344 research outputs found
MultiMetEval: comparative and multi-objective analysis of genome-scale metabolic models
Comparative metabolic modelling is emerging as a novel field, supported by the development of reliable and standardized approaches for constructing genome-scale metabolic models in high throughput. New software solutions are needed to allow efficient comparative analysis of multiple models in the context of multiple cellular objectives. Here, we present the user-friendly software framework Multi-Metabolic Evaluator (MultiMetEval), built upon SurreyFBA, which allows the user to compose collections of metabolic models that together can be subjected to flux balance analysis. Additionally, MultiMetEval implements functionalities for multi-objective analysis by calculating the Pareto front between two cellular objectives. Using a previously generated dataset of 38 actinobacterial genome-scale metabolic models, we show how these approaches can lead to exciting novel insights. Firstly, after incorporating several pathways for the biosynthesis of natural products into each of these models, comparative flux balance analysis predicted that species like Streptomyces that harbour the highest diversity of secondary metabolite biosynthetic gene clusters in their genomes do not necessarily have the metabolic network topology most suitable for compound overproduction. Secondly, multi-objective analysis of biomass production and natural product biosynthesis in these actinobacteria shows that the well-studied occurrence of discrete metabolic switches during the change of cellular objectives is inherent to their metabolic network architecture. Comparative and multi-objective modelling can lead to insights that could not be obtained by normal flux balance analyses. MultiMetEval provides a powerful platform that makes these analyses straightforward for biologists. Sources and binaries of MultiMetEval are freely available from https://github.com/PiotrZakrzewski/MetEval/downloads
Bmi1 Confers Resistance to Oxidative Stress on Hematopoietic Stem Cells
The polycomb-group (PcG) proteins function as general regulators of stem cells. We previously reported that retrovirus-mediated overexpression of Bmi1, a gene encoding a core component of polycomb repressive complex (PRC) 1, maintained self-renewing hematopoietic stem cells (HSCs) during long-term culture. However, the effects of overexpression of Bmi1 on HSCs in vivo remained to be precisely addressed.In this study, we generated a mouse line where Bmi1 can be conditionally overexpressed under the control of the endogenous Rosa26 promoter in a hematopoietic cell-specific fashion (Tie2-Cre;R26Stop(FL)Bmi1). Although overexpression of Bmi1 did not significantly affect steady state hematopoiesis, it promoted expansion of functional HSCs during ex vivo culture and efficiently protected HSCs against loss of self-renewal capacity during serial transplantation. Overexpression of Bmi1 had no effect on DNA damage response triggered by ionizing radiation. In contrast, Tie2-Cre;R26Stop(FL)Bmi1 HSCs under oxidative stress maintained a multipotent state and generally tolerated oxidative stress better than the control. Unexpectedly, overexpression of Bmi1 had no impact on the level of intracellular reactive oxygen species (ROS).Our findings demonstrate that overexpression of Bmi1 confers resistance to stresses, particularly oxidative stress, onto HSCs. This thereby enhances their regenerative capacity and suggests that Bmi1 is located downstream of ROS signaling and negatively regulated by it
High-Throughput Analysis of Calcium Signalling Kinetics in Astrocytes Stimulated with Different Neurotransmitters
Astrocytes express a wide range of receptors for neurotransmitters and hormones that are coupled to increases in intracellular Ca2+ concentration, enabling them to detect activity in both neuronal and vascular networks. There is increasing evidence that astrocytes are able to discriminate between different Ca2+-linked stimuli, as the efficiency of some Ca2+ dependent processes – notably release of gliotransmitters – depends on the stimulus that initiates the Ca2+ signal. The spatiotemporal complexity of Ca2+ signals is substantial, and we here tested the hypothesis that variation in the kinetics of Ca2+ responses could offer a means of selectively engaging downstream targets, if agonists exhibited a “signature shape” in evoked Ca2+ response. To test this, astrocytes were