Modelling Desert Dune Fields Based on Discrete Dynamics

A mathematical formulation is developed to model the dynamics of sand dunes. The physical processes display strong non-linearity that has been taken into account in the model. When assessing the success of such a model in capturing physical features we monitor morphology, dune growth, dune migration and spatial patterns within a dune field. Following recent advances, the proposed model is based on a discrete lattice dynamics approach with new features taken into account which reflect physically observed mechanisms

Transcriptional control of glyoxalase 1 by Nrf2 provides a stress-responsive defence against dicarbonyl glycation

Abnormal cellular accumulation of the dicarbonyl metabolite MG (methylglyoxal) occurs on exposure to high glucose concentrations, inflammation, cell aging and senescence. It is associated with increased MG-adduct content of protein and DNA linked to increased DNA strand breaks and mutagenesis, mitochondrial dysfunction and ROS (reactive oxygen species) formation and cell detachment from the extracellular matrix. MG-mediated damage is countered by glutathione-dependent metabolism by Glo1 (glyoxalase 1). It is not known, however, whether Glo1 has stress-responsive up-regulation to counter periods of high MG concentration or dicarbonyl stress. We identified a functional ARE (antioxidant-response element) in the 5'-untranslated region of exon 1 of the mammalian Glo1 gene. Transcription factor Nrf2 (nuclear factor-erythroid 2 p45 subunit-related factor 2) binds to this ARE, increasing basal and inducible expression of Glo1. Activators of Nrf2 induced increased Glo1 mRNA, protein and activity. Increased expression of Glo1 decreased cellular and extracellular concentrations of MG, MG-derived protein adducts, mutagenesis and cell detachment. Hepatic, brain, heart, kidney and lung Glo1 mRNA and protein were decreased in Nrf2-/- mice, and urinary excretion of MG protein and nucleotide adducts were increased approximately 2-fold. We conclude that dicarbonyl stress is countered by up-regulation of Glo1 in the Nrf2 stress-responsive system, protecting protein and DNA from increased damage and preserving cell function

ReTrOS : a MATLAB toolbox for reconstructing transcriptional activity from gene and protein expression data

This work was supported through providing funds by the Biotechnology and Biological Sciences Research Council [BB/F005806/1, BB/F005237/1]; and the Engineering and Physical Sciences Research Council [EP/C544587/1 to DAR].BACKGROUND: Given the development of high-throughput experimental techniques, an increasing number of whole genome transcription profiling time series data sets, with good temporal resolution, are becoming available to researchers. The ReTrOS toolbox (Reconstructing Transcription Open Software) provides MATLAB-based implementations of two related methods, namely ReTrOS-Smooth and ReTrOS-Switch, for reconstructing the temporal transcriptional activity profile of a gene from given mRNA expression time series or protein reporter time series. The methods are based on fitting a differential equation model incorporating the processes of transcription, translation and degradation. RESULTS: The toolbox provides a framework for model fitting along with statistical analyses of the model with a graphical interface and model visualisation. We highlight several applications of the toolbox, including the reconstruction of the temporal cascade of transcriptional activity inferred from mRNA expression data and protein reporter data in the core circadian clock in Arabidopsis thaliana, and how such reconstructed transcription profiles can be used to study the effects of different cell lines and conditions. CONCLUSIONS: The ReTrOS toolbox allows users to analyse gene and/or protein expression time series where, with appropriate formulation of prior information about a minimum of kinetic parameters, in particular rates of degradation, users are able to infer timings of changes in transcriptional activity. Data from any organism and obtained from a range of technologies can be used as input due to the flexible and generic nature of the model and implementation. The output from this software provides a useful analysis of time series data and can be incorporated into further modelling approaches or in hypothesis generation.Publisher PDFPeer reviewe

Transcription factor Pit-1 affects transcriptional timing in the dual-promoter human prolactin gene

