School of Mathematics and Statistics - Research Publications
Now showing items 1-12 of 464
Youth Depression Alleviation with Anti-inflammatory Agents (YoDA-A): a randomised clinical trial of rosuvastatin and aspirin
BACKGROUND: Inflammation contributes to the pathophysiology of major depressive disorder (MDD), and anti-inflammatory strategies might therefore have therapeutic potential. This trial aimed to determine whether adjunctive aspirin or rosuvastatin, compared with placebo, reduced depressive symptoms in young people (15-25 years). METHODS: YoDA-A, Youth Depression Alleviation with Anti-inflammatory Agents, was a 12-week triple-blind, randomised, controlled trial. Participants were young people (aged 15-25 years) with moderate to severe MDD (MADRS mean at baseline 32.5 ± 6.0; N = 130; age 20.2 ± 2.6; 60% female), recruited between June 2013 and June 2017 across six sites in Victoria, Australia. In addition to treatment as usual, participants were randomised to receive aspirin (n = 40), rosuvastatin (n = 48), or placebo (n = 42), with assessments at baseline and weeks 4, 8, 12, and 26. The primary outcome was change in the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to week 12. RESULTS: At the a priori primary endpoint of MADRS differential change from baseline at week 12, there was no significant difference between aspirin and placebo (1.9, 95% CI (- 2.8, 6.6), p = 0.433), or rosuvastatin and placebo (- 4.2, 95% CI (- 9.1, 0.6), p = 0.089). For rosuvastatin, secondary outcomes on self-rated depression and global impression, quality of life, functioning, and mania were not significantly different from placebo. Aspirin was inferior to placebo on the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q-SF) at week 12. Statins were superior to aspirin on the MADRS, the Clinical Global Impressions Severity Scale (CGI-S), and the Negative Problem Orientation Questionnaire scale (NPOQ) at week 12. CONCLUSIONS: The addition of either aspirin or rosuvastatin did not to confer any beneficial effect over and above routine treatment for depression in young people. Exploratory comparisons of secondary outcomes provide limited support for a potential therapeutic role for adjunctive rosuvastatin, but not for aspirin, in youth depression. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12613000112763. Registered on 30/01/2013.
Assessment of serum symmetric dimethylarginine and creatinine concentrations in hyperthyroid cats before and after a fixed dose of orally administered radioiodine
Background: Serum symmetric dimethylarginine (SDMA) is a sensitive renal biomarker for detecting early chronic kidney disease (CKD) in nonhyperthyroid cats, but knowledge regarding its performance in hyperthyroid cats remains limited. Objectives: To determine the relationship between serum SDMA, creatinine and total thyroxine (TT4) concentrations in hyperthyroid cats before (T0) and 3 months after (T1) receiving a PO fixed dose of radioiodine. Animals: Eighty client‐owned hyperthyroid cats. Methods: Prospective cohort study. Serum TT4, and SDMA, creatinine concentrations, and urine specific gravity were measured at T0 and T1. Nonparametric tests were used to determine the relationship among SDMA, and creatinine and TT4 concentrations. Agreement between SDMA and creatinine regarding CKD staging at both time points was assessed using Goodman and Kruskal's gamma statistic. Results: Mean serum SDMA concentration increased after treatment of hyperthyroidism. However, 21 of 75 cats experienced a decrease in SDMA between T0 and T1, whereas creatinine decreased in only 2 cats. A moderate correlation between SDMA and creatinine was seen at T1 (r = 0.53; P < .001) but not at T0 (r = 0.13; P = .25). Where assessable at T1, poor agreement was observed between SDMA and creatinine and CKD stage (Goodman and Kruskal's gamma 0.20; P = .29). Conclusions and clinical importance: Discordant outcomes between SDMA and creatinine after radioiodine treatment in cats with hyperthyroidism suggest extrarenal factors may interfere with the reliability of SDMA to adequately reflect renal function. As a result, SDMA should not be interpreted in isolation in hyperthyroid cats treated with radioiodine.
A few clarifications on MIRIBEL
(NATURE PUBLISHING GROUP, 2020-01-01)
We are inspired by the responses1,2,3,4 to our recently proposed ‘reporting standards’ for bio–nano research (Minimum Information Reporting in Bio–Nano Experimental Literature — MIRIBEL)5. However, we wish to clarify several points made in MIRIBEL and discuss a few concerns raised by the community, with a view toward encouraging uptake of the MIRIBEL standard and improving future research.
