enumerating equivalence classes of solutions

When a problem has more than one solution, it is often important, depending on the underlying context, to enumerate (i.e., to list) them all. Even when the enumeration can be done in polynomial delay, that is, spending no more than polynomial time to go from one solution to the next, this can be costly as the number of solutions themselves may be huge, including sometimes exponential. Furthermore, depending on the application, many of these solutions can be considered equivalent. The problem of an efficient enumeration of the equivalence classes or of one representative per class (without generating all the solutions), although identified as a need in many areas, has been addressed only for very few specific cases. In this paper, we provide a general framework that solves this problem in polynomial delay for a wide variety of contexts, including optimization ones that can be addressed by dynamic programming algorithms, and for certain types of equivalence relations between solutions

An asymmetric approach to preserve common intervals while sorting by reversals

Dias Vieira Braga M, Gautier C, Sagot M-F. An asymmetric approach to preserve common intervals while sorting by reversals. Algorithms for Molecular Biology. 2009;4(1):16.Background: The reversal distance and optimal sequences of reversals to transform a genome into another are useful tools to analyse evolutionary scenarios. However, the number of sequences is huge and some additional criteria should be used to obtain a more accurate analysis. One strategy is searching for sequences that respect constraints, such as the common intervals (clusters of co-localised genes). Another approach is to explore the whole space of sorting sequences, eventually grouping them into classes of equivalence. Recently both strategies started to be put together, to restrain the space to the sequences that respect constraints. In particular an algorithm has been proposed to list classes whose sorting sequences do not break the common intervals detected between the two inital genomes A and B. This approach may reduce the space of sequences and is symmetric (the result of the analysis sorting A into B can be obtained from the analysis sorting B into A). Results: We propose an alternative approach to restrain the space of sorting sequences, using progressive instead of initial detection of common intervals (the list of common intervals is updated after applying each reversal). This may reduce the space of sequences even more, but is shown to be asymmetric. Conclusions: We suggest that our method may be more realistic when the relation ancestor-descendant between the analysed genomes is clear and we apply it to do a better characterisation of the evolutionary scenario of the bacterium Rickettsia felis with respect to one of its ancestors

A polynomial time biclustering algorithm for finding approximate expression patterns in gene expression time series

<p>Abstract</p> <p>Background</p> <p>The ability to monitor the change in expression patterns over time, and to observe the emergence of coherent temporal responses using gene expression time series, obtained from microarray experiments, is critical to advance our understanding of complex biological processes. In this context, biclustering algorithms have been recognized as an important tool for the discovery of local expression patterns, which are crucial to unravel potential regulatory mechanisms. Although most formulations of the biclustering problem are NP-hard, when working with time series expression data the interesting biclusters can be restricted to those with contiguous columns. This restriction leads to a tractable problem and enables the design of efficient biclustering algorithms able to identify all maximal contiguous column coherent biclusters.</p> <p>Methods</p> <p>In this work, we propose <it>e</it>-CCC-Biclustering, a biclustering algorithm that finds and reports all maximal contiguous column coherent biclusters with approximate expression patterns in time polynomial in the size of the time series gene expression matrix. This polynomial time complexity is achieved by manipulating a discretized version of the original matrix using efficient string processing techniques. We also propose extensions to deal with missing values, discover anticorrelated and scaled expression patterns, and different ways to compute the errors allowed in the expression patterns. We propose a scoring criterion combining the statistical significance of expression patterns with a similarity measure between overlapping biclusters.</p> <p>Results</p> <p>We present results in real data showing the effectiveness of <it>e</it>-CCC-Biclustering and its relevance in the discovery of regulatory modules describing the transcriptomic expression patterns occurring in <it>Saccharomyces cerevisiae </it>in response to heat stress. In particular, the results show the advantage of considering approximate patterns when compared to state of the art methods that require exact matching of gene expression time series.</p> <p>Discussion</p> <p>The identification of co-regulated genes, involved in specific biological processes, remains one of the main avenues open to researchers studying gene regulatory networks. The ability of the proposed methodology to efficiently identify sets of genes with similar expression patterns is shown to be instrumental in the discovery of relevant biological phenomena, leading to more convincing evidence of specific regulatory mechanisms.</p> <p>Availability</p> <p>A prototype implementation of the algorithm coded in Java together with the dataset and examples used in the paper is available in <url>http://kdbio.inesc-id.pt/software/e-ccc-biclustering</url>.</p

