Exact score distribution computation for ontological similarity searches

<p>Abstract</p> <p>Background</p> <p>Semantic similarity searches in ontologies are an important component of many bioinformatic algorithms, e.g., finding functionally related proteins with the Gene Ontology or phenotypically similar diseases with the Human Phenotype Ontology (HPO). We have recently shown that the performance of semantic similarity searches can be improved by ranking results according to the probability of obtaining a given score at random rather than by the scores themselves. However, to date, there are no algorithms for computing the exact distribution of semantic similarity scores, which is necessary for computing the exact <it>P</it>-value of a given score.</p> <p>Results</p> <p>In this paper we consider the exact computation of score distributions for similarity searches in ontologies, and introduce a simple null hypothesis which can be used to compute a <it>P</it>-value for the statistical significance of similarity scores. We concentrate on measures based on Resnik's definition of ontological similarity. A new algorithm is proposed that collapses subgraphs of the ontology graph and thereby allows fast score distribution computation. The new algorithm is several orders of magnitude faster than the naive approach, as we demonstrate by computing score distributions for similarity searches in the HPO. It is shown that exact <it>P</it>-value calculation improves clinical diagnosis using the HPO compared to approaches based on sampling.</p> <p>Conclusions</p> <p>The new algorithm enables for the first time exact <it>P</it>-value calculation via exact score distribution computation for ontology similarity searches. The approach is applicable to any ontology for which the annotation-propagation rule holds and can improve any bioinformatic method that makes only use of the raw similarity scores. The algorithm was implemented in Java, supports any ontology in OBO format, and is available for non-commercial and academic usage under: <url>https://compbio.charite.de/svn/hpo/trunk/src/tools/significance/</url></p

Histone Acetylation-Mediated Regulation of the Hippo Pathway

The Hippo pathway is a signaling cascade recently found to play a key role in tumorigenesis therefore understanding the mechanisms that regulate it should open new opportunities for cancer treatment. Available data indicate that this pathway is controlled by signals from cell-cell junctions however the potential role of nuclear regulation has not yet been described. Here we set out to verify this possibility and define putative mechanism(s) by which it might occur. By using a luciferase reporter of the Hippo pathway, we measured the effects of different nuclear targeting drugs and found that chromatin-modifying agents, and to a lesser extent certain DNA damaging drugs, strongly induced activity of the reporter. This effect was not mediated by upstream core components (i.e. Mst, Lats) of the Hippo pathway, but through enhanced levels of the Hippo transducer TAZ. Investigation of the underlying mechanism led to the finding that cancer cell exposure to histone deacetylase inhibitors induced secretion of growth factors and cytokines, which in turn activate Akt and inhibit the GSK3 beta associated protein degradation complex in drug-affected as well as in their neighboring cells. Consequently, expression of EMT genes, cell migration and resistance to therapy were induced. These processes were suppressed by using pyrvinium, a recently described small molecule activator of the GSK 3 beta associated degradation complex. Overall, these findings shed light on a previously unrecognized phenomenon by which certain anti-cancer agents may paradoxically promote tumor progression by facilitating stabilization of the Hippo transducer TAZ and inducing cancer cell migration and resistance to therapy. Pharmacological targeting of the GSK3 beta associated degradation complex may thus represent a unique approach to treat cancer. © 2013 Basu et al

Genome-wide linkage scan for colorectal cancer susceptibility genes supports linkage to chromosome 3q

Background: Colorectal cancer is one of the most common causes of cancer-related mortality. The disease is clinically and genetically heterogeneous though a strong hereditary component has been identified. However, only a small proportion of the inherited susceptibility can be ascribed to dominant syndromes, such as Hereditary Non-Polyposis Colorectal Cancer (HNPCC) or Familial Adenomatous Polyposis (FAP). In an attempt to identify novel colorectal cancer predisposing genes, we have performed a genome-wide linkage analysis in 30 Swedish non-FAP/non-HNPCC families with a strong family history of colorectal cancer.Methods: Statistical analysis was performed using multipoint parametric and nonparametric linkage.Results: Parametric analysis under the assumption of locus homogeneity excluded any common susceptibility regions harbouring a predisposing gene for colorectal cancer. However, several loci on chromosomes 2q, 3q, 6q, and 7q with suggestive linkage were detected in the parametric analysis under the assumption of locus heterogeneity as well as in the nonparametric analysis. Among these loci, the locus on chromosome 3q21.1- q26.2 was the most consistent finding providing positive results in both parametric and nonparametric analyses Heterogeneity LOD score (HLOD) = 1.90, alpha = 0.45, Non-Parametric LOD score (NPL) = 2.1).Conclusion: The strongest evidence of linkage was seen for the region on chromosome 3. Interestingly, the same region has recently been reported as the most significant finding in a genome-wide analysis performed with SNP arrays; thus our results independently support the finding on chromosome 3q

