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Sample records for dynamically stabilized microtubules

  1. Aging of dynamically stabilized microtubules

    CERN Document Server

    Ebbinghaus, M

    2009-01-01

    The microtubule network, an important part of the cytoskeleton, is constantly remodeled by alternating phases of growth and shrinkage of individual filaments. Plus-end tracking proteins (+TIPs) interact with the microtubule and in many cases alter its dynamics. While it is established that the prototypal CLIP-170 enhances microtubule stability by increasing rescues, the plus-end tracking mechanism is still under debate. We present a model for microtubule dynamics in which a rescue factor is dynamically added to the filament while growing. As a consequence, the filament shows aging behavior which should be experimentally accessible and thus allow one to exclude some hypothesized models of the inclusion of rescue factors at the microtubule plus end. Additionally, we show the strong influence of the cell geometry on the quantitative results.

  2. Microtubule Dynamicity Is More Important than Stability in Memory Formation: an In Vivo Study.

    Science.gov (United States)

    Atarod, Deyhim; Eskandari-Sedighi, Ghazaleh; Pazhoohi, Farid; Karimian, Seyed Morteza; Khajeloo, Mojtaba; Riazi, Gholam Hossein

    2015-06-01

    It has been shown that microtubule (MT) activity and dynamics can have huge impacts on synaptic plasticity and memory formation. This is mainly due to various functions of MTs in neurons; MTs are involved in dendritic spine formation, axonal transportation, neuronal polarity, and receptor trafficking. Recent studies from our group and other labs have suggested the possible role of brain MT dynamicity and activity in memory; however, there is a need for more detailed studies regarding this aspect. In this study, we have tried to evaluate the importance of microtubule dynamicity rather than stability in memory formation in vivo. In order to investigate the role of MT stability in memory formation, we treated mice with paclitaxel-a classic microtubule-stabilizing agent. We then studied the behavior of treated animals using Morris water maze (MWM) test. To measure the effect of injected paclitaxel on MT polymerization kinetics, we conducted polymerization assays on brain extracts of the same paclitaxel-treated animals. Our results show that paclitaxel treatment affects animals' memory in a negative way and treated animals behave poorly in MWM compared to control group. In addition, our kinetics studies show that MT stability is significantly increased in brain extracts from paclitaxel-treated mice, but MT dynamics is reduced. Thus, we suggest that dynamicity is a very important feature of MT protein structures, and regarding memory formation, dynamicity is more important than stability and high activity.

  3. Dynamics of Microtubule Instabilities

    CERN Document Server

    Antal, T; Redner, S

    2007-01-01

    We investigate the dynamics of an idealized model of microtubule growth that evolves by: (i) attachment of guanosine triphosphate (GTP) at rate lambda, (ii) conversion of GTP to guanosine diphosphate (GDP) at rate 1, and (iii) detachment of GDP at rate mu. As a function of these rates, a microtubule can grow steadily or its length can fluctuate wildly. For mu=0, we find the exact tubule and GTP cap length distributions, and power-law length distributions of GTP and GDP islands. For mu=infinity, we argue that the time between catastrophes, where the microtubule shrinks to zero length, scales as exp(lambda). We also find the phase boundary between a growing and shrinking microtubule.

  4. Expression of Nucleolin Affects Microtubule Dynamics.

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    Xavier Gaume

    Full Text Available Nucleolin is present in diverse cellular compartments and is involved in a variety of cellular processes from nucleolar structure and function to intracellular trafficking, cell adhesion and migration. Recently, nucleolin has been localized at the mature centriole where it is involved in microtubule nucleation and anchoring. Although this new function of nucleolin linked to microtubule regulation has been identified, the global effects of nucleolin on microtubule dynamics have not been addressed yet. In the present study, we analyzed the roles of nucleolin protein levels on global microtubule dynamics by tracking the EB3 microtubule plus end binding protein in live cells. We have found that during microtubule growth phases, nucleolin affects both the speed and life time of polymerization and by analyzing catastrophe events, we showed that nucleolin reduces catastrophe frequency. This new property of nucleolin was then confirmed in a cold induced microtubule depolymerization experiment in which we have found that cold resistant microtubules were totally destabilized in nucleolin depleted cells. Altogether, our data demonstrate a new function of nucleolin on microtubule stabilization, thus bringing novel insights into understanding the multifunctional properties of nucleolin in healthy and cancer cells.

  5. Taxol crystals can masquerade as stabilized microtubules.

    Directory of Open Access Journals (Sweden)

    Margit Foss

    Full Text Available Taxol is a potent anti-mitotic drug used in chemotherapy, angioplastic stents, and cell biology research. By binding and stabilizing microtubules, Taxol inhibits their dynamics, crucial for cell division, motility, and survival. The drug has also been reported to induce formation of asters and bundles composed of stabilized microtubules. Surprisingly, at commonly used concentrations, Taxol forms crystals that rapidly bind fluorescent tubulin subunits, generating structures with an uncanny resemblance to microtubule asters and bundles. Kinetic and topological considerations suggest that tubulin subunits, rather than microtubules, bind the crystals. This sequestration of tubulin from the subunit pool would be expected to shift the equilibrium of free to polymerized tubulin to disfavor assembly. Our results imply that some previously reported Taxol-induced asters or bundles could include or be composed of tubulin-decorated Taxol crystals. Thus, reevaluation of certain morphological, chemical, and physical properties of Taxol-treated microtubules may be necessary. Moreover, our findings suggest a novel mechanism for chemotherapy-induced cytotoxicity in non-dividing cells, with far-reaching medical implications.

  6. Regulation of a dynamic interaction between two microtubule-binding proteins, EB1 and TIP150, by the mitotic p300/CBP-associated factor (PCAF) orchestrates kinetochore microtubule plasticity and chromosome stability during mitosis.

    Science.gov (United States)

    Ward, Tarsha; Wang, Ming; Liu, Xing; Wang, Zhikai; Xia, Peng; Chu, Youjun; Wang, Xiwei; Liu, Lifang; Jiang, Kai; Yu, Huijuan; Yan, Maomao; Wang, Jianyu; Hill, Donald L; Huang, Yuejia; Zhu, Tongge; Yao, Xuebiao

    2013-05-31

    The microtubule cytoskeleton network orchestrates cellular dynamics and chromosome stability in mitosis. Although tubulin acetylation is essential for cellular plasticity, it has remained elusive how kinetochore microtubule plus-end dynamics are regulated by p300/CBP-associated factor (PCAF) acetylation in mitosis. Here, we demonstrate that the plus-end tracking protein, TIP150, regulates dynamic kinetochore-microtubule attachments by promoting the stability of spindle microtubule plus-ends. Suppression of TIP150 by siRNA results in metaphase alignment delays and perturbations in chromosome biorientation. TIP150 is a tetramer that binds an end-binding protein (EB1) dimer through the C-terminal domains, and overexpression of the C-terminal TIP150 or disruption of the TIP150-EB1 interface by a membrane-permeable peptide perturbs chromosome segregation. Acetylation of EB1-PCAF regulates the TIP150 interaction, and persistent acetylation perturbs EB1-TIP150 interaction and accurate metaphase alignment, resulting in spindle checkpoint activation. Suppression of the mitotic checkpoint serine/threonine protein kinase, BubR1, overrides mitotic arrest induced by impaired EB1-TIP150 interaction, but cells exhibit whole chromosome aneuploidy. Thus, the results identify a mechanism by which the TIP150-EB1 interaction governs kinetochore microtubule plus-end plasticity and establish that the temporal control of the TIP150-EB1 interaction by PCAF acetylation ensures chromosome stability in mitosis.

  7. Regulation of a Dynamic Interaction between Two Microtubule-binding Proteins, EB1 and TIP150, by the Mitotic p300/CBP-associated Factor (PCAF) Orchestrates Kinetochore Microtubule Plasticity and Chromosome Stability during Mitosis*

    Science.gov (United States)

    Ward, Tarsha; Wang, Ming; Liu, Xing; Wang, Zhikai; Xia, Peng; Chu, Youjun; Wang, Xiwei; Liu, Lifang; Jiang, Kai; Yu, Huijuan; Yan, Maomao; Wang, Jianyu; Hill, Donald L.; Huang, Yuejia; Zhu, Tongge; Yao, Xuebiao

    2013-01-01

    The microtubule cytoskeleton network orchestrates cellular dynamics and chromosome stability in mitosis. Although tubulin acetylation is essential for cellular plasticity, it has remained elusive how kinetochore microtubule plus-end dynamics are regulated by p300/CBP-associated factor (PCAF) acetylation in mitosis. Here, we demonstrate that the plus-end tracking protein, TIP150, regulates dynamic kinetochore-microtubule attachments by promoting the stability of spindle microtubule plus-ends. Suppression of TIP150 by siRNA results in metaphase alignment delays and perturbations in chromosome biorientation. TIP150 is a tetramer that binds an end-binding protein (EB1) dimer through the C-terminal domains, and overexpression of the C-terminal TIP150 or disruption of the TIP150-EB1 interface by a membrane-permeable peptide perturbs chromosome segregation. Acetylation of EB1-PCAF regulates the TIP150 interaction, and persistent acetylation perturbs EB1-TIP150 interaction and accurate metaphase alignment, resulting in spindle checkpoint activation. Suppression of the mitotic checkpoint serine/threonine protein kinase, BubR1, overrides mitotic arrest induced by impaired EB1-TIP150 interaction, but cells exhibit whole chromosome aneuploidy. Thus, the results identify a mechanism by which the TIP150-EB1 interaction governs kinetochore microtubule plus-end plasticity and establish that the temporal control of the TIP150-EB1 interaction by PCAF acetylation ensures chromosome stability in mitosis. PMID:23595990

  8. Integrin-linked kinase regulates interphase and mitotic microtubule dynamics.

    Directory of Open Access Journals (Sweden)

    Simin Lim

    Full Text Available Integrin-linked kinase (ILK localizes to both focal adhesions and centrosomes in distinct multiprotein complexes. Its dual function as a kinase and scaffolding protein has been well characterized at focal adhesions, where it regulates integrin-mediated cell adhesion, spreading, migration and signaling. At the centrosomes, ILK regulates mitotic spindle organization and centrosome clustering. Our previous study showed various spindle defects after ILK knockdown or inhibition that suggested alteration in microtubule dynamics. Since ILK expression is frequently elevated in many cancer types, we investigated the effects of ILK overexpression on microtubule dynamics. We show here that overexpressing ILK in HeLa cells was associated with a shorter duration of mitosis and decreased sensitivity to paclitaxel, a chemotherapeutic agent that suppresses microtubule dynamics. Measurement of interphase microtubule dynamics revealed that ILK overexpression favored microtubule depolymerization, suggesting that microtubule destabilization could be the mechanism behind the decreased sensitivity to paclitaxel, which is known to stabilize microtubules. Conversely, the use of a small molecule inhibitor selective against ILK, QLT-0267, resulted in suppressed microtubule dynamics, demonstrating a new mechanism of action for this compound. We further show that treatment of HeLa cells with QLT-0267 resulted in higher inter-centromere tension in aligned chromosomes during mitosis, slower microtubule regrowth after cold depolymerization and the presence of a more stable population of spindle microtubules. These results demonstrate that ILK regulates microtubule dynamics in both interphase and mitotic cells.

  9. Microtubule stabilization reduces scarring and causes axon regeneration after spinal cord injury

    NARCIS (Netherlands)

    F. Hellal (Farida); A. Hurtado (Andres); J. Ruschel (Jörg); K.C. Flynn (Kevin); C.J. Laskowski (Claudia); M. Umlauf (Martina); L.C. Kapitein (Lukas); D. Strikis (Dinara); V. Lemmon (Vance); J. Bixby (John); C.C. Hoogenraad (Casper); F. Bradke (Frank)

    2011-01-01

    textabstractHypertrophic scarring and poor intrinsic axon growth capacity constitute major obstacles for spinal cord repair. These processes are tightly regulated by microtubule dynamics. Here, moderate microtubule stabilization decreased scar formation after spinal cord injury in rodents through va

  10. Structural investigations into the binding mode of novel neolignans Cmp10 and Cmp19 microtubule stabilizers by in silico molecular docking, molecular dynamics, and binding free energy calculations.

    Science.gov (United States)

    Tripathi, Shubhandra; Kumar, Akhil; Kumar, B Sathish; Negi, Arvind S; Sharma, Ashok

    2016-06-01

    Microtubule stabilizers provide an important mode of treatment via mitotic cell arrest of cancer cells. Recently, we reported two novel neolignans derivatives Cmp10 and Cmp19 showing anticancer activity and working as microtubule stabilizers at micromolar concentrations. In this study, we have explored the binding site, mode of binding, and stabilization by two novel microtubule stabilizers Cmp10 and Cmp19 using in silico molecular docking, molecular dynamics (MD) simulation, and binding free energy calculations. Molecular docking studies were performed to explore the β-tubulin binding site of Cmp10 and Cmp19. Further, MD simulations were used to probe the β-tubulin stabilization mechanism by Cmp10 and Cmp19. Binding affinity was also compared for Cmp10 and Cmp19 using binding free energy calculations. Our docking results revealed that both the compounds bind at Ptxl binding site in β-tubulin. MD simulation studies showed that Cmp10 and Cmp19 binding stabilizes M-loop (Phe272-Val288) residues of β-tubulin and prevent its dynamics, leading to a better packing between α and β subunits from adjacent tubulin dimers. In addition, His229, Ser280 and Gln281, and Arg278, Thr276, and Ser232 were found to be the key amino acid residues forming H-bonds with Cmp10 and Cmp19, respectively. Consequently, binding free energy calculations indicated that Cmp10 (-113.655 kJ/mol) had better binding compared to Cmp19 (-95.216 kJ/mol). This study provides useful insight for better understanding of the binding mechanism of Cmp10 and Cmp19 and will be helpful in designing novel microtubule stabilizers.

  11. Microtubules Modulate F-actin Dynamics during Neuronal Polarization.

    Science.gov (United States)

    Zhao, Bing; Meka, Durga Praveen; Scharrenberg, Robin; König, Theresa; Schwanke, Birgit; Kobler, Oliver; Windhorst, Sabine; Kreutz, Michael R; Mikhaylova, Marina; Calderon de Anda, Froylan

    2017-08-29

    Neuronal polarization is reflected by different dynamics of microtubule and filamentous actin (F-actin). Axonal microtubules are more stable than those in the remaining neurites, while dynamics of F-actin in axonal growth cones clearly exceed those in their dendritic counterparts. However, whether a functional interplay exists between the microtubule network and F-actin dynamics in growing axons and whether this interplay is instrumental for breaking cellular symmetry is currently unknown. Here, we show that an increment on microtubule stability or number of microtubules is associated with increased F-actin dynamics. Moreover, we show that Drebrin E, an F-actin and microtubule plus-end binding protein, mediates this cross talk. Drebrin E segregates preferentially to growth cones with a higher F-actin treadmilling rate, where more microtubule plus-ends are found. Interruption of the interaction of Drebrin E with microtubules decreases F-actin dynamics and arrests neuronal polarization. Collectively the data show that microtubules modulate F-actin dynamics for initial axon extension during neuronal development.

  12. Deceivingly dynamic: Learning-dependent changes in stathmin and microtubules.

    Science.gov (United States)

    Uchida, Shusaku; Shumyatsky, Gleb P

    2015-10-01

    Microtubules, one of the major cytoskeletal structures, were previously considered stable and only indirectly involved in synaptic structure and function in mature neurons. However, recent evidence demonstrates that microtubules are dynamic and have an important role in synaptic structure, synaptic plasticity, and memory. In particular, learning induces changes in microtubule turnover and stability, and pharmacological manipulation of microtubule dynamics alters synaptic plasticity and long-term memory. These learning-induced changes in microtubules are controlled by the phosphoprotein stathmin, whose only known cellular activity is to negatively regulate microtubule formation. During the first eight hours following learning, changes in the phosphorylation of stathmin go through two phases causing biphasic shifts in microtubules stability/instability. These shifts, in turn, regulate memory formation by controlling in the second phase synaptic transport of the GluA2 subunit of AMPA receptors. Improper regulation of stathmin and microtubule dynamics has been observed in aged animals and in patients with Alzheimer's disease and depression. Thus, recent work on stathmin and microtubules has identified new molecular players in the early stages of memory encoding.

  13. In vitro assembly of plant tubulin in the absence of microtubule-stabilizing reagents

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    The assembly of microtubules is essential for physiological functions of microtubules. Addition of microtubule-stabilizing reagents or microtubule "seeds" is usually necessary for plant tubulin assembly in vitro, which hinders the investigation of plant microtubule dynamics. In the present note, highly purified plant tubulins have been obtained from lily pollen, a non-microtubule-stabilizing reagent or microtubule "seed" system for plant tubulin assembly has been established and the analysis of plant tubulin assembly performed. Experiment results showed that purified tubulin polymerized in vitro, and a typical microtubule structure was observed with electron microscopy. The kinetics curve of tubulin assembly exhibited typical "parabola". The presence of taxol significantly altered the character of plant tubulin assembly, including that abnormal microtubules were assembled and the critical concentration for plant tubulin assembly was decreased exceedingly from 3 mg/mL in the absence of taxol to 0.043 mg/mL in the presence of taxol.

  14. The dual specificity phosphatase Cdc14B bundles and stabilizes microtubules

    Energy Technology Data Exchange (ETDEWEB)

    Plumley, Hyekyung [ORNL; Liu, Yie [ORNL; Gomez, Marla V [ORNL; Wang, Yisong [ORNL

    2005-01-01

    The Cdc14 dual-specificity phosphatases regulate key events in the eukaryotic cell cycle. However, little is known about the function of mammalian CDC14B family members. Here, we demonstrate that subcellular localization of CDC14B protein is cell cycle regulated. CDC14B can bind, bundle, and stabilize microtubules in vitro independently of its catalytic activity. Basic amino acid residues within the nucleolar targeting domain are important for both retaining CDC14B in the nucleolus and preventing microtubule bundling. Overexpression of CDC14B resulted in the formation of cytoplasmic CDC14B and microtubule bundles in interphase cells. These microtubule bundles were resistant to microtubule depolymerization reagents and enriched in acetylated -tubulin. Expression of cytoplasmic forms of CDC14B impaired microtubule nucleation from the microtubule organization center. CDC14B is thus a novel microtubule-bundling and -stabilizing protein, whose regulated subcellular localization may help modulate spindle and microtubule dynamics in mitosis.

  15. Stochastic Model of Microtubule Dynamics

    Science.gov (United States)

    Hryniv, Ostap; Martínez Esteban, Antonio

    2017-10-01

    We introduce a continuous time stochastic process on strings made of two types of particle, whose dynamics mimics that of microtubules in a living cell. The long term behaviour of the system is described in terms of the velocity v of the string end. We show that v is an analytic function of its parameters and study its monotonicity properties. We give a complete characterisation of the phase diagram of the model and derive several criteria of the growth (v>0) and the shrinking (v<0) regimes of the dynamics.

  16. Microtubule stability and MAPI B upregulation control neuritogenesis in CAD cells

    Institute of Scientific and Technical Information of China (English)

    Wen LI; Jin-tang XIA; Yue FENG

    2006-01-01

    Aim: To study the role of microtubule dynamics and microtubule associated protein 1B (MAP1B) in regulation of the neurite extension in CAD catecholaminergic neuronal cell line. Methods: The neuritogenesis of the CAD cells was abolished by inhibiting microtubule polymerization with nocodazole and by blocking microtubule depolymerization with taxol. MAP1B and tubulin protein expression was detected by Western blot. Immunofluorescent staining of tubulins was observed by fluorescent and confocal microscopy. Results: Microtubule dynamics was essential for CAD neurite extension. Dosage analysis revealed that neurite extension was much more sensitive to nocodazole than to taxol, suggesting a functional requirement for highly active microtubule assembly. A remarkable upregulation of MAP1B protein was detected during neurite extension accompanied with increased microtubule stability. Conclusion: Upregulation of MAP1B leads to the stabilization of newly formed microtubules in the developing neurites, which in turn promotes neurite extension.

  17. SAS-4 is recruited to a dynamic structure in newly forming centrioles that is stabilized by the gamma-tubulin-mediated addition of centriolar microtubules.

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    Dammermann, Alexander; Maddox, Paul S; Desai, Arshad; Oegema, Karen

    2008-02-25

    Centrioles are surrounded by pericentriolar material (PCM), which is proposed to promote new centriole assembly by concentrating gamma-tubulin. Here, we quantitatively monitor new centriole assembly in living Caenorhabditis elegans embryos, focusing on the conserved components SAS-4 and SAS-6. We show that SAS-4 and SAS-6 are coordinately recruited to the site of new centriole assembly and reach their maximum levels during S phase. Centriolar SAS-6 is subsequently reduced by a mechanism intrinsic to the early assembly pathway that does not require progression into mitosis. Centriolar SAS-4 remains in dynamic equilibrium with the cytoplasmic pool until late prophase, when it is stably incorporated in a step that requires gamma-tubulin and microtubule assembly. These results indicate that gamma-tubulin in the PCM stabilizes the nascent daughter centriole by promoting microtubule addition to its outer wall. Such a mechanism may help restrict new centriole assembly to the vicinity of preexisting parent centrioles that recruit PCM.

  18. Oxidative stress decreases microtubule growth and stability in ventricular myocytes

    OpenAIRE

    Drum, BML; Yuan, C.; Li, L; Liu, Q.; Wordeman, L; Santana, LF

    2016-01-01

    © 2016 Elsevier Ltd.Microtubules (MTs) have many roles in ventricular myocytes, including structural stability, morphological integrity, and protein trafficking. However, despite their functional importance, dynamic MTs had never been visualized in living adult myocytes. Using adeno-associated viral vectors expressing the MT-associated protein plus end binding protein 3 (EB3) tagged with EGFP, we were able to perform live imaging and thus capture and quantify MT dynamics in ventricular myocyt...

  19. Microtubule dynamics: Caps, catastrophes, and coupled hydrolysis

    DEFF Research Database (Denmark)

    Flyvbjerg, H.; Holy, T.E.; Leibler, S.

    1996-01-01

    individual tubulin dimers, an ignored. In this cap model, GTP hydrolysis is assumed to be stochastic and uncoupled to microtubule growth. Different rates of hydrolysis are assumed for GTP in the cap's interior and for GTP at its boundary with hydrolyzed parts of the microtubule. Expectation values...... and probability distributions relating to available experimental data are derived. Caps are found to be short and the total rate of hydrolysis at a microtubule end is found to be dynamically coupled to growth. The so-called catastrophe rate is a simple function of the microtubule growth rare and fits experimental...... of microtubule growth before dilution. The GTP content of microtubules is found and its rare of hydrolysis is determined under the circumstances created in an experiment designed to measure this GTP content. It is concluded that this experiment's failure to register any GTP content is consistent with the model...

  20. A novel role for aquaporin-5 in enhancing microtubule organization and stability.

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    Venkataramana K Sidhaye

    Full Text Available Aquaporin-5 (AQP5 is a water-specific channel located on the apical surface of airway epithelial cells. In addition to regulating transcellular water permeability, AQP5 can regulate paracellular permeability, though the mechanisms by which this occurs have not been determined. Microtubules also regulate paracellular permeability. Here, we report that AQP5 promotes microtubule assembly and helps maintain the assembled microtubule steady state levels with slower turnover dynamics in cells. Specifically, reduced levels of AQP5 correlated with lower levels of assembled microtubules and decreased paracellular permeability. In contrast, overexpression of AQP5 increased assembly of microtubules, with evidence of increased MT stability, and promoted the formation of long straight microtubules in the apical domain of the epithelial cells. These findings indicate that AQP5-mediated regulation of microtubule dynamics modulates airway epithelial barrier properties and epithelial function.

  1. Plk phosphorylation regulates the microtubule-stabilizing protein TCTP.

    Science.gov (United States)

    Yarm, Frederic R

    2002-09-01

    The mitotic polo-like kinases have been implicated in the formation and function of bipolar spindles on the basis of their respective localizations and mutant phenotypes. To date, this putative regulation has been limited to a kinesin-like motor protein, a centrosomal structural protein, and two microtubule-associated proteins (MAPs). In this study, another spindle-regulating protein, the mammalian non-MAP microtubule-binding and -stabilizing protein, the translationally controlled tumor protein (TCTP), was identified as a putative Plk-interacting clone by a two-hybrid screen. Plk phosphorylates TCTP on two serine residues in vitro and cofractionates with the majority of kinase activity toward TCTP in mitotic cell lysates. In addition, these sites were demonstrated to be phosphorylated in vivo. Overexpression of a Plk phosphorylation site-deficient mutant of TCTP induced a dramatic increase in the number of multinucleate cells, rounded cells with condensed ball-like nuclei, and cells undergoing cell death, similar to both the reported anti-Plk antibody microinjection and the low-concentration taxol treatment phenotypes. These results suggest that phosphorylation decreases the microtubule-stabilizing activity of TCTP and promotes the increase in microtubule dynamics that occurs after metaphase.

  2. Regulation of microtubule stability and mitotic progression by survivin.

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    Giodini, Alessandra; Kallio, Marko J; Wall, Nathan R; Gorbsky, Gary J; Tognin, Simona; Marchisio, Pier Carlo; Symons, Marc; Altieri, Dario C

    2002-05-01

    Survivin is a member of the inhibitor of apoptosis (IAP) gene family, which has been implicated in both preservation of cell viability and regulation of mitosis in cancer cells. Here, we show that HeLa cells microinjected with a polyclonal antibody to survivin exhibited delayed progression in prometaphase (31.5 +/- 6.9 min) and metaphase (126.8 +/- 73.8 min), as compared with control injected cells (prometaphase, 21.5 +/- 3.3 min; metaphase, 18.9 +/- 4.5 min; P mitotic spindles severely depleted of microtubules and occasionally underwent apoptosis without exiting the mitotic block or thereafter. Forced expression of survivin in HeLa cells profoundly influenced microtubule dynamics with reduction of pole-to-pole distance at metaphase (8.57 +/- 0.21 microm versus 10.58 +/- 0.19 microm; P microtubules against nocodazole-induced depolymerization in vivo. These data demonstrate that survivin functions at cell division to control microtubule stability and assembly of a normal mitotic spindle. This pathway may facilitate checkpoint evasion and promote resistance to chemotherapy in cancer.

  3. Stabilizing versus destabilizing the microtubules: a double-edge sword for an effective cancer treatment option?

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    Fanale, Daniele; Bronte, Giuseppe; Passiglia, Francesco; Calò, Valentina; Castiglia, Marta; Di Piazza, Florinda; Barraco, Nadia; Cangemi, Antonina; Catarella, Maria Teresa; Insalaco, Lavinia; Listì, Angela; Maragliano, Rossella; Massihnia, Daniela; Perez, Alessandro; Toia, Francesca; Cicero, Giuseppe; Bazan, Viviana

    2015-01-01

    Microtubules are dynamic and structural cellular components involved in several cell functions, including cell shape, motility, and intracellular trafficking. In proliferating cells, they are essential components in the division process through the formation of the mitotic spindle. As a result of these functions, tubulin and microtubules are targets for anticancer agents. Microtubule-targeting agents can be divided into two groups: microtubule-stabilizing, and microtubule-destabilizing agents. The former bind to the tubulin polymer and stabilize microtubules, while the latter bind to the tubulin dimers and destabilize microtubules. Alteration of tubulin-microtubule equilibrium determines the disruption of the mitotic spindle, halting the cell cycle at the metaphase-anaphase transition and, eventually, resulting in cell death. Clinical application of earlier microtubule inhibitors, however, unfortunately showed several limits, such as neurological and bone marrow toxicity and the emergence of drug-resistant tumor cells. Here we review several natural and synthetic microtubule-targeting agents, which showed antitumor activity and increased efficacy in comparison to traditional drugs in various preclinical and clinical studies. Cryptophycins, combretastatins, ombrabulin, soblidotin, D-24851, epothilones and discodermolide were used in clinical trials. Some of them showed antiangiogenic and antivascular activity and others showed the ability to overcome multidrug resistance, supporting their possible use in chemotherapy.

  4. Stabilizing versus Destabilizing the Microtubules: A Double-Edge Sword for an Effective Cancer Treatment Option?

    Science.gov (United States)

    Fanale, Daniele; Bronte, Giuseppe; Passiglia, Francesco; Calò, Valentina; Castiglia, Marta; Di Piazza, Florinda; Barraco, Nadia; Cangemi, Antonina; Catarella, Maria Teresa; Insalaco, Lavinia; Listì, Angela; Maragliano, Rossella; Massihnia, Daniela; Perez, Alessandro; Toia, Francesca; Cicero, Giuseppe; Bazan, Viviana

    2015-01-01

    Microtubules are dynamic and structural cellular components involved in several cell functions, including cell shape, motility, and intracellular trafficking. In proliferating cells, they are essential components in the division process through the formation of the mitotic spindle. As a result of these functions, tubulin and microtubules are targets for anticancer agents. Microtubule-targeting agents can be divided into two groups: microtubule-stabilizing, and microtubule-destabilizing agents. The former bind to the tubulin polymer and stabilize microtubules, while the latter bind to the tubulin dimers and destabilize microtubules. Alteration of tubulin-microtubule equilibrium determines the disruption of the mitotic spindle, halting the cell cycle at the metaphase-anaphase transition and, eventually, resulting in cell death. Clinical application of earlier microtubule inhibitors, however, unfortunately showed several limits, such as neurological and bone marrow toxicity and the emergence of drug-resistant tumor cells. Here we review several natural and synthetic microtubule-targeting agents, which showed antitumor activity and increased efficacy in comparison to traditional drugs in various preclinical and clinical studies. Cryptophycins, combretastatins, ombrabulin, soblidotin, D-24851, epothilones and discodermolide were used in clinical trials. Some of them showed antiangiogenic and antivascular activity and others showed the ability to overcome multidrug resistance, supporting their possible use in chemotherapy. PMID:26484003

  5. Stabilizing versus Destabilizing the Microtubules: A Double-Edge Sword for an Effective Cancer Treatment Option?

    Directory of Open Access Journals (Sweden)

    Daniele Fanale

    2015-01-01

    Full Text Available Microtubules are dynamic and structural cellular components involved in several cell functions, including cell shape, motility, and intracellular trafficking. In proliferating cells, they are essential components in the division process through the formation of the mitotic spindle. As a result of these functions, tubulin and microtubules are targets for anticancer agents. Microtubule-targeting agents can be divided into two groups: microtubule-stabilizing, and microtubule-destabilizing agents. The former bind to the tubulin polymer and stabilize microtubules, while the latter bind to the tubulin dimers and destabilize microtubules. Alteration of tubulin-microtubule equilibrium determines the disruption of the mitotic spindle, halting the cell cycle at the metaphase-anaphase transition and, eventually, resulting in cell death. Clinical application of earlier microtubule inhibitors, however, unfortunately showed several limits, such as neurological and bone marrow toxicity and the emergence of drug-resistant tumor cells. Here we review several natural and synthetic microtubule-targeting agents, which showed antitumor activity and increased efficacy in comparison to traditional drugs in various preclinical and clinical studies. Cryptophycins, combretastatins, ombrabulin, soblidotin, D-24851, epothilones and discodermolide were used in clinical trials. Some of them showed antiangiogenic and antivascular activity and others showed the ability to overcome multidrug resistance, supporting their possible use in chemotherapy.

  6. GDP-tubulin incorporation into growing microtubules modulates polymer stability.

    Science.gov (United States)

    Valiron, Odile; Arnal, Isabelle; Caudron, Nicolas; Job, Didier

    2010-06-04

    Microtubule growth proceeds through the endwise addition of nucleotide-bound tubulin dimers. The microtubule wall is composed of GDP-tubulin subunits, which are thought to come exclusively from the incorporation of GTP-tubulin complexes at microtubule ends followed by GTP hydrolysis within the polymer. The possibility of a direct GDP-tubulin incorporation into growing polymers is regarded as hardly compatible with recent structural data. Here, we have examined GTP-tubulin and GDP-tubulin incorporation into polymerizing microtubules using a minimal assembly system comprised of nucleotide-bound tubulin dimers, in the absence of free nucleotide. We find that GDP-tubulin complexes can efficiently co-polymerize with GTP-tubulin complexes during microtubule assembly. GDP-tubulin incorporation into microtubules occurs with similar efficiency during bulk microtubule assembly as during microtubule growth from seeds or centrosomes. Microtubules formed from GTP-tubulin/GDP-tubulin mixtures display altered microtubule dynamics, in particular a decreased shrinkage rate, apparently due to intrinsic modifications of the polymer disassembly properties. Thus, although microtubules polymerized from GTP-tubulin/GDP-tubulin mixtures or from homogeneous GTP-tubulin solutions are both composed of GDP-tubulin subunits, they have different dynamic properties, and this may reveal a novel form of microtubule "structural plasticity."

  7. GDP-Tubulin Incorporation into Growing Microtubules Modulates Polymer Stability*

    Science.gov (United States)

    Valiron, Odile; Arnal, Isabelle; Caudron, Nicolas; Job, Didier

    2010-01-01

    Microtubule growth proceeds through the endwise addition of nucleotide-bound tubulin dimers. The microtubule wall is composed of GDP-tubulin subunits, which are thought to come exclusively from the incorporation of GTP-tubulin complexes at microtubule ends followed by GTP hydrolysis within the polymer. The possibility of a direct GDP-tubulin incorporation into growing polymers is regarded as hardly compatible with recent structural data. Here, we have examined GTP-tubulin and GDP-tubulin incorporation into polymerizing microtubules using a minimal assembly system comprised of nucleotide-bound tubulin dimers, in the absence of free nucleotide. We find that GDP-tubulin complexes can efficiently co-polymerize with GTP-tubulin complexes during microtubule assembly. GDP-tubulin incorporation into microtubules occurs with similar efficiency during bulk microtubule assembly as during microtubule growth from seeds or centrosomes. Microtubules formed from GTP-tubulin/GDP-tubulin mixtures display altered microtubule dynamics, in particular a decreased shrinkage rate, apparently due to intrinsic modifications of the polymer disassembly properties. Thus, although microtubules polymerized from GTP-tubulin/GDP-tubulin mixtures or from homogeneous GTP-tubulin solutions are both composed of GDP-tubulin subunits, they have different dynamic properties, and this may reveal a novel form of microtubule “structural plasticity.” PMID:20371874

  8. Visualization of microtubule growth in living platelets reveals a dynamic marginal band with multiple microtubules

    NARCIS (Netherlands)

    S. Patel-Hett (Sunita); J.L. Richardson (Jennifer); H. Schulze (Harald); K. Drabek (Ksenija); N.A. Isaac (Natasha); K. Hoffmeister (Karin); R.A. Shivdasani (Ramesh); J.C. Bulinski (J. Chloë); N.J. Galjart (Niels); J.H. Hartwig (John); J. Italiano (Joseph)

    2008-01-01

    textabstractThe marginal band of microtubules maintains the discoid shape of resting blood platelets. Although studies of platelet microtubule coil structure conclude that it is composed of a single microtubule, no investigations of its dynamics exist. In contrast to previous studies, permeabilized

  9. Tau neurofibrillary pathology and microtubule stability.

    Science.gov (United States)

    Michaelis, Mary L; Dobrowsky, Rick T; Li, Guibin

    2002-12-01

    We previously reported that nonomolar concentrations of Taxol and several structurally diverse microtubule (MT)-stabilizing agents significantly enhanced the survival of neurons in the presence of fibrils of amyloid beta peptide (Abeta). Pretreatment of neurons with MT-stabilizing drugs also blocked Abeta-induced activation of tau hyperphosphorylation. Although tau is a substrate for several kinases, we initially focused on cdk5, as this tau kinase has been shown to be activated in Abeta-treated neurons and Alzheimer's disease (AD) brain. In an in vitro kinase assay, Taxol inhibited activation of cdk5 by Abeta. In addition, the proposed cellular cascade in which calpain activation leads to cleavage of the cdk5 regulator, p35, to the strong kinase activator p25 was also prevented. Taxol did not directly inhibit the activity of either cdk5 or calpain, indicating that other cellular components are required for the effect of the drug on Abeta activation of tau phosphorylation. Our results suggest that drugs that interact with MTs can alter signaling events in neurons, possibly because some MTs play a role in organizing protein complexes involved in responses to Abeta. Thus the cytoskeletal network may serve as a biosensor of cellular well-being.

  10. The Drosophila microtubule-associated protein mars stabilizes mitotic spindles by crosslinking microtubules through its N-terminal region.

    Directory of Open Access Journals (Sweden)

    Gang Zhang

    Full Text Available Correct segregation of genetic material relies on proper assembly and maintenance of the mitotic spindle. How the highly dynamic microtubules (MTs are maintained in stable mitotic spindles is a key question to be answered. Motor and non-motor microtubule associated proteins (MAPs have been reported to stabilize the dynamic spindle through crosslinking adjacent MTs. Mars, a novel MAP, is essential for the early development of Drosophila embryos. Previous studies showed that Mars is required for maintaining an intact mitotic spindle but did not provide a molecular mechanism for this function. Here we show that Mars is able to stabilize the mitotic spindle in vivo. Both in vivo and in vitro data reveal that the N-terminal region of Mars functions in the stabilization of the mitotic spindle by crosslinking adjacent MTs.

  11. Oxidative stress decreases microtubule growth and stability in ventricular myocytes.

    Science.gov (United States)

    Drum, Benjamin M L; Yuan, Can; Li, Lei; Liu, Qinghang; Wordeman, Linda; Santana, L Fernando

    2016-04-01

    Microtubules (MTs) have many roles in ventricular myocytes, including structural stability, morphological integrity, and protein trafficking. However, despite their functional importance, dynamic MTs had never been visualized in living adult myocytes. Using adeno-associated viral vectors expressing the MT-associated protein plus end binding protein 3 (EB3) tagged with EGFP, we were able to perform live imaging and thus capture and quantify MT dynamics in ventricular myocytes in real time under physiological conditions. Super-resolution nanoscopy revealed that EB1 associated in puncta along the length of MTs in ventricular myocytes. The vast (~80%) majority of MTs grew perpendicular to T-tubules at a rate of 0.06μm∗s(-1) and growth was preferentially (82%) confined to a single sarcomere. Microtubule catastrophe rate was lower near the Z-line than M-line. Hydrogen peroxide increased the rate of catastrophe of MTs ~7-fold, suggesting that oxidative stress destabilizes these structures in ventricular myocytes. We also quantified MT dynamics after myocardial infarction (MI), a pathological condition associated with increased production of reactive oxygen species (ROS). Our data indicate that the catastrophe rate of MTs increases following MI. This contributed to decreased transient outward K(+) currents by decreasing the surface expression of Kv4.2 and Kv4.3 channels after MI. On the basis of these data, we conclude that, under physiological conditions, MT growth is directionally biased and that increased ROS production during MI disrupts MT dynamics, decreasing K(+) channel trafficking.

  12. Dynamics and regulation of plant interphase microtubules: a comparative view.

    Science.gov (United States)

    Hashimoto, Takashi

    2003-12-01

    Microtubule and actin cytoskeletons are fundamental to a variety of cellular activities within eukaryotic organisms. Extensive information on the dynamics and functions of microtubules, as well as on their regulatory proteins, have been revealed in fungi and animals, and corresponding pictures are now slowly emerging in plants. During interphase, plant cells contain highly dynamic cortical microtubules that organize into ordered arrays, which are apparently regulated by distinct groups of microtubule regulators. Comparison with fungal and animal microtubules highlights both conserved and unique mechanisms for the regulation of the microtubule cytoskeleton in plants.

  13. Mmb1p binds mitochondria to dynamic microtubules

    Science.gov (United States)

    Fu, Chuanhai; Jain, Deeptee; Costa, Judite; Velve-Casquillas, Guilhem; Tran, Phong T.

    2015-01-01

    Summary Background Mitochondria form a dynamics tubular network within the cell. Proper mitochondria movement and distribution are critical for their localized function in cell metabolism, growth, and survival. In mammalian cells, mechanisms of mitochondria positioning appear dependent on the microtubule cytoskeleton, with kinesin or dynein motors carrying mitochondria as cargos and distributing them throughout the microtubule network. Interestingly, the timescale of microtubule dynamics occurs in seconds, and the timescale of mitochondria distribution occurs in minutes. How does the cell couple these two time constants? Results Fission yeast also relies on microtubules for mitochondria distribution. We report here a new microtubule-dependent but motor-independent mechanism for proper mitochondria positioning in fission yeast. We identify the protein mmb1p, which binds to mitochondria and microtubules. Mmb1p attaches the tubular mitochondria to the microtubule lattice at multiple discrete interaction sites. Mmb1 deletion causes mitochondria to aggregate, with the long-term consequence of defective mitochondria distribution and cell death. Mmb1p decreases microtubule dynamicity. Conclusion Mmb1p is a new microtubule-mitochondria binding protein. We propose that mmb1p act to couple long-term mitochondria distribution to short-term microtubule dynamics by attenuating microtubule dynamics, thus enhancing the mitochondria-microtubule interaction time. PMID:21856157

  14. Laminin/β1 integrin signal triggers axon formation by promoting microtubule assembly and stabilization

    Institute of Scientific and Technical Information of China (English)

    Wen-Liang Lei; Shi-Ge Xing; Cai-Yun Deng; Xiang-Chun Ju; Xing-Yu Jiang; Zhen-Ge Luo

    2012-01-01

    Axon specification during neuronal polarization is closely associated with increased microtubule stabilization in one of the neurites of unpolarized neuron,but how this increased microtubule stability is achieved is unclear.Here,we show that extracellular matrix (ECM) component laminin promotes neuronal polarization via regulating directional microtubule assembly through β1 integrin (Itgb1).Contact with laminin coated on culture substrate or polystyrene beads was sufficient for axon specification of undifferentiated neurites in cultured hippocampal neurons and cortical slices.Active Itgb1 was found to be concentrated in laminin-contacting neurites.Axon formation was promoted and abolished by enhancing and attenuating Itgbl signaling,respectively.Interestingly,laminin contact promoted plus-end microtubule assembly in a manner that required Itgbl.Moreover,stabilizing microtubules partially prevented polarization defects caused by ltgbl downregulation.Finally,genetic ablation of ltgbl in dorsal telencephalic progenitors caused deficits in axon development of cortical pyramidal neurons.Thus,laminin/Itgb1 signaling plays an instructive role in axon initiation and growth,both in vitro and in vivo,through the regulation of microtubule assembly.This study has established a linkage between an extrinsic factor and intrinsic cytoskeletai dynamics during neuronal polarization.

  15. Microtubules: dynamically unstable stochastic phase-switching polymers

    Science.gov (United States)

    Zakharov, P. N.; Arzhanik, V. K.; Ulyanov, E. V.; Gudimchuk, N. B.; Ataullakhanov, F. I.

    2016-08-01

    One of the simplest molecular motors, a biological microtubule, is reviewed as an example of a highly nonequilibrium molecular machine capable of stochastic transitions between slow growth and rapid disassembly phases. Basic properties of microtubules are described, and various approaches to simulating their dynamics, from statistical chemical kinetics models to molecular dynamics models using the Metropolis Monte Carlo and Brownian dynamics methods, are outlined.

  16. Long astral microtubules and RACK-1 stabilize polarity domains during maintenance phase in Caenorhabditis elegans embryos.

    Directory of Open Access Journals (Sweden)

    Erkang Ai

    Full Text Available Cell polarity is a very well conserved process important for cell differentiation, cell migration, and embryonic development. After the establishment of distinct cortical domains, polarity cues have to be stabilized and maintained within a fluid and dynamic membrane to achieve proper cell asymmetry. Microtubules have long been thought to deliver the signals required to polarize a cell. While previous studies suggest that microtubules play a key role in the establishment of polarity, the requirement of microtubules during maintenance phase remains unclear. In this study, we show that depletion of Caenorhabditis elegans RACK-1, which leads to short astral microtubules during prometaphase, specifically affects maintenance of cortical PAR domains and Dynamin localization. We then investigated the consequence of knocking down other factors that also abolish astral microtubule elongation during polarity maintenance phase. We found a correlation between short astral microtubules and the instability of PAR-6 and PAR-2 domains during maintenance phase. Our data support a necessary role for astral microtubules in the maintenance phase of cell polarity.

  17. A novel p21-activated kinase binds the actin and microtubule networks and induces microtubule stabilization

    Science.gov (United States)

    Cau, Julien; Faure, Sandrine; Comps, Michel; Delsert, Claude; Morin, Nathalie

    2001-01-01

    Coordination of the different cytoskeleton networks in the cell is of central importance for morphogenesis, organelle transport, and motility. The Rho family proteins are well characterized for their effects on the actin cytoskeleton, but increasing evidence indicates that they may also control microtubule (MT) dynamics. Here, we demonstrate that a novel Cdc42/Rac effector, X-p21-activated kinase (PAK)5, colocalizes and binds to both the actin and MT networks and that its subcellular localization is regulated during cell cycle progression. In transfected cells, X-PAK5 promotes the formation of stabilized MTs that are associated in bundles and interferes with MTs dynamics, slowing both the elongation and shrinkage rates and inducing long paused periods. X-PAK5 subcellular localization is regulated tightly, since coexpression with active Rac or Cdc42 induces its shuttling to actin-rich structures. Thus, X-PAK5 is a novel MT-associated protein that may communicate between the actin and MT networks during cellular responses to environmental conditions. PMID:11733543

  18. Dietary flavonoid fisetin binds to β-tubulin and disrupts microtubule dynamics in prostate cancer cells.

    Science.gov (United States)

    Mukhtar, Eiman; Adhami, Vaqar Mustafa; Sechi, Mario; Mukhtar, Hasan

    2015-10-28

    Microtubule targeting based therapies have revolutionized cancer treatment; however, resistance and side effects remain a major limitation. Therefore, novel strategies that can overcome these limitations are urgently needed. We made a novel discovery that fisetin, a hydroxyflavone, is a microtubule stabilizing agent. Fisetin binds to tubulin and stabilizes microtubules with binding characteristics far superior than paclitaxel. Surface plasmon resonance and computational docking studies suggested that fisetin binds to β-tubulin with superior affinity compared to paclitaxel. Fisetin treatment of human prostate cancer cells resulted in robust up-regulation of microtubule associated proteins (MAP)-2 and -4. In addition, fisetin treated cells were enriched in α-tubulin acetylation, an indication of stabilization of microtubules. Fisetin significantly inhibited PCa cell proliferation, migration, and invasion. Nudc, a protein associated with microtubule motor dynein/dynactin complex that regulates microtubule dynamics, was inhibited with fisetin treatment. Further, fisetin treatment of a P-glycoprotein overexpressing multidrug-resistant cancer cell line NCI/ADR-RES inhibited the viability and colony formation. Our results offer in vitro proof-of-concept for fisetin as a microtubule targeting agent. We suggest that fisetin could be developed as an adjuvant for treatment of prostate and other cancer types. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  19. Effects of spermine binding on Taxol-stabilized microtubules

    Science.gov (United States)

    Cheng, Shengfeng; Regmi, Chola

    Previous studies have shown that polyamines such as spermine present in cells at physiological concentrations can facilitate the polymerization of tubulins into microtubules (MTs). A recent experiment demonstrates that in the presence of high-concentration spermine, Taxol-stabilized MTs undergo a shape transformation into inverted tubulin tubules (ITTs), the outside surface of which corresponds to the inside surface of a regular MT. However, the molecular mechanism underlying the shape transformation of MTs into ITTs is unclear. We perform all atom molecular dynamics simulations on Taxol-stabilized MT sheets containing two protofilaments surrounded by spermine ions. The spermine concentration is varied from 0 to 25mM to match the range probed experimentally. We identify important spermine binding regions on the MT surface and the influence of the spermine binding on the structure and dynamics of MTs. In contrast to Taxol, our results show that spermine binding seems to decrease the flexibility of tubulin proteins, resulting in weaker tubulin-tubulin contacts and promoting the bending of protofilaments into curved protofilaments, inverted rings, and eventually inverted tubules.

  20. Taxol(®): The First Microtubule Stabilizing Agent.

    Science.gov (United States)

    Yang, Chia-Ping Huang; Horwitz, Susan Band

    2017-08-09

    Taxol(®), an antitumor drug with significant activity, is the first microtubule stabilizing agent described in the literature. This short review of the mechanism of action of Taxol(®) emphasizes the research done in the Horwitz' laboratory. It discusses the contribution of photoaffinity labeled analogues of Taxol(®) toward our understanding of the binding site of the drug on the microtubule. The importance of hydrogen/deuterium exchange experiments to further our insights into the stabilization of microtubules by Taxol(®) is addressed. The development of drug resistance, a major problem that arises in the clinic, is discussed. Studies describing differential drug binding to distinct β-tubulin isotypes are presented. Looking forward, it is suggested that the β-tubulin isotype content of a tumor may influence its responses to Taxol(®).

  1. Total synthesis of the potent microtubule-stabilizing agent (+)-discodermolide.

    Science.gov (United States)

    Harried, Scott S; Lee, Christopher P; Yang, Ge; Lee, Tony I H; Myles, David C

    2003-08-22

    The total synthesis of the potent microtubule-stabilizing, antimitotic agent (+)-discodermolide is described. The convergent synthetic strategy takes advantage of the diastereoselective alkylation of a ketone enolate to establish the key C15-C16 bond. The synthesis is amenable to preparation of gram-scale quantities of (+)-discodermolide and analogues.

  2. Direct Modulation of Microtubule Stability Contributes to Anthracene General Anesthesia

    Science.gov (United States)

    Emerson, Daniel J.; Weiser, Brian P.; Psonis, John; Liao, Zhengzheng; Taratula, Olena; Fiamengo, Ashley; Wang, Xiaozhao; Sugasawa, Keizo; Smith, Amos B.; Eckenhoff, Roderic G; Dmochowski, Ivan J.

    2013-01-01

    Recently, we identified 1-aminoanthracene as a fluorescent general anesthetic. To investigate the mechanism of action, a photoactive analogue, 1-azidoanthracene, was synthesized. Administration of 1-azidoanthracene to albino stage 40–47 tadpoles was found to immobilize animals upon near-UV irradiation of the forebrain region. The immobilization was often reversible, but it was characterized by a longer duration consistent with covalent attachment of the ligand to functionally important targets. IEF/SDS-PAGE examination of irradiated tadpole brain homogenate revealed labeled protein, identified by mass spectrometry as β-tubulin. In vitro assays with aminoanthracene-cross-linked tubulin indicated inhibition of microtubule polymerization, similar to colchicine. Tandem mass spectrometry confirmed anthracene binding near the colchicine site. Stage 40–47 tadpoles were also incubated 1 h with microtubule stabilizing agents, epothilone D or discodermolide, followed by dosing with 1-aminoanthracene. The effective concentration of 1-aminoanthracene required to immobilize the tadpoles was significantly increased in the presence of either microtubule stabilizing agent. Epothilone D similarly mitigated the effects of a clinical neurosteroid general anesthetic, allopregnanolone, believed to occupy the colchicine site in tubulin. We conclude that neuronal microtubules are “on-pathway” targets for anthracene general anesthetics and may also represent functional targets for some neurosteroid general anesthetics. PMID:23484901

  3. Microtubule dynamics in the peripheral nervous system: A matter of balance.

    Science.gov (United States)

    Almeida-Souza, Leonardo; Timmerman, Vincent; Janssens, Sophie

    2011-11-01

    The special architecture of neurons in the peripheral nervous system, with axons extending for long distances, represents a major challenge for the intracellular transport system. Two recent studies show that mutations in the small heat shock protein HSPB1, which cause an axonal type of Charcot-Marie-Tooth (CMT) neuropathy, affect microtubule dynamics and impede axonal transport. Intriguingly, while at presymptomatic age the neurons in the mutant HSPB1 mouse show a hyperstable microtubule network, at postsymptomatic age, the microtubule network completely lost its stability as reflected by a marked decrease in tubulin acetylation levels. We here propose a model explaining the role of microtubule stabilization and tubulin acetylation in the pathogenesis of HSPB1 mutations.

  4. Aurora B suppresses microtubule dynamics and limits central spindle size by locally activating KIF4A

    Science.gov (United States)

    Nunes Bastos, Ricardo; Gandhi, Sapan R.; Baron, Ryan D.; Gruneberg, Ulrike; Nigg, Erich A.

    2013-01-01

    Anaphase central spindle formation is controlled by the microtubule-stabilizing factor PRC1 and the kinesin KIF4A. We show that an MKlp2-dependent pool of Aurora B at the central spindle, rather than global Aurora B activity, regulates KIF4A accumulation at the central spindle. KIF4A phosphorylation by Aurora B stimulates the maximal microtubule-dependent ATPase activity of KIF4A and promotes its interaction with PRC1. In the presence of phosphorylated KIF4A, microtubules grew more slowly and showed long pauses in growth, resulting in the generation of shorter PRC1-stabilized microtubule overlaps in vitro. Cells expressing only mutant forms of KIF4A lacking the Aurora B phosphorylation site overextended the anaphase central spindle, demonstrating that this regulation is crucial for microtubule length control in vivo. Aurora B therefore ensures that suppression of microtubule dynamic instability by KIF4A is restricted to a specific subset of microtubules and thereby contributes to central spindle size control in anaphase. PMID:23940115

  5. The Role of Molecular Microtubule Motors and the Microtubule Cytoskeleton in Stress Granule Dynamics

    Directory of Open Access Journals (Sweden)

    Kristen M. Bartoli

    2011-01-01

    Full Text Available Stress granules (SGs are cytoplasmic foci that appear in cells exposed to stress-induced translational inhibition. SGs function as a triage center, where mRNAs are sorted for storage, degradation, and translation reinitiation. The underlying mechanisms of SGs dynamics are still being characterized, although many key players have been identified. The main components of SGs are stalled 48S preinitiation complexes. To date, many other proteins have also been found to localize in SGs and are hypothesized to function in SG dynamics. Most recently, the microtubule cytoskeleton and associated motor proteins have been demonstrated to function in SG dynamics. In this paper, we will discuss current literature examining the function of microtubules and the molecular microtubule motors in SG assembly, coalescence, movement, composition, organization, and disassembly.

  6. Polo-like kinase-1 regulates kinetochore–microtubule dynamics and spindle checkpoint silencing

    Science.gov (United States)

    Liu, Dan; Davydenko, Olga

    2012-01-01

    Polo-like kinase-1 (Plk1) is a highly conserved kinase with multiple mitotic functions. Plk1 localizes to prometaphase kinetochores and is reduced at metaphase kinetochores, similar to many checkpoint signaling proteins, but Plk1 is not required for spindle checkpoint function. Plk1 is also implicated in stabilizing kinetochore–microtubule attachments, but these attachments are most stable when kinetochore Plk1 levels are low at metaphase. Therefore, it is unclear how Plk1 function at kinetochores can be understood in the context of its dynamic localization. In this paper, we show that Plk1 activity suppresses kinetochore–microtubule dynamics to stabilize initial attachments in prometaphase, and Plk1 removal from kinetochores is necessary to maintain dynamic microtubules in metaphase. Constitutively targeting Plk1 to kinetochores maintained high activity at metaphase, leading to reduced interkinetochore tension and intrakinetochore stretch, a checkpoint-dependent mitotic arrest, and accumulation of microtubule attachment errors. Together, our data show that Plk1 dynamics at kinetochores control two critical mitotic processes: initially establishing correct kinetochore–microtubule attachments and subsequently silencing the spindle checkpoint. PMID:22908307

  7. Nonlinear dynamics of C-terminal tails in cellular microtubules

    Science.gov (United States)

    Sekulic, Dalibor L.; Sataric, Bogdan M.; Zdravkovic, Slobodan; Bugay, Aleksandr N.; Sataric, Miljko V.

    2016-07-01

    The mechanical and electrical properties, and information processing capabilities of microtubules are the permanent subject of interest for carrying out experiments in vitro and in silico, as well as for theoretical attempts to elucidate the underlying processes. In this paper, we developed a new model of the mechano-electrical waves elicited in the rows of very flexible C-terminal tails which decorate the outer surface of each microtubule. The fact that C-terminal tails play very diverse roles in many cellular functions, such as recruitment of motor proteins and microtubule-associated proteins, motivated us to consider their collective dynamics as the source of localized waves aimed for communication between microtubule and associated proteins. Our approach is based on the ferroelectric liquid crystal model and it leads to the effective asymmetric double-well potential which brings about the conditions for the appearance of kink-waves conducted by intrinsic electric fields embedded in microtubules. These kinks can serve as the signals for control and regulation of intracellular traffic along microtubules performed by processive motions of motor proteins, primarly from kinesin and dynein families. On the other hand, they can be precursors for initiation of dynamical instability of microtubules by recruiting the proper proteins responsible for the depolymerization process.

  8. The von Hippel-Lindau tumor suppressor protein influences microtubule dynamics at the cell periphery.

    NARCIS (Netherlands)

    Lolkema, M.P.; Mehra, N.; Jorna, A.S.; Beest, M. van; Giles, R.H.; Voest, E.E.

    2004-01-01

    The von Hippel-Lindau (VHL) protein protects microtubules (MTs) from destabilization by nocodazole treatment. Based on this fixed-cell assay with static end points, VHL has been reported to directly stabilize the MT cytoskeleton. To investigate the dynamic changes in MTs induced by VHL in living cel

  9. Alterations in ovarian cancer cell adhesion drive taxol resistance by increasing microtubule dynamics in a FAK-dependent manner.

    Science.gov (United States)

    McGrail, Daniel J; Khambhati, Niti N; Qi, Mark X; Patel, Krishan S; Ravikumar, Nithin; Brandenburg, Chandler P; Dawson, Michelle R

    2015-04-17

    Chemorefractory ovarian cancer patients show extremely poor prognosis. Microtubule-stabilizing Taxol (paclitaxel) is a first-line treatment against ovarian cancer. Despite the close interplay between microtubules and cell adhesion, it remains unknown if chemoresistance alters the way cells adhere to their extracellular environment, a process critical for cancer metastasis. To investigate this, we isolated Taxol-resistant populations of OVCAR3 and SKOV3 ovarian cancer cell lines. Though Taxol-resistant cells neither effluxed more drug nor gained resistance to other chemotherapeutics, they did display increased microtubule dynamics. These changes in microtubule dynamics coincided with faster attachment rates and decreased adhesion strength, which correlated with increased surface β1-integrin expression and decreased focal adhesion formation, respectively. Adhesion strength correlated best with Taxol-sensitivity, and was found to be independent of microtubule polymerization but dependent on focal adhesion kinase (FAK), which was up-regulated in Taxol-resistant cells. FAK inhibition also decreased microtubule dynamics to equal levels in both populations, indicating alterations in adhesive signaling are up-stream of microtubule dynamics. Taken together, this work demonstrates that Taxol-resistance dramatically alters how ovarian cancer cells adhere to their extracellular environment causing down-stream increases in microtubule dynamics, providing a therapeutic target that may improve prognosis by not only recovering drug sensitivity, but also decreasing metastasis.

  10. Nonlinear dynamics of C–terminal tails in cellular microtubules

    Energy Technology Data Exchange (ETDEWEB)

    Sekulic, Dalibor L., E-mail: dalsek@uns.ac.rs; Sataric, Bogdan M.; Sataric, Miljko V. [University of Novi Sad, Faculty of Technical Sciences, Novi Sad (Serbia); Zdravkovic, Slobodan [University of Belgrade, Institute of Nuclear Sciences Vinca, Belgrade (Serbia); Bugay, Aleksandr N. [Laboratory of Radiation Biology, Joint Institute for Nuclear Research, Dubna (Russian Federation)

    2016-07-15

    The mechanical and electrical properties, and information processing capabilities of microtubules are the permanent subject of interest for carrying out experiments in vitro and in silico, as well as for theoretical attempts to elucidate the underlying processes. In this paper, we developed a new model of the mechano–electrical waves elicited in the rows of very flexible C–terminal tails which decorate the outer surface of each microtubule. The fact that C–terminal tails play very diverse roles in many cellular functions, such as recruitment of motor proteins and microtubule–associated proteins, motivated us to consider their collective dynamics as the source of localized waves aimed for communication between microtubule and associated proteins. Our approach is based on the ferroelectric liquid crystal model and it leads to the effective asymmetric double-well potential which brings about the conditions for the appearance of kink–waves conducted by intrinsic electric fields embedded in microtubules. These kinks can serve as the signals for control and regulation of intracellular traffic along microtubules performed by processive motions of motor proteins, primarly from kinesin and dynein families. On the other hand, they can be precursors for initiation of dynamical instability of microtubules by recruiting the proper proteins responsible for the depolymerization process.

  11. Sulfo-SMCC Prevents Annealing of Taxol-Stabilized Microtubules In Vitro

    CERN Document Server

    Prabhune, Meenakshi; Schmidt, Christoph F

    2015-01-01

    Microtubule structure and functions have been widely studied in vitro and in cells. Research has shown that cysteines on tubulin play a crucial role in the polymerization of microtubules. Here, we show that blocking sulfhydryl groups of cysteines in taxol-stabilized polymerized microtubules with a commonly used chemical crosslinker prevents temporal end-to-end annealing of microtubules in vitro. This can dramatically affect the length distribution of the microtubules. The crosslinker sulfosuccinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate, sulfo-SMCC, consists of a maleimide and a N-hydroxysuccinimide ester group to bind to sulfhydryl groups and primary amines, respectively. Interestingly, addition of a maleimide dye alone does not show the same prevention of annealing in stabilized microtubules. This study shows that the sulfhydryl groups of cysteines of tubulin that are vital for the polymerization are also important for the subsequent annealing of microtubules.

  12. Modeling the Effects of Drug Binding on the Dynamic Instability of Microtubules

    CERN Document Server

    Hinow, Peter; Lopus, Manu; Jordan, Mary Ann; Tuszynski, Jack A

    2010-01-01

    We propose a stochastic model that accounts for the growth, catastrophe and rescue processes of steady state microtubules assembled from MAP-free tubulin. Both experimentally and theoretically we study the perturbation of microtubule dynamic instability by S-methyl-D-DM1, a synthetic derivative of the microtubule-targeted agent maytansine and a potential anticancer agent. We find that to be an effective suppressor of microtubule dynamics a drug must primarily suppress the loss of GDP tubulin from the microtubule tip.

  13. Synergistic suppression of microtubule dynamics by discodermolide and paclitaxel in non-small cell lung carcinoma cells.

    Science.gov (United States)

    Honore, Stéphane; Kamath, Kathy; Braguer, Diane; Horwitz, Susan Band; Wilson, Leslie; Briand, Claudette; Jordan, Mary Ann

    2004-07-15

    Discodermolide is a new microtubule-targeted antimitotic drug in Phase I clinical trials that, like paclitaxel, stabilizes microtubule dynamics and enhances microtubule polymer mass in vitro and in cells. Despite their apparently similar binding sites on microtubules, discodermolide acts synergistically with paclitaxel to inhibit proliferation of A549 human lung cancer cells (L. Martello et al., Clin. Cancer Res., 6: 1978-1987, 2000). To understand their synergy, we examined the effects of the two drugs singly and in combination in A549 cells and found that, surprisingly, their antiproliferative synergy is related to their ability to synergistically inhibit microtubule dynamic instability and mitosis. The combination of discodermolide and paclitaxel at their antiproliferative IC(50)s (7 nm for discodermolide and 2 nm for paclitaxel) altered all of the parameters of dynamic instability synergistically except the time-based rescue frequency. For example, together the drugs inhibited overall microtubule dynamicity by 71%, but each drug individually inhibited dynamicity by only 24%, giving a combination index (CI) of 0.23. Discodermolide and paclitaxel also synergistically blocked cell cycle progression at G(2)-M (41, 9.6, and 16% for both drugs together, for discodermolide alone, and for paclitaxel alone, respectively; CI = 0.59), and they synergistically enhanced apoptosis (CI = 0.85). Microtubules are unique receptors for drugs. The results suggest that ligands that bind to large numbers of binding sites on an individual microtubule can interact in a poorly understood manner to synergistically suppress microtubule dynamic instability and inhibit both mitosis and cell proliferation, with important consequences for combination clinical therapy with microtubule-targeted drugs.

  14. Conformational mechanism for the stability of microtubule-kinetochore attachments

    CERN Document Server

    Bertalan, Zsolt; Maiato, Helder; Zapperi, Stefano

    2014-01-01

    Regulating the stability of microtubule(MT)-kinetochore attachments is fundamental to avoiding mitotic errors and ensure proper chromosome segregation during cell division. While biochemical factors involved in this process have been identified, its mechanics still needs to be better understood. Here we introduce and simulate a mechanical model of MT-kinetochore interactions in which the stability of the attachment is ruled by the geometrical conformations of curling MT-protofilaments entangled in kinetochore fibrils. The model allows us to reproduce with good accuracy in vitro experimental measurements of the detachment times of yeast kinetochores from MTs under external pulling forces. Numerical simulations suggest that geometrical features of MT-protofilaments may play an important role in the switch between stable and unstable attachments.

  15. Changes in microtubule stability and density in myelin-deficient shiverer mouse CNS axons

    Science.gov (United States)

    Kirkpatrick, L. L.; Witt, A. S.; Payne, H. R.; Shine, H. D.; Brady, S. T.

    2001-01-01

    Altered axon-Schwann cell interactions in PNS myelin-deficient Trembler mice result in changed axonal transport rates, neurofilament and microtubule-associated protein phosphorylation, neurofilament density, and microtubule stability. To determine whether PNS and CNS myelination have equivalent effects on axons, neurofilaments, and microtubules in CNS, myelin-deficient shiverer axons were examined. The genetic defect in shiverer is a deletion in the myelin basic protein (MBP) gene, an essential component of CNS myelin. As a result, shiverer mice have little or no compact CNS myelin. Slow axonal transport rates in shiverer CNS axons were significantly increased, in contrast to the slowing in demyelinated PNS nerves. Even more striking were substantial changes in the composition and properties of microtubules in shiverer CNS axons. The density of axonal microtubules is increased, reflecting increased expression of tubulin in shiverer, and the stability of microtubules is drastically reduced in shiverer axons. Shiverer transgenic mice with two copies of a wild-type myelin basic protein transgene have an intermediate level of compact myelin, making it possible to determine whether the actual level of compact myelin is an important regulator of axonal microtubules. Both increased microtubule density and reduced microtubule stability were still observed in transgenic mouse nerves, indicating that signals beyond synaptogenesis and the mere presence of compact myelin are required for normal regulation of the axonal microtubule cytoskeleton.

  16. Dietary flavonoid fisetin binds to β-tubulin and disrupts microtubule dynamics in prostate cancer cells

    OpenAIRE

    Mukhtar, Eiman; Adhami, Vaqar Mustafa; Sechi, Mario; Mukhtar, Hasan

    2015-01-01

    Microtubule targeting based therapies have revolutionized cancer treatment; however, resistance and side effects remain a major limitation. Therefore, novel strategies that can overcome these limitations are urgently needed. We made a novel discovery that fisetin, a hydroxyflavone, is a microtubule stabilizing agent. Fisetin binds to tubulin and stabilizes microtubules with binding characteristics far superior than paclitaxel. Surface plasmon resonance and computational docking studies sugges...

