Publications by category
Journal articles
Richards DM, Walker JJ, Tabak J (2020). Ion channel noise shapes the electrical activity of endocrine cells.
PLoS Comput Biol,
16(4).
Abstract:
Ion channel noise shapes the electrical activity of endocrine cells.
Endocrine cells in the pituitary gland typically display either spiking or bursting electrical activity, which is related to the level of hormone secretion. Recent work, which combines mathematical modelling with dynamic clamp experiments, suggests the difference is due to the presence or absence of a few large-conductance potassium channels. Since endocrine cells only contain a handful of these channels, it is likely that stochastic effects play an important role in the pattern of electrical activity. Here, for the first time, we explicitly determine the effect of such noise by studying a mathematical model that includes the realistic noisy opening and closing of ion channels. This allows us to investigate how noise affects the electrical activity, examine the origin of spiking and bursting, and determine which channel types are responsible for the greatest noise. Further, for the first time, we address the role of cell size in endocrine cell electrical activity, finding that larger cells typically display more bursting, while the smallest cells almost always only exhibit spiking behaviour.
Abstract.
Author URL.
Full text.
Passmore JB, Carmichael RE, Schrader TA, Godinho LF, Ferdinandusse S, Lismont C, Wang Y, Hacker C, Islinger M, Fransen M, et al (2020). Mitochondrial fission factor (MFF) is a critical regulator of peroxisome maturation.
Biochim Biophys Acta Mol Cell Res,
1867(7).
Abstract:
Mitochondrial fission factor (MFF) is a critical regulator of peroxisome maturation.
Peroxisomes are highly dynamic subcellular compartments with important functions in lipid and ROS metabolism. Impaired peroxisomal function can lead to severe metabolic disorders with developmental defects and neurological abnormalities. Recently, a new group of disorders has been identified, characterised by defects in the membrane dynamics and division of peroxisomes rather than by loss of metabolic functions. However, the contribution of impaired peroxisome plasticity to the pathophysiology of those disorders is not well understood. Mitochondrial fission factor (MFF) is a key component of both the peroxisomal and mitochondrial division machinery. Patients with MFF deficiency present with developmental and neurological abnormalities. Peroxisomes (and mitochondria) in patient fibroblasts are highly elongated as a result of impaired organelle division. The majority of studies into MFF-deficiency have focused on mitochondrial dysfunction, but the contribution of peroxisomal alterations to the pathophysiology is largely unknown. Here, we show that MFF deficiency does not cause alterations to overall peroxisomal biochemical function. However, loss of MFF results in reduced import-competency of the peroxisomal compartment and leads to the accumulation of pre-peroxisomal membrane structures. We show that peroxisomes in MFF-deficient cells display alterations in peroxisomal redox state and intra-peroxisomal pH. Removal of elongated peroxisomes through induction of autophagic processes is not impaired. A mathematical model describing key processes involved in peroxisome dynamics sheds further light into the physical processes disturbed in MFF-deficient cells. The consequences of our findings for the pathophysiology of MFF-deficiency and related disorders with impaired peroxisome plasticity are discussed.
Abstract.
Author URL.
Full text.
Richards DM (2020). Receptor Models of Phagocytosis: the Effect of Target Shape.
Adv Exp Med Biol,
1246, 55-70.
Abstract:
Receptor Models of Phagocytosis: the Effect of Target Shape.
Phagocytosis is a remarkably complex process, requiring simultaneous organisation of the cell membrane, the cytoskeleton, receptors and various signalling molecules. As can often be the case, mathematical modelling is able to penetrate some of this complexity, identifying the key biophysical components and generating understanding that would take far longer with a purely experimental approach. This chapter will review a particularly important class of phagocytosis model, championed in recent years, that primarily focuses on the role of receptors during the engulfment process. These models are pertinent to a host of unsolved questions in the subject, including the rate of cup growth during uptake, the role of both intra- and extracellular noise, and the precise differences between phagocytosis and other forms of endocytosis. In particular, this chapter will focus on the effect of target shape and orientation, including how these influence the rate and final outcome of phagocytic engulfment.
Abstract.
Author URL.
Castro IG, Richards DM, Metz J, Costello JL, Passmore JB, Schrader TA, Gouveia A, Ribeiro D, Schrader M (2018). A role for Mitochondrial Rho GTPase 1 (MIRO1) in motility and membrane dynamics of peroxisomes.
Traffic,
19(3), 229-242.
Full text.
Richards DM, Endres RG (2017). How cells engulf: a review of theoretical approaches to phagocytosis.
Reports on Progress in Physics,
80(12), 126601-126601.
Full text.