A alpha-Divergence-Based Approach for Robust Dictionary Learning
(Institute of Electrical and Electronics Engineers, 2019-11-01)
In this paper, a robust sequential dictionary learning (DL) algorithm is presented. The proposed algorithm is motivated from the maximum likelihood perspective on dictionary learning and its link to the minimization of the Kullback-Leibler divergence. It is obtained by using a robust loss function in the data fidelity term of the DL objective instead of the usual quadratic loss. The proposed robust loss function is derived from the α-divergence as an alternative to the Kullback-Leibler divergence, which leads to a quadratic loss. Compared to other robust approaches, the proposed loss has the advantage of belonging to class of redescending M-estimators, guaranteeing inference stability from large deviations from the Gaussian nominal noise model. The algorithm is obtained by solving a sequence of penalized rank-1 matrix approximation problems, where the ℓ 1 -norm is introduced as a penalty promoting sparsity and then using a block coordinate descent approach to estimate the unknowns. Performance comparison with similar robust DL algorithms on digit recognition, background removal, and gray-scale image denoising is performed highlighting efficacy of the proposed algorithm.
Is cell migration or proliferation dominant in the formation of linear arrays of oligodendrocytes?
Oligodendrocytes are the myelin-producing cells of the central nervous system that are responsible for electrically insulating axons to speed the propagation of electrical impulses. A striking feature of oligodendrocyte development within white matter is that the cell bodies of many oligodendrocyte progenitor cells become organised into discrete linear arrays of three or more cells before they differentiate into myelin-producing oligodendrocytes. These linear arrays align parallel to the direction of the axons within white matter tracts and are believed to play an important role in the co-ordination of myelination. Guided by experimental data on the abundance and composition of linear arrays in the corpus callosum of the postnatal mouse brain, we construct discrete and continuous models of linear array generation to specifically investigate the relative influence of cell migration, proliferation, differentiation and death of oligodendroglia upon the genesis of linear arrays during early postnatal development. We demonstrate that only models that incorporate significant cell migration can replicate all of the experimental observations on number of arrays, number of cells in arrays and total cell count of oligodendroglia within a given area of the corpus callosum. These models are also necessary to accurately reflect experimental data on the abundance of linear arrays composed of oligodendrocytes that derive from progenitors of different clonal origins.
Evidence for Cooperative Selection of Axons for Myelination by Adjacent Oligodendrocytes in the Optic Nerve
(PUBLIC LIBRARY SCIENCE, 2016-11-09)
The cellular mechanisms that regulate the topographic arrangement of myelin internodes along axons remain largely uncharacterized. Recent clonal analysis of oligodendrocyte morphologies in the mouse optic nerve revealed that adjacent oligodendrocytes frequently formed adjacent internodes on one or more axons in common, whereas oligodendrocytes in the optic nerve were never observed to myelinate the same axon more than once. By modelling the process of axonal selection at the single cell level, we demonstrate that internode length and primary process length constrain the capacity of oligodendrocytes to myelinate the same axon more than once. On the other hand, probabilistic analysis reveals that the observed juxtaposition of myelin internodes among common sets of axons by adjacent oligodendrocytes is highly unlikely to occur by chance. Our analysis may reveal a hitherto unknown level of communication between adjacent oligodendrocytes in the selection of axons for myelination. Together, our analyses provide novel insights into the mechanisms that define the spatial organization of myelin internodes within white matter at the single cell level.
3D hybrid modelling of vascular network formation
(ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD, 2017-02-07)
We develop an off-lattice, agent-based model to describe vasculogenesis, the de novo formation of blood vessels from endothelial progenitor cells during development. The endothelial cells that comprise our vessel network are viewed as linearly elastic spheres that move in response to the forces they experience. We distinguish two types of endothelial cells: vessel elements are contained within the network and tip cells are located at the ends of vessels. Tip cells move in response to mechanical forces caused by interactions with neighbouring vessel elements and the local tissue environment, chemotactic forces and a persistence force which accounts for their tendency to continue moving in the same direction. Vessel elements are subject to similar mechanical forces but are insensitive to chemotaxis. An angular persistence force representing interactions with the local tissue is introduced to stabilise buckling instabilities caused by cell proliferation. Only vessel elements proliferate, at rates which depend on their degree of stretch: elongated elements have increased rates of proliferation, and compressed elements have reduced rates. Following division, the fate of the new cell depends on the local mechanical environment: the probability of forming a new sprout is increased if the parent vessel is highly compressed and the probability of being incorporated into the parent vessel increased if the parent is stretched. Simulation results reveal that our hybrid model can reproduce the key qualitative features of vasculogenesis. Extensive parameter sensitivity analyses show that significant changes in network size and morphology are induced by varying the chemotactic sensitivity of tip cells, and the sensitivities of the proliferation rate and the sprouting probability to mechanical stretch. Varying the chemotactic sensitivity directly influences the directionality of the networks. The degree of branching, and thereby the density of the networks, is influenced by the sprouting probability. Glyphs that simultaneously depict several network properties are introduced to show how these and other network quantities change over time and also as model parameters vary. We also show how equivalent glyphs constructed from in vivo data could be used to discriminate between normal and tumour vasculature and, in the longer term, for model validation. We conclude that our biomechanical hybrid model can generate vascular networks that are qualitatively similar to those generated from in vitro and in vivo experiments.