  17. Dietary flavonoid fisetin binds to β-tubulin and disrupts microtubule dynamics in prostate cancer cells

    OpenAIRE

    Mukhtar, Eiman; Adhami, Vaqar Mustafa; Sechi, Mario; Mukhtar, Hasan

    2015-01-01

    Microtubule targeting based therapies have revolutionized cancer treatment; however, resistance and side effects remain a major limitation. Therefore, novel strategies that can overcome these limitations are urgently needed. We made a novel discovery that fisetin, a hydroxyflavone, is a microtubule stabilizing agent. Fisetin binds to tubulin and stabilizes microtubules with binding characteristics far superior than paclitaxel. Surface plasmon resonance and computational docking studies sugges...

  18. Tank binding kinase 1 is a centrosome-associated kinase necessary for microtubule dynamics and mitosis.

    Science.gov (United States)

    Pillai, Smitha; Nguyen, Jonathan; Johnson, Joseph; Haura, Eric; Coppola, Domenico; Chellappan, Srikumar

    2015-12-10

    TANK Binding Kinase 1 (TBK1) is a non-canonical IκB kinase that contributes to KRAS-driven lung cancer. Here we report that TBK1 plays essential roles in mammalian cell division. Specifically, levels of active phospho-TBK1 increase during mitosis and localize to centrosomes, mitotic spindles and midbody, and selective inhibition or silencing of TBK1 triggers defects in spindle assembly and prevents mitotic progression. TBK1 binds to the centrosomal protein CEP170 and to the mitotic apparatus protein NuMA, and both CEP170 and NuMA are TBK1 substrates. Further, TBK1 is necessary for CEP170 centrosomal localization and binding to the microtubule depolymerase Kif2b, and for NuMA binding to dynein. Finally, selective disruption of the TBK1-CEP170 complex augments microtubule stability and triggers defects in mitosis, suggesting that TBK1 functions as a mitotic kinase necessary for microtubule dynamics and mitosis.

  19. Microtubule-stabilizing agents as potential therapeutics for neurodegenerative disease.

    Science.gov (United States)

    Brunden, Kurt R; Trojanowski, John Q; Smith, Amos B; Lee, Virginia M-Y; Ballatore, Carlo

    2014-09-15

    Microtubules (MTs), cytoskeletal elements found in all mammalian cells, play a significant role in cell structure and in cell division. They are especially critical in the proper functioning of post-mitotic central nervous system neurons, where MTs serve as the structures on which key cellular constituents are trafficked in axonal projections. MTs are stabilized in axons by the MT-associated protein tau, and in several neurodegenerative diseases, including Alzheimer's disease, frontotemporal lobar degeneration, and Parkinson's disease, tau function appears to be compromised due to the protein dissociating from MTs and depositing into insoluble inclusions referred to as neurofibrillary tangles. This loss of tau function is believed to result in alterations of MT structure and function, resulting in aberrant axonal transport that likely contributes to the neurodegenerative process. There is also evidence of axonal transport deficiencies in other neurodegenerative diseases, including amyotrophic lateral sclerosis and Huntington's disease, which may result, at least in part, from MT alterations. Accordingly, a possible therapeutic strategy for such neurodegenerative conditions is to treat with MT-stabilizing agents, such as those that have been used in the treatment of cancer. Here, we review evidence of axonal transport and MT deficiencies in a number of neurodegenerative diseases, and summarize the various classes of known MT-stabilizing agents. Finally, we highlight the growing evidence that small molecule MT-stabilizing agents provide benefit in animal models of neurodegenerative disease and discuss the desired features of such molecules for the treatment of these central nervous system disorders.

  20. Nonlinear Dynamics of Dipoles in Microtubules: Pseudo-Spin Model

    CERN Document Server

    Nesterov, Alexander I; Berman, Gennady P; Mavromatos, Nick E

    2016-01-01

    We perform a theoretical study of the dynamics of the electric field excitations in a microtubule by taking into consideration the realistic cylindrical geometry, dipole-dipole interactions of the tubulin-based protein heterodimers, the radial electric field produced by the solvent, and a possible degeneracy of energy states of individual heterodimers. The consideration is done in the frames of the classical pseudo-spin model. We derive the system of nonlinear dynamical ordinary differential equations of motion for interacting dipoles, and the continuum version of these equations. We obtain the solutions of these equations in the form of snoidal waves, solitons, kinks, and localized spikes. Our results will help to a better understanding of the functional properties of microtubules including the motor protein dynamics and the information transfer processes. Our considerations are based on classical dynamics. Some speculations on the role of possible quantum effects are also made.

  1. Nonlinear dynamics of dipoles in microtubules: Pseudospin model.

    Science.gov (United States)

    Nesterov, Alexander I; Ramírez, Mónica F; Berman, Gennady P; Mavromatos, Nick E

    2016-06-01

    We perform a theoretical study of the dynamics of the electric field excitations in a microtubule by taking into consideration the realistic cylindrical geometry, dipole-dipole interactions of the tubulin-based protein heterodimers, the radial electric field produced by the solvent, and a possible degeneracy of energy states of individual heterodimers. The consideration is done in the frame of the classical pseudospin model. We derive the system of nonlinear dynamical partial differential equations of motion for interacting dipoles and the continuum version of these equations. We obtain the solutions of these equations in the form of snoidal waves, solitons, kinks, and localized spikes. Our results will help to achieve a better understanding of the functional properties of microtubules including the motor protein dynamics and the information transfer processes. Our considerations are based on classical dynamics. Some speculations on the role of possible quantum effects are also made.

  2. Suppression of microtubule dynamics by discodermolide by a novel mechanism is associated with mitotic arrest and inhibition of tumor cell proliferation.

    Science.gov (United States)

    Honore, Stéphane; Kamath, Kathy; Braguer, Diane; Wilson, Leslie; Briand, Claudette; Jordan, Mary Ann

    2003-12-01

    Discodermolide is a new microtubule-targeted drug in Phase I clinical trials that inhibits tumor growth and induces G(2)-M cell cycle arrest. It is effective against paclitaxel-resistant cell lines and acts synergistically in combination with paclitaxel. Suppression of microtubule dynamics by microtubule-targeted drugs has been hypothesized to be responsible for their ability to inhibit mitotic progression and cell proliferation. To determine whether discodermolide blocks mitosis by an effect on microtubule dynamics, we analyzed the effects of discodermolide on microtubule dynamics in living A549 human lung cancer cells during interphase at concentrations that block mitosis and inhibit cell proliferation. We found that discodermolide (7-166 nM) significantly suppressed microtubule dynamic instability. At the IC(50) for proliferation (7 nM discodermolide, 72 h), overall dynamicity was reduced by 23%. The principal parameters of dynamic instability suppressed by discodermolide were the microtubule shortening rate and length shortened. In addition, discodermolide markedly increased the frequency of rescued catastrophes. At the discodermolide concentration that resulted in 50% of maximal mitotic block (83 nM, 20 h), most microtubules were completely non-dynamic, no anaphases occurred, and all spindles were abnormal. The dynamicity of the remaining dynamic microtubules was reduced by 62%. The results indicate that a principal mechanism of inhibition of cell proliferation and mitotic block by discodermolide is suppression of microtubule dynamics. Importantly, the results indicate significant additional stabilizing effects of discodermolide on microtubule dynamics as compared with those of paclitaxel that may in turn reflect differences in their binding sites and their effects on tubulin conformation.

  3. EWSR1 regulates mitosis by dynamically influencing microtubule acetylation.

    Science.gov (United States)

    Wang, Yi-Long; Chen, Hui; Zhan, Yi-Qun; Yin, Rong-Hua; Li, Chang-Yan; Ge, Chang-Hui; Yu, Miao; Yang, Xiao-Ming

    2016-08-17

    EWSR1, participating in transcription and splicing, has been identified as a translocation partner for various transcription factors, resulting in translocation, which in turn plays crucial roles in tumorigenesis. Recent studies have investigated the role of EWSR1 in mitosis. However, the effect of EWSR1 on mitosis is poorly understood. Here, we observed that depletion of EWSR1 resulted in cell cycle arrest in the mitotic phase, mainly due to an increase in the time from nuclear envelope breakdown to metaphase, resulting in a high percentage of unaligned chromosomes and multipolar spindles. We also demonstrated that EWSR1 is a spindle-associated protein that interacts with α-tubulin during mitosis. EWSR1 depletion increased the cold-sensitivity of spindle microtubules, and decreased the rate of spindle assembly. EWSR1 regulated the level of microtubule acetylation in the mitotic spindle; microtubule acetylation was rescued in EWSR1-depleted mitotic cells following suppression of HDAC6 activity by its specific inhibitor or siRNA treatment. In summary, these results suggest that EWSR1 regulates the acetylation of microtubules in a cell cycle-dependent manner through its dynamic location on spindle MTs, and may be a novel regulator for mitosis progress independent of its translocation.

  4. ErbB2-dependent chemotaxis requires microtubule capture and stabilization coordinated by distinct signaling pathways.

    Directory of Open Access Journals (Sweden)

    Khedidja Benseddik

    Full Text Available Activation of the ErbB2 receptor tyrosine kinase stimulates breast cancer cell migration. Cell migration is a complex process that requires the synchronized reorganization of numerous subcellular structures including cell-to-matrix adhesions, the actin cytoskeleton and microtubules. How the multiple signaling pathways triggered by ErbB2 coordinate, in time and space, the various processes involved in cell motility, is poorly defined. We investigated the mechanism whereby ErbB2 controls microtubules and chemotaxis. We report that activation of ErbB2 increased both cell velocity and directed migration. Impairment of the Cdc42 and RhoA GTPases, but not of Rac1, prevented the chemotactic response. RhoA is a key component of the Memo/ACF7 pathway whereby ErbB2 controls microtubule capture at the leading edge. Upon Memo or ACF7 depletion, microtubules failed to reach the leading edge and cells lost their ability to follow the chemotactic gradient. Constitutive ACF7 targeting to the membrane in Memo-depleted cells reestablished directed migration. ErbB2-mediated activation of phospholipase C gamma (PLCγ also contributed to cell guidance. We further showed that PLCγ signaling, via classical protein kinases C, and Memo signaling converged towards a single pathway controlling the microtubule capture complex. Finally, inhibiting the PI3K/Akt pathway did not affect microtubule capture, but disturbed microtubule stability, which also resulted in defective chemotaxis. PI3K/Akt-dependent stabilization of microtubules involved repression of GSK3 activity on the one hand and inhibition of the microtubule destabilizing protein, Stathmin, on the other hand. Thus, ErbB2 triggers distinct and complementary pathways that tightly coordinate microtubule capture and microtubule stability to control chemotaxis.

  5. A mutation of the fission yeast EB1 overcomes negative regulation by phosphorylation and stabilizes microtubules

    Energy Technology Data Exchange (ETDEWEB)

    Iimori, Makoto; Ozaki, Kanako [Graduate School of Biostudies, Kyoto University, Kitashirakawa-Oiwake cho, Sakyo ku, Kyoto, 606-8502 (Japan); Chikashige, Yuji [Kobe Advanced ICT Research Center, National Institute of Information and Communications Technology, Kobe, 651-2492 (Japan); Habu, Toshiyuki [Graduate School of Biostudies, Kyoto University, Kitashirakawa-Oiwake cho, Sakyo ku, Kyoto, 606-8502 (Japan); Radiation Biology Center, Kyoto University, Yoshida-Konoe cho, Sakyo ku, Kyoto, 606-8501 (Japan); Hiraoka, Yasushi [Kobe Advanced ICT Research Center, National Institute of Information and Communications Technology, Kobe, 651-2492 (Japan); Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita, 565-0871 (Japan); Maki, Takahisa; Hayashi, Ikuko [Graduate School of Nanobioscience, Yokohama City University, Tsurumi, Yokohama, 230-0045 (Japan); Obuse, Chikashi [Graduate School of Life Science, Hokkaido University, Sapporo 001-0021 (Japan); Matsumoto, Tomohiro, E-mail: tmatsumo@house.rbc.kyoto-u.ac.jp [Graduate School of Biostudies, Kyoto University, Kitashirakawa-Oiwake cho, Sakyo ku, Kyoto, 606-8502 (Japan); Radiation Biology Center, Kyoto University, Yoshida-Konoe cho, Sakyo ku, Kyoto, 606-8501 (Japan)

    2012-02-01

    Mal3 is a fission yeast homolog of EB1, a plus-end tracking protein (+ TIP). We have generated a mutation (89R) replacing glutamine with arginine in the calponin homology (CH) domain of Mal3. Analysis of the 89R mutant in vitro has revealed that the mutation confers a higher affinity to microtubules and enhances the intrinsic activity to promote the microtubule-assembly. The mutant Mal3 is no longer a + TIP, but binds strongly the microtubule lattice. Live cell imaging has revealed that while the wild type Mal3 proteins dissociate from the tip of the growing microtubules before the onset of shrinkage, the mutant Mal3 proteins persist on microtubules and reduces a rate of shrinkage after a longer pausing period. Consequently, the mutant Mal3 proteins cause abnormal elongation of microtubules composing the spindle and aster. Mal3 is phosphorylated at a cluster of serine/threonine residues in the linker connecting the CH and EB1-like C-terminal motif domains. The phosphorylation occurs in a microtubule-dependent manner and reduces the affinity of Mal3 to microtubules. We propose that because the 89R mutation is resistant to the effect of phosphorylation, it can associate persistently with microtubules and confers a stronger stability of microtubules likely by reinforcing the cylindrical structure. -- Highlights: Black-Right-Pointing-Pointer We characterize a mutation (mal3-89R) in fission yeast homolog of EB1. Black-Right-Pointing-Pointer The mutation enhances the activity to assemble microtubules. Black-Right-Pointing-Pointer Mal3 is phosphorylated in a microtubule-dependent manner. Black-Right-Pointing-Pointer The phosphorylation negatively regulates the Mal3 activity.

  6. Structural microtubule cap: Stability, catastrophe, rescue, and third state

    DEFF Research Database (Denmark)

    Flyvbjerg, H.; Chretien, D.; Janosi, I.M.

    2002-01-01

    Microtubules polymerize from GTP-liganded tubulin dinners, but are essentially made of GDP-liganded tubulin. We investigate the tug-of-war resulting from the fact that GDP-liganded tubulin favors a curved configuration, but is forced to remain in a straight one when part of a microtubule. We point...... of two well-established facts: protofilaments made of GDP-liganded tubulin have intrinsic curvature, and microtubules are elastic, made from material that can yield to forces, in casu its own intrinsic forces. We explore possible properties of this structural cap, and demonstrate 1) how it allows both...

  7. The microtubule stabilizing agent discodermolide is a potent inducer of accelerated cell senescence.

    Science.gov (United States)

    Klein, Laura E; Freeze, B Scott; Smith, Amos B; Horwitz, Susan Band

    2005-03-01

    Discodermolide is a microtubule stabilizing agent that suppresses dynamic instability and blocks cells in mitosis. Selection of A549 nonsmall cell lung carcinoma cells with increasing concentrations of discodermolide yielded a clone that proliferated in 8 nM. When these cells were exposed to any concentration greater than 8 nM, replication ceased and the cells developed a flattened, enlarged, granular morphology. Accelerated senescence was demonstrated by a functional beta-galactosidase activity at pH 6. When parental A549 cells were treated with IC50-concentrations of doxorubicin, Taxol or discodermolide, the latter two drugs quickly produced aberrant mitosis. However, discodermolide, but not Taxol, also produced a large increase in senescence-associated beta-galactosidase activity and altered levels of known senescence markers. Although some of these differences between Taxol and discodermolide were dose dependent, only discodermolide produced a doxorubicin-like induction of a senescence phenotype, including a senescence-associated beta-galactosidase activity, up-regulation of PAI-1 and p66Shc, and a strong, sustained, Erk1/2 activation. This research provides insights into the mechanism of action of discodermolide and provides the first demonstration of a microtubule stabilizing agent that inhibits tumor cell growth with a powerful induction of accelerated senescence.

  8. Kinetochore microtubule dynamics and the metaphase-anaphase transition.

    Science.gov (United States)

    Zhai, Y; Kronebusch, P J; Borisy, G G

    1995-11-01

    We have quantitatively studied the dynamic behavior of kinetochore fiber microtubules (kMTs); both turnover and poleward transport (flux) in metaphase and anaphase mammalian cells by fluorescence photoactivation. Tubulin derivatized with photoactivatable fluorescein was microinjected into prometaphase LLC-PK and PtK1 cells and allowed to incorporate to steady-state. A fluorescent bar was generated across the MTs in a half-spindle of the mitotic cells using laser irradiation and the kinetics of fluorescence redistribution were determined in terms of a double exponential decay process. The movement of the activated zone was also measured along with chromosome movement and spindle elongation. To investigate the possible regulation of MT transport at the metaphase-anaphase transition, we performed double photoactivation analyses on the same spindles as the cell advanced from metaphase to anaphase. We determined values for the turnover of kMTs (t1/2 = 7.1 +/- 2.4 min at 30 degrees C) and demonstrated that the turnover of kMTs in metaphase is approximately an order of magnitude slower than that for non-kMTs. In anaphase, kMTs become dramatically more stable as evidenced by a fivefold increase in the fluorescence redistribution half-time (t1/2 = 37.5 +/- 8.5 min at 30 degrees C). Our results also indicate that MT transport slows abruptly at anaphase onset to one-half the metaphase value. In early anaphase, MT depolymerization at the kinetochore accounted, on average, for 84% of the rate of chromosome movement toward the pole whereas the relative contribution of MT transport and depolymerization at the pole contributed 16%. These properties reflect a dramatic shift in the dynamic behavior of kMTs at the metaphase-anaphase transition. A release-capture model is presented in which the stability of kMTs is increased at the onset of anaphase through a reduction in the probability of MT release from the kinetochore. The reduction in MT transport at the metaphase

  9. An epigenetic regulator emerges as microtubule minus-end binding and stabilizing factor in mitosis

    OpenAIRE

    Meunier, Sylvain; Shvedunova, Maria; Van Nguyen, Nhuong; Ávila, Leonor; Vernos, Isabelle; Akhtar, Asifa

    2015-01-01

    The evolutionary conserved NSL complex is a prominent epigenetic regulator controlling expression of thousands of genes. Here we uncover a novel function of the NSL complex members in mitosis. As the cell enters mitosis, KANSL1 and KANSL3 undergo a marked relocalisation from the chromatin to the mitotic spindle. By stabilizing microtubule minus ends in a RanGTP-dependent manner, they are essential for spindle assembly and chromosome segregation. Moreover, we identify KANSL3 as a microtubule m...

  10. Statistical mechanics provides novel insights into microtubule stability and mechanism of shrinkage.

    Science.gov (United States)

    Jain, Ishutesh; Inamdar, Mandar M; Padinhateeri, Ranjith

    2015-02-01

    Microtubules are nano-machines that grow and shrink stochastically, making use of the coupling between chemical kinetics and mechanics of its constituent protofilaments (PFs). We investigate the stability and shrinkage of microtubules taking into account inter-protofilament interactions and bending interactions of intrinsically curved PFs. Computing the free energy as a function of PF tip position, we show that the competition between curvature energy, inter-PF interaction energy and entropy leads to a rich landscape with a series of minima that repeat over a length-scale determined by the intrinsic curvature. Computing Langevin dynamics of the tip through the landscape and accounting for depolymerization, we calculate the average unzippering and shrinkage velocities of GDP protofilaments and compare them with the experimentally known results. Our analysis predicts that the strength of the inter-PF interaction (E(s)(m)) has to be comparable to the strength of the curvature energy (E(b)(m)) such that E(s)(m) - E(b)(m) ≈ 1kBT, and questions the prevalent notion that unzippering results from the domination of bending energy of curved GDP PFs. Our work demonstrates how the shape of the free energy landscape is crucial in explaining the mechanism of MT shrinkage where the unzippered PFs will fluctuate in a set of partially peeled off states and subunit dissociation will reduce the length.

  11. Statistical mechanics provides novel insights into microtubule stability and mechanism of shrinkage.

    Directory of Open Access Journals (Sweden)

    Ishutesh Jain

    2015-02-01

    Full Text Available Microtubules are nano-machines that grow and shrink stochastically, making use of the coupling between chemical kinetics and mechanics of its constituent protofilaments (PFs. We investigate the stability and shrinkage of microtubules taking into account inter-protofilament interactions and bending interactions of intrinsically curved PFs. Computing the free energy as a function of PF tip position, we show that the competition between curvature energy, inter-PF interaction energy and entropy leads to a rich landscape with a series of minima that repeat over a length-scale determined by the intrinsic curvature. Computing Langevin dynamics of the tip through the landscape and accounting for depolymerization, we calculate the average unzippering and shrinkage velocities of GDP protofilaments and compare them with the experimentally known results. Our analysis predicts that the strength of the inter-PF interaction (E(s(m has to be comparable to the strength of the curvature energy (E(b(m such that E(s(m - E(b(m ≈ 1kBT, and questions the prevalent notion that unzippering results from the domination of bending energy of curved GDP PFs. Our work demonstrates how the shape of the free energy landscape is crucial in explaining the mechanism of MT shrinkage where the unzippered PFs will fluctuate in a set of partially peeled off states and subunit dissociation will reduce the length.

  12. TOG Proteins Are Spatially Regulated by Rac-GSK3β to Control Interphase Microtubule Dynamics.

    Directory of Open Access Journals (Sweden)

    Kathryn P Trogden

    Full Text Available Microtubules are regulated by a diverse set of proteins that localize to microtubule plus ends (+TIPs where they regulate dynamic instability and mediate interactions with the cell cortex, actin filaments, and organelles. Although individual +TIPs have been studied in depth and we understand their basic contributions to microtubule dynamics, there is a growing body of evidence that these proteins exhibit cross-talk and likely function to collectively integrate microtubule behavior and upstream signaling pathways. In this study, we have identified a novel protein-protein interaction between the XMAP215 homologue in Drosophila, Mini spindles (Msps, and the CLASP homologue, Orbit. These proteins have been shown to promote and suppress microtubule dynamics, respectively. We show that microtubule dynamics are regionally controlled in cells by Rac acting to suppress GSK3β in the peripheral lamellae/lamellipodium. Phosphorylation of Orbit by GSK3β triggers a relocalization of Msps from the microtubule plus end to the lattice. Mutation of the Msps-Orbit binding site revealed that this interaction is required for regulating microtubule dynamic instability in the cell periphery. Based on our findings, we propose that Msps is a novel Rac effector that acts, in partnership with Orbit, to regionally regulate microtubule dynamics.

  13. Taxol differentially modulates the dynamics of microtubules assembled from unfractionated and purified beta-tubulin isotypes.

    Science.gov (United States)

    Derry, W B; Wilson, L; Khan, I A; Luduena, R F; Jordan, M A

    1997-03-25

    Substoichiometric binding of taxol to tubulin in microtubules potently suppresses microtubule dynamics, which appears to be the most sensitive antiproliferative mechanism of taxol. To determine whether the beta-tubulin isotype composition of a microtubule can modulate sensitivity to taxol, we measured the effects of substoichiometric ratios of taxol bound to tubulin in microtubules on the dynamics of microtubules composed of purified alphabeta(II)-, alphabeta(III)-, or alphabeta(IV)-tubulin isotypes and compared the results with the effects of taxol on microtubules assembled from unfractionated tubulin. Substoichiometric ratios of bound taxol in microtubules assembled from purified beta-tubulin isotypes or unfractionated tubulin potently suppressed the shortening rates and the lengths shortened per shortening event. Correlation of the suppression of the shortening rate with the stoichiometry of bound taxol revealed that microtubules composed of purified alphabeta(II)-, alphabeta(III)-, and alphabeta(IV)-tubulin were, respectively, 1.6-, 7.4-, and 7.2-fold less sensitive to the effects of bound taxol than microtubules assembled from unfractionated tubulin. These results indicate that taxol differentially modulates microtubule dynamics depending upon the beta-tubulin isotype composition. The results are consistent with recent studies correlating taxol resistance in tumor cells with increased levels of beta(III0- and beta(IV)-tubulin expression and suggest that altered cellular expression of beta-tubulin isotypes can be an important mechanism by which tumor cells develop resistance to taxol.

  14. Distinct pose of discodermolide in taxol binding pocket drives a complementary mode of microtubule stabilization.

    Science.gov (United States)

    Khrapunovich-Baine, Marina; Menon, Vilas; Verdier-Pinard, Pascal; Smith, Amos B; Angeletti, Ruth Hogue; Fiser, Andras; Horwitz, Susan Band; Xiao, Hui

    2009-12-15

    The microtubule cytoskeleton has proven to be an effective target for cancer therapeutics. One class of drugs, known as microtubule stabilizing agents (MSAs), binds to microtubule polymers and stabilizes them against depolymerization. The prototype of this group of drugs, Taxol, is an effective chemotherapeutic agent used extensively in the treatment of human ovarian, breast, and lung carcinomas. Although electron crystallography and photoaffinity labeling experiments determined that the binding site for Taxol is in a hydrophobic pocket in beta-tubulin, little was known about the effects of this drug on the conformation of the entire microtubule. A recent study from our laboratory utilizing hydrogen-deuterium exchange (HDX) in concert with various mass spectrometry (MS) techniques has provided new information on the structure of microtubules upon Taxol binding. In the current study we apply this technique to determine the binding mode and the conformational effects on chicken erythrocyte tubulin (CET) of another MSA, discodermolide, whose synthetic analogues may have potential use in the clinic. We confirmed that, like Taxol, discodermolide binds to the taxane binding pocket in beta-tubulin. However, as opposed to Taxol, which has major interactions with the M-loop, discodermolide orients itself away from this loop and toward the N-terminal H1-S2 loop. Additionally, discodermolide stabilizes microtubules mainly via its effects on interdimer contacts, specifically on the alpha-tubulin side, and to a lesser extent on interprotofilament contacts between adjacent beta-tubulin subunits. Also, our results indicate complementary stabilizing effects of Taxol and discodermolide on the microtubules, which may explain the synergy observed between the two drugs in vivo.

  15. Contributions of microtubule dynamic instability and rotational diffusion to kinetochore capture

    CERN Document Server

    Blackwell, Robert; Edelmaier, Christopher; Gergely, Zachary R; Flynn, Patrick J; Montes, Salvador; Crapo, Ammon; Doostan, Alireza; McIntosh, J Richard; Glaser, Matthew A; Betterton, Meredith D

    2016-01-01

    Microtubule dynamic instability allows search and capture of kinetochores during spindle formation, an important process for accurate chromosome segregation during cell division. Recent work has found that microtubule rotational diffusion about minus-end attachment points contributes to kinetochore capture in fission yeast, but the relative contributions of dynamic instability and rotational diffusion are not well understood. We have developed a biophysical model of kinetochore capture in small fission-yeast nuclei using hybrid Brownian dynamics/kinetic Monte Carlo simulation techniques. With this model, we have studied the importance of dynamic instability and microtubule rotational diffusion for kinetochore capture, both to the lateral surface of a microtubule and at or near its end. Over a range of biologically relevant parameters, microtubule rotational diffusion decreased capture time, but made a relatively small contribution compared to dynamic instability. At most, rotational diffusion reduced capture ...

  16. Stathmin regulates microtubule dynamics and microtubule organizing center polarization in activated T cells.

    Science.gov (United States)

    Filbert, Erin L; Le Borgne, Marie; Lin, Joseph; Heuser, John E; Shaw, Andrey S

    2012-06-01

    Polarization of T cells involves reorientation of the microtubule organizing center (MTOC). Because activated ERK is localized at the immunological synapse, we investigated its role by showing that ERK activation is important for MTOC polarization. Suspecting that ERK phosphorylates a regulator of microtubules, we next focused on stathmin, a known ERK substrate. Our work indicates that during T cell activation, ERK is recruited to the synapse, allowing it to phosphorylate stathmin molecules near the immunological synapse. Supporting an important role of stathmin phosphorylation in T cell activation, we showed that T cell activation results in increased microtubule growth rate dependent on the presence of stathmin. The significance of this finding was demonstrated by results showing that CTLs from stathmin(-/-) mice displayed defective MTOC polarization and defective target cell cytolysis. These data implicate stathmin as a regulator of the microtubule network during T cell activation.

  17. CDK-1 Inhibition in G2 Stabilizes Kinetochore-Microtubules in the following Mitosis.

    Science.gov (United States)

    Gayek, A Sophia; Ohi, Ryoma

    2016-01-01

    Cell proliferation is driven by cyclical activation of cyclin-dependent kinases (CDKs), which produce distinct biochemical cell cycle phases. Mitosis (M phase) is orchestrated by CDK-1, complexed with mitotic cyclins. During M phase, chromosomes are segregated by a bipolar array of microtubules called the mitotic spindle. The essential bipolarity of the mitotic spindle is established by the kinesin-5 Eg5, but factors influencing the maintenance of spindle bipolarity are not fully understood. Here, we describe an unexpected link between inhibiting CDK-1 before mitosis and bipolar spindle maintenance. Spindles in human RPE-1 cells normally collapse to monopolar structures when Eg5 is inhibited at metaphase. However, we found that inhibition of CDK-1 in the G2 phase of the cell cycle improved the ability of RPE-1 cells to maintain spindle bipolarity without Eg5 activity in the mitosis immediately after release from CDK-1 inhibition. This improved bipolarity maintenance correlated with an increase in the stability of kinetochore-microtubules, the subset of microtubules that link chromosomes to the spindle. The improvement in bipolarity maintenance after CDK-1 inhibition in G2 required both the kinesin-12 Kif15 and increased stability of kinetochore-microtubules. Consistent with increased kinetochore-microtubule stability, we find that inhibition of CDK-1 in G2 impairs mitotic fidelity by increasing the incidence of lagging chromosomes in anaphase. These results suggest that inhibition of CDK-1 in G2 causes unpredicted effects in mitosis, even after CDK-1 inhibition is relieved.

  18. Synthesis and high content cell-based profiling of simplified analogues of the microtubule stabilizer (+)-discodermolide.

    Science.gov (United States)

    Minguez, Jose M; Giuliano, Kenneth A; Balachandran, Raghavan; Madiraju, Charitha; Curran, Dennis P; Day, Billy W

    2002-12-01

    (+)-Discodermolide, a C24:4, trihydroxylated, octamethyl, carbamate-bearing fatty acid lactone originally isolated from a Caribbean sponge, has proven to be the most potent of the microtubule-stabilizing agents. Recent studies suggest that it or its analogues may have advantages over other classes of microtubule-stabilizing agents. (+)-Discodermolide's complex molecular architecture has made structure-activity relationship analysis in this class of compounds a formidable task. The goal of this study was to prepare simplified analogues of (+)-discodermolide and to analyze their biological activities to expand structure-activity relationships. A small library of analogues was prepared wherein the (+)-discodermolide methyl groups at C-14 and C-16 and the C-7 hydroxyl were removed, and the lactone was replaced by simple esters. The library components were analyzed for microtubule-stabilizing actions in vitro, antiproliferative activity against a small panel of human carcinoma cells, and cell signaling, microtubule architecture and mitotic spindle alterations by a multiparameter fluorescence cell-based screening technique. The results show that even drastic structural simplification can lead to analogues with actions related to microtubule targeting and signal transduction, but that these subtle effects were illuminated only through the high information content cell-based screen.

  19. Microtubule stabilization triggers the plus-end accumulation of Kif18A/kinesin-8.

    Science.gov (United States)

    Masuda, Natsuko; Shimodaira, Tetsuhiro; Shiu, Shu-Jen; Tokai-Nishizumi, Noriko; Yamamoto, Tadashi; Ohsugi, Miho

    2011-01-01

    The precise control of spindle microtubule (MT) dynamics is essential for chromosome capture and alignment. Kif18A/kinesin-8, an essential regulator of kinetochore MT dynamics, accumulates at its plus-ends in metaphase but not prometaphase cells. The underlying mechanism of time-dependent and kinetochore MT-specific plus-end accumulation of Kif18A is unknown. Here, we examined the factors required for the MT plus-end accumulation of Kif18A. In Eg5 inhibitor-treated cells, Kif18A localized along the MTs in the monopolar spindle and rarely accumulated at their plus-ends, indicating that MT-kinetochore association was not sufficient to induce Kif18A accumulation. In contrast, taxol treatment triggered the rapid MT plus-end accumulation of Kif18A regardless of kinetochore association. Furthermore, Aurora B inhibitor-induced stabilization of the plus-ends of kinetochore MTs promoted the plus-end accumulation of Kif18A. In the absence of Kif18A, treatment with taxol but not Eg5 inhibitor causes highly elongated mitotic MTs, suggesting the importance of plus-end accumulation for the MT length-controlling activity of Kif18A. Taken together, we propose that there is a mutual regulation of kinetochore MT plus-end dynamics and Kif18A accumulation, which may contribute to the highly regulated and ordered changes in kinetochore MT dynamics during chromosome congression and oscillation.

  20. A plus-end raft to control microtubule dynamics and function.

    Science.gov (United States)

    Galjart, Niels; Perez, Franck

    2003-02-01

    Cells require a properly oriented and organised microtubule array to transmit positional information. Recent data have revealed a heterogeneous population of microtubule-binding proteins that accumulates mainly at distal ends of polymerising microtubules. Two mechanisms may account for this concentration: transient immobilisation, which involves association of proteins with growing ends, followed by release more proximally; and deposition at ends via a molecular motor. As with lipid rafts, protein concentration at distal ends may allow a cascade of interactions in the restricted area of a microtubule plus end. This may, in turn, control the dynamic behaviour of this cytoskeletal network and its anchoring to other structures.

  1. Dependency of microtubule-associated proteins (MAPs) for tubulin stability and assembly; use of estramustine phosphate in the study of microtubules.

    Science.gov (United States)

    Fridén, B; Wallin, M

    1991-07-10

    Microtubule-associated proteins (MAPs) were separated from tubulin with several different methods. The ability of the isolated MAPs to reinduce assembly of phosphocellulose purified tubulin differed markedly between the different methods. MAPs isolated by addition of 0.35 M NaCl to taxol-stabilized microtubules stimulated tubulin assembly most effectively, while addition of 0.6 M NaCl produced MAPs with a substantially lower ability to stimulate tubulin assembly. The second best preparation was achieved with phosphocellulose chromatographic separation of MAPs with 0.6 M NaCl elution. The addition of estramustine phosphate to microtubules reconstituted of MAPs prepared by 0.35 M NaCl or phosphocellulose chromatography, induced less disassembly than for microtubules assembled from unseparated proteins, and was almost without effect on microtubules reconstituted from MAPs prepared by taxol and 0.6 M NaCl. Estramustine phosphate binds to the tubulin binding part of the MAPs, and the results do therefore indicate that the MAPs are altered by the separation methods. Since the MAPs are regarded as highly stable molecules, one probable alteration could be aggregation of the MAPs, as also indicated by the results. The purified tubulin itself seemed not to be affected by the phosphocellulose purification, since the microtubule proteins were unchanged by the low buffer strenght used during the cromatography. However, the assembly competence after a prolonged incubation of the microtubule proteins at 4 degrees C was dependent on intact bindings between the tubulin and MAPs.

  2. Microtubule dynamics control HGF-induced lung endothelial barrier enhancement.

    Directory of Open Access Journals (Sweden)

    Xinyong Tian

    Full Text Available Microtubules (MT play a vital role in many cellular functions, but their role in peripheral actin cytoskeletal dynamics which is essential for control of endothelial barrier and monolayer integrity is less understood. We have previously described the enhancement of lung endothelial cell (EC barrier by hepatocyte growth factor (HGF which was associated with Rac1-mediated remodeling of actin cytoskeleton. This study investigated involvement of MT-dependent mechanisms in the HGF-induced enhancement of EC barrier. HGF-induced Rac1 activation was accompanied by phosphorylation of stathmin, a regulator of MT dynamics. HGF also stimulated MT peripheral growth monitored by time lapse imaging and tracking analysis of EB-1-decorated MT growing tips, and increased the pool of acetylated tubulin. These effects were abolished by EC pretreatment with HGF receptor inhibitor, downregulation of Rac1 pathway, or by expression of a stathmin-S63A phosphorylation deficient mutant. Expression of stathmin-S63A abolished the HGF protective effects against thrombin-induced activation of RhoA cascade, permeability increase, and EC barrier dysfunction. These results demonstrate a novel MT-dependent mechanism of HGF-induced EC barrier regulation via Rac1/PAK1/stathmin-dependent control of MT dynamics.

  3. Microtubules as key coordinators of nuclear envelope and endoplasmic reticulum dynamics during mitosis.

    Science.gov (United States)

    Schlaitz, Anne-Lore

    2014-07-01

    During mitosis, cells comprehensively restructure their interior to promote the faithful inheritance of DNA and cytoplasmic contents. In metazoans, this restructuring entails disassembly of the nuclear envelope, redistribution of its components into the endoplasmic reticulum (ER) and eventually nuclear envelope reassembly around the segregated chromosomes. The microtubule cytoskeleton has recently emerged as a critical regulator of mitotic nuclear envelope and ER dynamics. Microtubules and associated molecular motors tear open the nuclear envelope in prophase and remove nuclear envelope remnants from chromatin. Additionally, two distinct mechanisms of microtubule-based regulation of ER dynamics operate later in mitosis. First, association of the ER with microtubules is reduced, preventing invasion of ER into the spindle area, and second, organelle membrane is actively cleared from metaphase chromosomes. However, we are only beginning to understand the role of microtubules in shaping and distributing ER and other organelles during mitosis. © 2014 WILEY Periodicals, Inc.

  4. An epigenetic regulator emerges as microtubule minus-end binding and stabilizing factor in mitosis.

    Science.gov (United States)

    Meunier, Sylvain; Shvedunova, Maria; Van Nguyen, Nhuong; Avila, Leonor; Vernos, Isabelle; Akhtar, Asifa

    2015-08-05

    The evolutionary conserved NSL complex is a prominent epigenetic regulator controlling expression of thousands of genes. Here we uncover a novel function of the NSL complex members in mitosis. As the cell enters mitosis, KANSL1 and KANSL3 undergo a marked relocalisation from the chromatin to the mitotic spindle. By stabilizing microtubule minus ends in a RanGTP-dependent manner, they are essential for spindle assembly and chromosome segregation. Moreover, we identify KANSL3 as a microtubule minus-end-binding protein, revealing a new class of mitosis-specific microtubule minus-end regulators. By adopting distinct functions in interphase and mitosis, KANSL proteins provide a link to coordinate the tasks of faithful expression and inheritance of the genome during different phases of the cell cycle.

  5. Dynamic microtubules regulate dendritic spine morphology and synaptic plasticity

    NARCIS (Netherlands)

    Jaworski, J.; Kapitein, L.C.; Montenegro Gouveia, S.; Dortland, B.R.; Wulf, P.S.; Grigoriev, I.; Camera, P.; Spangler, S.A.; Di Stefano, P.; Demmers, J.; Krugers, H.; Defilippi, P.; Akhmanova, A.; Hoogenraad, C.C.

    2009-01-01

    Dendritic spines are the major sites of excitatory synaptic input, and their morphological changes have been linked to learning and memory processes. Here, we report that growing microtubule plus ends decorated by the microtubule tip-tracking protein EB3 enter spines and can modulate spine morpholog

  6. Microtubule-based nanomaterials: Exploiting nature's dynamic biopolymers.

    Science.gov (United States)

    Bachand, George D; Spoerke, Erik D; Stevens, Mark J

    2015-06-01

    For more than a decade now, biomolecular systems have served as an inspiration for the development of synthetic nanomaterials and systems that are capable of reproducing many of unique and emergent behaviors of living systems. One intriguing element of such systems may be found in a specialized class of proteins known as biomolecular motors that are capable of performing useful work across multiple length scales through the efficient conversion of chemical energy. Microtubule (MT) filaments may be considered within this context as their dynamic assembly and disassembly dissipate energy, and perform work within the cell. MTs are one of three cytoskeletal filaments in eukaryotic cells, and play critical roles in a range of cellular processes including mitosis and vesicular trafficking. Based on their function, physical attributes, and unique dynamics, MTs also serve as a powerful archetype of a supramolecular filament that underlies and drives multiscale emergent behaviors. In this review, we briefly summarize recent efforts to generate hybrid and composite nanomaterials using MTs as biomolecular scaffolds, as well as computational and synthetic approaches to develop synthetic one-dimensional nanostructures that display the enviable attributes of the natural filaments.

  7. Learning-induced and stathmin-dependent changes in microtubule stability are critical for memory and disrupted in ageing.

    Science.gov (United States)

    Uchida, Shusaku; Martel, Guillaume; Pavlowsky, Alice; Takizawa, Shuichi; Hevi, Charles; Watanabe, Yoshifumi; Kandel, Eric R; Alarcon, Juan Marcos; Shumyatsky, Gleb P

    2014-07-10

    Changes in the stability of microtubules regulate many biological processes, but their role in memory remains unclear. Here we show that learning causes biphasic changes in the microtubule-associated network in the hippocampus. In the early phase, stathmin is dephosphorylated, enhancing its microtubule-destabilizing activity by promoting stathmin-tubulin binding, whereas in the late phase these processes are reversed leading to an increase in microtubule/KIF5-mediated localization of the GluA2 subunit of AMPA receptors at synaptic sites. A microtubule stabilizer paclitaxel decreases or increases memory when applied at the early or late phases, respectively. Stathmin mutations disrupt changes in microtubule stability, GluA2 localization, synaptic plasticity and memory. Aged wild-type mice show impairments in stathmin levels, changes in microtubule stability and GluA2 localization. Blocking GluA2 endocytosis rescues memory deficits in stathmin mutant and aged wild-type mice. These findings demonstrate a role for microtubules in memory in young adult and aged individuals.

  8. Microtubule Dynamics and Oscillating State for Mitotic Spindle

    CERN Document Server

    Rashid-Shomali, Safura

    2010-01-01

    We present a physical mechanism that can cause the mitotic spindle to oscillate. The driving force for this mechanism emerges from the polymerization of astral microtubules interacting with the cell cortex. We show that Brownian ratchet model for growing microtubules reaching the cell cortex, mediate an effective mass to the spindle body and therefore force it to oscillate. We compare the predictions of this mechanism with the previous mechanisms which were based on the effects of motor proteins. Finally we combine the effects of microtubules polymerization and motor proteins, and present the detailed phase diagram for possible oscillating states.

  9. The extracellular matrix protein TGFBI induces microtubule stabilization and sensitizes ovarian cancers to paclitaxel.

    Science.gov (United States)

    Ahmed, Ahmed Ashour; Mills, Anthony D; Ibrahim, Ashraf E K; Temple, Jillian; Blenkiron, Cherie; Vias, Maria; Massie, Charlie E; Iyer, N Gopalakrishna; McGeoch, Adam; Crawford, Robin; Nicke, Barbara; Downward, Julian; Swanton, Charles; Bell, Stephen D; Earl, Helena M; Laskey, Ronald A; Caldas, Carlos; Brenton, James D

    2007-12-01

    The extracellular matrix (ECM) can induce chemotherapy resistance via AKT-mediated inhibition of apoptosis. Here, we show that loss of the ECM protein TGFBI (transforming growth factor beta induced) is sufficient to induce specific resistance to paclitaxel and mitotic spindle abnormalities in ovarian cancer cells. Paclitaxel-resistant cells treated with recombinant TGFBI protein show integrin-dependent restoration of paclitaxel sensitivity via FAK- and Rho-dependent stabilization of microtubules. Immunohistochemical staining for TGFBI in paclitaxel-treated ovarian cancers from a prospective clinical trial showed that morphological changes of paclitaxel-induced cytotoxicity were restricted to areas of strong expression of TGFBI. These data show that ECM can mediate taxane sensitivity by modulating microtubule stability.

  10. Microtubule-associated protein-4 controls nanovesicle dynamics and T cell activation.

    Science.gov (United States)

    Bustos-Morán, Eugenio; Blas-Rus, Noelia; Martin-Cófreces, Noa Beatriz; Sánchez-Madrid, Francisco

    2017-04-01

    The immune synapse (IS) is a specialized structure formed at the contact area between T lymphocytes and antigen-presenting cells (APCs) that is essential for the adaptive immune response. Proper T cell activation requires its polarization towards the APC, which is highly dependent on the tubulin cytoskeleton. Microtubule-associated protein-4 (MAP4) is a microtubule (MT)-stabilizing protein that controls MTs in physiological processes, such as cell division, migration, vesicular transport or primary cilia formation. In this study, we assessed the role of MAP4 in T cell activation. MAP4 decorates the pericentrosomal area and MTs of the T cell, and it is involved in MT detyrosination and stable assembly in response to T cell activation. In addition, MAP4 prompts the timely translocation of the MT-organizing center (MTOC) towards the IS and the dynamics of signaling nanovesicles that sustains T cell activation. However, MAP4 acts as a negative regulator of other T cell activation-related signals, including diacylglycerol (DAG) production and IL2 secretion. Our data indicate that MAP4 acts as a checkpoint molecule that balances positive and negative hallmarks of T cell activation.

  11. Integrated modeling methodology for microtubule dynamics and Taxol kinetics with experimentally identifiable parameters.

    Science.gov (United States)

    Zhao, He; Sokhansanj, Bahrad A

    2007-10-01

    Microtubule dynamics play a critical role in cell function and stress response, modulating mitosis, morphology, signaling, and transport. Drugs such as paclitaxel (Taxol) can impact tubulin polymerization and affect microtubule dynamics. While theoretical methods have been previously proposed to simulate microtubule dynamics, we develop a methodology here that can be used to compare model predictions with experimental data. Our model is a hybrid of (1) a simple two-state stochastic formulation of tubulin polymerization kinetics and (2) an equilibrium approximation for the chemical kinetics of Taxol drug binding to microtubule ends. Model parameters are biologically realistic, with values taken directly from experimental measurements. Model validation is conducted against published experimental data comparing optical measurements of microtubule dynamics in cultured cells under normal and Taxol-treated conditions. To compare model predictions with experimental data requires applying a "windowing" strategy on the spatiotemporal resolution of the simulation. From a biological perspective, this is consistent with interpreting the microtubule "pause" phenomenon as at least partially an artifact of spatiotemporal resolution limits on experimental measurement.

  12. The molecular dynamics of crawling migration in microtubule-disrupted keratocytes.

    Science.gov (United States)

    Nakashima, Hitomi; Okimura, Chika; Iwadate, Yoshiaki

    2015-01-01

    Cell-crawling migration plays an essential role in complex biological phenomena. It is now generally believed that many processes essential to such migration are regulated by microtubules in many cells, including fibroblasts and neurons. However, keratocytes treated with nocodazole, which is an inhibitor of microtubule polymerization - and even keratocyte fragments that contain no microtubules - migrate at the same velocity and with the same directionality as normal keratocytes. In this study, we discovered that not only these migration properties, but also the molecular dynamics that regulate such properties, such as the retrograde flow rate of actin filaments, distributions of vinculin and myosin II, and traction forces, are also the same in nocodazole-treated keratocytes as those in untreated keratocytes. These results suggest that microtubules are not in fact required for crawling migration of keratocytes, either in terms of migrating properties or of intracellular molecular dynamics.

  13. Dynamics of microtubule asters in microfabricated chambers: The role of catastrophes

    Science.gov (United States)

    Faivre-Moskalenko, Cendrine; Dogterom, Marileen

    2002-01-01

    Recent in vivo as well as in vitro experiments have indicated that microtubule pushing alone is sufficient to position a microtubule-organizing center within a cell. Here, we investigate the effect of catastrophes on the dynamics of microtubule asters within microfabricated chambers that mimic the confining geometry of living cells. The use of a glass bead as the microtubule-organizing center allows us to manipulate the aster by using optical tweezers. In the case in which microtubules preexist, we show that because of microtubule buckling, repositioning almost never occurs after relocation with the optical tweezers, although initial microtubule growth always leads the aster to the geometrical center of the chamber. When a catastrophe promoter is added, we find instead that the aster is able to efficiently explore the chamber geometry even after being relocated with the optical tweezers. As predicted by theoretical calculations, the results of our in vitro experiments clearly demonstrate the need for catastrophes for proper positioning in a confining geometry. These findings correlate with recent observations of nuclear positioning in fission yeast cells. PMID:12486218

  14. A new function of microtubule-associated protein tau: involvement in chromosome stability.

    Science.gov (United States)

    Rossi, Giacomina; Dalprà, Leda; Crosti, Francesca; Lissoni, Sara; Sciacca, Francesca L; Catania, Marcella; Di Fede, Giuseppe; Mangieri, Michela; Giaccone, Giorgio; Croci, Danilo; Tagliavini, Fabrizio

    2008-06-15

    Tau is a microtubule-associated protein that promotes assembly and stabilization of cytoskeleton microtubules. It is mostly expressed in neuronal and glial cells but it is also present in non-neural cells such as fibroblasts and lymphocytes. An altered tau produces cytoskeleton pathology resulting in neurodegenerative diseases such as Alzheimer's disease and tauopathies. Tau has been suggested to be a multifunctional protein, due to its localization in different cellular compartments. However its further functions are still unclear. We analyzed the distribution of tau in human skin fibroblasts showing its localization in the nucleus and along mitotic chromosomes. Then, we investigated if an altered tau, such as the P301L mutated protein associated with frontotemporal dementia, could produce nuclear pathology. We found that patients carrying the mutation consistently had several chromosome aberrations in their fibroblasts and lymphocytes: chromosome and chromatid breakages or gaps, aneuploidies, translocations, in addition to chromatin bridges and decondensed chromosomes. Our findings argue for a role of tau in chromosome stability by means of its interaction with both microtubules and chromatin.

  15. Highly Transient Molecular Interactions Underlie the Stability of Kinetochore–Microtubule Attachment During Cell Division

    OpenAIRE

    Zaytsev, Anatoly V.; Ataullakhanov, Fazly I; Grishchuk, Ekaterina L.

    2013-01-01

    Chromosome segregation during mitosis is mediated by spindle microtubules that attach to chromosomal kinetochores with strong yet labile links. The exact molecular composition of the kinetochore–microtubule interface is not known but microtubules are thought to bind to kinetochores via the specialized microtubule-binding sites, which contain multiple microtubule-binding proteins. During prometaphase the lifetime of microtubule attachments is short but in metaphase it increases 3-fold, presuma...

  16. Push or Pull? -- Cryo-Electron Microscopy of Microtubule's Dynamic Instability and Its Roles in the Kinetochore

    Science.gov (United States)

    Wang, Hong-Wei

    2009-03-01

    Microtubule is a biopolymer made up of alpha-beta-tubulin heterodimers. The tubulin dimers assemble head-to-tail as protofilaments and about 13 protofilaments interact laterally to form a hollow cylindrical structure which is the microtubule. As the major cytoskeleton in all eukaryotic cells, microtubules have the intrinsic property to switch stochastically between growth and shrinkage phases, a phenomenon termed as their dynamic instability. Microtubule's dynamic instability is closely related to the types of nucleotide (GTP or GDP) that binds to the beta-tubulin. We have biochemically trapped two types of assembly states of tubulin with GTP or GDP bound representing the polymerizing and depolymerizing ends of microtubules respectively. Using cryo-electron microscopy, we have elucidated the structures of these intermediate assemblies, showing that tubulin protofilaments demonstrate various curvatures and form different types of lateral interactions depending on the nucleotide states of tubulin and the temperature. Our work indicates that during the microtubule's dynamic cycle, tubulin undergoes various assembly states. These states, different from the straight microtubule, lend the highly dynamic and complicated behavior of microtubules. Our study of microtubule's interaction with certain kinetochore complexes suggests that the intermediate assemblies are responsible for specific mechanical forces that are required during the mitosis or meiosis. Our discoveries strongly suggest that a microtubule is a molecular machine rather than a simple cellular scaffold.

  17. Stability of dynamical systems

    CERN Document Server

    Liao, Xiaoxin; Yu, P 0

    2007-01-01

    The main purpose of developing stability theory is to examine dynamic responses of a system to disturbances as the time approaches infinity. It has been and still is the object of intense investigations due to its intrinsic interest and its relevance to all practical systems in engineering, finance, natural science and social science. This monograph provides some state-of-the-art expositions of major advances in fundamental stability theories and methods for dynamic systems of ODE and DDE types and in limit cycle, normal form and Hopf bifurcation control of nonlinear dynamic systems.ʺ Presents

  18. Calcium-independent disruption of microtubule dynamics by nanosecond pulsed electric fields in U87 human glioblastoma cells

    Science.gov (United States)

    Carr, Lynn; Bardet, Sylvia M.; Burke, Ryan C.; Arnaud-Cormos, Delia; Leveque, Philippe; O’Connor, Rodney P.

    2017-01-01

    High powered, nanosecond duration, pulsed electric fields (nsPEF) cause cell death by a mechanism that is not fully understood and have been proposed as a targeted cancer therapy. Numerous chemotherapeutics work by disrupting microtubules. As microtubules are affected by electrical fields, this study looks at the possibility of disrupting them electrically with nsPEF. Human glioblastoma cells (U87-MG) treated with 100, 10 ns, 44 kV/cm pulses at a frequency of 10 Hz showed a breakdown of their interphase microtubule network that was accompanied by a reduction in the number of growing microtubules. This effect is temporally linked to loss of mitochondrial membrane potential and independent of cellular swelling and calcium influx, two factors that disrupt microtubule growth dynamics. Super-resolution microscopy revealed microtubule buckling and breaking as a result of nsPEF application, suggesting that nsPEF may act directly on microtubules. PMID:28117459

  19. Calcium-independent disruption of microtubule dynamics by nanosecond pulsed electric fields in U87 human glioblastoma cells.

    Science.gov (United States)

    Carr, Lynn; Bardet, Sylvia M; Burke, Ryan C; Arnaud-Cormos, Delia; Leveque, Philippe; O'Connor, Rodney P

    2017-01-24

    High powered, nanosecond duration, pulsed electric fields (nsPEF) cause cell death by a mechanism that is not fully understood and have been proposed as a targeted cancer therapy. Numerous chemotherapeutics work by disrupting microtubules. As microtubules are affected by electrical fields, this study looks at the possibility of disrupting them electrically with nsPEF. Human glioblastoma cells (U87-MG) treated with 100, 10 ns, 44 kV/cm pulses at a frequency of 10 Hz showed a breakdown of their interphase microtubule network that was accompanied by a reduction in the number of growing microtubules. This effect is temporally linked to loss of mitochondrial membrane potential and independent of cellular swelling and calcium influx, two factors that disrupt microtubule growth dynamics. Super-resolution microscopy revealed microtubule buckling and breaking as a result of nsPEF application, suggesting that nsPEF may act directly on microtubules.

  20. Autoinhibition of TBCB regulates EB1-mediated microtubule dynamics.

    Science.gov (United States)

    Carranza, Gerardo; Castaño, Raquel; Fanarraga, Mónica L; Villegas, Juan Carlos; Gonçalves, João; Soares, Helena; Avila, Jesus; Marenchino, Marco; Campos-Olivas, Ramón; Montoya, Guillermo; Zabala, Juan Carlos

    2013-01-01

    Tubulin cofactors (TBCs) participate in the folding, dimerization, and dissociation pathways of the tubulin dimer. Among them, TBCB and TBCE are two CAP-Gly domain-containing proteins that together efficiently interact with and dissociate the tubulin dimer. In the study reported here we showed that TBCB localizes at spindle and midzone microtubules during mitosis. Furthermore, the motif DEI/M-COO(-) present in TBCB, which is similar to the EEY/F-COO(-) element characteristic of EB proteins, CLIP-170, and α-tubulin, is required for TBCE-TBCB heterodimer formation and thus for tubulin dimer dissociation. This motif is responsible for TBCB autoinhibition, and our analysis suggests that TBCB is a monomer in solution. Mutants of TBCB lacking this motif are derepressed and induce microtubule depolymerization through an interaction with EB1 associated with microtubule tips. TBCB is also able to bind to the chaperonin complex CCT containing α-tubulin, suggesting that it could escort tubulin to facilitate its folding and dimerization, recycling or degradation.

  1. A polarised population of dynamic microtubules mediates homeostatic length control in animal cells.

    Directory of Open Access Journals (Sweden)

    Remigio Picone

    Full Text Available Because physical form and function are intimately linked, mechanisms that maintain cell shape and size within strict limits are likely to be important for a wide variety of biological processes. However, while intrinsic controls have been found to contribute to the relatively well-defined shape of bacteria and yeast cells, the extent to which individual cells from a multicellular animal control their plastic form remains unclear. Here, using micropatterned lines to limit cell extension to one dimension, we show that cells spread to a characteristic steady-state length that is independent of cell size, pattern width, and cortical actin. Instead, homeostatic length control on lines depends on a population of dynamic microtubules that lead during cell extension, and that are aligned along the long cell axis as the result of interactions of microtubule plus ends with the lateral cell cortex. Similarly, during the development of the zebrafish neural tube, elongated neuroepithelial cells maintain a relatively well-defined length that is independent of cell size but dependent upon oriented microtubules. A simple, quantitative model of cellular extension driven by microtubules recapitulates cell elongation on lines, the steady-state distribution of microtubules, and cell length homeostasis, and predicts the effects of microtubule inhibitors on cell length. Together this experimental and theoretical analysis suggests that microtubule dynamics impose unexpected limits on cell geometry that enable cells to regulate their length. Since cells are the building blocks and architects of tissue morphogenesis, such intrinsically defined limits may be important for development and homeostasis in multicellular organisms.

  2. The microtubule-stabilizing drug Epothilone D increases axonal sprouting following transection injury in vitro.

    Science.gov (United States)

    Brizuela, Mariana; Blizzard, Catherine A; Chuckowree, Jyoti A; Dawkins, Edgar; Gasperini, Robert J; Young, Kaylene M; Dickson, Tracey C

    2015-05-01

    Neuronal cytoskeletal alterations, in particular the loss and misalignment of microtubules, are considered a hallmark feature of the degeneration that occurs after traumatic brain injury (TBI). Therefore, microtubule-stabilizing drugs are attractive potential therapeutics for use following TBI. The best-known drug in this category is Paclitaxel, a widely used anti-cancer drug that has produced promising outcomes when employed in the treatment of various animal models of nervous system trauma. However, Paclitaxel is not ideal for the treatment of patients with TBI due to its limited blood-brain barrier (BBB) permeability. Herein we have characterized the effect of the brain penetrant microtubule-stabilizing agent Epothilone D (Epo D) on post-injury axonal sprouting in an in vitro model of CNS trauma. Epo D was found to modulate axonal sprout number in a dose dependent manner, increasing the number of axonal sprouts generated post-injury. Elevated sprouting was observed when analyzing the total population of injured neurons, as well as in selective analysis of Thy1-YFP-labeled excitatory neurons. However, we found no effect of Epo D on axonal sprout length or outgrowth speed. These findings indicate that Epo D specifically affects injury-induced axonal sprout generation, but not net growth. Our investigation demonstrates that primary cultures of cortical neurons are tolerant of Epo D exposure, and that Epo D significantly increases their regenerative response following structural injury. Therefore Epo D may be a potent therapeutic for enhancing regeneration following CNS injury. This article is part of a Special Issue entitled 'Traumatic Brain Injury'.

  3. The bound conformation of microtubule-stabilizing agents: NMR insights into the bioactive 3D structure of discodermolide and dictyostatin.

    Science.gov (United States)

    Canales, Angeles; Matesanz, Ruth; Gardner, Nicola M; Andreu, José Manuel; Paterson, Ian; Díaz, J Fernando; Jiménez-Barbero, Jesús

    2008-01-01

    A protocol based on a combination of NMR experimental data with molecular mechanics calculations and docking procedures has been employed to determine the microtubule-bound conformation of two microtubule-stabilizing agents, discodermolide (DDM) and dictyostatin (DCT). The data indicate that tubulin in assembled microtubules recognizes DDM through a conformational selection process, with minor changes in the molecular skeleton between the major conformer in water solution and that bound to assembled microtubules. For DCT, the deduced bound geometry presents some key conformation differences around certain torsion angles, with respect to the major conformer in solution, and still displays mobility even when bound. The bound conformer of DCT resembles that of DDM and provides very similar contacts with the receptor. Competition experiments indicate that both molecules compete with the taxane-binding site. A model of the binding mode of DDM and DCT to tubulin is proposed.

  4. Integrins Regulate Apical Constriction via Microtubule Stabilization in the Drosophila Eye Disc Epithelium

    Directory of Open Access Journals (Sweden)

    Vilaiwan M. Fernandes

    2014-12-01

    Full Text Available During morphogenesis, extracellular signals trigger actomyosin contractility in subpopulations of cells to coordinate changes in cell shape. To illuminate the link between signaling-mediated tissue patterning and cytoskeletal remodeling, we study the progression of the morphogenetic furrow (MF, the wave of apical constriction that traverses the Drosophila eye imaginal disc preceding photoreceptor neurogenesis. Apical constriction depends on actomyosin contractility downstream of the Hedgehog (Hh and bone morphogenetic protein (BMP pathways. We identify a role for integrin adhesion receptors in MF progression. We show that Hh and BMP regulate integrin expression, the loss of which disrupts apical constriction and slows furrow progression; conversely, elevated integrins accelerate furrow progression. We present evidence that integrins regulate MF progression by promoting microtubule stabilization, since reducing microtubule stability rescues integrin-mediated furrow acceleration. Thus, integrins act as a genetic link between tissue-level signaling events and morphological change at the cellular level, leading to morphogenesis and neurogenesis in the eye.

  5. Mechanical stress induced mechanism of microtubule catastrophes.

    Science.gov (United States)

    Hunyadi, Viktória; Chrétien, Denis; Jánosi, Imre M

    2005-05-13

    Microtubules assembled in vitro from pure tubulin can switch occasionally from growing to shrinking states or resume assembly, an unusual behavior termed "dynamic instability of microtubule growth". Its origin remains unclear and several models have been proposed, including occasional switching of the microtubules into energetically unfavorable configurations during assembly. In this study, we have asked whether the excess energy accumulated in these configurations would be of sufficient magnitude to destabilize the capping region that must exist at the end of growing microtubules. For this purpose, we have analyzed the frequency distribution of microtubules assembled in vitro from pure tubulin, and modeled the different mechanical constraints accumulated in their wall. We find that the maximal excess energy that the microtubule lattice can store is in the order of 11 kBT per dimer. Configurations that require distortions up to approximately 20 kBT are allowed at the expense of a slight conformational change, and larger distortions are not observed. Modeling of the different elastic deformations suggests that the excess energy is essentially induced by protofilament skewing, microtubule radial curvature change and inter-subunit shearing, distortions that must destabilize further the tubulin subunits interactions. These results are consistent with the hypothesis that unfavorable closure events may trigger the catastrophes observed at low tubulin concentration in vitro. In addition, we propose a novel type of representation that describes the stability of microtubule assembly systems, and which might be of considerable interest to study the effects of stabilizing and destabilizing factors on microtubule structure and dynamics.

  6. Thymoquinone disrupts the microtubule dynamics in fission yeast Schizosaccharomyces pombe

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    Nusrat Masood

    2016-11-01

    Full Text Available Mad2 deletion strain of Schizosaccharomyces pombe was found to be sensitive to thymoquinone, a signature molecule present in Nigella sativa in a dose-dependent manner. Mad2 protein is an indispensable part of mitotic spindle checkpoint complex and is required for the cell cycle arrest in response to the spindle defects. Although the expression of α tubulin was not affected in thymoquinone treated cells, but the expression of β-tubulin was reduced. Further, the absence of microtubule in thymoquinone treated cells suggests its involvement in tubulin polymerization. Molecular docking studies revealed that thymoquinone specifically binds to β-tubulin near the Taxotere binding site of Tub1 (Tubulin α-β dimer. These studies additionally showed that thymoquinone interacts with the residues present in chain B, which is an inherent part of Mad2 protein of mitotic checkpoint complex (MCC. We concluded that the thymoquinone disrupts the microtubule polymerization that leads to the requirement of spindle checkpoint protein for the cell survival.

  7. Label-Free Imaging of Single Microtubule Dynamics Using Spatial Light Interference Microscopy.

    Science.gov (United States)

    Kandel, Mikhail E; Teng, Kai Wen; Selvin, Paul R; Popescu, Gabriel

    2017-01-24

    Due to their diameter, of only 24 nm, single microtubules are extremely challenging to image without the use of extrinsic contrast agents. As a result, fluorescence tagging is the common method to visualize their motility. However, such investigation is limited by photobleaching and phototoxicity. We experimentally demonstrate the capability of combining label-free spatial light interference microscopy (SLIM) with numerical processing for imaging single microtubules in a gliding assay. SLIM combines four different intensity images to obtain the optical path length map associated with the sample. Because of the use of broadband fields, the sensitivity to path length is better than 1 nm without (temporal) averaging and better than 0.1 nm upon averaging. Our results indicate that SLIM can image the dynamics of microtubules in a full field of view, of 200 × 200 μm(2), over many hours. Modeling the microtubule transport via the diffusion-advection equation, we found that the dispersion relation yields the standard deviation of the velocity distribution, without the need for tracking individual tubes. Interestingly, during a 2 h window, the microtubules begin to decelerate, at 100 pm/s(2) over a 20 min period. Thus, SLIM is likely to serve as a useful tool for understanding molecular motor activity, especially over large time scales, where fluorescence methods are of limited utility.

  8. Dynein and mast/orbit/CLASP have antagonistic roles in regulating kinetochore-microtubule plus-end dynamics.

    Science.gov (United States)

    Reis, Rita; Feijão, Tália; Gouveia, Susana; Pereira, António J; Matos, Irina; Sampaio, Paula; Maiato, Helder; Sunkel, Claudio E

    2009-07-15

    Establishment and maintenance of the mitotic spindle requires the balanced activity of microtubule-associated proteins and motors. In this study we have addressed how the microtubule plus-end tracking protein mast/orbit/CLASP and cytoplasmic dynein regulate this process in Drosophila melanogaster embryos and S2 cells. We show that mast accumulates at kinetochores early in mitosis, which is followed by a poleward streaming upon microtubule attachment. This leads to a reduction of mast levels at kinetochores during metaphase and anaphase that depends largely on the microtubule minus end-directed motor cytoplasmic dynein. Surprisingly, we also found that co-depletion of dynein rescues spindle bipolarity in mast-depleted cells, while restoring normal microtubule poleward flux. Our results suggest that mast and dynein have antagonistic roles in the local regulation of microtubule plus-end dynamics at kinetochores, which are important for the maintenance of spindle bipolarity and normal spindle length.

  9. KATNAL1 regulation of sertoli cell microtubule dynamics is essential for spermiogenesis and male fertility.

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    Lee B Smith

    Full Text Available Spermatogenesis is a complex process reliant upon interactions between germ cells (GC and supporting somatic cells. Testicular Sertoli cells (SC support GCs during maturation through physical attachment, the provision of nutrients, and protection from immunological attack. This role is facilitated by an active cytoskeleton of parallel microtubule arrays that permit transport of nutrients to GCs, as well as translocation of spermatids through the seminiferous epithelium during maturation. It is well established that chemical perturbation of SC microtubule remodelling leads to premature GC exfoliation demonstrating that microtubule remodelling is an essential component of male fertility, yet the genes responsible for this process remain unknown. Using a random ENU mutagenesis approach, we have identified a novel mouse line displaying male-specific infertility, due to a point mutation in the highly conserved ATPase domain of the novel KATANIN p60-related microtubule severing protein Katanin p60 subunit A-like1 (KATNAL1. We demonstrate that Katnal1 is expressed in testicular Sertoli cells (SC from 15.5 days post-coitum (dpc and that, consistent with chemical disruption models, loss of function of KATNAL1 leads to male-specific infertility through disruption of SC microtubule dynamics and premature exfoliation of spermatids from the seminiferous epithelium. The identification of KATNAL1 as an essential regulator of male fertility provides a significant novel entry point into advancing our understanding of how SC microtubule dynamics promotes male fertility. Such information will have resonance both for future treatment of male fertility and the development of non-hormonal male contraceptives.