First LIGO search for gravitational wave bursts from cosmic (super)strings

We report on a matched-filter search for gravitational wave bursts from cosmic string cusps using LIGO data from the fourth science run (S4) which took place in February and March 2005. No gravitational waves were detected in 14.9 days of data from times when all three LIGO detectors were operating. We interpret the result in terms of a frequentist upper limit on the rate of gravitational wave bursts and use the limits on the rate to constrain the parameter space (string tension, reconnection probability, and loop sizes) of cosmic string models.Comment: 11 pages, 3 figures. Replaced with version submitted to PR

Stacked Search for Gravitational Waves from the 2006 SGR 1900+14 Storm

We present the results of a LIGO search for short-duration gravitational waves (GWs) associated with the 2006 March 29 SGR 1900+14 storm. A new search method is used, "stacking'' the GW data around the times of individual soft-gamma bursts in the storm to enhance sensitivity for models in which multiple bursts are accompanied by GW emission. We assume that variation in the time difference between burst electromagnetic emission and potential burst GW emission is small relative to the GW signal duration, and we time-align GW excess power time-frequency tilings containing individual burst triggers to their corresponding electromagnetic emissions. We use two GW emission models in our search: a fluence-weighted model and a flat (unweighted) model for the most electromagnetically energetic bursts. We find no evidence of GWs associated with either model. Model-dependent GW strain, isotropic GW emission energy E_GW, and \gamma = E_GW / E_EM upper limits are estimated using a variety of assumed waveforms. The stacking method allows us to set the most stringent model-dependent limits on transient GW strain published to date. We find E_GW upper limit estimates (at a nominal distance of 10 kpc) of between 2x10^45 erg and 6x10^50 erg depending on waveform type. These limits are an order of magnitude lower than upper limits published previously for this storm and overlap with the range of electromagnetic energies emitted in SGR giant flares.Comment: 7 pages, 3 figure

All-sky LIGO Search for Periodic Gravitational Waves in the Early S5 Data

We report on an all-sky search with the LIGO detectors for periodic gravitational waves in the frequency range 50--1100 Hz and with the frequency's time derivative in the range -5.0E-9 Hz/s to zero. Data from the first eight months of the fifth LIGO science run (S5) have been used in this search, which is based on a semi-coherent method (PowerFlux) of summing strain power. Observing no evidence of periodic gravitational radiation, we report 95% confidence-level upper limits on radiation emitted by any unknown isolated rotating neutron stars within the search range. Strain limits below 1.E-24 are obtained over a 200-Hz band, and the sensitivity improvement over previous searches increases the spatial volume sampled by an average factor of about 100 over the entire search band. For a neutron star with nominal equatorial ellipticity of 1.0E-6, the search is sensitive to distances as great as 500 pc--a range that could encompass many undiscovered neutron stars, albeit only a tiny fraction of which would likely be rotating fast enough to be accessible to LIGO. This ellipticity is at the upper range thought to be sustainable by conventional neutron stars and well below the maximum sustainable by a strange quark star.Comment: 6 pages, 1 figur

Search for Gravitational Wave Bursts from Soft Gamma Repeaters

We present the results of a LIGO search for short-duration gravitational waves (GWs) associated with Soft Gamma Repeater (SGR) bursts. This is the first search sensitive to neutron star f-modes, usually considered the most efficient GW emitting modes. We find no evidence of GWs associated with any SGR burst in a sample consisting of the 27 Dec. 2004 giant flare from SGR 1806-20 and 190 lesser events from SGR 1806-20 and SGR 1900+14 which occurred during the first year of LIGO's fifth science run. GW strain upper limits and model-dependent GW emission energy upper limits are estimated for individual bursts using a variety of simulated waveforms. The unprecedented sensitivity of the detectors allows us to set the most stringent limits on transient GW amplitudes published to date. We find upper limit estimates on the model-dependent isotropic GW emission energies (at a nominal distance of 10 kpc) between 3x10^45 and 9x10^52 erg depending on waveform type, detector antenna factors and noise characteristics at the time of the burst. These upper limits are within the theoretically predicted range of some SGR models.Comment: 6 pages, 1 Postscript figur

Quantum state preparation and macroscopic entanglement in gravitational-wave detectors

Long-baseline laser-interferometer gravitational-wave detectors are operating at a factor of 10 (in amplitude) above the standard quantum limit (SQL) within a broad frequency band. Such a low classical noise budget has already allowed the creation of a controlled 2.7 kg macroscopic oscillator with an effective eigenfrequency of 150 Hz and an occupation number of 200. This result, along with the prospect for further improvements, heralds the new possibility of experimentally probing macroscopic quantum mechanics (MQM) - quantum mechanical behavior of objects in the realm of everyday experience - using gravitational-wave detectors. In this paper, we provide the mathematical foundation for the first step of a MQM experiment: the preparation of a macroscopic test mass into a nearly minimum-Heisenberg-limited Gaussian quantum state, which is possible if the interferometer's classical noise beats the SQL in a broad frequency band. Our formalism, based on Wiener filtering, allows a straightforward conversion from the classical noise budget of a laser interferometer, in terms of noise spectra, into the strategy for quantum state preparation, and the quality of the prepared state. Using this formalism, we consider how Gaussian entanglement can be built among two macroscopic test masses, and the performance of the planned Advanced LIGO interferometers in quantum-state preparation