Richards DM, Endres RG (2016). Target shape dependence in a simple model of receptor-mediated endocytosis and phagocytosis.
Proceedings of the National Academy of Sciences of the United States of America,
113, 6113-6118.
Abstract:
Target shape dependence in a simple model of receptor-mediated endocytosis and phagocytosis
Phagocytosis and receptor-mediated endocytosis are vitally important particle uptake mechanisms in many cell types, ranging fromsingle-cell organisms to immune cells. In both processes, engulfment by the cell depends critically on both particle shape and orientation. However, most previous theoretical work has focused only on spherical particles and hence disregards the wide-ranging particle shapes occurring in nature, such as those of bacteria. Here, by implementing a simple model in one and two dimensions, we compare and contrast receptormediated endocytosis and phagocytosis for a range of biologically relevant shapes, including spheres, ellipsoids, capped cylinders, and hourglasses. We find awhole range of different engulfment behaviors with some ellipsoids engulfing faster than spheres, and that phagocytosis is able to engulf a greater range of target shapes than other types of endocytosis. Further, the 2D model can explain why some nonspherical particles engulf fastest (not at all) when presented to the membrane tip-first (lying flat). Our work reveals how some bacteria may avoid being internalized simply because of their shape, and suggests shapes for optimal drug delivery.
Abstract.
Full text.
Micali G, Aquino G, Richards DM, Endres RG (2015). Accurate Encoding and Decoding by Single Cells: Amplitude Versus Frequency Modulation. PLOS Computational Biology, 11(6), e1004222-e1004222.
Richards DM, Saunders TE (2015). Spatiotemporal Analysis of Different Mechanisms for Interpreting Morphogen Gradients. Biophysical Journal, 108(8), 2061-2073.
Richards DM, Endres RG (2014). The Mechanism of Phagocytosis: Two Stages of Engulfment. Biophysical Journal, 107(7), 1542-1553.
Richards D, Berry S, Howard M (2013). Illustrations of Mathematical Modeling in Biology: Epigenetics, Meiosis, and an Outlook. Cold Spring Harbor Symposia on Quantitative Biology, 77(0), 175-181.
Richards DM, Hempel AM, Flärdh K, Buttner MJ, Howard M (2012). Mechanistic basis of branch-site selection in filamentous bacteria.
PLoS Computational Biology,
8(3).
Abstract:
Mechanistic basis of branch-site selection in filamentous bacteria
Many filamentous organisms, such as fungi, grow by tip-extension and by forming new branches behind the tips. A similar growth mode occurs in filamentous bacteria, including the genus Streptomyces, although here our mechanistic understanding has been very limited. The Streptomyces protein DivIVA is a critical determinant of hyphal growth and localizes in foci at hyphal tips and sites of future branch development. However, how such foci form was previously unknown. Here, we show experimentally that DivIVA focus-formation involves a novel mechanism in which new DivIVA foci break off from existing tip-foci, bypassing the need for initial nucleation or de novo branch-site selection. We develop a mathematical model for DivIVA-dependent growth and branching, involving DivIVA focus-formation by tip-focus splitting, focus growth, and the initiation of new branches at a critical focus size. We quantitatively fit our model to the experimentally-measured tip-to-branch and branch-to-branch length distributions. The model predicts a particular bimodal tip-to-branch distribution results from tip-focus splitting, a prediction we confirm experimentally. Our work provides mechanistic understanding of a novel mode of hyphal growth regulation that may be widely employed. © 2012 Richards et al.
Abstract.
Richards DM, Greer E, Martin AC, Moore G, Shaw PJ, Howard M (2012). Quantitative Dynamics of Telomere Bouquet Formation. PLoS Computational Biology, 8(12), e1002812-e1002812.
Flardh K, Richards DM, Hempel AM, Howard M, Buttner MJ (2012). Regulation of apical growth and hyphal branching in Streptomyces.
CURRENT OPINION IN MICROBIOLOGY,
15(6), 737-743.
Author URL.
Hempel AM, Cantlay S, Molle V, Wang S-B, Naldrett MJ, Parker JL, Richards DM, Jung Y-G, Buttner MJ, Flardh K, et al (2012). The Ser/Thr protein kinase AfsK regulates polar growth and hyphal branching in the filamentous bacteria Streptomyces. Proceedings of the National Academy of Sciences, 109(35), E2371-E2379.
Richards DM (2008). The one-loop five-graviton amplitude and the effective action. Journal of High Energy Physics, 2008(10), 042-042.
Richards DM (2008). The one-loopH2R3andH2(∇H)2Rterms in the effective action. Journal of High Energy Physics, 2008(10), 043-043.
