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  • JOURNAL ARTICLE
    Attard MI, Dawes TJW, de Marvao A, Biffi C, Shi W, Wharton J, Rhodes CJ, Ghataorhe P, Gibbs JSR, Howard LSGE, Rueckert D, Wilkins MR, O'Regan DPet al., 2018,

    Metabolic pathways associated with right ventricular adaptation to pulmonary hypertension: 3D analysis of cardiac magnetic resonance imaging.

    , Eur Heart J Cardiovasc Imaging

    Aims: We sought to identify metabolic pathways associated with right ventricular (RV) adaptation to pulmonary hypertension (PH). We evaluated candidate metabolites, previously associated with survival in pulmonary arterial hypertension, and used automated image segmentation and parametric mapping to model their relationship to adverse patterns of remodelling and wall stress. Methods and results: In 312 PH subjects (47.1% female, mean age 60.8 ± 15.9 years), of which 182 (50.5% female, mean age 58.6 ± 16.8 years) had metabolomics, we modelled the relationship between the RV phenotype, haemodynamic state, and metabolite levels. Atlas-based segmentation and co-registration of cardiac magnetic resonance imaging was used to create a quantitative 3D model of RV geometry and function-including maps of regional wall stress. Increasing mean pulmonary artery pressure was associated with hypertrophy of the basal free wall (β = 0.29) and reduced relative wall thickness (β = -0.38), indicative of eccentric remodelling. Wall stress was an independent predictor of all-cause mortality (hazard ratio = 1.27, P = 0.04). Six metabolites were significantly associated with elevated wall stress (β = 0.28-0.34) including increased levels of tRNA-specific modified nucleosides and fatty acid acylcarnitines, and decreased levels (β = -0.40) of sulfated androgen. Conclusion: Using computational image phenotyping, we identify metabolic profiles, reporting on energy metabolism and cellular stress-response, which are associated with adaptive RV mechanisms to PH.

  • JOURNAL ARTICLE
    Dawes TJW, de Marvao A, Shi W, Rueckert D, Cook SA, O'Regan DPet al., 2018,

    Identifying the optimal regional predictor of right ventricular global function: a high-resolution three-dimensional cardiac magnetic resonance study.

    , Anaesthesia

    Right ventricular (RV) function has prognostic value in acute, chronic and peri-operative disease, although the complex RV contractile pattern makes rapid assessment difficult. Several two-dimensional (2D) regional measures estimate RV function, however the optimal measure is not known. High-resolution three-dimensional (3D) cardiac magnetic resonance cine imaging was acquired in 300 healthy volunteers and a computational model of RV motion created. Points where regional function was significantly associated with global function were identified and a 2D, optimised single-point marker (SPM-O) of global function developed. This marker was prospectively compared with tricuspid annular plane systolic excursion (TAPSE), septum-freewall displacement (SFD) and their fractional change (TAPSE-F, SFD-F) in a test cohort of 300 patients in the prediction of RV ejection fraction. RV ejection fraction was significantly associated with systolic function in a contiguous 7.3 cm2 patch of the basal RV freewall combining transverse (38%), longitudinal (35%) and circumferential (27%) contraction and coinciding with the four-chamber view. In the test cohort, all single-point surrogates correlated with RV ejection fraction (p < 0.010), but correlation (R) was higher for SPM-O (R = 0.44, p < 0.001) than TAPSE (R = 0.24, p < 0.001) and SFD (R = 0.22, p < 0.001), and non-significantly higher than TAPSE-F (R = 0.40, p < 0.001) and SFD-F (R = 0.43, p < 0.001). SPM-O explained more of the observed variance in RV ejection fraction (19%) and predicted it more accurately than any other 2D marker (median error 2.8 ml vs 3.6 ml, p < 0.001). We conclude that systolic motion of the basal RV freewall predicts global function more accurately than other 2D estimators. However, no markers summarise 3D contractile patterns, limiting their predictive accuracy.

  • JOURNAL ARTICLE
    Thomas P, Terradot G, Danos V, Weisse AYet al., 2018,

    Sources, propagation and consequences of stochasticity in cellular growth

    , NATURE COMMUNICATIONS, Vol: 9, ISSN: 2041-1723
  • JOURNAL ARTICLE
    Dawes TJW, Cai J, Quinlan M, de Marvao A, Ostrowski PJ, Tokarczuk PF, Watson GMJ, Wharton J, Howard LSGE, Gibbs JSR, Cook SA, Wilkins MR, O'Regan DPet al., 2018,

    Fractal Analysis of Right Ventricular Trabeculae in Pulmonary Hypertension

    , RADIOLOGY, Vol: 288, Pages: 386-395, ISSN: 0033-8419
  • CONFERENCE PAPER
    Altuncu MT, Mayer E, Yaliraki SN, Barahona Met al., 2018,

    From Text to Topics in Healthcare Records: An Unsupervised Graph Partitioning Methodology