exposed to three different receptor agonists (ATP, glutamate and histamine) and the resultant Ca2+ signals were analysed for systematic differences in kinetics that depended on the initiating stimulus. We found substantial heterogeneity between cells in the time course of Ca2+ responses, but the variation did not correlate with the type or concentration of the stimulus. Using a simple metric to quantify the extent of difference between populations, it was found that the variation between agonists was insufficient to allow signal discrimination. We conclude that the time course of global intracellular Ca2+ signals does not offer the cells a means for distinguishing between different neurotransmitters
Pirt, a TRPV1 Modulator, Is Required for Histamine-Dependent and -Independent Itch
Itch, or pruritus, is an important clinical problem whose molecular basis has yet to be understood. Recent work has begun to identify genes that contribute to detecting itch at the molecular level. Here we show that Pirt, known to play a vital part in sensing pain through modulation of the transient receptor potential vanilloid 1 (TRPV1) channel, is also necessary for proper itch sensation. Pirt−/− mice exhibit deficits in cellular and behavioral responses to various itch-inducing compounds, or pruritogens. Pirt contributes to both histaminergic and nonhistaminergic itch and, crucially, is involved in forms of itch that are both TRPV1-dependent and -independent. Our findings demonstrate that the function of Pirt extends beyond nociception via TRPV1 regulation to its role as a critical component in several itch signaling pathways
Diffractive Dijet Production at sqrt(s)=630 and 1800 GeV at the Fermilab Tevatron
We report a measurement of the diffractive structure function of
the antiproton obtained from a study of dijet events produced in association
with a leading antiproton in collisions at GeV at the
Fermilab Tevatron. The ratio of at GeV to
obtained from a similar measurement at GeV is compared with
expectations from QCD factorization and with theoretical predictions. We also
report a measurement of the (-Pomeron) and ( of parton in
Pomeron) dependence of at GeV. In the region
, GeV and , is
found to be of the form , which obeys
- factorization.Comment: LaTeX, 9 pages, Submitted to Phys. Rev. Letter
Search for Kaluza-Klein Graviton Emission in Collisions at TeV using the Missing Energy Signature
We report on a search for direct Kaluza-Klein graviton production in a data
sample of 84 of \ppb collisions at = 1.8 TeV, recorded
by the Collider Detector at Fermilab. We investigate the final state of large
missing transverse energy and one or two high energy jets. We compare the data
with the predictions from a -dimensional Kaluza-Klein scenario in which
gravity becomes strong at the TeV scale. At 95% confidence level (C.L.) for
=2, 4, and 6 we exclude an effective Planck scale below 1.0, 0.77, and 0.71
TeV, respectively.Comment: Submitted to PRL, 7 pages 4 figures/Revision includes 5 figure
A Study of B0 -> J/psi K(*)0 pi+ pi- Decays with the Collider Detector at Fermilab
We report a study of the decays B0 -> J/psi K(*)0 pi+ pi-, which involve the
creation of a u u-bar or d d-bar quark pair in addition to a b-bar -> c-bar(c
s-bar) decay. The data sample consists of 110 1/pb of p p-bar collisions at
sqrt{s} = 1.8 TeV collected by the CDF detector at the Fermilab Tevatron
collider during 1992-1995. We measure the branching ratios to be BR(B0 -> J/psi
K*0 pi+ pi-) = (8.0 +- 2.2 +- 1.5) * 10^{-4} and BR(B0 -> J/psi K0 pi+ pi-) =
(1.1 +- 0.4 +- 0.2) * 10^{-3}. Contributions to these decays are seen from
psi(2S) K(*)0, J/psi K0 rho0, J/psi K*+ pi-, and J/psi K1(1270)
Measurement of the average time-integrated mixing probability of b-flavored hadrons produced at the Tevatron
We have measured the number of like-sign (LS) and opposite-sign (OS) lepton
pairs arising from double semileptonic decays of and -hadrons,
pair-produced at the Fermilab Tevatron collider. The data samples were
collected with the Collider Detector at Fermilab (CDF) during the 1992-1995
collider run by triggering on the existence of and candidates
in an event. The observed ratio of LS to OS dileptons leads to a measurement of
the average time-integrated mixing probability of all produced -flavored
hadrons which decay weakly, (stat.)
(syst.), that is significantly larger than the world average .Comment: 47 pages, 10 figures, 15 tables Submitted to Phys. Rev.
- …