Publications by year
2020
Richards DM, Walker JJ, Tabak J (2020). Ion channel noise shapes the electrical activity of endocrine cells.
PLoS Comput Biol,
16(4).
Abstract:
Ion channel noise shapes the electrical activity of endocrine cells.
Endocrine cells in the pituitary gland typically display either spiking or bursting electrical activity, which is related to the level of hormone secretion. Recent work, which combines mathematical modelling with dynamic clamp experiments, suggests the difference is due to the presence or absence of a few large-conductance potassium channels. Since endocrine cells only contain a handful of these channels, it is likely that stochastic effects play an important role in the pattern of electrical activity. Here, for the first time, we explicitly determine the effect of such noise by studying a mathematical model that includes the realistic noisy opening and closing of ion channels. This allows us to investigate how noise affects the electrical activity, examine the origin of spiking and bursting, and determine which channel types are responsible for the greatest noise. Further, for the first time, we address the role of cell size in endocrine cell electrical activity, finding that larger cells typically display more bursting, while the smallest cells almost always only exhibit spiking behaviour.
Abstract.
Author URL.
Full text.
Passmore JB, Carmichael RE, Schrader TA, Godinho LF, Ferdinandusse S, Lismont C, Wang Y, Hacker C, Islinger M, Fransen M, et al (2020). Mitochondrial fission factor (MFF) is a critical regulator of peroxisome maturation.
Biochim Biophys Acta Mol Cell Res,
1867(7).
Abstract:
Mitochondrial fission factor (MFF) is a critical regulator of peroxisome maturation.
Peroxisomes are highly dynamic subcellular compartments with important functions in lipid and ROS metabolism. Impaired peroxisomal function can lead to severe metabolic disorders with developmental defects and neurological abnormalities. Recently, a new group of disorders has been identified, characterised by defects in the membrane dynamics and division of peroxisomes rather than by loss of metabolic functions. However, the contribution of impaired peroxisome plasticity to the pathophysiology of those disorders is not well understood. Mitochondrial fission factor (MFF) is a key component of both the peroxisomal and mitochondrial division machinery. Patients with MFF deficiency present with developmental and neurological abnormalities. Peroxisomes (and mitochondria) in patient fibroblasts are highly elongated as a result of impaired organelle division. The majority of studies into MFF-deficiency have focused on mitochondrial dysfunction, but the contribution of peroxisomal alterations to the pathophysiology is largely unknown. Here, we show that MFF deficiency does not cause alterations to overall peroxisomal biochemical function. However, loss of MFF results in reduced import-competency of the peroxisomal compartment and leads to the accumulation of pre-peroxisomal membrane structures. We show that peroxisomes in MFF-deficient cells display alterations in peroxisomal redox state and intra-peroxisomal pH. Removal of elongated peroxisomes through induction of autophagic processes is not impaired. A mathematical model describing key processes involved in peroxisome dynamics sheds further light into the physical processes disturbed in MFF-deficient cells. The consequences of our findings for the pathophysiology of MFF-deficiency and related disorders with impaired peroxisome plasticity are discussed.
Abstract.
Author URL.
Full text.
Richards DM (2020). Receptor Models of Phagocytosis: the Effect of Target Shape.
Adv Exp Med Biol,
1246, 55-70.
Abstract:
Receptor Models of Phagocytosis: the Effect of Target Shape.
Phagocytosis is a remarkably complex process, requiring simultaneous organisation of the cell membrane, the cytoskeleton, receptors and various signalling molecules. As can often be the case, mathematical modelling is able to penetrate some of this complexity, identifying the key biophysical components and generating understanding that would take far longer with a purely experimental approach. This chapter will review a particularly important class of phagocytosis model, championed in recent years, that primarily focuses on the role of receptors during the engulfment process. These models are pertinent to a host of unsolved questions in the subject, including the rate of cup growth during uptake, the role of both intra- and extracellular noise, and the precise differences between phagocytosis and other forms of endocytosis. In particular, this chapter will focus on the effect of target shape and orientation, including how these influence the rate and final outcome of phagocytic engulfment.
Abstract.
Author URL.
2018
Castro IG, Richards DM, Metz J, Costello JL, Passmore JB, Schrader TA, Gouveia A, Ribeiro D, Schrader M (2018). A role for Mitochondrial Rho GTPase 1 (MIRO1) in motility and membrane dynamics of peroxisomes.
Traffic,
19(3), 229-242.
Full text.
2017
Richards DM, Endres RG (2017). How cells engulf: a review of theoretical approaches to phagocytosis.
Reports on Progress in Physics,
80(12), 126601-126601.
Full text.