  10. Enhanced Antitumor Activity with Combining Effect of mTOR Inhibition and Microtubule Stabilization in Hepatocellular Carcinoma

    Science.gov (United States)

    Zhou, Qian; Wong, Chi Hang; Lau, Cecilia Pik Yuk; Hui, Connie Wun Chun; Lui, Vivian Wai Yan; Chan, Stephen Lam; Yeo, Winnie

    2013-01-01

    Mammalian target of rapamycin (mTOR) and the microtubules are shown to be potential targets for treating hepatocellular carcinoma (HCC). PI3K/Akt/mTOR activation is associated with resistance to microtubule inhibitors. Here, we evaluated the antitumor activity by cotargeting of the mTOR (using allosteric mTOR inhibitor everolimus) and the microtubules (using novel microtubule-stabilizing agent patupilone) in HCC models. In vitro studies showed that either targeting mTOR signaling with everolimus or targeting microtubules with patupilone was able to suppress HCC cell growth in a dose-dependent manner. Cotargeting of the mTOR (by everolimus) and the microtubules (by patupilone, at low nM) resulted in enhanced growth inhibition in HCC cells (achieving maximal growth inhibition of 60–87%), demonstrating potent antitumor activity of this combination. In vivo studies showed that everolimus treatment alone for two weeks was able to inhibit the growth of Hep3B xenografts. Strikingly, the everolimus/patupilone combination induced a more significant antitumor activity. Mechanistic study demonstrated that this enhanced antitumor effect was accompanied by marked cell apoptosis induction and antiangiogenic activity, which were more significant than single-agent treatments. Our findings demonstrated that the everolimus/patupilone combination, which had potent antitumor activity, was a potential therapeutic strategy for HCC. PMID:23509629

  11. Enhanced Antitumor Activity with Combining Effect of mTOR Inhibition and Microtubule Stabilization in Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Qian Zhou

    2013-01-01

    Full Text Available Mammalian target of rapamycin (mTOR and the microtubules are shown to be potential targets for treating hepatocellular carcinoma (HCC. PI3K/Akt/mTOR activation is associated with resistance to microtubule inhibitors. Here, we evaluated the antitumor activity by cotargeting of the mTOR (using allosteric mTOR inhibitor everolimus and the microtubules (using novel microtubule-stabilizing agent patupilone in HCC models. In vitro studies showed that either targeting mTOR signaling with everolimus or targeting microtubules with patupilone was able to suppress HCC cell growth in a dose-dependent manner. Cotargeting of the mTOR (by everolimus and the microtubules (by patupilone, at low nM resulted in enhanced growth inhibition in HCC cells (achieving maximal growth inhibition of 60–87%, demonstrating potent antitumor activity of this combination. In vivo studies showed that everolimus treatment alone for two weeks was able to inhibit the growth of Hep3B xenografts. Strikingly, the everolimus/patupilone combination induced a more significant antitumor activity. Mechanistic study demonstrated that this enhanced antitumor effect was accompanied by marked cell apoptosis induction and antiangiogenic activity, which were more significant than single-agent treatments. Our findings demonstrated that the everolimus/patupilone combination, which had potent antitumor activity, was a potential therapeutic strategy for HCC.

  12. Synthesis and biological assessment of simplified analogues of the potent microtubule stabilizer (+)-discodermolide.

    Science.gov (United States)

    Mínguez, José M; Kim, Sun-Young; Giuliano, Kenneth A; Balachandran, Raghavan; Madiraju, Charitha; Day, Billy W; Curran, Dennis P

    2003-07-31

    An efficient, convergent and stereocontrolled synthesis of simplified analogues of the potent antimitotic agent (+)-discodermolide has been achieved and several small libraries have been prepared. In all the libraries, the discodermolide methyl groups at C14 and C16 and the C7 hydroxy group were removed and the lactone was replaced by simple esters. Other modifications introduced in each series of analogues were related to C11, C17 and C19 of the natural product. Key elements of the synthetic strategy included (a) elaboration of the main subunits from a common intermediate and (b) fragment couplings using Wittig reactions to install the (Z)-olefins. Library components were analyzed for microtubule-stabilizing actions in vitro, for displacement of [3H]paclitaxel from its binding site on tubulin, for antiproliferative activity against human carcinoma cells, and for cell signaling and mitotic spindle alterations by a multiparameter fluorescence cell-based screening technique. The results show that even significant structural simplification can lead to analogues with actions related to microtubule targeting.

  13. Titanium dioxide nanoparticles alter cellular morphology via disturbing the microtubule dynamics

    Science.gov (United States)

    Mao, Zhilei; Xu, Bo; Ji, Xiaoli; Zhou, Kun; Zhang, Xuemei; Chen, Minjian; Han, Xiumei; Tang, Qiusha; Wang, Xinru; Xia, Yankai

    2015-04-01

    Titanium dioxide (TiO2) nanoparticles (NPs) have been widely used in our daily lives, for example, in the areas of sunscreens, cosmetics, toothpastes, food products, and nanomedical reagents. Recently, increasing concern has been raised about their neurotoxicity, but the mechanisms underlying such toxic effects are still unknown. In this work, we employed a human neuroblastoma cell line (SH-SY5Y) to study the effects of TiO2 NPs on neurological systems. Our results showed that TiO2 NPs did not affect cell viability but induced noticeable morphological changes until 100 μg ml-1. Immunofluorescence detection showed disorder, disruption, retraction, and decreased intensity of the microtubules after TiO2 NPs treatment. Both α and β tubule expressions did not change in the TiO2 NP-treated group, but the percentage of soluble tubules was increased. A microtubule dynamic study in living cells indicated that TiO2 NPs caused a lower growth rate and a higher shortening rate of microtubules as well as shortened lifetimes of de novo microtubules. TiO2 NPs did not cause changes in the expression and phosphorylation state of tau proteins, but a tau-TiO2 NP interaction was observed. TiO2 NPs could interact with tubule heterodimers, microtubules and tau proteins, which led to the instability of microtubules, thus contributing to the neurotoxicity of TiO2 NPs.Titanium dioxide (TiO2) nanoparticles (NPs) have been widely used in our daily lives, for example, in the areas of sunscreens, cosmetics, toothpastes, food products, and nanomedical reagents. Recently, increasing concern has been raised about their neurotoxicity, but the mechanisms underlying such toxic effects are still unknown. In this work, we employed a human neuroblastoma cell line (SH-SY5Y) to study the effects of TiO2 NPs on neurological systems. Our results showed that TiO2 NPs did not affect cell viability but induced noticeable morphological changes until 100 μg ml-1. Immunofluorescence detection showed disorder

  14. Differential effects of natural product microtubule stabilizers on microtubule assembly: single agent and combination studies with taxol, epothilone B, and discodermolide.

    Science.gov (United States)

    Gertsch, Jürg; Meier, Sarah; Müller, Martin; Altmann, Karl-Heinz

    2009-01-01

    A systematic comparison has been performed of the morphology and stability of microtubules (MTs) induced by the potent microtubule-stabilizing agents (MSAs) taxol, epothilone B (Epo B), and discodermolide (DDM) under GTP-free conditions. DDM-induced tubulin polymerization occurred significantly faster than that induced by taxol and Epo B. At the same time, tubulin polymers assembled from soluble tubulin by DDM were morphologically distinct (shorter and less ordered) from those induced by either taxol or Epo B, as demonstrated by electron microscopy. Exposure of MSA-induced tubulin polymers to ultrasound revealed the DDM-based polymers to be less stable to this type of physical stress than those formed with either Epo B or taxol. Interestingly, MT assembly in the presence of both DDM and taxol appeared to produce a distinct new type of MT polymer with a mixed morphology between those of DDM- and taxol-induced structures. The observed differences in MT morphology and stability might be related, at least partly, to differences in intramicrotubular tubulin isotype distribution, as DDM showed a different pattern of beta-tubulin isotype usage in the assembly process.

  15. LARG and mDia1 link Galpha12/13 to cell polarity and microtubule dynamics.

    Science.gov (United States)

    Goulimari, Polyxeni; Knieling, Helga; Engel, Ulrike; Grosse, Robert

    2008-01-01

    Regulation of cell polarity is a process observed in all cells. During directed migration, cells orientate their microtubule cytoskeleton and the microtubule-organizing-center (MTOC), which involves integrins and downstream Cdc42 and glycogen synthase kinase-3beta activity. However, the contribution of G protein-coupled receptor signal transduction for MTOC polarity is less well understood. Here, we report that the heterotrimeric Galpha(12) and Galpha(13) proteins are necessary for MTOC polarity and microtubule dynamics based on studies using Galpha(12/13)-deficient mouse embryonic fibroblasts. Cell polarization involves the Galpha(12/13)-interacting leukemia-associated RhoGEF (LARG) and the actin-nucleating diaphanous formin mDia1. Interestingly, LARG associates with pericentrin and localizes to the MTOC and along microtubule tracks. We propose that Galpha(12/13) proteins exert essential functions linking extracellular signals to microtubule dynamics and cell polarity via RhoGEF and formin activity.

  16. Proteomics of cancer cell lines resistant to microtubule-stabilizing agents

    DEFF Research Database (Denmark)

    Albrethsen, Jakob; Angeletti, Ruth H; Horwitz, Susan Band

    2014-01-01

    resistance to the class of MIAs known as microtubule-stabilizing agents (MSA). The human lung cancer cell line A549 was compared with two drug-resistant daughter cell lines, a taxol-resistant cell line (AT12) and an epothilone B (EpoB)-resistant cell line (EpoB40). The ovarian cancer cell line Hey......-resistant cells. Differential abundance of 14-3-3σ, galectin-1 and phosphorylation of stathmin are worthy of further studies as candidate predictive biomarkers for MSAs. This is especially true for galectin-1, a β-galactose-binding lectin that mediates tumor invasion and metastasis. Galectin-1 was greatly...... in resistance to MSAs....

  17. Erucin, the major isothiocyanate in arugula (Eruca sativa, inhibits proliferation of MCF7 tumor cells by suppressing microtubule dynamics.

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    Olga Azarenko

    Full Text Available Consumption of cruciferous vegetables is associated with reduced risk of various types of cancer. Isothiocyanates including sulforaphane and erucin are believed to be responsible for this activity. Erucin [1-isothiocyanato-4-(methylthiobutane], which is metabolically and structurally related to sulforaphane, is present in large quantities in arugula (Eruca sativa, Mill., kohlrabi and Chinese cabbage. However, its cancer preventive mechanisms remain poorly understood. We found that erucin inhibits proliferation of MCF7 breast cancer cells (IC50 = 28 µM in parallel with cell cycle arrest at mitosis (IC50 = 13 µM and apoptosis, by a mechanism consistent with impairment of microtubule dynamics. Concentrations of 5-15 µM erucin suppressed the dynamic instability of microtubules during interphase in the cells. Most dynamic instability parameters were inhibited, including the rates and extents of growing and shortening, the switching frequencies between growing and shortening, and the overall dynamicity. Much higher erucin concentrations were required to reduce the microtubule polymer mass. In addition, erucin suppressed dynamic instability of microtubules reassembled from purified tubulin in similar fashion. The effects of erucin on microtubule dynamics, like those of sulforaphane, are similar qualitatively to those of much more powerful clinically-used microtubule-targeting anticancer drugs, including taxanes and the vinca alkaloids. The results suggest that suppression of microtubule dynamics by erucin and the resulting impairment of critically important microtubule-dependent cell functions such as mitosis, cell migration and microtubule-based transport may be important in its cancer preventive activities.

  18. Erucin, the major isothiocyanate in arugula (Eruca sativa), inhibits proliferation of MCF7 tumor cells by suppressing microtubule dynamics.

    Science.gov (United States)

    Azarenko, Olga; Jordan, Mary Ann; Wilson, Leslie

    2014-01-01

    Consumption of cruciferous vegetables is associated with reduced risk of various types of cancer. Isothiocyanates including sulforaphane and erucin are believed to be responsible for this activity. Erucin [1-isothiocyanato-4-(methylthio)butane], which is metabolically and structurally related to sulforaphane, is present in large quantities in arugula (Eruca sativa, Mill.), kohlrabi and Chinese cabbage. However, its cancer preventive mechanisms remain poorly understood. We found that erucin inhibits proliferation of MCF7 breast cancer cells (IC50 = 28 µM) in parallel with cell cycle arrest at mitosis (IC50 = 13 µM) and apoptosis, by a mechanism consistent with impairment of microtubule dynamics. Concentrations of 5-15 µM erucin suppressed the dynamic instability of microtubules during interphase in the cells. Most dynamic instability parameters were inhibited, including the rates and extents of growing and shortening, the switching frequencies between growing and shortening, and the overall dynamicity. Much higher erucin concentrations were required to reduce the microtubule polymer mass. In addition, erucin suppressed dynamic instability of microtubules reassembled from purified tubulin in similar fashion. The effects of erucin on microtubule dynamics, like those of sulforaphane, are similar qualitatively to those of much more powerful clinically-used microtubule-targeting anticancer drugs, including taxanes and the vinca alkaloids. The results suggest that suppression of microtubule dynamics by erucin and the resulting impairment of critically important microtubule-dependent cell functions such as mitosis, cell migration and microtubule-based transport may be important in its cancer preventive activities.

  19. AKAP9, a Regulator of Microtubule Dynamics, Contributes to Blood-Testis Barrier Function.

    Science.gov (United States)

    Venkatesh, Deepak; Mruk, Dolores; Herter, Jan M; Cullere, Xavier; Chojnacka, Katarzyna; Cheng, C Yan; Mayadas, Tanya N

    2016-02-01

    The blood-testis barrier (BTB), formed between adjacent Sertoli cells, undergoes extensive remodeling to facilitate the transport of preleptotene spermatocytes across the barrier from the basal to apical compartments of the seminiferous tubules for further development and maturation into spermatozoa. The actin cytoskeleton serves unique structural and supporting roles in this process, but little is known about the role of microtubules and their regulators during BTB restructuring. The large isoform of the cAMP-responsive scaffold protein AKAP9 regulates microtubule dynamics and nucleation at the Golgi. We found that conditional deletion of Akap9 in mice after the initial formation of the BTB at puberty leads to infertility. Akap9 deletion results in marked alterations in the organization of microtubules in Sertoli cells and a loss of barrier integrity despite a relatively intact, albeit more apically localized F-actin and BTB tight junctional proteins. These changes are accompanied by a loss of haploid spermatids due to impeded meiosis. The barrier, however, progressively reseals in older Akap9 null mice, which correlates with a reduction in germ cell apoptosis and a greater incidence of meiosis. However, spermiogenesis remains defective, suggesting additional roles for AKAP9 in this process. Together, our data suggest that AKAP9 and, by inference, the regulation of the microtubule network are critical for BTB function and subsequent germ cell development during spermatogenesis.

  20. Tobacco mutants with reduced microtubule dynamics are less susceptible to TMV.

    Science.gov (United States)

    Ouko, Maurice O; Sambade, Adrian; Brandner, Katrin; Niehl, Annette; Peña, Eduardo; Ahad, Abdul; Heinlein, Manfred; Nick, Peter

    2010-06-01

    A panel of seven SR1 tobacco mutants (ATER1 to ATER7) derived via T-DNA activation tagging and screening for resistance to a microtubule assembly inhibitor, ethyl phenyl carbamate, were used to study the role of microtubules during infection and spread of tobacco mosaic virus (TMV). In one of these lines, ATER2, alpha-tubulin is shifted from the tyrosinylated into the detyrosinated form, and the microtubule plus-end marker GFP-EB1 moves significantly slower when expressed in the background of the ATER2 mutant as compared with the SR1 wild type. The efficiency of cell-to-cell movement of TMV encoding GFP-tagged movement protein (MP-GFP) is reduced in ATER2 accompanied by a reduced association of MP-GFP with plasmodesmata. This mutant is also more tolerant to viral infection as compared with the SR1 wild type, implying that reduced microtubule dynamics confer a comparative advantage in face of TMV infection.

  1. Active Erk Regulates Microtubule Stability in H-ras-Transformed Cells

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    Rene E. Harrison

    2001-01-01

    Full Text Available Increasing evidence suggests that activated erk regulates cell functions, at least in part, by mechanisms that do not require gene transcription. Here we show that the map kinase, erk, decorates microtubules (MTs and mitotic spindles in both parental and mutant active rastransfected 10T1 /2 fibroblasts and MCF10A breast epithelial cells. Approximately 20% of total cellular erk decorated MTs in both cell lines. A greater proportion of activated erk was associated with MTs in the presence of mutant active H-ras than in parental cells. Activation of erk by the ras pathway coincided with a decrease in the stability of MT, as detected by a stability marker. The MKK1 inhibitor, PD98059 and transfection of a dominant negative MKK1 blocked ras-induced instability of MTs but did not modify the association of erk with MTs or affect MT stability of the parental cells. These results indicate that the subset of active erk kinase that associates with MTs contributes to their instability in the presence of a mutant active ras. The MT-associated subset of active erk likely contributes to the enhanced invasive and proliferative abilities of cells containing mutant active H-ras.

  2. Daple Coordinates Planar Polarized Microtubule Dynamics in Ependymal Cells and Contributes to Hydrocephalus

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    Maki Takagishi

    2017-07-01

    Full Text Available Motile cilia in ependymal cells, which line the cerebral ventricles, exhibit a coordinated beating motion that drives directional cerebrospinal fluid (CSF flow and guides neuroblast migration. At the apical cortex of these multi-ciliated cells, asymmetric localization of planar cell polarity (PCP proteins is required for the planar polarization of microtubule dynamics, which coordinates cilia orientation. Daple is a disheveled-associating protein that controls the non-canonical Wnt signaling pathway and cell motility. Here, we show that Daple-deficient mice present hydrocephalus and their ependymal cilia lack coordinated orientation. Daple regulates microtubule dynamics at the anterior side of ependymal cells, which in turn orients the cilial basal bodies required for the directional cerebrospinal fluid flow. These results demonstrate an important role for Daple in planar polarity in motile cilia and provide a framework for understanding the mechanisms and functions of planar polarization in the ependymal cells.

  3. PAR-1/MARK: a kinase essential for maintaining the dynamic state of microtubules.

    Science.gov (United States)

    Hayashi, Kenji; Suzuki, Atsushi; Ohno, Shigeo

    2012-01-01

    The serine/threonine kinase, PAR-1, is an essential component of the evolutionary-conserved polarity-regulating system, PAR-aPKC system, which plays indispensable roles in establishing asymmetric protein distributions and cell polarity in various biological contexts (Suzuki, A. and Ohno, S. (2006). J. Cell Sci., 119: 979-987; Matenia, D. and Mandelkow, E.M. (2009). Trends Biochem. Sci., 34: 332-342). PAR-1 is also known as MARK, which phosphorylates classical microtubule-associated proteins (MAPs) and detaches MAPs from microtubules (Matenia, D. and Mandelkow, E.M. (2009). Trends Biochem. Sci., 34: 332-342). This MARK activity of PAR-1 suggests its role in microtubule (MT) dynamics, but surprisingly, only few studies have been carried out to address this issue. Here, we summarize our recent study on live imaging analysis of MT dynamics in PAR-1b-depleted cells, which clearly demonstrated the positive role of PAR-1b in maintaining MT dynamics (Hayashi, K., Suzuki, A., Hirai, S., Kurihara, Y., Hoogenraad, C.C., and Ohno, S. (2011). J. Neurosci., 31: 12094-12103). Importantly, our results further revealed the novel physiological function of PAR-1b in maintaining dendritic spine morphology in mature neurons.

  4. Synchrotron Small Angle X-Ray Scattering Quantitatively Detects Angstrom Level Changes in the Average Radius of Taxol-Stabilized Microtubules Decorated with the Microtubule-Associated-Protein Tau

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Myung Chul; Raviv, Uri; Needleman, Daniel J; Safinya, Cyrus R [Materials Department, University of California Santa Barbara, CA 93106 (United States); Li, Youli [Materials Research Laboratory, University of California Santa Barbara, CA 93106 (United States); Miller, Herbert P; Wilson, Leslie; Feinstein, Stuart C [Molecular, Cellular, and Developmental Biology Departments, University of California Santa Barbara, CA 93106 (United States); Kim, Mahn Won, E-mail: myungchul.choi@gmail.com, E-mail: safinya@mrl.ucsb.edu [Department of Physics, KAIST, Daejeon 305-701, S. Korea (Korea, Republic of)

    2011-01-01

    With the emerging proteomics era the scientific community is beginning the daunting task of understanding the structures and functions of a large number of self-assembling proteins. Here, our study was concerned with the effect of the microtubule-associated-protein (MAP) tau on the assembled structure of taxol-stabilized microtubules. Significantly, the synchrotron small angle x-ray scattering (SAXS) technique is able to quantitatively detect angstrom level changes in the average diameter of the microtubules modeled as a simple hollow nanotube with a fixed wall thickness. We show that the electrostatic binding of MAP tau isoforms to taxol-stabilized MTs leads to a controlled increase in the average radius of microtubules with increasing coverage of tau on the MT surface. The increase in the average diameter results from an increase in the distribution of protofilament numbers in MTs upon binding of MAP tau.

  5. Combing and self-assembly phenomena in dry films of Taxol-stabilized microtubules

    Directory of Open Access Journals (Sweden)

    Rose Franck

    2007-01-01

    Full Text Available AbstractMicrotubules are filamentous proteins that act as a substrate for the translocation of motor proteins. As such, they may be envisioned as a scaffold for the self-assembly of functional materials and devices. Physisorption, self-assembly and combing are here investigated as a potential prelude to microtubule-templated self-assembly. Dense films of self-assembled microtubules were successfully produced, as well as patterns of both dendritic and non-dendritic bundles of microtubules. They are presented in the present paper and the mechanism of their formation is discussed.

  6. A TOGL domain specifically targets yeast CLASP to kinetochores to stabilize kinetochore microtubules.

    Science.gov (United States)

    Funk, Caroline; Schmeiser, Verena; Ortiz, Jennifer; Lechner, Johannes

    2014-05-26

    Cytoplasmic linker-associated proteins (CLASPs) are proposed to function in cell division based on their ability to bind tubulin via arrayed tumor overexpressed gene (TOG)-like (TOGL) domains. Structure predictions suggest that CLASPs have at least two TOGL domains. We show that only TOGL2 of Saccharomyces cerevisiae CLASP Stu1 binds to tubulin and is required for polymerization of spindle microtubules (MTs) in vivo. In contrast, TOGL1 recruits Stu1 to kinetochores (KTs), where it is essential for the stability and tension-dependent regulation of KT MTs. Stu1 is also recruited to spindle MTs by different mechanisms depending on the mitotic phase: in metaphase, Stu1 binds directly to the MT lattice, whereas in anaphase, it is localized indirectly to the spindle midzone. In both phases, the activity of TOGL2 is essential for interpolar MT stability, whereas TOGL1 is not involved. Thus, the two TOGL domains of yeast CLASP have different activities and execute distinct mitotic functions. © 2014 Funk et al.

  7. The ability to induce microtubule acetylation is a general feature of formin proteins.

    Directory of Open Access Journals (Sweden)

    Susan F Thurston

    Full Text Available Cytoplasmic microtubules exist as distinct dynamic and stable populations within the cell. Stable microtubules direct and maintain cell polarity and it is thought that their stabilization is dependent on coordinative organization between the microtubule network and the actin cytoskeleton. A growing body of work suggests that some members of the formin family of actin remodeling proteins also regulate microtubule organization and stability. For example, we showed previously that expression of the novel formin INF1 is sufficient to induce microtubule stabilization and tubulin acetylation, but not tubulin detyrosination. An important issue with respect to the relationship between formins and microtubules is the determination of which formin domains mediate microtubule stabilization. INF1 has a distinct microtubule-binding domain at its C-terminus and the endogenous INF1 protein is associated with the microtubule network. Surprisingly, the INF1 microtubule-binding domain is not essential for INF1-induced microtubule acetylation. We show here that expression of the isolated FH1 + FH2 functional unit of INF1 is sufficient to induce microtubule acetylation independent of the INF1 microtubule-binding domain. It is not yet clear whether or not microtubule stabilization is a general property of all mammalian formins; therefore we expressed constitutively active derivatives of thirteen of the fifteen mammalian formin proteins in HeLa and NIH3T3 cells and measured their effects on stress fiber formation, MT organization and MT acetylation. We found that expression of the FH1 + FH2 unit of the majority of mammalian formins is sufficient to induce microtubule acetylation. Our results suggest that the regulation of microtubule acetylation is likely a general formin activity and that the FH2 should be thought of as a dual-function domain capable of regulating both actin and microtubule networks.

  8. Enhanced dynamic instability of microtubules in a ROS free inert environment.

    Science.gov (United States)

    Islam, Md Sirajul; Kabir, Arif Md Rashedul; Inoue, Daisuke; Sada, Kazuki; Kakugo, Akira

    2016-04-01

    Reactive oxygen species (ROS), one of the regulators in various biological processes, have recently been suspected to modulate microtubule (MT) dynamics in cells. However due to complicated cellular environment and unavailability of any in vitro investigation, no detail is understood yet. Here, by performing simple in vitro investigations, we have unveiled the effect of ROS on MT dynamics. By studying dynamic instability of MTs in a ROS free environment and comparing with that in the presence of ROS, we disclosed that MTs showed enhanced dynamics in the ROS free environment. All the parameters that define dynamic instability of MTs e.g., growth and shrinkage rates, rescue and catastrophe frequencies were significantly affected by the presence of ROS. This work clearly reveals the role of ROS in modulating MT dynamics in vitro, and would be a great help in understanding the role of ROS in regulation of MT dynamics in cells.

  9. Fission yeast mtr1p regulates interphase microtubule cortical dwell-time

    Directory of Open Access Journals (Sweden)

    Frédérique Carlier-Grynkorn

    2014-06-01

    Full Text Available The microtubule cytoskeleton plays important roles in cell polarity, motility and division. Microtubules inherently undergo dynamic instability, stochastically switching between phases of growth and shrinkage. In cells, some microtubule-associated proteins (MAPs and molecular motors can further modulate microtubule dynamics. We present here the fission yeast mtr1+, a new regulator of microtubule dynamics that appears to be not a MAP or a motor. mtr1-deletion (mtr1Δ primarily results in longer microtubule dwell-time at the cell tip cortex, suggesting that mtr1p acts directly or indirectly as a destabilizer of microtubules. mtr1p is antagonistic to mal3p, the ortholog of mammalian EB1, which stabilizes microtubules. mal3Δ results in short microtubules, but can be partially rescued by mtr1Δ, as the double mutant mal3Δ mtr1Δ exhibits longer microtubules than mal3Δ single mutant. By sequence homology, mtr1p is predicted to be a component of the ribosomal quality control complex. Intriguingly, deletion of a predicted ribosomal gene, rps1801, also resulted in longer microtubule dwell-time similar to mtr1Δ. The double-mutant mal3Δ rps1801Δ also exhibits longer microtubules than mal3Δ single mutant alone. Our study suggests a possible involvement of mtr1p and the ribosome complex in modulating microtubule dynamics.

  10. Regulation of Kif15 localization and motility by the C-terminus of TPX2 and microtubule dynamics

    Science.gov (United States)

    Mann, Barbara J.; Balchand, Sai K.; Wadsworth, Patricia

    2017-01-01

    Mitotic motor proteins generate force to establish and maintain spindle bipolarity, but how they are temporally and spatially regulated in vivo is unclear. Prior work demonstrated that a microtubule-associated protein, TPX2, targets kinesin-5 and kinesin-12 motors to spindle microtubules. The C-terminal domain of TPX2 contributes to the localization and motility of the kinesin-5, Eg5, but it is not known whether this domain regulates kinesin-12, Kif15. We found that the C-terminal domain of TPX2 contributes to the localization of Kif15 to spindle microtubules in cells and suppresses motor walking in vitro. Kif15 and Eg5 are partially redundant motors, and overexpressed Kif15 can drive spindle formation in the absence of Eg5 activity. Kif15-dependent bipolar spindle formation in vivo requires the C-terminal domain of TPX2. In the spindle, fluorescent puncta of GFP-Kif15 move toward the equatorial region at a rate equivalent to microtubule growth. Reduction of microtubule growth with paclitaxel suppresses GFP-Kif15 motility, demonstrating that dynamic microtubules contribute to Kif15 behavior. Our results show that the C-terminal region of TPX2 regulates Kif15 in vitro, contributes to motor localization in cells, and is required for Kif15 force generation in vivo and further reveal that dynamic microtubules contribute to Kif15 behavior in vivo. PMID:27852894

  11. Mathematical modeling of the intracellular protein dynamics: the importance of active transport along microtubules.

    Science.gov (United States)

    Szymańska, Zuzanna; Parisot, Martin; Lachowicz, Mirosław

    2014-12-21

    In this paper we propose a mathematical model of protein and mRNA transport inside a cell. The spatio-temporal model takes into account the active transport along microtubules in the cytoplasm as well as diffusion and is able to reproduce the oscillatory changes in protein concentration observed in many experimental data. In the model the protein and the mRNA interact with each other that allows us to classify the model as a simple gene regulatory network. The proposed model is generic and may be adapted to specific signaling pathways. On the basis of numerical simulations, we formulate a new hypothesis that the oscillatory dynamics is allowed by the mRNA active transport along microtubules from the nucleus to distant locations.

  12. Mechanism of dynamic reorientation of cortical microtubules due to mechanical stress

    CERN Document Server

    Muratov, Alexander

    2015-01-01

    Directional growth caused by gravitropism and corresponding bending of plant cells has been explored since 19th century, however, many aspects of mechanisms underlying the perception of gravity at the molecular level are still not well known. Perception of gravity in root and shoot gravitropisms is usually attributed to gravisensitive cells, called statocytes, which exploit sedimentation of macroscopic and heavy organelles, amyloplasts, to sense the direction of gravity. Gravity stimulus is then transduced into distal elongation zone, which is several mm far from statocytes, where it causes stretching. It is suggested that gravity stimulus is conveyed by gradients in auxin flux. We propose a theoretical model that may explain how concentration gradients and/or stretching may indirectly affect the global orientation of cortical microtubules, attached to the cell membrane and induce their dynamic reorientation perpendicular to the gradients. In turn, oriented microtubules arrays direct the growth and orientatio...

  13. The Salmonella effector SseJ disrupts microtubule dynamics when ectopically expressed in normal rat kidney cells

    Science.gov (United States)

    Raines, Sally A.; Hodgkinson, Michael R.; Dowle, Adam A.

    2017-01-01

    Salmonella effector protein SseJ is secreted by Salmonella into the host cell cytoplasm where it can then modify host cell processes. Whilst host cell small GTPase RhoA has previously been shown to activate the acyl-transferase activity of SseJ we show here an un-described effect of SseJ protein production upon microtubule dynamism. SseJ prevents microtubule collapse and this is independent of SseJ’s acyl-transferase activity. We speculate that the effects of SseJ on microtubules would be mediated via its known interactions with the small GTPases of the Rho family. PMID:28235057

  14. Persistence Length of Stable Microtubules

    Science.gov (United States)

    Hawkins, Taviare; Mirigian, Matthew; Yasar, M. Selcuk; Ross, Jennifer

    2011-03-01

    Microtubules are a vital component of the cytoskeleton. As the most rigid of the cytoskeleton filaments, they give shape and support to the cell. They are also essential for intracellular traffic by providing the roadways onto which organelles are transported, and they are required to reorganize during cellular division. To perform its function in the cell, the microtubule must be rigid yet dynamic. We are interested in how the mechanical properties of stable microtubules change over time. Some ``stable'' microtubules of the cell are recycled after days, such as in the axons of neurons or the cilia and flagella. We measured the persistence length of freely fluctuating taxol-stabilized microtubules over the span of a week and analyzed them via Fourier decomposition. As measured on a daily basis, the persistence length is independent of the contour length. Although measured over the span of the week, the accuracy of the measurement and the persistence length varies. We also studied how fluorescently-labeling the microtubule affects the persistence length and observed that a higher labeling ratio corresponded to greater flexibility. National Science Foundation Grant No: 0928540 to JLR.

  15. ATX-2, the C. elegans Ortholog of Human Ataxin-2, Regulates Centrosome Size and Microtubule Dynamics.

    Directory of Open Access Journals (Sweden)

    Michael D Stubenvoll

    2016-09-01

    Full Text Available Centrosomes are critical sites for orchestrating microtubule dynamics, and exhibit dynamic changes in size during the cell cycle. As cells progress to mitosis, centrosomes recruit more microtubules (MT to form mitotic bipolar spindles that ensure proper chromosome segregation. We report a new role for ATX-2, a C. elegans ortholog of Human Ataxin-2, in regulating centrosome size and MT dynamics. ATX-2, an RNA-binding protein, forms a complex with SZY-20 in an RNA-independent fashion. Depleting ATX-2 results in embryonic lethality and cytokinesis failure, and restores centrosome duplication to zyg-1 mutants. In this pathway, SZY-20 promotes ATX-2 abundance, which inversely correlates with centrosome size. Centrosomes depleted of ATX-2 exhibit elevated levels of centrosome factors (ZYG-1, SPD-5, γ-Tubulin, increasing MT nucleating activity but impeding MT growth. We show that ATX-2 influences MT behavior through γ-Tubulin at the centrosome. Our data suggest that RNA-binding proteins play an active role in controlling MT dynamics and provide insight into the control of proper centrosome size and MT dynamics.

  16. [Study of a lysis medium stabilizing microfilaments and microtubules in vitro and in vivo].

    Science.gov (United States)

    Foucault, G; Raymond, M N; Coffe, G; Pudles, J

    1984-01-01

    Determination of experimental conditions which allow the evaluation of the variations in the ratio of non polymerized and polymerized forms of actin and tubulin during the reorganization of the cytoskeletal cell system is of most valuable importance. In order to prepare cell homogenates which would reflect the in vivo situation, we tested in vitro a lysis medium which stabilized both microfilaments and microtubules, which were determined by DNase inhibition assays and colchicine binding assays respectively. This lysis medium containing 10 mM potassium phosphate, 1mM magnesium chloride, 5 mM EGTA, 1 M hexylene glycol, 1% Triton X-100, pH 6.4, used at 4 degrees C a) diffused rapidly into the cells; b) did not denature actin and tubulin; c) did not displace the equilibrium between non polymerized and polymerized forms of actin and tubulin, allowing biochemical assays on cell homogenates; d) blocked the evolution of the cytoskeletal system and permitted structural studies; e) and allowed the decoration of microfilaments by heavy meromyosin.

  17. A model for the regulatory network controlling the dynamics of kinetochore microtubule plus-ends and poleward flux in metaphase.

    Science.gov (United States)

    Fernandez, Nicolas; Chang, Qiang; Buster, Daniel W; Sharp, David J; Ma, Ao

    2009-05-12

    Tight regulation of kinetochore microtubule dynamics is required to generate the appropriate position and movement of chromosomes on the mitotic spindle. A widely studied but mysterious aspect of this regulation occurs during metaphase when polymerization of kinetochore microtubule plus-ends is balanced by depolymerization at their minus-ends. Thus, kinetochore microtubules maintain a constant net length, allowing chromosomes to persist at the spindle equator, but consist of tubulin subunits that continually flux toward spindle poles. Here, we construct a feasible network of regulatory proteins for controlling kinetochore microtubule plus-end dynamics, which was combined with a Monte Carlo algorithm to simulate metaphase tubulin flux. We also test the network model by combining it with a force-balancing model explicitly taking force generators into account. Our data reveal how relatively simple interrelationships among proteins that stimulate microtubule plus-end polymerization, depolymerization, and dynamicity can induce robust flux while accurately predicting apparently contradictory results of knockdown experiments. The model also provides a simple and robust physical mechanism through which the regulatory networks at kinetochore microtubule plus- and minus-ends could communicate.

  18. Microtubule heterogeneity of Ornithogalum umbellatum ovary epidermal cells: non-stable cortical microtubules and stable lipotubuloid microtubules

    Directory of Open Access Journals (Sweden)

    Maria Kwiatkowska

    2011-07-01

    Full Text Available Lipotubuloids, structures containing lipid bodies and microtubules, are described in ovary epidermalcells of Ornithogalum umbellatum. Microtubules of lipotubuloids can be fixed in electron microscope fixativecontaining only buffered OsO4 or in glutaraldehyde with OsO4 post-fixation, or in a mixture of OsO4 and glutaraldehyde[1]. None of these substances fixes cortical microtubules of ovary epidermis of this plant which ischaracterized by dynamic longitudinal growth. However, cortical microtubules can be fixed with cold methanolaccording immunocytological methods with the use of b-tubulin antibodies and fluorescein. The existence ofcortical microtubules has also been evidenced by EM observations solely after the use of taxol, microtubulestabilizer, and fixation in a glutaraldehyde/OsO4 mixture. These microtubules mostly lie transversely, sometimesobliquely, and rarely parallel to the cell axis. Staining, using Ruthenium Red and silver hexamine, has revealedthat lipotubuloid microtubules surface is covered with polysaccharides. The presumption has been made thatthe presence of a polysaccharide layer enhances the stability of lipotubuloid microtubules.

  19. Misato Controls Mitotic Microtubule Generation by Stabilizing the TCP-1 Tubulin Chaperone Complex [corrected].

    Science.gov (United States)

    Palumbo, Valeria; Pellacani, Claudia; Heesom, Kate J; Rogala, Kacper B; Deane, Charlotte M; Mottier-Pavie, Violaine; Gatti, Maurizio; Bonaccorsi, Silvia; Wakefield, James G

    2015-06-29

    Mitotic spindles are primarily composed of microtubules (MTs), generated by polymerization of α- and β-Tubulin hetero-dimers. Tubulins undergo a series of protein folding and post-translational modifications in order to fulfill their functions. Defects in Tubulin polymerization dramatically affect spindle formation and disrupt chromosome segregation. We recently described a role for the product of the conserved misato (mst) gene in regulating mitotic MT generation in flies, but the molecular function of Mst remains unknown. Here, we use affinity purification mass spectrometry (AP-MS) to identify interacting partners of Mst in the Drosophila embryo. We demonstrate that Mst associates stoichiometrically with the hetero-octameric Tubulin Chaperone Protein-1 (TCP-1) complex, with the hetero-hexameric Tubulin Prefoldin complex, and with proteins having conserved roles in generating MT-competent Tubulin. We show that RNAi-mediated in vivo depletion of any TCP-1 subunit phenocopies the effects of mutations in mst or the Prefoldin-encoding gene merry-go-round (mgr), leading to monopolar and disorganized mitotic spindles containing few MTs. Crucially, we demonstrate that Mst, but not Mgr, is required for TCP-1 complex stability and that both the efficiency of Tubulin polymerization and Tubulin stability are drastically compromised in mst mutants. Moreover, our structural bioinformatic analyses indicate that Mst resembles the three-dimensional structure of Tubulin monomers and might therefore occupy the TCP-1 complex central cavity. Collectively, our results suggest that Mst acts as a co-factor of the TCP-1 complex, playing an essential role in the Tubulin-folding processes required for proper assembly of spindle MTs.

  20. An anillin-Ect2 complex stabilizes central spindle microtubules at the cortex during cytokinesis.

    Directory of Open Access Journals (Sweden)

    Paul Frenette

    Full Text Available Cytokinesis occurs due to the RhoA-dependent ingression of an actomyosin ring. During anaphase, the Rho GEF (guanine nucleotide exchange factor Ect2 is recruited to the central spindle via its interaction with MgcRacGAP/Cyk-4, and activates RhoA in the central plane of the cell. Ect2 also localizes to the cortex, where it has access to RhoA. The N-terminus of Ect2 binds to Cyk-4, and the C-terminus contains conserved DH (Dbl homologous and PH (Pleckstrin Homology domains with GEF activity. The PH domain is required for Ect2's cortical localization, but its molecular function is not known. In cultured human cells, we found that the PH domain interacts with anillin, a contractile ring protein that scaffolds actin and myosin and interacts with RhoA. The anillin-Ect2 interaction may require Ect2's association with lipids, since a novel mutation in the PH domain, which disrupts phospholipid association, weakens their interaction. An anillin-RacGAP50C (homologue of Cyk-4 complex was previously described in Drosophila, which may crosslink the central spindle to the cortex to stabilize the position of the contractile ring. Our data supports an analogous function for the anillin-Ect2 complex in human cells and one hypothesis is that this complex has functionally replaced the Drosophila anillin-RacGAP50C complex. Complexes between central spindle proteins and cortical proteins could regulate the position of the contractile ring by stabilizing microtubule-cortical interactions at the division plane to ensure the generation of active RhoA in a discrete zone.

  1. PACSIN1, a Tau-interacting protein, regulates axonal elongation and branching by facilitating microtubule instability.

    Science.gov (United States)

    Liu, Yingying; Lv, Kaosheng; Li, Zenglong; Yu, Albert C H; Chen, Jianguo; Teng, Junlin

    2012-11-16

    Tau is a major member of the neuronal microtubule-associated proteins. It promotes tubulin assembly and stabilizes axonal microtubules. Previous studies have demonstrated that Tau forms cross-bridges between microtubules, with some particles located on cross-bridges, suggesting that some proteins interact with Tau and might be involved in regulating Tau-related microtubule dynamics. This study reports that PACSIN1 interacts with Tau in axon. PACSIN1 blockade results in impaired axonal elongation and a higher number of primary axonal branches in mouse dorsal root ganglia neurons, which is induced by increasing the binding ability of Tau to microtubules. In PACSIN1-blocked dorsal root ganglia neurons, a greater amount of Tau is inclined to accumulate in the central domain of growth cones, and it promotes the stability of the microtubule network. Taken together, these results suggest that PACSIN1 is an important Tau binding partner in regulating microtubule dynamics and forming axonal plasticity.

  2. Rac-GTPases Regulate Microtubule Stability and Axon Growth of Cortical GABAergic Interneurons.

    Science.gov (United States)

    Tivodar, Simona; Kalemaki, Katerina; Kounoupa, Zouzana; Vidaki, Marina; Theodorakis, Kostas; Denaxa, Myrto; Kessaris, Nicoletta; de Curtis, Ivan; Pachnis, Vassilis; Karagogeos, Domna

    2015-09-01

    Cortical interneurons are characterized by extraordinary functional and morphological diversity. Although tremendous progress has been made in uncovering molecular and cellular mechanisms implicated in interneuron generation and function, several questions still remain open. Rho-GTPases have been implicated as intracellular mediators of numerous developmental processes such as cytoskeleton organization, vesicle trafficking, transcription, cell cycle progression, and apoptosis. Specifically in cortical interneurons, we have recently shown a cell-autonomous and stage-specific requirement for Rac1 activity within proliferating interneuron precursors. Conditional ablation of Rac1 in the medial ganglionic eminence leads to a 50% reduction of GABAergic interneurons in the postnatal cortex. Here we examine the additional role of Rac3 by analyzing Rac1/Rac3 double-mutant mice. We show that in the absence of both Rac proteins, the embryonic migration of medial ganglionic eminence-derived interneurons is further impaired. Postnatally, double-mutant mice display a dramatic loss of cortical interneurons. In addition, Rac1/Rac3-deficient interneurons show gross cytoskeletal defects in vitro, with the length of their leading processes significantly reduced and a clear multipolar morphology. We propose that in the absence of Rac1/Rac3, cortical interneurons fail to migrate tangentially towards the pallium due to defects in actin and microtubule cytoskeletal dynamics.

  3. Cell Biology: Microtubule Collisions to the Rescue.

    Science.gov (United States)

    Gardner, Melissa K

    2016-12-19

    The proper regulation of microtubule lengths is fundamental to their cellular function. New work now reports that the collision of a growing microtubule end with another object, such as a microtubule, can contribute to the regulation of microtubule lengths by leaving behind damage that ultimately acts to stabilize the microtubule network. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Microtubules Are Essential for Guard-Cell Function in Vicia and Arabidopsis

    Institute of Scientific and Technical Information of China (English)

    William Eisinger; David Ehrhardt; Winslow Briggs

    2012-01-01

    Radially arranged cortical microtubules are a prominent feature of guard cells.Guard cells expressing GFPtubulin showed consistent changes in the appearance of microtubules when stomata opened or closed.Guard cells showed fewer microtubule structures as stomata closed,whether induced by transfer to darkness,ABA,hydrogen peroxide,or sodium hydrogen carbonate.Guard cells kept in the dark (closed stomata) showed increases in microtubule structures and stomatal aperture on light treatment.GFP-EB1,marking microtubule growing plus ends,showed no change in number of plus ends or velocity of assembly on stomatal closure.Since the number of growing plus ends and the rate of plus-end growth did not change when microtubule structure numbers declined,microtubule instability and/or rearrangement must be responsible for the apparent loss of microtubules.Guard cells with closed stomata showed more cytosolic GFP-fluorescence than those with open stomata as cortical microtubules became disassembled,although with a large net loss in total fluorescence.Microtubule-targeted drugs blocked guard-cell function in Vicia and Arabidopsis.Oryzalin disrupted guard-cell microtubules and prevented stomatal opening and taxol stabilized guard-cell microtubules and delayed stomatal closure.Gas exchange measurements indicated that the transgenes for fluorescent-labeled proteins did not disrupt normal stomatal function.These dynamic changes in guard-cell microtubules combined with our inhibitor studies provide evidence for an active role of microtubules in guard-cell function.

  5. Visualization and analysis of microtubule dynamics using dual color-coded display of plus-end labels.

    Directory of Open Access Journals (Sweden)

    Amy K Garrison

    Full Text Available Investigating spatial and temporal control of microtubule dynamics in live cells is critical to understanding cell morphogenesis in development and disease. Tracking fluorescently labeled plus-end-tracking proteins over time has become a widely used method to study microtubule assembly. Here, we report a complementary approach that uses only two images of these labels to visualize and analyze microtubule dynamics at any given time. Using a simple color-coding scheme, labeled plus-ends from two sequential images are pseudocolored with different colors and then merged to display color-coded ends. Based on object recognition algorithms, these colored ends can be identified and segregated into dynamic groups corresponding to four events, including growth, rescue, catastrophe, and pause. Further analysis yields not only their spatial distribution throughout the cell but also provides measurements such as growth rate and direction for each labeled end. We have validated the method by comparing our results with ground-truth data derived from manual analysis as well as with data obtained using the tracking method. In addition, we have confirmed color-coded representation of different dynamic events by analyzing their history and fate. Finally, we have demonstrated the use of the method to investigate microtubule assembly in cells and provided guidance in selecting optimal image acquisition conditions. Thus, this simple computer vision method offers a unique and quantitative approach to study spatial regulation of microtubule dynamics in cells.

  6. Hoxb1b controls oriented cell division, cell shape and microtubule dynamics in neural tube morphogenesis.

    Science.gov (United States)

    Zigman, Mihaela; Laumann-Lipp, Nico; Titus, Tom; Postlethwait, John; Moens, Cecilia B

    2014-02-01

    Hox genes are classically ascribed to function in patterning the anterior-posterior axis of bilaterian animals; however, their role in directing molecular mechanisms underlying morphogenesis at the cellular level remains largely unstudied. We unveil a non-classical role for the zebrafish hoxb1b gene, which shares ancestral functions with mammalian Hoxa1, in controlling progenitor cell shape and oriented cell division during zebrafish anterior hindbrain neural tube morphogenesis. This is likely distinct from its role in cell fate acquisition and segment boundary formation. We show that, without affecting major components of apico-basal or planar cell polarity, Hoxb1b regulates mitotic spindle rotation during the oriented neural keel symmetric mitoses that are required for normal neural tube lumen formation in the zebrafish. This function correlates with a non-cell-autonomous requirement for Hoxb1b in regulating microtubule plus-end dynamics in progenitor cells in interphase. We propose that Hox genes can influence global tissue morphogenesis by control of microtubule dynamics in individual cells in vivo.

  7. Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance

    Science.gov (United States)

    Tischfield, Max A.; Baris, Hagit N.; Wu, Chen; Rudolph, Guenther; Van Maldergem, Lionel; He, Wei; Chan, Wai-Man; Andrews, Caroline; Demer, Joseph L.; Robertson, Richard L.; Mackey, David A.; Ruddle, Jonathan B.; Bird, Thomas D.; Gottlob, Irene; Pieh, Christina; Traboulsi, Elias I.; Pomeroy, Scott L.; Hunter, David G.; Soul, Janet S.; Newlin, Anna; Sabol, Louise J.; Doherty, Edward J.; de Uzcátegui, Clara E.; de Uzcátegui, Nicolas; Collins, Mary Louise Z.; Sener, Emin C.; Wabbels, Bettina; Hellebrand, Heide; Meitinger, Thomas; de Berardinis, Teresa; Magli, Adriano; Schiavi, Costantino; Pastore-Trossello, Marco; Koc, Feray; Wong, Agnes M.; Levin, Alex V.; Geraghty, Michael T.; Descartes, Maria; Flaherty, Maree; Jamieson, Robyn V.; Møller, H. U.; Meuthen, Ingo; Callen, David F.; Kerwin, Janet; Lindsay, Susan; Meindl, Alfons; Gupta, Mohan L.; Pellman, David; Engle, Elizabeth C.

    2011-01-01

    We report that eight heterozygous missense mutations in TUBB3, encoding the neuron-specific β-tubulin isotype III, result in a spectrum of human nervous system disorders we now call the TUBB3 syndromes. Each mutation causes the ocular motility disorder CFEOM3, whereas some also result in intellectual and behavioral impairments, facial paralysis, and/or later-onset axonal sensorimotor polyneuropathy. Neuroimaging reveals a spectrum of abnormalities including hypoplasia of oculomotor nerves, and dysgenesis of the corpus callosum, anterior commissure, and corticospinal tracts. A knock-in disease mouse model reveals axon guidance defects without evidence of cortical cell migration abnormalities. We show the disease-associated mutations can impair tubulin heterodimer formation in vitro, although folded mutant heterodimers can still polymerize into microtubules. Modeling each mutation in yeast tubulin demonstrates that all alter dynamic instability whereas a subset disrupts the interaction of microtubules with kinesin motors. These findings demonstrate normal TUBB3 is required for axon guidance and maintenance in mammals. PMID:20074521

  8. Discodermolide, a cytotoxic marine agent that stabilizes microtubules more potently than taxol.

    Science.gov (United States)

    ter Haar, E; Kowalski, R J; Hamel, E; Lin, C M; Longley, R E; Gunasekera, S P; Rosenkranz, H S; Day, B W

    1996-01-01

    Computer-assisted structure analysis indicated (+)-discodermolide, a polyhydroxylated alkatetraene lactone marine natural product, was an antimitotic compound, and we confirmed this prediction. Previous work had shown an accumulation of discodermolide-treated cells in the G2/M portion of the cell cycle, and we have now found that discodermolide arrests Burkitt lymphoma cells in mitosis. Discodermolide-treated breast carcinoma cells displayed spectacular rearrangement of the microtubule cytoskeleton, including extensive microtubule bundling. Microtubule rearrangement that occurred with 10 nM discodermolide required 1 microM taxol. Discodermolide had equally impressive effects on tubulin assembly in vitro. Near-total polymerization occurred at 0 degree C with tubulin plus microtubule-associated proteins (MAPs) under conditions in which taxol at an identical concentration was inactive. Without MAPs and/or without GTP, tubulin assembly was also more vigorous with discodermolide than with taxol under every reaction condition examined. Discodermolide-induced polymer differed from taxol-induced polymer in that it was completely stable at 0 degree C in the presence of high concentrations of Ca2+. In a quantitative assay designed to select for agents more effective than taxol in inducing assembly, discodermolide had an EC50 value of 3.2 microM versus 23 microM for taxol.

  9. Tubulin assembly, taxoid site binding, and cellular effects of the microtubule-stabilizing agent dictyostatin.

    Science.gov (United States)

    Madiraju, Charitha; Edler, Michael C; Hamel, Ernest; Raccor, Brianne S; Balachandran, Raghavan; Zhu, Guangyu; Giuliano, Kenneth A; Vogt, Andreas; Shin, Youseung; Fournier, Jean-Hugues; Fukui, Yoshikazu; Brückner, Arndt M; Curran, Dennis P; Day, Billy W

    2005-11-15

    (-)-Dictyostatin is a sponge-derived, 22-member macrolactone natural product shown to cause cells to accumulate in the G2/M phase of the cell cycle, with changes in intracellular microtubules analogous to those observed with paclitaxel treatment. Dictyostatin also induces assembly of purified tubulin more rapidly than does paclitaxel, and nearly as vigorously as does dictyostatin's close structural congener, (+)-discodermolide (Isbrucker et al. (2003), Biochem. Pharmacol. 65, 75-82). We used synthetic (-)-dictyostatin to study its biochemical and cytological activities in greater detail. The antiproliferative activity of dictyostatin did not differ greatly from that of paclitaxel or discodermolide. Like discodermolide, dictyostatin retained antiproliferative activity against human ovarian carcinoma cells resistant to paclitaxel due to beta-tubulin mutations and caused conversion of cellular soluble tubulin pools to microtubules. Detailed comparison of the abilities of dictyostatin and discodermolide to induce tubulin assembly demonstrated that the compounds had similar potencies. Dictyostatin inhibited the binding of radiolabeled discodermolide to microtubules more potently than any other compound examined, and dictyostatin and discodermolide had equivalent activity as inhibitors of the binding of both radiolabeled epothilone B and paclitaxel to microtubules. These results are consistent with the idea that the macrocyclic structure of dictyostatin represents the template for the bioactive conformation of discodermolide.

  10. Role of CLASP2 in microtubule stabilization and the regulation of persistent motility.

    NARCIS (Netherlands)

    Drabek, K.; Ham, M. van der; Stepanova, T.; Draegestein, K.; Horssen, R. van; Sayas, C.L.; Akhmanova, A.; Hagen, T. Ten; Smits, R.; Fodde, R.; Grosveld, F.; Galjart, N.

    2006-01-01

    In motile fibroblasts, stable microtubules (MTs) are oriented toward the leading edge of cells. How these polarized MT arrays are established and maintained, and the cellular processes they control, have been the subject of many investigations. Several MT "plus-end-tracking proteins," or +TIPs, have

  11. Resistance to discodermolide, a microtubule-stabilizing agent and senescence inducer, is 4E-BP1–dependent

    OpenAIRE

    Chao, Suzan K.; Lin, Juan; Brouwer-Visser, Jurriaan; Smith, Amos B.; Horwitz, Susan Band; McDaid, Hayley M.

    2010-01-01

    Discodermolide is a microtubule-stabilizing agent that induces accelerated cell senescence. A discodermolide-resistant cell line, AD32, was generated from the human lung cancer cell line A549. We hypothesize that the major resistance mechanism in these cells is escape from accelerated senescence. AD32 cells have decreased levels of 4E-BP1 mRNA and protein, relative to the parental discodermolide-sensitive A549 cells. Lentiviral-mediated re-expression of wild-type 4E-BP1 in AD32 cells increase...

  12. Siva1 suppresses epithelial-mesenchymal transition and metastasis of tumor cells by inhibiting stathmin and stabilizing microtubules.

    Science.gov (United States)

    Li, Nan; Jiang, Peng; Du, Wenjing; Wu, Zhengsheng; Li, Cong; Qiao, Mengran; Yang, Xiaolu; Wu, Mian

    2011-08-02

    Epithelial-mesenchymal transition (EMT) enables epithelial cells to acquire motility and invasiveness that are characteristic of mesenchymal cells. It plays an important role in development and tumor cell metastasis. However, the mechanisms of EMT and their dysfunction in cancer cells are still not well understood. Here we report that Siva1 interacts with stathmin, a microtubule destabilizer. Siva1 inhibits stathmin's activity directly as well as indirectly through Ca(2+)/calmodulin-dependent protein kinase II-mediated phosphorylation of stathmin at Ser16. Via the inhibition of stathmin, Siva1 enhances the formation of microtubules and impedes focal adhesion assembly, cell migration, and EMT. Low levels of Siva1 and Ser16-phosphorylated stathmin correlate with high metastatic states of human breast cancer cells. In mouse models, knockdown of Siva1 promotes cancer dissemination, whereas overexpression of Siva1 inhibits it. These results suggest that microtubule dynamics are critical for EMT. Furthermore, they reveal an important role for Siva1 in suppressing cell migration and EMT and indicate that down-regulation of Siva1 may contribute to tumor cell metastasis.

  13. CLIP-170 facilitates the formation of kinetochore-microtubule attachments.

    Science.gov (United States)

    Tanenbaum, Marvin E; Galjart, Niels; van Vugt, Marcel A T M; Medema, René H

    2006-01-11

    CLIP-170 is a microtubule 'plus end tracking' protein involved in several microtubule-dependent processes in interphase. At the onset of mitosis, CLIP-170 localizes to kinetochores, but at metaphase, it is no longer detectable at kinetochores. Although RNA interference (RNAi) experiments have suggested an essential role for CLIP-170 during mitosis, the molecular function of CLIP-170 in mitosis has not yet been revealed. Here, we used a combination of high-resolution microscopy and RNAi-mediated depletion to study the function of CLIP-170 in mitosis. We found that CLIP-170 dynamically localizes to the outer most part of unattached kinetochores and to the ends of growing microtubules. In addition, we provide evidence that a pool of CLIP-170 is transported along kinetochore-microtubules by the dynein/dynactin complex. Interference with CLIP-170 expression results in defective chromosome congression and diminished kinetochore-microtubule attachments, but does not detectibly affect microtubule dynamics or kinetochore-microtubule stability. Taken together, our results indicate that CLIP-170 facilitates the formation of kinetochore-microtubule attachments, possibly through direct capture of microtubules at the kinetochore.

  14. Analysis of dynamic instability of steady-state microtubules in vitro by video-enhanced differential interference contrast microscopy with an appendix by Emin Oroudjev.

    Science.gov (United States)

    Yenjerla, Mythili; Lopus, Manu; Wilson, Leslie

    2010-01-01

    Microtubules are major constituents of the cytoskeleton which display dynamic properties. They exhibit dynamic instability which is defined as the stochastic switching between growing and shortening at microtubule ends. Dynamic instability plays an important role in diverse cellular functions including cell migration and mitosis. Many successful antimitotic drugs and microtubule-associated proteins (MAPs) are known to modulate microtubule dynamics, and it is important to analyze the in vitro dynamic instability of microtubules to study the mechanism of action of microtubule-targeted therapeutics and MAPs. In this chapter, we describe a method to analyze the in vitro dynamic instability of microtubules at steady state using video-enhanced differential contrast (VE-DIC) microscopy in detail. In this method, microtubules are assembled to steady state at 30 degrees C with MAP-free tubulin in a slide chamber in the presence of GTP, using sea urchin axonemes as nucleating seeds. Images of microtubules are enhanced and recorded in real time by a video camera and an image processor connected to a DIC microscope which is maintained at 30 degrees C. We use two software programs to track and analyze the growing and shortening of plus or minus ends of microtubules in the real-time images recorded using VE-DIC. In this chapter, we describe the instructions to use the tracking software Real Time Measurement II (RTM II) program. The instructions to use the analysis software Microtubule Life History Analysis Procedures (MT-LHAP) in Igor Pro software have been described in detail in an appendix (Oroudjev, 2010) following this chapter.

  15. Dynamic assembly of polymer nanotube networks via kinesin powered microtubule filaments

    Science.gov (United States)

    Paxton, Walter F.; Bouxsein, Nathan F.; Henderson, Ian M.; Gomez, Andrew; Bachand, George D.

    2015-06-01

    We describe for the first time how biological nanomotors may be used to actively self-assemble mesoscale networks composed of diblock copolymer nanotubes. The collective force generated by multiple kinesin nanomotors acting on a microtubule filament is large enough to overcome the energy barrier required to extract nanotubes from polymer vesicles comprised of poly(ethylene oxide-b-butadiene) in spite of the higher force requirements relative to extracting nanotubes from lipid vesicles. Nevertheless, large-scale polymer networks were dynamically assembled by the motors. These networks displayed enhanced robustness, persisting more than 24 h post-assembly (compared to 4-5 h for corresponding lipid networks). The transport of materials in and on the polymer membranes differs substantially from the transport on analogous lipid networks. Specifically, our data suggest that polymer mobility in nanotubular structures is considerably different from planar or 3D structures, and is stunted by 1D confinement of the polymer subunits. Moreover, quantum dots adsorbed onto polymer nanotubes are completely immobile, which is related to this 1D confinement effect and is in stark contrast to the highly fluid transport observed on lipid tubules.We describe for the first time how biological nanomotors may be used to actively self-assemble mesoscale networks composed of diblock copolymer nanotubes. The collective force generated by multiple kinesin nanomotors acting on a microtubule filament is large enough to overcome the energy barrier required to extract nanotubes from polymer vesicles comprised of poly(ethylene oxide-b-butadiene) in spite of the higher force requirements relative to extracting nanotubes from lipid vesicles. Nevertheless, large-scale polymer networks were dynamically assembled by the motors. These networks displayed enhanced robustness, persisting more than 24 h post-assembly (compared to 4-5 h for corresponding lipid networks). The transport of materials in and on

  16. The Dynamics of Stability

    DEFF Research Database (Denmark)

    Hedegaard, Troels Fage

    politiske aktører der greb disse muligheder. Disse historiske faktorer, der hjalp med at skabe opbakning til velfærdsstaten, er dog blevet svækket med tiden, mens støtten til modellen forbliver stabil. Denne umiddelbare modsætning er denne afhandlings omdrejningspunkt. Derfor vender jeg I denne afhandling...... trække på policy feedback teori, som den primære teoretiske ramme, og ud fra dette beskrive og teste sociale mekanismer der kan forklare den vedvarende opbakning til velfærdsmodellen. Disse social mekanismer eksisterer ikke kun i de nordiske lande, men skulle være mere udbredt her, og kan dermed hjælpe...

  17. The mesh is a network of microtubule connectors that stabilizes individual kinetochore fibers of the mitotic spindle.

    Science.gov (United States)

    Nixon, Faye M; Gutiérrez-Caballero, Cristina; Hood, Fiona E; Booth, Daniel G; Prior, Ian A; Royle, Stephen J

    2015-06-19

    Kinetochore fibers (K-fibers) of the mitotic spindle are force-generating units that power chromosome movement during mitosis. K-fibers are composed of many microtubules that are held together throughout their length. Here, we show, using 3D electron microscopy, that K-fiber microtubules (MTs) are connected by a network of MT connectors. We term this network 'the mesh'. The K-fiber mesh is made of linked multipolar connectors. Each connector has up to four struts, so that a single connector can link up to four MTs. Molecular manipulation of the mesh by overexpression of TACC3 causes disorganization of the K-fiber MTs. Optimal stabilization of K-fibers by the mesh is required for normal progression through mitosis. We propose that the mesh stabilizes K-fibers by pulling MTs together and thereby maintaining the integrity of the fiber. Our work thus identifies the K-fiber meshwork of linked multipolar connectors as a key integrator and determinant of K-fiber structure and function.

  18. An antitubulin agent BCFMT inhibits proliferation of cancer cells and induces cell death by inhibiting microtubule dynamics.

    Directory of Open Access Journals (Sweden)

    Ankit Rai

    Full Text Available Using cell based screening assay, we identified a novel anti-tubulin agent (Z-5-((5-(4-bromo-3-chlorophenylfuran-2-ylmethylene-2-thioxothiazolidin-4-one (BCFMT that inhibited proliferation of human cervical carcinoma (HeLa (IC(50, 7.2 ± 1.8 µM, human breast adenocarcinoma (MCF-7 (IC(50, 10.0 ± 0.5 µM, highly metastatic breast adenocarcinoma (MDA-MB-231 (IC(50, 6.0 ± 1 µM, cisplatin-resistant human ovarian carcinoma (A2780-cis (IC(50, 5.8 ± 0.3 µM and multi-drug resistant mouse mammary tumor (EMT6/AR1 (IC(50, 6.5 ± 1 µM cells. Using several complimentary strategies, BCFMT was found to inhibit cancer cell proliferation at G2/M phase of the cell cycle apparently by targeting microtubules. In addition, BCFMT strongly suppressed the dynamics of individual microtubules in live MCF-7 cells. At its half maximal proliferation inhibitory concentration (10 µM, BCFMT reduced the rates of growing and shortening phases of microtubules in MCF-7 cells by 37 and 40%, respectively. Further, it increased the time microtubules spent in the pause (neither growing nor shortening detectably state by 135% and reduced the dynamicity (dimer exchange per unit time of microtubules by 70%. In vitro, BCFMT bound to tubulin with a dissociation constant of 8.3 ± 1.8 µM, inhibited tubulin assembly and suppressed GTPase activity of microtubules. BCFMT competitively inhibited the binding of BODIPY FL-vinblastine to tubulin with an inhibitory concentration (K(i of 5.2 ± 1.5 µM suggesting that it binds to tubulin at the vinblastine site. In cultured cells, BCFMT-treatment depolymerized interphase microtubules, perturbed the spindle organization and accumulated checkpoint proteins (BubR1 and Mad2 at the kinetochores. BCFMT-treated MCF-7 cells showed enhanced nuclear accumulation of p53 and its downstream p21, which consequently activated apoptosis in these cells. The results suggested that BCFMT inhibits proliferation of several types of cancer cells including drug

  19. Microtubules are Essential for Mitochondrial Dynamics-Fission, Fusion, and Motility- in Dictyostelium discoideum.

    Directory of Open Access Journals (Sweden)

    Laken C. Woods

    2016-03-01

    Full Text Available Mitochondrial function is dependent upon mitochondrial structure which is in turn dependent upon mitochondrial dynamics, including fission, fusion, and motility. Here we examined the relationship between mitochondrial dynamics and the cytoskeleton in Dictyostelium discoideum. Using time-lapse analysis, we quantified mitochondrial fission, fusion, and motility in the presence of cytoskeleton disrupting pharmaceuticals and the absence of the potential mitochondria-cytoskeleton linker protein, CluA. Our results indicate that microtubules are essential for mitochondrial movement, as well as fission and fusion; actin plays a less significant role, perhaps selecting the mitochondria for transport. We also suggest that CluA is not a linker protein but plays an unidentified role in mitochondrial fission and fusion. The significance of our work is to gain further insight into the role the cytoskeleton plays in mitochondrial dynamics and function. By better understanding these processes we can better appreciate the underlying mitochondrial contributions to many neurological disorders characterized by altered mitochondrial dynamics, structure, and/or function.

  20. Folding of the Tau Protein on Microtubules.

    Science.gov (United States)

    Kadavath, Harindranath; Jaremko, Mariusz; Jaremko, Łukasz; Biernat, Jacek; Mandelkow, Eckhard; Zweckstetter, Markus

    2015-08-24

    Microtubules are regulated by microtubule-associated proteins. However, little is known about the structure of microtubule-associated proteins in complex with microtubules. Herein we show that the microtubule-associated protein Tau, which is intrinsically disordered in solution, locally folds into a stable structure upon binding to microtubules. While Tau is highly flexible in solution and adopts a β-sheet structure in amyloid fibrils, in complex with microtubules the conserved hexapeptides at the beginning of the Tau repeats two and three convert into a hairpin conformation. Thus, binding to microtubules stabilizes a unique conformation in Tau. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Tension-dependent regulation of microtubule dynamics at kinetochores can explain metaphase congression in yeast

    National Research Council Canada - National Science Library

    Gardner, Melissa K; Pearson, Chad G; Sprague, Brian L; Zarzar, Ted R; Bloom, Kerry; Salmon, E D; Odde, David J

    2005-01-01

    During metaphase in budding yeast mitosis, sister kinetochores are tethered to opposite poles and separated, stretching their intervening chromatin, by singly attached kinetochore microtubules (kMTs...

