A detailed genome-wide reconstruction of mouse metabolism based on human Recon 1

<p>Abstract</p> <p>Background</p> <p>Well-curated and validated network reconstructions are extremely valuable tools in systems biology. Detailed metabolic reconstructions of mammals have recently emerged, including human reconstructions. They raise the question if the various successful applications of microbial reconstructions can be replicated in complex organisms.</p> <p>Results</p> <p>We mapped the published, detailed reconstruction of human metabolism (Recon 1) to other mammals. By searching for genes homologous to Recon 1 genes within mammalian genomes, we were able to create draft metabolic reconstructions of five mammals, including the mouse. Each draft reconstruction was created in compartmentalized and non-compartmentalized version via two different approaches. Using gap-filling algorithms, we were able to produce all cellular components with three out of four versions of the mouse metabolic reconstruction. We finalized a functional model by iterative testing until it passed a predefined set of 260 validation tests. The reconstruction is the largest, most comprehensive mouse reconstruction to-date, accounting for 1,415 genes coding for 2,212 gene-associated reactions and 1,514 non-gene-associated reactions.</p> <p>We tested the mouse model for phenotype prediction capabilities. The majority of predicted essential genes were also essential in vivo. However, our non-tissue specific model was unable to predict gene essentiality for many of the metabolic genes shown to be essential in vivo. Our knockout simulation of the lipoprotein lipase gene correlated well with experimental results, suggesting that softer phenotypes can also be simulated.</p> <p>Conclusions</p> <p>We have created a high-quality mouse genome-scale metabolic reconstruction, iMM1415 (<it>Mus Musculus</it>, 1415 genes). We demonstrate that the mouse model can be used to perform phenotype simulations, similar to models of microbe metabolism. Since the mouse is an important experimental organism, this model should become an essential tool for studying metabolic phenotypes in mice, including outcomes from drug screening.</p

Predicting the Effects of Reservoir Water Level Management on the Reproductive Output of a Riparian Songbird

Dams and reservoirs alter natural water flow regimes with adverse effects on natural ecosystems. Quantifying and reducing these effects are important as global demands for energy and water, and the number of dams and reservoir, increase. However, costs and logistic constraints typically preclude experimental assessment of reservoir effects on the environment. We developed a stochastic individual-based model (IBM), parameterized using empirical data, to estimate the annual productivity of yellow warblers that breed in riparian habitat within the footprint of the Arrow Lakes Reservoir in British Columbia, Canada. The IBM incorporated information on breeding phenology, nest site selection, brood parasitism, daily nest survival, re-nesting probabilities and post-fledging survival. We used the IBM to estimate the effect of four different water management scenarios on annual productivity. We found that the IBM accurately estimated average nest success (0.39 ± 0.10 SD), the proportion of females that produced at least one fledgling during a breeding season (0.56 ± 0.11), and annual fledging success (2.06 ± 0.43) under current conditions. The IBM estimated that reservoir operations currently reduce the annual productivity of this population by 37%, from an average of 1.62 to 1.06 independent young/female. Delaying when reservoir water levels reach 435m asl (the minimum elevation occupied by yellow warblers) by approximately 2 weeks was predicted to increase annual productivity to 1.44 independent young/female. The standardized effect on annual productivity of reducing the maximum elevation of the reservoir so that yellow warbler habitat is not inundated (Cohen’s d = 1.52) or delaying when water is stored (Cohen’s d = 0.83) was primarily driven by inundation effects on post-fledging survival. Reservoir operation effects on breeding birds will be species specific, but this IBM can easily be modified to allow the environmental impacts on the entire breeding bird community to be incorporated into water management decisions

Mitf is a master regulator of the v-ATPase, forming a control module for cellular homeostasis with v-ATPase and TORC1

Post-print (lokagerð höfundar)The v-ATPase is a fundamental eukaryotic enzyme that is central to cellular homeostasis. Although its impact on key metabolic regulators such as TORC1 is well documented, our knowledge of mechanisms that regulate v-ATPase activity is limited. Here, we report that the Drosophila transcription factor Mitf is a master regulator of this holoenzyme. Mitf directly controls transcription of all 15 v-ATPase components through M-box cis-sites and this coordinated regulation affects holoenzyme activity in vivo. In addition, through the v-ATPase, Mitf promotes the activity of TORC1, which in turn negatively regulates Mitf. We provide evidence that Mitf, v-ATPase and TORC1 form a negative regulatory loop that maintains each of these important metabolic regulators in relative balance. Interestingly, direct regulation of v-ATPase genes by human MITF also occurs in cells of the melanocytic lineage, showing mechanistic conservation in the regulation of the v-ATPase by MITF family proteins in fly and mammals. Collectively, this evidence points to an ancient module comprising Mitf, v-ATPase and TORC1 that serves as a dynamic modulator of metabolism for cellular homeostasis.This work was supported by the National Institutes of Health, National Eye Institute [grant number R01EY017097 to F.P.]; an RPB Unrestricted Grant and Lions District 20-Y1 award to the Dept. of Ophthalmology, SUNY-UMU (F.P.); the Icelandic Research Fund [grant numbers 130230-053 and 152715-051 to E.S.] a PHC Jules Verne 2014 grant [grant number 31891VM to E.S. and L.L.]; a grant from the Ligue Nationale Contre le Cancer (Equipe labellisee), INCa, Canceropole, Ile de France and Labex CelTisPhyBio [grant number ANR-11-LBX-0038 to L.L.]; and the Ludwig Institute for Cancer Research and the Harry J Lloyd Trust (to C.G.).Peer Reviewe