What is the optimal distribution of myelin along a single axon?
The myelin sheath that insulates some axons in the central nervous system allows for faster signal conduction. Previously, axons were thought to be either unmyelinated or fully myelinated. Recent experimental work has discovered a new pattern of myelination (intermittent myelination) along axons in the mouse brain, in which long unmyelinated axon segments are followed by myelinated segments of comparable length. We use a computational model to explore how myelin distribution (in particular intermittent myelination) affects conduction velocity. We find that although fully myelinated axons minimize conduction velocity, varying the spatial distribution of a fixed amount of myelin along a partially myelinated axon leads to considerable variation in the conduction velocity for action potentials. Whether sodium ion channel number or sodium ion channel density is held constant as the area of the unmyelinated segments increases has a strong influence on the optimal pattern of myelin and the conduction velocity.
Distinguishing cell shoving mechanisms
(PUBLIC LIBRARY SCIENCE, 2018-03-12)
Motivated by in vitro time-lapse images of ovarian cancer spheroids inducing mesothelial cell clearance, the traditional agent-based model of cell migration, based on simple volume exclusion, was extended to include the possibility that a cell seeking to move into an occupied location may push the resident cell, and any cells neighbouring it, out of the way to occupy that location. In traditional discrete models of motile cells with volume exclusion such a move would be aborted. We introduce a new shoving mechanism which allows cells to choose the direction to shove cells that expends the least amount of shoving effort (to account for the likely resistance of cells to being pushed). We call this motility rule 'smart shoving'. We examine whether agent-based simulations of different shoving mechanisms can be distinguished on the basis of single realisations and averages over many realisations. We emphasise the difficulty in distinguishing cell mechanisms from cellular automata simulations based on snap-shots of cell distributions, site-occupancy averages and the evolution of the number of cells of each species averaged over many realisations. This difficulty suggests the need for higher resolution cell tracking.
Evolution of cancer cell populations under cytotoxic therapy and treatment optimisation: insight from a phenotype-structured model
(EDP Sciences, 2019-07-04)
We consider a phenotype-structured model of evolutionary dynamics in a population of cancer cells exposed to the action of a cytotoxic drug. The model consists of a nonlocal parabolic equation governing the evolution of the cell population density function. We develop a novel method for constructing exact solutions to the model equation, which allows for a systematic investigation of the way in which the size and the phenotypic composition of the cell population change in response to variations of the drug dose and other evolutionary parameters. Moreover, we address numerical optimal control for a calibrated version of the model based on biological data from the existing literature, in order to identify the drug delivery schedule that makes it possible to minimise either the population size at the end of the treatment or the average population size during the course of treatment. The results obtained challenge the notion that traditional high-dose therapy represents a “one-fits-all solution” in anticancer therapy by showing that the continuous administration of a relatively low dose of the cytotoxic drug performs more closely to i.e. the optimal dosing regimen to minimise the average size of the cancer cell population during the course of treatment.
Persistent exclusion processes: Inertia, drift, mixing, and correlation
(AMER PHYSICAL SOC, 2019-10-30)
In many biological systems, motile agents exhibit random motion with short-term directional persistence, together with crowding effects arising from spatial exclusion. We formulate and study a class of lattice-based models for multiple walkers with motion persistence and spatial exclusion in one and two dimensions, and use a mean-field approximation to investigate relevant population-level partial differential equations in the continuum limit. We show that this model of a persistent exclusion process is in general well described by a nonlinear diffusion equation. With reference to results presented in the current literature, our results reveal that the nonlinearity arises from the combination of motion persistence and volume exclusion, with linearity in terms of the canonical diffusion or heat equation being recovered in either the case of persistence without spatial exclusion, or spatial exclusion without persistence. We generalize our results to include systems of multiple species of interacting, motion-persistent walkers, as well as to incorporate a global drift in addition to persistence. These models are shown to be governed approximately by systems of nonlinear advection-diffusion equations. By comparing the prediction of the mean-field approximation to stochastic simulation results, we assess the performance of our results. Finally, we also address the problem of inferring the presence of persistence from simulation results, with a view to application to experimental cell-imaging data.