  2. Tubulin bond energies and microtubule biomechanics determined from nanoindentation in silico

    CERN Document Server

    Kononova, Olga; Theisen, Kelly E; Marx, Kenneth A; Dima, Ruxandra I; Ataullakhanov, Fazly I; Grishchuk, Ekaterina L; Barsegov, Valeri

    2015-01-01

    Microtubules, the primary components of the chromosome segregation machinery, are stabilized by longitudinal and lateral non-covalent bonds between the tubulin subunits. However, the thermodynamics of these bonds and the microtubule physico-chemical properties are poorly understood. Here, we explore the biomechanics of microtubule polymers using multiscale computational modeling and nanoindentations in silico of a contiguous microtubule fragment. A close match between the simulated and experimental force-deformation spectra enabled us to correlate the microtubule biomechanics with dynamic structural transitions at the nanoscale. Our mechanical testing revealed that the compressed MT behaves as a system of rigid elements interconnected through a network of lateral and longitudinal elastic bonds. The initial regime of continuous elastic deformation of the microtubule is followed by the transition regime, during which the microtubule lattice undergoes discrete structural changes, which include first the reversib...

  3. Mammalian diaphanous-related formin 1 regulates GSK3β-dependent microtubule dynamics required for T cell migratory polarization.

    Directory of Open Access Journals (Sweden)

    Baoxia Dong

    Full Text Available The mammalian diaphanous-related formin (mDia1, a Rho-regulated cytoskeletal modulator, has been shown to promote T lymphocyte chemotaxis and interaction with antigen presenting cells, but the mechanisms underpinning mDia1 roles in these processes have not been defined. Here we show that mDia1(-/- T cells exhibit impaired lymphocyte function-associated antigen 1 (LFA-1-mediated T cell adhesion, migration and in vivo trafficking. These defects are associated with impaired microtubule (MT polarization and stabilization, altered MT dynamics and reduced peripheral clustering of the MT plus-end-protein, adenomatous polyposis coli (APC in migrating T cells following LFA-1-engagement. Loss of mDia1 also leads to impaired inducible inactivation of the glycogen synthase kinase (GSK 3β as well as hyperphosphorylation and reduced levels of APC in migrating T cells. These findings identify essential roles for the mDia1 formin in modulating GSK3β-dependent MT contributions to induction of T-cell polarity, adhesion and motility.

  4. Mammalian diaphanous-related formin 1 regulates GSK3β-dependent microtubule dynamics required for T cell migratory polarization.

    Science.gov (United States)

    Dong, Baoxia; Zhang, Steven S; Gao, Wen; Su, Haichun; Chen, Jun; Jin, Fuzi; Bhargava, Ajay; Chen, Xiequn; Jorgensen, Lars; Alberts, Arthur S; Zhang, Jinyi; Siminovitch, Katherine A

    2013-01-01

    The mammalian diaphanous-related formin (mDia1), a Rho-regulated cytoskeletal modulator, has been shown to promote T lymphocyte chemotaxis and interaction with antigen presenting cells, but the mechanisms underpinning mDia1 roles in these processes have not been defined. Here we show that mDia1(-/-) T cells exhibit impaired lymphocyte function-associated antigen 1 (LFA-1)-mediated T cell adhesion, migration and in vivo trafficking. These defects are associated with impaired microtubule (MT) polarization and stabilization, altered MT dynamics and reduced peripheral clustering of the MT plus-end-protein, adenomatous polyposis coli (APC) in migrating T cells following LFA-1-engagement. Loss of mDia1 also leads to impaired inducible inactivation of the glycogen synthase kinase (GSK) 3β as well as hyperphosphorylation and reduced levels of APC in migrating T cells. These findings identify essential roles for the mDia1 formin in modulating GSK3β-dependent MT contributions to induction of T-cell polarity, adhesion and motility.

  5. The condition for dynamic stability

    NARCIS (Netherlands)

    Hof, AL; Gazendam, MGJ; Sinke, WE

    The well-known condition for standing stability in static situations is that the vertical projection of the centre of mass (CoM) should be within the base of support (BoS). On the basis of a simple inverted pendulum model, an extension of this rule is proposed for dynamical situations: the position

  6. Dynamical stability of Hamiltonian systems

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Dynamical stability has become the center of study on Hamiltonian system. In this article we intro-duce the recent development in some areas closely related to this topic, such as the KAM theory, Mather theory, Arnolddiffusion and non-singular collision of n-body problem.

  7. The condition for dynamic stability

    NARCIS (Netherlands)

    Hof, AL; Gazendam, MGJ; Sinke, WE

    2005-01-01

    The well-known condition for standing stability in static situations is that the vertical projection of the centre of mass (CoM) should be within the base of support (BoS). On the basis of a simple inverted pendulum model, an extension of this rule is proposed for dynamical situations: the position

  8. FoxO regulates microtubule dynamics and polarity to promote dendrite branching in Drosophila sensory neurons.

    Science.gov (United States)

    Sears, James C; Broihier, Heather T

    2016-10-01

    The size and shape of dendrite arbors are defining features of neurons and critical determinants of neuronal function. The molecular mechanisms establishing arborization patterns during development are not well understood, though properly regulated microtubule (MT) dynamics and polarity are essential. We previously found that FoxO regulates axonal MTs, raising the question of whether it also regulates dendritic MTs and morphology. Here we demonstrate that FoxO promotes dendrite branching in all classes of Drosophila dendritic arborization (da) neurons. FoxO is required both for initiating growth of new branches and for maintaining existing branches. To elucidate FoxO function, we characterized MT organization in both foxO null and overexpressing neurons. We find that FoxO directs MT organization and dynamics in dendrites. Moreover, it is both necessary and sufficient for anterograde MT polymerization, which is known to promote dendrite branching. Lastly, FoxO promotes proper larval nociception, indicating a functional consequence of impaired da neuron morphology in foxO mutants. Together, our results indicate that FoxO regulates dendrite structure and function and suggest that FoxO-mediated pathways control MT dynamics and polarity.

  9. Microtubule dynamics from mating through the first zygotic division in the budding yeast Saccharomyces cerevisiae.

    Science.gov (United States)

    Maddox, P; Chin, E; Mallavarapu, A; Yeh, E; Salmon, E D; Bloom, K

    1999-03-08

    We have used time-lapse digital imaging microscopy to examine cytoplasmic astral microtubules (Mts) and spindle dynamics during the mating pathway in budding yeast Saccharomyces cerevisiae. Mating begins when two cells of opposite mating type come into proximity. The cells arrest in the G1 phase of the cell cycle and grow a projection towards one another forming a shmoo projection. Imaging of microtubule dynamics with green fluorescent protein (GFP) fusions to dynein or tubulin revealed that the nucleus and spindle pole body (SPB) became oriented and tethered to the shmoo tip by a Mt-dependent search and capture mechanism. Dynamically unstable astral Mts were captured at the shmoo tip forming a bundle of three or four astral Mts. This bundle changed length as the tethered nucleus and SPB oscillated toward and away from the shmoo tip at growth and shortening velocities typical of free plus end astral Mts (approximately 0.5 micrometer/min). Fluorescent fiduciary marks in Mt bundles showed that Mt growth and shortening occurred primarily at the shmoo tip, not the SPB. This indicates that Mt plus end assembly/disassembly was coupled to pushing and pulling of the nucleus. Upon cell fusion, a fluorescent bar of Mts was formed between the two shmoo tip bundles, which slowly shortened (0.23 +/- 0.07 micrometer/min) as the two nuclei and their SPBs came together and fused (karyogamy). Bud emergence occurred adjacent to the fused SPB approximately 30 min after SPB fusion. During the first mitosis, the SPBs separated as the spindle elongated at a constant velocity (0.75 micrometer/min) into the zygotic bud. There was no indication of a temporal delay at the 2-micrometer stage of spindle morphogenesis or a lag in Mt nucleation by replicated SPBs as occurs in vegetative mitosis implying a lack of normal checkpoints. Thus, the shmoo tip appears to be a new model system for studying Mt plus end dynamic attachments and much like higher eukaryotes, the first mitosis after haploid

  10. The Dynamic Pollen Tube Cytoskeleton: Live Cell Studies Using Actin-Binding and Microtubule-Binding Reporter Proteins

    Institute of Scientific and Technical Information of China (English)

    Alice Y. Cheung; Qiao-hong Duan; Silvia Santos Costa; Barend H.J.de Graaf; Veronica S.Di Stilio; Jose Feijo; Hen-Ming Wu

    2008-01-01

    Pollen tubes elongate within the pistil to transport sperm cells to the embryo sac for fertilization.Growth occurs exclusively at the tube apex,rendering pollen tube elongation a most dramatic polar cell growth process.A hall-mark pollen tube feature is its cytoskeleton,which comprises elaborately organized and dynamic actin microfilaments and microtubules.Pollen tube growth is dependent on the actin cytoskeleton;its organization and regulation have been exalined extensively by various approaches.including fluorescent protein labeled actin-binding proteins in live cell studies.Using the previously described GFP-NtADF1 and GFP-LIADF1, and a new actin reporter protein NtPLIM2b-GFP,we re-affirm that the predominant actin structures in elongating tobacco and lily pollen tubes are long,streaming actin cables along the pollen tube shank,and a subapical structure comprising shorter actin cables.The subapical collection of actin microfilaments undergoes dynamic changes,giving rise to the appearance of structures that range from basket-or funnel-shaped,mesh-like to a subtle ring.NtPLIM2b-GFP is used in combination with a guanine nucleotide exchange factor for the Rho GTPases,AtROP-GEF1,to illustrate the use of these actin reporter proteins to explore the linkage between the polar cell growth process and its actin cytoskeleton.Contrary to the actin cytoskeleton,microtubules appear not to play a direct role in supporting the polar cell growth process in angiosperm pollen tubes.Using a microtubule reporter protein based on the microtubule end-binding protein from Arabidopsis AtEB1,GFP-AtEB1,we show that the extensive microtubule network in elongating pollen tubes displays varying degrees of dynamics.These reporter proteins provide versatile tools to explore the functional connection between major structural and signaling components of the polar pollen tube growth process.

  11. The potent microtubule-stabilizing agent (+)-discodermolide induces apoptosis in human breast carcinoma cells--preliminary comparisons to paclitaxel.

    Science.gov (United States)

    Balachandran, R; ter Haar, E; Welsh, M J; Grant, S G; Day, B W

    1998-01-01

    (+)-Discodermolide, a sponge-derived natural product, stabilizes microtubules more potently than paclitaxel despite the lack of any obvious structural similarities between the drugs. It competitively inhibits the binding of paclitaxel to tubulin polymers, hypernucleates microtubule assembly more potently than paclitaxel, and inhibits the growth of paclitaxel-resistant ovarian and colon carcinoma cells. Because paclitaxel shows clinical promise for breast cancer treatment, its effects in a series of human breast cancer cells were compared to those of (+)-discodermolide. Growth inhibition, cell and nuclear morphological, and electrophoretic and flow cytometric analyses were performed on (+)-discodermolide-treated MCF-7 and MDA-MB231 cells. (+)-Discodermolide potently inhibited the growth of both cell types (IC50 Discodermolide-treated cells exhibited condensed and highly fragmented nuclei. Flow cytometric comparison of cells treated with either drug at 10 nM, a concentration well below that achieved clinically with paclitaxel, showed both caused cell cycle perturbation and induction of a hypodiploid cell population. (+)-Discodermolide caused these effects more extensively and at earlier time points. The timing and type of high molecular weight DNA fragmentation induced by the two agents was consistent with induction of apoptosis. The results suggest that (+)-discodermolide has promise as a new chemotherapeutic agent against breast and other cancers.

  12. Janus Compounds, 5-Chloro-N4-methyl-N4-aryl-9H-pyrimido[4,5-b]indole-2,4-diamines, Cause Both Microtubule Depolymerizing and Stabilizing Effects

    Directory of Open Access Journals (Sweden)

    Cristina C. Rohena

    2016-12-01

    Full Text Available While evaluating a large library of compounds designed to inhibit microtubule polymerization, we identified four compounds that have unique effects on microtubules. These compounds cause mixed effects reminiscent of both microtubule depolymerizers and stabilizers. Immunofluorescence evaluations showed that each compound initially caused microtubule depolymerization and, surprisingly, with higher concentrations, microtubule bundles were also observed. There were subtle differences in the propensity to cause these competing effects among the compounds with a continuum of stabilizing and destabilizing effects. Tubulin polymerization experiments confirmed the differential effects and, while each of the compounds increased the initial rate of tubulin polymerization at high concentrations, total tubulin polymer was not enhanced at equilibrium, likely because of the dueling depolymerization effects. Modeling studies predict that the compounds bind to tubulin within the colchicine site and confirm that there are differences in their potential interactions that might underlie their distinct effects on microtubules. Due to their dual properties of microtubule stabilization and destabilization, we propose the name Janus for these compounds after the two-faced Roman god. The identification of synthetically tractable, small molecules that elicit microtubule stabilizing effects is a significant finding with the potential to identify new mechanisms of microtubule stabilization.

  13. Automated screening of microtubule growth dynamics identifies MARK2 as a regulator of leading edge microtubules downstream of Rac1 in migrating cells.

    Directory of Open Access Journals (Sweden)

    Yukako Nishimura

    Full Text Available Polarized microtubule (MT growth in the leading edge is critical to directed cell migration, and is mediated by Rac1 GTPase. To find downstream targets of Rac1 that affect MT assembly dynamics, we performed an RNAi screen of 23 MT binding and regulatory factors and identified RNAi treatments that suppressed changes in MT dynamics induced by constitutively activated Rac1. By analyzing fluorescent EB3 dynamics with automated tracking, we found that RNAi treatments targeting p150(glued, APC2, spastin, EB1, Op18, or MARK2 blocked Rac1-mediated MT growth in lamellipodia. MARK2 was the only protein whose RNAi targeting additionally suppressed Rac1 effects on MT orientation in lamellipodia, and thus became the focus of further study. We show that GFP-MARK2 rescued effects of MARK2 depletion on MT growth lifetime and orientation, and GFP-MARK2 localized in lamellipodia in a Rac1-activity-dependent manner. In a wound-edge motility assay, MARK2-depleted cells failed to polarize their centrosomes or exhibit oriented MT growth in the leading edge, and displayed defects in directional cell migration. Thus, automated image analysis of MT assembly dynamics identified MARK2 as a target regulated downstream of Rac1 that promotes oriented MT growth in the leading edge to mediate directed cell migration.

  14. Basin stability in delayed dynamics

    Science.gov (United States)

    Leng, Siyang; Lin, Wei; Kurths, Jürgen

    2016-02-01

    Basin stability (BS) is a universal concept for complex systems studies, which focuses on the volume of the basin of attraction instead of the traditional linearization-based approach. It has a lot of applications in real-world systems especially in dynamical systems with a phenomenon of multi-stability, which is even more ubiquitous in delayed dynamics such as the firing neurons, the climatological processes, and the power grids. Due to the infinite dimensional property of the space for the initial values, how to properly define the basin’s volume for delayed dynamics remains a fundamental problem. We propose here a technique which projects the infinite dimensional initial state space to a finite-dimensional Euclidean space by expanding the initial function along with different orthogonal or nonorthogonal basis. A generalized concept of basin’s volume in delayed dynamics and a highly practicable calculating algorithm with a cross-validation procedure are provided to numerically estimate the basin of attraction in delayed dynamics. We show potential applicabilities of this approach by applying it to study several representative systems of biological or/and physical significance, including the delayed Hopfield neuronal model with multistability and delayed complex networks with synchronization dynamics.

  15. plusTipTracker: Quantitative image analysis software for the measurement of microtubule dynamics.

    Science.gov (United States)

    Applegate, Kathryn T; Besson, Sebastien; Matov, Alexandre; Bagonis, Maria H; Jaqaman, Khuloud; Danuser, Gaudenz

    2011-11-01

    Here we introduce plusTipTracker, a Matlab-based open source software package that combines automated tracking, data analysis, and visualization tools for movies of fluorescently-labeled microtubule (MT) plus end binding proteins (+TIPs). Although +TIPs mark only phases of MT growth, the plusTipTracker software allows inference of additional MT dynamics, including phases of pause and shrinkage, by linking collinear, sequential growth tracks. The algorithm underlying the reconstruction of full MT trajectories relies on the spatially and temporally global tracking framework described in Jaqaman et al. (2008). Post-processing of track populations yields a wealth of quantitative phenotypic information about MT network architecture that can be explored using several visualization modalities and bioinformatics tools included in plusTipTracker. Graphical user interfaces enable novice Matlab users to track thousands of MTs in minutes. In this paper, we describe the algorithms used by plusTipTracker and show how the package can be used to study regional differences in the relative proportion of MT subpopulations within a single cell. The strategy of grouping +TIP growth tracks for the analysis of MT dynamics has been introduced before (Matov et al., 2010). The numerical methods and analytical functionality incorporated in plusTipTracker substantially advance this previous work in terms of flexibility and robustness. To illustrate the enhanced performance of the new software we thus compare computer-assembled +TIP-marked trajectories to manually-traced MT trajectories from the same movie used in Matov et al. (2010).

  16. Dynamics of centrosome translocation and microtubule organization in neocortical neurons during distinct modes of polarization.

    Science.gov (United States)

    Sakakibara, Akira; Sato, Toshiyuki; Ando, Ryota; Noguchi, Namiko; Masaoka, Makoto; Miyata, Takaki

    2014-05-01

    Neuronal migration and process formation require cytoskeletal organization and remodeling. Recent studies suggest that centrosome translocation is involved in initial axon outgrowth, while the role of centrosomal positioning is not clear. Here, we examine relations between centrosomal positioning, axonogenesis, and microtubule (MT) polarization in multipolar and bipolar neocortical neurons. We monitored dynamic movements of centrosomes and MT plus ends in migratory neurons in embryonic mouse cerebral slices. In locomoting bipolar neurons, the centrosome oriented toward the pia-directed leading process. Bipolar neurons displayed dense MT plus end dynamics in leading processes, while trailing processes showed clear bidirectional MTs. In migrating multipolar neurons, new processes emerged irrespective of centrosome localization, followed by centrosome reorientations toward the dominant process. Anterograde movements of MT plus ends occurred in growing processes and retrograde movements were observed after retraction of the distal tip. In multipolar neurons, axon formed by tangential extension of a dominant process and the centrosome oriented toward the growing axon, while in locomoting neurons, an axon formed opposite to the direction of migration and the centrosome localized to the base of the leading process. Our data suggest that MT organization may alter centrosomal localization and that centrosomal positioning does not necessarily direct process formation.

  17. Cathepsin B mediates caspase-independent cell death induced by microtubule stabilizing agents in non-small cell lung cancer cells.

    NARCIS (Netherlands)

    Broker, L.E.; Huisman, C.; Span, SW; Rodriguez, J.A.; Kruyt, F.A.E.; Giaccone, G.

    2004-01-01

    We have previously reported that the microtubule stabilizing agents (MSAs) paclitaxel, epothilone B and discodermolide induce caspase-independent cell death in non-small cell lung cancer (NSCLC) cells. Here we present two lines of evidence indicating a central role for the lysosomal protease catheps

  18. Tumor suppressor protein DAB2IP participates in chromosomal stability maintenance through activating spindle assembly checkpoint and stabilizing kinetochore-microtubule attachments

    Science.gov (United States)

    Yu, Lan; Shang, Zeng-Fu; Abdisalaam, Salim; Lee, Kyung-Jong; Gupta, Arun; Hsieh, Jer-Tsong; Asaithamby, Aroumougame; Chen, Benjamin P.C.; Saha, Debabrata

    2016-01-01

    Defects in kinetochore-microtubule (KT-MT) attachment and the spindle assembly checkpoint (SAC) during cell division are strongly associated with chromosomal instability (CIN). CIN has been linked to carcinogenesis, metastasis, poor prognosis and resistance to cancer therapy. We previously reported that the DAB2IP is a tumor suppressor, and that loss of DAB2IP is often detected in advanced prostate cancer (PCa) and is indicative of poor prognosis. Here, we report that the loss of DAB2IP results in impaired KT-MT attachment, compromised SAC and aberrant chromosomal segregation. We discovered that DAB2IP directly interacts with Plk1 and its loss inhibits Plk1 kinase activity, thereby impairing Plk1-mediated BubR1 phosphorylation. Loss of DAB2IP decreases the localization of BubR1 at the kinetochore during mitosis progression. In addition, the reconstitution of DAB2IP enhances the sensitivity of PCa cells to microtubule stabilizing drugs (paclitaxel, docetaxel) and Plk1 inhibitor (BI2536). Our findings demonstrate a novel function of DAB2IP in the maintenance of KT-MT structure and SAC regulation during mitosis which is essential for chromosomal stability. PMID:27568005

  19. Recruitment of EB1, a master regulator of microtubule dynamics, to the surface of the Theileria annulata schizont.

    Directory of Open Access Journals (Sweden)

    Kerry L Woods

    2013-05-01

    Full Text Available The apicomplexan parasite Theileria annulata transforms infected host cells, inducing uncontrolled proliferation and clonal expansion of the parasitized cell population. Shortly after sporozoite entry into the target cell, the surrounding host cell membrane is dissolved and an array of host cell microtubules (MTs surrounds the parasite, which develops into the transforming schizont. The latter does not egress to invade and transform other cells. Instead, it remains tethered to host cell MTs and, during mitosis and cytokinesis, engages the cell's astral and central spindle MTs to secure its distribution between the two daughter cells. The molecular mechanism by which the schizont recruits and stabilizes host cell MTs is not known. MT minus ends are mostly anchored in the MT organizing center, while the plus ends explore the cellular space, switching constantly between phases of growth and shrinkage (called dynamic instability. Assuming the plus ends of growing MTs provide the first point of contact with the parasite, we focused on the complex protein machinery associated with these structures. We now report how the schizont recruits end-binding protein 1 (EB1, a central component of the MT plus end protein interaction network and key regulator of host cell MT dynamics. Using a range of in vitro experiments, we demonstrate that T. annulata p104, a polymorphic antigen expressed on the schizont surface, functions as a genuine EB1-binding protein and can recruit EB1 in the absence of any other parasite proteins. Binding strictly depends on a consensus SxIP motif located in a highly disordered C-terminal region of p104. We further show that parasite interaction with host cell EB1 is cell cycle regulated. This is the first description of a pathogen-encoded protein to interact with EB1 via a bona-fide SxIP motif. Our findings provide important new insight into the mode of interaction between Theileria and the host cell cytoskeleton.

  20. Recruitment of EB1, a Master Regulator of Microtubule Dynamics, to the Surface of the Theileria annulata Schizont

    KAUST Repository

    Woods, Kerry L.

    2013-05-09

    The apicomplexan parasite Theileria annulata transforms infected host cells, inducing uncontrolled proliferation and clonal expansion of the parasitized cell population. Shortly after sporozoite entry into the target cell, the surrounding host cell membrane is dissolved and an array of host cell microtubules (MTs) surrounds the parasite, which develops into the transforming schizont. The latter does not egress to invade and transform other cells. Instead, it remains tethered to host cell MTs and, during mitosis and cytokinesis, engages the cell\\'s astral and central spindle MTs to secure its distribution between the two daughter cells. The molecular mechanism by which the schizont recruits and stabilizes host cell MTs is not known. MT minus ends are mostly anchored in the MT organizing center, while the plus ends explore the cellular space, switching constantly between phases of growth and shrinkage (called dynamic instability). Assuming the plus ends of growing MTs provide the first point of contact with the parasite, we focused on the complex protein machinery associated with these structures. We now report how the schizont recruits end-binding protein 1 (EB1), a central component of the MT plus end protein interaction network and key regulator of host cell MT dynamics. Using a range of in vitro experiments, we demonstrate that T. annulata p104, a polymorphic antigen expressed on the schizont surface, functions as a genuine EB1-binding protein and can recruit EB1 in the absence of any other parasite proteins. Binding strictly depends on a consensus SxIP motif located in a highly disordered C-terminal region of p104. We further show that parasite interaction with host cell EB1 is cell cycle regulated. This is the first description of a pathogen-encoded protein to interact with EB1 via a bona-fide SxIP motif. Our findings provide important new insight into the mode of interaction between Theileria and the host cell cytoskeleton. 2013 Woods et al.

  1. Non-critical string theory formulation of microtubule dynamics and quantum aspects of brain function

    CERN Document Server

    Mavromatos, Nikolaos E

    1995-01-01

    Microtubule (MT) networks, subneural paracrystalline cytosceletal structures, seem to play a fundamental role in the neurons. We cast here the complicated MT dynamics in the form of a 1+1-dimensional non-critical string theory, thus enabling us to provide a consistent quantum treatment of MTs, including enviromental {\\em friction} effects. We suggest, thus, that the MTs are the microsites, in the brain, for the emergence of stable, macroscopic quantum coherent states, identifiable with the {\\em preconscious states}. Quantum space-time effects, as described by non-critical string theory, trigger then an {\\em organized collapse} of the coherent states down to a specific or {\\em conscious state}. The whole process we estimate to take {\\cal O}(1\\,{\\rm sec}), in excellent agreement with a plethora of experimental/observational findings. The {\\em microscopic arrow of time}, endemic in non-critical string theory, and apparent here in the self-collapse process, provides a satisfactory and simple resolution to the age...

  2. Mechanical properties of a complete microtubule revealed through molecular dynamics simulation.

    Science.gov (United States)

    Wells, David B; Aksimentiev, Aleksei

    2010-07-21

    Microtubules (MTs) are the largest type of cellular filament, essential in processes ranging from mitosis and meiosis to flagellar motility. Many of the processes depend critically on the mechanical properties of the MT, but the elastic moduli, notably the Young's modulus, are not directly revealed in experiment, which instead measures either flexural rigidity or response to radial deformation. Molecular dynamics (MD) is a method that allows the mechanical properties of single biomolecules to be investigated through computation. Typically, MD requires an atomic resolution structure of the molecule, which is unavailable for many systems, including MTs. By combining structural information from cryo-electron microscopy and electron crystallography, we have constructed an all-atom model of a complete MT and used MD to determine its mechanical properties. The simulations revealed nonlinear axial stress-strain behavior featuring a pronounced softening under extension, a possible plastic deformation transition under radial compression, and a distinct asymmetry in response to the two senses of twist. This work demonstrates the possibility of combining different levels of structural information to produce all-atom models suitable for quantitative MD simulations, which extends the range of systems amenable to the MD method and should enable exciting advances in our microscopic knowledge of biology. Copyright (c) 2010 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  3. Stabilization strategies for unstable dynamics.

    Directory of Open Access Journals (Sweden)

    Devjani J Saha

    Full Text Available BACKGROUND: When humans are faced with an unstable task, two different stabilization mechanisms are possible: a high-stiffness strategy, based on the inherent elastic properties of muscles/tools/manipulated objects, or a low-stiffness strategy, based on an explicit positional feedback mechanism. Specific constraints related to the dynamics of the task and/or the neuromuscular system often force people to adopt one of these two strategies. METHODOLOGY/FINDINGS: This experiment was designed such that subjects could achieve stability using either strategy, with a marked difference in terms of effort and control requirements between the two strategies. The task was to balance a virtual mass in an unstable environment via two elastic linkages that connected the mass to each hand. The dynamics of the mass under the influence of the unstable force field and the forces applied through the linkages were simulated using a bimanual, planar robot. The two linkages were non-linear, with a stiffness that increased with the amount of stretch. The mass could be stabilized by stretching the linkages to achieve a stiffness that was greater than the instability coefficient of the unstable field (high-stiffness, or by balancing the mass with sequences of small force impulses (low-stiffness. The results showed that 62% of the subjects quickly adopted the high-stiffness strategy, with stiffness ellipses that were aligned along the direction of instability. The remaining subjects applied the low-stiffness strategy, with no clear preference for the orientation of the stiffness ellipse. CONCLUSIONS: The choice of a strategy was based on the bimanual coordination of the hands: high-stiffness subjects achieved stability quickly by separating the hands to stretch the linkages, while the low-stiffness subjects kept the hands close together and took longer to achieve stability but with lower effort. We suggest that the existence of multiple solutions leads to different types

  4. Catechol-o-methyltransferase expression and 2-methoxyestradiol affect microtubule dynamics and modify steroid receptor signaling in leiomyoma cells.

    Directory of Open Access Journals (Sweden)

    Salama A Salama

    Full Text Available CONTEXT: Development of optimal medicinal treatments of uterine leiomyomas represents a significant challenge. 2-Methoxyestradiol (2ME is an endogenous estrogen metabolite formed by sequential action of CYP450s and catechol-O-methyltransferase (COMT. Our previous study demonstrated that 2ME is a potent antiproliferative, proapoptotic, antiangiogenic, and collagen synthesis inhibitor in human leiomyomas cells (huLM. OBJECTIVES: Our objectives were to investigate whether COMT expression, by the virtue of 2ME formation, affects the growth of huLM, and to explore the cellular and molecular mechanisms whereby COMT expression or treatment with 2ME affect these cells. RESULTS: Our data demonstrated that E(2-induced proliferation was less pronounced in cells over-expressing COMT or treated with 2ME (500 nM. This effect on cell proliferation was associated with microtubules stabilization and diminution of estrogen receptor alpha (ERalpha and progesterone receptor (PR transcriptional activities, due to shifts in their subcellular localization and sequestration in the cytoplasm. In addition, COMT over expression or treatment with 2ME reduced the expression of hypoxia-inducible factor -1alpha (HIF-1 alpha and the basal level as well as TNF-alpha-induced aromatase (CYP19 expression. CONCLUSIONS: COMT over expression or treatment with 2ME stabilize microtubules, ameliorates E(2-induced proliferation, inhibits ERalpha and PR signaling, and reduces HIF-1 alpha and CYP19 expression in human uterine leiomyoma cells. Thus, microtubules are a candidate target for treatment of uterine leiomyomas. In addition, the naturally occurring microtubule-targeting agent 2ME represents a potential new therapeutic for uterine leiomyomas.

  5. Insights into the interaction of discodermolide and docetaxel with tubulin. Mapping the binding sites of microtubule-stabilizing agents by using an integrated NMR and computational approach.

    Science.gov (United States)

    Canales, Angeles; Rodríguez-Salarichs, Javier; Trigili, Chiara; Nieto, Lidia; Coderch, Claire; Andreu, José Manuel; Paterson, Ian; Jiménez-Barbero, Jesús; Díaz, J Fernando

    2011-08-19

    The binding interactions of two antitumor agents that target the paclitaxel site, docetaxel and discodermolide, to unassembled α/β-tubulin heterodimers and microtubules have been studied using biochemical and NMR techniques. The use of discodermolide as a water-soluble paclitaxel biomimetic and extensive NMR experiments allowed the detection of binding of microtubule-stabilizing agents to unassembled tubulin α/β-heterodimers. The bioactive 3D structures of docetaxel and discodermolide bound to α/β-heterodimers were elucidated and compared to those bound to microtubules, where subtle changes in the conformations of docetaxel in its different bound states were evident. Moreover, the combination of experimental TR-NOE and STD NMR data with CORCEMA-ST calculations indicate that docetaxel and discodermolide target an additional binding site at the pore of the microtubules, which is different from the internal binding site at the lumen previously determined by electron crystallography. Binding to this pore site can then be considered as the first ligand-protein recognition event that takes place in advance of the drug internalization process and interaction with the lumen of the microtubules.

  6. Insights from an erroneous kinetochore-microtubule attachment state.

    Science.gov (United States)

    Cane, Stuart; McGilvray, Philip T; Maresca, Thomas J

    2013-01-01

    Faithful distribution of the genome requires that sister kinetochores, which assemble on each chromatid during cell division, interact with dynamic microtubules from opposite spindle poles in a configuration called chromosome biorientation. Biorientation produces tension that increases the affinity of kinetochores for microtubules via ill-defined mechanisms. Non-bioriented kinetochore-microtubule (kt-MT) interactions are prevalent but short-lived due to an error correction pathway that reduces the affinity of kinetochores for microtubules. Interestingly, incorrect kt-MT interactions can be stabilized by experimentally applying force to misoriented chromosomes. Here, a live-cell force assay is utilized to characterize the molecular composition of a common type of improper kt-MT attachment. Our force-related studies are also discussed in the context of current models for tension-dependent stabilization of kt-MT interactions.

  7. Electric fields generated by synchronized oscillations of microtubules, centrosomes and chromosomes regulate the dynamics of mitosis and meiosis

    Directory of Open Access Journals (Sweden)

    Zhao Yue

    2012-07-01

    Full Text Available Abstract Super-macromolecular complexes play many important roles in eukaryotic cells. Classical structural biological studies focus on their complicated molecular structures, physical interactions and biochemical modifications. Recent advances concerning intracellular electric fields generated by cell organelles and super-macromolecular complexes shed new light on the mechanisms that govern the dynamics of mitosis and meiosis. In this review we synthesize this knowledge to provide an integrated theoretical model of these cellular events. We suggest that the electric fields generated by synchronized oscillation of microtubules, centrosomes, and chromatin fibers facilitate several events during mitosis and meiosis, including centrosome trafficking, chromosome congression in mitosis and synapsis between homologous chromosomes in meiosis. These intracellular electric fields are generated under energy excitation through the synchronized electric oscillations of the dipolar structures of microtubules, centrosomes and chromosomes, three of the super-macromolecular complexes within an animal cell.

  8. Electric fields generated by synchronized oscillations of microtubules, centrosomes and chromosomes regulate the dynamics of mitosis and meiosis.

    Science.gov (United States)

    Zhao, Yue; Zhan, Qimin

    2012-07-02

    Super-macromolecular complexes play many important roles in eukaryotic cells. Classical structural biological studies focus on their complicated molecular structures, physical interactions and biochemical modifications. Recent advances concerning intracellular electric fields generated by cell organelles and super-macromolecular complexes shed new light on the mechanisms that govern the dynamics of mitosis and meiosis. In this review we synthesize this knowledge to provide an integrated theoretical model of these cellular events. We suggest that the electric fields generated by synchronized oscillation of microtubules, centrosomes, and chromatin fibers facilitate several events during mitosis and meiosis, including centrosome trafficking, chromosome congression in mitosis and synapsis between homologous chromosomes in meiosis. These intracellular electric fields are generated under energy excitation through the synchronized electric oscillations of the dipolar structures of microtubules, centrosomes and chromosomes, three of the super-macromolecular complexes within an animal cell.

  9. Coordination of microtubule and microfilament dynamics by Drosophila Rho1, Spire and Cappuccino.

    Science.gov (United States)

    Rosales-Nieves, Alicia E; Johndrow, James E; Keller, Lani C; Magie, Craig R; Pinto-Santini, Delia M; Parkhurst, Susan M

    2006-04-01

    The actin-nucleation factors Spire and Cappuccino (Capu) regulate the onset of ooplasmic streaming in Drosophila melanogaster. Although this streaming event is microtubule-based, actin assembly is required for its timing. It is not understood how the interaction of microtubules and microfilaments is mediated in this context. Here, we demonstrate that Capu and Spire have microtubule and microfilament crosslinking activity. The spire locus encodes several distinct protein isoforms (SpireA, SpireC and SpireD). SpireD was recently shown to nucleate actin, but the activity of the other isoforms has not been addressed. We find that SpireD does not have crosslinking activity, whereas SpireC is a potent crosslinker. We show that SpireD binds to Capu and inhibits F-actin/microtubule crosslinking, and activated Rho1 abolishes this inhibition, establishing a mechanistic basis for the regulation of Capu and Spire activity. We propose that Rho1, cappuccino and spire are elements of a conserved developmental cassette that is capable of directly mediating crosstalk between microtubules and microfilaments.

  10. Fission yeast mitochondria are distributed by dynamic microtubules in a motor-independent manner

    Science.gov (United States)

    Li, Tianpeng; Zheng, Fan; Cheung, Martin; Wang, Fengsong; Fu, Chuanhai

    2015-01-01

    The cytoskeleton plays a critical role in regulating mitochondria distribution. Similar to axonal mitochondria, the fission yeast mitochondria are distributed by the microtubule cytoskeleton, but this is regulated by a motor-independent mechanism depending on the microtubule associated protein mmb1p as the absence of mmb1p causes mitochondria aggregation. In this study, using a series of chimeric proteins to control the subcellular localization and motility of mitochondria, we show that a chimeric molecule containing a microtubule binding domain and the mitochondria outer membrane protein tom22p can restore the normal interconnected mitochondria network in mmb1-deletion (mmb1∆) cells. In contrast, increasing the motility of mitochondria by using a chimeric molecule containing a kinesin motor domain and tom22p cannot rescue mitochondria aggregation defects in mmb1∆ cells. Intriguingly a chimeric molecule carrying an actin binding domain and tom22p results in mitochondria associated with actin filaments at the actomyosin ring during mitosis, leading to cytokinesis defects. These findings suggest that the passive motor-independent microtubule-based mechanism is the major contributor to mitochondria distribution in wild type fission yeast cells. Hence, we establish that attachment to microtubules, but not kinesin-dependent movement and the actin cytoskeleton, is required and crucial for proper mitochondria distribution in fission yeast. PMID:26046468

  11. Ochratoxin A: apoptosis and aberrant exit from mitosis due to perturbation of microtubule dynamics?

    Science.gov (United States)

    Rached, Eva; Pfeiffer, Erika; Dekant, Wolfgang; Mally, Angela

    2006-07-01

    Ochratoxin A (OTA) is a potent nephrotoxin and causes high incidences of renal tumors in rodents. The molecular events leading to tumor formation by OTA are not well defined. Early pathological changes observed in kidneys of rats treated with OTA in vivo include frequent mitotic and abnormally enlarged cells, detachment of tubule cells, and apoptosis within the S3 segment of the proximal tubule, suggesting that OTA may interfere with molecules involved in the regulation of cell division and apoptosis. In this study, treatment of immortalized human kidney epithelial (IHKE) cells with OTA (0-50 microM) resulted in a time- and dose-dependent increase in apoptosis and activation of c-Jun N-terminal kinase. At the same time, OTA blocked metaphase/anaphase transition and led to the formation of aberrant mitotic figures and giant cells with abnormally enlarged and/or multiple nuclei, sometimes still connected by chromatin bridges. Immunostaining of the mitotic apparatus using an alpha-tubulin antibody revealed defects in spindle formation. In addition, OTA inhibited microtubule assembly in a concentration-dependent manner in a cell-free, in vitro assay. Interestingly, treatment with OTA also resulted in activation of the transcription factor nuclear factor kappa B (NFkappaB), which has recently been shown to promote cell survival during mitotic cell cycle arrest. Based on these observations, we hypothesize that the mechanism by which OTA promotes tumor formation involves interference with microtubuli dynamics and mitotic spindle formation, resulting in apoptosis or-in the presence of survival signals such as stimulation of the NFkappaB pathway-premature exit from mitosis. Aberrant exit from mitosis resulting in blocked or asymmetric cell division may favor the occurrence of cytogenetic abnormalities and may therefore play a critical role in renal tumor formation by OTA.

  12. Multiple centrosomal microtubule organising centres and increased microtubule stability are early features of VP-16-induced apoptosis in CCRF-CEM cells.

    Science.gov (United States)

    Pittman, S; Geyp, M; Fraser, M; Ellem, K; Peaston, A; Ireland, C

    1997-06-01

    Microtubular reorganisation contributing to apoptotic morphology occurs in normal and neoplastic cells undergoing apoptosis induced by cytotoxic drugs [1-3]. The aim of this study was to correlate the changes in the microtubules (MTs) with behavior of the centrosome in apoptotic cells, and to see whether post-translational changes in tubulin occurred with the emergence of apoptotic MT bands. Apoptosis was induced in the human T-cell leukaemia line (CCRF-CEM) by treatment with 17 microM etoposide over a 4 h period. The time course of changes was assessed using flow cytometry (FCM) and immunocytochemistry in cells labelled for a centrosomal antigen (CSP-alpha) or alpha-tubulins. One hour following treatment we observed multiple centrosomal microtubule organising centres (MTOCs) associated with the nucleus and the transient appearance of a subset of stable MTs detected with an antibody specific for acetylated alpha-tubulin, as the bands of MTs which lobulate the nucleus are formed. The altered properties of the MTs thus reflect changes in function as apoptosis progresses.

  13. HURP is a Ran-importin beta-regulated protein that stabilizes kinetochore microtubules in the vicinity of chromosomes

    NARCIS (Netherlands)

    Silljé, Herman H W; Nagel, Susanna; Körner, Roman; Nigg, Erich A

    2006-01-01

    BACKGROUND: Formation of a bipolar mitotic spindle in somatic cells requires the cooperation of two assembly pathways, one based on kinetochore capture by centrosomal microtubules, the other on RanGTP-mediated microtubule organization in the vicinity of chromosomes. How RanGTP regulates kinetochore-

  14. Escape from Mitotic Arrest: An Unexpected Connection Between Microtubule Dynamics and Epigenetic Regulation of Centromeric Chromatin in Schizosaccharomyces pombe.

    Science.gov (United States)

    George, Anuja A; Walworth, Nancy C

    2015-12-01

    Accurate chromosome segregation is necessary to ensure genomic integrity. Segregation depends on the proper functioning of the centromere, kinetochore, and mitotic spindle microtubules and is monitored by the spindle assembly checkpoint (SAC). In the fission yeast Schizosaccharomyces pombe, defects in Dis1, a microtubule-associated protein that influences microtubule dynamics, lead to mitotic arrest as a result of an active SAC and consequent failure to grow at low temperature. In a mutant dis1 background (dis1-288), loss of function of Msc1, a fission yeast homolog of the KDM5 family of proteins, suppresses the growth defect and promotes normal mitosis. Genetic analysis implicates a histone deacetylase (HDAC)-linked pathway in suppression because HDAC mutants clr6-1, clr3∆, and sir2∆, though not hos2∆, also promote normal mitosis in the dis1-288 mutant. Suppression of the dis phenotype through loss of msc1 function requires the spindle checkpoint protein Mad2 and is limited by the presence of the heterochromatin-associated HP1 protein homolog Swi6. We speculate that alterations in histone acetylation promote a centromeric chromatin environment that compensates for compromised dis1 function by allowing for successful kinetochore-microtubule interactions that can satisfy the SAC. In cells arrested in mitosis by mutation of dis1, loss of function of epigenetic determinants such as Msc1 or specific HDACs can promote cell survival. Because the KDM5 family of proteins has been implicated in human cancers, an appreciation of the potential role of this family of proteins in chromosome segregation is warranted.

  15. Stability Analysis of MEMS Gyroscope Dynamic Systems

    OpenAIRE

    M. Naser-Moghadasi; S. A. Olamaei; F. Setoudeh

    2013-01-01

    In this paper, the existence of a common quadratic Lyapunov function for stability analysis of MEMS Gyroscope dynamic systems has been studied then a new method based on stochastic stability of MEMS Gyroscope system has been proposed.

  16. Stability in dynamical systems I

    Energy Technology Data Exchange (ETDEWEB)

    Courant, E.D.; Ruth, R.D.; Weng, W.T.

    1984-08-01

    We have reviewed some of the basic techniques which can be used to analyze stability in nonlinear dynamical systems, particularly in circular particle accelerators. We have concentrated on one-dimensional systems in the examples in order to simply illustrate the general techniques. We began with a review of Hamiltonian dynamics and canonical transformations. We then reviewed linear equations with periodic coefficients using the basic techniques from accelerator theory. To handle nonlinear terms we developed a canonical perturbation theory. From this we calculated invariants and the amplitude dependence of the frequency. This led us to resonances. We studied the cubic resonance in detail by using a rotating coordinate system in phase space. We then considered a general isolated nonlinear resonance. In this case we calculated the width of the resonance and estimated the spacing of resonances in order to use the Chirikov criterion to restrict the validity of the analysis. Finally the resonance equation was reduced to the pendulum equation, and we examined the motion on a separatrix. This brought us to the beginnings of stochastic behavior in the neighborhood of the separatrix. It is this complex behavior in the neighborhood of the separatrix which causes the perturbation theory used here to diverge in many cases. In spite of this the methods developed here have been and are used quite successfully to study nonlinear effects in nearly integrable systems. When used with caution and in conjunction with numerical work they give tremendous insight into the nature of the phase space structure and the stability of nonlinear differential equations. 14 references.

  17. The bornavirus-derived human protein EBLN1 promotes efficient cell cycle transit, microtubule organisation and genome stability

    Science.gov (United States)

    Myers, Katie N.; Barone, Giancarlo; Ganesh, Anil; Staples, Christopher J.; Howard, Anna E.; Beveridge, Ryan D.; Maslen, Sarah; Skehel, J. Mark; Collis, Spencer J.

    2016-01-01

    It was recently discovered that vertebrate genomes contain multiple endogenised nucleotide sequences derived from the non-retroviral RNA bornavirus. Strikingly, some of these elements have been evolutionary maintained as open reading frames in host genomes for over 40 million years, suggesting that some endogenised bornavirus-derived elements (EBL) might encode functional proteins. EBLN1 is one such element established through endogenisation of the bornavirus N gene (BDV N). Here, we functionally characterise human EBLN1 as a novel regulator of genome stability. Cells depleted of human EBLN1 accumulate DNA damage both under non-stressed conditions and following exogenously induced DNA damage. EBLN1-depleted cells also exhibit cell cycle abnormalities and defects in microtubule organisation as well as premature centrosome splitting, which we attribute in part, to improper localisation of the nuclear envelope protein TPR. Our data therefore reveal that human EBLN1 possesses important cellular functions within human cells, and suggest that other EBLs present within vertebrate genomes may also possess important cellular functions. PMID:27739501

  18. Dynamic behavior of GFP-CLIP-170 reveals fast protein turnover on microtubule plus ends.

    NARCIS (Netherlands)

    K.A. Drägestein (Katharina Asja); W.A. van Cappellen (Gert); J.A.J. van Haren (Jeffrey); G.D. Tsibidis (George); A.S. Akhmanova (Anna); T.A. Knoch (Tobias); F.G. Grosveld (Frank); N.J. Galjart (Niels)

    2008-01-01

    textabstractMicrotubule (MT) plus end – tracking proteins (+TIPs) specifi cally recognize the ends of growing MTs. +TIPs are involved in diverse cellular processes such as cell division, cell migration, and cell polarity. Although +TIP tracking is important for these processes, the mechanisms underl

  19. In vitro reconstitution of dynamic microtubules interacting with actin filament networks

    NARCIS (Netherlands)

    Preciado Lopez, M.; Huber, F.; Grigoriev, Ilya; Steinmetz, M.O.; Akhmanova, Anna; Dogterom, M.; Koenderink, G.H.

    2014-01-01

    Interactions between microtubules and actin filaments (F-actin) are essential for eukaryotic cell migration, polarization, growth, and division. Although the importance of these interactions has been long recognized, the inherent complexity of the cell interior hampers a detailed mechanistic study o

  20. Mechanical Models of Microtubule Bundle Collapse in Alzheimer's Disease

    Science.gov (United States)

    Sendek, Austin; Singh, Rajiv; Cox, Daniel

    2013-03-01

    Amyloid-beta aggregates initiate Alzheimer's disease, and downstream trigger degradation of tau proteins that act as microtubule bundle stabilizers and mechanical spacers. Currently it is unclear which of tau cutting by proteases, tau phosphorylation, or tau aggregation are responsible for cytoskeleton degradation., We construct a percolation simulation of the microtubule bundle using a molecular spring model for the taus and including depletion force attraction between microtubules and membrane/actin cytoskeletal surface tension. The simulation uses a fictive molecular dynamics to model the motion of the individual microtubules within the bundle as a result of random tau removal, and calculates the elastic modulus of the bundle as the tau concentration falls. We link the tau removal steps to kinetic tau steps in various models of tau degradation. Supported by US NSF Grant DMR 1207624

  1. Resistance to discodermolide, a microtubule-stabilizing agent and senescence inducer, is 4E-BP1-dependent.

    Science.gov (United States)

    Chao, Suzan K; Lin, Juan; Brouwer-Visser, Jurriaan; Smith, Amos B; Horwitz, Susan Band; McDaid, Hayley M

    2011-01-01

    Discodermolide is a microtubule-stabilizing agent that induces accelerated cell senescence. A discodermolide-resistant cell line, AD32, was generated from the human lung cancer cell line A549. We hypothesize that the major resistance mechanism in these cells is escape from accelerated senescence. AD32 cells have decreased levels of 4E-BP1 mRNA and protein, relative to the parental discodermolide-sensitive A549 cells. Lentiviral-mediated re-expression of wild-type 4E-BP1 in AD32 cells increased the proliferation rate and reverted resistance to discodermolide via restoration of discodermolide-induced accelerated senescence. Consistent with this, cell growth and response to discodermolide was confirmed in vivo using tumor xenograft models. Furthermore, reintroduction of a nonphosphorylatable mutant (Thr-37/46 Ala) of 4E-BP1 was able to partially restore sensitivity and enhance proliferation in AD32 cells, suggesting that these effects are independent of phosphorylation by mTORC1. Microarray profiling of AD32-resistant cells versus sensitive A549 cells, and subsequent unbiased gene ontology analysis, identified molecular pathways and functional groupings of differentially expressed mRNAs implicated in overcoming discodermolide-induced senescence. The most statistically significant classes of differentially expressed genes included p53 signaling, G2/M checkpoint regulation, and genes involved in the role of BRCA1 in the DNA damage response. Consistent with this, p53 protein expression was up-regulated and had increased nuclear localization in AD32 cells relative to parental A549 cells. Furthermore, the stability of p53 was enhanced in AD32 cells. Our studies propose a role for 4E-BP1 as a regulator of discodermolide-induced accelerated senescence.

  2. Potent antiproliferative cembrenoids accumulate in tobacco upon infection with Rhodococcus fascians and trigger unusual microtubule dynamics in human glioblastoma cells.

    Directory of Open Access Journals (Sweden)

    Aminata P Nacoulma

    Full Text Available AIMS: Though plant metabolic changes are known to occur during interactions with bacteria, these were rarely challenged for pharmacologically active compounds suitable for further drug development. Here, the occurrence of specific chemicals with antiproliferative activity against human cancer cell lines was evidenced in hyperplasia (leafy galls induced when plants interact with particular phytopathogens, such as the Actinomycete Rhodococcus fascians. METHODS: We examined leafy galls fraction F3.1.1 on cell proliferation, cell division and cytoskeletal disorganization of human cancer cell lines using time-lapse videomicroscopy imaging, combined with flow cytometry and immunofluorescence analysis. We determined the F3.1.1-fraction composition by gas chromatography coupled to mass spectrometry. RESULTS: The leafy galls induced on tobacco by R. fascians yielded fraction F3.1.1 which inhibited proliferation of glioblastoma U373 cells with an IC50 of 4.5 µg/mL, F.3.1.1 was shown to increase cell division duration, cause nuclear morphological deformations and cell enlargement, and, at higher concentrations, karyokinesis defects leading to polyploidization and apoptosis. F3.1.1 consisted of a mixture of isomers belonging to the cembrenoids. The cellular defects induced by F3.1.1 were caused by a peculiar cytoskeletal disorganization, with the occurrence of fragmented tubulin and strongly organized microtubule aggregates within the same cell. Colchicine, paclitaxel, and cembrene also affected U373 cell proliferation and karyokinesis, but the induced microtubule rearrangement was very different from that provoked by F3.1.1. Altogether our data indicate that the cembrenoid isomers in F3.1.1 have a unique mode of action and are able to simultaneously modulate microtubule polymerization and stability.

  3. The octarepeat region of hamster PrP (PrP51-91) enhances the formation of microtubule and antagonize Cu~(2+)-induced microtubule-disrupting activity

    Institute of Scientific and Technical Information of China (English)

    Xiaoli Li; Chenfang Dong; Song Shi; Guirong Wang; Yuan Li; Xin Wang; Qi Shi; Chan Tian; Ruimin Zhou; Chen Gao; Xiaoping Dong

    2009-01-01

    Prion protein (PrP) is considered to associate with microtubule and its major component, tubulin. In the present study, octarepeat region of PrP (PrP51-91) was expressed in prokaryotic-expressing system. Using GST pull-down assay and co-immunoprecipitation, the mol-ecular interaction between PrP51-91 and tubulin was observed. Our data also demonstrated that PrP51-91 could efficiently stimulate microtubule assembly in vitro, indicating a potential effect of PrP on microtu-bule dynamics. Moreover, PrP51-91 was confirmed to be able to antagonize Cu~(2+)-induced microtubule-disrupt-ing activity in vivo, partially protecting against Cu~(2+) intoxication to culture cells and stabilize cellular micro-tubule structure. The association of the octarepeat region of PrP with tubulin may further provide insight into the biological function of PrP in the neurons.

  4. Local Dynamic Stability Associated with Load Carrying

    Directory of Open Access Journals (Sweden)

    Jian Liu

    2013-03-01

    Conclusion: Current study confirmed the sensitivity of local dynamic stability measure in load carrying situation. It was concluded that load carrying tasks were associated with declined local dynamic stability, which may result in increased risk of fall accident. This finding has implications in preventing fall accidents associated with occupational load carrying.

  5. Trait diversity promotes stability of community dynamics

    DEFF Research Database (Denmark)

    Zhang, Lai; Thygesen, Uffe Høgsbro; Knudsen, Kim;

    2013-01-01

    The theoretical exploration of how diversity influences stability has traditionally been approached by species-centric methods. Here we offer an alternative approach to the diversity–stability problem by examining the stability and dynamics of size and trait distributions of individuals. The anal...

  6. PSD-95 alters microtubule dynamics via an association with EB3

    Science.gov (United States)

    Sweet, Eric S.; Previtera, Michelle L.; Fernández, Jose R.; Charych, Erik I.; Tseng, Chia-Yi; Kwon, Munjin; Starovoytov, Valentin; Zheng, James Q.; Firestein, Bonnie L.

    2011-01-01

    Little is known about how the neuronal cytoskeleton is regulated when a dendrite decides whether to branch or not. Previously, we reported that postsynaptic density protein 95 (PSD-95) acts as a stop signal for dendrite branching. It is yet to be elucidated how PSD-95 affects the cytoskeleton and how this regulation relates to the dendritic arbor. Here, we show that the SH3 (src homology 3) domain of PSD-95 interacts with a proline-rich region within the microtubule end-binding protein EB3. Overexpression of PSD-95 or mutant EB3 results in a decreased lifetime of EB3 comets in dendrites. In line with these data, transfected rat neurons show that overexpression of PSD-95 results in less organized microtubules at dendritic branch points and decreased dendritogensis. The interaction between PSD-95 and EB3 elucidates a function for a novel region of EB3 and provides a new and important mechanism for the regulation of microtubules in determining dendritic morphology. PMID:21248129

  7. Theory of dynamic force spectroscopy for kinetochore-microtubule attachments: rupture force distribution

    CERN Document Server

    Ghanti, Dipanwita

    2016-01-01

    Application of pulling force, under force-clamp conditions, to kinetochore-microtubule attachments {\\it in-vitro} revealed a catch-bond-like behavior. In an earlier paper ({\\it Sharma et al. Phys. Biol. (2014)} the physical origin of this apparently counter-intuitive phenomenon was traced to the nature of the force-dependence of the (de-)polymerization kinetics of the microtubules. In this brief communication that work is extended to situations where the external forced is ramped up till the attachment gets ruptured. In spite of the fundamental differences in the underlying mechanisms, the trend of variation of the rupture force distribution observed in our model kinetochore-microtubule attachment with the increasing loading rate is qualitatively similar to that displayed by the catch bonds formed in some other ligand-receptor systems. Our theoretical predictions can be tested experimentally by a straightforward modification of the protocol for controlling the force in the optical trap set up that was used in...

  8. Cep70 promotes microtubule assembly in vitro by increasing microtubule elongation

    Institute of Scientific and Technical Information of China (English)

    Xingjuan Shi; Jun Wang; Yunfan Yang; Yuan Ren; Jun Zhou; Dengwen Li

    2012-01-01

    Microtubules are dynamic cytoskeletal polymers present in all eukaryotic cells,In animal cells,they are organized by the centrosome,the major microtubule-organizing center.Many centrosomal proteins act coordinately to modulate microtubule assembly and organization.Our previous work has shown that Cep70,a novel centrosomal protein regulates microtubule assembly and organization in mammalian cells.However,the molecular details remain to be investigated,in this study,we investigated the molecular mechanism of how Cep70 regulates microtubule assembly using purified proteins.Our data showed that Cep70 increased the microtubule length without affecting the microtubule number in the purified system.These results demonstrate that Cep70 could directly regulate microtubule assembly by promoting microtubule elongation instead of microtubule nucleation.

  9. Biomechanics of Posterior Dynamic Stabilization Systems

    Directory of Open Access Journals (Sweden)

    D. U. Erbulut

    2013-01-01

    Full Text Available Spinal rigid instrumentations have been used to fuse and stabilize spinal segments as a surgical treatment for various spinal disorders to date. This technology provides immediate stability after surgery until the natural fusion mass develops. At present, rigid fixation is the current gold standard in surgical treatment of chronic back pain spinal disorders. However, such systems have several drawbacks such as higher mechanical stress on the adjacent segment, leading to long-term degenerative changes and hypermobility that often necessitate additional fusion surgery. Dynamic stabilization systems have been suggested to address adjacent segment degeneration, which is considered to be a fusion-associated phenomenon. Dynamic stabilization systems are designed to preserve segmental stability, to keep the treated segment mobile, and to reduce or eliminate degenerative effects on adjacent segments. This paper aimed to describe the biomechanical aspect of dynamic stabilization systems as an alternative treatment to fusion for certain patients.

  10. Geometry and stability of dynamical systems

    CERN Document Server

    Punzi, Raffaele

    2008-01-01

    We reconsider both the global and local stability of solutions of continuously evolving dynamical systems from a geometric perspective. We clarify that an unambiguous definition of stability generally requires the choice of additional geometric structure that is not intrinsic to the dynamical system itself. While global Lyapunov stability is based on the choice of seminorms on the vector bundle of perturbations, we propose a definition of local stability based on the choice of a linear connection. We show how this definition reproduces known stability criteria for second order dynamical systems. In contrast to the general case, the special geometry of Lagrangian systems provides completely intrinsic notions of global and local stability. We demonstrate that these do not suffer from the limitations occurring in the analysis of the Maupertuis-Jacobi geodesics associated to natural Lagrangian systems.

  11. The acetylenic tricyclic bis(cyano enone), TBE-31, targets microtubule dynamics and cell polarity in migrating cells.

    Science.gov (United States)

    Chan, Eddie; Saito, Akira; Honda, Tadashi; Di Guglielmo, Gianni M

    2016-04-01

    Cell migration is dependent on the microtubule network for structural support as well as for the proper delivery and positioning of polarity proteins at the leading edge of migrating cells. Identification of drugs that target cytoskeletal-dependent cell migration and protein transport in polarized migrating cells is important in understanding the cell biology of normal and tumor cells and can lead to new therapeutic targets in disease processes. Here, we show that the tricyclic compound TBE-31 directly binds to tubulin and interferes with microtubule dynamics, as assessed by end binding 1 (EB1) live cell imaging. Interestingly, this interference is independent of in vitro tubulin polymerization. Using immunofluorescence microscopy, we also observed that TBE-31 interferes with the polarity of migratory cells. The polarity proteins Rac1, IQGAP and Tiam1 were localized at the leading edge of DMSO-treated migrating cell, but were observed to be in multiple protrusions around the cell periphery of TBE-31-treated cells. Finally, we observed that TBE-31 inhibits the migration of Rat2 fibroblasts with an IC50 of 0.75 μM. Taken together, our results suggest that the inhibition of cell migration by TBE-31 may result from the improper maintenance of cell polarity of migrating cells.

  12. A Short History of Posterior Dynamic Stabilization

    Directory of Open Access Journals (Sweden)

    Cengiz Gomleksiz

    2012-01-01

    Full Text Available Interspinous spacers were developed to treat local deformities such as degenerative spondylolisthesis. To treat patients with chronic instability, posterior pedicle fixation and rod-based dynamic stabilization systems were developed as alternatives to fusion surgeries. Dynamic stabilization is the future of spinal surgery, and in the near future, we will be able to see the development of new devices and surgical techniques to stabilize the spine. It is important to follow the development of these technologies and to gain experience using them. In this paper, we review the literature and discuss the dynamic systems, both past and present, used in the market to treat lumbar degeneration.

  13. Kinetochore-microtubule attachment is sufficient to satisfy the human spindle assembly checkpoint.

    Science.gov (United States)

    Etemad, Banafsheh; Kuijt, Timo E F; Kops, Geert J P L

    2015-12-01

    The spindle assembly checkpoint (SAC) is a genome surveillance mechanism that protects against aneuploidization. Despite profound progress on understanding mechanisms of its activation, it remains unknown what aspect of chromosome-spindle interactions is monitored by the SAC: kinetochore-microtubule attachment or the force generated by dynamic microtubules that signals stable biorientation of chromosomes? To answer this, we uncoupled these two processes by expressing a non-phosphorylatable version of the main microtubule-binding protein at kinetochores (HEC1-9A), causing stabilization of incorrect kinetochore-microtubule attachments despite persistent activity of the error-correction machinery. The SAC is fully functional in HEC1-9A-expressing cells, yet cells in which chromosomes cannot biorient but are stably attached to microtubules satisfy the SAC and exit mitosis. SAC satisfaction requires neither intra-kinetochore stretching nor dynamic microtubules. Our findings support the hypothesis that in human cells the end-on interactions of microtubules with kinetochores are sufficient to satisfy the SAC without the need for microtubule-based pulling forces.

  14. Microtubule assembly affects bone mass by regulating both osteoblast and osteoclast functions: stathmin deficiency produces an osteopenic phenotype in mice.

    Science.gov (United States)

    Liu, Hongbin; Zhang, Rongrong; Ko, Seon-Yle; Oyajobi, Babatunde O; Papasian, Christopher J; Deng, Hong-Wen; Zhang, Shujun; Zhao, Ming

    2011-09-01

    Cytoskeleton microtubules regulate various cell signaling pathways that are involved in bone cell function. We recently reported that inhibition of microtubule assembly by microtubule-targeting drugs stimulates osteoblast differentiation and bone formation. To further elucidate the role of microtubules in bone homeostasis, we characterized the skeletal phenotype of mice null for stathmin, an endogenous protein that inhibits microtubule assembly. In vivo micro-computed tomography (µCT) and histology revealed that stathmin deficiency results in a significant reduction of bone mass in adult mice concurrent with decreased osteoblast and increased osteoclast numbers in bone tissues. Phenotypic analyses of primary calvarial cells and bone marrow cells showed that stathmin deficiency inhibited osteoblast differentiation and induced osteoclast formation. In vitro overexpression studies showed that increased stathmin levels enhanced osteogenic differentiation of preosteoblast MC3T3-E1 cells and mouse bone marrow-derived cells and attenuated osteoclast formation from osteoclast precursor Raw264.7 cells and bone marrow cells. Results of immunofluorescent studies indicated that overexpression of stathmin disrupted radial microtubule filaments, whereas deficiency of stathmin stabilized the microtubule network structure in these bone cells. In addition, microtubule-targeting drugs that inhibit microtubule assembly and induce osteoblast differentiation lost these effects in the absence of stathmin. Collectively, these results suggest that stathmin, which alters microtubule dynamics, plays an essential role in maintenance of postnatal bone mass by regulating both osteoblast and osteoclast functions in bone. \\

  15. The microtubule aster formation and its role in nuclear envelope assembly around the sperm chromatin in Xenopus egg extracts

    Institute of Scientific and Technical Information of China (English)

    YANG Ning; CHEN Zhongcai; LU Ping; ZHANG Chuanmao; ZHAI Zhonghe; TANG Xiaowei

    2003-01-01

    Nuclear envelope is a dynamic structure in the cell cycle. At the beginning of mitosis, nuclear envelope breaks down and its components disperse into the cytoplasm. At the end of mitosis, nuclear envelope reassembles using the dispersed components. Searching for the mechanisms of the nuclear disassembly and reassembly has for a long time been one of the key projects for cell biologists. In this report we show that microtubules take a role in the nuclear envelope assembly around the sperm chromatin in Xenopus egg extracts. Microtubule cytoskeleton has been demonstrated to take roles in the transport of intracellular membranes such as Golgi and ER vesicles. We found that the nuclear envelope assembly needs functional microtubules. At the beginning of the nuclear assembly, microtubules nucleated to form a microtubule aster around the centrosome at the base of the sperm head. Using the microtubule drug colchicine to disrupt the microtubule nucleation, nuclear envelope reassembly was seriously inhibited. If the microtubules were stabilized by taxol, another microtubule drug, the nuclear envelope reassembly was also interfered, although a significantly large aster formed around the chromatin. Based on these observations, we propose that microtubules play an important role in the nuclear envelope reassembly maybe by transporting the nuclear envelope precursors to the chromatin surfaces.

  16. Phosphorylation of EB2 by Aurora B and CDK1 ensures mitotic progression and genome stability.

    Science.gov (United States)

    Iimori, Makoto; Watanabe, Sugiko; Kiyonari, Shinichi; Matsuoka, Kazuaki; Sakasai, Ryo; Saeki, Hiroshi; Oki, Eiji; Kitao, Hiroyuki; Maehara, Yoshihiko

    2016-03-31

    Temporal regulation of microtubule dynamics is essential for proper progression of mitosis and control of microtubule plus-end tracking proteins by phosphorylation is an essential component of this regulation. Here we show that Aurora B and CDK1 phosphorylate microtubule end-binding protein 2 (EB2) at multiple sites within the amino terminus and a cluster of serine/threonine residues in the linker connecting the calponin homology and end-binding homology domains. EB2 phosphorylation, which is strictly associated with mitotic entry and progression, reduces the binding affinity of EB2 for microtubules. Expression of non-phosphorylatable EB2 induces stable kinetochore microtubule dynamics and delays formation of bipolar metaphase plates in a microtubule binding-dependent manner, and leads to aneuploidy even in unperturbed mitosis. We propose that Aurora B and CDK1 temporally regulate the binding affinity of EB2 for microtubules, thereby ensuring kinetochore microtubule dynamics, proper mitotic progression and genome stability.

  17. Efficient syntheses of 25,26-dihydrodictyostatin and 25,26-dihydro-6-epi-dictyostatin, two potent new microtubule-stabilizing agents

    Directory of Open Access Journals (Sweden)

    María Jiménez

    2011-10-01

    Full Text Available The dictyostatins are powerful microtubule-stabilizing agents that have shown antiproliferative activity against a variety of human cancer cell lines. Two highly active analogs of dictyostatin, 25,26-dihydrodictyostatin and 25,26-dihydro-6-epi-dictyostatin, were prepared by a new streamlined total synthesis route. Three complete carbon fragments were prepared to achieve maximum convergency. These were coupled by a Horner–Wadsworth–Emmons reaction sequence and an esterification. A late stage Nozaki–Hiyama–Kishi reaction was then used to form the 22-membered macrolide. The stereoselectivity of this reaction depended on the configurations of the nearby stereocenter at C6.

