Dynamic Epistasis under Varying Environmental Perturbations

Epistasis describes the phenomenon that mutations at different loci do not have independent effects with regard to certain phenotypes. Understanding the global epistatic landscape is vital for many genetic and evolutionary theories. Current knowledge for epistatic dynamics under multiple conditions is limited by the technological difficulties in experimentally screening epistatic relations among genes. We explored this issue by applying flux balance analysis to simulate epistatic landscapes under various environmental perturbations. Specifically, we looked at gene-gene epistatic interactions, where the mutations were assumed to occur in different genes. We predicted that epistasis tends to become more positive from glucose-abundant to nutrient-limiting conditions, indicating that selection might be less effective in removing deleterious mutations in the latter. We also observed a stable core of epistatic interactions in all tested conditions, as well as many epistatic interactions unique to each condition. Interestingly, genes in the stable epistatic interaction network are directly linked to most other genes whereas genes with condition-specific epistasis form a scale-free network. Furthermore, genes with stable epistasis tend to have similar evolutionary rates, whereas this co-evolving relationship does not hold for genes with condition-specific epistasis. Our findings provide a novel genome-wide picture about epistatic dynamics under environmental perturbations.Comment: 22 pages, 9 figure

A robust and efficient method for estimating enzyme complex abundance and metabolic flux from expression data

A major theme in constraint-based modeling is unifying experimental data, such as biochemical information about the reactions that can occur in a system or the composition and localization of enzyme complexes, with highthroughput data including expression data, metabolomics, or DNA sequencing. The desired result is to increase predictive capability resulting in improved understanding of metabolism. The approach typically employed when only gene (or protein) intensities are available is the creation of tissue-specific models, which reduces the available reactions in an organism model, and does not provide an objective function for the estimation of fluxes, which is an important limitation in many modeling applications. We develop a method, flux assignment with LAD (least absolute deviation) convex objectives and normalization (FALCON), that employs metabolic network reconstructions along with expression data to estimate fluxes. In order to use such a method, accurate measures of enzyme complex abundance are needed, so we first present a new algorithm that addresses quantification of complex abundance. Our extensions to prior techniques include the capability to work with large models and significantly improved run-time performance even for smaller models, an improved analysis of enzyme complex formation logic, the ability to handle very large enzyme complex rules that may incorporate multiple isoforms, and depending on the model constraints, either maintained or significantly improved correlation with experimentally measured fluxes. FALCON has been implemented in MATLAB and ATS, and can be downloaded from: https://github.com/bbarker/FALCON. ATS is not required to compile the software, as intermediate C source code is available, and binaries are provided for Linux x86-64 systems. FALCON requires use of the COBRA Toolbox, also implemented in MATLAB.Comment: 30 pages, 12 figures, 4 table

Effect of improving representation of horizontal and vertical cloud structure on the Earth's global radiation budget. Part I: review and parametrization

A poor representation of cloud structure in a general circulation model (GCM) is widely recognised as a potential source of error in the radiation budget. Here, we develop a new way of representing both horizontal and vertical cloud structure in a radiation scheme. This combines the ‘Tripleclouds’ parametrization, which introduces inhomogeneity by using two cloudy regions in each layer as opposed to one, each with different water content values, with ‘exponential-random’ overlap, in which clouds in adjacent layers are not overlapped maximally, but according to a vertical decorrelation scale. This paper, Part I of two, aims to parametrize the two effects such that they can be used in a GCM. To achieve this, we first review a number of studies for a globally applicable value of fractional standard deviation of water content for use in Tripleclouds. We obtain a value of 0.75 ± 0.18 from a variety of different types of observations, with no apparent dependence on cloud type or gridbox size. Then, through a second short review, we create a parametrization of decorrelation scale for use in exponential-random overlap, which varies the scale linearly with latitude from 2.9 km at the Equator to 0.4 km at the poles. When applied to radar data, both components are found to have radiative impacts capable of offsetting biases caused by cloud misrepresentation. Part II of this paper implements Tripleclouds and exponential-random overlap into a radiation code and examines both their individual and combined impacts on the global radiation budget using re-analysis data

Radiative Corrections to Double Dalitz Decays: Effects on Invariant Mass Distributions and Angular Correlations

We review the theory of meson decays to two lepton pairs, including the cases of identical as well as non-identical leptons, as well as CP-conserving and CP-violating couplings. A complete lowest-order calculation of QED radiative corrections to these decays is discussed, and comparisons of predicted rates and kinematic distributions between tree-level and one-loop-corrected calculations are presented for both pi-zero and K-zero decays.Comment: 25 pages, 18 figures, added figures and commentar

Too Little, Too Late: How the Tidal Evolution of Hot Jupiters affects Transit Surveys of Clusters

The tidal evolution of hot Jupiters may change the efficiency of transit surveys of stellar clusters. The orbital decay that hot Jupiters suffer may result in their destruction, leaving fewer transiting planets in older clusters. We calculate the impact tidal evolution has for different assumed stellar populations, including that of 47~Tuc, a globular cluster that was the focus of an intense HST search for transits. We find that in older clusters one expects to detect fewer transiting planets by a factor of two for surveys sensitive to Jupiter-like planets in orbits out to 0.5~AU, and up to a factor of 25 for surveys sensitive to Jupiter-like planets in orbits out to 0.08~AU. Additionally, tidal evolution affects the distribution of transiting planets as a function of semi-major axis, producing larger orbital period gaps for transiting planets as the age of the cluster increases. Tidal evolution can explain the lack of detected exoplanets in 47~Tuc without invoking other mechanisms. Four open clusters residing within the {\em Kepler} fields of view have ages that span 0.4-8~Gyr--if {\em Kepler} can observe a significant number of planets in these clusters, it will provide key tests for our tidal evolution hypothesis. Finally, our results suggest that observers wishing to discover transiting planets in clusters must have sufficient accuracy to detect lower mass planets, search larger numbers of cluster members, or have longer observation windows to be confident that a significant number of transits will occur for a population of stars.Comment: 23 pages including 6 figures, accepted to Ap

