50 research outputs found

    An Atlas of Network Topologies Reveals Design Principles for <i>Caenorhabditis elegans</i> Vulval Precursor Cell Fate Patterning

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    <div><p>The vulval precursor cell (VPC) fate patterning in <i>Caenorhabditis elegans</i> is a classic model experimental system for cell fate determination and patterning in development. Despite its apparent simplicity (six neighboring cells arranged in one dimension) and many experimental and computational efforts, the patterning strategy and mechanism remain controversial due to incomplete knowledge of the complex biology. Here, we carry out a comprehensive computational analysis and obtain a reservoir of all possible network topologies that are capable of VPC fate patterning under the simulation of various biological environments and regulatory rules. We identify three patterning strategies: sequential induction, morphogen gradient and lateral antagonism, depending on the features of the signal secreted from the anchor cell. The strategy of lateral antagonism, which has not been reported in previous studies of VPC patterning, employs a mutual inhibition of the 2° cell fate in neighboring cells. Robust topologies are built upon minimal topologies with basic patterning strategies and have more flexible and redundant implementations of modular functions. By simulated mutation, we find that all three strategies can reproduce experimental error patterns of mutants. We show that the topology derived by mapping currently known biochemical pathways to our model matches one of our identified functional topologies. Furthermore, our robustness analysis predicts a possible missing link related to the lateral antagonism strategy. Overall, we provide a theoretical atlas of all possible functional networks in varying environments, which may guide novel discoveries of the biological interactions in vulval development of <i>Caenorhabditis elegans</i> and related species.</p></div

    The <i>C</i>. <i>elegans</i> VPC patterning system and the coarse-grained model.

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    <p>(A) VPC differentiation. (B) Coarse-grained modeling of VPC patterning. The two-node model with 10 links numbered from 1 to 10 is shown in the left panel. Dashed lines represent intercellular interactions and solid lines intracellular interactions. The modeling system of five Pn.p cells along with their initial and target values is shown in the upper-right panel. The ODE functions of two examples are shown in the lower-right panel.</p

    Top topologies for different ratios of diffusible to membrane-bound intercellular regulation.

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    <p><i>Q</i> values of top topologies for different ratios of diffusible to membrane-bound intercellular regulation are plotted. “Only_M” means only membrane-bound and “Only_D” means only diffusible. “Random” means the ratio is evenly sampled from (0, 1). “D = 0.01M, 0.5M, M, 2M” means the ratios of diffusible to membrane-bound are 0.01, 0.5, 1, and 2, respectively. Four cases of different S2 values (0, 0.01, 0.1 and 0.5) are shown from top panel to bottom panel.</p

    Behaviors of topologies under simulated mutant conditions of AC signaling.

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    <p>(A) Robustness (<i>Q</i> value) of topologies under varying AC signal conditions; <i>left</i>: representative topologies for three strategies, from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0131397#pone.0131397.g004" target="_blank">Fig 4</a>; <i>middle</i>: top topologies with “AND” rule, from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0131397#pone.0131397.g003" target="_blank">Fig 3</a>; <i>right</i>: top topologies with “AND & Additive” rule, from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0131397#pone.0131397.g003" target="_blank">Fig 3</a>. (B) Pie charts show the number and percentage of robust topologies that reproduce expected mutant patterns reported in Ref. [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0131397#pone.0131397.ref026" target="_blank">26</a>] with “AND” rule (<i>top</i>) and “Combined AND & Additive” rule (<i>bottom</i>). (C, D) Average frequency of expected mutant patterns produced by different types of topologies in 1,000 runs of simulation with functional parameters under AC ablation (C) and EGF overexpression (D). The expected mutant patterns are from Ref. [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0131397#pone.0131397.ref026" target="_blank">26</a>]. Results of simulation in “Combined AND & Additive” rule are shown. (E) Expected mutant patterns reproduced by representative topologies for three strategies under AC ablation and EGF overexpression. The top two most-frequent patterns along with corresponding occurrences from total 1,000 runs of simulation are shown. Simulation was modeled with “Combined AND & Additive” rule.</p

    Biological network and its mapping to 1P-2P-5P-3N-4N.