  18. Effects of silver ions (Ag+) on contractile ring function and microtubule dynamics during first cleavage in Ilyanassa obsoleta

    Science.gov (United States)

    Conrad, A. H.; Stephens, A. P.; Paulsen, A. Q.; Schwarting, S. S.; Conrad, G. W.; Spooner, B. S. (Principal Investigator)

    1994-01-01

    The terminal phase of cell division involves tight constriction of the cleavage furrow contractile ring, stabilization/elongation of the intercellular bridge, and final separation of the daughter cells. At first cleavage, the fertilized eggs of the mollusk, Ilyanassa obsoleta, form two contractile rings at right angles to each other in the same cytoplasm that constrict to tight necks and partition the egg into a trefoil shape. The cleavage furrow contractile ring (CF) normally constricts around many midbody microtubules (MTs) and results in cleavage; the polar lobe constriction contractile ring (PLC) normally constricts around very few MTs and subsequently relaxes without cleavage. In the presence of Ag+ ions, the PLC 1) begins MT-dependent rapid constriction sooner than controls, 2) encircles more MTs than control egg PLCs, 3) elongates much more than control PLCs, and 4) remains tightly constricted and effectively cleaves the polar lobe from the egg. If Ag(+)-incubated eggs are returned to normal seawater at trefoil, tubulin fluorescence disappears from the PLC neck and the neck relaxes. If nocodazole, a drug that depolymerizes MTs, is added to Ag(+)-incubated eggs during early PLC constriction, the PLC is not stabilized and eventually relaxes. However, if nocodazole is added to Ag(+)-incubated eggs at trefoil, tubulin fluorescence disappears from the PLC neck but the neck remains constricted. These results suggest that Ag+ accelerates and gradually stabilizes the PLC constriction by a mechanism that is initially MT-dependent, but that progressively becomes MT-independent.

  19. Laulimalide induces dose-dependent modulation of microtubule behaviour in the C. elegans embryo.

    Directory of Open Access Journals (Sweden)

    Megha Bajaj

    Full Text Available Laulimalide is a microtubule-binding drug that was originally isolated from marine sponges. High concentrations of laulimalide stabilize microtubules and inhibit cell division similarly to paclitaxel; however, there are important differences with respect to the nature of the specific cellular defects between these two drugs and their binding sites on the microtubule. In this study, we used Caenorhabditis elegans embryos to investigate the acute effects of laulimalide on microtubules in vivo, with a direct comparison to paclitaxel. We observed surprising dose-dependent effects for laulimalide, whereby microtubules were stabilized at concentrations above 100 nM, but destabilized at concentrations between 50 and 100 nM. Despite this behaviour at low concentrations, laulimalide acted synergistically with paclitaxel to stabilize microtubules when both drugs were used at sub-effective concentrations, consistent with observations of synergistic interactions between these two drugs in other systems. Our results indicate that laulimalide induces a concentration-dependent, biphasic change in microtubule polymer dynamics in the C. elegans embryo.

  20. Reliability Analysis of Dynamic Stability in Waves

    DEFF Research Database (Denmark)

    Søborg, Anders Veldt

    2004-01-01

    exhibit sufficient characteristics with respect to slope at zero heel (GM value), maximum leverarm, positive range of stability and area below the leverarm curve. The rule-based requirements to calm water leverarm curves are entirely based on experience obtained from vessels in operation and recorded......The assessment of a ship's intact stability is traditionally based on a semi-empirical deterministic concept that evaluates the characteristics of ship's calm water restoring leverarm curves. Today the ship is considered safe with respect to dynamic stability if its calm water leverarm curves...... accidents in the past. The rules therefore only leaves little room for evaluation and improvement of safety of a ship's dynamic stability. A few studies have evaluated the probability of ship stability loss in waves using Monte Carlo simulations. However, since this probability may be in the order of 10...

  1. Dynamic stability experiment of Maglev systems

    Energy Technology Data Exchange (ETDEWEB)

    Cai, Y.; Mulcahy, T.M.; Chen, S.S. [and others

    1995-04-01

    This report summarizes the research performed on Maglev vehicle dynamic stability at Argonne National Laboratory during the past few years. It also documents magnetic-force data obtained from both measurements and calculations. Because dynamic instability is not acceptable for any commercial Maglev system, it is important to consider this phenomenon in the development of all Maglev systems. This report presents dynamic stability experiments on Maglev systems and compares their numerical simulation with predictions calculated by a nonlinear dynamic computer code. Instabilities of an electrodynamic system (EDS)-type vehicle model were obtained from both experimental observations and computer simulations for a five-degree-of-freedom Maglev vehicle moving on a guideway consisting of double L-shaped aluminum segments attached to a rotating wheel. The experimental and theoretical analyses developed in this study identify basic stability characteristics and future research needs of Maglev systems.

  2. Unifying dynamical and structural stability of equilibria

    Science.gov (United States)

    Arnoldi, Jean-François; Haegeman, Bart

    2016-09-01

    We exhibit a fundamental relationship between measures of dynamical and structural stability of linear dynamical systems-e.g. linearized models in the vicinity of equilibria. We show that dynamical stability, quantified via the response to external perturbations (i.e. perturbation of dynamical variables), coincides with the minimal internal perturbation (i.e. perturbations of interactions between variables) able to render the system unstable. First, by reformulating a result of control theory, we explain that harmonic external perturbations reflect the spectral sensitivity of the Jacobian matrix at the equilibrium, with respect to constant changes of its coefficients. However, for this equivalence to hold, imaginary changes of the Jacobian's coefficients have to be allowed. The connection with dynamical stability is thus lost for real dynamical systems. We show that this issue can be avoided, thus recovering the fundamental link between dynamical and structural stability, by considering stochastic noise as external and internal perturbations. More precisely, we demonstrate that a linear system's response to white-noise perturbations directly reflects the intensity of internal white-noise disturbance that it can accommodate before becoming stochastically unstable.

  3. Binding of PTEN to specific PDZ domains contributes to PTEN protein stability and phosphorylation by microtubule-associated serine/threonine kinases.

    Science.gov (United States)

    Valiente, Miguel; Andrés-Pons, Amparo; Gomar, Beatriz; Torres, Josema; Gil, Anabel; Tapparel, Caroline; Antonarakis, Stylianos E; Pulido, Rafael

    2005-08-12

    The tumor suppressor phosphatase PTEN is a key regulator of cell growth and apoptosis that interacts with PDZ domains from regulatory proteins, including MAGI-1/2/3, hDlg, and MAST205. Here we identified novel PTEN-binding PDZ domains within the MAST205-related proteins, syntrophin-associated serine/threonine kinase and MAST3, characterized the regions of PTEN involved in its interaction with distinctive PDZ domains, and analyzed the functional consequences on PTEN of PDZ domain binding. Using a panel of PTEN mutations, as well as PTEN chimeras containing distinct domains of the related protein TPTE, we found that the PTP and C2 domains of PTEN do not affect PDZ domain binding and that the C-terminal tail of PTEN (residues 350-403) provides selectivity to recognize specific PDZ domains from MAGI-2, hDlg, and MAST205. Binding of PTEN to the PDZ-2 domain from MAGI-2 increased PTEN protein stability. Furthermore, binding of PTEN to the PDZ domains from microtubule-associated serine/threonine kinases facilitated PTEN phosphorylation at its C terminus by these kinases. Our results suggest an important role for the C-terminal region of PTEN in the selective association with scaffolding and/or regulatory molecules and provide evidence that PDZ domain binding stabilizes PTEN and targets this tumor suppressor for phosphorylation by microtubule-associated serine/threonine kinases.

  4. Hybrid Dynamical Systems Modeling, Stability, and Robustness

    CERN Document Server

    Goebel, Rafal; Teel, Andrew R

    2012-01-01

    Hybrid dynamical systems exhibit continuous and instantaneous changes, having features of continuous-time and discrete-time dynamical systems. Filled with a wealth of examples to illustrate concepts, this book presents a complete theory of robust asymptotic stability for hybrid dynamical systems that is applicable to the design of hybrid control algorithms--algorithms that feature logic, timers, or combinations of digital and analog components. With the tools of modern mathematical analysis, Hybrid Dynamical Systems unifies and generalizes earlier developments in continuous-time and discret

  5. Centriolar CPAP/SAS-4 Imparts Slow Processive Microtubule Growth.

    Science.gov (United States)

    Sharma, Ashwani; Aher, Amol; Dynes, Nicola J; Frey, Daniel; Katrukha, Eugene A; Jaussi, Rolf; Grigoriev, Ilya; Croisier, Marie; Kammerer, Richard A; Akhmanova, Anna; Gönczy, Pierre; Steinmetz, Michel O

    2016-05-23

    Centrioles are fundamental and evolutionarily conserved microtubule-based organelles whose assembly is characterized by microtubule growth rates that are orders of magnitude slower than those of cytoplasmic microtubules. Several centriolar proteins can interact with tubulin or microtubules, but how they ensure the exceptionally slow growth of centriolar microtubules has remained mysterious. Here, we bring together crystallographic, biophysical, and reconstitution assays to demonstrate that the human centriolar protein CPAP (SAS-4 in worms and flies) binds and "caps" microtubule plus ends by associating with a site of β-tubulin engaged in longitudinal tubulin-tubulin interactions. Strikingly, we uncover that CPAP activity dampens microtubule growth and stabilizes microtubules by inhibiting catastrophes and promoting rescues. We further establish that the capping function of CPAP is important to limit growth of centriolar microtubules in cells. Our results suggest that CPAP acts as a molecular lid that ensures slow assembly of centriolar microtubules and, thereby, contributes to organelle length control.

  6. Detailed Per-residue Energetic Analysis Explains the Driving Force for Microtubule Disassembly.

    Directory of Open Access Journals (Sweden)

    Ahmed T Ayoub

    2015-06-01

    Full Text Available Microtubules are long filamentous hollow cylinders whose surfaces form lattice structures of αβ-tubulin heterodimers. They perform multiple physiological roles in eukaryotic cells and are targets for therapeutic interventions. In our study, we carried out all-atom molecular dynamics simulations for arbitrarily long microtubules that have either GDP or GTP molecules in the E-site of β-tubulin. A detailed energy balance of the MM/GBSA inter-dimer interaction energy per residue contributing to the overall lateral and longitudinal structural stability was performed. The obtained results identified the key residues and tubulin domains according to their energetic contributions. They also identified the molecular forces that drive microtubule disassembly. At the tip of the plus end of the microtubule, the uneven distribution of longitudinal interaction energies within a protofilament generates a torque that bends tubulin outwardly with respect to the cylinder's axis causing disassembly. In the presence of GTP, this torque is opposed by lateral interactions that prevent outward curling, thus stabilizing the whole microtubule. Once GTP hydrolysis reaches the tip of the microtubule (lateral cap, lateral interactions become much weaker, allowing tubulin dimers to bend outwards, causing disassembly. The role of magnesium in the process of outward curling has also been demonstrated. This study also showed that the microtubule seam is the most energetically labile inter-dimer interface and could serve as a trigger point for disassembly. Based on a detailed balance of the energetic contributions per amino acid residue in the microtubule, numerous other analyses could be performed to give additional insights into the properties of microtubule dynamic instability.

  7. Vehicle lateral dynamics stabilization using active suspension

    Directory of Open Access Journals (Sweden)

    Drobný V.

    2008-12-01

    Full Text Available The paper deals with the investigation of active nonlinear suspension control in order to stabilize the lateral vehicle motion in similar way as systems like ESP do. The lateral stabilization of vehicle based on braking forces can be alternatively provided by the different setting of suspension forces. The basis of this control is the nonlinear property of the tyres. The vehicle has at least four wheels and it gives one or more redundant vertical forces that can be used for the different distribution of vertical suspension forces in such a way that resulting lateral and/or longitudinal forces create the required correction moment for lateral dynamic vehicle stabilization.

  8. Cell cycle-dependent microtubule-based dynamic transport of cytoplasmic dynein in mammalian cells.

    Directory of Open Access Journals (Sweden)

    Takuya Kobayashi

    Full Text Available BACKGROUND: Cytoplasmic dynein complex is a large multi-subunit microtubule (MT-associated molecular motor involved in various cellular functions including organelle positioning, vesicle transport and cell division. However, regulatory mechanism of the cell-cycle dependent distribution of dynein has not fully been understood. METHODOLOGY/PRINCIPAL FINDINGS: Here we report live-cell imaging of cytoplasmic dynein in HeLa cells, by expressing multifunctional green fluorescent protein (mfGFP-tagged 74-kDa intermediate chain (IC74. IC74-mfGFP was successfully incorporated into functional dynein complex. In interphase, dynein moved bi-directionally along with MTs, which might carry cargos such as transport vesicles. A substantial fraction of dynein moved toward cell periphery together with EB1, a member of MT plus end-tracking proteins (+TIPs, suggesting +TIPs-mediated transport of dynein. In late-interphase and prophase, dynein was localized at the centrosomes and the radial MT array. In prometaphase and metaphase, dynein was localized at spindle MTs where it frequently moved from spindle poles toward chromosomes or cell cortex. +TIPs may be involved in the transport of spindle dyneins. Possible kinetochore and cortical dyneins were also observed. CONCLUSIONS AND SIGNIFICANCE: These findings suggest that cytoplasmic dynein is transported to the site of action in preparation for the following cellular events, primarily by the MT-based transport. The MT-based transport may have greater advantage than simple diffusion of soluble dynein in rapid and efficient transport of the limited concentration of the protein.

  9. Optomechanical proposal for monitoring microtubule mechanical vibrations

    Science.gov (United States)

    Barzanjeh, Sh.; Salari, V.; Tuszynski, J. A.; Cifra, M.; Simon, C.

    2017-07-01

    Microtubules provide the mechanical force required for chromosome separation during mitosis. However, little is known about the dynamic (high-frequency) mechanical properties of microtubules. Here, we theoretically propose to control the vibrations of a doubly clamped microtubule by tip electrodes and to detect its motion via the optomechanical coupling between the vibrational modes of the microtubule and an optical cavity. In the presence of a red-detuned strong pump laser, this coupling leads to optomechanical-induced transparency of an optical probe field, which can be detected with state-of-the art technology. The center frequency and line width of the transparency peak give the resonance frequency and damping rate of the microtubule, respectively, while the height of the peak reveals information about the microtubule-cavity field coupling. Our method opens the new possibilities to gain information about the physical properties of microtubules, which will enhance our capability to design physical cancer treatment protocols as alternatives to chemotherapeutic drugs.

  10. Mechanism for the catastrophe-promoting activity of the microtubule destabilizer Op18/stathmin.

    Science.gov (United States)

    Gupta, Kamlesh K; Li, Chunlei; Duan, Aranda; Alberico, Emily O; Kim, Oleg V; Alber, Mark S; Goodson, Holly V

    2013-12-17

    Regulation of microtubule dynamic instability is crucial for cellular processes, ranging from mitosis to membrane transport. Stathmin (also known as oncoprotein 18/Op18) is a prominent microtubule destabilizer that acts preferentially on microtubule minus ends. Stathmin has been studied intensively because of its association with multiple types of cancer, but its mechanism of action remains controversial. Two models have been proposed. One model is that stathmin promotes microtubule catastrophe indirectly, and does so by sequestering tubulin; the other holds that stathmin alters microtubule dynamics by directly destabilizing growing microtubules. Stathmin's sequestration activity is well established, but the mechanism of any direct action is mysterious because stathmin binds to microtubules very weakly. To address these issues, we have studied interactions between stathmin and varied tubulin polymers. We show that stathmin binds tightly to Dolastatin-10 tubulin rings, which mimic curved tubulin protofilaments, and that stathmin depolymerizes stabilized protofilament-rich polymers. These observations lead us to propose that stathmin promotes catastrophe by binding to and acting upon protofilaments exposed at the tips of growing microtubules. Moreover, we suggest that stathmin's minus-end preference results from interactions between stathmin's N terminus and the surface of α-tubulin that is exposed only at the minus end. Using computational modeling of microtubule dynamics, we show that these mechanisms could account for stathmin's observed activities in vitro, but that both the direct and sequestering activities are likely to be relevant in a cellular context. Taken together, our results suggest that stathmin can promote catastrophe by direct action on protofilament structure and interactions.

  11. Stability and dynamics of magnetocapillary interactions

    CERN Document Server

    Chinomona, Rujeko; Mitchell, William H; Yao, Yao; Spagnolie, Saverio E

    2014-01-01

    Recent experiments have shown that floating ferromagnetic beads, under the influence of an oscillating background magnetic field, can move along a liquid-air interface in a sustained periodic locomotion [Lumay et al., Soft Matter, 2013, 9, 2420]. Dynamic activity arises from a periodically induced dipole-dipole repulsion between the beads acting in concert with capillary attraction. We investigate analytically and numerically the stability and dynamics of this magnetocapillary swimming, and explore other related topics including the steady and periodic equilibrium configurations of two and three beads. The swimming speed and system stability depend on a dimensionless measure of the relative repulsive and attractive forces which we term the magnetocapillary number. An oscillatory magnetic field may stabilize an otherwise unstable collinear configuration, and striking behaviors are observed in fast transitions to and from locomotory states, offering insight into the behavior and self-assembly of interface-bound...

  12. Models for microtubule cargo transport coupling the Langevin equation to stochastic stepping motor dynamics: Caring about fluctuations.

    Science.gov (United States)

    Bouzat, Sebastián

    2016-01-01

    One-dimensional models coupling a Langevin equation for the cargo position to stochastic stepping dynamics for the motors constitute a relevant framework for analyzing multiple-motor microtubule transport. In this work we explore the consistence of these models focusing on the effects of the thermal noise. We study how to define consistent stepping and detachment rates for the motors as functions of the local forces acting on them in such a way that the cargo velocity and run-time match previously specified functions of the external load, which are set on the base of experimental results. We show that due to the influence of the thermal fluctuations this is not a trivial problem, even for the single-motor case. As a solution, we propose a motor stepping dynamics which considers memory on the motor force. This model leads to better results for single-motor transport than the approaches previously considered in the literature. Moreover, it gives a much better prediction for the stall force of the two-motor case, highly compatible with the experimental findings. We also analyze the fast fluctuations of the cargo position and the influence of the viscosity, comparing the proposed model to the standard one, and we show how the differences on the single-motor dynamics propagate to the multiple motor situations. Finally, we find that the one-dimensional character of the models impede an appropriate description of the fast fluctuations of the cargo position at small loads. We show how this problem can be solved by considering two-dimensional models.

  13. MVL-PLA2, a snake venom phospholipase A2, inhibits angiogenesis through an increase in microtubule dynamics and disorganization of focal adhesions.

    Directory of Open Access Journals (Sweden)

    Amine Bazaa

    Full Text Available Integrins are essential protagonists of the complex multi-step process of angiogenesis that has now become a major target for the development of anticancer therapies. We recently reported and characterized that MVL-PLA2, a novel phospholipase A2 from Macrovipera lebetina venom, exhibited anti-integrin activity. In this study, we show that MVL-PLA2 also displays potent anti-angiogenic properties. This phospholipase A2 inhibited adhesion and migration of human microvascular-endothelial cells (HMEC-1 in a dose-dependent manner without being cytotoxic. Using Matrigel and chick chorioallantoic membrane assays, we demonstrated that MVL-PLA2, as well as its catalytically inactivated form, significantly inhibited angiogenesis both in vitro and in vivo. We have also found that the actin cytoskeleton and the distribution of alphav beta3 integrin, a critical regulator of angiogenesis and a major component of focal adhesions, were disturbed after MVL-PLA2 treatment. In order to further investigate the mechanism of action of this protein on endothelial cells, we analyzed the dynamic instability behavior of microtubules in living endothelial cells. Interestingly, we showed that MVL-PLA2 significantly increased microtubule dynamicity in HMEC-1 cells by 40%. We propose that the enhancement of microtubule dynamics may explain the alterations in the formation of focal adhesions, leading to inhibition of cell adhesion and migration.

  14. The role of microtubule-associated protein 1B in axonal growth and neuronal migration in the central nervous system

    Institute of Scientific and Technical Information of China (English)

    Maoguang Yang; Xiaoyu Yang; Minfei Wu; Peng Xia; Chunxin Wang; Peng Yan; Qi Gao; Jian Liu; Haitao Wang; Xingwei Duan

    2012-01-01

    In this review, we discuss the role of microtubule-associated protein 1B (MAP1B) and its phosphorylation in axonal development and regeneration in the central nervous system. MAP1B exhibits similar functions during axonal development and regeneration. MAP1B and phosphorylated MAP1B in neurons and axons maintain a dynamic balance between cytoskeletal components, and regulate the stability and interaction of microtubules and actin to promote axonal growth, neural connectivity and regeneration in the central nervous system.

  15. External electric field effects on the mechanical properties of the αβ-tubulin dimer of microtubules: a molecular dynamics study.

    Science.gov (United States)

    Saeidi, H R; Lohrasebi, A; Mahnam, K

    2014-08-01

    The mechanical properties of the αβ-tubulin dimer of microtubules was modeled by using the molecular dynamics (MD) simulation method. The effect on the mechanical properties of the dimer of the existence and nonexistence of an applied electric field, either constant or periodic, was studied. Since there are charged or polar groups in the dimer structure, the electric field can interact with the dimer. The elastic constant and Young's modulus of the dimer were decreased when the dimer was exposed to a constant electric field of 0.03 V/nm. Furthermore, applying an oscillating electric field in the 1 GHz range to the dimer increased the elastic constant and Young's modulus of the dimer. These parameters were related to dimer rigidity and, consequently, in this frequency range, the application of electric fields may affect the function of microtubules.

  16. Linear Stability Analysis of Dynamical Quadratic Gravity

    CERN Document Server

    Ayzenberg, Dimitry; Yunes, Nicolas

    2013-01-01

    We perform a linear stability analysis of dynamical, quadratic gravity in the high-frequency, geometric optics approximation. This analysis is based on a study of gravitational and scalar modes propagating on spherically-symmetric and axially-symmetric, vacuum solutions of the theory. We find dispersion relations that do no lead to exponential growth of the propagating modes, suggesting the theory is linearly stable on these backgrounds. The modes are found to propagate at subluminal and superluminal speeds, depending on the propagating modes' direction relative to the background geometry, just as in dynamical Chern-Simons gravity.

  17. Topological stabilization for synchronized dynamics on networks

    Science.gov (United States)

    Cencetti, Giulia; Bagnoli, Franco; Battistelli, Giorgio; Chisci, Luigi; Di Patti, Francesca; Fanelli, Duccio

    2017-01-01

    A general scheme is proposed and tested to control the symmetry breaking instability of a homogeneous solution of a spatially extended multispecies model, defined on a network. The inherent discreteness of the space makes it possible to act on the topology of the inter-nodes contacts to achieve the desired degree of stabilization, without altering the dynamical parameters of the model. Both symmetric and asymmetric couplings are considered. In this latter setting the web of contacts is assumed to be balanced, for the homogeneous equilibrium to exist. The performance of the proposed method are assessed, assuming the Complex Ginzburg-Landau equation as a reference model. In this case, the implemented control allows one to stabilize the synchronous limit cycle, hence time-dependent, uniform solution. A system of coupled real Ginzburg-Landau equations is also investigated to obtain the topological stabilization of a homogeneous and constant fixed point.

  18. GDP-to-GTP exchange on the microtubule end can contribute to the frequency of catastrophe.

    Science.gov (United States)

    Piedra, Felipe-Andrés; Kim, Tae; Garza, Emily S; Geyer, Elisabeth A; Burns, Alexander; Ye, Xuecheng; Rice, Luke M

    2016-11-07

    Microtubules are dynamic polymers of αβ-tubulin that have essential roles in chromosome segregation and organization of the cytoplasm. Catastrophe-the switch from growing to shrinking-occurs when a microtubule loses its stabilizing GTP cap. Recent evidence indicates that the nucleotide on the microtubule end controls how tightly an incoming subunit will be bound (trans-acting GTP), but most current models do not incorporate this information. We implemented trans-acting GTP into a computational model for microtubule dynamics. In simulations, growing microtubules often exposed terminal GDP-bound subunits without undergoing catastrophe. Transient GDP exposure on the growing plus end slowed elongation by reducing the number of favorable binding sites on the microtubule end. Slower elongation led to erosion of the GTP cap and an increase in the frequency of catastrophe. Allowing GDP-to-GTP exchange on terminal subunits in simulations mitigated these effects. Using mutant αβ-tubulin or modified GTP, we showed experimentally that a more readily exchangeable nucleotide led to less frequent catastrophe. Current models for microtubule dynamics do not account for GDP-to-GTP exchange on the growing microtubule end, so our findings provide a new way of thinking about the molecular events that initiate catastrophe. © 2016 Piedra et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

  19. Longitudinal dynamic stability of a shuttle vehicle.

    Science.gov (United States)

    Vinh, N. X.; Laitone, E. V.

    1972-01-01

    Analytical study of the longitudinal dynamic stability of a nonrolling, lifting vehicle gliding at hypersonic speeds. The analysis applies to shuttle vehicles designed for operating up to the rim of a planetary atmosphere. A general nondimensional time transformation is introduced to derive a unified second-order linear differential equation for the angle of attack, valid for all types of reentry of a general type of vehicle. The stability of motion is discussed for two fundamental regimes of flight that are based on widely different assumptions. For near ballistic entry along a straight line trajectory, the equation reduces to a confluent hypergeometric equation, the solution of which can be expressed in terms of Whittaker's function. Using a theorem in the theory of stability of differential equations, criteria for damped oscillations are derived. It is shown that the aerodynamic criteria for stability are the same as for the case of ballistic entry. In addition, for each vehicle configuration, and specified planetary atmosphere, there exists an altitude range where the angle of attack frequency is nearly equal to the orbital frequency causing instability in pitch. This resonance instability is due to the ellipticity of the orbit. Criteria for eccentricity instability are derived.

  20. Stability studies of Solar Optical Telescope dynamics

    Science.gov (United States)

    Gullapalli, Sarma N.; Pal, Parimal K.; Ruthven, Gregory P.

    1987-01-01

    The Solar Optical Telescope (SOT) is designed to operate as an attached payload mounted on the Instrument Pointing System (IPS) in the cargo bay of the Shuttle Orbiter. Pointing and control of SOT is accomplished by an active Articulated Primary Mirror (APM), an active Tertiary Mirror (TM), an elaborate set of optical sensors, electromechanical actuators and programmable controllers. The structural interactions of this complex control system are significant factors in the stability of the SOT. The preliminary stability study results of the SOT dynamical system are presented. Structural transfer functions obtained from the NASTRAN model of the structure were used. These studies apply to a single degree of freedom (elevation). Fully integrated model studies will be conducted in the future.

  1. Reliability Analysis of Dynamic Stability in Waves

    DEFF Research Database (Denmark)

    Søborg, Anders Veldt

    2004-01-01

    exhibit sufficient characteristics with respect to slope at zero heel (GM value), maximum leverarm, positive range of stability and area below the leverarm curve. The rule-based requirements to calm water leverarm curves are entirely based on experience obtained from vessels in operation and recorded......-4 per ship year such brute force Monte-Carlo simulations are not always feasible due to the required computational resources. Previous studies of dynamic stability of ships in waves typically focused on the capsizing event. In this study the objective is to establish a procedure that can identify...... the distribution of the exceedance probability may be established by an estimation of the out-crossing rate of the "safe set" defined by the utility function. This out-crossing rate will be established using the so-called Madsen's Formula. A bi-product of this analysis is a set of short wave time series...

  2. Beam stability & nonlinear dynamics. Formal report

    Energy Technology Data Exchange (ETDEWEB)

    Parsa, Z. [ed.

    1996-12-31

    his Report includes copies of transparencies and notes from the presentations made at the Symposium on Beam Stability and Nonlinear Dynamics, December 3-5, 1996 at the Institute for Theoretical Physics, University of California, Santa Barbara California, that was made available by the authors. Editing, reduction and changes to the authors contributions were made only to fulfill the printing and publication requirements. We would like to take this opportunity and thank the speakers for their informative presentations and for providing copies of their transparencies and notes for inclusion in this Report.

  3. Dynamical Stability of Slip-stacking Particles

    CERN Document Server

    Eldred, Jeffrey

    2014-01-01

    We study the stability of particles in slip-stacking configuration, used to nearly double proton beam intensity at Fermilab. We introduce universal area factors to calculate the available phase space area for any set of beam parameters without individual simulation. We find perturbative solutions for stable particle trajectories. We establish Booster beam quality requirements to achieve 97\\% slip-stacking efficiency. We show that slip-stacking dynamics directly correspond to the driven pendulum and to the system of two standing-wave traps moving with respect to each other.

  4. Dynamical stability of slip-stacking particles

    Energy Technology Data Exchange (ETDEWEB)

    Eldred, Jeffrey; Zwaska, Robert

    2014-09-01

    We study the stability of particles in slip-stacking configuration, used to nearly double proton beam intensity at Fermilab. We introduce universal area factors to calculate the available phase space area for any set of beam parameters without individual simulation. We find perturbative solutions for stable particle trajectories. We establish Booster beam quality requirements to achieve 97% slip-stacking efficiency. We show that slip-stacking dynamics directly correspond to the driven pendulum and to the system of two standing-wave traps moving with respect to each other.

  5. Dynamical Stability of Slip-stacking Particles

    Energy Technology Data Exchange (ETDEWEB)

    Eldred, Jeffrey [Fermilab; Zwaska, Robert [Fermilab

    2014-09-04

    We study the stability of particles in slip-stacking configuration, used to nearly double proton beam intensity at Fermilab. We introduce universal area factors to calculate the available phase space area for any set of beam parameters without individual simulation. We find perturbative solutions for stable particle trajectories. We establish Booster beam quality requirements to achieve 97% slip-stacking efficiency. We show that slip-stacking dynamics directly correspond to the driven pendulum and to the system of two standing-wave traps moving with respect to each other.

  6. Dynamic and galvanic stability of stretchable supercapacitors.

    Science.gov (United States)

    Li, Xin; Gu, Taoli; Wei, Bingqing

    2012-12-12

    Stretchable electronics are emerging as a new technological advancement, since they can be reversibly stretched while maintaining functionality. To power stretchable electronics, rechargeable and stretchable energy storage devices become a necessity. Here, we demonstrate a facile and scalable fabrication of full stretchable supercapacitor, using buckled single-walled carbon nanotube macrofilms as the electrodes, an electrospun membrane of elastomeric polyurethane as the separator, and an organic electrolyte. We examine the electrochemical performance of the fully stretchable supercapacitors under dynamic stretching/releasing modes in different stretching strain rates, which reveal the true performance of the stretchable cells, compared to the conventional method of testing the cells under a statically stretched state. In addition, the self-discharge of the supercapacitor and the electrochemical behavior under bending mode are also examined. The stretchable supercapacitors show excellent cyclic stability under electrochemical charge/discharge during in situ dynamic stretching/releasing.

  7. Modeling microtubule oscillations

    DEFF Research Database (Denmark)

    Jobs, E.; Wolf, D.E.; Flyvbjerg, H.

    1997-01-01

    Synchronization of molecular reactions in a macroscopic volume may cause the volume's physical properties to change dynamically and thus reveal much about the reactions. As an example, experimental time series for so-called microtubule oscillations are analyzed in terms of a minimal model...... for this complex polymerization-depolymerization cycle. The model reproduces well the qualitatively different time series that result from different experimental conditions, and illuminates the role and importance of individual processes in the cycle. Simple experiments are suggested that can further test...... and define the model and the polymer's reaction cycle....

  8. Kinesin-12 motors cooperate to suppress microtubule catastrophes and drive the formation of parallel microtubule bundles.

    Science.gov (United States)

    Drechsler, Hauke; McAinsh, Andrew D

    2016-03-22

    Human Kinesin-12 (hKif15) plays a crucial role in assembly and maintenance of the mitotic spindle. These functions of hKif15 are partially redundant with Kinesin-5 (Eg5), which can cross-link and drive the extensile sliding of antiparallel microtubules. Although both motors are known to be tetramers, the functional properties of hKif15 are less well understood. Here we reveal how single or multiple Kif15 motors can cross-link, transport, and focus the plus-ends of intersecting microtubules. During transport, Kif15 motors step simultaneously along both microtubules with relative microtubule transport driven by a velocity differential between motor domain pairs. Remarkably, this differential is affected by the underlying intersection geometry: the differential is low on parallel and extreme on antiparallel microtubules where one motor domain pair becomes immobile. As a result, when intersecting microtubules are antiparallel, canonical transport of one microtubule along the other is allowed because one motor is firmly attached to one microtubule while it is stepping on the other. When intersecting microtubules are parallel, however, Kif15 motors can drive (biased) parallel sliding because the motor simultaneously steps on both microtubules that it cross-links. These microtubule rearrangements will focus microtubule plus-ends and finally lead to the formation of parallel bundles. At the same time, Kif15 motors cooperate to suppress catastrophe events at polymerizing microtubule plus-ends, raising the possibility that Kif15 motors may synchronize the dynamics of bundles that they have assembled. Thus, Kif15 is adapted to operate on parallel microtubule substrates, a property that clearly distinguishes it from the other tetrameric spindle motor, Eg5.

  9. The use of compressive sensing and peak detection in the reconstruction of microtubules length time series in the process of dynamic instability.

    Science.gov (United States)

    Mahrooghy, Majid; Yarahmadian, Shantia; Menon, Vineetha; Rezania, Vahid; Tuszynski, Jack A

    2015-10-01

    Microtubules (MTs) are intra-cellular cylindrical protein filaments. They exhibit a unique phenomenon of stochastic growth and shrinkage, called dynamic instability. In this paper, we introduce a theoretical framework for applying Compressive Sensing (CS) to the sampled data of the microtubule length in the process of dynamic instability. To reduce data density and reconstruct the original signal with relatively low sampling rates, we have applied CS to experimental MT lament length time series modeled as a Dichotomous Markov Noise (DMN). The results show that using CS along with the wavelet transform significantly reduces the recovery errors comparing in the absence of wavelet transform, especially in the low and the medium sampling rates. In a sampling rate ranging from 0.2 to 0.5, the Root-Mean-Squared Error (RMSE) decreases by approximately 3 times and between 0.5 and 1, RMSE is small. We also apply a peak detection technique to the wavelet coefficients to detect and closely approximate the growth and shrinkage of MTs for computing the essential dynamic instability parameters, i.e., transition frequencies and specially growth and shrinkage rates. The results show that using compressed sensing along with the peak detection technique and wavelet transform in sampling rates reduces the recovery errors for the parameters.

  10. Stability precision dynamic testing system on artillery

    Science.gov (United States)

    Wang, Chunyan; Li, Bo

    2014-12-01

    Dynamic feature of Weapon equipments is one of important performance index for evaluating the performance of the whole weapon system. The construction of target range in our country in fire control dynamic testing is relatively backward; therefore, it has greatly influenced the evaluation on the fire control system. In order to solve this problem, it's urgent to develop a new testing instrument so as to adjust to the armament research process and promote weapon system working more efficiently and thereby meeting the needs of modernization in national defense. This paper proposes a new measure which is used to test the stability precision of the fire control system, and it is installed on the moving base. Using the method, we develop a testing system which can test the stability precision of the fire control system and achieve a high precision results after testing. The innovation of the system is we can receive the image not only by CCD, but our eyes. It also adopts digital image-forming and image processing technique for real-time measurement and storing of the target information; it simultaneously adopts the method adjusting the platform and the corresponding fixture mounted on a sample to measure the stable precision and the precision of corner of stabilizator. In this paper, we make a description on the construction of the system and the idea of the designing of the optical system. Finally, we introduce the actual application of the system and testing results.

  11. Dynamic Analysis of Power System Voltage Stability.

    Science.gov (United States)

    Gebreselassie, Assefa

    This thesis investigates the effects of loads and voltage regulators on the dynamic voltage stability of power systems. The analysis focuses on the interactions of machine flux dynamics with loads and voltage control devices. The results are based on eigenvalue analysis of the linearized models and time simulation of the nonlinear models, using models from the Power System Toolbox, a Matlab -based package for the simulation and small signal analysis of nonlinear power systems. The voltage stability analysis results are developed using a single machine single load system with typical machine and network parameters and the NPCC 10-machine system. Dynamic models for generators, exciters and loads are used. The generator is modeled with a pair of poles and one damper circuit in both the d-axis and the q-axis. Saturation effects are included in the model. The IEEE Type DC1 DC commutator exciter model is used for all the exciters. Five different types of loads: constant impedance, constant current, constant power, a first order induction motor model (slip model) and a third order induction motor model (slip-flux model) are considered. The modes of instability and the stability limits of the different representation of loads are examined for two different operating modes of the exciters. The first, when all the exciters are on automatic control and the second when some exciters are on manual control. Modal participation factors are used to determine the characteristics of the critical modes. The characteristics of the unstable modes are verified by performing time simulation of the nonlinear models. Oscillatory and non-oscillatory instabilities are experienced by load buses when all the exciters are on automatic control and some exciters are on manual control respectively, for loads which are predominantly constant power and induction motors. It is concluded that the mode of instability does not depend on the type of loads but on the operating condition of the exciters

  12. ANALYSIS AND OPTIMISATION OF DYNAMIC STABILITY OF MOBILE WORKING MACHINES

    Directory of Open Access Journals (Sweden)

    Peter BIGOŠ

    2014-09-01

    Full Text Available This paper describes an investigation of the dynamic stability, which is specified for the mobile working machines. There are presented the basic theoretical principles of the stability theory together with an introduction of two illustrative examples of the dynamic stability analysis.

  13. Simplified discodermolide analogues: synthesis and biological evaluation of 4-epi-7-dehydroxy-14,16-didemethyl-(+)-discodermolides as microtubule-stabilizing agents.

    Science.gov (United States)

    Choy, Nakyen; Shin, Youseung; Nguyen, Phu Qui; Curran, Dennis P; Balachandran, Raghavan; Madiraju, Charitha; Day, Billy W

    2003-07-01

    Several novel analogues of (+)-discodermolide were synthesized via a convergent strategy that used Wittig reactions to append left and right side chains to a central scaffold and then tested for biological activity. Three of the analogues in the 4-epi-7-dehydroxy-14,16-didemethyl series, 6a-c, had interesting actions. The C3-methoxymethyl ether analogue 6b was more active in antiproliferative cell-based assays as well as in hypernucleation and paclitaxel site competition assays with isolated tubulin than the other analogues, including 6a, which contained a free hydroxyl group at the C3 position. The biological results validated the initial hypothesis that the C7 hydroxy group and the C14 and C16 methyl groups of (+)-discodermolide could be deleted without undermining activity. Although less potent than (+)-discodermolide and paclitaxel, compounds 6b and 6c both showed properties unique to (+)-discodermolide. These properties, particularly the capacity to cause hypernucleation of isolated tubulin at lower temperature than paclitaxel, as well as stabilizing preformed microtubules to cold disassembly, are considered mechanistically superior to those of paclitaxel. Other variations in the right and left sides of the discodermolide scaffold revealed additional structure/activity information.

  14. Theory for strength and stability of an unusual "ligand-receptor" bond: a microtubule attached to a wall by molecular motor tethers

    CERN Document Server

    Ghanti, Dipanwita

    2016-01-01

    A microtubule (MT) is a tubular stiff filament formed by a hierarchical organization of tubulin proteins. We develop a stochastic kinetic model for studying the strength and stability of a pre-formed attachment of a MT with a rigid wall where the MT is tethered to the wall by a group of motor proteins. Such an attachment, formed by the specific interactions between the MT and the motors, is an analog of ligand-receptor bonds, the MT and the motors anchored on the wall being the counterparts of the ligand and receptors, respectively. However, unlike other ligands, the length of a MT can change with time because of its polymerization-depolymerization kinetics. The simple model developed here is motivated by the MTs linked to the cell cortex by dynein motors. We present the theory for both force-ramp and force-clamp conditions. In the force-ramp protocol we investigate the strength of the attachment by assuming imposition of a time-dependent external load tension that increases linearly with time till the attach...

  15. Novos produtos naturais capazes de atuar na estabilização de microtúbulos, um importante alvo no combate ao câncer New natural products able to act on the stabilization of microtubules, an important target against cancer

    Directory of Open Access Journals (Sweden)

    Marcus Vinícius Nora de Souza

    2004-04-01

    Full Text Available Microtubules are involved in many aspects of cellular biology and represent an important target of anticancer chemotherapeutics. In the past five years, novel natural products such as epothilones, discodermolide, sarcodictyin, eleutherobin, and laulimalide, all of which have biological activities similar to those of paclitaxel (Taxolâ, have been discovered. Taxolâ is an important antitumor drug approved by the FDA for the treatment of ovarian, breast and non-small-cell lung carcinomas and became the first natural product described that stabilized microtubules avoiding the cellular replication. The present article reports new natural products that are able to act on the stabilization of microtubules.

  16. LKB1 destabilizes microtubules in myoblasts and contributes to myoblast differentiation.

    Directory of Open Access Journals (Sweden)

    Isma Mian

    Full Text Available BACKGROUND: Skeletal muscle myoblast differentiation and fusion into multinucleate myotubes is associated with dramatic cytoskeletal changes. We find that microtubules in differentiated myotubes are highly stabilized, but premature microtubule stabilization blocks differentiation. Factors responsible for microtubule destabilization in myoblasts have not been identified. FINDINGS: We find that a transient decrease in microtubule stabilization early during myoblast differentiation precedes the ultimate microtubule stabilization seen in differentiated myotubes. We report a role for the serine-threonine kinase LKB1 in both microtubule destabilization and myoblast differentiation. LKB1 overexpression reduced microtubule elongation in a Nocodazole washout assay, and LKB1 RNAi increased it, showing LKB1 destabilizes microtubule assembly in myoblasts. LKB1 levels and activity increased during myoblast differentiation, along with activation of the known LKB1 substrates AMP-activated protein kinase (AMPK and microtubule affinity regulating kinases (MARKs. LKB1 overexpression accelerated differentiation, whereas RNAi impaired it. CONCLUSIONS: Reduced microtubule stability precedes myoblast differentiation and the associated ultimate microtubule stabilization seen in myotubes. LKB1 plays a positive role in microtubule destabilization in myoblasts and in myoblast differentiation. This work suggests a model by which LKB1-induced microtubule destabilization facilitates the cytoskeletal changes required for differentiation. Transient destabilization of microtubules might be a useful strategy for enhancing and/or synchronizing myoblast differentiation.

  17. Dynesys dynamic stabilization-related facet arthrodesis.

    Science.gov (United States)

    Fay, Li-Yu; Chang, Peng-Yuan; Wu, Jau-Ching; Huang, Wen-Cheng; Wang, Chun-Hao; Tsai, Tzu-Yun; Tu, Tsung-Hsi; Chang, Hsuan-Kan; Wu, Ching-Lan; Cheng, Henrich

    2016-01-01

    OBJECTIVE Dynamic stabilization devices are designed to stabilize the spine while preserving some motion. However, there have been reports demonstrating limited motion at the instrumented level of the lumbar spine after Dynesys dynamic stabilization (DDS). The causes of this limited motion and its actual effects on outcomes after DDS remain elusive. In this study, the authors investigate the incidence of unintended facet arthrodesis after DDS and clinical outcomes. METHODS This retrospective study included 80 consecutive patients with 1- or 2-level lumbar spinal stenosis who underwent laminectomy and DDS. All medical records, radiological data, and clinical evaluations were analyzed. Imaging studies included pre- and postoperative radiographs, MR images, and CT scans. Clinical outcomes were measured by a visual analog scale (VAS) for back and leg pain, the Oswestry Disability Index (ODI), and Japanese Orthopaedic Association (JOA) scores. Furthermore, all patients had undergone postoperative CT for the detection of unintended arthrodesis of the facets at the indexed level, and range of motion was measured on standing dynamic radiographs. RESULTS A total of 70 patients (87.5%) with a mean age of 64.0 years completed the minimum 24-month postoperative follow-up (mean duration 29.9 months). Unintended facet arthrodesis at the DDS instrumented level was demonstrated by CT in 38 (54.3%) of the 70 patients. The mean age of patients who had facet arthrodesis was 9.8 years greater than that of the patients who did not (68.3 vs 58.5 years, p = 0.009). There were no significant differences in clinical outcomes, including VAS back and leg pain, ODI, and JOA scores between patients with and without the unintended facet arthrodesis. Furthermore, those patients older than 60 years were more likely to have unintended facet arthrodesis (OR 12.42) and immobile spinal segments (OR 2.96) after DDS. Regardless of whether unintended facet arthrodesis was present or not, clinical

  18. Physical Basis of Large Microtubule Aster Growth

    CERN Document Server

    Ishihara, Keisuke; Mitchison, Timothy J

    2016-01-01

    Microtubule asters - radial arrays of microtubules organized by centrosomes - play a fundamental role in the spatial coordination of animal cells. The standard model of aster growth assumes a fixed number of microtubules originating from the centrosomes. However, aster morphology in this model does not scale with cell size, and we recently found evidence for non-centrosomal microtubule nucleation. Here, we combine autocatalytic nucleation and polymerization dynamics to develop a biophysical model of aster growth. Our model predicts that asters expand as traveling waves and recapitulates all major aspects of aster growth. As the nucleation rate increases, the model predicts an explosive transition from stationary to growing asters with a discontinuous jump of the growth velocity to a nonzero value. Experiments in frog egg extract confirm the main theoretical predictions. Our results suggest that asters observed in large frog and amphibian eggs are a meshwork of short, unstable microtubules maintained by autoca...

  19. Investigation on shock waves stability in relativistic gas dynamics

    Directory of Open Access Journals (Sweden)

    Alexander Blokhin

    1993-05-01

    Full Text Available This paper is devoted to investigation of the linearized mixed problem of shock waves stability in relativistic gas dynamics. The problem of symmetrization of relativistic gas dynamics equations is also discussed.

  20. SDF1 reduces interneuron leading process branching through dual regulation of actin and microtubules.

    Science.gov (United States)

    Lysko, Daniel E; Putt, Mary; Golden, Jeffrey A

    2014-04-02

    Normal cerebral cortical function requires a highly ordered balance between projection neurons and interneurons. During development these two neuronal populations migrate from distinct progenitor zones to form the cerebral cortex, with interneurons originating in the more distant ganglionic eminences. Moreover, deficits in interneurons have been linked to a variety of neurodevelopmental disorders underscoring the importance of understanding interneuron development and function. We, and others, have identified SDF1 signaling as one important modulator of interneuron migration speed and leading process branching behavior in mice, although how SDF1 signaling impacts these behaviors remains unknown. We previously found SDF1 inhibited leading process branching while increasing the rate of migration. We have now mechanistically linked SDF1 modulation of leading process branching behavior to a dual regulation of both actin and microtubule organization. We find SDF1 consolidates actin at the leading process tip by de-repressing calpain protease and increasing proteolysis of branched-actin-supporting cortactin. Additionally, SDF1 stabilizes the microtubule array in the leading process through activation of the microtubule-associated protein doublecortin (DCX). DCX stabilizes the microtubule array by bundling microtubules within the leading process, reducing branching. These data provide mechanistic insight into the regulation of interneuron leading process dynamics during neuronal migration in mice and provides insight into how cortactin and DCX, a known human neuronal migration disorder gene, participate in this process.

  1. SDF1 Reduces Interneuron Leading Process Branching through Dual Regulation of Actin and Microtubules

    Science.gov (United States)

    Lysko, Daniel E.; Putt, Mary

    2014-01-01

    Normal cerebral cortical function requires a highly ordered balance between projection neurons and interneurons. During development these two neuronal populations migrate from distinct progenitor zones to form the cerebral cortex, with interneurons originating in the more distant ganglionic eminences. Moreover, deficits in interneurons have been linked to a variety of neurodevelopmental disorders underscoring the importance of understanding interneuron development and function. We, and others, have identified SDF1 signaling as one important modulator of interneuron migration speed and leading process branching behavior in mice, although how SDF1 signaling impacts these behaviors remains unknown. We previously found SDF1 inhibited leading process branching while increasing the rate of migration. We have now mechanistically linked SDF1 modulation of leading process branching behavior to a dual regulation of both actin and microtubule organization. We find SDF1 consolidates actin at the leading process tip by de-repressing calpain protease and increasing proteolysis of branched-actin-supporting cortactin. Additionally, SDF1 stabilizes the microtubule array in the leading process through activation of the microtubule-associated protein doublecortin (DCX). DCX stabilizes the microtubule array by bundling microtubules within the leading process, reducing branching. These data provide mechanistic insight into the regulation of interneuron leading process dynamics during neuronal migration in mice and provides insight into how cortactin and DCX, a known human neuronal migration disorder gene, participate in this process. PMID:24695713

  2. TCS1, a Microtubule-Binding Protein, Interacts with KCBP/ZWICHEL to Regulate Trichome Cell Shape in Arabidopsis thaliana.

    Directory of Open Access Journals (Sweden)

    Liangliang Chen

    2016-10-01

    Full Text Available How cell shape is controlled is a fundamental question in developmental biology, but the genetic and molecular mechanisms that determine cell shape are largely unknown. Arabidopsis trichomes have been used as a good model system to investigate cell shape at the single-cell level. Here we describe the trichome cell shape 1 (tcs1 mutants with the reduced trichome branch number in Arabidopsis. TCS1 encodes a coiled-coil domain-containing protein. Pharmacological analyses and observations of microtubule dynamics show that TCS1 influences the stability of microtubules. Biochemical analyses and live-cell imaging indicate that TCS1 binds to microtubules and promotes the assembly of microtubules. Further results reveal that TCS1 physically associates with KCBP/ZWICHEL, a microtubule motor involved in the regulation of trichome branch number. Genetic analyses indicate that kcbp/zwi is epistatic to tcs1 with respect to trichome branch number. Thus, our findings define a novel genetic and molecular mechanism by which TCS1 interacts with KCBP to regulate trichome cell shape by influencing the stability of microtubules.

  3. On the Dynamic Stability of a Missile

    Directory of Open Access Journals (Sweden)

    K.C. Sharma

    1977-01-01

    Full Text Available The P-method given by Parks and Pritchard has been used to discuss the stability behaviour of a missile in free flight. General stability criteria for aerodynamic stabilisation have been obtained for slowly varying coefficients. The effect of pressure gradient on the stability of a coasting rocket has been explicitly examined. It is observed that the positive Magnus moment parameter ensures stability whereas a negative moment parameter would enhance the requirements of a larger stability margin.

  4. Effect of microtubule-associated protein tau in dynamics of single-headed motor proteins KIF1A

    CERN Document Server

    Sparacino, J; Lamberti, P W

    2013-01-01

    Intracellular transport based on molecular motors and its regulation are crucial to the functioning of cells. Filamentary tracks of the cells are abundantly decorated with non-motile microtubule-associated proteins, such as tau. Motivated by experiments on kinesin-tau interactions [Dixit et al. Science 319, 1086 (2008)] we developed a stochastic model of interacting single-headed motor proteins KIF1A that also takes into account the interactions between motor proteins and tau molecules. Our model reproduce experimental observations and predicts significant effects of tau on bound time and run length which suggest an important role of tau in regulation of kinesin-based transport.

  5. TIPsy tour guides: How microtubule plus-end tracking proteins (+TIPs facilitate axon guidance

    Directory of Open Access Journals (Sweden)

    Elizabeth A Bearce

    2015-06-01

    Full Text Available The growth cone is a dynamic cytoskeletal vehicle, which drives the end of a developing axon. It serves to interpret and navigate through the complex landscape and guidance cues of the early nervous system. The growth cone’s distinctive cytoskeletal organization offers a fascinating platform to study how extracellular cues can be translated into mechanical outgrowth and turning behaviors. While many studies of cell motility highlight the importance of actin networks in signaling, adhesion, and propulsion, both seminal and emerging works in the field have highlighted a unique and necessary role for microtubules in growth cone navigation. Here, we focus on the role of singular pioneer microtubules, which extend into the growth cone periphery and are regulated by a diverse family of microtubule plus-end tracking proteins (+TIPs. These +TIPs accumulate at the dynamic ends of microtubules, where they are well-positioned to encounter and respond to key signaling events downstream of guidance receptors, catalyzing immediate changes in microtubule stability and actin cross-talk, that facilitate both axonal outgrowth and turning events.

  6. Dynamic flight stability of hovering insects

    Institute of Scientific and Technical Information of China (English)

    Mao Sun; Jikang Wang; Yan Xiong

    2007-01-01

    The equations of motion of an insect with flapping wings are derived and then simplified to that of a flying body using the "rigid body" assumption. On the basis of the simplified equations of motion, the longitudinal dynamic flight stability of four insects (hoverfly, cranefly, dronefly and hawkmoth) in hovering flight is studied (the mass of the insects ranging from 11 to 1,648 mg and wingbeat frequency from 26 to 157Hz). The method of computational fluid dynamics is used to compute the aerodynamic derivatives and the techniques of eigenvalue and eigenvector analysis are used to solve the equations of motion. The validity of the "rigid body" assumption is tested and how differencesin size and wing kinematics influence the applicability of the "rigid body" assumption is investigated. The primary findings are: (1) For insects considered in the present study and those with relatively high wingbeat frequency (hover-fly, drone fly and bumblebee), the "rigid body" assumptionis reasonable, and for those with relatively low wingbeatfrequency (cranefly and howkmoth), the applicability of the"rigid body" assumption is questionable. (2) The same three natural modes of motion as those reported recently for a bumblebee are identified, i.e., one unstable oscillatory mode,one stable fast subsidence mode and one stable slow subsidence mode. (3) Approximate analytical expressions of the eigenvalues, which give physical insight into the genesis of the natural modes of motion, are derived. The expressions identify the speed derivative Mu (pitching moment produced by unit horizontal speed) as the primary source of the unstable oscillatory mode and the stable fast subsidence mode and Zw (vertical force produced by unit vertical speed) as the primary source of the stable slow subsidence mode.

  7. Microtubules in Dendritic Spine Development

    OpenAIRE

    2008-01-01

    It is generally believed that only the actin cytoskeleton resides in dendritic spines and controls spine morphology and plasticity. Here we report that microtubules (MTs) are present in spines and that shRNA knockdown of the MT-plus end binding protein EB3 significantly reduces spine formation. Furthermore, stabilization and inhibition of MTs by low doses of taxol and nocodazole enhance and impair spine formation elicited by BDNF, respectively. Therefore, MTs play an important role in the con...

  8. Microtubule remodeling mediates the inhibition of store-operated calcium entry (SOCE) during mitosis in COS-7 cells.

    Science.gov (United States)

    Russa, Afadhali Denis; Ishikita, Naoyuki; Masu, Kazuki; Akutsu, Hitomi; Saino, Tomoyuki; Satoh, Yoh-ichi

    2008-12-01

    Regulation of the intracellular calcium ion concentration ([Ca(2+)](i)) is critical, because calcium signaling controls diverse and vital cellular processes such as secretion, proliferation, division, gene transcription, and apoptosis. Store-operated calcium entry (SOCE) is the main mechanism through which non-excitable cells replenish and thus maintain this delicate balance. There is limited evidence which indicates that SOCE may be inhibited during mitosis, and the mechanisms leading to the presumed inhibition has not been elucidated. In the present study, we examined and compared the [Ca(2+)](i) dynamics of COS-7 cells in mitotic and non-mitotic phases with special reference paid to SOCE. Laser scanning confocal microscopy to monitor [Ca(2+)](i) dynamics revealed that SOCE was progressively inhibited in mitosis and became virtually absent during the metaphase. We used various cytoskeletal modifying drugs and immunofluorescence to assess the contribution of microtubule and actin filaments in SOCE signaling. Nocodazole treatment caused microtubule reorganization and retraction from the cell periphery that mimicked the natural mitotic microtubule remodeling that was also accompanied by SOCE inhibition. Short exposure to paclitaxel, a microtubule-stabilizing drug, bolstered SOCE, whereas long exposure resulted in microtubule disruption and SOCE inhibition. Actin-modifying drugs did not affect SOCE. These findings indicate that mitotic microtubule remodeling plays a significant role in the inhibition of SOCE during mitosis.

  9. Pharmacologic reductions of total tau levels; implications for the role of microtubule dynamics in regulating tau expression

    Directory of Open Access Journals (Sweden)

    Dickey Chad A

    2006-07-01

    Full Text Available Abstract The microtubule-associated protein tau (MAPT is a pathological component of several neurodegenerative diseases and clinical dementias. Here, we have investigated the effects of a series of commercially available FDA-approved compounds and natural products on total tau protein levels using a cell-based approach that allows for the rapid and efficient measurement of changes in protein expression. Results The compounds that reduced tau largely fell within 3 functional categories with the largest percentage being microtubule regulators. Several of these candidates were validated in both a human neuroglioma and a human neuroblastoma cell line. While these drugs lead to a rapid reduction in tau protein levels, a selective decrease in MAPT mRNA expression was also observed. Conclusion These findings suggest that the identified compounds that reduce tau levels may act either through direct effects on the MAPT promoter itself or by altering a feedback transcriptional mechanism regulating MAPT transcription. This is particularly interesting in light of recent evidence suggesting that MAPT 5' UTR mutations in late-onset PD and PSP cases alter the expression of tau mRNA. In fact, one of the compounds we identified, rotenone, has been used extensively to model PD in rodents. These observations may provide key insights into the mechanism of tau turnover within the neuron while also providing the first evidence that selectively reducing tau protein levels may be possible using compounds that are FDA-approved for other uses.

  10. Tau Induces Cooperative Taxol Binding to Microtubules

    Science.gov (United States)

    Ross, Jennifer; Santangelo, Christian; Victoria, Makrides; Fygenson, Deborah

    2004-03-01

    Taxol and tau are two ligands which stabilize the microtubule (MT) lattice. Taxol is an anti-mitotic drug that binds β tubulin in the MT interior. Tau is a MT-associated protein that binds both α and β tubulin on the MT exterior. Both taxol and tau reduce MT dynamics and promote tubulin polymerization. Tau alone also acts as a buttress to bundle, stiffen, and space MTs. A structural study recently suggested that taxol and tau may interact by binding to the same site. Using fluorescence recovery after photobleaching, we find that tau induces taxol to bind MTs cooperatively depending on the tau concentration. We develop a model that correctly fits the data in the absence of tau and yields a measure of taxol cooperativity when tau is present.

  11. Impulsive Stabilization of Uncertain Dynamical Systems and Chaos Control

    Institute of Scientific and Technical Information of China (English)

    LIUBin; YAOJian; FANGJinqing; LIUXinzhi

    2004-01-01

    In this paper, a general impulsive control problem for uncertain dynamical systems is investigated.By utilizing the method of Lyapunov functions, a set of stability criteria for uncertain impulsive dynamical systems are established. These obtained results are then appliedto derive conditions under which an uncertain dynamical system can be robustly stabilized by an impulsive control law. Finally, we demonstrate our method by controlling the famous Lorenz system with uncertain perturbation.

  12. Wave->Diffusion Transition in Microtubules

    OpenAIRE

    2005-01-01

    In this paper the heat transport in microtubules (MT) is investigated. When the dimension of the structure is of the order of the de Broglie wave length the transport phenomena must be analyzed within quantum mechanics. In this paper we developed the Dirac type thermal equation for MT .The solution of the equation-the temperature fields for electrons can be wave type or diffusion type depending on the dynamics of the scattering. Key words: Microtubules ultrashort laser pulses, Dirac thermal e...

  13. Dynamic Stabilization in The Double-Well Duffing Oscillator

    CERN Document Server

    Kim, S Y; Kim, Sang-Yoon; Kim, Youngtae

    1999-01-01

    Bifurcations associated with stability of the saddle fixed point of the Poincaré map, arising from the unstable equilibrium point of the potential, are investigated in a forced Duffing oscillator with a double-well potential. One interesting behavior is the dynamic stabilization of the saddle fixed point. When the driving amplitude is increased through a threshold value, the saddle fixed point becomes stabilized via a pitchfork bifurcation. We note that this dynamic stabilization is similar to that of the inverted pendulum with a vertically oscillating suspension point. After the dynamic stabilization, the double-well Duffing oscillator behaves as the single-well Duffing oscillator, because the effect of the central potential barrier on the dynamics of the system becomes negligible.

  14. Rearrangements of microtubule cytoskeleton in stomatal closure of Arabidopsis induced by nitric oxide

    Institute of Scientific and Technical Information of China (English)

    ZHANG YongMei; WU ZhongYi; WANG XueChen; YU Rong

    2008-01-01

    NO (nitric oxide), known as a key signal molecule in plant, plays important roles in regulation of stomatal movement. In this study, microtubule dynamics and its possible mechanism in the NO signal pathway were investigated. The results were as follows: (ⅰ) In vivo stomatal aperture assays revealed that both vinblastine (microtubule-disrupting drug) and SNP (exogenous NO donor) prevented stomatal opening in the light, and vinblastine even could enhance the inhibitory effect of SNP, whereas taxol (a microtubule-stabilizing agent) was able to reduce this effect; (ⅱ) microtubules in the opening Arabi-dopsis guard cells expressing GFP:α-tubulin-6 (AtGFP:α-tubulin-6) were organized in parallel, straight and dense bundles, radiating from the ventral side to the dorsal side, and most of them were localized perpendicularly to the ventral wall; (ⅲ) under the same environmental conditions, treated with SNP for 30 min, the radial arrays of microtubules in guard cells began to break down, twisted partially and be-came oblique or exhibited a random pattern; (ⅳ) furthermore, the involvement of cytosolic Ca2+ in this event was tested. Stomatal aperture assays revealed that BAPTA-AM (a chelator of Ca2+) greatly sup-pressed the effect of NO on stomatal closure; however, it did not show the same function on stomatal closure induced by vinblastine. When BAPTA-AM was added to the SNP-pretreated solution, the SNP-induced disordered microtubulue cytoskeleton in guard cells underwent rearrangement in a time-dependent manner. After 30 min of treatment with BAPTA-AM, the cortical microtubules resumed the original radial distribution, almost the same as the control. All this indicates that NO may promote rearrangement of microtubule cytoskeleton via elevation of [Ca2+]cyt (free Ca2+ concentration in the cy-toplasm), finally leading to stomatal closure.

  15. The formin DIAPH1 (mDia1) regulates megakaryocyte proplatelet formation by remodeling the actin and microtubule cytoskeletons.

    Science.gov (United States)

    Pan, Jiajia; Lordier, Larissa; Meyran, Deborah; Rameau, Philippe; Lecluse, Yann; Kitchen-Goosen, Susan; Badirou, Idinath; Mokrani, Hayat; Narumiya, Shuh; Alberts, Arthur S; Vainchenker, William; Chang, Yunhua

    2014-12-18

    Megakaryocytes are highly specialized precursor cells that produce platelets via cytoplasmic extensions called proplatelets. Proplatelet formation (PPF) requires profound changes in microtubule and actin organization. In this work, we demonstrated that DIAPH1 (mDia1), a mammalian homolog of Drosophila diaphanous that works as an effector of the small GTPase Rho, negatively regulates PPF by controlling the dynamics of the actin and microtubule cytoskeletons. Moreover, we showed that inhibition of both DIAPH1 and the Rho-associated protein kinase (Rock)/myosin pathway increased PPF via coordination of both cytoskeletons. We provide evidence that 2 major effectors of the Rho GTPase pathway (DIAPH1 and Rock/myosin II) are involved not only in Rho-mediated stress fibers assembly, but also in the regulation of microtubule stability and dynamics during PPF.

  16. Microtubules, Tubulins and Associated Proteins.

    Science.gov (United States)

    Raxworthy, Michael J.

    1988-01-01

    Reviews much of what is known about microtubules, which are biopolymers consisting predominantly of subunits of the globular protein, tubulin. Describes the functions of microtubules, their structure and assembly, microtube associated proteins, and microtubule-disrupting agents. (TW)

  17. NONLINEAR THEORY OF DYNAMIC STABILITY FOR LAMINATED COMPOSITE CYLINDRICAL SHELLS

    Institute of Scientific and Technical Information of China (English)

    周承倜; 王列东

    2001-01-01

    Hamilton Principle was uaed to derive the general governing equations of nonlinear dynamic stability for laminated cylindrical shells in which, factors of nonlinear large deflection, transverse shear and longitudinal inertia force were concluded. Equations were solved by variational method. Analysis reveals that under the action of dynamic load,laminated cylindrical shells will fall into a state of parametric resonance and enter into the dynamic unstable region that causes dynamic instability of shells. Laminated shells of three typical composites were computed: i.e. T300/5 208 graphite epoxy E-glass epoxy, and ARALL shells. Results show that all factors will induce important influence for dynamic stability of laminated shells. So, in research of dynamic stability for laminated shells, to consider these factors is important.

  18. Stability of molecular dynamics simulations of classical systems

    DEFF Research Database (Denmark)

    Toxværd, Søren

    2012-01-01

    The existence of a shadow Hamiltonian for discrete classical dynamics, obtained by an asymptotic expansion for a discrete symplectic algorithm, is employed to determine the limit of stability for molecular dynamics (MD) simulations with respect to the time-increment h of the discrete dynamics....... The investigation is based on the stability of the shadow energy, obtained by including the first term in the asymptotic expansion, and on the exact solution of discrete dynamics for a single harmonic mode. The exact solution of discrete dynamics for a harmonic potential with frequency ω gives a criterion...... an improved stability with a factor of , but the overhead of computer time is a factor of at least two. The conclusion is that the second-order “Verlet”-algorithm, most commonly used in MD, is superior. It gives the exact dynamics within the limit of the asymptotic expansion and this limit can be estimated...

  19. STABILITY ANALYSIS OF THE DYNAMIC INPUT-OUTPUT SYSTEM

    Institute of Scientific and Technical Information of China (English)

    GuoChonghui; TangHuanwen

    2002-01-01

    The dynamic input-output model is well known in economic theory and practice. In this paper, the asymptotic stability and balanced growth solutions of the dynamic input-output system are considered. Under some natural assumptions which do not require the technical coefficient matrix to be indecomposable,it has been proved that the dynamic input-output system is not asymptotically stable and the closed dynamic input-output model has a balanced growth solution.

  20. The stability and dynamic behaviour of fluid-loaded structures

    CSIR Research Space (South Africa)

    Suliman, Ridhwaan

    2015-07-01

    Full Text Available ECCOMAS Young Investigators Conference 6th GACM Colloquium, July 20–23, 2015, Aachen, Germany The stability and dynamic behaviour of fluid-loaded structures R. Suliman, N. Peake Abstract. The deformation of slender elastic structures due...

  1. Molecular Pathway of Microtubule Organization at the Golgi Apparatus

    NARCIS (Netherlands)

    Wu, Jingchao; de Heus, Cecilia; Liu, Qingyang; Bouchet, Benjamin P; Noordstra, Ivar; Jiang, Kai; Hua, Shasha; Martin, Maud; Yang, Chao; Grigoriev, Ilya; Katrukha, Eugene A; Altelaar, A F Maarten; Hoogenraad, Casper C; Qi, Robert Z; Klumperman, Judith; Akhmanova, Anna

    2016-01-01

    The Golgi apparatus controls the formation of non-centrosomal microtubule arrays important for Golgi organization, polarized transport, cell motility, and cell differentiation. Here, we show that CAMSAP2 stabilizes and attaches microtubule minus ends to the Golgi through a complex of AKAP450 and myo

  2. A unified proof of dynamic stability of interior ESS for projection dynamics

    NARCIS (Netherlands)

    Joosten, Reinoud A.M.G.; Roorda, Berend

    2011-01-01

    We present a unified proof of dynamic stability for interior evolutionarily stable strategies for two recently introduced projection dynamics using the angle between certain vectors as a Lyapunov function.

