Two-dimensional enrichment analysis for mining high-level imaging genetic associations

Enrichment analysis has been widely applied in the genome-wide association studies (GWAS), where gene sets corresponding to biological pathways are examined for significant associations with a phenotype to help increase statistical power and improve biological interpretation. In this work, we expand the scope of enrichment analysis into brain imaging genetics, an emerging field that studies how genetic variation influences brain structure and function measured by neuroimaging quantitative traits (QT). Given the high dimensionality of both imaging and genetic data, we propose to study Imaging Genetic Enrichment Analysis (IGEA), a new enrichment analysis paradigm that jointly considers meaningful gene sets (GS) and brain circuits (BC) and examines whether any given GS-BC pair is enriched in a list of gene-QT findings. Using gene expression data from Allen Human Brain Atlas and imaging genetics data from Alzheimer's Disease Neuroimaging Initiative as test beds, we present an IGEA framework and conduct a proof-of-concept study. This empirical study identifies 12 significant high level two dimensional imaging genetics modules. Many of these modules are relevant to a variety of neurobiological pathways or neurodegenerative diseases, showing the promise of the proposal framework for providing insight into the mechanism of complex diseases

Interpreting microarray experiments via co-expressed gene groups analysis

International audienceMicroarray technology produces vast amounts of data by measuring simultaneously the expression levels of thousands of genes under hundreds of biological conditions. Nowadays, one of the principal challenges in bioinformatics is the interpretation of huge data using different sources of information. We propose a novel data analysis method named CGGA (Co-expressed Gene Groups Analysis) that automatically finds groups of genes that are functionally enriched, i.e. have the same functional annotations, and are co- expressed. CGGA automatically integrates the information of microarrays, i.e. gene expression profiles, with the functional annotations of the genes obtained by the genome-wide information sources such as Gene Ontology (GO)1. By applying CGGA to well-known microarray experiments, we have identified the principal functionally enriched and co-expressed gene groups, and we have shown that this approach enhances and accelerates the interpretation of DNA microarray experiments

Short-term effects of very low dose cadmium feeding on copper, manganese and iron homeostasis:A gastropod perspective

The available information on the interplay between low-dose cadmium intake and copper, manganese, and iron homeostasis in invertebrates is limited. We have currently studied the accumulation of these trace metals in the hepatopancreas of adult snails, Cantareus aspersus, following 14 and 28 days of exposure to low doses of dietary cadmium, up to 1 mg/kg dw (dry weight). The cadmium dose, but not the duration of exposure, had a significant effect on hepatopancreas copper deposition, the values being significantly elevated compared to controls. A significant peak in manganese levels at 14 days was found in snails administered the lowest cadmium dose. These increases occurred even in the absence of cadmium increase in the hepatopancreas. Our data suggest that low dose cadmium feeding can produce a transient disturbance in hepatopancreas copper and manganese homeostasis. Such responses may serve as early biomarkers of physiological changes occurring during the initial stages of cadmium intoxication

The general form of supersymmetric solutions of N=(1,0) U(1) and SU(2) gauged supergravities in six dimensions

We obtain necessary and sufficient conditions for a supersymmetric field configuration in the N=(1,0) U(1) or SU(2) gauged supergravities in six dimensions, and impose the field equations on this general ansatz. It is found that any supersymmetric solution is associated to an $SU(2)\ltimes \mathbb{R}^4$ structure. The structure is characterized by a null Killing vector which induces a natural 2+4 split of the six dimensional spacetime. A suitable combination of the field equations implies that the scalar curvature of the four dimensional Riemannian part, referred to as the base, obeys a second order differential equation. Bosonic fluxes introduce torsion terms that deform the $SU(2)\ltimes\mathbb{R}^4$ structure away from a covariantly constant one. The most general structure can be classified in terms of its intrinsic torsion. For a large class of solutions the gauge field strengths admit a simple geometrical interpretation: in the U(1) theory the base is K\"{a}hler, and the gauge field strength is the Ricci form; in the SU(2) theory, the gauge field strengths are identified with the curvatures of the left hand spin bundle of the base. We employ our general ansatz to construct new supersymmetric solutions; we show that the U(1) theory admits a symmetric Cahen-Wallach$_4\times S^2$ solution together with a compactifying pp-wave. The SU(2) theory admits a black string, whose near horizon limit is $AdS_3\times S_3$. We also obtain the Yang-Mills analogue of the Salam-Sezgin solution of the U(1) theory, namely $R^{1,2}\times S^3$, where the $S^3$ is supported by a sphaleron. Finally we obtain the additional constraints implied by enhanced supersymmetry, and discuss Penrose limits in the theories.Comment: 1+29 pages, late

