Saffman-Taylor fingers with kinetic undercooling

The mathematical model of a steadily propagating Saffman-Taylor finger in a Hele-Shaw channel has applications to two-dimensional interacting streamer discharges which are aligned in a periodic array. In the streamer context, the relevant regularisation on the interface is not provided by surface tension, but instead has been postulated to involve a mechanism equivalent to kinetic undercooling, which acts to penalise high velocities and prevent blow-up of the unregularised solution. Previous asymptotic results for the Hele-Shaw finger problem with kinetic undercooling suggest that for a given value of the kinetic undercooling parameter, there is a discrete set of possible finger shapes, each analytic at the nose and occupying a different fraction of the channel width. In the limit in which the kinetic undercooling parameter vanishes, the fraction for each family approaches 1/2, suggesting that this 'selection' of 1/2 by kinetic undercooling is qualitatively similar to the well-known analogue with surface tension. We treat the numerical problem of computing these Saffman-Taylor fingers with kinetic undercooling, which turns out to be more subtle than the analogue with surface tension, since kinetic undercooling permits finger shapes which are corner-free but not analytic. We provide numerical evidence for the selection mechanism by setting up a problem with both kinetic undercooling and surface tension, and numerically taking the limit that the surface tension vanishes.Comment: 10 pages, 6 figures, accepted for publication by Physical Review

A two-compartment mechanochemical model of the roles of\ud transforming growth factor β and tissue tension in dermal wound healing

The repair of dermal tissue is a complex process of interconnected phenomena, where cellular, chemical and mechanical aspects all play a role, both in an autocrine and in a paracrine fashion. Recent experimental results have shown that transforming growth factor−β (TGFβ) and tissue mechanics play roles in regulating cell proliferation, differentiation and the production of extracellular materials. We have developed a 1D mathematical model that considers the interaction between the cellular, chemical and mechanical phenomena, allowing the combination of TGFβ and tissue stress to inform the activation of fibroblasts to myofibroblasts. Additionally, our model incorporates the observed feature of residual stress by considering the changing zero-stress state in the formulation for effective strain. Using this model, we predict that the continued presence of TGFβ in dermal wounds will produce contractures due to the persistence of myofibroblasts; in contrast, early elimination of TGFβ significantly reduces the myofibroblast numbers resulting in an increase in wound size. Similar results were obtained by varying the rate at which fibroblasts differentiate to myofibroblasts and by changing the myofibroblast apoptotic rate. Taken together, the implication is that elevated levels of myofibroblasts is the key factor behind wounds healing with excessive contraction, suggesting that clinical strategies which aim to reduce the myofibroblast density may reduce the appearance of contractures

A fibrocontractive mechanochemical model of dermal wound\ud closure incorporating realistic growth factor kinetics

Fibroblasts and their activated phenotype, myofibroblasts, are the primary cell types involved in the contraction associated with dermal wound healing. Recent experimental evidence indicates that the transformation from fibroblasts to myofibroblasts involves two distinct processes: the cells are stimulated to change phenotype by the combined actions of transforming growth factor β (TGFβ) and mechanical tension. This observation indicates a need for a detailed exploration of the effect of the strong interactions between the mechanical changes and growth factors in dermal wound healing. We review the experimental findings in detail and develop a model of dermal wound healing that incorporates these phenomena. Our model includes the interactions between TGFβ and collagenase, providing a more biologically realistic form for the growth factor kinetics than those included in previous mechanochemical descriptions. A comparison is made between the model predictions and experimental data on human dermal wound healing and all the essential features are well matched

Determination of the Membrane Topology of the Small EF-Hand Ca2+-Sensing Proteins CaBP7 and CaBP8

The CaBPs represent a subfamily of small EF-hand containing calcium (Ca2+)-sensing proteins related to calmodulin that regulate key ion channels in the mammalian nervous system. In a recent bioinformatic analyses we determined that CaBP7 and CaBP8 form an evolutionarily distinct branch within the CaBPs (also known as the calneurons) a finding that is consistent with earlier observations characterising a putative C-terminal transmembrane (TM) spanning helix in each of these proteins which is essential for their sub-cellular targeting to the Golgi apparatus and constitutive secretory vesicles. The C-terminal position of the predicted TM-helix suggests that CaBP7 and CaBP8 could be processed in a manner analogous to tail-anchored integral membrane proteins which exhibit the ability to insert across membranes post-translationally. In this study we have investigated the topology of CaBP7 and CaBP8 within cellular membranes through a combination of trypsin protection and epitope accessibility analyses. Our results indicate that the TM-helices of CaBP7 and CaBP8 insert fully across membranes such that their extreme C-termini are luminal. The observed type-II membrane topology is consistent with processing of CaBP7 and CaBP8 as true tail-anchored proteins. This targeting mechanism is distinct from any other calmodulin related Ca2+-sensor and conceivably underpins unique physiological functions of these proteins

Evolution and functional diversity of the Calcium Binding Proteins (CaBPs)

The mammalian central nervous system (CNS) exhibits a remarkable ability to process, store, and transfer information. Key to these activities is the use of highly regulated and unique patterns of calcium signals encoded by calcium channels and decoded by families of specific calcium-sensing proteins. The largest family of eukaryotic calcium sensors is those related to the small EF-hand containing protein calmodulin (CaM). In order to maximize the usefulness of calcium as a signaling species and to permit the evolution and fine tuning of the mammalian CNS, families of related proteins have arisen that exhibit characteristic calcium binding properties and tissue-, cellular-, and sub-cellular distribution profiles. The Calcium Binding Proteins (CaBPs) represent one such family of vertebrate specific CaM like proteins that have emerged in recent years as important regulators of essential neuronal target proteins. Bioinformatic analyses indicate that the CaBPs consist of two subfamilies and that the ancestral members of these are CaBP1 and CaBP8. The CaBPs have distinct intracellular localizations based on different targeting mechanisms including a novel type-II transmembrane domain in CaBPs 7 and 8 (otherwise known as calneuron II and calneuron I, respectively). Recent work has led to the identification of new target interactions and possible functions for the CaBPs suggesting that they have multiple physiological roles with relevance for the normal functioning of the CNS