  3. Measurement of Binding Force between Microtubule-Associated Protein and Microtubule

    Institute of Scientific and Technical Information of China (English)

    XU Chun-Hua; GUO Hong-Lian; QU E; LI Zhao-Lin; YUAN Ming; CHENG Bing-Ying; ZHANG Dao-Zhong

    2007-01-01

    Microtubule-associated proteins (MAPs) are important proteins in cells. They can regulate the organization,dynamics and function of microtubules. We measure the binding force between microtubule and a new plant MAP, i.e. AtMAP65-1, by dual-optical tweezers. The force is obtained to be 14.6±3.5 pN from the data statistics and analysis. This force measurement is helpful to understand the function and mechanism of MAPs from the mechanical point of view and lays the groundwork for future measurements of the mechanical properties of other biological macro-molecules.

  4. The von Hippel-Lindau tumour suppressor interacts with microtubules through kinesin-2

    NARCIS (Netherlands)

    Lolkema, M.P.J.K.; Mans, D.A.; Snijckers, C.M.J.T.; Noort, Mascha van; Beest, M. van; Voest, E.E.; Giles, R.H.

    2007-01-01

    Synthesis and maintenance of primary cilia are regulated by the von Hippel-Lindau (VHL) tumour suppressor protein. Recent studies indicate that this regulation is linked to microtubule-dependent functions of pVHL such as orienting microtubule growth and increasing plus-end microtubule stability, how

  5. MPT0B098, a Microtubule Inhibitor, Suppresses JAK2/STAT3 Signaling Pathway through Modulation of SOCS3 Stability in Oral Squamous Cell Carcinoma.

    Directory of Open Access Journals (Sweden)

    Hsuan-Yu Peng

    Full Text Available Microtubule inhibitors have been shown to inhibit Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3 signal transduction pathway in various cancer cells. However, little is known of the mechanism by which the microtubule inhibitors inhibit STAT3 activity. In the present study, we examined the effect of a novel small-molecule microtubule inhibitor, MPT0B098, on STAT3 signaling in oral squamous cell carcinoma (OSCC. Treatment of various OSCC cells with MPT0B098 induced growth inhibition, cell cycle arrest and apoptosis, as well as increased the protein level of SOCS3. The accumulation of SOCS3 protein enhanced its binding to JAK2 and TYK2 which facilitated the ubiquitination and degradation of JAK2 and TYK2, resulting in a loss of STAT3 activity. The inhibition of STAT3 activity led to sensitization of OSCC cells to MPT0B098 cytotoxicity, indicating that STAT3 is a key mediator of drug resistance in oral carcinogenesis. Moreover, the combination of MPT0B098 with the clinical drug cisplatin or 5-FU significantly augmented growth inhibition and apoptosis in OSCC cells. Taken together, our results provide a novel mechanism for the action of MPT0B098 in which the JAK2/STAT3 signaling pathway is suppressed through the modulation of SOCS3 protein level. The findings also provide a promising combinational therapy of MPT0B098 for OSCC.

  6. Arabidopsis phospholipase D alpha 1-derived phosphatidic acid regulates microtubule organization and cell development under microtubule-interacting drugs treatment.

    Science.gov (United States)

    Zhang, Qun; Qu, Yana; Wang, Qing; Song, Ping; Wang, Peipei; Jia, Qianru; Guo, Jinhe

    2017-01-01

    Phospholipase D (PLD) and its product phosphatidic acid (PA) are emerging as essential regulators of cytoskeleton organization in plants. However, the underlying molecular mechanisms of PA-mediated microtubule reorganization in plants remain largely unknown. In this study, we used pharmacological and genetic approaches to analyze the function of Arabidopsis thaliana PLDα1 in the regulation of microtubule organization and cell development in response to microtubule-affecting drugs. Treatment with the microtubule-stabilizing drug paclitaxel resulted in less growth inhibition and decreased rightward slant of roots, longitudinal alignment of microtubules, and enhanced length of hypocotyl epidermal cells in the pldα1 mutant, the phenotype of which was rescued by exogenous application of PA. Moreover, the pldα1 mutant was sensitive to the microtubule-disrupting drugs oryzalin and propyzamide in terms of seedling survival ratio, left-skewing angle of roots and microtubule organization. In addition, both disruption and stabilization of microtubules induced by drugs activated PLDα1 activity. Our findings demonstrate that in A. thaliana, PLDα1/PA might regulate cell development by modulating microtubule organization in an activity-dependent manner.

  7. Dynamic stabilization of Rayleigh-Taylor instability in ablation fronts

    Directory of Open Access Journals (Sweden)

    Piriz A.R.

    2013-11-01

    Full Text Available Dynamic stabilization of Rayleigh-Taylor instability in an ablation front is studied by considering the simplest possible modulations in the acceleration. Explicit analytical expressions for the instability growth rate and for the boundaries of the stability region are obtained by considering a sequence of Dirac deltas. Besides, general square waves allow for studying the effect of the driving asymmetries on the stability region as well as the optimization process. The essential role of compressibility is phenomenologically addressed in order to find the constraints it imposes on the stability region.

  8. CLASP1, astrin and Kif2b form a molecular switch that regulates kinetochore-microtubule dynamics to promote mitotic progression and fidelity.

    Science.gov (United States)

    Manning, Amity L; Bakhoum, Samuel F; Maffini, Stefano; Correia-Melo, Clara; Maiato, Helder; Compton, Duane A

    2010-10-20

    Accurate chromosome segregation during mitosis requires precise coordination of various processes, such as chromosome alignment, maturation of proper kinetochore-microtubule (kMT) attachments, correction of erroneous attachments, and silencing of the spindle assembly checkpoint (SAC). How these fundamental aspects of mitosis are coordinately and temporally regulated is poorly understood. In this study, we show that the temporal regulation of kMT attachments by CLASP1, astrin and Kif2b is central to mitotic progression and chromosome segregation fidelity. In early mitosis, a Kif2b-CLASP1 complex is recruited to kinetochores to promote chromosome movement, kMT turnover, correction of attachment errors, and maintenance of SAC signalling. However, during metaphase, this complex is replaced by an astrin-CLASP1 complex, which promotes kMT stability, chromosome alignment, and silencing of the SAC. We show that these two complexes are differentially recruited to kinetochores and are mutually exclusive. We also show that other kinetochore proteins, such as Kif18a, affect kMT attachments and chromosome movement through these proteins. Thus, CLASP1-astrin-Kif2b complex act as a central switch at kinetochores that defines mitotic progression and promotes fidelity by temporally regulating kMT attachments.

  9. Stabilization of structure-preserving power networks with market dynamics

    CERN Document Server

    Stegink, Tjerk W; van der Schaft, Arjan J

    2016-01-01

    This paper studies the problem of maximizing the social welfare while stabilizing both the physical power network as well as the market dynamics. For the physical power grid a third-order structure-preserving model is considered involving both frequency and voltage dynamics. By applying the primal-dual gradient method to the social welfare problem, a distributed dynamic pricing algorithm in port-Hamiltonian form is obtained. After interconnection with the physical system a closed-loop port-Hamiltonian system of differential-algebraic equations is obtained, whose properties are exploited to prove local asymptotic stability of the optimal points.

  10. A study of microtubule dipole lattices

    Science.gov (United States)

    Nandi, Shubhendu

    Microtubules are cytoskeletal protein polymers orchestrating a host of important cellular functions including, but not limited to, cell support, cell division, cell motility and cell transport. In this thesis, we construct a toy-model of the microtubule lattice composed of vector Ising spins representing tubulin molecules, the building block of microtubules. Nearest-neighbor and next-to-nearest neighbor interactions are considered within an anisotropic dielectric medium. As a consequence of the helical topology, we observe that certain spin orientations render the lattice frustrated with nearest neighbor ferroelectric and next-to-nearest neighbor antiferroelectric bonds. Under these conditions, the lattice displays the remarkable property of stabilizing certain spin patterns that are robust to thermal fluctuations. We model this behavior in the framework of a generalized Ising model known as the J1 - J2 model and theoretically determine the set of stable patterns. Employing Monte-Carlo methods, we demonstrate the stability of such patterns in the microtubule lattice at human physiological temperatures. This suggests a novel biological mechanism for storing information in living organisms, whereby the tubulin spin (dipole moment) states become information bits and information gets stored in microtubules in a way that is robust to thermal fluctuations.

  11. General theory for the mechanics of confined microtubule asters

    Science.gov (United States)

    Ma, Rui; Laan, Liedewij; Dogterom, Marileen; Pavin, Nenad; Jülicher, Frank

    2014-01-01

    In cells, dynamic microtubules organize into asters or spindles to assist positioning of organelles. Two types of forces are suggested to contribute to the positioning process: (i) microtubule-growth based pushing forces; and (ii) motor protein mediated pulling forces. In this paper, we present a general theory to account for aster positioning in a confinement of arbitrary shape. The theory takes account of microtubule nucleation, growth, catastrophe, slipping, as well as interaction with cortical force generators. We calculate microtubule distributions and forces acting on microtubule organizing centers in a sphere and in an ellipsoid. Positioning mechanisms based on both pushing forces and pulling forces can be distinguished in our theory for different parameter regimes or in different geometries. In addition, we investigate positioning of microtubule asters in the case of asymmetric distribution of motors. This analysis enables us to characterize situations relevant for Caenorrhabditis elegans embryos.

  12. Dynamic stability of repulsive-force maglev suspension systems

    Energy Technology Data Exchange (ETDEWEB)

    Cai, Y.; Rote, D.M.; Mulcahy, T.M.; Wang, Z. [and others

    1996-11-01

    This report summarizes the research performed on maglev vehicle dynamic stability at Argonne National Laboratory during the past few years. It also documents both measured and calculated magnetic-force data. Because dynamic instability is not acceptable for any commercial maglev system, it is important to consider this phenomenon in the development of all maglev systems. This report presents dynamic stability experiments on maglev systems and compares the results with predictions calculated by a nonlinear-dynamics computer code. Instabilities of an electrodynamic-suspension system type vehicle model were obtained by experimental observation and computer simulation of a five-degree-of-freedom maglev vehicle moving on a guideway that consists of a pair of L-shaped aluminum conductors attached to a rotating wheel. The experimental and theoretical analyses developed in this study identify basic stability characteristics and future research needs of maglev systems.

  13. ANALYSIS OF NONLINEAR DYNAMIC STABILITY OF LIQUID-CONVEYING PIPES

    Institute of Scientific and Technical Information of China (English)

    张立翔; 黄文虎

    2002-01-01

    Nonlinearly dynamic stability of flexible liquid-conveying pipe in fluid structure interaction was analyzed by using modal disassembling technique. The effects of Poisson,Junction and Friction couplings in the wave-flowing-vibration system on the pipe dynamic stability were included in the analytical model constituted by four nonlinear differential equations. An analyzing example of cantilevered pipe was done to illustrate the dynamic stability characteristics of the pipe in the full coupling mechanisms, and the phase curves related to the first four modal motions were drawn. The results show that the dynamic stable characteristics of the pipe are very complicated in the complete coupling mechanisms, and the kinds of the singularity points corresponding to the various modal motions are different.

  14. Microtubules: A network for solitary waves

    Directory of Open Access Journals (Sweden)

    Zdravković Slobodan

    2017-01-01

    Full Text Available In the present paper we deal with nonlinear dynamics of microtubules. The structure and role of microtubules in cells are explained as well as one of models explaining their dynamics. Solutions of the crucial nonlinear differential equation depend on used mathematical methods. Two commonly used procedures, continuum and semi-discrete approximations, are explained. These solutions are solitary waves usually called as kink solitons, breathers and bell-type solitons. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. III45010

  15. Dynamic stability of passive dynamic walking on an irregular surface.

    Science.gov (United States)

    Su, Jimmy Li-Shin; Dingwell, Jonathan B

    2007-12-01

    Falls that occur during walking are a significant health problem. One of the greatest impediments to solve this problem is that there is no single obviously "correct" way to quantify walking stability. While many people use variability as a proxy for stability, measures of variability do not quantify how the locomotor system responds to perturbations. The purpose of this study was to determine how changes in walking surface variability affect changes in both locomotor variability and stability. We modified an irreducibly simple model of walking to apply random perturbations that simulated walking over an irregular surface. Because the model's global basin of attraction remained fixed, increasing the amplitude of the applied perturbations directly increased the risk of falling in the model. We generated ten simulations of 300 consecutive strides of walking at each of six perturbation amplitudes ranging from zero (i.e., a smooth continuous surface) up to the maximum level the model could tolerate without falling over. Orbital stability defines how a system responds to small (i.e., "local") perturbations from one cycle to the next and was quantified by calculating the maximum Floquet multipliers for the model. Local stability defines how a system responds to similar perturbations in real time and was quantified by calculating short-term and long-term local exponential rates of divergence for the model. As perturbation amplitudes increased, no changes were seen in orbital stability (r(2)=2.43%; p=0.280) or long-term local instability (r(2)=1.0%; p=0.441). These measures essentially reflected the fact that the model never actually "fell" during any of our simulations. Conversely, the variability of the walker's kinematics increased exponentially (r(2)>or=99.6%; pwalking stability are related to each other and to risk of falling.

  16. Stability of dynamic response of suspension bridges

    Science.gov (United States)

    Capsoni, Antonio; Ardito, Raffaele; Guerrieri, Andrea

    2017-04-01

    The potential occurrence of internal parametric resonance phenomena has been recently indicated as a potential contributory cause of the appearance of critical dynamic states in long-span suspension bridges. At the same time, suspension bridges, in view of their flexibility, are prone to aeroelastic response, such as vortex shedding, torsional divergence and flutter. In this paper, a non-linear dynamic model of a suspension bridge is devised, with the purpose of providing a first attempt toward a unified framework for the study of aeroelastic and internal resonance instabilities. Inspired by the pioneering work of Herrmann and Hauger, the analyses have been based on a linearized formulation that is able to represent the main structural non-linear effects and the coupling given by aerodynamic forces. The results confirm that the interaction between aeroelastic effects and non-linear internal resonance leads to unstable conditions for wind speeds which can be lower than the critical threshold for standard aeroelastic predictions.

  17. Repurposing of phentolamine as a potential anticancer agent against human castration-resistant prostate cancer: A central role on microtubule stabilization and mitochondrial apoptosis pathway.

    Science.gov (United States)

    Ho, Chen-Hsun; Hsu, Jui-Ling; Liu, Shih-Ping; Hsu, Lih-Ching; Chang, Wei-Ling; Chao, Chuck C-K; Guh, Jih-Hwa

    2015-09-01

    Drug repurposing of phentolamine, an α-adrenoceptor antagonist, as an anticancer agent has been studied in human castration-resistant prostate cancer (CRPC). Cell proliferation was examined by sulforhodamine B and CFSE staining assays. Cell cycle progression and mitochondrial membrane potential (ΔΨm) were detected by flow cytometric analysis. Protein expression was detected by Western blotting. Effect on tubulin/microtubule was determined using confocal immunofluorescence microscopic examination, microtubule assembly detection, tubulin turbidity assay, and binding assay. Several assessments were used to characterize apoptotic signaling pathways and combinatory effect. Phentolamine induced anti-proliferative effect in PC-3 and DU-145, two CRPC cell lines, and P-glycoprotein (P-gp) overexpressing cells. This effect was not significantly reduced in paclitaxel-resistant cells. Rhodamine 123 efflux assay showed that phentolamine was not a P-gp substrate. Phentolamine induced mitotic arrest of the cell cycle and formation of hyperdiploid cells, followed by an increase of apoptosis. Mitotic arrest was confirmed by cyclin B1 up-regulation, Cdk1 activation, and a dramatic increase of mitotic protein phosphorylation. Both in vitro and cellular identification demonstrated that phentolamine, similar to paclitaxel, induced tubulin polymerization and formation of multiple nuclei. Besides, it did not compete with paclitaxel binding on tubulin. Phentolamine induced the phosphorylation and degradation of Bcl-2 and Bcl-xL, two anti-apoptotic Bcl-2 family members, and the loss of ΔΨm indicating the induction of mitochondrial damage. It ultimately induced the activation of caspase-9, -8, and -3 and apoptotic cell death. Moreover, combination treatment with phentolamine and paclitaxel caused a synergistic apoptosis. The data suggest that phentolamine is a potential anticancer agent. In contrast to a wide variety of microtubule disrupting agents, phentolamine induces microtubule

  18. Power system dynamics stability and control

    CERN Document Server

    Padiyar, K R

    2008-01-01

    Modern power systems tend to be very Complex not only due to increasing Demand for quality power, but also on Account of extensive interconnections and increasing dependence on control for optimum utilization for existing resources. A good Knowledge of system dynamics and control is Essential for secure operation of the system. This book is intended to serve the needs of the Student and practicing engineers. A Large number of illustrative examples are included to provide an insight into the application of the theory.

  19. Alignment of Microtubule Imagery

    OpenAIRE

    Yu, Feiyang; Oerlemans, Ard; Bakker, Erwin M.

    2011-01-01

    This work discusses preliminary work aimed at simulating and visualizing the growth process of a tiny structure inside the cell---the microtubule. Difficulty of recording the process lies in the fact that the tissue preparation method for electronic microscopes is highly destructive to live cells. Here in this paper, our approach is to take pictures of microtubules at different time slots and then appropriately combine these images into a coherent video. Experimental results are given on real...

  20. Alignment of Microtubule Imagery

    CERN Document Server

    Yu, Feiyang; Bakker, Erwin M

    2011-01-01

    This work discusses preliminary work aimed at simulating and visualizing the growth process of a tiny structure inside the cell---the microtubule. Difficulty of recording the process lies in the fact that the tissue preparation method for electronic microscopes is highly destructive to live cells. Here in this paper, our approach is to take pictures of microtubules at different time slots and then appropriately combine these images into a coherent video. Experimental results are given on real data.

  1. Dynamical stability of the Holographic System with Two Competing Orders

    CERN Document Server

    Du, Yiqiang; Tian, Yu; Zhang, Hongbao

    2016-01-01

    We investigate the dynamical stability of the holographic system with two order parameters, which exhibits competition and coexistence of condensations. In the linear regime, we have developed the gauge dependent formalism to calculate the quasi-normal modes by gauge fixing, which turns out be considerably convenient. Furthermore, by giving different Gaussian wave packets as perturbations at the initial time, we numerically evolve the full nonlinear system until it arrives at the final equilibrium state. Our results show that the dynamical stability is consistent with the thermodynamical stability. Interestingly, the dynamical evolution, as well as the quasi-normal modes, shows that the relaxation time of this model is generically much longer than the simplest holographic system. We also find that the late time behavior can be well captured by the lowest lying quasi-normal modes except for the non-vanishing order towards the single ordered phase. To our knowledge, this exception is the first counter example t...

  2. Handbook of electrical power system dynamics modeling, stability, and control

    CERN Document Server

    Eremia, Mircea

    2013-01-01

    Complete guidance for understanding electrical power system dynamics and blackouts This handbook offers a comprehensive and up-to-date treatment of power system dynamics. Addressing the full range of topics, from the fundamentals to the latest technologies in modeling, stability, and control, Handbook of Electrical Power System Dynamics provides engineers with hands-on guidance for understanding the phenomena leading to blackouts so they can design the most appropriate solutions for a cost-effective and reliable operation. Focusing on system dynamics, the book details

  3. Nanodomain stabilization dynamics in plasma membranes of biological cells

    Science.gov (United States)

    Das, Tamal; Maiti, Tapas K.; Chakraborty, Suman

    2011-02-01

    We discover that a synergistically amplifying role of stabilizing membrane proteins and continuous lipid recycling can explain the physics governing the stability, polydispersity, and dynamics of lipid raft domains in plasma membranes of biological cells. We establish the conjecture using a generalized order parameter based on theoretical formalism, endorsed by detailed scaling arguments and domain mapping. Quantitative agreements with morphological distributions of raft complexes, as obtained from Förster resonance energy transfer based visualization, support the present theoretical conjecture.

  4. Human SAS-6 C-Terminus Nucleates and Promotes Microtubule Assembly in Vitro by Binding to Microtubules.

    Science.gov (United States)

    Gupta, Hindol; Badarudeen, Binshad; George, Athira; Thomas, Geethu Emily; Gireesh, K K; Manna, Tapas K

    2015-10-20

    Centrioles are essential components of the animal centrosome and play crucial roles in the formation of cilia and flagella. They are cylindrical structures composed of nine triplet microtubules organized around a central cartwheel. Recent studies have identified spindle assembly abnormal protein SAS-6 as a critical component necessary for formation of the cartwheel. However, the molecular details of how the cartwheel participates in centriolar microtubule assembly have not been clearly understood. In this report, we show that the C-terminal tail (residues 470-657) of human SAS-6, HsSAS-6 C, the region that has been shown to extend toward the centriolar wall where the microtubule triplets are organized, nucleated and induced microtubule polymerization in vitro. The N-terminus (residues 1-166) of HsSAS-6, the domain known to be involved in formation of the central hub of the cartwheel, did not, however, exert any effect on microtubule polymerization. HsSAS-6 C bound to the microtubules and localized along the lengths of the microtubules in vitro. Microtubule pull-down and coimmunoprecipitation (Co-IP) experiments with S-phase synchronized HeLa cell lysates showed that the endogenous HsSAS-6 coprecipitated with the microtubules, and it mediated interaction with tubulin. Isothermal calorimetry titration and size exclusion chromatography showed that HsSAS-6 C bound to the αβ-tubulin dimer in vitro. The results demonstrate that HsSAS-6 possesses an intrinsic microtubule assembly promoting activity and further implicate that its outer exposed C-terminal tail may play critical roles in microtubule assembly and stabilizing microtubule attachment with the centriolar cartwheel.

  5. Solar Dynamic Power System Stability Analysis and Control

    Science.gov (United States)

    Momoh, James A.; Wang, Yanchun

    1996-01-01

    The objective of this research is to conduct dynamic analysis, control design, and control performance test of solar power system. Solar power system consists of generation system and distribution network system. A bench mark system is used in this research, which includes a generator with excitation system and governor, an ac/dc converter, six DDCU's and forty-eight loads. A detailed model is used for modeling generator. Excitation system is represented by a third order model. DDCU is represented by a seventh order system. The load is modeled by the combination of constant power and constant impedance. Eigen-analysis and eigen-sensitivity analysis are used for system dynamic analysis. The effects of excitation system, governor, ac/dc converter control, and the type of load on system stability are discussed. In order to improve system transient stability, nonlinear ac/dc converter control is introduced. The direct linearization method is used for control design. The dynamic analysis results show that these controls affect system stability in different ways. The parameter coordination of controllers are recommended based on the dynamic analysis. It is concluded from the present studies that system stability is improved by the coordination of control parameters and the nonlinear ac/dc converter control stabilize system oscillation caused by the load change and system fault efficiently.

  6. Generalized Extreme Value distribution parameters as dynamical indicators of Stability

    CERN Document Server

    Faranda, Davide; Turchetti, Giorgio; Vaienti, Sandro

    2011-01-01

    We introduce a new dynamical indicator of stability based on the Extreme Value statistics showing that it provides an insight on the local stability properties of dynamical systems. The indicator perform faster than other based on the iteration of the tangent map since it requires only the evolution of the original systems and, in the chaotic regions, gives further information about the information dimension of the attractor. A numerical validation of the method is presented through the analysis of the motions in a Standard map.

  7. Impulsive dynamics and stabilization of a single wheel robot

    Institute of Scientific and Technical Information of China (English)

    Ou Yongsheng; Wu Xinyu; Xu Yangsheng

    2011-01-01

    The impulsive motion of a dynamically stabilized robot-Gyrover, which is a single-wheel gyroscopically stabilized robot is studied. A method based on the D' Alembert-Lagrange principle is proposed to develop the impulsive dynamic model of the single wheel robot. This method that can be used to find ways to investigate a single wheel mobile robot rolling on a rough terrain is tested using the experimental platform Gyrover. The conditions of falling over without actuators are addressed. Simulations that validate the analysis are provided as well.

  8. Pedicle Screw-Based Posterior Dynamic Stabilization: Literature Review

    Directory of Open Access Journals (Sweden)

    Dilip K. Sengupta

    2012-01-01

    Full Text Available Posterior dynamic stabilization (PDS indicates motion preservation devices that are aimed for surgical treatment of activity related mechanical low back pain. A large number of such devices have been introduced during the last 2 decades, without biomechanical design rationale, or clinical evidence of efficacy to address back pain. Implant failure is the commonest complication, which has resulted in withdrawal of some of the PDS devices from the market. In this paper the authors presented the current understanding of clinical instability of lumbar motions segment, proposed a classification, and described the clinical experience of the pedicle screw-based posterior dynamic stabilization devices.

  9. DYNAMICAL STABILITY OF VISCOELASTIC COLUMN WITH FRACTIONAL DERIVATIVE CONSTITUTIVE RELATION

    Institute of Scientific and Technical Information of China (English)

    李根国; 朱正佑; 程昌钧

    2001-01-01

    The dynamic stability of simple supported viscoelastic column, subjected to a periodic axial force, is investigated. The viscoelastic material was assumed to obey the fractional derivative constitutive relation. The governing equation of motion was derived as a weakly singular Volterra integro-partial-differential equation, and it was simplified into a weakly singular Volterra integro-ordinary-differential equation by the Galerkin method. In terms of the averaging method, the dynamical stability was analyzed. A new numerical method is proposed to avoid storing all history data. Numerical examples are presented and the numerical results agree with the analytical ones.

  10. Computational Methods for Dynamic Stability and Control Derivatives

    Science.gov (United States)

    Green, Lawrence L.; Spence, Angela M.; Murphy, Patrick C.

    2004-01-01

    Force and moment measurements from an F-16XL during forced pitch oscillation tests result in dynamic stability derivatives, which are measured in combinations. Initial computational simulations of the motions and combined derivatives are attempted via a low-order, time-dependent panel method computational fluid dynamics code. The code dynamics are shown to be highly questionable for this application and the chosen configuration. However, three methods to computationally separate such combined dynamic stability derivatives are proposed. One of the separation techniques is demonstrated on the measured forced pitch oscillation data. Extensions of the separation techniques to yawing and rolling motions are discussed. In addition, the possibility of considering the angles of attack and sideslip state vector elements as distributed quantities, rather than point quantities, is introduced.

  11. Innovation networking between stability and political dynamics

    DEFF Research Database (Denmark)

    Koch, Christian

    2004-01-01

    of the contribution is to challenge and transcend these notions and develop an understanding of innovation networks as an interplay between stable and dynamic elements, where political processes in innovation are much more than a disruptive and even a counterproductive feature. It reviews the growing number......This contribution views innovation as a social activity of building networks, using software product development in multicompany alliances and networks as example. Innovation networks are frequently understood as quite stable arrangements characterised by high trust among the participants. The aim...... of studies that highlight the political aspect of innovation. The paper reports on a study of innovation processes conducted within the EU—TSER-programme and a study made under the banner of management of technology. Intensive field studies in two constellations of enterprises were carried out. One...

  12. Role of reflex dynamics in spinal stability: intrinsic muscle stiffness alone is insufficient for stability.

    Science.gov (United States)

    Moorhouse, Kevin M; Granata, Kevin P

    2007-01-01

    Spinal stability is related to both the intrinsic stiffness of active muscle as well as neuromuscular reflex response. However, existing analyses of spinal stability ignore the role of the reflex response, focusing solely on the intrinsic muscle stiffness associated with voluntary activation patterns in the torso musculature. The goal of this study was to empirically characterize the role of reflex components of spinal stability during voluntary trunk extension exertions. Pseudorandom position perturbations of the torso and associated driving forces were recorded in 11 healthy adults. Nonlinear systems-identification analyses of the measured data provided an estimate of total systems dynamics that explained 81% of the movement variability. Proportional intrinsic response was less than zero in more than 60% of the trials, e.g. mean value of P(INT) during the 20% maximum voluntary exertion trunk extension exertions -415+/-354N/m. The negative value indicated that the intrinsic muscle stiffness was not sufficient to stabilize the spine without reflex response. Reflexes accounted for 42% of the total stabilizing trunk stiffness. Both intrinsic and reflex components of stiffness increased significantly with trunk extension effort. Results reveal that reflex dynamics are a necessary component in the stabilizing control of spinal stability.

  13. S. pombe kinesins-8 promote both nucleation and catastrophe of microtubules.

    Directory of Open Access Journals (Sweden)

    Muriel Erent

    Full Text Available The kinesins-8 were originally thought to be microtubule depolymerases, but are now emerging as more versatile catalysts of microtubule dynamics. We show here that S. pombe Klp5-436 and Klp6-440 are non-processive plus-end-directed motors whose in vitro velocities on S. pombe microtubules at 7 and 23 nm s(-1 are too slow to keep pace with the growing tips of dynamic interphase microtubules in living S. pombe. In vitro, Klp5 and 6 dimers exhibit a hitherto-undescribed combination of strong enhancement of microtubule nucleation with no effect on growth rate or catastrophe frequency. By contrast in vivo, both Klp5 and Klp6 promote microtubule catastrophe at cell ends whilst Klp6 also increases the number of interphase microtubule arrays (IMAs. Our data support a model in which Klp5/6 bind tightly to free tubulin heterodimers, strongly promoting the nucleation of new microtubules, and then continue to land as a tubulin-motor complex on the tips of growing microtubules, with the motors then dissociating after a few seconds residence on the lattice. In vivo, we predict that only at cell ends, when growing microtubule tips become lodged and their growth slows down, will Klp5/6 motor activity succeed in tracking growing microtubule tips. This mechanism would allow Klp5/6 to detect the arrival of microtubule tips at cells ends and to amplify the intrinsic tendency for microtubules to catastrophise in compression at cell ends. Our evidence identifies Klp5 and 6 as spatial regulators of microtubule dynamics that enhance both microtubule nucleation at the cell centre and microtubule catastrophe at the cell ends.

  14. Dynamic flight stability of a hovering model dragonfly.

    Science.gov (United States)

    Liang, Bin; Sun, Mao

    2014-05-07

    The longitudinal dynamic flight stability of a model dragonfly at hovering flight is studied, using the method of computational fluid dynamics to compute the stability derivatives and the techniques of eigenvalue and eigenvector analysis for solving the equations of motion. Three natural modes of motion are identified for the hovering flight: one unstable oscillatory mode, one stable fast subsidence mode and one stable slow subsidence mode. The flight is dynamically unstable owing to the unstable oscillatory mode. The instability is caused by a pitch-moment derivative with respect to horizontal velocity. The damping force and moment derivatives (with respect to horizontal and vertical velocities and pitch-rotational velocity, respectively) weaken the instability considerably. The aerodynamic interaction between the forewing and the hindwing does not have significant effect on the stability properties. The dragonfly has similar stability derivatives, hence stability properties, to that of a one-wing-pair insect at normal hovering, but there are differences in how the derivatives are produced because of the highly inclined stroke plane of the dragonfly.

  15. EB1 targets to kinetochores with attached, polymerizing microtubules.

    Science.gov (United States)

    Tirnauer, Jennifer S; Canman, Julie C; Salmon, E D; Mitchison, Timothy J

    2002-12-01

    Microtubule polymerization dynamics at kinetochores is coupled to chromosome movements, but its regulation there is poorly understood. The plus end tracking protein EB1 is required both for regulating microtubule dynamics and for maintaining a euploid genome. To address the role of EB1 in aneuploidy, we visualized its targeting in mitotic PtK1 cells. Fluorescent EB1, which localized to polymerizing ends of astral and spindle microtubules, was used to track their polymerization. EB1 also associated with a subset of attached kinetochores in late prometaphase and metaphase, and rarely in anaphase. Localization occurred in a narrow crescent, concave toward the centromere, consistent with targeting to the microtubule plus end-kinetochore interface. EB1 did not localize to kinetochores lacking attached kinetochore microtubules in prophase or early prometaphase, or upon nocodazole treatment. By time lapse, EB1 specifically targeted to kinetochores moving antipoleward, coupled to microtubule plus end polymerization, and not during plus end depolymerization. It localized independently of spindle bipolarity, the spindle checkpoint, and dynein/dynactin function. EB1 is the first protein whose targeting reflects kinetochore directionality, unlike other plus end tracking proteins that show enhanced kinetochore binding in the absence of microtubules. Our results suggest EB1 may modulate kinetochore microtubule polymerization and/or attachment.

  16. Stability of Surface Nanobubbles: A Molecular Dynamics Study

    NARCIS (Netherlands)

    Maheshwari, Shantanu; Hoef, van der Martin; Zhang, Xuehua; Lohse, Detlef

    2016-01-01

    The stability and growth or dissolution of a single surface nanobubble on a chemically patterned surface are studied by molecular dynamics simulations of binary mixtures consisting of Lennard-Jones (LJ) particles. Our simulations reveal how pinning of the three-phase contact line on the surface can

  17. EXPONENTIAL STABILITY OF INTERVAL DYNAMICAL SYSTEM WITH MULTIDELAY

    Institute of Scientific and Technical Information of China (English)

    孙继涛; 张银萍; 刘永清; 邓飞其

    2002-01-01

    Using the matrix measure and delay differential inequality, the sufficient conditions were obtained for exponential stability of interval dynamical system with multidelay. These conditions are an improvement and extension of the results achieved in earlier papers presented by LIAO, LIU, ZHANG, SUN, et al.

  18. Dynamic Transfer Schemes and Stability of International Climate Coalitions

    NARCIS (Netherlands)

    Nagashima, M.N.; Dellink, R.B.; Ierland, van E.C.

    2006-01-01

    This paper examines the formation and stability of coalitions in international climate agreements with a combined game-theoretic and integrated assessment model. The empirical model comprises twelve regions and investigates partial coalition formation in a one-shot cartel game. We argue that a dynam

  19. Exponential stability of dynamic equations on time scales

    Directory of Open Access Journals (Sweden)

    Raffoul Youssef N

    2005-01-01

    Full Text Available We investigate the exponential stability of the zero solution to a system of dynamic equations on time scales. We do this by defining appropriate Lyapunov-type functions and then formulate certain inequalities on these functions. Several examples are given.

  20. Differentiable dynamical systems an introduction to structural stability and hyperbolicity

    CERN Document Server

    Wen, Lan

    2016-01-01

    This is a graduate text in differentiable dynamical systems. It focuses on structural stability and hyperbolicity, a topic that is central to the field. Starting with the basic concepts of dynamical systems, analyzing the historic systems of the Smale horseshoe, Anosov toral automorphisms, and the solenoid attractor, the book develops the hyperbolic theory first for hyperbolic fixed points and then for general hyperbolic sets. The problems of stable manifolds, structural stability, and shadowing property are investigated, which lead to a highlight of the book, the \\Omega-stability theorem of Smale. While the content is rather standard, a key objective of the book is to present a thorough treatment for some tough material that has remained an obstacle to teaching and learning the subject matter. The treatment is straightforward and hence could be particularly suitable for self-study. Selected solutions are available electronically for instructors only. Please send email to textbooks@ams.org for more informatio...

  1. Disassembly of actin filaments by botulinum C2 toxin and actin-filament-disrupting agents induces assembly of microtubules in human leukaemia cell lines.

    Science.gov (United States)

    Uematsu, Yosuke; Kogo, Yasusi; Ohishi, Iwao

    2007-03-01

    C(2) toxin produced by Clostridium botulinum types C and D ADP-ribosylates actin monomers and inactivates their polymerization activities. The disassembly of actin filaments by C(2) toxin induces a polarization of cultured human leukaemia cell lines. The polarization induced by C(2) toxin was temperature dependent and was prevented by nocodazole, a microtubule-disrupting agent, whereas it was promoted by paclitaxel, a microtubule-stabilizing agent. The fluorescence staining of polarized cells indicated an increase in microtubule assembly accompanying disassembly of actin filaments. Furthermore, several actin-filament-disrupting agents, other than C(2) toxin, also induced microtubule assembly and cell polarization, irrespective of their different mechanisms of action. The effects induced by some of the agents, which have lower binding affinities for actin, were reversible in response to the re-assembly of actin filaments. Thus the disassembly of actin filaments by C(2) toxin and actin-filament-disrupting agents induces assembly of microtubules followed by polarization of human leukaemia cell lines, indicating that the assembly/disassembly equilibrium of actin filaments influences the dynamics of microtubules, which control cell morphology and, in turn, diverse cellular processes.

  2. Adaptive steady-state stabilization for nonlinear dynamical systems

    Science.gov (United States)

    Braun, David J.

    2008-07-01

    By means of LaSalle’s invariance principle, we propose an adaptive controller with the aim of stabilizing an unstable steady state for a wide class of nonlinear dynamical systems. The control technique does not require analytical knowledge of the system dynamics and operates without any explicit knowledge of the desired steady-state position. The control input is achieved using only system states with no computer analysis of the dynamics. The proposed strategy is tested on Lorentz, van der Pol, and pendulum equations.

  3. Multiple-node basin stability in complex dynamical networks

    Science.gov (United States)

    Mitra, Chiranjit; Choudhary, Anshul; Sinha, Sudeshna; Kurths, Jürgen; Donner, Reik V.

    2017-03-01

    Dynamical entities interacting with each other on complex networks often exhibit multistability. The stability of a desired steady regime (e.g., a synchronized state) to large perturbations is critical in the operation of many real-world networked dynamical systems such as ecosystems, power grids, the human brain, etc. This necessitates the development of appropriate quantifiers of stability of multiple stable states of such systems. Motivated by the concept of basin stability (BS) [P. J. Menck et al., Nat. Phys. 9, 89 (2013), 10.1038/nphys2516], we propose here the general framework of multiple-node basin stability for gauging the global stability and robustness of networked dynamical systems in response to nonlocal perturbations simultaneously affecting multiple nodes of a system. The framework of multiple-node BS provides an estimate of the critical number of nodes that, when simultaneously perturbed, significantly reduce the capacity of the system to return to the desired stable state. Further, this methodology can be applied to estimate the minimum number of nodes of the network to be controlled or safeguarded from external perturbations to ensure proper operation of the system. Multiple-node BS can also be utilized for probing the influence of spatially localized perturbations or targeted attacks to specific parts of a network. We demonstrate the potential of multiple-node BS in assessing the stability of the synchronized state in a deterministic scale-free network of Rössler oscillators and a conceptual model of the power grid of the United Kingdom with second-order Kuramoto-type nodal dynamics.

  4. Do prokaryotes contain microtubules?

    Science.gov (United States)

    Bermudes, D.; Hinkle, G.; Margulis, L.

    1994-01-01

    In eukaryotic cells, microtubules are 24-nm-diameter tubular structures composed of a class of conserved proteins called tubulin. They are involved in numerous cell functions including ciliary motility, nerve cell elongation, pigment migration, centrosome formation, and chromosome movement. Although cytoplasmic tubules and fibers have been observed in bacteria, some with diameters similar to those of eukaryotes, no homologies to eukaryotic microtubules have been established. Certain groups of bacteria including azotobacters, cyanobacteria, enteric bacteria, and spirochetes have been frequently observed to possess microtubule-like structures, and others, including archaebacteria, have been shown to be sensitive to drugs that inhibit the polymerization of microtubules. Although little biochemical or molecular biological information is available, the differences observed among these prokaryotic structures suggest that their composition generally differs among themselves as well as from that of eukaryotes. We review the distribution of cytoplasmic tubules in prokaryotes, even though, in all cases, their functions remain unknown. At least some tend to occur in cells that are large, elongate, and motile, suggesting that they may be involved in cytoskeletal functions, intracellular motility, or transport activities comparable to those performed by eukaryotic microtubules. In Escherichia coli, the FtsZ protein is associated with the formation of a ring in the division zone between the newly forming offspring cells. Like tubulin, FtsZ is a GTPase and shares with tubulin a 7-amino-acid motif, making it a promising candidate in which to seek the origin of tubulins.

  5. Kinetochore-Dependent Microtubule Rescue Ensures Their Efficient and Sustained Interactions in Early Mitosis

    Science.gov (United States)

    Gandhi, Sapan R.; Gierliński, Marek; Mino, Akihisa; Tanaka, Kozo; Kitamura, Etsushi; Clayton, Lesley; Tanaka, Tomoyuki U.

    2011-01-01

    Summary How kinetochores regulate microtubule dynamics to ensure proper kinetochore-microtubule interactions is unknown. Here, we studied this during early mitosis in Saccharomyces cerevisiae. When a microtubule shrinks and its plus end reaches a kinetochore bound to its lateral surface, the microtubule end attempts to tether the kinetochore. This process often fails and, responding to this failure, microtubule rescue (conversion from shrinkage to growth) occurs, preventing kinetochore detachment from the microtubule end. This rescue is promoted by Stu2 transfer (ortholog of vertebrate XMAP215/ch-TOG) from the kinetochore to the microtubule end. Meanwhile, microtubule rescue distal to the kinetochore is also promoted by Stu2, which is transported by a kinesin-8 motor Kip3 along the microtubule from the kinetochore. Microtubule extension following rescue facilitates interaction with other widely scattered kinetochores, diminishing long delays in collecting the complete set of kinetochores by microtubules. Thus, kinetochore-dependent microtubule rescue ensures efficient and sustained kinetochore-microtubule interactions in early mitosis. PMID:22075150

  6. Pseudomonas aeruginosa exotoxin Y-mediated tau hyperphosphorylation impairs microtubule assembly in pulmonary microvascular endothelial cells.

    Directory of Open Access Journals (Sweden)

    Ron Balczon

    Full Text Available Pseudomonas aeruginosa uses a type III secretion system to introduce the adenylyl and guanylyl cyclase exotoxin Y (ExoY into the cytoplasm of endothelial cells. ExoY induces Tau hyperphosphorylation and insolubility, microtubule breakdown, barrier disruption and edema, although the mechanism(s responsible for microtubule breakdown remain poorly understood. Here we investigated both microtubule behavior and centrosome activity to test the hypothesis that ExoY disrupts microtubule dynamics. Fluorescence microscopy determined that infected pulmonary microvascular endothelial cells contained fewer microtubules than control cells, and further studies demonstrated that the microtubule-associated protein Tau was hyperphosphorylated following infection and dissociated from microtubules. Disassembly/reassembly studies determined that microtubule assembly was disrupted in infected cells, with no detectable effects on either microtubule disassembly or microtubule nucleation by centrosomes. This effect of ExoY on microtubules was abolished when the cAMP-dependent kinase phosphorylation site (Ser-214 on Tau was mutated to a non-phosphorylatable form. These studies identify Tau in microvascular endothelial cells as the target of ExoY in control of microtubule architecture following pulmonary infection by Pseudomonas aeruginosa and demonstrate that phosphorylation of tau following infection decreases microtubule assembly.

  7. Microtubule doublets are double-track railways for intraflagellar transport trains.

    Science.gov (United States)

    Stepanek, Ludek; Pigino, Gaia

    2016-05-06

    The cilium is a large macromolecular machine that is vital for motility, signaling, and sensing in most eukaryotic cells. Its conserved core structure, the axoneme, contains nine microtubule doublets, each comprising a full A-microtubule and an incomplete B-microtubule. However, thus far, the function of this doublet geometry has not been understood. We developed a time-resolved correlative fluorescence and three-dimensional electron microscopy approach to investigate the dynamics of intraflagellar transport (IFT) trains, which carry ciliary building blocks along microtubules during the assembly and disassembly of the cilium. Using this method, we showed that each microtubule doublet is used as a bidirectional double-track railway: Anterograde IFT trains move along B-microtubules, and retrograde trains move along A-microtubules. Thus, the microtubule doublet geometry provides direction-specific rails to coordinate bidirectional transport of ciliary components.

  8. CYLD Regulates Noscapine Activity in Acute Lymphoblastic Leukemia via a Microtubule-Dependent Mechanism.

    Science.gov (United States)

    Yang, Yunfan; Ran, Jie; Sun, Lei; Sun, Xiaodong; Luo, Youguang; Yan, Bing; Tala; Liu, Min; Li, Dengwen; Zhang, Lei; Bao, Gang; Zhou, Jun

    2015-01-01

    Noscapine is an orally administrable drug used worldwide for cough suppression and has recently been demonstrated to disrupt microtubule dynamics and possess anticancer activity. However, the molecular mechanisms regulating noscapine activity remain poorly defined. Here we demonstrate that cylindromatosis (CYLD), a microtubule-associated tumor suppressor protein, modulates the activity of noscapine both in cell lines and in primary cells of acute lymphoblastic leukemia (ALL). Flow cytometry and immunofluorescence microscopy reveal that CYLD increases the ability of noscapine to induce mitotic arrest and apoptosis. Examination of cellular microtubules as well as in vitro assembled microtubules shows that CYLD enhances the effect of noscapine on microtubule polymerization. Microtubule cosedimentation and fluorescence titration assays further reveal that CYLD interacts with microtubule outer surface and promotes noscapine binding to microtubules. These findings thus demonstrate CYLD as a critical regulator of noscapine activity and have important implications for ALL treatment.

  9. The validity and reliability of a dynamic neuromuscular stabilization-heel sliding test for core stability.

    Science.gov (United States)

    Cha, Young Joo; Lee, Jae Jin; Kim, Do Hyun; You, Joshua Sung H

    2017-07-21

    Core stabilization plays an important role in the regulation of postural stability. To overcome shortcomings associated with pain and severe core instability during conventional core stabilization tests, we recently developed the dynamic neuromuscular stabilization-based heel sliding (DNS-HS) test. The purpose of this study was to establish the criterion validity and test-retest reliability of the novel DNS-HS test. Twenty young adults with core instability completed both the bilateral straight leg lowering test (BSLLT) and DNS-HS test for the criterion validity study and repeated the DNS-HS test for the test-retest reliability study. Criterion validity was determined by comparing hip joint angle data that were obtained from BSLLT and DNS-HS measures. The test-retest reliability was determined by comparing hip joint angle data. Criterion validity was (ICC2,3) = 0.700 (pcore stability measures. Test-retest reliability was (ICC3,3) = 0.953 (pcore stability measures. Test-retest reliability data suggests that DNS-HS core stability was a reliable test for core stability. Clinically, the DNS-HS test is useful to objectively quantify core instability and allow early detection and evaluation.

  10. Multiscale Polar Theory of Microtubule and Motor-Protein Assemblies

    Science.gov (United States)

    Gao, Tong; Blackwell, Robert; Glaser, Matthew A.; Betterton, M. D.; Shelley, Michael J.

    2015-01-01

    Microtubules and motor proteins are building blocks of self-organized subcellular biological structures such as the mitotic spindle and the centrosomal microtubule array. These same ingredients can form new “bioactive” liquid-crystalline fluids that are intrinsically out of equilibrium and which display complex flows and defect dynamics. It is not yet well understood how microscopic activity, which involves polarity-dependent interactions between motor proteins and microtubules, yields such larger-scale dynamical structures. In our multiscale theory, Brownian dynamics simulations of polar microtubule ensembles driven by cross-linking motors allow us to study microscopic organization and stresses. Polarity sorting and cross-link relaxation emerge as two polar-specific sources of active destabilizing stress. On larger length scales, our continuum Doi-Onsager theory captures the hydrodynamic flows generated by polarity-dependent active stresses. The results connect local polar structure to flow structures and defect dynamics. PMID:25679909

  11. Robust adaptive output stabilization using dynamic normalizing signal

    Institute of Scientific and Technical Information of China (English)

    Haixia SU; Xuejun XIE; Haikuan LIU

    2007-01-01

    For a class of nonlinear systems with dynamic uncertainties,robust adaptive stabilization problem is considered in this paper.Firstly,by introducing an observer,an augmented system is obtained.Based on the system,we construct an exp-ISpS Lyapunov function for the unmodeled dynamics,prove that the unmodeled dynamics is exp-ISpS,and then obtain a dynamic normalizing signal to counteract the dynamic disturbances.By the backstepping technique,an adaptive controller is given,it is proved that all the signals in the adaptive control system are globally uniformly ultimately bounded,and the output can be regulated to the origin with any prescribed accuracy.A simulation example further demonstrates the efficiency of the control scheme.

  12. Stability theory for dynamic equations on time scales

    CERN Document Server

    Martynyuk, Anatoly A

    2016-01-01

    This monograph is a first in the world to present three approaches for stability analysis of solutions of dynamic equations. The first approach is based on the application of dynamic integral inequalities and the fundamental matrix of solutions of linear approximation of dynamic equations. The second is based on the generalization of the direct Lyapunovs method for equations on time scales, using scalar, vector and matrix-valued auxiliary functions. The third approach is the application of auxiliary functions (scalar, vector, or matrix-valued ones) in combination with differential dynamic inequalities. This is an alternative comparison method, developed for time continuous and time discrete systems. In recent decades, automatic control theory in the study of air- and spacecraft dynamics and in other areas of modern applied mathematics has encountered problems in the analysis of the behavior of solutions of time continuous-discrete linear and/or nonlinear equations of perturbed motion. In the book “Men of Ma...

  13. Dynamical stability and evolution of the discs of Sc galaxies

    CERN Document Server

    Fuchs, B

    1997-01-01

    We examine the local stability of galactic discs against axisymmetric density perturbations with special attention to the different dynamics of the stellar and gaseous components. In particular the discs of the Milky Way and of NGC 6946 are studied. The Milky Way is shown to be stable, whereas the inner parts of NGC 6946, a typical Sc galaxy from the Kennicutt (1989) sample, are dynamically unstable. The ensuing dynamical evolution of the composite disc is studied by numerical simulations. The evolution is so fierce that the stellar disc heats up dynamically on a short time scale to such a degree, which seems to contradict the morphological appearance of the galaxy. The star formation rate required to cool the disc dynamically is estimated. Even if the star formation rate in NGC 6946 is at present high enough to meet this requirement, it is argued that the discs of Sc galaxies cannot sustain such a high star formation rate for longer periods.

  14. Dynamical behavior and Jacobi stability analysis of wound strings

    Energy Technology Data Exchange (ETDEWEB)

    Lake, Matthew J. [Naresuan University, The Institute for Fundamental Study, ' ' The Tah Poe Academia Institute' ' , Phitsanulok (Thailand); Thailand Center of Excellence in Physics, Ministry of Education, Bangkok (Thailand); Harko, Tiberiu [Babes-Bolyai University, Department of Physics, Cluj-Napoca (Romania); University College London, Department of Mathematics, London (United Kingdom)

    2016-06-15

    We numerically solve the equations of motion (EOM) for two models of circular cosmic string loops with windings in a simply connected internal space. Since the windings cannot be topologically stabilized, stability must be achieved (if at all) dynamically. As toy models for realistic compactifications, we consider windings on a small section of R{sup 2}, which is valid as an approximation to any simply connected internal manifold if the winding radius is sufficiently small, and windings on an S{sup 2} of constant radius R. We then use Kosambi-Cartan-Chern (KCC) theory to analyze the Jacobi stability of the string equations and determine bounds on the physical parameters that ensure dynamical stability of the windings. We find that, for the same initial conditions, the curvature and topology of the internal space have nontrivial effects on the microscopic behavior of the string in the higher dimensions, but that the macroscopic behavior is remarkably insensitive to the details of the motion in the compact space. This suggests that higher-dimensional signatures may be extremely difficult to detect in the effective (3+1)-dimensional dynamics of strings compactified on an internal space, even if configurations with nontrivial windings persist over long time periods. (orig.)

  15. Maximum Allowable Dynamic Load of Mobile Manipulators with Stability Consideration

    Directory of Open Access Journals (Sweden)

    Heidary H. R.

    2015-09-01

    Full Text Available High payload to mass ratio is one of the advantages of mobile robot manipulators. In this paper, a general formula for finding the maximum allowable dynamic load (MADL of wheeled mobile robot is presented. Mobile manipulators operating in field environments will be required to manipulate large loads, and to perform such tasks on uneven terrain, which may cause the system to reach dangerous tip-over instability. Therefore, the method is expanded for finding the MADL of mobile manipulators with stability consideration. Moment-Height Stability (MHS criterion is used as an index for the system stability. Full dynamic model of wheeled mobile base and mounted manipulator is considered with respect to the dynamic of non-holonomic constraint. Then, a method for determination of the maximum allowable loads is described, subject to actuator constraints and by imposing the stability limitation as a new constraint. The actuator torque constraint is applied by using a speed-torque characteristics curve of a typical DC motor. In order to verify the effectiveness of the presented algorithm, several simulation studies considering a two-link planar manipulator, mounted on a mobile base are presented and the results are discussed.

  16. On the dynamics of turbulent transport near marginal stability

    Energy Technology Data Exchange (ETDEWEB)

    Diamond, P.H. [California Univ., San Diego, La Jolla, CA (United States). Dept. of Physics]|[General Atomics, San Diego, CA (United States); Hahm, T.S. [Princeton Univ., NJ (United States). Plasma Physics Lab.

    1995-03-01

    A general methodology for describing the dynamics of transport near marginal stability is formulated. Marginal stability is a special case of the more general phenomenon of self-organized criticality. Simple, one field models of the dynamics of tokamak plasma self-organized criticality have been constructed, and include relevant features such as sheared mean flow and transport bifurcations. In such models, slow mode (i.e. large scale, low frequency transport events) correlation times determine the behavior of transport dynamics near marginal stability. To illustrate this, impulse response scaling exponents (z) and turbulent diffusivities (D) have been calculated for the minimal (Burgers) and sheared flow models. For the minimal model, z = 1 (indicating ballastic propagation) and D {approximately}(S{sub 0}{sup 2}){sup 1/3}, where S{sub 0}{sup 2} is the noise strength. With an identically structured noise spectrum and flow with shearing rate exceeding the ambient decorrelation rate for the largest scale transport events, diffusion is recovered with z = 2 and D {approximately} (S{sub 0}{sup 2}){sup 3/5}. This indicates a qualitative change in the dynamics, as well as a reduction in losses. These results are consistent with recent findings from {rho} scaling scans. Several tokamak transport experiments are suggested.

  17. Stabilization of computational procedures for constrained dynamical systems

    Science.gov (United States)

    Park, K. C.; Chiou, J. C.

    1988-01-01

    A new stabilization method of treating constraints in multibody dynamical systems is presented. By tailoring a penalty form of the constraint equations, the method achieves stabilization without artificial damping and yields a companion matrix differential equation for the constraint forces; hence, the constraint forces are obtained by integrating the companion differential equation for the constraint forces in time. A principal feature of the method is that the errors committed in each constraint condition decay with its corresponding characteristic time scale associated with its constraint force. Numerical experiments indicate that the method yields a marked improvement over existing techniques.

  18. Dynamics and Adaptive Control for Stability Recovery of Damaged Aircraft

    Science.gov (United States)

    Nguyen, Nhan; Krishnakumar, Kalmanje; Kaneshige, John; Nespeca, Pascal

    2006-01-01

    This paper presents a recent study of a damaged generic transport model as part of a NASA research project to investigate adaptive control methods for stability recovery of damaged aircraft operating in off-nominal flight conditions under damage and or failures. Aerodynamic modeling of damage effects is performed using an aerodynamic code to assess changes in the stability and control derivatives of a generic transport aircraft. Certain types of damage such as damage to one of the wings or horizontal stabilizers can cause the aircraft to become asymmetric, thus resulting in a coupling between the longitudinal and lateral motions. Flight dynamics for a general asymmetric aircraft is derived to account for changes in the center of gravity that can compromise the stability of the damaged aircraft. An iterative trim analysis for the translational motion is developed to refine the trim procedure by accounting for the effects of the control surface deflection. A hybrid direct-indirect neural network, adaptive flight control is proposed as an adaptive law for stabilizing the rotational motion of the damaged aircraft. The indirect adaptation is designed to estimate the plant dynamics of the damaged aircraft in conjunction with the direct adaptation that computes the control augmentation. Two approaches are presented 1) an adaptive law derived from the Lyapunov stability theory to ensure that the signals are bounded, and 2) a recursive least-square method for parameter identification. A hardware-in-the-loop simulation is conducted and demonstrates the effectiveness of the direct neural network adaptive flight control in the stability recovery of the damaged aircraft. A preliminary simulation of the hybrid adaptive flight control has been performed and initial data have shown the effectiveness of the proposed hybrid approach. Future work will include further investigations and high-fidelity simulations of the proposed hybrid adaptive Bight control approach.

  19. Dynamic Stability of Euler Beams under Axial Unsteady Wind Force

    Directory of Open Access Journals (Sweden)

    You-Qin Huang

    2014-01-01

    Full Text Available Dynamic instability of beams in complex structures caused by unsteady wind load has occurred more frequently. However, studies on the parametric resonance of beams are generally limited to harmonic loads, while arbitrary dynamic load is rarely involved. The critical frequency equation for simply supported Euler beams with uniform section under arbitrary axial dynamic forces is firstly derived in this paper based on the Mathieu-Hill equation. Dynamic instability regions with high precision are then calculated by a presented eigenvalue method. Further, the dynamically unstable state of beams under the wind force with any mean or fluctuating component is determined by load normalization, and the wind-induced parametric resonant response is computed by the Runge-Kutta approach. Finally, a measured wind load time-history is input into the dynamic system to indicate that the proposed methods are effective. This study presents a new method to determine the wind-induced dynamic stability of Euler beams. The beam would become dynamically unstable provided that the parametric point, denoting the relation between load properties and structural frequency, is located in the instability region, no matter whether the wind load component is large or not.

  20. Interconnections between cell wall polymers, wall mechanics, and cortical microtubules: Teasing out causes and consequences.

    Science.gov (United States)

    Xiao, Chaowen; Anderson, Charles T

    2016-09-01

    In plants, cell wall components including cellulose, hemicelluloses, and pectins interact with each other to form complex extracellular network structures that control cell growth and maintain cell shape. However, it is still not clear exactly how different wall polymers interact, how the conformations and interactions of cell wall polymers relate to wall mechanics, and how these factors impinge on intracellular structures such as the cortical microtubule cytoskeleton. Here, based on studies of Arabidopsis thaliana xxt1 xxt2 mutants, which lack detectable xyloglucan in their walls and display aberrant wall mechanics, altered cellulose patterning and biosynthesis, and reduced cortical microtubule stability, we discuss the potential relationships between cell wall biosynthesis, wall mechanics, and cytoskeletal dynamics in an effort to better understand their roles in controlling plant growth and morphogenesis.

  1. Depolymerizing kinesins Kip3 and MCAK shape cellular microtubule architecture by differential control of catastrophe.

    Science.gov (United States)

    Gardner, Melissa K; Zanic, Marija; Gell, Christopher; Bormuth, Volker; Howard, Jonathon

    2011-11-23

    Microtubules are dynamic filaments whose ends alternate between periods of slow growth and rapid shortening as they explore intracellular space and move organelles. A key question is how regulatory proteins modulate catastrophe, the conversion from growth to shortening. To study this process, we reconstituted microtubule dynamics in the absence and presence of the kinesin-8 Kip3 and the kinesin-13 MCAK. Surprisingly, we found that, even in the absence of the kinesins, the microtubule catastrophe frequency depends on the age of the microtubule, indicating that catastrophe is a multistep process. Kip3 slowed microtubule growth in a length-dependent manner and increased the rate of aging. In contrast, MCAK eliminated the aging process. Thus, both kinesins are catastrophe factors; Kip3 mediates fine control of microtubule length by narrowing the distribution of maximum lengths prior to catastrophe, whereas MCAK promotes rapid restructuring of the microtubule cytoskeleton by making catastrophe a first-order random process.

  2. Microtubule's conformational cap

    DEFF Research Database (Denmark)

    Chretien, D.; Janosi, I.; Taveau, J.C.

    1999-01-01

    The molecular mechanisms that allow elongation of the unstable microtubule lattice remain unclear. It is usually thought that the GDP-liganded tubulin lattice is capped by a small layer of GTP- or GDP-P(i)-liganded molecules, the so called "GTP-cap". Here, we point-out that the elastic properties...

  3. Classical and quantum stability of higher-derivative dynamics

    CERN Document Server

    Kaparulin, D S; Sharapov, A A

    2014-01-01

    We observe that a wide class of higher-derivative systems admits a bounded integral of motion that ensures the classical stability of dynamics, while the canonical energy is unbounded. We use the concept of a Lagrange anchor to demonstrate that the bounded integral of motion is connected with the time-translation invariance. A procedure is suggested for switching on interactions in free higher-derivative systems without breaking their stability. We also demonstrate the quantization technique that keeps the higher-derivative dynamics stable at quantum level. The general construction is illustrated by the examples of the Pais-Uhlenbeck oscillator, higher-derivative scalar field model, and the Podolsky electrodynamics. For all these models, the positive integrals of motion are explicitly constructed and the interactions are included such that keep the system stable.

  4. Development of a transfer function method for dynamic stability measurement

    Science.gov (United States)

    Johnson, W.

    1977-01-01

    Flutter testing method based on transfer function measurements is developed. The error statistics of several dynamic stability measurement methods are reviewed. It is shown that the transfer function measurement controls the error level by averaging the data and correlating the input and output. The method also gives a direct estimate of the error in the response measurement. An algorithm is developed for obtaining the natural frequency and damping ratio of low damped modes of the system, using integrals of the transfer function in the vicinity of a resonant peak. Guidelines are given for selecting the parameters in the transfer function measurement. Finally, the dynamic stability measurement technique is applied to data from a wind tunnel test of a proprotor and wing model.

  5. Adaptive Dynamic Programming for Control Algorithms and Stability

    CERN Document Server

    Zhang, Huaguang; Luo, Yanhong; Wang, Ding

    2013-01-01

    There are many methods of stable controller design for nonlinear systems. In seeking to go beyond the minimum requirement of stability, Adaptive Dynamic Programming for Control approaches the challenging topic of optimal control for nonlinear systems using the tools of  adaptive dynamic programming (ADP). The range of systems treated is extensive; affine, switched, singularly perturbed and time-delay nonlinear systems are discussed as are the uses of neural networks and techniques of value and policy iteration. The text features three main aspects of ADP in which the methods proposed for stabilization and for tracking and games benefit from the incorporation of optimal control methods: • infinite-horizon control for which the difficulty of solving partial differential Hamilton–Jacobi–Bellman equations directly is overcome, and  proof provided that the iterative value function updating sequence converges to the infimum of all the value functions obtained by admissible control law sequences; • finite-...

  6. Exponential Stability of Stochastic Nonlinear Dynamical Price System with Delay

    Directory of Open Access Journals (Sweden)

    Wenli Zhu

    2013-01-01

    Full Text Available Based on Lyapunov stability theory, Itô formula, stochastic analysis, and matrix theory, we study the exponential stability of the stochastic nonlinear dynamical price system. Using Taylor's theorem, the stochastic nonlinear system with delay is reduced to an n-dimensional semilinear stochastic differential equation with delay. Some sufficient conditions of exponential stability and corollaries for such price system are established by virtue of Lyapunov function. The time delay upper limit is solved by using our theoretical results when the system is exponentially stable. Our theoretical results show that if the classical price Rayleigh equation is exponentially stable, so is its perturbed system with delay provided that both the time delay and the intensity of perturbations are small enough. Two examples are presented to illustrate our results.

  7. Experimental Study on the Dynamic Stability of the IXV Configuration

    OpenAIRE

    Gülhan, Ali; Klevanski, Josef; Gawehn, Thomas

    2015-01-01

    Dynamic stability of the IXV configuration has been investigated using free oscillation measurement technique in the Trisonic Windtunnel (TMK). In the transonic Mach number range an escalating behavior of the pitching moment damping derivative has been observed, although the vehicle is statically stable. At Mach 0.8 the vehicle showed the most unstable behavior. The instability becomes weaker with increasing Mach number. At Mach number 1.1 the vehicle is only slight...

  8. Structural Optimization of Machine Gun Based on Dynamic Stability Concept

    Institute of Scientific and Technical Information of China (English)

    LI Yong-jian; WANG Rui-lin; ZHANG Ben-jun

    2008-01-01

    Improving the firing accuracy is a final goal of structural optimization of machine guns. The main factors which affect the dispersion accuracy of machine gun are analyzed. Based on the concept of dynamic stability, a structural optimization model is built up, and the sensitivity of dispersion accuracy to design variables is analyzed. The optimization results of a type of machine gun show that the method is valid, feasible, and can be used as a guide to the structural optimization of other automatic weapons.

  9. Dynamic stabilization for degenerative spondylolisthesis and lumbar spinal instability.

    Science.gov (United States)

    Ohtonari, Tatsuya; Nishihara, Nobuharu; Suwa, Katsuyasu; Ota, Taisei; Koyama, Tsunemaro

    2014-01-01

    Lumbar interbody fusion is a widely accepted surgical procedure for patients with lumbar degenerative spondylolisthesis and lumbar spinal instability in the active age group. However, in elderly patients, it is often questionable whether it is truly necessary to construct rigid fixation for a short period of time. In recent years, we have been occasionally performing posterior dynamic stabilization in elderly patients with such lumbar disorders. Posterior dynamic stabilization was performed in 12 patients (6 women, 70.9 ± 5.6 years old at the time of operation) with lumbar degenerative spondylolisthesis in whom % slip was less than 20% or instability associated with lumbar disc herniation between March 2011 and March 2013. Movement occurs through the connector linked to the pedicle screw. In practice, 9 pairs of D connector system where the rod moves in the perpendicular direction alone and 8 pairs of Dynamic connector system where the connector linked to the pedicle screw rotates in the sagittal direction were installed. The observation period was 77-479 days, and the mean recovery rate of lumbar Japanese Orthopedic Association (JOA) score was 65.6 ± 20.8%. There was progression of slippage due to slight loosening in a case with lumbar degenerative spondylolisthesis, but this did not lead to exacerbation of the symptoms. Although follow-up was short, there were no symptomatic adjacent vertebral and disc disorders during this period. Posterior dynamic stabilization may diminish the development of adjacent vertebral or disc disorders due to lumbar interbody fusion, especially in elderly patients, and it may be a useful procedure that facilitates decompression and ensures a certain degree of spinal stabilization.

  10. Facet joint changes after application of lumbar nonfusion dynamic stabilization.

    Science.gov (United States)

    Lee, Soo Eon; Jahng, Tae-Ahn; Kim, Hyun Jib

    2016-01-01

    OBJECTIVE The long-term effects on adjacent-segment pathology after nonfusion dynamic stabilization is unclear, and, in particular, changes at the adjacent facet joints have not been reported in a clinical study. This study aims to compare changes in the adjacent facet joints after lumbar spinal surgery. METHODS Patients who underwent monosegmental surgery at L4-5 with nonfusion dynamic stabilization using the Dynesys system (Dynesys group) or transforaminal lumbar interbody fusion with pedicle screw fixation (fusion group) were retrospectively compared. Facet joint degeneration was evaluated at each segment using the CT grading system. RESULTS The Dynesys group included 15 patients, while the fusion group included 22 patients. The preoperative facet joint degeneration CT grades were not different between the 2 groups. Compared with the preoperative CT grades, 1 side of the facet joints at L3-4 and L4-5 had significantly more degeneration in the Dynesys group. In the fusion group, significant facet joint degeneration developed on both sides at L2-3, L3-4, and L5-S1. The subjective back and leg pain scores were not different between the 2 groups during follow-up, but functional outcome based on the Oswestry Disability Index improved less in the fusion group than in the Dynesys group. CONCLUSIONS Nonfusion dynamic stabilization using the Dynesys system had a greater preventative effect on facet joint degeneration in comparison with that obtained using fusion surgery. The Dynesys system, however, resulted in facet joint degeneration at the instrumented segments and above. An improved physiological nonfusion dynamic stabilization system for lumbar spinal surgery should be developed.

