Genetic and functional characterization of disease associations explains comorbidity

Understanding relationships between diseases, such as comorbidities, has important socio-economic implications, ranging from clinical study design to health care planning. Most studies characterize disease comorbidity using shared genetic origins, ignoring pathway-based commonalities between diseases. In this study, we define the disease pathways using an interactome-based extension of known disease-genes and introduce several measures of functional overlap. The analysis reveals 206 significant links among 94 diseases, giving rise to a highly clustered disease association network. We observe that around 95% of the links in the disease network, though not identified by genetic overlap, are discovered by functional overlap. This disease network portraits rheumatoid arthritis, asthma, atherosclerosis, pulmonary diseases and Crohn's disease as hubs and thus pointing to common inflammatory processes underlying disease pathophysiology. We identify several described associations such as the inverse comorbidity relationship between Alzheimer's disease and neoplasms. Furthermore, we investigate the disruptions in protein interactions by mapping mutations onto the domains involved in the interaction, suggesting hypotheses on the causal link between diseases. Finally, we provide several proof-of-principle examples in which we model the effect of the mutation and the change of the association strength, which could explain the observed comorbidity between diseases caused by the same genetic alterations

Early specification of dopaminergic phenotype during ES cell differentiation-8

<p><b>Copyright information:</b></p><p>Taken from "Early specification of dopaminergic phenotype during ES cell differentiation"</p><p>http://www.biomedcentral.com/1471-213X/7/86</p><p>BMC Developmental Biology 2007;7():86-86.</p><p>Published online 18 Jul 2007</p><p>PMCID:PMC1978208.</p><p></p> day 3–4 or day 7 and allowed to differentiate for a further 7 days under various conditions. No difference was observed in the number of neurons that expressed TH in unsorted control cultures, reconstituted cultures, sorted GFPcells re-placed onto PA6 or onto PDL-Laminin coated plastic (A) or when plated back onto different coatings or feeder cells (B). Likewise, no difference was found in the generation of TH expressing neurons between neural progenitors sorted at day 3–4 and day 7(C)

Early specification of dopaminergic phenotype during ES cell differentiation-1

<p><b>Copyright information:</b></p><p>Taken from "Early specification of dopaminergic phenotype during ES cell differentiation"</p><p>http://www.biomedcentral.com/1471-213X/7/86</p><p>BMC Developmental Biology 2007;7():86-86.</p><p>Published online 18 Jul 2007</p><p>PMCID:PMC1978208.</p><p></p> 3 or day 7. Following re-plating and differentiation, cultures were fixed and double stained with antibody against β-III-tubulin (green) and TH (red). A similar number of TH expressing neurons was produced by PA6-derived progenitors after being re-plated on PA6 (A) or PDL/Laminin (B) as compared to unsorted controls (C). -GFP expressing neural progenitors purified at day 3–4 (D, D', D") generated a similar proportion of TH expressing neurons as compared to those isolated at day 7 (E, E', E"). Scale bar = 100 μm

Early specification of dopaminergic phenotype during ES cell differentiation-6

<p><b>Copyright information:</b></p><p>Taken from "Early specification of dopaminergic phenotype during ES cell differentiation"</p><p>http://www.biomedcentral.com/1471-213X/7/86</p><p>BMC Developmental Biology 2007;7():86-86.</p><p>Published online 18 Jul 2007</p><p>PMCID:PMC1978208.</p><p></p>ied based on GFP reporter expression from the locus (A, B). FACS plots showing the isolation of GFPneural progenitors from GFPES cell differentiated progeny and PA6 cells (C – E). Gates were set based on plots of PA6 cells + wild type ES cells (C) and wild type ES cells alone (D). FACS sorting was performed either on day 7 (F) or day 3–4 (G). -GFPcells and GFPdifferentiated ES cell population were subsequently cultured under neuronal differentiation conditions either on PDL/laminin or in co-culture with PA6 cells. After a total of 14 days in cultures, cells were fixed and processed for immunocytochemistry. FL1 = GFP, FL2 = PE, R2 = GFPneural progenitors, R5 = GFPdifferentiated ES cells. Arrowhead points PA6-enriched cell population. Scale bar = 100 μm

