Boolean Models of Bistable Biological Systems

This paper presents an algorithm for approximating certain types of dynamical systems given by a system of ordinary delay differential equations by a Boolean network model. Often Boolean models are much simpler to understand than complex differential equations models. The motivation for this work comes from mathematical systems biology. While Boolean mechanisms do not provide information about exact concentration rates or time scales, they are often sufficient to capture steady states and other key dynamics. Due to their intuitive nature, such models are very appealing to researchers in the life sciences. This paper is focused on dynamical systems that exhibit bistability and are desc ribedby delay equations. It is shown that if a certain motif including a feedback loop is present in the wiring diagram of the system, the Boolean model captures the bistability of molecular switches. The method is appl ied to two examples from biology, the lac operon and the phage lambda lysis/lysogeny switch

The Regulatory Network for Petal Anthocyanin Pigmentation is Shaped by the MYB5a/NEGAN Transcription Factor in Mimulus

Much of the visual diversity of angiosperms is due to the frequent evolution of novel pigmentation patterns in flowers. The gene network responsible for anthocyanin pigmentation, in particular, has become a model for investigating how genetic changes give rise to phenotypic innovation. In the monkeyflower genus Mimulus, an evolutionarily recent gain of petal lobe anthocyanin pigmentation in M. luteus var. variegatus was previously mapped to genomic region pla2. Here, we use sequence and expression analysis, followed by transgenic manipulation of gene expression, to identify MYB5a—orthologous to the NEGAN transcriptional activator from M. lewisii—as the gene responsible for the transition to anthocyanin-pigmented petals in M. l. variegatus. In other monkeyflower taxa, MYB5a/NEGAN is part of a reaction-diffusion network that produces semi-repeating spotting patterns, such as the array of spots in the nectar guides of both M. lewisii and M. guttatus. Its co-option for the evolution of an apparently non-patterned trait—the solid petal lobe pigmentation of M. l. variegatus—illustrates how reaction-diffusion can contribute to evolutionary novelty in non-obvious ways. Transcriptome sequencing of a MYB5a RNAi line of M. l. variegatus reveals that this genetically simple change, which we hypothesize to be a regulatory mutation in cis to MYB5a, has cascading effects on gene expression, not only on the enzyme-encoding genes traditionally thought of as the targets of MYB5a but also on all of its known partners in the anthocyanin regulatory network

Quantum Cosmology of Kantowski-Sachs like Models

The Wheeler-DeWitt equation for a class of Kantowski-Sachs like models is completely solved. The generalized models include the Kantowski-Sachs model with cosmological constant and pressureless dust. Likewise contained is a joined model which consists of a Kantowski-Sachs cylinder inserted between two FRW half--spheres. The (second order) WKB approximation is exact for the wave functions of the complete set and this facilitates the product structure of the wave function for the joined model. In spite of the product structure the wave function can not be interpreted as admitting no correlations between the different regions. This problem is due to the joining procedure and may therefore be present for all joined models. Finally, the {s}ymmetric {i}nitial {c}ondition (SIC) for the wave function is analyzed and compared with the ``no bouindary'' condition. The consequences of the different boundary conditions for the arrow of time are briefly mentioned.Comment: 21 pages, uses LaTeX2e, epsf.sty and float.sty, three figures (50 kb); changes: one figure added, new interpretation of quantizing procedure for the joined model and many minor change

Neuronopathic Gaucher disease in the mouse: viable combined selective saposin C deficiency and mutant glucocerebrosidase (V394L) mice with glucosylsphingosine and glucosylceramide accumulation and progressive neurological deficits