Modulation of phosphatidylinositol 4-phosphate levels by CaBP7 controls cytokinesis in mammalian cells

Calcium and phosphoinositide signaling regulate cell division in model systems, but their significance in mammalian cells is unclear. Calcium-binding protein-7 (CaBP7) is a phosphatidylinositol 4-kinaseIIIβ (PI4KIIIβ) inhibitor required during cytokinesis in mammalian cells, hinting at a link between these pathways. Here we characterize a novel association of CaBP7 with lysosomes that cluster at the intercellular bridge during cytokinesis in HeLa cells. We show that CaBP7 regulates lysosome clustering and that PI4KIIIβ is essential for normal cytokinesis. CaBP7 depletion induces lysosome mislocalization, extension of intercellular bridge lifetime, and cytokinesis failure. These data connect phosphoinositide and calcium pathways to lysosome localization and normal cytokinesis in mammalian cells

Gait dynamics in mouse models of Parkinson's disease and Huntington's disease

BACKGROUND: Gait is impaired in patients with Parkinson's disease (PD) and Huntington's disease (HD), but gait dynamics in mouse models of PD and HD have not been described. Here we quantified temporal and spatial indices of gait dynamics in a mouse model of PD and a mouse model of HD. METHODS: Gait indices were obtained in C57BL/6J mice treated with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 30 mg/kg/day for 3 days) for PD, the mitochondrial toxin 3-nitropropionic acid (3NP, 75 mg/kg cumulative dose) for HD, or saline. We applied ventral plane videography to generate digital paw prints from which indices of gait and gait variability were determined. Mice walked on a transparent treadmill belt at a speed of 34 cm/s after treatments. RESULTS: Stride length was significantly shorter in MPTP-treated mice (6.6 ± 0.1 cm vs. 7.1 ± 0.1 cm, P < 0.05) and stride frequency was significantly increased (5.4 ± 0.1 Hz vs. 5.0 ± 0.1 Hz, P < 0.05) after 3 administrations of MPTP, compared to saline-treated mice. The inability of some mice treated with 3NP to exhibit coordinated gait was due to hind limb failure while forelimb gait dynamics remained intact. Stride-to-stride variability was significantly increased in MPTP-treated and 3NP-treated mice compared to saline-treated mice. To determine if gait disturbances due to MPTP and 3NP, drugs affecting the basal ganglia, were comparable to gait disturbances associated with motor neuron diseases, we also studied gait dynamics in a mouse model of amyotrophic lateral sclerosis (ALS). Gait variability was not increased in the SOD1 G93A transgenic model of ALS compared to wild-type control mice. CONCLUSION: The distinct characteristics of gait and gait variability in the MPTP model of Parkinson's disease and the 3NP model of Huntington's disease may reflect impairment of specific neural pathways involved

Pathologic Correlation of PET-CT Based Auto Contouring for Radiation Planning in Lung Cancer

Purpose/Objective(s): Radiation therapy in lung cancer relies on CT and functional imaging (FDG-PET) to delineate tumor volumes. Semi-automatic contouring tools have been developed for PET to improve on the inter-observer bias of manual contouring and intrinsic differences in imaging equipment. A common method involves using a threshold at a given percentage of the max activity, which may be less accurate with smaller tumors and tumors with low source to background ratio. To overcome this deficiency, a gradient algorithm, which detects changes in image counts at the border of the tumor, has been developed. Few studies have correlated these methods to pathological specimens. American Society for Therapeutic Radiation Oncology (ASTRO) 52nd Annual Meeting October 31 - November 4, San Diego, C

Characterisation of the Interaction of the C-Terminus of the Dopamine D2 Receptor with Neuronal Calcium Sensor-1

NCS-1 is a member of the neuronal calcium sensor (NCS) family of EF-hand Ca2+ binding proteins which has been implicated in several physiological functions including regulation of neurotransmitter release, membrane traffic, voltage gated Ca2+ channels, neuronal development, synaptic plasticity, and learning. NCS-1 binds to the dopamine D2 receptor, potentially affecting its internalisation and controlling dopamine D2 receptor surface expression. The D2 receptor binds NCS-1via a short 16-residue cytoplasmic C-terminal tail. We have used NMR and fluorescence spectroscopy to characterise the interactions between the NCS-1/Ca2+ and D2 peptide. The data show that NCS-1 binds D2 peptide with a Kd of ∼14.3 µM and stoichiometry of peptide binding to NCS-1 of 2∶1. NMR chemical shift mapping confirms that D2 peptide binds to the large, solvent-exposed hydrophobic groove, on one face of the NCS-1 molecule, with residues affected by the presence of the peptide spanning both the N and C-terminal portions of the protein. The NMR and mutagenesis data further show that movement of the C-terminal helix 11 of NCS-1 to fully expose the hydrophobic groove is important for D2 peptide binding. Molecular docking using restraints derived from the NMR chemical shift data, together with the experimentally-derived stoichiometry, produced a model of the complex between NCS-1 and the dopamine receptor, in which two molecules of the receptor are able to simultaneously bind to the NCS-1 monomer