Gene transcription occurs in short bursts interspersed with silent periods, and these kinetics can be altered by promoter structure. The effect of alternate promoter architecture on transcription bursting is not known. We studied the human prolactin (hPRL) gene that contains two promoters, a pituitary-specific promoter that requires the transcription factor Pit-1, and displays dramatic transcriptional bursting activity, and an alternate upstream promoter that is active in non-pituitary tissues. We studied large hPRL genomic fragments with luciferase reporters, and used bacterial artificial chromosome (BAC) recombineering to manipulate critical promoter regions. Stochastic switch mathematical modelling of single-cell time-lapse luminescence image data revealed that the Pit-1-dependent promoter showed longer, higher-amplitude transcriptional bursts. Knockdown studies confirmed that the presence of Pit-1 stabilised and prolonged periods of active transcription. Pit-1 therefore plays an active role in establishing the timing of transcription cycles, in addition to its cell-specific functions

Mathematical modelling of the dynamics and morphology of aeolian dunes and dune fields

The aim of this thesis is to model the dynamics of free sand dunes. In the first part, a new theoretical scheme is presented to model the shape and migration speed of a sand dune at equilibrium. Unlike earlier models it does not require iterative calculations of the interaction between the wind flow and the topography. As the first step, a self-consistent model which describes two- dimensional dune migration is introduced, which is comprised of a grain-scale model of sand deposition in the lee of dune and the assumption of equilibrium. The model gives quantitative relations between sand grain diameter, wind velocity on level ground and dune height. By further incorporating theory based on aerodynamics, the wind-directional profile of barchan dunes can be estimated. The thesis goes on to develop a computer simulation model that describes the three-dimensional morphology and dynamics of an aeolian dune field. Following recent advances, the proposed model is based on an approach using discrete lattice dynamics. In the model, dunes are treated as accumulations of 'sand slabs' on a two-dimensional lattice, whose motion is the result of wind-directional sand transport and avalanching. By incorporating new features, which reflect physically observed mechanisms, the model can simulate dunes whose individual shape and collective patterns are similar to those observed in nature. The model can also quantitatively simulate dune growth and dune migration. Some dune patterns can be explained by the model in terms of seasonally changing wind direction and sand availability (initial sand depth). These two approaches are complimentary. Some results in this thesis may be applicable to the morphology and dynamics observed in subaqueous and other terrestrial bedforms

Oscillatory Notch-pathway activity in a delay model of neuronal differentiation

Lateral inhibition resulting from a double-negative feedback loop underlies the assignment of different fates to cells in many developmental processes. Previous studies have shown that the presence of time delays in models of lateral inhibition can result in significant oscillatory transients before patterned steady states are reached. We study the impact of local feedback loops in a model of lateral inhibition based on the Notch signaling pathway, elucidating the roles of intracellular and intercellular delays in controlling the overall system behavior. The model exhibits both in-phase and out-of-phase oscillatory modes and oscillation death. Interactions between oscillatory modes can generate complex behaviors such as intermittent oscillations. Our results provide a framework for exploring the recent observation of transient Notch-pathway oscillations during fate assignment in vertebrate neurogenesis

N–H and N–C Bond Dissociation Pathways in Ultraviolet Photodissociation of Dimethylamine

We investigated the interlinked N–H and N–C photochemistry of primary and secondary amines via the state-resolved detection of vibrationally excited CH3 product and H atom product by 200–235 nm dimethylamine photodissociation using resonance-enhanced multiphoton ionization (REMPI) and velocity map imaging (VMI) techniques. The out-of-plane bending (ν2) vibrationally excited CH3 showed a bimodal translational energy distribution that became unimodal with a near-zero product yield at longer photolysis wavelengths (λphotolysis). In contrast, a unimodal distribution was observed for the C–H stretching (νCH) vibrationally excited CH3 products with an almost constant product yield in the examined λphotolysis region. We ascribed the state-specific energy releases of the CH3 products to two reaction pathways based on calculations of the potential energy surface (PES): the direct N–CH3 dissociation pathway and the indirect N–CH3 dissociation pathway via the N–H bond conical intersection. Meanwhile, the H atom product showed a bimodal energy distribution similar to the ammonia photodissociation model, with an excited-state counterproduct channel that became accessible at a shorter λphotolysis. These results suggest that the N–H and N–C bond dissociations are connected, and these dissociations cause different photochemistry between primary/secondary amines and tertiary amines