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    <p>(A) The key known pathways in VPC patterning. The proteins and pathways in green correspond to the AC node; those in blue correspond to the 1° node; those in red correspond to the 2° node; and gray indicates that they are repressed in that cell. The regulations among different nodes are labeled with the corresponding links in the topology 1P-2P-5P-3N-4N and in different colors. (B) <i>Q</i> values of the topologies that contain 1P-2P-5P-3N-4N. (C) Inferred network constructed based on known links and our inferred link 10N, which is an inhibitory regulation between the 2° nodes of neighboring Pn.p cells. The known links are in gray. (D) Mutant patterns produced by topologies 1P-2P-5P-3N-4N and 1P-2P-5P-3N-4N-10N under AC ablation and EGF overexpression. The top two most-frequent patterns along with their occurrences from total 1,000 runs of simulation are shown. Simulation was modeled with “Combined AND & Additive” rule.</p

    Minimal topologies and top topologies for S2 = 0, 0.1, and 0.5.

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    <p>The left column lists all the identified minimal topologies with both regulatory rules. “AND” rule is marked as “x”, and “Combined AND & Additive” rule is marked as “+”. For each rule, the <i>Q</i> value and <i>M</i>-score are labeled below the topology, where <i>M</i>-score is labeled in parentheses directly following the <i>Q</i> value. Most minimal topologies are shared by both regulatory rules except 1P-2P-3N-6P for S2 = 0.5, which is minimal topology only with “AND” rule. The top topologies identified with “AND” rule (middle column) and “Combined AND & Additive” rule (right column) are shown. Typical topologies with highest <i>Q</i> values are selected. <i>Q</i> value for each topology is labeled below the topology.</p

    Different strategies to achieve the pattern.

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    <p>Sequential induction strategy (A), morphogen gradient strategy (B), and lateral antagonism strategy (C) are shown. These strategies are common with both “AND” and “Combined AND & Additive” rules. For each strategy, a simple description of the strategy, representative topology, and the S2 level are listed in the table. Below the table shows the mechanism of representative topology: on the left is a sketch of the topology; in the middle is the graph that shows the regulation among the AC, 1°, and 2° nodes in the 1° (middle) and 2° cells (two sides), where the heavy full lines indicate acting or strong regulation and fine dashed lines indicate no or weak regulation; on the right draws the dynamical value of each node in the 1° cell and 2° cells with increasing time.</p

    Flowchart describing the selection of studies included in the meta-analyses.

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    <p>Flowchart describing the selection of studies included in the meta-analyses.</p

    Risk Factors for Rebleeding of Aneurysmal Subarachnoid Hemorrhage: A Meta-Analysis

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    <div><p>Background</p><p>Rebleeding is a serious complication of aneurysmal subarachnoid hemorrhaging. To date, there are conflicting data regarding the factors contributing to rebleeding and their significance.</p><p>Methods</p><p>A systematic review of PubMed and Embase databases was conducted for studies pertaining to aneurysmal subarachnoid hemorrhage (aSAH) and rebleeding in order to assess the associated risk factors. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated from fourteen studies comprised of a total of 5693 patients that met the inclusion criteria.</p><p>Results</p><p>Higher rebleeding rates were observed < 6 h after the initial aSAH (OR  = 3.22, 95% CI  = 1.46–7.12), and were associated with high systolic blood pressure (OR  = 1.93, 95% CI  = 1.31–2.83), poor Hunt-Hess grade (III–IV) (OR  = 3.43, 95% CI  = 2.33–5.05), intracerebral or intraventricular hematomas (OR  = 1.65, 95% CI  = 1.33–2.05), posterior circulation aneurysms (OR  = 2.15, 95% CI  = 1.32–3.49), and aneurysms >10 mm in size (OR  = 1.70, 95% CI  = 1.35–2.14).</p><p>Conclusions</p><p>Aneurysmal rebleeding occurs more frequently within the first 6 hours after the initial aSAH. Risk factors associated with rebleeding include high systolic pressure, the presence of an intracerebral or intraventricular hematoma, poor Hunt-Hess grade (III-IV), aneurysms in the posterior circulation, and an aneurysm >10 mm in size.</p></div

    Additional file 8: of Nanog induced intermediate state in regulating stem cell differentiation and reprogramming

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    Figure S3. Parameter sensitivity analysis for the model. Illustration of the relative changes of the low-Nanog distribution ratio (blue bar), the average Oct4 level (green bar), and the average Nanog level of high-Nanog population (red bar). (TIFF 699 kb
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