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Murray P.J.,Mathematical Institute | Maini P.K.,Mathematical Institute | Maini P.K.,Oxford Center for Integrative Systems Biology | Baker R.E.,Mathematical Institute
Developmental Biology | Year: 2013

The discovery over the last 15 years of molecular clocks and gradients in the pre-somitic mesoderm of numerous vertebrate species has added significant weight to Cooke and Zeeman's 'clock and wavefront' model of somitogenesis, in which a travelling wavefront determines the spatial position of somite formation and the somitogenesis clock controls periodicity (Cooke and Zeeman, 1976). However, recent high-throughput measurements of spatiotemporal patterns of gene expression in different zebrafish mutant backgrounds allow further quantitative evaluation of the clock and wavefront hypothesis. In this study we describe how our recently proposed model, in which oscillator coupling drives the propagation of an emergent wavefront, can be used to provide mechanistic and testable explanations for the following observed phenomena in zebrafish embryos: (a) the variation in somite measurements across a number of zebrafish mutants; (b) the delayed formation of somites and the formation of 'salt and pepper' patterns of gene expression upon disruption of oscillator coupling; and (c) spatial correlations in the 'salt and pepper' patterns in Delta-Notch mutants. In light of our results, we propose a number of plausible experiments that could be used to further test the model. © 2012 Elsevier Inc.


Murray P.J.,Mathematical Institute | Maini P.K.,Mathematical Institute | Maini P.K.,Oxford Center for Integrative Systems Biology | Baker R.E.,Mathematical Institute
Journal of Theoretical Biology | Year: 2011

The currently accepted interpretation of the clock and wavefront model of somitogenesis is that a posteriorly moving molecular gradient sequentially slows the rate of clock oscillations, resulting in a spatial readout of temporal oscillations. However, while molecular components of the clocks and wavefronts have now been identified in the pre-somitic mesoderm (PSM), there is not yet conclusive evidence demonstrating that the observed molecular wavefronts act to slow clock oscillations. Here we present an alternative formulation of the clock and wavefront model in which oscillator coupling, already known to play a key role in oscillator synchronisation, plays a fundamentally important role in the slowing of oscillations along the anterior-posterior (AP) axis. Our model has three parameters which can be determined, in any given species, by the measurement of three quantities: the clock period in the posterior PSM, somite length and the length of the PSM. A travelling wavefront, which slows oscillations along the AP axis, is an emergent feature of the model. Using the model we predict: (a) the distance between moving stripes of gene expression; (b) the number of moving stripes of gene expression and (c) the oscillator period profile along the AP axis. Predictions regarding the stripe data are verified using existing zebrafish data. We simulate a range of experimental perturbations and demonstrate how the model can be used to unambiguously define a reference frame along the AP axis. Comparing data from zebrafish, chick, mouse and snake, we demonstrate that: (a) variation in patterning profiles is accounted for by a single nondimensional parameter; the ratio of coupling strengths; and (b) the period profile along the AP axis is conserved across species. Thus the model is consistent with the idea that, although the genes involved in pattern propagation in the PSM vary, there is a conserved patterning mechanism across species. © 2011 Elsevier Ltd.


Tindall M.J.,University of Reading | Gaffney E.A.,Mathematical Institute | Maini P.K.,Mathematical Institute | Maini P.K.,Oxford Center for Integrative Systems Biology | Armitage J.P.,Oxford Center for Integrative Systems Biology
Wiley Interdisciplinary Reviews: Systems Biology and Medicine | Year: 2012

Research into understanding bacterial chemotactic systems has become a paradigm for Systems Biology. Experimental and theoretical researchers have worked hand-in-hand for over 40 years to understand the intricate behavior driving bacterial species, in particular how such small creatures, usually not more than 5 μm in length, detect and respond to small changes in their extracellular environment. In this review we highlight the importance that theoretical modeling has played in providing new insight and understanding into bacterial chemotaxis. We begin with an overview of the bacterial chemotaxis sensory response, before reviewing the role of theoretical modeling in understanding elements of the system on the single cell scale and features underpinning multiscale extensions to population models. © 2012 Wiley Periodicals, Inc.