Early specification of dopaminergic phenotype during ES cell differentiation-4

<p><b>Copyright information:</b></p><p>Taken from "Early specification of dopaminergic phenotype during ES cell differentiation"</p><p>http://www.biomedcentral.com/1471-213X/7/86</p><p>BMC Developmental Biology 2007;7():86-86.</p><p>Published online 18 Jul 2007</p><p>PMCID:PMC1978208.</p><p></p>and allowed to differentiate for a further 7 days under various conditions. No differences was found in the proportion of TH expressing cells generated by unsorted control cultures, sorted GFPneural progenitors re-placed on PA6 or PDL-Laminin coated plastic (A). In unsorted control cultures, the number of TH expressing neurons increased when SHH/FGF8 was applied during differentiation. However, addition of SHH/FGF8 to purified -GFP cells had no effect on the number of TH expressing neurons produced

Early specification of dopaminergic phenotype during ES cell differentiation-2

<p><b>Copyright information:</b></p><p>Taken from "Early specification of dopaminergic phenotype during ES cell differentiation"</p><p>http://www.biomedcentral.com/1471-213X/7/86</p><p>BMC Developmental Biology 2007;7():86-86.</p><p>Published online 18 Jul 2007</p><p>PMCID:PMC1978208.</p><p></p> day 3–4 or day 7 and allowed to differentiate for a further 7 days under various conditions. No difference was observed in the number of neurons that expressed TH in unsorted control cultures, reconstituted cultures, sorted GFPcells re-placed onto PA6 or onto PDL-Laminin coated plastic (A) or when plated back onto different coatings or feeder cells (B). Likewise, no difference was found in the generation of TH expressing neurons between neural progenitors sorted at day 3–4 and day 7(C)

Early specification of dopaminergic phenotype during ES cell differentiation-5

<p><b>Copyright information:</b></p><p>Taken from "Early specification of dopaminergic phenotype during ES cell differentiation"</p><p>http://www.biomedcentral.com/1471-213X/7/86</p><p>BMC Developmental Biology 2007;7():86-86.</p><p>Published online 18 Jul 2007</p><p>PMCID:PMC1978208.</p><p></p> K) or from monolayer culture (F, I, L-O), were purified by FACS. Cells were either collected onto slides by cytospin (A-C) or re-plated on PA6 or PDL/laminin and allowed for differentiation for a further 7 days (D-O). Cells collected on slides were examined for the expression of midbrain dopaminergic progenitor markers by immunostaining using antibodies against FoxA2 (A), En1 (B) and Lmx1a (C). Cultures were processed for the expression of midbrain dopaminergic neuron markers including Nurr1 (D-F), En1 (G-I), and Pitx3 (J-L) in conjunction with TH (inset E, H, K). Nurr1, En1 and Pitx3 was detected in cells derived from PA6 formed progenitors (D, E, G, H, J, K) whereas only Nurr1 (F, M-O) was found to be expressed in cells derived from monolayer-derived neural progenitors. Scalebar for A-C and M-O = 10 μm, scalebar for D, E, G, H, J, K = 50 μm and scalebar for F, I, L = 50 μm

Accurate and fast path computation on large urban road networks: A general approach

<div><p>Accurate and fast path computation is essential for applications such as onboard navigation systems and traffic network routing. While a number of heuristic algorithms have been developed in the past few years for faster path queries, the accuracy of them are always far below satisfying. In this paper, we first develop an agglomerative graph partitioning method for generating high balanced traverse distance partitions, and we constitute a three-level graph model based on the graph partition scheme for structuring the urban road network. Then, we propose a new hierarchical path computation algorithm, which benefits from the hierarchical graph model and utilizes a region pruning strategy to significantly reduce the search space without compromising the accuracy. Finally, we present a detailed experimental evaluation on the real urban road network of New York City, and the experimental results demonstrate the effectiveness of the proposed approach to generate optimal fast paths and to facilitate real-time routing applications.</p></div

Illustration of the three-level graph model.

<p>Illustration of the three-level graph model.</p

Path computation within the subgraph region of <i>SP</i>₂(<i>G</i>_<i>d</i>,<i>G</i>_<i>s</i>).

<p>Path computation within the subgraph region of <i>SP</i>₂(<i>G</i>_<i>d</i>,<i>G</i>_<i>s</i>).</p