International organisations and anti-terrorist sanctions: no accountability for human rights violations?

The targeted sanctions adopted by the UN Security Council against individuals and entities suspected of association with terrorism are managed through procedures that infringe fundamental human rights, and there are no mechanisms for actual accountability. With the exception of the ECJ in Kadi, municipal and regional courts tend to consider the UN Security Council's resolutions and domestic measures implementing them outside the scope of judicial review. This article argues that the Security Council is bound to observe human rights even in the context of international security action, and that States are not exonerated from international responsibility for violations committed under the umbrella of Chapter VII resolutions

Supersymmetric AdS_5 solutions of M-theory

We analyse the most general supersymmetric solutions of D=11 supergravity consisting of a warped product of five-dimensional anti-de-Sitter space with a six-dimensional Riemannian space M_6, with four-form flux on M_6. We show that M_6 is partly specified by a one-parameter family of four-dimensional Kahler metrics. We find a large family of new explicit regular solutions where M_6 is a compact, complex manifold which is topologically a two-sphere bundle over a four-dimensional base, where the latter is either (i) Kahler-Einstein with positive curvature, or (ii) a product of two constant-curvature Riemann surfaces. After dimensional reduction and T-duality, some solutions in the second class are related to a new family of Sasaki-Einstein spaces which includes T^{1,1}/Z_2. Our general analysis also covers warped products of five-dimensional Minkowski space with a six-dimensional Riemannian space.Comment: 40 pages. v2: minor changes, eqs. (2.22) and (D.12) correcte

Using ILP to Identify Pathway Activation Patterns in Systems Biology

We show a logical aggregation method that, combined with propositionalization methods, can construct novel structured biological features from gene expression data. We do this to gain understanding of pathway mechanisms, for instance, those associated with a particular disease. We illustrate this method on the task of distinguishing between two types of lung cancer; Squamous Cell Carcinoma (SCC) and Adenocarcinoma (AC). We identify pathway activation patterns in pathways previously implicated in the development of cancers. Our method identified a model with comparable predictive performance to the winning algorithm of a recent challenge, while providing biologically relevant explanations that may be useful to a biologist

SLEPR: A Sample-Level Enrichment-Based Pathway Ranking Method — Seeking Biological Themes through Pathway-Level Consistency

Analysis of microarray and other high throughput data often involves identification of genes consistently up or down-regulated across samples as the first step in extraction of biological meaning. This gene-level paradigm can be limited as a result of valid sample fluctuations and biological complexities. In this report, we describe a novel method, SLEPR, which eliminates this limitation by relying on pathway-level consistencies. Our method first selects the sample-level differentiated genes from each individual sample, capturing genes missed by other analysis methods, ascertains the enrichment levels of associated pathways from each of those lists, and then ranks annotated pathways based on the consistency of enrichment levels of individual samples from both sample classes. As a proof of concept, we have used this method to analyze three public microarray datasets with a direct comparison with the GSEA method, one of the most popular pathway-level analysis methods in the field. We found that our method was able to reproduce the earlier observations with significant improvements in depth of coverage for validated or expected biological themes, but also produced additional insights that make biological sense. This new method extends existing analyses approaches and facilitates integration of different types of HTP data