Madzvamuse A.,University of Sussex | Gaffney E.A.,University of Oxford | Maini P.K.,University of Oxford | Maini P.K.,Oxford Center for Integrative Systems Biology
Journal of Mathematical Biology | Year: 2010

By using asymptotic theory, we generalise the Turing diffusively-driven instability conditions for reaction-diffusion systems with slow, isotropic domain growth. There are two fundamental biological differences between the Turing conditions on fixed and growing domains, namely: (i) we need not enforce cross nor pure kinetic conditions and (ii) the restriction to activator-inhibitor kinetics to induce pattern formation on a growing biological system is no longer a requirement. Our theoretical findings are confirmed and reinforced by numerical simulations for the special cases of isotropic linear, exponential and logistic growth profiles. In particular we illustrate an example of a reaction-diffusion system which cannot exhibit a diffusively-driven instability on a fixed domain but is unstable in the presence of slow growth. © Springer-Verlag 2009.


Schwarzlander M.,University of Oxford | Schwarzlander M.,University of Bonn | Logan D.C.,University of Saskatchewan | Johnston I.G.,Clarendon Laboratory | And 7 more authors.
Plant Cell | Year: 2012

Mitochondrial ATP synthesis is driven by a membrane potential across the inner mitochondrial membrane; this potential is generated by the proton-pumping electron transport chain. A balance between proton pumping and dissipation of the proton gradient by ATP-synthase is critical to avoid formation of excessive reactive oxygen species due to overreduction of the electron transport chain. Here, we report a mechanism that regulates bioenergetic balance in individual mitochondria: a transient partial depolarization of the inner membrane. Single mitochondria in living Arabidopsis thaliana root cells undergo sporadic rapid cycles of partial dissipation and restoration of membrane potential, as observed by real-time monitoring of the fluorescence of the lipophilic cationic dye tetramethyl rhodamine methyl ester. Pulsing is induced in tissues challenged by high temperature, H 2O 2, or cadmium. Pulses were coincident with a pronounced transient alkalinization of the matrix and are therefore not caused by uncoupling protein or by the opening of a nonspecific channel, which would lead to matrix acidification. Instead, a pulse is the result of Ca 2+ influx, which was observed coincident with pulsing; moreover, inhibitors of calcium transport reduced pulsing. We propose a role for pulsing as a transient uncoupling mechanism to counteract mitochondrial dysfunction and reactive oxygen species production. © 2012 American Society of Plant Biologists. All rights reserved.


Doux J.P.F.,University Utrecht | Hall B.A.,Oxford Center for Integrative Systems Biology | Killian J.A.,University Utrecht
Biophysical Journal | Year: 2012

The orientation of lipid headgroups may serve as a powerful sensor of electrostatic interactions in membranes. As shown previously by 2H NMR measurements, the headgroup of phosphatidylcholine (PC) behaves like an electrometer and varies its orientation according to the membrane surface charge. Here, we explored the use of solid-state 14N NMR as a relatively simple and label-free method to study the orientation of the PC headgroup in model membrane systems of varying composition. We found that 14N NMR is sufficiently sensitive to detect small changes in headgroup orientation upon introduction of positively and negatively charged lipids and we developed an approach to directly convert the 14N quadrupolar splittings into an average orientation of the PC polar headgroup. Our results show that inclusion of cholesterol or mixing of lipids with different length acyl chains does not significantly affect the orientation of the PC headgroup. In contrast, measurements with cationic (KALP), neutral (Ac-KALP), and pH-sensitive (HALP) transmembrane peptides show very systematic changes in headgroup orientation, depending on the amount of charge in the peptide side chains and on their precise localization at the interface, as modulated by varying the extent of hydrophobic peptide/lipid mismatch. Finally, our measurements suggest an unexpectedly strong preferential enrichment of the anionic lipid phosphatidylglycerol around the cationic KALP peptide in ternary mixtures with PC. We believe that these results are important for understanding protein/lipid interactions and that they may help parametrization of membrane properties in computational studies. © 2012 Biophysical Society.