Gaucher disease is caused by defective acid β-glucosidase (GCase) function. Saposin C is a lysosomal protein needed for optimal GCase activity. To test the in vivo effects of saposin C on GCase, saposin C deficient mice (C−/−) were backcrossed to point mutated GCase (V394L/V394L) mice. The resultant mice (4L;C*) began to exhibit CNS abnormalities ∼30 days: first as hindlimb paresis, then progressive tremor and ataxia. Death occurred ∼48 days due to neurological deficits. Axonal degeneration was evident in brain stem, spinal cord and white matter of cerebellum accompanied by increasing infiltration of the brain stem, cortex and thalamus by CD68 positive microglial cells and activation of astrocytes. Electron microscopy showed inclusion bodies in neuronal processes and degenerating cells. Accumulation of p62 and Lamp2 were prominent in the brain suggesting the impairment of autophagosome/lysosome function. This phenotype was different from either V394L/V394L or C−/− alone. Relative to V394L/V394L mice, 4L;C* mice had diminished GCase protein and activity. Marked increases (20- to 30-fold) of glucosylsphingosine (GS) and moderate elevation (1.5- to 3-fold) of glucosylceramide (GC) were in 4L;C* brains. Visceral tissues had increases of GS and GC, but no storage cells were found. Neuronal cells in thick hippocampal slices from 4L;C* mice had significantly attenuated long-term potentiation, presumably resulting from substrate accumulation. The 4L;C* mouse mimics the CNS phenotype and biochemistry of some type 3 (neuronopathic) variants of Gaucher disease and is a unique model suitable for testing pharmacological chaperone and substrate reduction therapies, and investigating the mechanisms of neuronopathic Gaucher disease

Starobinsky Model in Schroedinger Description

In the Starobinsky inflationary model inflation is driven by quantum corrections to the vacuum Einstein equation. We reduce the Wheeler-DeWitt equation corresponding to the Starobinsky model to a Schroedinger form containing time. The Schroedinger equation is solved with a Gaussian ansatz. Using the prescription for the normalization constant of the wavefunction given in our previous work, we show that the Gaussian ansatz demands Hawking type initial conditions for the wavefunction of the universe. The wormholes induce randomness in initial states suggesting a basis for time-contained description of the Wheeler-DeWitt equation.Comment: 19 Pages, LaTeX, no figure, gross typographical mistake

In search of the origins and enduring impact of agile software development

The Agile Manifesto is a philosophical touchpoint for all agile software development (ASD) methods. We examine the manifesto and some of its associated agile methods in an effort to identify the major impacts of ASD. We have encountered some difficulty in delineating agile and non-agile software processes, which is partially the result of terminological confusion. It is clear from the volume of published research that ASD has made a significant contribution, and we have identified two lasting and important impacts. Firstly, the reduction in iteration durations and secondly, the push for reduced levels of documentation (especially in relation to software requirements). Other aspects of the Agile Manifesto may not have exerted a significant impact; for example, the use of tooling to automate processes has become central to continuous software engineering (CSE) and may not be wholly congruent with the manifesto. Furthermore, many organisations may still rely on business contracts despite calls in the manifesto for greater levels of informal customer collaboration

Arrow of time in a recollapsing quantum universe

We show that the Wheeler-DeWitt equation with a consistent boundary condition is only compatible with an arrow of time that formally reverses in a recollapsing universe. Consistency of these opposite arrows is facilitated by quantum effects in the region of the classical turning point. Since gravitational time dilation diverges at horizons, collapsing matter must then start re-expanding ``anticausally" (controlled by the reversed arrow) before horizons or singularities can form. We also discuss the meaning of the time-asymmetric expression used in the definition of ``consistent histories". We finally emphasize that there is no mass inflation nor any information loss paradox in this scenario.Comment: Many conceptual clarifications include

Symbolic Versus Numerical Computation and Visualization of Parameter Regions for Multistationarity of Biological Networks

We investigate models of the mitogenactivated protein kinases (MAPK) network, with the aim of determining where in parameter space there exist multiple positive steady states. We build on recent progress which combines various symbolic computation methods for mixed systems of equalities and inequalities. We demonstrate that those techniques benefit tremendously from a newly implemented graph theoretical symbolic preprocessing method. We compare computation times and quality of results of numerical continuation methods with our symbolic approach before and after the application of our preprocessing.Comment: Accepted into Proc. CASC 201