A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldPreviously, we reported germline DNA variants associated with risk of urinary bladder cancer (UBC) in Dutch and Icelandic subjects. Here we expanded the Icelandic sample set and tested the top 20 markers from the combined analysis in several European case-control sample sets, with a total of 4,739 cases and 45,549 controls. The T allele of rs798766 on 4p16.3 was found to associate with UBC (odds ratio = 1.24, P = 9.9 x 10(-12)). rs798766 is located in an intron of TACC3, 70 kb from FGFR3, which often harbors activating somatic mutations in low-grade, noninvasive UBC. Notably, rs798766[T] shows stronger association with low-grade and low-stage UBC than with more aggressive forms of the disease and is associated with higher risk of recurrence in low-grade stage Ta tumors. The frequency of rs798766[T] is higher in Ta tumors that carry an activating mutation in FGFR3 than in Ta tumors with wild-type FGFR3. Our results show a link between germline variants, somatic mutations of FGFR3 and risk of UBC.info:eu-repo/grantAgreement/EC/FP7/21807

Polarization and migration in the zebrafish posterior lateral line system

<div><p>Collective cell migration plays an important role in development. Here, we study the posterior lateral line primordium (PLLP) a group of about 100 cells, destined to form sensory structures, that migrates from head to tail in the zebrafish embryo. We model mutually inhibitory FGF-Wnt signalling network in the PLLP and link tissue subdivision (Wnt receptor and FGF receptor activity domains) to receptor-ligand parameters. We then use a 3D cell-based simulation with realistic cell-cell adhesion, interaction forces, and chemotaxis. Our model is able to reproduce experimentally observed motility with leading cells migrating up a gradient of CXCL12a, and trailing (FGF receptor active) cells moving actively by chemotaxis towards FGF ligand secreted by the leading cells. The 3D simulation framework, combined with experiments, allows an investigation of the role of cell division, chemotaxis, adhesion, and other parameters on the shape and speed of the PLLP. The 3D model demonstrates reasonable behaviour of control as well as mutant phenotypes.</p></div

Recovery after partial ablation.

<p>As in laser ablation from [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005451#pcbi.1005451.ref008" target="_blank">8</a>], part of the PLLP is removed in the simulation, and recovery observed. Top row: the front segment (WntR active cells) is removed, leaving only FGFR active cells; the PLLP stalls and cannot continue. Middle row: the rear portion is removed, leaving a few FGFR cells behind; the PLLP migration continues. Bottom row: the middle segment is removed. Motion is stalled while the trailing FGFR active cluster catches up with the front. Once the clusters have merged, migration resumes.</p

Analysis of mutual inhibition dynamics leads to model insights.

<p>The scaled mutual inhibition <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005451#pcbi.1005451.e015" target="_blank">Eq (7)</a> can have one of four possible behaviours represented by nullclines in the <i>W</i>_<i>R</i> <i>F</i>_<i>R</i> phase plane. (<i>F</i>_<i>R</i> nullcline in black, <i>W</i>_<i>R</i> nullcline in red.) (a) Bistability, in which either a high Wnt receptor (<i>W</i>_<i>R</i>) or high FGF (<i>F</i>_<i>R</i>) receptor expressing state can result, depending on initial conditions. (b) A Wnt-receptor expressing state always result, (c) a coexistence-state, with both Wnt and FGF receptors expressed, and (d) an FGF only receptor expression state exists. When the Hill coefficients <i>n</i>, <i>m</i> are large, the steady states (appropriately scaled) occur approximately at a subset of the points {(1, 0), (1, 1), (0, 1)} and transitions between the four qualitative outcomes displayed in this figure can be summarized by simple inequalities in terms of aggregate quantities <i>ϕ</i> and <i>ω</i>, see <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005451#pcbi.1005451.e017" target="_blank">Eq (7c)</a>.</p

Successful migration in the discrete cell model.

<p>Simulations of the migrating primordium showing WntR expressing cells (red), FGFR expressing cells (green), WntR and FGFR expressing cells (yellow) and indeterminate cells (grey). Left: at 2 min, Right: at 100 min. Bottom row: concentrations of CXCL12a (red), FGF (green) and Wnt (blue). Parameters as in Table A in Supporting Information <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005451#pcbi.1005451.s006" target="_blank">S6 Text</a>. Parameter Estimation and Values. See Fig. C in Supporting Information <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005451#pcbi.1005451.s005" target="_blank">S5 Text</a>. Additional results and details, for a more detailed time sequence and Supporting Information <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005451#pcbi.1005451.s007" target="_blank">S1 Movie</a>. 3D simulation of PLLP migration, for a 4 hour movie of the simulation results.</p