The Rac-FRET mouse reveals tight spatiotemporal control of Rac activity in primary cells and tissues

The small G protein family Rac has numerous regulators that integrate extracellular signals into tight spatiotemporal maps of its activity to promote specific cell morphologies and responses. Here, we have generated a mouse strain, Rac-FRET, which ubiquitously expresses the Raichu-Rac biosensor. It enables FRET imaging and quantification of Rac activity in live tissues and primary cells without affecting cell properties and responses. We assessed Rac activity in chemotaxing Rac-FRET neutrophils and found enrichment in leading-edge protrusions and unexpected longitudinal shifts and oscillations during protruding and stalling phases of migration. We monitored Rac activity in normal or disease states of intestinal, liver, mammary, pancreatic, and skin tissue, in response to stimulation or inhibition and upon genetic manipulation of upstream regulators, revealing unexpected insights into Rac signaling during disease development. The Rac-FRET strain is a resource that promises to fundamentally advance our understanding of Rac-dependent responses in primary cells and native environments

Etoposide Reduces Peroxynitrite-Induced Cytotoxicity via Direct Scavenging Effect

Previously, we reported that glucose-deprived astrocytes are more vulnerable to the cytotoxicity of peroxynitrite, the reaction product of nitric oxide and superoxide anion. The augmented vulnerability of glucose-deprived astrocytes to peroxynitrite cytotoxicity was dependent on their proliferation rate. Inhibition of cell cycle progression has been shown to inhibit the apoptotic cell death occurring in cerebral ischemia-reperfusion. In the present study, we demonstrate that the increased death of glucose-deprived astrocytes by peroxynitrte was largely blocked by the cell cycle phase G2/M transition blocker etoposide. However, the cytoprotective effect of etoposide was not associated with its inhibition of cell cycle progression. Instead, etoposide effectively scavenged peroxynitrite. However, etoposide did not scavenge individual nitric oxide and superoxide anion and it did not prevent the hydrogen peroxide-induced cytotoxicity. The present results indicate that etoposide prevents the toxicity of peroxynitrite in astrocytes by directly scavenging peroxynitrite, not by inhibiting cell cycle progression

Polyelectrolyte-Clay-Protein Layer Films on Microfluidic PDMS Bioreactor Surfaces for Primary Murine Bone Marrow Culture

Poly(dimethylsiloxane) (PDMS) microbioreactors with computerized perfusion controls would be useful for engineering the bone marrow microenvironment. However, previous efforts to grow primary bone marrow cells on PDMS substrates have not been successful due to the weak attachment of cells to the PDMS surface even with adsorption of cell adhesive proteins such as collagen or fibronectin. In this work, modification of the surface of PDMS with biofunctional multilayer coatings is shown to promote marrow cell attachment and spreading. An automated microfluidic perfusion system is used to create multiple types of polyelectrolyte nanoscale coatings simultaneously in multiple channels based on layer-by-layer deposition of PDDA (poly(diallyldimethyl ammonium chloride)), clay, type IV collagen and fibronectin. Adherent primary bone marrow cells attached and spread best on a surface with composition of (PDDA/clay) 5 (Collagen/Fibronectin) 2 with negatively charged fibronectin exposed on the top, remaining well spread and proliferating for at least two weeks. Compared to traditional more macroscopic layer-by-layer methods, this microfluidic nanocomposite process has advantages of greater flow control, automatic processing, multiplexed fabrication, and use of lesser amounts of polymers and protein solutions.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/57408/1/2701_ftp.pd

Is tidal heating sufficient to explain bloated exoplanets? Consistent calculations accounting for finite initial eccentricity

In this paper, we present the consistent evolution of short-period exoplanets coupling the tidal and gravothermal evolution of the planet. Contrarily to previous similar studies, our calculations are based on the complete tidal evolution equations of the Hut model, valid at any order in eccentricity, obliquity and spin. We demonstrate, both analytically and numerically, that, except if the system was formed with a nearly circular orbit (e<0.2), solving consistently the complete tidal equations is mandatory to derive correct tidal evolution histories. We show that calculations based on tidal models truncated at second order in eccentricity, as done in all previous studies, lead to erroneous tidal evolutions. As a consequence, tidal energy dissipation rates are severely underestimated in all these calculations and the characteristic timescales for the various orbital parameters evolutions can be wrong by up to three orders in magnitude. Based on these complete, consistent calculations, we revisit the viability of the tidal heating hypothesis to explain the anomalously large radius of transiting giant planets. We show that, even though tidal dissipation does provide a substantial contribution to the planet's heat budget and can explain some of the moderately bloated hot-Jupiters, this mechanism can not explain alone the properties of the most inflated objects, including HD 209458b. Indeed, solving the complete tidal equations shows that enhanced tidal dissipation and thus orbit circularization occur too early during the planet's evolution to provide enough extra energy at the present epoch. In that case another mechanisms, such as stellar irradiation induced surface winds dissipating in the planet's tidal bulges, or inefficient convection in the planet's interior must be invoked, together with tidal dissipation, to provide all the pieces of the abnormally large exoplanet puzzle.Comment: 14 pages, 10 figures, Accepted for publication in Astronomy and Astrophysics