2016
Richards DM, Endres RG (2016). Target shape dependence in a simple model of receptor-mediated endocytosis and phagocytosis.
Proceedings of the National Academy of Sciences of the United States of America,
113, 6113-6118.
Abstract:
Target shape dependence in a simple model of receptor-mediated endocytosis and phagocytosis
Phagocytosis and receptor-mediated endocytosis are vitally important particle uptake mechanisms in many cell types, ranging fromsingle-cell organisms to immune cells. In both processes, engulfment by the cell depends critically on both particle shape and orientation. However, most previous theoretical work has focused only on spherical particles and hence disregards the wide-ranging particle shapes occurring in nature, such as those of bacteria. Here, by implementing a simple model in one and two dimensions, we compare and contrast receptormediated endocytosis and phagocytosis for a range of biologically relevant shapes, including spheres, ellipsoids, capped cylinders, and hourglasses. We find awhole range of different engulfment behaviors with some ellipsoids engulfing faster than spheres, and that phagocytosis is able to engulf a greater range of target shapes than other types of endocytosis. Further, the 2D model can explain why some nonspherical particles engulf fastest (not at all) when presented to the membrane tip-first (lying flat). Our work reveals how some bacteria may avoid being internalized simply because of their shape, and suggests shapes for optimal drug delivery.
Abstract.
Full text.
2015
Micali G, Aquino G, Richards DM, Endres RG (2015). Accurate Encoding and Decoding by Single Cells: Amplitude Versus Frequency Modulation. PLOS Computational Biology, 11(6), e1004222-e1004222.
Richards DM, Saunders TE (2015). Spatiotemporal Analysis of Different Mechanisms for Interpreting Morphogen Gradients. Biophysical Journal, 108(8), 2061-2073.
2014
Richards DM, Endres RG (2014). The Mechanism of Phagocytosis: Two Stages of Engulfment. Biophysical Journal, 107(7), 1542-1553.
2013
Richards D, Berry S, Howard M (2013). Illustrations of Mathematical Modeling in Biology: Epigenetics, Meiosis, and an Outlook. Cold Spring Harbor Symposia on Quantitative Biology, 77(0), 175-181.
2012
Richards DM, Hempel AM, Flärdh K, Buttner MJ, Howard M (2012). Mechanistic basis of branch-site selection in filamentous bacteria.
PLoS Computational Biology,
8(3).
Abstract:
Mechanistic basis of branch-site selection in filamentous bacteria
Many filamentous organisms, such as fungi, grow by tip-extension and by forming new branches behind the tips. A similar growth mode occurs in filamentous bacteria, including the genus Streptomyces, although here our mechanistic understanding has been very limited. The Streptomyces protein DivIVA is a critical determinant of hyphal growth and localizes in foci at hyphal tips and sites of future branch development. However, how such foci form was previously unknown. Here, we show experimentally that DivIVA focus-formation involves a novel mechanism in which new DivIVA foci break off from existing tip-foci, bypassing the need for initial nucleation or de novo branch-site selection. We develop a mathematical model for DivIVA-dependent growth and branching, involving DivIVA focus-formation by tip-focus splitting, focus growth, and the initiation of new branches at a critical focus size. We quantitatively fit our model to the experimentally-measured tip-to-branch and branch-to-branch length distributions. The model predicts a particular bimodal tip-to-branch distribution results from tip-focus splitting, a prediction we confirm experimentally. Our work provides mechanistic understanding of a novel mode of hyphal growth regulation that may be widely employed. © 2012 Richards et al.
Abstract.
Richards DM, Greer E, Martin AC, Moore G, Shaw PJ, Howard M (2012). Quantitative Dynamics of Telomere Bouquet Formation. PLoS Computational Biology, 8(12), e1002812-e1002812.
Flardh K, Richards DM, Hempel AM, Howard M, Buttner MJ (2012). Regulation of apical growth and hyphal branching in Streptomyces.
CURRENT OPINION IN MICROBIOLOGY,
15(6), 737-743.
Author URL.
Hempel AM, Cantlay S, Molle V, Wang S-B, Naldrett MJ, Parker JL, Richards DM, Jung Y-G, Buttner MJ, Flardh K, et al (2012). The Ser/Thr protein kinase AfsK regulates polar growth and hyphal branching in the filamentous bacteria Streptomyces. Proceedings of the National Academy of Sciences, 109(35), E2371-E2379.
2008
Richards DM (2008). The one-loop five-graviton amplitude and the effective action. Journal of High Energy Physics, 2008(10), 042-042.
Richards DM (2008). The one-loopH2R3andH2(∇H)2Rterms in the effective action. Journal of High Energy Physics, 2008(10), 043-043.