  11. Dynamic stability and phase resetting during biped gait

    Science.gov (United States)

    Nomura, Taishin; Kawa, Kazuyoshi; Suzuki, Yasuyuki; Nakanishi, Masao; Yamasaki, Taiga

    2009-06-01

    Dynamic stability during periodic biped gait in humans and in a humanoid robot is considered. Here gait systems of human neuromusculoskeletal system and a humanoid are simply modeled while keeping their mechanical properties plausible. We prescribe periodic gait trajectories in terms of joint angles of the models as a function of time. The equations of motion of the models are then constrained by one of the prescribed gait trajectories to obtain types of periodically forced nonlinear dynamical systems. Simulated gait of the models may or may not fall down during gait, since the constraints are made only for joint angles of limbs but not for the motion of the body trunk. The equations of motion can exhibit a limit cycle solution (or an oscillatory solution that can be considered as a limit cycle practically) for each selected gait trajectory, if an initial condition is set appropriately. We analyze the stability of the limit cycle in terms of Poincaré maps and the basin of attraction of the limit cycle in order to examine how the stability depends on the prescribed trajectory. Moreover, the phase resetting of gait rhythm in response to external force perturbation is modeled. Since we always prescribe a gait trajectory in this study, reacting gait trajectories during the phase resetting are also prescribed. We show that an optimally prescribed reacting gait trajectory with an appropriate amount of the phase resetting can increase the gait stability. Neural mechanisms for generation and modulation of the gait trajectories are discussed.

  12. Dynamical behavior and Jacobi stability analysis of wound strings

    CERN Document Server

    Lake, Matthew J

    2016-01-01

    We numerically solve the equations of motion (EOM) for two models of circular cosmic string loops with windings in a simply connected internal space. Since the windings cannot be topologically stabilized, stability must be achieved (if at all) dynamically. As toy models for realistic compactifications, we consider windings on a small section of $\\mathbb{R}^2$, which is valid as an approximation to any simply connected internal manifold if the winding radius is sufficiently small, and windings on an $S^2$ of constant radius $\\mathcal{R}$. We then use Kosambi-Cartan-Chern (KCC) theory to analyze the Jacobi stability of the string equations and determine bounds on the physical parameters that ensure dynamical stability of the windings. We find that, for the same initial conditions, the curvature and topology of the internal space have nontrivial effects on the microscopic behavior of the string in the higher dimensions, but that the macroscopic behavior is remarkably insensitive to the details of the motion in t...

  13. A Point Dynamic Model for Stability Analysis of the PGSFR

    Energy Technology Data Exchange (ETDEWEB)

    Ha, Pham Nhu Viet; Choi, Sun Rock; Lee, Min Jae; Kang, Chang Moo; Kim, Sang Ji [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2015-05-15

    To ensure the enhanced safety criteria for an advanced reactor system, the PGSFR design is highly based on the inherent safety mechanisms, i.e., passive responses to abnormal and emergency conditions, and thereby minimizes the need for active or engineered safety systems. In this regard, various inherent reactivity feedbacks in the PGSFR including thermal expansion of the sodium coolant, fuel temperature change, thermal bowing of the fuel, thermal expansion of the core and structure, and thermal expansion of the control rod drive line should be carefully evaluated in the design process. Of primary importance is to clarify the influence of the inherent reactivity feedbacks on the reactor dynamics and stability against small reactivity disturbances under power operating conditions. The reactor response to such small reactivity disturbances is determined by the interaction of the various reactivity coefficients, magnitude of the initial reactivity insertion, and nature of the heat removal system. It was shown that the stability property of the PGSFR is the same for all the three considered forcing functions. Furthermore, the PGSFR was found to be inherently stable thanks to the inherent negative reactivity coefficients and its stability is even more enhanced with fuel burnup in the equilibrium cycle. Especially, the conditions under which the PGSFR can become unstable in the presence of one or more positive reactivity coefficients were revealed. As a result, this study can provide designers useful information about the reactor dynamics along with the impacts of positive reactivity coefficients for further improvements of the reactor stability under power operating conditions.

  14. Dynamic remedial action scheme using online transient stability analysis

    Science.gov (United States)

    Shrestha, Arun

    Economic pressure and environmental factors have forced the modern power systems to operate closer to their stability limits. However, maintaining transient stability is a fundamental requirement for the operation of interconnected power systems. In North America, power systems are planned and operated to withstand the loss of any single or multiple elements without violating North American Electric Reliability Corporation (NERC) system performance criteria. For a contingency resulting in the loss of multiple elements (Category C), emergency transient stability controls may be necessary to stabilize the power system. Emergency control is designed to sense abnormal conditions and subsequently take pre-determined remedial actions to prevent instability. Commonly known as either Remedial Action Schemes (RAS) or as Special/System Protection Schemes (SPS), these emergency control approaches have been extensively adopted by utilities. RAS are designed to address specific problems, e.g. to increase power transfer, to provide reactive support, to address generator instability, to limit thermal overloads, etc. Possible remedial actions include generator tripping, load shedding, capacitor and reactor switching, static VAR control, etc. Among various RAS types, generation shedding is the most effective and widely used emergency control means for maintaining system stability. In this dissertation, an optimal power flow (OPF)-based generation-shedding RAS is proposed. This scheme uses online transient stability calculation and generator cost function to determine appropriate remedial actions. For transient stability calculation, SIngle Machine Equivalent (SIME) technique is used, which reduces the multimachine power system model to a One-Machine Infinite Bus (OMIB) equivalent and identifies critical machines. Unlike conventional RAS, which are designed using offline simulations, online stability calculations make the proposed RAS dynamic and adapting to any power system

  15. Dynamical stability of the holographic system with two competing orders

    Energy Technology Data Exchange (ETDEWEB)

    Du, Yiqiang [School of Physics, University of Chinese Academy of Sciences,Beijing 100049 (China); Lan, Shan-Quan [Department of Physics, Beijing Normal University,Beijing 100875 (China); Tian, Yu [School of Physics, University of Chinese Academy of Sciences,Beijing 100049 (China); State Key Laboratory of Theoretical Physics,Institute of Theoretical Physics, Chinese Academy of Science,Beijing 100190 (China); Zhang, Hongbao [Department of Physics, Beijing Normal University,Beijing 100875 (China); Theoretische Natuurkunde, Vrije Universiteit Brussel and The International Solvay Institutes,Pleinlaan 2, B-1050 Brussels (Belgium)

    2016-01-04

    We investigate the dynamical stability of the holographic system with two order parameters, which exhibits competition and coexistence of condensations. In the linear regime, we have developed the gauge dependent formalism to calculate the quasi-normal modes by gauge fixing, which turns out be considerably convenient. Furthermore, by giving different Gaussian wave packets as perturbations at the initial time, we numerically evolve the full nonlinear system until it arrives at the final equilibrium state. Our results show that the dynamical stability is consistent with the thermodynamical stability. Interestingly, the dynamical evolution, as well as the quasi-normal modes, shows that the relaxation time of this model is generically much longer than the simplest holographic system. We also find that the late time behavior can be well captured by the lowest lying quasi-normal modes except for the non-vanishing order towards the single ordered phase. To our knowledge, this exception is the first counter example to the general belief that the late time behavior towards a final stable state can be captured by the lowest lying quasi-normal modes. In particular, a double relation is found for this exception in certain cases.

  16. Dynein prevents erroneous kinetochore-microtubule attachments in mitosis.

    Science.gov (United States)

    Barisic, Marin; Maiato, Helder

    2015-01-01

    Equal distribution of the genetic material during cell division relies on efficient congression of chromosomes to the metaphase plate. Prior to their alignment, the Dynein motor recruited to kinetochores transports a fraction of laterally-attached chromosomes along microtubules toward the spindle poles. By doing that, Dynein not only contributes to chromosome movements, but also prevents premature stabilization of end-on kinetochore-microtubule attachments. This is achieved by 2 parallel mechanisms: 1) Dynein-mediated poleward movement of chromosomes counteracts opposite polar-ejection forces (PEFs) on chromosome arms by the microtubule plus-end-directed motors chromokinesins. Otherwise, they could stabilize erroneous syntelic kinetochore-microtubule attachments and lead to the random ejection of chromosomes away from the spindle poles; and 2) By transporting chromosomes to the spindle poles, Dynein brings the former to the zone of highest Aurora A kinase activity, further destabilizing kinetochore-microtubule attachments. Thus, Dynein plays an important role in keeping chromosome segregation error-free by preventing premature stabilization of kinetochore-microtubule attachments near the spindle poles.

  17. Stationary Stability for Evolutionary Dynamics in Finite Populations

    Directory of Open Access Journals (Sweden)

    Marc Harper

    2016-08-01

    Full Text Available We demonstrate a vast expansion of the theory of evolutionary stability to finite populations with mutation, connecting the theory of the stationary distribution of the Moran process with the Lyapunov theory of evolutionary stability. We define the notion of stationary stability for the Moran process with mutation and generalizations, as well as a generalized notion of evolutionary stability that includes mutation called an incentive stable state (ISS candidate. For sufficiently large populations, extrema of the stationary distribution are ISS candidates and we give a family of Lyapunov quantities that are locally minimized at the stationary extrema and at ISS candidates. In various examples, including for the Moran and Wright–Fisher processes, we show that the local maxima of the stationary distribution capture the traditionally-defined evolutionarily stable states. The classical stability theory of the replicator dynamic is recovered in the large population limit. Finally we include descriptions of possible extensions to populations of variable size and populations evolving on graphs.

  18. The Microtubule Regulatory Protein Stathmin Is Required to Maintain the Integrity of Axonal Microtubules in Drosophila.

    Directory of Open Access Journals (Sweden)

    Jason E Duncan

    Full Text Available Axonal transport, a form of long-distance, bi-directional intracellular transport that occurs between the cell body and synaptic terminal, is critical in maintaining the function and viability of neurons. We have identified a requirement for the stathmin (stai gene in the maintenance of axonal microtubules and regulation of axonal transport in Drosophila. The stai gene encodes a cytosolic phosphoprotein that regulates microtubule dynamics by partitioning tubulin dimers between pools of soluble tubulin and polymerized microtubules, and by directly binding to microtubules and promoting depolymerization. Analysis of stai function in Drosophila, which has a single stai gene, circumvents potential complications with studies performed in vertebrate systems in which mutant phenotypes may be compensated by genetic redundancy of other members of the stai gene family. This has allowed us to identify an essential function for stai in the maintenance of the integrity of axonal microtubules. In addition to the severe disruption in the abundance and architecture of microtubules in the axons of stai mutant Drosophila, we also observe additional neurological phenotypes associated with loss of stai function including a posterior paralysis and tail-flip phenotype in third instar larvae, aberrant accumulation of transported membranous organelles in stai deficient axons, a progressive bang-sensitive response to mechanical stimulation reminiscent of the class of Drosophila mutants used to model human epileptic seizures, and a reduced adult lifespan. Reductions in the levels of Kinesin-1, the primary anterograde motor in axonal transport, enhance these phenotypes. Collectively, our results indicate that stai has an important role in neuronal function, likely through the maintenance of microtubule integrity in the axons of nerves of the peripheral nervous system necessary to support and sustain long-distance axonal transport.

  19. Dynamic flight stability of a bumblebee in forward flight

    Institute of Scientific and Technical Information of China (English)

    Yan Xiong; Mao Sun

    2008-01-01

    The longitudinal dynamic flight stability of a bumblebee in forward flight is studied.The method of computational fluid dynamics is used to compute the aerodynamic derivatives and the techniques of eigenvalue and eigenvector analysis are employed for solving the equations of motion.The primary findings are as the following.The forward flight of the bumblebee is not dynamically stable due to the existence of one(or two)unstable or approximately neutrally stable natural modes of motion.At hovering to medium flight speed[flight speed ue=(0-3.5)m s-1;advance ratio J=0-0.44],the flight is weakly unstable or approximately neutrally stable;at high speed(ue=4.5 m s-1;J=0.57),the flight becomes strongly unstable(initial disturbance double its value in only 3.5 wingbeats).

  20. Dynamics and stability of a vertical water bridge

    CERN Document Server

    Namin, Reza Montazeri

    2013-01-01

    A vertical connection of water is formed when a high voltage electrode is dipped in and pulled out of a container of deionized water. We considered the formation, stability and dynamical characteristics of this vertical water bridge. For the first time in this field, we observed instabilities in the bridge that led to an oscillatory behaviour which is categorized in three dynamical regimes and supplied explanations on the physics behind these varied motions. We report the formation of macroscopic droplets during this motion, which their dynamics revealed that they are electrically charged. In some cases the droplets would be levitating when the electric force opposes the gravity. Also the steady bridge is thoroughly studied regarding its geometry and a set of quantitative data is presented using dimensionless numbers, which brings the possibility of direct quantitative comparison between theory and experiments. Our results shed light on the physics behind this phenomenon and the horizontal water bridge, which...

  1. Acentrosomal Microtubule Assembly in Mitosis: The Where, When, and How.

    Science.gov (United States)

    Meunier, Sylvain; Vernos, Isabelle

    2016-02-01

    In mitosis the cell assembles the bipolar spindle, a microtubule (MT)-based apparatus that segregates the duplicated chromosomes into two daughter cells. Most animal cells enter mitosis with duplicated centrosomes that provide an active source of dynamic MTs. However, it is now established that spindle assembly relies on the nucleation of acentrosomal MTs occurring around the chromosomes after nuclear envelope breakdown, and on pre-existing microtubules. Where chromosome-dependent MT nucleation occurs, when MT amplification takes place and how the two pathways function are still key questions that generate some controversies. We reconcile the data and present an integrated model accounting for acentrosomal microtubule assembly in the dividing cell.

  2. Studying neuronal microtubule organization and microtubule-associated proteins using single molecule localization microscopy

    NARCIS (Netherlands)

    Chazeau, Anaël; Katrukha, Eugene A; Hoogenraad, Casper C; Kapitein, Lukas C

    2016-01-01

    The formation and maintenance of highly polarized neurons critically depends on the proper organization of the microtubule (MT) cytoskeleton. In axons, MTs are uniformly oriented with their plus-end pointing outward whereas in mature dendrites MTs have mixed orientations. MT organization and dynamic

  3. Dynamic stability of spine using stability-based optimization and muscle spindle reflex.

    Science.gov (United States)

    Zeinali-Davarani, Shahrokh; Hemami, Hooshang; Barin, Kamran; Shirazi-Adl, Aboulfazl; Parnianpour, Mohamad

    2008-02-01

    A computational method for simulation of 3-D movement of the trunk under the control of 48 anatomically oriented muscle actions was developed. Neural excitation of muscles was set based on inverse dynamics approach along with the stability-based optimization. The effect of muscle spindle reflex response on the trunk movement stability was evaluated upon the application of a perturbation moment. The method was used to simulate the trunk movement from the upright standing to 60 degrees of flexion. Incorporation of the stability condition as an additional constraint in the optimization resulted in an increase in antagonistic activities demonstrating that the antagonistic co-activation acts to increase the trunk stability in response to self-induced postural internal perturbation. In presence of a 30 Nm flexion perturbation moment, muscle spindles decreased the induced deviation of the position and velocity profiles from the desired ones. The stability-generated co-activation decreased the reflexive response of muscle spindles to the perturbation demonstrating that the rise in muscle co-activation can ameliorate the corruption of afferent neural sensory system at the expense of higher loading of the spine.

  4. The microtubule plus-end-tracking protein CLIP-170 associates with the spermatid manchette and is essential for spermatogenesis.

    NARCIS (Netherlands)

    A.S. Akhmanova (Anna); A.L. Mausset-Bonnefont (Anne-Laure); W.A. van Cappellen (Gert); N. Keijzer (Nanda); C.C. Hoogenraad (Casper); T. Stepanova (Tatiana); K. Drabek (Ksenija); J. van der Wees (Jacqueline); M. Mommaas (Mieke); J. Onderwater (Jos); H. van der Meulen (Hans); M.E. Tanenbaum (Marvin); R.H. Medema (Rene); J.W. Hoogerbrugge (Jos); J.T.M. Vreeburg (Jan); E.J. Uringa; J.A. Grootegoed (Anton); F.G. Grosveld (Frank); N.J. Galjart (Niels)

    2005-01-01

    textabstractCLIP-170 is a microtubule "plus-end-tracking protein" implicated in the control of microtubule dynamics, dynactin localization, and the linking of endosomes to microtubules. To investigate the function of mouse CLIP-170, we generated CLIP-170 knockout and GFP-CLIP-170 knock-in alleles. R

  5. The microtubule plus-end-tracking protein CLIP-170 associates with the spermatid manchette and is essential for spermatogenesis

    NARCIS (Netherlands)

    Akhmanova, A.S.; Mausset-Bonnefont, A.-L.; Cappellen, W. van; Keijzer, N.; Hoogenraad, C.C.; Stepanova, T.; Drabek, K.; Wees, J. van der; Mommaas, M.; Onderwater, J.; Meulen, H. van der; Tanenbaum, M.E.; Medema, R.H.; Hoogerbrugge, J.; Vreeburg, J.; Uringa, E.-J.; Grootegoed, J.A.; Grosveld, F.; Galjart, N.

    2005-01-01

    CLIP-170 is a microtubule "plus-end-tracking protein" implicated in the control of microtubule dynamics, dynactin localization, and the linking of endosomes to microtubules. To investigate the function of mouse CLIP-170, we generated CLIP-170 knockout and GFP-CLIP-170 knock-in alleles. Residual CLIP

  6. Predator interference and stability of predator-prey dynamics.

    Science.gov (United States)

    Přibylová, Lenka; Berec, Luděk

    2015-08-01

    Predator interference, that is, a decline in the per predator consumption rate as predator density increases, is generally thought to promote predator-prey stability. Indeed, this has been demonstrated in many theoretical studies on predator-prey dynamics. In virtually all of these studies, the stabilization role is demonstrated as a weakening of the paradox of enrichment. With predator interference, stable limit cycles that appear as a result of environmental enrichment occur for higher values of the environmental carrying capacity of prey, and even a complete absence of the limit cycles can happen. Here we study predator-prey dynamics using the Rosenzweig-MacArthur-like model in which the Holling type II functional response has been replaced by a predator-dependent family which generalizes many of the commonly used descriptions of predator interference. By means of a bifurcation analysis we show that sufficiently strong predator interference may bring about another stabilizing mechanism. In particular, hysteresis combined with (dis)appearance of stable limit cycles imply abrupt increases in both the prey and predator densities and enhanced persistence and resilience of the predator-prey system. We encourage refitting the previously collected data on predator consumption rates as well as for conducting further predation experiments to see what functional response from the explored family is the most appropriate.

  7. Assessment of current criteria for dynamic stability of container vessels

    Science.gov (United States)

    Stanca, C.; Ancuta, C.; Acomi, N.; Andrei, C.

    2016-08-01

    Container vessels sailing through heavy weather are exposed to a significant variation of stability due to specific shape of the hull combined with the action of the waves. Even if the weather forecast is transmitted to vessels, the way of acting it is a matter of officers’ experience. The Maritime Safety Committee, under the International Maritime Organization, has approved the Guidance to the master for avoiding dangerous situations in adverse weather and sea conditions. Adverse weather conditions include wind induced waves or heavy swell. The development of dangerous phenomena such as surf-riding and broaching to, syncronious and parametric rollings is a result of a these adverse conditions which has to be encountered by the vessels. Understanding the dynamic stability of the vessel in the waves and ship's behaviour based on mathematical and physical rules is a difficult task, any effort in order to assess these components are salutary. To avoid excessive acceleration and forces which can damage the hull of the vessel, lashing and integrity of containers, course and speed may need to be changed for the vessel's motion in heavy seas. Specific software have been developed as aids for evaluating the response of the vessel in heavy seas according to parameters variations. The paper aims at assessing of current criteria for dynamic stability of a container vessel model ship in order to determine the ways for avoiding dangerous conditions. The results should be regarded as a supporting tool during the decision making process.

  8. Electrostatically biased binding of kinesin to microtubules.

    Directory of Open Access Journals (Sweden)

    Barry J Grant

    2011-11-01

    Full Text Available The minimum motor domain of kinesin-1 is a single head. Recent evidence suggests that such minimal motor domains generate force by a biased binding mechanism, in which they preferentially select binding sites on the microtubule that lie ahead in the progress direction of the motor. A specific molecular mechanism for biased binding has, however, so far been lacking. Here we use atomistic Brownian dynamics simulations combined with experimental mutagenesis to show that incoming kinesin heads undergo electrostatically guided diffusion-to-capture by microtubules, and that this produces directionally biased binding. Kinesin-1 heads are initially rotated by the electrostatic field so that their tubulin-binding sites face inwards, and then steered towards a plus-endwards binding site. In tethered kinesin dimers, this bias is amplified. A 3-residue sequence (RAK in kinesin helix alpha-6 is predicted to be important for electrostatic guidance. Real-world mutagenesis of this sequence powerfully influences kinesin-driven microtubule sliding, with one mutant producing a 5-fold acceleration over wild type. We conclude that electrostatic interactions play an important role in the kinesin stepping mechanism, by biasing the diffusional association of kinesin with microtubules.

  9. Strategy switching in the stabilization of unstable dynamics.

    Directory of Open Access Journals (Sweden)

    Jacopo Zenzeri

    Full Text Available In order to understand mechanisms of strategy switching in the stabilization of unstable dynamics, this work investigates how human subjects learn to become skilled users of an underactuated bimanual tool in an unstable environment. The tool, which consists of a mass and two hand-held non-linear springs, is affected by a saddle-like force-field. The non-linearity of the springs allows the users to determine size and orientation of the tool stiffness ellipse, by using different patterns of bimanual coordination: minimal stiffness occurs when the two spring terminals are aligned and stiffness size grows by stretching them apart. Tool parameters were set such that minimal stiffness is insufficient to provide stable equilibrium whereas asymptotic stability can be achieved with sufficient stretching, although at the expense of greater effort. As a consequence, tool users have two possible strategies for stabilizing the mass in different regions of the workspace: 1 high stiffness feedforward strategy, aiming at asymptotic stability and 2 low stiffness positional feedback strategy aiming at bounded stability. The tool was simulated by a bimanual haptic robot with direct torque control of the motors. In a previous study we analyzed the behavior of naïve users and we found that they spontaneously clustered into two groups of approximately equal size. In this study we trained subjects to become expert users of both strategies in a discrete reaching task. Then we tested generalization capabilities and mechanism of strategy-switching by means of stabilization tasks which consist of tracking moving targets in the workspace. The uniqueness of the experimental setup is that it addresses the general problem of strategy-switching in an unstable environment, suggesting that complex behaviors cannot be explained in terms of a global optimization criterion but rather require the ability to switch between different sub-optimal mechanisms.

  10. Globally visualizing the microtubule-dependent transport behaviors of influenza virus in live cells.

    Science.gov (United States)

    Liu, Shu-Lin; Zhang, Li-Juan; Wang, Zhi-Gang; Zhang, Zhi-Ling; Wu, Qiu-Mei; Sun, En-Ze; Shi, Yun-Bo; Pang, Dai-Wen

    2014-04-15

    Understanding the microtubule-dependent behaviors of viruses in live cells is very meaningful for revealing the mechanisms of virus infection and endocytosis. Herein, we used a quantum dots-based single-particle tracking technique to dynamically and globally visualize the microtubule-dependent transport behaviors of influenza virus in live cells. We found that the intersection configuration of microtubules can interfere with the transport behaviors of the virus in live cells, which lead to the changing and long-time pausing of the transport behavior of viruses. Our results revealed that most of the viruses moved along straight microtubules rapidly and unidirectionally from the cell periphery to the microtubule organizing center (MTOC) near the bottom of the cell, and the viruses were confined in the grid of microtubules near the top of the cell and at the MTOC near the bottom of the cell. These results provided deep insights into the influence of entire microtubule geometry on the virus infection.

  11. Kinematic variability, fractal dynamics and local dynamic stability of treadmill walking

    Directory of Open Access Journals (Sweden)

    Terrier Philippe

    2011-02-01

    Full Text Available Abstract Background Motorized treadmills are widely used in research or in clinical therapy. Small kinematics, kinetics and energetics changes induced by Treadmill Walking (TW as compared to Overground Walking (OW have been reported in literature. The purpose of the present study was to characterize the differences between OW and TW in terms of stride-to-stride variability. Classical (Standard Deviation, SD and non-linear (fractal dynamics, local dynamic stability methods were used. In addition, the correlations between the different variability indexes were analyzed. Methods Twenty healthy subjects performed 10 min TW and OW in a random sequence. A triaxial accelerometer recorded trunk accelerations. Kinematic variability was computed as the average SD (MeanSD of acceleration patterns among standardized strides. Fractal dynamics (scaling exponent α was assessed by Detrended Fluctuation Analysis (DFA of stride intervals. Short-term and long-term dynamic stability were estimated by computing the maximal Lyapunov exponents of acceleration signals. Results TW did not modify kinematic gait variability as compared to OW (multivariate T2, p = 0.87. Conversely, TW significantly modified fractal dynamics (t-test, p = 0.01, and both short and long term local dynamic stability (T2 p = 0.0002. No relationship was observed between variability indexes with the exception of significant negative correlation between MeanSD and dynamic stability in TW (3 × 6 canonical correlation, r = 0.94. Conclusions Treadmill induced a less correlated pattern in the stride intervals and increased gait stability, but did not modify kinematic variability in healthy subjects. This could be due to changes in perceptual information induced by treadmill walking that would affect locomotor control of the gait and hence specifically alter non-linear dependencies among consecutive strides. Consequently, the type of walking (i.e. treadmill or overground is important to consider in

  12. A Chimeric Cetuximab-Functionalized Corona as a Potent Delivery System for Microtubule-Destabilizing Nanocomplexes to Hepatocellular Carcinoma Cells: A Focus on EGFR and Tubulin Intracellular Dynamics.

    Science.gov (United States)

    Poojari, Radhika; Kini, Sudarshan; Srivastava, Rohit; Panda, Dulal

    2015-11-01

    In this study, we have developed microtubule destabilizing agents combretastatin A4 (CA4) or 2-methoxyestradiol (2ME) encapsulated poly(d,l-lactide-co-glycolide)-b-poly(ethylene glycol) (PLGA-b-PEG) nanocomplexes for targeted delivery to human hepatocellular carcinoma (HCC) cells. An epidermal growth factor receptor (EGFR) is known to be overexpressed in HCC cells. Therefore, the targeting moiety cetuximab (Cet), an anti-EGFR chimeric monoclonal antibody, is functionalized on the surface of these diblock copolymeric coronas. Cetuximab is associated with the extracellular domain of the EGFR; therefore, the uptake of the cetuximab conjugated nanocomplexes occurred efficiently in EGFR overexpressing HCC cells indicating potent internalization of the complex. The cetuximab targeted-PLGA-b-PEG nanocomplexes encapsulating CA4 or 2ME strongly inhibited phospho-EGFR expression, depolymerized microtubules, produced spindle abnormalities, stalled mitosis, and induced apoptosis in Huh7 cells compared to the free drugs, CA4 or 2ME. Further, the combinatorial strategy of targeted nanocomplexes, Cet-PLGA-b-PEG-CA4 NP and Cet-PLGA-b-PEG-2ME NP, significantly reduced the migration of Huh7 cells, and markedly enhanced the anticancer effects of the microtubule-targeted drugs in Huh7 cells compared to the free drugs, CA4 or 2ME. The results indicated that EGFR receptor-mediated internalization via cetuximab facilitated enhanced uptake of the nanocomplexes leading to potent anticancer efficacy in Huh7 cells. Cetuximab-functionalized PLGA-b-PEG nanocomplexes possess a strong potential for the targeted delivery of CA4 or 2ME in EGFR overexpressed HCC cells, and the strategy may be useful for selectively targeting microtubules in these cells.

  13. Dynamic Modeling, Testing, and Stability Analysis of an Ornithoptic Blimp

    Institute of Scientific and Technical Information of China (English)

    John Dietl; Thomas Herrmann; Gregory Reich; Ephrahim Garcia

    2011-01-01

    In order to study omithopter flight and to improve a dynamic model of flapping propulsion,a series of tests are conducted on a flapping-wing blimp.The blimp is designed and constructed from mylar plastic and balsa wood as a test platform for aerodynamics and flight dynamics.The blimp,2.3 meters long and 420 gram mass,is propelled by its flapping wings.Due to buoyancy the wings have no lift requirement so that the distinction between lift and propulsion can be analyzed in a flight platform at low flight speeds.The blimp is tested using a Vicon motion tracking system and various initial conditions are tested including accelerating flight from standstill,decelerating from an initial speed higher than its steady state,and from its steady-state speed but disturbed in pitch angle.Test results are used to estimate parameters in a coupled quasi-steady aerodynamics/Newtonian flight dynamics model.This model is then analyzed using Floquet theory to determine local dynamic modes and stability.It is concluded that the dynamic model adequately describes the vehicle's nonlinear behavior near the steady-state velocity and that the vehicle's linearized modes are akin to those of a fixed-wing aircraft.

  14. A thermodynamic model of microtubule assembly and disassembly.

    Directory of Open Access Journals (Sweden)

    Bernard M A G Piette

    Full Text Available Microtubules are self-assembling polymers whose dynamics are essential for the normal function of cellular processes including chromosome separation and cytokinesis. Therefore understanding what factors effect microtubule growth is fundamental to our understanding of the control of microtubule based processes. An important factor that determines the status of a microtubule, whether it is growing or shrinking, is the length of the GTP tubulin microtubule cap. Here, we derive a Monte Carlo model of the assembly and disassembly of microtubules. We use thermodynamic laws to reduce the number of parameters of our model and, in particular, we take into account the contribution of water to the entropy of the system. We fit all parameters of the model from published experimental data using the GTP tubulin dimer attachment rate and the lateral and longitudinal binding energies of GTP and GDP tubulin dimers at both ends. Also we calculate and incorporate the GTP hydrolysis rate. We have applied our model and can mimic published experimental data, which formerly suggested a single layer GTP tubulin dimer microtubule cap, to show that these data demonstrate that the GTP cap can fluctuate and can be several microns long.

  15. A thermodynamic model of microtubule assembly and disassembly.

    Science.gov (United States)

    Piette, Bernard M A G; Liu, Junli; Peeters, Kasper; Smertenko, Andrei; Hawkins, Timothy; Deeks, Michael; Quinlan, Roy; Zakrzewski, Wojciech J; Hussey, Patrick J

    2009-08-11

    Microtubules are self-assembling polymers whose dynamics are essential for the normal function of cellular processes including chromosome separation and cytokinesis. Therefore understanding what factors effect microtubule growth is fundamental to our understanding of the control of microtubule based processes. An important factor that determines the status of a microtubule, whether it is growing or shrinking, is the length of the GTP tubulin microtubule cap. Here, we derive a Monte Carlo model of the assembly and disassembly of microtubules. We use thermodynamic laws to reduce the number of parameters of our model and, in particular, we take into account the contribution of water to the entropy of the system. We fit all parameters of the model from published experimental data using the GTP tubulin dimer attachment rate and the lateral and longitudinal binding energies of GTP and GDP tubulin dimers at both ends. Also we calculate and incorporate the GTP hydrolysis rate. We have applied our model and can mimic published experimental data, which formerly suggested a single layer GTP tubulin dimer microtubule cap, to show that these data demonstrate that the GTP cap can fluctuate and can be several microns long.

  16. Thermal stability of marks gold nanoparticles: A molecular dynamics simulation

    Science.gov (United States)

    Jia, Yanlin; Li, Siqi; Qi, Weihong; Wang, Mingpu; Li, Zhou; Wang, Zhixing

    2017-03-01

    Molecular dynamics (MDs) simulations were used to explore the thermal stability of Au nanoparticles (NPs) with decahedral, cuboctahedral, icosahedral and Marks NPs. According to the calculated cohesive energy and melting temperature, the Marks NPs have a higher cohesive energy and melting temperature compared to these other shapes. The Lindemann index, radial distribution function, deformation parameters, mean square displacement and self-diffusivity have been used to characterize the structure variation during heating. This work may inspire researchers to prepare Marks NPs and apply them in different fields.

  17. Sites of glucose transporter-4 vesicle fusion with the plasma membrane correlate spatially with microtubules.

    Directory of Open Access Journals (Sweden)

    Jennine M Dawicki-McKenna

    Full Text Available In adipocytes, vesicles containing glucose transporter-4 (GLUT4 redistribute from intracellular stores to the cell periphery in response to insulin stimulation. Vesicles then fuse with the plasma membrane, facilitating glucose transport into the cell. To gain insight into the details of microtubule involvement, we examined the spatial organization and dynamics of microtubules in relation to GLUT4 vesicle trafficking in living 3T3-L1 adipocytes using total internal reflection fluorescence (TIRF microscopy. Insulin stimulated an increase in microtubule density and curvature within the TIRF-illuminated region of the cell. The high degree of curvature and abrupt displacements of microtubules indicate that substantial forces act on microtubules. The time course of the microtubule density increase precedes that of the increase in intensity of fluorescently-tagged GLUT4 in this same region of the cell. In addition, portions of the microtubules are highly curved and are pulled closer to the cell cortex, as confirmed by Parallax microscopy. Microtubule disruption delayed and modestly reduced GLUT4 accumulation at the plasma membrane. Quantitative analysis revealed that fusions of GLUT4-containing vesicles with the plasma membrane, detected using insulin-regulated aminopeptidase with a pH-sensitive GFP tag (pHluorin, preferentially occur near microtubules. Interestingly, long-distance vesicle movement along microtubules visible at the cell surface prior to fusion does not appear to account for this proximity. We conclude that microtubules may be important in providing spatial information for GLUT4 vesicle fusion.

  18. Stability and dynamics of membrane-spanning DNA nanopores

    Science.gov (United States)

    Maingi, Vishal; Burns, Jonathan R.; Uusitalo, Jaakko J.; Howorka, Stefan; Marrink, Siewert J.; Sansom, Mark S. P.

    2017-03-01

    Recently developed DNA-based analogues of membrane proteins have advanced synthetic biology. A fundamental question is how hydrophilic nanostructures reside in the hydrophobic environment of the membrane. Here, we use multiscale molecular dynamics (MD) simulations to explore the structure, stability and dynamics of an archetypical DNA nanotube inserted via a ring of membrane anchors into a phospholipid bilayer. Coarse-grained MD reveals that the lipids reorganize locally to interact closely with the membrane-spanning section of the DNA tube. Steered simulations along the bilayer normal establish the metastable nature of the inserted pore, yielding a force profile with barriers for membrane exit due to the membrane anchors. Atomistic, equilibrium simulations at two salt concentrations confirm the close packing of lipid around of the stably inserted DNA pore and its cation selectivity, while revealing localized structural fluctuations. The wide-ranging and detailed insight informs the design of next-generation DNA pores for synthetic biology or biomedicine.

  19. Inhibition of kinesin-5 improves regeneration of injured axons by a novel microtubule-based mechanism

    Institute of Scientific and Technical Information of China (English)

    Peter W. Baas; Andrew J. Matamoros

    2015-01-01

    Microtubules have been identiifed as a powerful target for augmenting regeneration of injured adult axons in the central nervous system. Drugs that stabilize microtubules have shown some promise, but there are concerns that abnormally stabilizing microtubules may have only limited beneifts for regeneration, while at the same time may be detrimental to the normal work that microtubules perform for the axon. Kinesin-5 (also called kif11 or Eg5), a molecular motor protein best known for its crucial role in mitosis, acts as a brake on microtubule movements by other motor proteins in the axon. Drugs that inhibit kinesin-5, originally developed to treat cancer, result in greater mobility of microtubules in the axon and an overall shift in the forces on the microtubule array. As a result, the axon grows faster, retracts less, and more readily enters environments that are inhibitory to axonal regeneration. Thus, drugs that inhibit kinesin-5 offer a novel microtubule-based means to boost axonal regeneration without the concerns that ac-company abnormal stabilization of the microtubule array. Even so, inhibiting kinesin-5 is not without its own caveats, such as potential problems with navigation of the regenerating axon to its target, as well as morphological effects on dendrites that could affect learning and memory if the drugs reach the brain.

  20. Inhibition of kinesin-5 improves regeneration of injured axons by a novel microtubule-based mechanism

    Directory of Open Access Journals (Sweden)

    Peter W Baas

    2015-01-01

    Full Text Available Microtubules have been identified as a powerful target for augmenting regeneration of injured adult axons in the central nervous system. Drugs that stabilize microtubules have shown some promise, but there are concerns that abnormally stabilizing microtubules may have only limited benefits for regeneration, while at the same time may be detrimental to the normal work that microtubules perform for the axon. Kinesin-5 (also called kif11 or Eg5, a molecular motor protein best known for its crucial role in mitosis, acts as a brake on microtubule movements by other motor proteins in the axon. Drugs that inhibit kinesin-5, originally developed to treat cancer, result in greater mobility of microtubules in the axon and an overall shift in the forces on the microtubule array. As a result, the axon grows faster, retracts less, and more readily enters environments that are inhibitory to axonal regeneration. Thus, drugs that inhibit kinesin-5 offer a novel microtubule-based means to boost axonal regeneration without the concerns that accompany abnormal stabilization of the microtubule array. Even so, inhibiting kinesin-5 is not without its own caveats, such as potential problems with navigation of the regenerating axon to its target, as well as morphological effects on dendrites that could affect learning and memory if the drugs reach the brain.

  1. A Dynamic Stability Criterion for Ice Shelves and Tidewater Glaciers

    Science.gov (United States)

    Bassis, J. N.; Fricker, H. A.; Minster, J.

    2006-12-01

    The collapse of the Antarctic ice shelves could have dramatic consequences for the mass balance of the Antarctic ice sheet and, as a result, sea level rise. It is therefore imperative to improve our knowledge of the mechanisms that lead to ice shelf retreat. The mechanism that has the potential to remove the largest amounts of mass rapidly is iceberg calving. However, the processes and mechanisms that lead to iceberg calving are still poorly understood. Motivated by the complexity of the short-time scale behavior of ice fracture we seek a dynamic stability criterion that predicts the onset of ice shelf retreat based on dimensional analysis. In our approach, rather than attempt to model the initiation and propagation of individual fractures, we look for a non-dimensional number that describes the overall ice shelf stability. We also make the assumption that the same criterion, valid for ice shelves, also applies to tidewater glaciers. This enables us to test our criterion against a larger set of ice shelves and calving glaciers. Our analysis predicts that retreat will occur when a non-dimensional number that we call the "terminus stability number", decreases below a critical value. We show that this criterion is valid for calving glaciers in Alaska, for several glaciers around Greenland as well as for three Antarctic ice shelves. This stability analysis has much in common with classic hydrodynamic stability theory, where the onset of instability is related to non-dimensional numbers that are largely independent of geometry or other situation specific variables.

  2. Non-Linear Dynamics and Stability of Circular Cylindrical Shells Containing Flowing Fluid. Part i: Stability

    Science.gov (United States)

    AMABILI, M.; PELLICANO, F.; PAÏDOUSSIS, M. P.

    1999-08-01

    The study presented is an investigation of the non-linear dynamics and stability of simply supported, circular cylindrical shells containing inviscid incompressible fluid flow. Non-linearities due to large-amplitude shell motion are considered by using the non-linear Donnell's shallow shell theory, with account taken of the effect of viscous structural damping. Linear potential flow theory is applied to describe the fluid-structure interaction. The system is discretiszd by Galerkin's method, and is investigated by using a model involving seven degrees of freedom, allowing for travelling wave response of the shell and shell axisymmetric contraction. Two different boundary conditions are applied to the fluid flow beyond the shell, corresponding to: (i) infinite baffles (rigid extensions of the shell), and (ii) connection with a flexible wall of infinite extent in the longitudinal direction, permitting solution by separation of variables; they give two different kinds of dynamical behaviour of the system, as a consequence of the fact that axisymmetric contraction, responsible for the softening non-linear dynamical behaviour of shells, is not allowed if the fluid flow beyond the shell is constrained by rigid baffles. Results show that the system loses stability by divergence.

  3. Effects of the KIF2C neck peptide on microtubules: lateral disintegration of microtubules and β-structure formation.

    Science.gov (United States)

    Shimizu, Youské; Shimizu, Takashi; Nara, Masayuki; Kikumoto, Mahito; Kojima, Hiroaki; Morii, Hisayuki

    2013-04-01

    Members of the kinesin-13 sub-family, including KIF2C, depolymerize microtubules. The positive charge-rich 'neck' region extending from the N-terminus of the catalytic head is considered to be important in the depolymerization activity. Chemically synthesized peptides, covering the basic region (A182-E200), induced a sigmoidal increase in the turbidity of a microtubule suspension. The increase was suppressed by salt addition or by reduction of basicity by amino acid substitutions. Electron microscopic observations revealed ring structures surrounding the microtubules at high peptide concentrations. Using the peptide A182-D218, we also detected free thin straight filaments, probably protofilaments disintegrated from microtubules. Therefore, the neck region, even without the catalytic head domain, may induce lateral disintegration of microtubules. With microtubules lacking anion-rich C-termini as a result of subtilisin treatment, addition of the peptide induced only a moderate increase in turbidity, and rings and protofilaments were rarely detected, while aggregations, also thought to be caused by lateral disintegration, were often observed in electron micrographs. Thus, the C-termini are not crucial for the action of the peptides in lateral disintegration but contribute to structural stabilization of the protofilaments. Previous structural studies indicated that the neck region of KIF2C is flexible, but our IR analysis suggests that the cation-rich region (K190-A204) forms β-structure in the presence of microtubules, which may be of significance with regard to the action of the neck region. Therefore, the neck region of KIF2C is sufficient to cause disintegration of microtubules into protofilaments, and this may contribute to the ability of KIF2C to cause depolymerization of microtubules.

  4. Dynamic plate osteosynthesis for fracture stabilization: how to do it

    Directory of Open Access Journals (Sweden)

    Juerg Sonderegger

    2010-01-01

    Full Text Available Plate osteosynthesis is one treatment option for the stabilization of long bones. It is widely accepted to achieve bone healing with a dynamic and biological fixation where the perfusion of the bone is left intact and micromotion at the fracture gap is allowed. The indications for a dynamic plate osteosynthesis include distal tibial and femoral fractures, some midshaft fractures, and adolescent tibial and femoral fractures with not fully closed growth plates. Although many lower limb shaft fractures are managed successfully with intramedullary nails, there are some important advantages of open-reduction-and-plate fixation: the risk of malalignment, anterior knee pain, or nonunion seems to be lower. The surgeon performing a plate osteosynthesis has the possibility to influence fixation strength and micromotion at the fracture gap. Long plates and oblique screws at the plate ends increase fixation strength. However, the number of screws does influence stiffness and stability. Lag screws and screws close to the fracture site reduce micromotion dramatically. Dynamic plate osteosynthesis can be achieved by applying some simple rules: long plates with only a few screws should be used. Oblique screws at the plate ends increase the pullout strength. Two or three holes at the fracture site should be omitted. Lag screws, especially through the plate, must be avoided whenever possible. Compression is not required. Locking plates are recommended only in fractures close to the joint. When respecting these basic concepts, dynamic plate osteosynthesis is a safe procedure with a high healing and a low complication rate. 

  5. Dynamic simulation of universal spacer in Dynesys dynamic stabilization system for human vertebra

    Institute of Scientific and Technical Information of China (English)

    Sung-Min KIM; In-Chul YANG; Seung-Yeol LEE; Sung-Youn CHO

    2009-01-01

    The aim of this study is to analyze the simulated behavior of universal spacer in Dynesys dynamic stabilization system inserted in human vertebra. Dynesys, so-called "Dynamic neutralization system for the spine", dynamic stabilization system is a new concept in the surgical treatment of lower back pain recently. Universal spacer used as flexible material is to stabilize the spine and the material property of universal spacer is polycarbonate urethane. Universal spacer may apply different kinematic behaviors at implanted level in vertebra. Spinal range of motion(SROM) of inter-vertebra with installed Dynesys dynamic stabilization system was studied using Adams+LifeMOD as simulation software package. The vertebra model was set up to closely resemble the in-vivo conditions. Inter-vertebra rotations were measured by post processor of Adams and compared with the intact values. SROMs of the flexion, extension, lateral bending, and axial rotation of human virtual models were measured, where three spinal fixation systems such as rigid system, Dynesys system, and fused system were installed. As a result, the value of SROM is decreased in flexion-extension and lateral bending when the spinal fixation system is implanted. The movement of Dynesys system is similar to that of intact model by allowing the movement of lumbar. This means that the Dynesys system is proved to be safe and effective in the treatment of unstable spinal condition.

  6. Capture of microtubule plus-ends at the actin cortex promotes axophilic neuronal migration by enhancing microtubule tension in the leading process.

    Science.gov (United States)

    Hutchins, B Ian; Wray, Susan

    2014-01-01

    Microtubules are a critical part of neuronal polarity and leading process extension, thus microtubule movement plays an important role in neuronal migration. However, the dynamics of microtubules during the forward movement of the nucleus into the leading process (nucleokinesis) is unclear and may be dependent on the cell type and mode of migration used. In particular, little is known about cytoskeletal changes during axophilic migration, commonly used in anteroposterior neuronal migration. We recently showed that leading process actin flow in migrating GnRH neurons is controlled by a signaling cascade involving IP3 receptors, CaMKK, AMPK, and RhoA. In the present study, microtubule dynamics were examined in GnRH neurons. Failure of the migration of these cells leads to the neuroendocrine disorder Kallmann Syndrome. Microtubules translocated forward along the leading process shaft during migration, but reversed direction and moved toward the nucleus when migration stalled. Blocking calcium release through IP3 receptors halted migration and induced the same reversal of microtubule translocation, while blocking cortical actin flow prevented microtubules from translocating toward the distal leading process. Super-resolution imaging revealed that microtubule plus-end tips are captured at the actin cortex through calcium-dependent mechanisms. This work shows that cortical actin flow draws the microtubule network forward through calcium-dependent capture in order to promote nucleokinesis, revealing a novel mechanism engaged by migrating neurons to facilitate movement.

  7. Electricity Market Stochastic Dynamic Model and Its Mean Stability Analysis

    Directory of Open Access Journals (Sweden)

    Zhanhui Lu

    2014-01-01

    Full Text Available Based on the deterministic dynamic model of electricity market proposed by Alvarado, a stochastic electricity market model, considering the random nature of demand sides, is presented in this paper on the assumption that generator cost function and consumer utility function are quadratic functions. The stochastic electricity market model is a generalization of the deterministic dynamic model. Using the theory of stochastic differential equations, stochastic process theory, and eigenvalue techniques, the determining conditions of the mean stability for this electricity market model under small Gauss type random excitation are provided and testified theoretically. That is, if the demand elasticity of suppliers is nonnegative and the demand elasticity of consumers is negative, then the stochastic electricity market model is mean stable. It implies that the stability can be judged directly by initial data without any computation. Taking deterministic electricity market data combined with small Gauss type random excitation as numerical samples to interpret random phenomena from a statistical perspective, the results indicate the conclusions above are correct, valid, and practical.

  8. Skipping Posterior Dynamic Transpedicular Stabilization for Distant Segment Degenerative Disease

    Directory of Open Access Journals (Sweden)

    Bilgehan Solmaz

    2012-01-01

    Full Text Available Objective. To date, there is still no consensus on the treatment of spinal degenerative disease. Current surgical techniques to manage painful spinal disorders are imperfect. In this paper, we aimed to evaluate the prospective results of posterior transpedicular dynamic stabilization, a novel surgical approach that skips the segments that do not produce pain. This technique has been proven biomechanically and radiologically in spinal degenerative diseases. Methods. A prospective study of 18 patients averaging 54.94 years of age with distant spinal segment degenerative disease. Indications consisted of degenerative disc disease (57%, herniated nucleus pulposus (50%, spinal stenosis (14.28%, degenerative spondylolisthesis (14.28%, and foraminal stenosis (7.1%. The Oswestry Low-Back Pain Disability Questionnaire and visual analog scale (VAS for pain were recorded preoperatively and at the third and twelfth postoperative months. Results. Both the Oswestry and VAS scores showed significant improvement postoperatively (P<0.05. We observed complications in one patient who had spinal epidural hematoma. Conclusion. We recommend skipping posterior transpedicular dynamic stabilization for surgical treatment of distant segment spinal degenerative disease.

  9. Dynamic blade row compression component model for stability studies

    Science.gov (United States)

    Tesch, W. A.; Steenken, W. G.

    1976-01-01

    This paper describes a generalized dynamic model which has been developed for use in compression component aerodynamic stability studies. The model is a one-dimensional, pitch-line, blade row, lumped volume system. Arbitrary placement of blade free volumes upstream, within, and downstream of the compression component as well as the removal of bleed flow from the exit of any rotor or stator are model options. The model has been applied to a two-stage fan and an eight-stage compressor. The clean inlet pressure ratio/flow maps and the surge line have been reproduced, thereby validating the capability of the dynamic model to reproduce the steady-flow characteristics of the compression component. A method for determining the onset of an aerodynamic instability which is associated with surge is described. Sinusoidally time-varying inlet and exit boundary conditions have been applied to the eight stage compressor as examples of the manner in which this model may be used for stability studies.

  10. TPX2 phosphorylation maintains metaphase spindle length by regulating microtubule flux

    Science.gov (United States)

    Fu, Jingyan; Bian, Minglei; Xin, Guangwei; Deng, Zhaoxuan; Luo, Jia; Guo, Xiao; Chen, Hao; Wang, Yao; Jiang, Qing

    2015-01-01

    A steady-state metaphase spindle maintains constant length, although the microtubules undergo intensive dynamics. Tubulin dimers are incorporated at plus ends of spindle microtubules while they are removed from the minus ends, resulting in poleward movement. Such microtubule flux is regulated by the microtubule rescue factors CLASPs at kinetochores and depolymerizing protein Kif2a at the poles, along with other regulators of microtubule dynamics. How microtubule polymerization and depolymerization are coordinated remains unclear. Here we show that TPX2, a microtubule-bundling protein and activator of Aurora A, plays an important role. TPX2 was phosphorylated by Aurora A during mitosis. Its phospho-null mutant caused short metaphase spindles coupled with low microtubule flux rate. Interestingly, phosphorylation of TPX2 regulated its interaction with CLASP1 but not Kif2a. The effect of its mutant in shortening the spindle could be rescued by codepletion of CLASP1 and Kif2a that abolished microtubule flux. Together we propose that Aurora A–dependent TPX2 phosphorylation controls mitotic spindle length through regulating microtubule flux. PMID:26240182

  11. Study on modeling of vehicle dynamic stability and control technique

    Institute of Scientific and Technical Information of China (English)

    GAO Yun-ting; LI Pan-feng

    2012-01-01

    In order to solve the problem of enhancing the vehicle driving stability and safety,which has been the hot question researched by scientific and engineering in the vehicle industry,the new control method was investigated.After the analysis of tire moving characteristics and the vehicle stress analysis,the tire model based on the extension pacejka magic formula which combined longitudinal motion and lateral motion was developed and a nonlinear vehicle dynamical stability model with seven freedoms was made.A new model reference adaptive control project which made the slip angle and yaw rate of vehicle body as the output and feedback variable in adjusting the torque of vehicle body to control the vehicle stability was designed.A simulation model was also built in Matlab/Simulink to evaluate this control project.It was made up of many mathematical subsystem models mainly including the tire model module,the yaw moment calculation module,the center of mass parameter calculation module,tire parameter calculation module of multiple and so forth.The severe lane change simulation result shows that this vehicle model and the model reference adaptive control method have an excellent performance.

  12. Analysis of Soybean Microtubule Persistence Length; New Evidence on the Correlation between Structural Composition and Mechanical Properties

    Science.gov (United States)

    Shojania Feizabadi, Mitra; Winton, Carly; Barrientos, Jimmy

    2012-02-01

    Recent studies on microtubules composed of different β tubulin isotypes indicate their different functionality in terms of their dynamical behavior or the mechanism of their interaction with chemotherapeutic drugs. Along these lines, the result of our recent study measuring the rigidity of neural and non-neural samples of microtubules with different β tubulin isotype compositions suggests that the distinguished mechanical properties of microtubules, such as rigidity, may also be associated with the different distribution of their β tubulin isotypes. In our current study, we have reported the persistence length of a single soybean microtubule. This plant microtubule has a structural composition different from that of mammalian microtubules. Under the same experimental methods of measurement, the soybean microtubules showed a different persistence length as compared to the value of the persistence length that we estimated in the study of both single Bovine Brain and MCF7 microtubules.

  13. Steady-state EB cap size fluctuations are determined by stochastic microtubule growth and maturation.

    Science.gov (United States)

    Rickman, Jamie; Duellberg, Christian; Cade, Nicholas I; Griffin, Lewis D; Surrey, Thomas

    2017-03-28

    Growing microtubules are protected from depolymerization by the presence of a GTP or GDP/Pi cap. End-binding proteins of the EB1 family bind to the stabilizing cap, allowing monitoring of its size in real time. The cap size has been shown to correlate with instantaneous microtubule stability. Here we have quantitatively characterized the properties of cap size fluctuations during steady-state growth and have developed a theory predicting their timescale and amplitude from the kinetics of microtubule growth and cap maturation. In contrast to growth speed fluctuations, cap size fluctuations show a characteristic timescale, which is defined by the lifetime of the cap sites. Growth fluctuations affect the amplitude of cap size fluctuations; however, cap size does not affect growth speed, indicating that microtubules are far from instability during most of their time of growth. Our theory provides the basis for a quantitative understanding of microtubule stability fluctuations during steady-state growth.

  14. Research on Optimization, Dynamics and Stability of Stairclimbing Wheelchair

    Directory of Open Access Journals (Sweden)

    Shashank Shekhar Sahoo

    2016-03-01

    Full Text Available Since the invention of the wheel, man has always sought to reduce effort to get things done easily. Ultimately, it has resulted in the invention of the Robot, an Engineering Marvel. Up until now, the major factor that hampers widespread usage of robots is locomotion and maneuverability. They are not fit enough to conform even to the most commonplace terrain such as stairs. To overcome this, we are proposing a stair climbing wheelchair robot that looks a lot like a normal wheelchair but with additional stair-climbing functionality to adjust itself according to the height of the step The primarily goal of the prescribed manuscript herewith is to analyze the functional requirements, optimization methods, dynamics and stability during a tracked robotic wheelchair’s climbing of stairs mechanism. At first, the mechanical structure of the wheelchair is designed and the hardware composition of its full control system is devised. Secondly, based on the analysis of its stairs‐climbing process, the dynamical model of stairs‐climbing is established by using the classical mechanics method. Next, through simulation and experiments, the effectiveness of the dynamical model, its stability evaluation and performance parameters is verified. Such procedures will help in establishing a strong fundamental foundation steps to design and develop a standalone semi-autonomous wheelchair that will help and enable a physically challenged person by leg to climb difficult terrains like staircase and speed-breakers with ease and comfort. This design encompasses Renesas’s Arduino compatible GR-KAEDE boards, servo motors, high torque DC motors and various peripheral devices as incorporated in design diagram. We have also extended the application of wheelchair by integrating collision avoidance mechanism.

  15. Microtubule-associated proteins and tubulin interaction by isothermal titration calorimetry.

    Science.gov (United States)

    Tsvetkov, P O; Barbier, P; Breuzard, G; Peyrot, V; Devred, F

    2013-01-01

    Microtubules play an important role in a number of vital cell processes such as cell division, intracellular transport, and cell architecture. The highly dynamic structure of microtubules is tightly regulated by a number of stabilizing and destabilizing microtubule-associated proteins (MAPs), such as tau and stathmin. Because of their importance, tubulin-MAPs interactions have been extensively studied using various methods that provide researchers with complementary but sometimes contradictory thermodynamic data. Isothermal titration calorimetry (ITC) is the only direct thermodynamic method that enables a full thermodynamic characterization (stoichiometry, enthalpy, entropy of binding, and association constant) of the interaction after a single titration experiment. This method has been recently applied to study tubulin-MAPs interactions in order to bring new insights into molecular mechanisms of tubulin regulation. In this chapter, we review the technical specificity of this method and then focus on the use of ITC in the investigation of tubulin-MAPs binding. We describe technical issues which could arise during planning and carrying out the ITC experiments, in particular with fragile proteins such as tubulin. Using examples of stathmin and tau, we demonstrate how ITC can be used to gain major insights into tubulin-MAP interaction. Copyright © 2013 Elsevier Inc. All rights reserved.

  16. Kinesin-5-independent mitotic spindle assembly requires the antiparallel microtubule crosslinker Ase1 in fission yeast

    Science.gov (United States)

    Rincon, Sergio A.; Lamson, Adam; Blackwell, Robert; Syrovatkina, Viktoriya; Fraisier, Vincent; Paoletti, Anne; Betterton, Meredith D.; Tran, Phong T.

    2017-05-01

    Bipolar spindle assembly requires a balance of forces where kinesin-5 produces outward pushing forces to antagonize the inward pulling forces from kinesin-14 or dynein. Accordingly, Kinesin-5 inactivation results in force imbalance leading to monopolar spindle and chromosome segregation failure. In fission yeast, force balance is restored when both kinesin-5 Cut7 and kinesin-14 Pkl1 are deleted, restoring spindle bipolarity. Here we show that the cut7Δpkl1Δ spindle is fully competent for chromosome segregation independently of motor activity, except for kinesin-6 Klp9, which is required for anaphase spindle elongation. We demonstrate that cut7Δpkl1Δ spindle bipolarity requires the microtubule antiparallel bundler PRC1/Ase1 to recruit CLASP/Cls1 to stabilize microtubules. Brownian dynamics-kinetic Monte Carlo simulations show that Ase1 and Cls1 activity are sufficient for initial bipolar spindle formation. We conclude that pushing forces generated by microtubule polymerization are sufficient to promote spindle pole separation and the assembly of bipolar spindle in the absence of molecular motors.

  17. The non-catalytic domains of Drosophila katanin regulate its abundance and microtubule-disassembly activity.

    Directory of Open Access Journals (Sweden)

    Kyle D Grode

    Full Text Available Microtubule severing is a biochemical reaction that generates an internal break in a microtubule and regulation of microtubule severing is critical for cellular processes such as ciliogenesis, morphogenesis, and meiosis and mitosis. Katanin is a conserved heterodimeric ATPase that severs and disassembles microtubules, but the molecular determinants for regulation of microtubule severing by katanin remain poorly defined. Here we show that the non-catalytic domains of Drosophila katanin regulate its abundance and activity in living cells. Our data indicate that the microtubule-interacting and trafficking (MIT domain and adjacent linker region of the Drosophila katanin catalytic subunit Kat60 cooperate to regulate microtubule severing in two distinct ways. First, the MIT domain and linker region of Kat60 decrease its abundance by enhancing its proteasome-dependent degradation. The Drosophila katanin regulatory subunit Kat80, which is required to stabilize Kat60 in cells, conversely reduces the proteasome-dependent degradation of Kat60. Second, the MIT domain and linker region of Kat60 augment its microtubule-disassembly activity by enhancing its association with microtubules. On the basis of our data, we propose that the non-catalytic domains of Drosophila katanin serve as the principal sites of integration of regulatory inputs, thereby controlling its ability to sever and disassemble microtubules.

  18. Dynamic stability of sequential stimulus representations in adapting neuronal networks

    Directory of Open Access Journals (Sweden)

    Renato Carlos Farinha Duarte

    2014-10-01

    Full Text Available The ability to acquire and maintain appropriate representations of time-varying, sequentialstimulus events is a fundamental feature of neocortical circuits and a necessary first step towardsmore specialized information processing. The dynamical properties of such representationsdepend on the current state of the circuit, which is determined primarily by the ongoing, internallygenerated activity, setting the ground state from which input-specific transformations emerge.Here, we begin by demonstrating that timing-dependent synaptic plasticity mechanisms havean important role to play in the active maintenance of an ongoing dynamics characterized byasynchronous and irregular firing, closely resembling cortical activity in vivo. Incoming stimuli,acting as perturbations of the local balance of excitation and inhibition, require fast adaptiveresponses to prevent the development of unstable activity regimes, such as those characterizedby a high degree of population-wide synchrony. We establish a link between such pathologicalnetwork activity, which is circumvented by the action of plasticity, and a reduced computationalcapacity. Additionally, we demonstrate that the action of plasticity shapes and stabilizes thetransient network states exhibited in the presence of sequentially presented stimulus events,allowing the development of adequate and discernible stimulus representations. The mainfeature responsible for the increased discriminability of stimulus-driven population responsesin plastic networks is shown to be the decorrelating action of inhibitory plasticity and theconsequent maintenance of the asynchronous irregular dynamic regime both for ongoing activityand stimulus-driven responses, whereas excitatory plasticity is shown to play only a marginalrole.

  19. Dynamic Stabilization of Metal Oxide–Water Interfaces

    Energy Technology Data Exchange (ETDEWEB)

    McBriarty, Martin E. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States). Physical Sciences Division; von Rudorff, Guido Falk [Univ. College London (United Kingdom). Dept. of Physics and Astronomy; Stubbs, Joanne E. [Univ. of Chicago, IL (United States). Center for Advanced Radiation Sources (CARS); Eng, Peter J. [Univ. of Chicago, IL (United States). Center for Advanced Radiation Sources (CARS); Blumberger, Jochen [Univ. College London (United Kingdom). Dept. of Physics and Astronomy; Rosso, Kevin M. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States). Physical Sciences Division

    2017-02-08

    Metal oxide growth, dissolution, and redox reactivity depend on the structure and dynamics at the interface with aqueous solution. We present the most definitive analysis to date of the hydrated naturally abundant r-cut (11$\\bar{0}$2) termination of the iron oxide hematite (α-Fe2O3). In situ synchrotron X-ray scattering analysis reveals a ridged lateral arrangement of adsorbed water molecules hydrogen bonded to terminal aquo groups. Large-scale hybrid-functional density functional theory-based molecular dynamics (DFT-MD) simulations show how this structure is dynamically stabilized by picosecond exchange between aquo groups and adsorbed water, even under nominally dry conditions. Surface pKa prediction based on bond valence analysis suggests that water exchange may influence the proton transfer reactions associated with acid/base reactivity at the interface. Our findings rectify inconsistencies between existing models and may be extended to resolving more complex electrochemical phenomena at metal oxide-water interfaces.

  20. Mechanical modulation of cardiac microtubules.

    Science.gov (United States)

    White, Ed

    2011-07-01

    Microtubules are a major component of the cardiac myocyte cytoskeleton. Interventions that alter it may influence cardiac mechanical and electrical activity by disrupting the trafficking of proteins to and from the surface membrane by molecular motors such as dynein, which use microtubules as tracks to step along. Free tubulin dimers may transfer GTP to the α-subunits of G-proteins, thus an increase in free tubulin could increase the activity of G-proteins; evidence for and against such a role exists. There is more general agreement that microtubules act as compression-resisting structures within myocytes, influencing visco-elasticity of myocytes and increasing resistance to shortening when proliferated and resisting deformation from longitudinal shear stress. In response to pressure overload, there can be post-translational modifications resulting in more stable microtubules and an increase in microtubule density. This is accompanied by contractile dysfunction of myocytes which can be reversed by microtubule disruption. There are reports of mechanically induced changes in electrical activity that are dependent upon microtubules, but at present, a consensus is lacking on whether disruption or proliferation would be beneficial in the prevention of arrhythmias. Microtubules certainly play a role in the response of cardiac myocytes to mechanical stimulation, the exact nature and significance of this role is still to be fully determined.

  1. Stability of power systems coupled with market dynamics

    Science.gov (United States)

    Meng, Jianping

    This Ph.D. thesis presented here spans two relatively independent topics. The first part, Chapter 2 is self-contained, and is dedicated to studies of new algorithms for power system state estimation. The second part, encompassing the remaining chapters, is dedicated to stability analysis of power system coupled with market dynamics. The first part of this thesis presents improved Newton's methods employing efficient vectorized calculations of higher order derivatives in power system state estimation problems. The improved algorithms are proposed based on an exact Newton's method using the second order terms. By efficiently computing an exact gain matrix, combined with a special optimal multiplier method, the new algorithms show more reliable convergence compared with the existing methods of normal equations, orthogonal decomposition, and Hachtel's sparse tableau. Our methods are able to handle ill-conditioned problems, yet show minimal penalty in computational cost for well-conditioned cases. These claims are illustrated through the standard IEEE 118 and 300 bus test examples. The second part of the thesis focuses on stability analysis of market/power systems. The work presented is motivated by an emerging problem. As the frequency of market based dispatch updates increases, there will inevitably be interaction between the dynamics of markets determining the generator dispatch commands, and the physical response of generators and network interconnections, necessitating the development of stability analysis for such coupled systems. We begin with numeric tests using different market models, with detailed machine/exciter/turbine/governor dynamics, in the New England 39 bus test system. A progression of modeling refinements are introduced, including such non-ideal effects as time delays. Electricity market parameter identification algorithms are also studied based on real time data from the PJM electricity market. Finally our power market model is augmented by optimal

  2. In vivo and in vitro effects of the mitochondrial uncoupler FCCP on microtubules.

    Science.gov (United States)

    Maro, B; Marty, M C; Bornens, M

    1982-01-01

    FCCP (carbonylcyanide-p-trifluoromethoxyphenylhydrazone), a potent uncoupler of oxidative phosphorylation, induces the complete disruption of cellular microtubules. A further analysis of this effect on BHK21 cells has shown that a decrease in the number of microtubules can be observed 15 min after adding FCCP and there is complete disruption after 60 min. Regrowth of microtubules was initiated 30 min after removal of FCCP, in marked contrast with the rapid reversion observed when microtubules are disrupted by nocodazole. A similar delay was required for the recovery of mitochondrial function as assessed by rhodamine 123 labelling. The effect of FCCP on microtubules was partially inhibited by preincubation of the cells with NaN3, suggesting that FCCP acts on microtubules through mitochondria. FCCP did not depolymerize microtubules of cells permeabilized with Triton X-100. In vitro polymerisation of microtubule protein was only slightly diminished by concentrations of FCCP which provoke complete disassembly in vivo. SDS-polyacrylamide gel electrophoresis (SDS-PAGE) analysis of the microtubules polymerized in vitro in the presence of FCCP showed a reduced amount of high mol. wt. proteins, mainly MAP 2, associated with them. In an attempt to reproduce the mitochondrial effects of FCCP in vitro, we checked the effects of alkaline pH and calcium on microtubule protein polymerization in the presence of FCCP. FCCP did not influence the calcium inhibitory effect but did significantly increase the inhibitory effect of alkaline pH. We conclude that FCCP could depolymerise microtubules in vivo through a dual operation: increasing the intracellular pH by the disruption of the mitochondrial H+ gradient and decreasing the stability of microtubules by impairing the binding of microtubule-associated proteins.