Popp F.,Ludwig Maximilians University of Munich | Armitage J.P.,Oxford Center for Integrative Systems Biology | Armitage J.P.,University of Oxford | Schuler D.,Ludwig Maximilians University of Munich
Nature Communications | Year: 2014

Most motile bacteria navigate within gradients of external chemical stimuli by regulating the length of randomly oriented swimming episodes. Magnetotactic bacteria are characterized by chains of intracellular ferromagnetic nanoparticles and their ability to sense the geomagnetic field, which is believed to facilitate directed motion, but is not well understood at the behavioural and molecular level. Here, we show that cells of Magnetospirillum gryphiswaldense unexpectedly display swimming polarity that depends on aerotactic signal transduction through one of its four chemotaxis operons (cheOp1). Growth of cells in magnetic fields superimposed on oxygen gradients results in a gradual inherited bias of swimming runs with one of the cell poles leading, such that the resulting overall swimming direction of entire populations can be reversed by changes in oxygen concentration. These findings clearly show that there is a direct molecular link between aerotactic sensing and the determination of magnetotactic polarity, through the sensory pathway, CheOp1. © 2014 Macmillan Publishers Limited. All rights reserved.


Thalhammer A.,Oxford Center for Integrative Systems Biology | Hansen A.S.,Oxford Center for Integrative Systems Biology | El-Sagheer A.H.,University of Southampton | El-Sagheer A.H.,Suez Canal University | And 2 more authors.
Chemical Communications | Year: 2011

Cytosine-5-methylation stabilises DNA duplexes and is associated with transcriptional repression; 5-methylcytosine undergoes hydroxylation to 5-hydroxymethylcytosine, a modification of unknown biological function. Spectroscopic and calorimetric analyses show that 5-hydroxymethylcytosine introduction reverses the stabilising effect of 5-methylcytosine, suggesting that in some contexts, 5-methylcytosine hydroxylation may, along with other factors, contribute to the alleviation of transcriptional repression. © 2011 The Royal Society of Chemistry.


Munz M.,University of Oxford | Munz M.,Oxford Center for Integrative Systems Biology | Hein J.,University of Oxford | Hein J.,Oxford Center for Integrative Systems Biology | And 2 more authors.
PLoS Computational Biology | Year: 2012

In molecular recognition, it is often the case that ligand binding is coupled to conformational change in one or both of the binding partners. Two hypotheses describe the limiting cases involved; the first is the induced fit and the second is the conformational selection model. The conformational selection model requires that the protein adopts conformations that are similar to the ligand-bound conformation in the absence of ligand, whilst the induced-fit model predicts that the ligand-bound conformation of the protein is only accessible when the ligand is actually bound. The flexibility of the apo protein clearly plays a major role in these interpretations. For many proteins involved in signaling pathways there is the added complication that they are often promiscuous in that they are capable of binding to different ligand partners. The relationship between protein flexibility and promiscuity is an area of active research and is perhaps best exemplified by the PDZ domain family of proteins. In this study we use molecular dynamics simulations to examine the relationship between flexibility and promiscuity in five PDZ domains: the human Dvl2 (Dishevelled-2) PDZ domain, the human Erbin PDZ domain, the PDZ1 domain of InaD (inactivation no after-potential D protein) from fruit fly, the PDZ7 domain of GRIP1 (glutamate receptor interacting protein 1) from rat and the PDZ2 domain of PTP-BL (protein tyrosine phosphatase) from mouse. We show that despite their high structural similarity, the PDZ binding sites have significantly different dynamics. Importantly, the degree of binding pocket flexibility was found to be closely related to the various characteristics of peptide binding specificity and promiscuity of the five PDZ domains. Our findings suggest that the intrinsic motions of the apo structures play a key role in distinguishing functional properties of different PDZ domains and allow us to make predictions that can be experimentally tested. © 2012 Münz et al.


Obara B.,Oxford search Center | Fricker M.,University of Oxford | Gavaghan D.,Oxford Center for Integrative Systems Biology | Grau V.,University of Oxford
IEEE Transactions on Image Processing | Year: 2012

Many biomedical applications require detection of curvilinear structures in images and would benefit from automatic or semiautomatic segmentation to allow high-throughput measurements. Here, we propose a contrast-independent approach to identify curvilinear structures based on oriented phase congruency, i.e., the phase congruency tensor (PCT). We show that the proposed method is largely insensitive to intensity variations along the curve and provides successful detection within noisy regions. The performance of the PCT is evaluated by comparing it with state-of-the-art intensity-based approaches on both synthetic and real biological images. © 1992-2012 IEEE.

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