A comparative sequence analysis reveals a common GBD/FH3-FH1-FH2-DAD architecture in formins from Dictyostelium, fungi and metazoa

BACKGROUND: Formins are multidomain proteins defined by a conserved FH2 (formin homology 2) domain with actin nucleation activity preceded by a proline-rich FH1 (formin homology 1) domain. Formins act as profilin-modulated processive actin nucleators conserved throughout a wide range of eukaryotes. RESULTS: We present a detailed sequence analysis of the 10 formins (ForA to J) identified in the genome of the social amoeba Dictyostelium discoideum. With the exception of ForI and ForC all other formins conform to the domain structure GBD/FH3-FH1-FH2-DAD, where DAD is the Diaphanous autoinhibition domain and GBD/FH3 is the Rho GTPase-binding domain/formin homology 3 domain that we propose to represent a single domain. ForC lacks a FH1 domain, ForI lacks recognizable GBD/FH3 and DAD domains and ForA, E and J have additional unique domains. To establish the relationship between formins of Dictyostelium and other organisms we constructed a phylogenetic tree based on the alignment of FH2 domains. Real-time PCR was used to study the expression pattern of formin genes. Expression of forC, D, I and J increased during transition to multi-cellular stages, while the rest of genes displayed less marked developmental variations. During sexual development, expression of forH and forI displayed a significant increase in fusion competent cells. CONCLUSION: Our analysis allows some preliminary insight into the functionality of Dictyostelium formins: all isoforms might display actin nucleation activity and, with the exception of ForI, might also be susceptible to autoinhibition and to regulation by Rho GTPases. The architecture GBD/FH3-FH1-FH2-DAD appears common to almost all Dictyostelium, fungal and metazoan formins, for which we propose the denomination of conventional formins, and implies a common regulatory mechanism

Formin 1-Isoform IV Deficient Cells Exhibit Defects in Cell Spreading and Focal Adhesion Formation

Background: Regulation of the cytoskeleton is a central feature of cell migration. The formin family of proteins controls the rate of actin nucleation at its barbed end. Thus, formins are predicted to contribute to several important cell processes such as locomotion, membrane ruffling, vesicle endocytosis, and stress fiber formation and disassociation. Methodology/Principal Findings: In this study we investigated the functional role of Formin1-isoform4 (Fmn1-IV) by using genetically null primary cells that displayed augmented protrusive behaviour during wound healing and delayed cell spreading. Cells deficient of Fmn1-IV also showed reduced efficiency of focal adhesion formation. Additionally, we generated an enhanced green fluorescence protein (EGFP)-fused Fmn1-IV knock-in mouse to monitor the endogenous subcellular localization of Fmn1-IV. Its localization was found within the cytoplasm and along microtubules, yet it was largely excluded from adherens junctions. Conclusions/Significance: It was determined that Fmn1-IV, as an actin nucleator, contributes to protrusion of the cell’s leading edge and focal adhesion formation, thus contributing to cell motility

Formin1 Mediates the Induction of Dendritogenesis and Synaptogenesis by Neurogenin3 in Mouse Hippocampal Neurons

Neurogenin3, a proneural transcription factor controlled by Notch receptor, has been recently shown to regulate dendritogenesis and synaptogenesis in mouse hippocampal neurons. However, little is known about the molecular mechanisms involved in these actions of Ngn3. We have used a microarray analysis to identify Ngn3 regulated genes related with cytoskeleton dynamics. One of such genes is Fmn1, whose protein, Formin1, is associated with actin and microtubule cytoskeleton. Overexpression of the Fmn1 isoform-Ib in cultured mouse hippocampal neurons induced an increase in the number of primary dendrites and in the number of glutamatergic synaptic inputs at 4 days in vitro. The same changes were provoked by overexpression of Ngn3. In addition downregulation of Fmn1 by the use of Fmn1-siRNAs impaired such morphological and synaptic changes induced by Ngn3 overexpression in neurons. These results reveal a previously unknown involvement of Formin1 in dendritogenesis and synaptogenesis and indicate that this protein is a key component of the Ngn3 signaling pathway that controls neuronal differentiation