    Electronic Healthcare Records contain large volumes of unstructured data,including extensive free text. Yet this source of detailed information oftenremains under-used because of a lack of methodologies to extract interpretablecontent in a timely manner. Here we apply network-theoretical tools to analysefree text in Hospital Patient Incident reports from the National HealthService, to find clusters of documents with similar content in an unsupervisedmanner at different levels of resolution. We combine deep neural networkparagraph vector text-embedding with multiscale Markov Stability communitydetection applied to a sparsified similarity graph of document vectors, andshowcase the approach on incident reports from Imperial College Healthcare NHSTrust, London. The multiscale community structure reveals different levels ofmeaning in the topics of the dataset, as shown by descriptive terms extractedfrom the clusters of records. We also compare a posteriori against hand-codedcategories assigned by healthcare personnel, and show that our approachoutperforms LDA-based models. Our content clusters exhibit good correspondencewith two levels of hand-coded categories, yet they also provide further medicaldetail in certain areas and reveal complementary descriptors of incidentsbeyond the external classification taxonomy.

  • JOURNAL ARTICLE
    Arnaudon A, Holm D, Sommer S, 2018,

    String methods for stochastic image and shape matching

    , Journal of Mathematical Imaging and Vision, Vol: 60, Pages: 953-967, ISSN: 0924-9907

    Matching of images and analysis of shape differences is traditionally pursued by energy minimization of paths of deformations acting to match the shape objects. In the large deformation diffeomorphic metric mapping (LDDMM) framework, iterative gradient descents on the matching functional lead to matching algorithms informally known as Beg algorithms. When stochasticity is introduced to model stochastic variability of shapes and to provide more realistic models of observed shape data, the corresponding matching problem can be solved with a stochastic Beg algorithm, similar to the finite-temperature string method used in rare event sampling. In this paper, we apply a stochastic model compatible with the geometry of the LDDMM framework to obtain a stochastic model of images and we derive the stochastic version of the Beg algorithm which we compare with the string method and an expectation-maximization optimization of posterior likelihoods. The algorithm and its use for statistical inference is tested on stochastic LDDMM landmarks and images.

  • JOURNAL ARTICLE
    Liu D, Mannan AA, Han Y, Oyarzún DA, Zhang Fet al., 2018,

    Dynamic metabolic control: towards precision engineering of metabolism.

    , J Ind Microbiol Biotechnol, Vol: 45, Pages: 535-543

    Advances in metabolic engineering have led to the synthesis of a wide variety of valuable chemicals in microorganisms. The key to commercializing these processes is the improvement of titer, productivity, yield, and robustness. Traditional approaches to enhancing production use the "push-pull-block" strategy that modulates enzyme expression under static control. However, strains are often optimized for specific laboratory set-up and are sensitive to environmental fluctuations. Exposure to sub-optimal growth conditions during large-scale fermentation often reduces their production capacity. Moreover, static control of engineered pathways may imbalance cofactors or cause the accumulation of toxic intermediates, which imposes burden on the host and results in decreased production. To overcome these problems, the last decade has witnessed the emergence of a new technology that uses synthetic regulation to control heterologous pathways dynamically, in ways akin to regulatory networks found in nature. Here, we review natural metabolic control strategies and recent developments in how they inspire the engineering of dynamically regulated pathways. We further discuss the challenges of designing and engineering dynamic control and highlight how model-based design can provide a powerful formalism to engineer dynamic control circuits, which together with the tools of synthetic biology, can work to enhance microbial production.

  • JOURNAL ARTICLE
    Thomas P, 2018,

    Analysis of Cell Size Homeostasis at the Single-Cell and Population Level

    , FRONTIERS IN PHYSICS, Vol: 6, ISSN: 2296-424X
  • JOURNAL ARTICLE
    Arnaudon A, 2018,

    Structure preserving noise and dissipation in the Toda lattice

    , Journal of Physics A: Mathematical and Theoretical, Vol: 51, ISSN: 1751-8113

    In this paper, we use Flaschka's change of variables of the open Toda latticeand its interpretation in term of the group structure of the LU factorisationas a coadjoint motion on a certain dual of Lie algebra to implement a structurepreserving noise and dissipation. Both preserve the structure of coadjointorbit, that is the space of symmetric tri-diagonal matrices and arise as a newtype of multiplicative noise and nonlinear dissipation of the Toda lattice. Weinvestigate some of the properties of these deformations and in particular thecontinuum limit as a stochastic Burger equation with a nonlinear viscosity.This work is meant to be exploratory, and open more questions that we cananswer with simple mathematical tools and without numerical simulations.

  • JOURNAL ARTICLE
    Tomazou M, Barahona M, Polizzi KM, Stan G-Bet al., 2018,

    Computational Re-design of Synthetic Genetic Oscillators for Independent Amplitude and Frequency Modulation

    , CELL SYSTEMS, Vol: 6, Pages: 508-+, ISSN: 2405-4712

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