Model of For3p-Mediated Actin Cable Assembly in Fission Yeast

Formin For3p nucleates actin cables at the tips of fission yeast cells for polarized cell growth. The results of prior experiments have suggested a possible mechanism for actin cable assembly that involves association of For3p near cell tips, For3p-mediated actin polymerization, retrograde flow of actin cables toward the cell center, For3p dissociation from cell tips, and cable disassembly. We used analytical and computational modeling to test the validity and implications of the proposed coupled For3p/actin mechanism. We compared the model to prior experiments quantitatively and generated predictions for the expected behavior of the actin cable system upon changes of parameter values. We found that the model generates stable steady states with realistic values of rate constants and actin and For3p concentrations. Comparison of our results to previous experiments monitoring the FRAP of For3p-3GFP and the response of actin cables to treatments with actin depolymerizing drugs provided further support for the model. We identified the set of parameter values that produces results in agreement with experimental observations. We discuss future experiments that will help test the model's predictions and eliminate other possible mechanisms. The results of the model suggest that flow of actin cables may establish actin and For3p concentration gradients in the cytoplasm that could be important in global cell patterning

GRISOTTO: A greedy approach to improve combinatorial algorithms for motif discovery with prior knowledge

<p>Abstract</p> <p>Background</p> <p>Position-specific priors (PSP) have been used with success to boost EM and Gibbs sampler-based motif discovery algorithms. PSP information has been computed from different sources, including orthologous conservation, DNA duplex stability, and nucleosome positioning. The use of prior information has not yet been used in the context of combinatorial algorithms. Moreover, priors have been used only independently, and the gain of combining priors from different sources has not yet been studied.</p> <p>Results</p> <p>We extend RISOTTO, a combinatorial algorithm for motif discovery, by post-processing its output with a greedy procedure that uses prior information. PSP's from different sources are combined into a scoring criterion that guides the greedy search procedure. The resulting method, called GRISOTTO, was evaluated over 156 yeast TF ChIP-chip sequence-sets commonly used to benchmark prior-based motif discovery algorithms. Results show that GRISOTTO is at least as accurate as other twelve state-of-the-art approaches for the same task, even without combining priors. Furthermore, by considering combined priors, GRISOTTO is considerably more accurate than the state-of-the-art approaches for the same task. We also show that PSP's improve GRISOTTO ability to retrieve motifs from mouse ChiP-seq data, indicating that the proposed algorithm can be applied to data from a different technology and for a higher eukaryote.</p> <p>Conclusions</p> <p>The conclusions of this work are twofold. First, post-processing the output of combinatorial algorithms by incorporating prior information leads to a very efficient and effective motif discovery method. Second, combining priors from different sources is even more beneficial than considering them separately.</p

Regulation of LRRK2 Expression Points to a Functional Role in Human Monocyte Maturation

Genetic variants of Leucine-Rich Repeat Kinase 2 (LRRK2) are associated with a significantly enhanced risk for Parkinson disease, the second most common human neurodegenerative disorder. Despite major efforts, our understanding of LRRK2 biological function and regulation remains rudimentary. In the present study we analyze LRRK2 mRNA and protein expression in sub-populations of human peripheral blood mononuclear cells (PBMCs). LRRK2 mRNA and protein was found in circulating CD19+ B cells and in CD14+ monocytes, whereas CD4+ and CD8+ T cells were devoid of LRRK2 mRNA. Within CD14+ cells the CD14+CD16+ sub-population of monocytes exhibited high levels of LRRK2 protein, in contrast to CD14+CD16- cells. However both populations expressed LRRK2 mRNA. As CD14+CD16+ cells represent a more mature subset of monocytes, we monitored LRRK2 expression after in vitro treatment with various stress factors known to induce monocyte activation. We found that IFN-γ in particular robustly increased LRRK2 mRNA and protein levels in monocytes concomitant with a shift of CD14+CD16− cells towards CD14+CD16+cells. Interestingly, the recently described LRRK2 inhibitor IN-1 attenuated this shift towards CD14+CD16+ after IFN-γ stimulation. Based on these findings we speculate that LRRK2 might have a role in monocyte maturation. Our results provide further evidence for the emerging role of LRRK2 in immune cells and regulation at the transcriptional and translational level. Our data might also reflect an involvement of peripheral and brain immune cells in the disease course of PD, in line with increasing awareness of the role of the immune system in PD