  3. Dynamical stability of a many-body Kapitza pendulum

    Energy Technology Data Exchange (ETDEWEB)

    Citro, Roberta, E-mail: citro@sa.infn.it [Dipartimento di Fisica “E. R. Caianiello” and Spin-CNR, Universita’ degli Studi di Salerno, Via Giovanni Paolo II, I-84084 Fisciano (Italy); Dalla Torre, Emanuele G., E-mail: emanuele.dalla-torre@biu.ac.il [Department of Physics, Bar Ilan University, Ramat Gan 5290002 (Israel); Department of Physics, Harvard University, Cambridge, MA 02138 (United States); D’Alessio, Luca [Department of Physics, The Pennsylvania State University, University Park, PA 16802 (United States); Department of Physics, Boston University, Boston, MA 02215 (United States); Polkovnikov, Anatoli [Department of Physics, Boston University, Boston, MA 02215 (United States); Babadi, Mehrtash [Department of Physics, Harvard University, Cambridge, MA 02138 (United States); Institute for Quantum Information and Matter, California Institute of Technology, Pasadena, CA 91125 (United States); Oka, Takashi [Department of Applied Physics, University of Tokyo, Tokyo, 113-8656 (Japan); Demler, Eugene [Department of Physics, Harvard University, Cambridge, MA 02138 (United States)

    2015-09-15

    We consider a many-body generalization of the Kapitza pendulum: the periodically-driven sine–Gordon model. We show that this interacting system is dynamically stable to periodic drives with finite frequency and amplitude. This finding is in contrast to the common belief that periodically-driven unbounded interacting systems should always tend to an absorbing infinite-temperature state. The transition to an unstable absorbing state is described by a change in the sign of the kinetic term in the Floquet Hamiltonian and controlled by the short-wavelength degrees of freedom. We investigate the stability phase diagram through an analytic high-frequency expansion, a self-consistent variational approach, and a numeric semiclassical calculation. Classical and quantum experiments are proposed to verify the validity of our results.

  4. U32: Vehicle Stability and Dynamics: Longer Combination Vehicles

    Energy Technology Data Exchange (ETDEWEB)

    Petrolino, Joseph [National Transportation Research Center (NTRC); Spezia, Tony [National Transportation Research Center (NTRC); Arant, Michael [Clemson University; Broshears, Eric [Auburn University, Auburn, Alabama; Chitwood, Caleb [Battelle; Colbert, Jameson [Auburn University, Auburn, Alabama; Hathaway, Richard [Western Michigan University; Keil, Mitch [Western Michigan University; LaClair, Tim J [ORNL; Pape, Doug [Battelle; Patterson, Jim [Hendrickson; Pittro, Collin [Battelle

    2011-01-01

    This study investigated the safety and stability of longer combination vehicles (LCVs), in particular a triple trailer combination behind a commercial tractor, which has more complicated dynamics than the more common tractor in combination with a single semitrailer. The goal was to measure and model the behavior of LCVs in simple maneuvers. Example maneuvers tested and modeled were single and double lane changes, a gradual lane change, and a constant radius curve. In addition to test track data collection and a brief highway test, two computer models of LCVs were developed. One model is based on TruckSim , a lumped parameter model widely used for single semitrailer combinations. The other model was built in Adams software, which more explicitly models the geometry of the components of the vehicle, in terms of compliant structural members. Among other results, the models were able to duplicate the experimentally measured rearward amplification behavior that is characteristic of multi-unit combination vehicles.

  5. Controllability, observability, realizability, and stability of dynamic linear systems

    Directory of Open Access Journals (Sweden)

    John M. Davis

    2009-03-01

    Full Text Available We develop a linear systems theory that coincides with the existing theories for continuous and discrete dynamical systems, but that also extends to linear systems defined on nonuniform time scales. The approach here is based on generalized Laplace transform methods (e.g. shifts and convolution from the recent work [13]. We study controllability in terms of the controllability Gramian and various rank conditions (including Kalman's in both the time invariant and time varying settings and compare the results. We explore observability in terms of both Gramian and rank conditions and establish related realizability results. We conclude by applying this systems theory to connect exponential and BIBO stability problems in this general setting. Numerous examples are included to show the utility of these results.

  6. Controllability, Observability, Reachability, and Stability of Dynamic Linear Systems

    CERN Document Server

    Jackson, Billy J; Gravagne, Ian A; Marks, Robert J

    2009-01-01

    We develop a linear systems theory that coincides with the existing theories for continuous and discrete dynamical systems, but that also extends to linear systems defined on nonuniform time domains. The approach here is based on generalized Laplace transform methods (e.g. shifts and convolution) from our recent work \\cite{DaGrJaMaRa}. We study controllability in terms of the controllability Gramian and various rank conditions (including Kalman's) in both the time invariant and time varying settings and compare the results. We also explore observability in terms of both Gramian and rank conditions as well as realizability results. We conclude by applying this systems theory to connect exponential and BIBO stability problems in this general setting. Numerous examples are included to show the utility of these results.

  7. Carotenoid incorporation into microsomes: yields, stability and membrane dynamics

    Science.gov (United States)

    Socaciu, Carmen; Jessel, Robert; Diehl, Horst A.

    2000-12-01

    The carotenoids β-carotene (BC), lycopene (LYC), lutein (LUT), zeaxanthin (ZEA), canthaxanthin (CTX) and astaxanthin (ASTA) have been incorporated into pig liver microsomes. Effective incorporation concentrations in the range of about 1-6 nmol/mg microsomal protein were obtained. A stability test at room temperature revealed that after 3 h BC and LYC had decayed totally whereas, gradually, CTX (46%), LUT (21%), ASTA (17%) and ZEA (5%) decayed. Biophysical parameters of the microsomal membrane were changed hardly by the incorporation of carotenoids. A small rigidification may occur. Membrane anisotropy seems to offer only a small tolerance for incorporation of carotenoids and seems to limit the achievable incorporation concentrations of the carotenoids into microsomes. Microsomes instead of liposomes should be preferred as a membrane model to study mutual effects of carotenoids and membrane dynamics.

  8. Dynamic Stability Analysis Using High-Order Interpolation

    Directory of Open Access Journals (Sweden)

    Juarez-Toledo C.

    2012-10-01

    Full Text Available A non-linear model with robust precision for transient stability analysis in multimachine power systems is proposed. The proposed formulation uses the interpolation of Lagrange and Newton's Divided Difference. The High-Order Interpolation technique developed can be used for evaluation of the critical conditions of the dynamic system.The technique is applied to a 5-area 45-machine model of the Mexican interconnected system. As a particular case, this paper shows the application of the High-Order procedure for identifying the slow-frequency mode for a critical contingency. Numerical examples illustrate the method and demonstrate the ability of the High-Order technique to isolate and extract temporal modal behavior.

  9. Molecular dynamics simulation of thermal stability of nanocrystalline vanadium

    Institute of Scientific and Technical Information of China (English)

    WEI; Mingzhi; XIAO; Shifang; YUAN; Xiaojian; HU; Wangyu

    2006-01-01

    The microstructure and thermal stability of nanocrystalline vanadium with an average grain size ranging from 2.86 to 7.50 nm are calculated by means of the analytic embedded-atom method and molecular dynamics. The grain boundary and nanocrystalline grain atoms are differentiated by the common neighbor analysis method. The results indicate that the fraction of grain boundary increases with the grain size decreasing, and the mean energy of atoms is higher than that of coarse crystals. The thermal-stable temperatures of nanocrystalline vanadium are determined from the evolution of atomic energy, fraction of grain boundary and radial distribution function. It is shown that the stable temperature decreases obviously with the grain size decreasing. In addition the reasons which cause the grain growth of nanocrystalline vanadium are discussed.

  10. Stability properties of elementary dynamic models of membrane transport.

    Science.gov (United States)

    Hernández, Julio A

    2003-01-01

    Living cells are characterized by their capacity to maintain a stable steady state. For instance, cells are able to conserve their volume, internal ionic composition and electrical potential difference across the plasma membrane within values compatible with the overall cell functions. The dynamics of these cellular variables is described by complex integrated models of membrane transport. Some clues for the understanding of the processes involved in global cellular homeostasis may be obtained by the study of the local stability properties of some partial cellular processes. As an example of this approach, I perform, in this study, the neighborhood stability analysis of some elementary integrated models of membrane transport. In essence, the models describe the rate of change of the intracellular concentration of a ligand subject to active and passive transport across the plasma membrane of an ideal cell. The ligand can be ionic or nonionic, and it can affect the cell volume or the plasma membrane potential. The fundamental finding of this study is that, within the physiological range, the steady states are asymptotically stable. This basic property is a necessary consequence of the general forms of the expressions employed to describe the active and passive fluxes of the transported ligand.

  11. Dynamic-Stability Characteristics of Premixed Methane Oxy-Combustion

    KAUST Repository

    Shroll, Andrew P.

    2012-01-01

    This work explores the dynamic stability characteristics of premixed CH 4/O 2/CO 2 mixtures in a 50 kW swirl stabilized combustor. In all cases, the methane-oxygen mixture is stoichiometric, with different dilution levels of carbon dioxide used to control the flame temperature (T ad). For the highest T ad\\'s, the combustor is unstable at the first harmonic of the combustor\\'s natural frequency. As the temperature is reduced, the combustor jumps to fundamental mode and then to a low-frequency mode whose value is well below the combustor\\'s natural frequency, before eventually reaching blowoff. Similar to the case of CH 4/air mixtures, the transition from one mode to another is predominantly a function of the T ad of the reactive mixture, despite significant differences in laminar burning velocity and/or strained flame consumption speed between air and oxy-fuel mixtures for a given T ad. High speed images support this finding by revealing similar vortex breakdown modes and thus similar turbulent flame geometries that change as a function of flame temperature. Copyright © 2012 American Society of Mechanical Engineers.

  12. Push-me-pull-you: how microtubules organize the cell interior.

    Science.gov (United States)

    Tolić-Nørrelykke, Iva M

    2008-09-01

    Dynamic organization of the cell interior, which is crucial for cell function, largely depends on the microtubule cytoskeleton. Microtubules move and position organelles by pushing, pulling, or sliding. Pushing forces can be generated by microtubule polymerization, whereas pulling typically involves microtubule depolymerization or molecular motors, or both. Sliding between a microtubule and another microtubule, an organelle, or the cell cortex is also powered by molecular motors. Although numerous examples of microtubule-based pushing and pulling in living cells have been observed, it is not clear why different cell types and processes employ different mechanisms. This review introduces a classification of microtubule-based positioning strategies and discusses the efficacy of pushing and pulling. The positioning mechanisms based on microtubule pushing are efficient for movements over small distances, and for centering of organelles in symmetric geometries. Mechanisms based on pulling, on the other hand, are typically more elaborate, but are necessary when the distances to be covered by the organelles are large, and when the geometry is asymmetric and complex. Thus, taking into account cell geometry and the length scale of the movements helps to identify general principles of the intracellular layout based on microtubule forces.

  13. Push-me-pull-you: how microtubules organize the cell interior

    Science.gov (United States)

    2008-01-01

    Dynamic organization of the cell interior, which is crucial for cell function, largely depends on the microtubule cytoskeleton. Microtubules move and position organelles by pushing, pulling, or sliding. Pushing forces can be generated by microtubule polymerization, whereas pulling typically involves microtubule depolymerization or molecular motors, or both. Sliding between a microtubule and another microtubule, an organelle, or the cell cortex is also powered by molecular motors. Although numerous examples of microtubule-based pushing and pulling in living cells have been observed, it is not clear why different cell types and processes employ different mechanisms. This review introduces a classification of microtubule-based positioning strategies and discusses the efficacy of pushing and pulling. The positioning mechanisms based on microtubule pushing are efficient for movements over small distances, and for centering of organelles in symmetric geometries. Mechanisms based on pulling, on the other hand, are typically more elaborate, but are necessary when the distances to be covered by the organelles are large, and when the geometry is asymmetric and complex. Thus, taking into account cell geometry and the length scale of the movements helps to identify general principles of the intracellular layout based on microtubule forces. PMID:18404264

  14. Applications of Computational Methods for Dynamic Stability and Control Derivatives

    Science.gov (United States)

    Green, Lawrence L.; Spence, Angela M.

    2004-01-01

    Initial steps in the application o f a low-order panel method computational fluid dynamic (CFD) code to the calculation of aircraft dynamic stability and control (S&C) derivatives are documented. Several capabilities, unique to CFD but not unique to this particular demonstration, are identified and demonstrated in this paper. These unique capabilities complement conventional S&C techniques and they include the ability to: 1) perform maneuvers without the flow-kinematic restrictions and support interference commonly associated with experimental S&C facilities, 2) easily simulate advanced S&C testing techniques, 3) compute exact S&C derivatives with uncertainty propagation bounds, and 4) alter the flow physics associated with a particular testing technique from those observed in a wind or water tunnel test in order to isolate effects. Also presented are discussions about some computational issues associated with the simulation of S&C tests and selected results from numerous surface grid resolution studies performed during the course of the study.

  15. Dynamic Stabilization of Metal Oxide–Water Interfaces

    Energy Technology Data Exchange (ETDEWEB)

    McBriarty, Martin E.; von Rudorff, Guido Falk; Stubbs, Joanne E.; Eng, Peter J.; Blumberger, Jochen; Rosso, Kevin M.

    2017-02-08

    The interaction of water with metal oxide surfaces plays a crucial role in the catalytic and geochemical behavior of metal oxides. In a vast majority of studies, the interfacial structure is assumed to arise from a relatively static lowest energy configuration of atoms, even at room temperature. Using hematite (α-Fe2O3) as a model oxide, we show through a direct comparison of in situ synchrotron X-ray scattering with density functional theory-based molecular dynamics simulations that the structure of the (1102) termination is dynamically stabilized by picosecond water exchange. Simulations show frequent exchanges between terminal aquo groups and adsorbed water in locations and with partial residence times consistent with experimentally determined atomic sites and fractional occupancies. Frequent water exchange occurs even for an ultrathin adsorbed water film persisting on the surface under a dry atmosphere. The resulting time-averaged interfacial structure consists of a ridged lateral arrangement of adsorbed water molecules hydrogen bonded to terminal aquo groups. Surface pKa prediction based on bond valence analysis suggests that water exchange will influence the proton-transfer reactions underlying the acid/base reactivity at the interface. Our findings provide important new insights for understanding complex interfacial chemical processes at metal oxide–water interfaces.

  16. Dynamics of microresonator frequency comb generation: models and stability

    Directory of Open Access Journals (Sweden)

    Hansson Tobias

    2016-06-01

    Full Text Available Microresonator frequency combs hold promise for enabling a new class of light sources that are simultaneously both broadband and coherent, and that could allow for a profusion of potential applications. In this article, we review various theoretical models for describing the temporal dynamics and formation of optical frequency combs. These models form the basis for performing numerical simulations that can be used in order to better understand the comb generation process, for example helping to identify the universal combcharacteristics and their different associated physical phenomena. Moreover, models allow for the study, design and optimization of comb properties prior to the fabrication of actual devices. We consider and derive theoretical formalisms based on the Ikeda map, the modal expansion approach, and the Lugiato-Lefever equation. We further discuss the generation of frequency combs in silicon resonators featuring multiphoton absorption and free-carrier effects. Additionally, we review comb stability properties and consider the role of modulational instability as well as of parametric instabilities due to the boundary conditions of the cavity. These instability mechanisms are the basis for comprehending the process of frequency comb formation, for identifying the different dynamical regimes and the associated dependence on the comb parameters. Finally, we also discuss the phenomena of continuous wave bi- and multistability and its relation to the observation of mode-locked cavity solitons.

  17. Dynamics of microresonator frequency comb generation: models and stability

    Science.gov (United States)

    Hansson, Tobias; Wabnitz, Stefan

    2016-06-01

    Microresonator frequency combs hold promise for enabling a new class of light sources that are simultaneously both broadband and coherent, and that could allow for a profusion of potential applications. In this article, we review various theoretical models for describing the temporal dynamics and formation of optical frequency combs. These models form the basis for performing numerical simulations that can be used in order to better understand the comb generation process, for example helping to identify the universal combcharacteristics and their different associated physical phenomena. Moreover, models allow for the study, design and optimization of comb properties prior to the fabrication of actual devices. We consider and derive theoretical formalisms based on the Ikeda map, the modal expansion approach, and the Lugiato-Lefever equation. We further discuss the generation of frequency combs in silicon resonators featuring multiphoton absorption and free-carrier effects. Additionally, we review comb stability properties and consider the role of modulational instability as well as of parametric instabilities due to the boundary conditions of the cavity. These instability mechanisms are the basis for comprehending the process of frequency comb formation, for identifying the different dynamical regimes and the associated dependence on the comb parameters. Finally, we also discuss the phenomena of continuous wave bi- and multistability and its relation to the observation of mode-locked cavity solitons.

  18. Xenopus oocyte wound healing as a model system for analysis of microtubule-actin interactions.

    Science.gov (United States)

    Zhang, Tong; Mandato, Craig A

    2007-01-01

    Microtubule-actin interactions are fundamental to many cellular processes such as cytokinesis and cellular locomotion. Investigating the mechanism of microtubule-actin interactions is the key to understand the cellular morphogenesis and related pathological processes. The abundance and highly dynamic nature of microtubules and F-actin raise a serious challenge when trying to distinguish between the real and fortuitous interactions within a cell. Xenopus oocyte wound model represents an ideal system to study microtubule-actin interactions as well as microtubule-dependent control of the actin polymerization. Here, we describe a series of cytoskeleton specific treatments in Xenopus oocyte wound healing experiments and use confocal fluorescence microscopy to analyze fixed oocytes to examine microtubule-actin interactions.

  19. Direct Cytoplasmic Delivery and Nuclear Targeting Delivery of HPMA-MT Conjugates in a Microtubules Dependent Fashion.

    Science.gov (United States)

    Zhong, Jiaju; Zhu, Xi; Luo, Kui; Li, Lian; Tang, Manlin; Liu, Yanxi; Zhou, Zhou; Huang, Yuan

    2016-09-06

    As the hearts of tumor cells, the nucleus is the ultimate target of many chemotherapeutic agents and genes. However, nuclear drug delivery is always hampered by multiple intracellular obstacles, such as low efficiency of lysosome escape and insufficient nuclear trafficking. Herein, an N-(2-hydroxypropyl) methacrylamide (HPMA) polymer-based drug delivery system was designed, which could achieve direct cytoplasmic delivery by a nonendocytic pathway and transport into the nucleus in a microtubules dependent fashion. A special targeting peptide (MT), derived from an endogenic parathyroid hormone-related protein, was conjugated to the polymer backbone, which could accumulate into the nucleus a by microtubule-mediated pathway. The in vitro studies found that low temperature and NaN3 could not influence the cell internalization of the conjugates. Besides, no obvious overlay of the conjugates with lysosome demonstrated that the polymer conjugates could enter the tumor cell cytoplasm by a nonendocytic pathway, thus avoiding the drug degradation in the lysosome. Furthermore, after suppression of the microtubule dynamics with microtubule stabilizing docetaxel (DTX) and destabilizing nocodazole (Noc), the nuclear accumulation of polymeric conjugates was significantly inhibited. Living cells fluorescence recovery after photobleaching study found that the nuclear import rate of conjugates was 2-fold faster compared with the DTX and Noc treated groups. These results demonstrated that the conjugates transported into the nucleus in a microtubules dependent way. Therefore, in addition to direct cytoplasmic delivery, our peptide conjugated polymeric platform could simultaneously mediate nuclear drug accumulation, which may open a new path for further intracellular genes/peptides delivery.

  20. Polyamine sharing between tubulin dimers favours microtubule nucleation and elongation via facilitated diffusion.

    Directory of Open Access Journals (Sweden)

    Alain Mechulam

    2009-01-01

    Full Text Available We suggest for the first time that the action of multivalent cations on microtubule dynamics can result from facilitated diffusion of GTP-tubulin to the microtubule ends. Facilitated diffusion can promote microtubule assembly, because, upon encountering a growing nucleus or the microtubule wall, random GTP-tubulin sliding on their surfaces will increase the probability of association to the target sites (nucleation sites or MT ends. This is an original explanation for understanding the apparent discrepancy between the high rate of microtubule elongation and the low rate of tubulin association at the microtubule ends in the viscous cytoplasm. The mechanism of facilitated diffusion requires an attraction force between two tubulins, which can result from the sharing of multivalent counterions. Natural polyamines (putrescine, spermidine, and spermine are present in all living cells and are potent agents to trigger tubulin self-attraction. By using an analytical model, we analyze the implication of facilitated diffusion mediated by polyamines on nucleation and elongation of microtubules. In vitro experiments using pure tubulin indicate that the promotion of microtubule assembly by polyamines is typical of facilitated diffusion. The results presented here show that polyamines can be of particular importance for the regulation of the microtubule network in vivo and provide the basis for further investigations into the effects of facilitated diffusion on cytoskeleton dynamics.

  1. Exercise of mechanisms of dynamic stability improves the stability state after an unexpected gait perturbation in elderly.

    Science.gov (United States)

    Bierbaum, Stefanie; Peper, Andreas; Arampatzis, Adamantios

    2013-10-01

    Unexpected changes during gait challenge elderly individuals to a greater degree than young adults. However, the adaptive potential of elderly seems to be retained, and therefore, the training of the mechanisms of dynamic stability as well as muscle strength training may improve the dynamic stability after unexpected perturbations. Thirty-eight subjects (65-75 years) participated in the study, divided into two experimental groups (stability training group, ST, n = 14 and mixed training group, MT, n = 14) and a control group (CG, n = 10). Both experimental groups performed exercises which focused on the mechanisms of dynamic stability. Additionally, the MT group executed a training to improve muscle strength. Session volume and duration were equal for both groups (14 weeks, twice a week, ~1.5 h per session). Pre- and post-intervention, subjects performed a gait protocol with an induced unexpected perturbation. Post-intervention, the margin of stability was significantly increased after the unexpected perturbation in the ST group, indicating an improvement in stability state (pre, -30.3 ± 5.9 cm; post, -24.1 ± 5.2 cm). Further, both intervention groups increased their base of support after the intervention to regain balance after gait perturbation, whereas only the ST group showed a statistically significant improvement (STpre, 90.9 ± 6.6 cm, STpost, 98.2 ± 8.5 cm; MTpre, 91.4 ± 6.2 cm; MTpost, 97.9 ± 12.7 cm). The CG showed no differences between pre- and post-measurements. The exercise of the mechanisms of dynamic stability led to a better application of these mechanisms after an unexpected perturbation during gait. We suggest that the repeated exercise of the mechanisms of dynamic stability contributes to significant improvements in postural stability. Additional strength training for healthy elderly individuals, however, shows no further effect on the ability to recover balance after unexpected perturbations during gait.

  2. Termination of Protofilament Elongation by Eribulin Induces Lattice Defects that Promote Microtubule Catastrophes

    NARCIS (Netherlands)

    Doodhi, Harinath; Prota, Andrea E; Rodríguez-García, Ruddi; Xiao, Hui; Custar, Daniel W; Bargsten, Katja; Katrukha, Eugene A; Hilbert, Manuel; Hua, Shasha; Jiang, Kai; Grigoriev, Ilya; Yang, Chia-Ping H; Cox, David; Horwitz, Susan Band; Kapitein, Lukas C; Akhmanova, Anna; Steinmetz, Michel O

    2016-01-01

    Microtubules are dynamic polymers built of tubulin dimers that attach in a head-to-tail fashion to form protofilaments, which further associate laterally to form a tube. Asynchronous elongation of individual protofilaments can potentially lead to an altered microtubule-end structure that promotes su

  3. Myomegalin is necessary for the formation of centrosomal and Golgi-derived microtubules

    Directory of Open Access Journals (Sweden)

    Régine Roubin

    2012-12-01

    The generation of cellular microtubules is initiated at specific sites such as the centrosome and the Golgi apparatus that contain nucleation complexes rich in γ-tubulin. The microtubule growing plus-ends are stabilized by plus-end tracking proteins (+TIPs, mainly EB1 and associated proteins. Myomegalin was identified as a centrosome/Golgi protein associated with cyclic nucleotide phosphodiesterase. We show here that Myomegalin exists as several isoforms. We characterize two of them. One isoform, CM-MMG, harbors a conserved domain (CM1, recently described as a nucleation activator, and is related to a family of γ-tubulin binding proteins, which includes Drosophila centrosomin. It localizes at the centrosome and at the cis-Golgi in an AKAP450-dependent manner. It recruits γ-tubulin nucleating complexes and promotes microtubule nucleation. The second isoform, EB-MMG, is devoid of CM1 domain and has a unique N-terminus with potential EB1-binding sites. It localizes at the cis-Golgi and can localize to microtubule plus-ends. EB-MMG binds EB1 and affects its loading on microtubules and microtubule growth. Depletion of Myomegalin by small interfering RNA delays microtubule growth from the centrosome and Golgi apparatus, and decreases directional migration of RPE1 cells. In conclusion, the Myomegalin gene encodes different isoforms that regulate microtubules. At least two of these have different roles, demonstrating a previously unknown mechanism to control microtubules in vertebrate cells.

  4. Dynamic Stability and Gravitational Balancing of Multiple Extended Bodies

    Science.gov (United States)

    Quadrelli, Marco

    2008-01-01

    Feasibility of a non-invasive compensation scheme was analyzed for precise positioning of a massive extended body in free fall using gravitational forces influenced by surrounding source masses in close proximity. The N-body problem of classical mechanics is a paradigm used to gain insight into the physics of the equivalent N-body problem subject to control forces. The analysis addressed how a number of control masses move around the proof mass so that the proof mass position can be accurately and remotely compensated when exogenous disturbances are acting on it, while its sensitivity to gravitational waves remains unaffected. Past methods to correct the dynamics of the proof mass have considered active electrostatic or capacitive methods, but the possibility of stray capacitances on the surfaces of the proof mass have prompted the investigation of other alternatives, such as the method presented in this paper. While more rigorous analyses of the problem should be carried out, the data show that, by means of a combined feedback and feed-forward control approach, the control masses succeeded in driving the proof mass along the specified trajectory, which implies that the proof mass can, in principle, be balanced via gravitational forces only while external perturbations are acting on it. This concept involves the dynamic stability of a group of massive objects interacting gravitationally under active control, and can apply to drag-free control of spacecraft during missions, to successor gravitational wave space borne sensors, or to any application requiring flying objects to be precisely controlled in position and attitude relative to another body via gravitational interactions only.

  5. Sufficient Conditions for Dynamical Output Feedback Stabilization Via the Circle Criterion

    OpenAIRE

    2003-01-01

    This paper suggests sufficient conditions for asymptotically stable dynamical output feedback controller design based on the circle criterion. It is shown that a dynamic output feedback stabilization problem with impending problems of finite escape time, previously attacked by observer-based design, can be successfully solved using circle criterion design. Stability of the closed-loop system is global and robust to parameter uncertainty.

  6. Crowding of molecular motors determines microtubule depolymerization

    CERN Document Server

    Reese, Louis; Frey, Erwin

    2011-01-01

    Assembly and disassembly dynamics of microtubules (MTs) is tightly controlled by MT associated proteins. Here, we investigate how plus-end-directed depolymerases of the kinesin-8 family regulate MT depolymerization dynamics. Employing an individual-based model, we reproduce experimental findings. Moreover, crowding is identified as the key regulatory mechanism of depolymerization dynamics. Our analysis gives two qualitatively distinct regimes. For motor densities above a particular threshold, a macroscopic traffic jam emerges at the plus-end and the MT dynamics become independent of the motor concentration. Below this threshold, microscopic traffic jams at the tip arise which cancel out the effect of the depolymerization kinetics such that the depolymerization speed is solely determined by the motor density. Because this density changes over the MT length, length-dependent regulation is possible. Remarkably, motor cooperativity does not affect the depolymerization speed but only the end-residence time of depo...

  7. Disruption of microtubule integrity initiates mitosis during CNS repair.

    Science.gov (United States)

    Bossing, Torsten; Barros, Claudia S; Fischer, Bettina; Russell, Steven; Shepherd, David

    2012-08-14

    Mechanisms of CNS repair have vital medical implications. We show that traumatic injury to the ventral midline of the embryonic Drosophila CNS activates cell divisions to replace lost cells. A pilot screen analyzing transcriptomes of single cells during repair pointed to downregulation of the microtubule-stabilizing GTPase mitochondrial Rho (Miro) and upregulation of the Jun transcription factor Jun-related antigen (Jra). Ectopic Miro expression can prevent midline divisions after damage, whereas Miro depletion destabilizes cortical β-tubulin and increases divisions. Disruption of cortical microtubules, either by chemical depolymerization or by overexpression of monomeric tubulin, triggers ectopic mitosis in the midline and induces Jra expression. Conversely, loss of Jra renders midline cells unable to replace damaged siblings. Our data indicate that upon injury, the integrity of the microtubule cytoskeleton controls cell division in the CNS midline, triggering extra mitosis to replace lost cells. The conservation of the identified molecules suggests that similar mechanisms may operate in vertebrates.

  8. Remarks on stability of the rotating shallow-water vortices in the frontal dynamics regime

    Energy Technology Data Exchange (ETDEWEB)

    Jelloul, M.B.; Zeitlin, V. [P. et M. Curie Univ., Paris (France). Lab. de Meteorologie Dynamique

    1999-12-01

    Stability properties of large-scale strongly nonlinear isolated vortices in the rotating shallow water on the f-plane are analysed. Working first in the framework of the balanced frontal dynamics equations, the authors demonstrate that vortices of arbitrary sign with monotonous profiles of the free-surface elevation are formally stable and establish criteria for nonlinear stability. Stability in the framework of the full rotating shallow-water equations is also discussed and a conditional stability criterion is obtained.

  9. Asymptotic Stability and Balanced Growth Solution of the Singular Dynamic Input-Output System*

    Institute of Scientific and Technical Information of China (English)

    ChonghuiGuo; HuanwenTang

    2004-01-01

    The dynamic input-output system is well known in economic theory and practice. In this paper the asymptotic stability and balanced growth solution of the dynamic input-output system are considered. Under three natural assumptions, we obtain four theorems about asymptotic stability and balanced growth solution of the dynamic input-output system and bring together in a unified manner some contributions scattered in the literature.

  10. Capu and Spire assemble a cytoplasmic actin mesh that maintains microtubule organization in the Drosophila oocyte.

    Science.gov (United States)

    Dahlgaard, Katja; Raposo, Alexandre A S F; Niccoli, Teresa; St Johnston, Daniel

    2007-10-01

    Mutants in the actin nucleators Cappuccino and Spire disrupt the polarized microtubule network in the Drosophila oocyte that defines the anterior-posterior axis, suggesting that microtubule organization depends on actin. Here, we show that Cappuccino and Spire organize an isotropic mesh of actin filaments in the oocyte cytoplasm. capu and spire mutants lack this mesh, whereas overexpressed truncated Cappuccino stabilizes the mesh in the presence of Latrunculin A and partially rescues spire mutants. Spire overexpression cannot rescue capu mutants, but prevents actin mesh disassembly at stage 10B and blocks late cytoplasmic streaming. We also show that the actin mesh regulates microtubules indirectly, by inhibiting kinesin-dependent cytoplasmic flows. Thus, the Capu pathway controls alternative states of the oocyte cytoplasm: when active, it assembles an actin mesh that suppresses kinesin motility to maintain a polarized microtubule cytoskeleton. When inactive, unrestrained kinesin movement generates flows that wash microtubules to the cortex.

  11. The Microtubule Minus-End-Binding Protein Patronin/PTRN-1 Is Required for Axon Regeneration in C. elegans

    Directory of Open Access Journals (Sweden)

    Marian Chuang

    2014-11-01

    Full Text Available Precise regulation of microtubule (MT dynamics is increasingly recognized as a critical determinant of axon regeneration. In contrast to developing neurons, mature axons exhibit noncentrosomal microtubule nucleation. The factors regulating noncentrosomal MT architecture in axon regeneration remain poorly understood. We report that PTRN-1, the C. elegans member of the Patronin/Nezha/calmodulin- and spectrin-associated protein (CAMSAP family of microtubule minus-end-binding proteins, is critical for efficient axon regeneration in vivo. ptrn-1-null mutants display generally normal developmental axon outgrowth but significantly impaired regenerative regrowth after laser axotomy. Unexpectedly, mature axons in ptrn-1 mutants display elevated numbers of dynamic axonal MTs before and after injury, suggesting that PTRN-1 inhibits MT dynamics. The CKK domain of PTRN-1 is necessary and sufficient for its functions in axon regeneration and MT dynamics and appears to stabilize MTs independent of minus-end localization. Whereas in developing neurons, PTRN-1 inhibits activity of the DLK-1 mitogen-activated protein kinase (MAPK cascade, we find that, in regeneration, PTRN-1 and DLK-1 function together to promote axonal regrowth.

  12. Termination of Protofilament Elongation by Eribulin Induces Lattice Defects that Promote Microtubule Catastrophes.

    Science.gov (United States)

    Doodhi, Harinath; Prota, Andrea E; Rodríguez-García, Ruddi; Xiao, Hui; Custar, Daniel W; Bargsten, Katja; Katrukha, Eugene A; Hilbert, Manuel; Hua, Shasha; Jiang, Kai; Grigoriev, Ilya; Yang, Chia-Ping H; Cox, David; Horwitz, Susan Band; Kapitein, Lukas C; Akhmanova, Anna; Steinmetz, Michel O

    2016-07-11

    Microtubules are dynamic polymers built of tubulin dimers that attach in a head-to-tail fashion to form protofilaments, which further associate laterally to form a tube. Asynchronous elongation of individual protofilaments can potentially lead to an altered microtubule-end structure that promotes sudden depolymerization, termed catastrophe [1-4]. However, how the dynamics of individual protofilaments relates to overall growth persistence has remained unclear. Here, we used the microtubule targeting anti-cancer drug Eribulin [5-7] to explore the consequences of stalled protofilament elongation on microtubule growth. Using X-ray crystallography, we first revealed that Eribulin binds to a site on β-tubulin that is required for protofilament plus-end elongation. Based on the structural information, we engineered a fluorescent Eribulin molecule. We demonstrate that single Eribulin molecules specifically interact with microtubule plus ends and are sufficient to either trigger a catastrophe or induce slow and erratic microtubule growth in the presence of EB3. Interestingly, we found that Eribulin increases the frequency of EB3 comet "splitting," transient events where a slow and erratically progressing comet is followed by a faster comet. This observation possibly reflects the "healing" of a microtubule lattice. Because EB3 comet splitting was also observed in control microtubules in the absence of any drugs, we propose that Eribulin amplifies a natural pathway toward catastrophe by promoting the arrest of protofilament elongation.

  13. Simulation of Dynamic Yaw Stability Derivatives of a Bird Using CFD

    CERN Document Server

    Moelyadi, M A

    2008-01-01

    Simulation results on dynamic yaw stability derivatives of a gull bird by means of computational fluid dynamics are presented. Two different kinds of motions are used for determining the dynamic yaw stability derivatives CNr and CNbeta . Concerning the first one, simple lateral translation and yaw rotary motions in yaw are considered. The second one consists of combined motions. To determine dynamic yaw stability derivatives of the bird, the simulation of an unsteady flow with a bird model showing a harmonic motion is performed. The unsteady flow solution for each time step is obtained by solving unsteady Euler equations based on a finite volume approach for a smaller reduced frequency. Then, an evaluation of unsteady forces and moments for one cycle is conducted using harmonic Fourier analysis. The results on the dynamic yaw stability derivatives for both simulations of the model motion show a good agreement.

  14. Elastic Dynamic Stability of Big-Span Power Transmission Tower Subjected to Seismic Excitations

    Institute of Scientific and Technical Information of China (English)

    ZHANG Hang; LI Li; FANG Qin-han; YE Kun

    2009-01-01

    By combining the time-history response analysis and the eigenvalue buckling analysis,this paper developed a computational procedure to study the elastic dynamic stability of a transmission tower by APDL language in ANSYS.The influences of different input directions of seismic excitations and damping ratio on the elastic dynamic stability of tower were discussed.The following conclusions were obtained:(1) Longitudinal direction of the transmission lines is the worst input direction of seismic excitation for the transmission tower.(2) Dead load has no significant effect on the critical load and the occurrence time of buckling.(3) Vertical input of seismic excitations has no great effect on the dynamic stability of the transmission tower.(4) Damping effect has an influence on the dynamic stability of the transmission tower; however,the inherent characteristics of dynamic buckling is not changed.

  15. CFD Based Determination of Dynamic Stability Derivatives in Yaw for a Bird

    Institute of Scientific and Technical Information of China (English)

    M. A. Moelyadi; G. Sachs

    2007-01-01

    Dynamic yaw stability derivatives of a gull bird are determined using Computational Fluid Dynamics(CFD) method. Two kinds of motions are applied for calculating the dynamic yaw stability derivatives CNr and CNβ. The first one relates to a lateral translation and, separately, to a yaw rotation. The second one consists of a combined translational and rotational motion. To determine dynamic yaw stability derivatives, the simulation of an unsteady flow with a bird model showing a harmonic motion is performed. The flow solution for each time step is obtained by solving unsteady Euler equations based on a finite volume approach for a small reduced frequency. Then, an evaluation of unsteady forces and moments for one cycle is conducted using harmonic Fourier analysis. The results of the dynamic yaw stability derivatives for both simulations of the model show a good agreement.

  16. Interactive domains in the molecular chaperone human alphaB crystallin modulate microtubule assembly and disassembly.

    Directory of Open Access Journals (Sweden)

    Joy G Ghosh

    Full Text Available Small heat shock proteins regulate microtubule assembly during cell proliferation and in response to stress through interactions that are poorly understood.Novel functions for five interactive sequences in the small heat shock protein and molecular chaperone, human alphaB crystallin, were investigated in the assembly/disassembly of microtubules and aggregation of tubulin using synthetic peptides and mutants of human alphaB crystallin.The interactive sequence (113FISREFHR(120 exposed on the surface of alphaB crystallin decreased microtubule assembly by approximately 45%. In contrast, the interactive sequences, (131LTITSSLSSDGV(142 and (156ERTIPITRE(164, corresponding to the beta8 strand and the C-terminal extension respectively, which are involved in complex formation, increased microtubule assembly by approximately 34-45%. The alphaB crystallin peptides, (113FISREFHR(120 and (156ERTIPITRE(164, inhibited microtubule disassembly by approximately 26-36%, and the peptides (113FISREFHR(120 and (131LTITSSLSSDGV(142 decreased the thermal aggregation of tubulin by approximately 42-44%. The (131LTITSSLSSDGV(142 and (156ERTIPITRE(164 peptides were more effective than the widely used anti-cancer drug, Paclitaxel, in modulating tubulinmicrotubule dynamics. Mutagenesis of these interactive sequences in wt human alphaB crystallin confirmed the effects of the alphaB crystallin peptides on microtubule assembly/disassembly and tubulin aggregation. The regulation of microtubule assembly by alphaB crystallin varied over a narrow range of concentrations. The assembly of microtubules was maximal at alphaB crystallin to tubulin molar ratios between 1:4 and 2:1, while molar ratios >2:1 inhibited microtubule assembly.Interactive sequences on the surface of human alphaB crystallin collectively modulate microtubule assembly through a dynamic subunit exchange mechanism that depends on the concentration and ratio of alphaB crystallin to tubulin. These are the first

  17. Optimal placement of unified power flow controllers to improve dynamic voltage stability using power system variable based voltage stability indices.

    Science.gov (United States)

    Albatsh, Fadi M; Ahmad, Shameem; Mekhilef, Saad; Mokhlis, Hazlie; Hassan, M A

    2015-01-01

    This study examines a new approach to selecting the locations of unified power flow controllers (UPFCs) in power system networks based on a dynamic analysis of voltage stability. Power system voltage stability indices (VSIs) including the line stability index (LQP), the voltage collapse proximity indicator (VCPI), and the line stability index (Lmn) are employed to identify the most suitable locations in the system for UPFCs. In this study, the locations of the UPFCs are identified by dynamically varying the loads across all of the load buses to represent actual power system conditions. Simulations were conducted in a power system computer-aided design (PSCAD) software using the IEEE 14-bus and 39- bus benchmark power system models. The simulation results demonstrate the effectiveness of the proposed method. When the UPFCs are placed in the locations obtained with the new approach, the voltage stability improves. A comparison of the steady-state VSIs resulting from the UPFCs placed in the locations obtained with the new approach and with particle swarm optimization (PSO) and differential evolution (DE), which are static methods, is presented. In all cases, the UPFC locations given by the proposed approach result in better voltage stability than those obtained with the other approaches.

  18. Optimal placement of unified power flow controllers to improve dynamic voltage stability using power system variable based voltage stability indices.

    Directory of Open Access Journals (Sweden)

    Fadi M Albatsh

    Full Text Available This study examines a new approach to selecting the locations of unified power flow controllers (UPFCs in power system networks based on a dynamic analysis of voltage stability. Power system voltage stability indices (VSIs including the line stability index (LQP, the voltage collapse proximity indicator (VCPI, and the line stability index (Lmn are employed to identify the most suitable locations in the system for UPFCs. In this study, the locations of the UPFCs are identified by dynamically varying the loads across all of the load buses to represent actual power system conditions. Simulations were conducted in a power system computer-aided design (PSCAD software using the IEEE 14-bus and 39- bus benchmark power system models. The simulation results demonstrate the effectiveness of the proposed method. When the UPFCs are placed in the locations obtained with the new approach, the voltage stability improves. A comparison of the steady-state VSIs resulting from the UPFCs placed in the locations obtained with the new approach and with particle swarm optimization (PSO and differential evolution (DE, which are static methods, is presented. In all cases, the UPFC locations given by the proposed approach result in better voltage stability than those obtained with the other approaches.

  19. Optimal Placement of Unified Power Flow Controllers to Improve Dynamic Voltage Stability Using Power System Variable Based Voltage Stability Indices

    Science.gov (United States)

    Albatsh, Fadi M.; Ahmad, Shameem; Mekhilef, Saad; Mokhlis, Hazlie; Hassan, M. A.

    2015-01-01

    This study examines a new approach to selecting the locations of unified power flow controllers (UPFCs) in power system networks based on a dynamic analysis of voltage stability. Power system voltage stability indices (VSIs) including the line stability index (LQP), the voltage collapse proximity indicator (VCPI), and the line stability index (Lmn) are employed to identify the most suitable locations in the system for UPFCs. In this study, the locations of the UPFCs are identified by dynamically varying the loads across all of the load buses to represent actual power system conditions. Simulations were conducted in a power system computer-aided design (PSCAD) software using the IEEE 14-bus and 39- bus benchmark power system models. The simulation results demonstrate the effectiveness of the proposed method. When the UPFCs are placed in the locations obtained with the new approach, the voltage stability improves. A comparison of the steady-state VSIs resulting from the UPFCs placed in the locations obtained with the new approach and with particle swarm optimization (PSO) and differential evolution (DE), which are static methods, is presented. In all cases, the UPFC locations given by the proposed approach result in better voltage stability than those obtained with the other approaches. PMID:25874560

  20. Motility and microtubule depolymerization mechanisms of the Kinesin-8 motor, KIF19A

    Science.gov (United States)

    Wang, Doudou; Nitta, Ryo; Morikawa, Manatsu; Yajima, Hiroaki; Inoue, Shigeyuki; Shigematsu, Hideki; Kikkawa, Masahide; Hirokawa, Nobutaka

    2016-01-01

    The kinesin-8 motor, KIF19A, accumulates at cilia tips and controls cilium length. Defective KIF19A leads to hydrocephalus and female infertility because of abnormally elongated cilia. Uniquely among kinesins, KIF19A possesses the dual functions of motility along ciliary microtubules and depolymerization of microtubules. To elucidate the molecular mechanisms of these functions we solved the crystal structure of its motor domain and determined its cryo-electron microscopy structure complexed with a microtubule. The features of KIF19A that enable its dual function are clustered on its microtubule-binding side. Unexpectedly, a destabilized switch II coordinates with a destabilized L8 to enable KIF19A to adjust to both straight and curved microtubule protofilaments. The basic clusters of L2 and L12 tether the microtubule. The long L2 with a characteristic acidic-hydrophobic-basic sequence effectively stabilizes the curved conformation of microtubule ends. Hence, KIF19A utilizes multiple strategies to accomplish the dual functions of motility and microtubule depolymerization by ATP hydrolysis. DOI: http://dx.doi.org/10.7554/eLife.18101.001 PMID:27690357

  1. Microtubule affinity-regulating kinase 4: structure, function, and regulation.

    Science.gov (United States)

    Naz, Farha; Anjum, Farah; Islam, Asimul; Ahmad, Faizan; Hassan, Md Imtaiyaz

    2013-11-01

    MAP/Microtubule affinity-regulating kinase 4 (MARK4) belongs to the family of serine/threonine kinases that phosphorylate the microtubule-associated proteins (MAP) causing their detachment from the microtubules thereby increasing microtubule dynamics and facilitating cell division, cell cycle control, cell polarity determination, cell shape alterations, etc. The MARK4 gene encodes two alternatively spliced isoforms, L and S that differ in their C-terminal region. These isoforms are differentially regulated in human tissues including central nervous system. MARK4L is a 752-residue-long polypeptide that is divided into three distinct domains: (1) protein kinase domain (59-314), (2) ubiquitin-associated domain (322-369), and (3) kinase-associated domain (703-752) plus 54 residues (649-703) involved in the proper folding and function of the enzyme. In addition, residues 65-73 are considered to be the ATP-binding domain and Lys88 is considered as ATP-binding site. Asp181 has been proposed to be the active site of MARK4 that is activated by phosphorylation of Thr214 side chain. The isoform MARK4S is highly expressed in the normal brain and is presumably involved in neuronal differentiation. On the other hand, the isoform MARK4L is upregulated in hepatocarcinoma cells and gliomas suggesting its involvement in cell cycle. Several biological functions are also associated with MARK4 including microtubule bundle formation, nervous system development, and positive regulation of programmed cell death. Therefore, MARK4 is considered as the most suitable target for structure-based rational drug design. Our sequence, structure- and function-based analysis should be helpful for better understanding of mechanisms of regulation of microtubule dynamics and MARK4 associated diseases.

  2. On the Nature and Shape of Tubulin Trails: Implications on Microtubule Self-Organization

    CERN Document Server

    Glade, Nicolas

    2012-01-01

    Microtubules, major elements of the cell skeleton are, most of the time, well organized in vivo, but they can also show self-organizing behaviors in time and/or space in purified solutions in vitro. Theoretical studies and models based on the concepts of collective dynamics in complex systems, reaction-diffusion processes and emergent phenomena were proposed to explain some of these behaviors. In the particular case of microtubule spatial self-organization, it has been advanced that microtubules could behave like ants, self-organizing by 'talking to each other' by way of hypothetic (because never observed) concentrated chemical trails of tubulin that are expected to be released by their disassembling ends. Deterministic models based on this idea yielded indeed like-looking spatio-temporal self-organizing behaviors. Nevertheless the question remains of whether microscopic tubulin trails produced by individual or bundles of several microtubules are intense enough to allow microtubule self-organization at a macr...

  3. Animal flight dynamics I. Stability in gliding flight.

    Science.gov (United States)

    Thomas, A L; Taylor, G K

    2001-10-07

    Stability is as essential to flying as lift itself, but previous discussions of how flying animals maintain stability have been limited in both number and scope. By developing the pitching moment equations for gliding animals and by discussing potential sources of roll and yaw stability, we consider the various sources of static stability used by gliding animals. We find that gliding animals differ markedly from aircraft in how they maintain stability. In particular, the pendulum stability provided when the centre of gravity lies below the wings is a much more important source of stability in flying animals than in most conventional aircraft. Drag-based stability also appears to be important for many gliding animals, whereas in aircraft, drag is usually kept to a minimum. One unexpected consequence of these differences is that the golden measure of static pitching stability in aircraft--the static margin--can only strictly be applied to flying animals if the equilibrium angle of attack is specified. We also derive several rules of thumb by which stable fliers can be identified. Stable fliers are expected to exhibit one or more of the following features: (1) Wings that are swept forward in slow flight. (2) Wings that are twisted down at the tips when swept back (wash-out) and twisted up at the tips when swept forwards (wash-in). (3) Additional lifting surfaces (canard, hindwings or a tail) inclined nose-up to the main wing if they lie forward of it, and nose-down if they lie behind it (longitudinal dihedral). Each of these predictions is directional--the opposite is expected to apply in unstable animals. In addition, animals with reduced stability are expected to display direct flight patterns in turbulent conditions, in contrast to the erratic flight patterns predicted for stable animals, in which large restoring forces are generated. Using these predictions, we find that flying animals possess a far higher degree of inherent stability than has generally been

  4. Overview of Orion Crew Module and Launch Abort Vehicle Dynamic Stability

    Science.gov (United States)

    Owens, Donald B.; Aibicjpm. Vamessa V.

    2011-01-01

    With the retirement of the Space Shuttle, NASA is designing a new spacecraft, called Orion, to fly astronauts to low earth orbit and beyond. Characterization of the dynamic stability of the Orion spacecraft is important for the design of the spacecraft and trajectory construction. Dynamic stability affects the stability and control of the Orion Crew Module during re-entry, especially below Mach = 2.0 and including flight under the drogues. The Launch Abort Vehicle is affected by dynamic stability as well, especially during the re-orientation and heatshield forward segments of the flight. The dynamic stability was assessed using the forced oscillation technique, free-to-oscillate, ballistic range, and sub-scale free-flight tests. All of the test techniques demonstrated that in heatshield-forward flight the Crew Module and Launch Abort Vehicle are dynamically unstable in a significant portion of their flight trajectory. This paper will provide a brief overview of the Orion dynamic aero program and a high-level summary of the dynamic stability characteristics of the Orion spacecraft.

  5. Static and dynamic stability analysis of the space shuttle vehicle-orbiter

    Science.gov (United States)

    Chyu, W. J.; Cavin, R. K.; Erickson, L. L.

    1978-01-01

    The longitudinal static and dynamic stability of a Space Shuttle Vehicle-Orbiter (SSV Orbiter) model is analyzed using the FLEXSTAB computer program. Nonlinear effects are accounted for by application of a correction technique in the FLEXSTAB system; the technique incorporates experimental force and pressure data into the linear aerodynamic theory. A flexible Orbiter model is treated in the static stability analysis for the flight conditions of Mach number 0.9 for rectilinear flight (1 g) and for a pull-up maneuver (2.5 g) at an altitude of 15.24 km. Static stability parameters and structural deformations of the Orbiter are calculated at trim conditions for the dynamic stability analysis, and the characteristics of damping in pitch are investigated for a Mach number range of 0.3 to 1.2. The calculated results for both the static and dynamic stabilities are compared with the available experimental data.

  6. Temporal stability in forest productivity increases with tree diversity due to asynchrony in species dynamics.

    Science.gov (United States)

    Morin, Xavier; Fahse, Lorenz; de Mazancourt, Claire; Scherer-Lorenzen, Michael; Bugmann, Harald

    2014-12-01

    Theory predicts a positive relationship between biodiversity and stability in ecosystem properties, while diversity is expected to have a negative impact on stability at the species level. We used virtual experiments based on a dynamic simulation model to test for the diversity-stability relationship and its underlying mechanisms in Central European forests. First our results show that variability in productivity between stands differing in species composition decreases as species richness and functional diversity increase. Second we show temporal stability increases with increasing diversity due to compensatory dynamics across species, supporting the biodiversity insurance hypothesis. We demonstrate that this pattern is mainly driven by the asynchrony of species responses to small disturbances rather than to environmental fluctuations, and is only weakly affected by the net biodiversity effect on productivity. Furthermore, our results suggest that compensatory dynamics between species may enhance ecosystem stability through an optimisation of canopy occupancy by coexisting species. © 2014 John Wiley & Sons Ltd/CNRS.

  7. Effects of pelvic stabilization on lumbar muscle activity during dynamic exercise.

    Science.gov (United States)

    San Juan, Jun G; Yaggie, James A; Levy, Susan S; Mooney, Vert; Udermann, Brian E; Mayer, John M

    2005-11-01

    Many commonly utilized low-back exercise devices offer mechanisms to stabilize the pelvis and to isolate the lumbar spine, but the value of these mechanisms remains unclear. The purpose of this study was to examine the effect of pelvic stabilization on the activity of the lumbar and hip extensor muscles during dynamic back extension exercise. Fifteen volunteers in good general health performed dynamic extension exercise in a seated upright position on a lumbar extension machine with and without pelvic stabilization. During exercise, surface electromyographic activity of the lumbar multifidus and biceps femoris was recorded. The activity of the multifidus was 51% greater during the stabilized condition, whereas there was no difference in the activity of the biceps femoris between conditions. This study demonstrates that pelvic stabilization enhances lumbar muscle recruitment during dynamic exercise on machines. Exercise specialists can use these data when designing exercise programs to develop low back strength.

  8. An Improved Force-Angle Stability Margin for Radial Symmetrical Hexapod Robot Subject to Dynamic Effects

    Directory of Open Access Journals (Sweden)

    Shidong Long

    2015-05-01

    Full Text Available This paper presents a study on stability monitoring for a radial symmetrical hexapod robot under dynamic conditions. The force-angle stability margin (FASM measure method has been chosen as the stability criterion. This is because it is suitable for the stability analysis, in terms of external forces or manipulator loads acting on the body. Considering that a radial symmetrical hexapod robot can tumble along the contact point besides tip-over axis, this paper proposes an improved FASM measure method. Furthermore, it provides the method for calculating the stability angle of contact point and simplifies the algorithm of FASM. To verify the improved FASM measure method, three potential dynamic situations have been simulated. The simulation results confirm that, under dynamic conditions, the improved FASM is efficient, simple in terms of calculation cost and sensitive to manipulator loads and external disturbances. This means it has practical value in on-line controllers.

  9. Evaluation on Stability of Stope Structure Based on Nonlinear Dynamics of Coupling Artificial Neural Network

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    The nonlinear dynamical behaviors of artificial neural network (ANN) and their application to science and engineering were summarized. The mechanism of two kinds of dynamical processes, i.e. weight dynamics and activation dynamics in neural networks, and the stability of computing in structural analysis and design were stated briefly. It was successfully applied to nonlinear neural network to evaluate the stability of underground stope structure in a gold mine. With the application of BP network, it is proven that the neuro-computing is a practical and advanced tool for solving large-scale underground rock engineering problems.

  10. Theory and analysis of nonlinear dynamics and stability in storage rings: A working group summary

    Energy Technology Data Exchange (ETDEWEB)

    Chattopadhyay, S.; Audy, P.; Courant, E.D.; Forest, E.; Guignard, G.; Hagel, J.; Heifets, S.; Keil, E.; Kheifets, S.; Mais, H.; Moshammer, H.; Pellegrini, C.; Pilat, F.; Suzuki, T.; Turchetti, G.; Warnock, R.L.

    1988-07-01

    A summary and commentary of the available theoretical and analytical tools and recent advances in the nonlinear dynamics, stability and aperture issues in storage rings are presented. 11 refs., 4 figs.

  11. Short term outcome of posterior dynamic stabilization system in degenerative lumbar diseases

    Directory of Open Access Journals (Sweden)

    Mingyuan Yang

    2014-01-01

    Conclusion: Dynamic stabilization system treating lumbar degenerative disease showed clinical benefits with motion preservation of the operated segments, but does not have the significant advantage on motion preservation at adjacent segments, to avoid the degeneration of adjacent intervertebral disk.

  12. Relationship between Core Stability Muscle Endurance and Static and Dynamic Balance in Basketball Players

    Directory of Open Access Journals (Sweden)

    farzaneh saki

    2016-03-01

    Full Text Available Objective: Balancing is the most basic function of the neuromuscular system in performing all simple and complex activities that contribute to health-related physical fitness. Core stability may be a contributing factor to static and dynamic balance. The aim of this study was to investigate the relationship between core stability muscle endurance and static and dynamic balance in basketball players. Methods: 100 basketball players (50 female and 50 male players were selected randomly based on the including criteria.To evaluate core stability muscle strength, a set of tests from core stability exercises was used. Static and dynamic balance were evaluated by Bass Stick and Y balance test respectively. Normality of the data was evaluated using the Kolmogorov Smirnoff test. Data analysis was performed by Spearman product moment coefficient test and independent samples t test. Significant level of p&le0/05 was used in all statistical analyses. Results: Results of t-test showed no significant difference between static balance in boys and girls, while significant differences were observed between dynamic balance and core stability in males and females. In other words, core stability and dynamic balance in boys were more than girls. Also, the results of correlation analysis showed a significant relationship between core stability and dynamic balance (p=0.00 However, no significant relationship was observed between core stability and static balance (p=0.451. Conclusion: Due to the correlation between muscle endurance and dynamic balance in the present study, it can be implied that core stability exercises can improve balance.

  13. Stability Analysis for Hand-arm-forearm Dynamic System

    Directory of Open Access Journals (Sweden)

    Florin Bausic

    2014-07-01

    Full Text Available In this paper we propose a model with four degrees of freedom for hand-arm-forearm dynamic system. Using experimental data from [9] by means of the Simulink program, is built block diagram to simulate the dynamic system motion and phase diagrams are drawn by using Matlab. From the interpretation of these diagrams result, for a set of parameters ( m, c, k, FO, ω , stable moves for the hand-arm-forearm dynamic system.

  14. The role of microtubules in contractile ring function

    Science.gov (United States)

    Conrad, A. H.; Paulsen, A. Q.; Conrad, G. W.; Spooner, B. S. (Principal Investigator)

    1992-01-01

    During cytokinesis, a cortical contractile ring forms around a cell, constricts to a stable tight neck and terminates in separation of the daughter cells. At first cleavage, Ilyanassa obsoleta embryos form two contractile rings simultaneously. The cleavage furrow (CF), in the animal hemisphere between the spindle poles, constricts to a stable tight neck and separates the daughter cells. The third polar lobe constriction (PLC-3), in the vegetal hemisphere below the spindle, constricts to a transient tight neck, but then relaxes, allowing the polar lobe cytoplasm to merge with one daughter cell. Eggs exposed to taxol, a drug that stabilizes microtubules, before the CF or the PLC-3 develop, fail to form CFs, but form stabilized tight PLCs. Eggs exposed to taxol at the time of PLC-3 formation develop varied numbers of constriction rings in their animal hemispheres and one PLC in their vegetal hemisphere, none of which relax. Eggs exposed to taxol after PLC-3 initiation form stabilized tight CFs and PLCs. At maximum constriction, control embryos display immunolocalization of nonextractable alpha-tubulin in their CFs, but not in their PLCs, and reveal, via electron microscopy, many microtubules extending through their CFs, but not through their PLCs. Embryos which form stabilized tightly constricted CFs and PLCs in the presence of taxol display immunolocalization of nonextractable alpha-tubulin in both constrictions and show many polymerized microtubules extending through both CFs and PLCs. These results suggest that the extension of microtubules through a tight contractile ring may be important for stabilizing that constriction and facilitating subsequent cytokinesis.

  15. The XMAP215-family protein DdCP224 is required for cortical interactions of microtubules

    Directory of Open Access Journals (Sweden)

    Hestermann Andrea

    2004-06-01

    Full Text Available Abstract Background Interactions of peripheral microtubule tips with the cell cortex are of crucial importance for nuclear migration, spindle orientation, centrosome positioning and directional cell movement. Microtubule plus end binding proteins are thought to mediate interactions of microtubule tips with cortical actin and membrane proteins in a dynein-dependent manner. XMAP215-family proteins are main regulators of microtubule plus end dynamics but so far they have not been implicated in the interactions of microtubule tips with the cell cortex. Results Here we show that overexpression of an N-terminal fragment of DdCP224, the Dictyostelium XMAP215 homologue, caused a collapse of the radial microtubule cytoskeleton, whereby microtubules lost contact with the cell cortex and were dragged behind like a comet tail of an unusually motile centrosome. This phenotype was indistinguishable from mutants overexpressing fragments of the dynein heavy chain or intermediate chain. Moreover, it was accompanied by dispersal of the Golgi apparatus and reduced cortical localization of the dynein heavy chain indicating a disrupted dynein/dynactin interaction. The interference of DdCP224 with cortical dynein function is strongly supported by the observations that DdCP224 and its N-terminal fragment colocalize with dynein and coimmunoprecipitate with dynein and dynactin. Conclusions Our data show that XMAP215-like proteins are required for the interaction of microtubule plus ends with the cell cortex in interphase cells and strongly suggest that this function is mediated by dynein.

  16. Test of Cable Products in Respect of Thermal and Dynamic Stability

    Directory of Open Access Journals (Sweden)

    M. A. Коrotkevich

    2010-01-01

    Full Text Available The paper considers conditions for selection of  power supply of the unit which is used for testing samples of cable products by thermal and dynamic stability currents. It has been shown that while conducting testing by thermal and dynamic stability currents at nominal cable voltage it is more justifiable to use a percussive energy accumulator, and in the case when the voltage is low an inductive energy accumulator is used.

  17. Relationship between Core Stability Muscle Endurance and Static and Dynamic Balance in Basketball Players

    OpenAIRE

    farzaneh saki; masumeh Baghban

    2016-01-01

    Objective: Balancing is the most basic function of the neuromuscular system in performing all simple and complex activities that contribute to health-related physical fitness. Core stability may be a contributing factor to static and dynamic balance. The aim of this study was to investigate the relationship between core stability muscle endurance and static and dynamic balance in basketball players. Methods: 100 basketball players (50 female and 50 male players) were selected randomly bas...

  18. Dynamic stability margin using a marker based system and Tekscan: a comparison of four gait conditions.

    Science.gov (United States)

    Lugade, Vipul; Kaufman, Kenton

    2014-01-01

    Stability during gait is maintained through control of the center of mass (CoM) position and velocity in relation to the base of support (BoS). The dynamic stability margin, or the interaction of the extrapolated center of mass with the closest boundary of the BoS, can reveal possible control errors during gait. The purpose of this study was to investigate a marker based method for defining the BoS, and compare the dynamic stability margin throughout gait in comparison to a BoS defined from foot pressure sensors. The root mean squared difference between these two methodologies ranged from 0.9 cm to 3.5 cm, when walking under four conditions: plantigrade, equinus, everted, and inverted. As the stability margin approaches -35 cm prior to contralateral heel strike, there was approximately 90% agreement between the two systems at this time point. Underestimation of the marker based dynamic stability margin or overestimation of the pressure based dynamic stability margin was due to inaccuracies in defining the medial boundary of the BoS. Overall, care must be taken to ensure similar definitions of the BoS are utilized when comparing the dynamic stability margin between participants and gait conditions.

  19. Role of Intrinsic and Reflexive Dynamics in the Control of Spinal Stability

    OpenAIRE

    Moorhouse, Kevin Michael

    2005-01-01

    Role of Intrinsic and Reflexive Dynamics in the Control of Spinal Stability Kevin M. Moorhouse Abstract Spinal stability describes the ability of the neuromuscular system to maintain equilibrium in the presence of kinematic and control variability, and may play an important role in the etiology of low-back disorders (LBDs). The primary mechanism for the neuromuscular control of spinal stability is the recruitment and control of active paraspinal muscle stiffness (i.e., trunk stif...

  20. A new transient stability margin based on dynamic security region and its applications

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    A new transient stability margin is proposed based on a new expression of dynamic security region (DSR) which is developed from the existing expression of DSR. Applications of the DSR based transient stability margin to contingency ranking and screening are discussed. Simulations in the 10-machine 39-bus New England system are performed to show the effectiveness of the proposed DSR based tran-sient stability margin.

  1. Investigation of biomechanical behavior of lumbar vertebral segments with dynamic stabilization device using finite element approach

    Science.gov (United States)

    Deoghare, Ashish B.; Kashyap, Siddharth; Padole, Pramod M.

    2013-03-01

    Degenerative disc disease is a major source of lower back pain and significantly alters the biomechanics of the lumbar spine. Dynamic stabilization device is a remedial technique which uses flexible materials to stabilize the affected lumbar region while preserving the natural anatomy of the spine. The main objective of this research work is to investigate the stiffness variation of dynamic stabilization device under various loading conditions under compression, axial rotation and flexion. Three dimensional model of the two segment lumbar spine is developed using computed tomography (CT) scan images. The lumbar structure developed is analyzed in ANSYS workbench. Two types of dynamic stabilization are considered: one with stabilizing device as pedicle instrumentation and second with stabilization device inserted around the inter-vertebral disc. Analysis suggests that proper positioning of the dynamic stabilization device is of paramount significance prior to the surgery. Inserting the device in the posterior region indicates the adverse effects as it shows increase in the deformation of the inter-vertebral disc. Analysis executed by positioning stabilizing device around the inter-vertebral disc yields better result for various stiffness values under compression and other loadings. [Figure not available: see fulltext.

  2. Differences in shielding versus trapping behaviour of dynamically stabilized NbTi cylinders

    CERN Document Server

    Häbel, E

    1977-01-01

    It was found experimentally that dynamically stabilized NbTi cylinders show, in contrast to general expectation, a stability behaviour for shielding of external magnetic fields different from that for trapping. This phenomenon is discussed and a theoretical interpretation is proposed. (10 refs).

  3. A Note on "Stability of the Constant Cost Dynamic Lot Size Model" by K. Richter

    NARCIS (Netherlands)

    S. van Hoesel (Stan); A.P.M. Wagelmans (Albert)

    1991-01-01

    textabstractIn a paper by K. Richter the stability regions of the dynamic lot size model with constant cost parameters are analyzed. In particular, an algorithm is suggested to compute the stability region of a so-called generalized solution. In general this region is only a subregion of the stabili

  4. Modulation of microtubule assembly by the HIV-1 Tat protein is strongly dependent on zinc binding to Tat

    Directory of Open Access Journals (Sweden)

    Muller Sylviane

    2008-07-01

    Full Text Available Abstract Background During HIV-1 infection, the Tat protein plays a key role by transactivating the transcription of the HIV-1 proviral DNA. In addition, Tat induces apoptosis of non-infected T lymphocytes, leading to a massive loss of immune competence. This apoptosis is notably mediated by the interaction of Tat with microtubules, which are dynamic components essential for cell structure and division. Tat binds two Zn2+ ions through its conserved cysteine-rich region in vitro, but the role of zinc in the structure and properties of Tat is still controversial. Results To investigate the role of zinc, we first characterized Tat apo- and holo-forms by fluorescence correlation spectroscopy and time-resolved fluorescence spectroscopy. Both of the Tat forms are monomeric and poorly folded but differ by local conformational changes in the vicinity of the cysteine-rich region. The interaction of the two Tat forms with tubulin dimers and microtubules was monitored by analytical ultracentrifugation, turbidity measurements and electron microscopy. At 20°C, both of the Tat forms bind tubulin dimers, but only the holo-Tat was found to form discrete complexes. At 37°C, both forms promoted the nucleation and increased the elongation rates of tubulin assembly. However, only the holo-Tat increased the amount of microtubules, decreased the tubulin critical concentration, and stabilized the microtubules. In contrast, apo-Tat induced a large amount of tubulin aggregates. Conclusion Our data suggest that holo-Tat corresponds to the active form, responsible for the Tat-mediated apoptosis.

  5. Motivational Dynamics in Language Learning: Change, Stability, and Context

    Science.gov (United States)

    Waninge, Freerkien; Dörnyei, Zoltán; De Bot, Kees

    2014-01-01

    Motivation as a variable in L2 development is no longer seen as the stable individual difference factor it was once believed to be: Influenced by process-oriented models and principles, and especially by the growing understanding of how complex dynamic systems work, researchers have been focusing increasingly on the dynamic and changeable nature…

  6. Phospholipase d activation correlates with microtubule reorganization in living plant cells.

    Science.gov (United States)

    Dhonukshe, Pankaj; Laxalt, Ana M; Goedhart, Joachim; Gadella, Theodorus W J; Munnik, Teun

    2003-11-01

    A phospholipase D (PLD) was shown recently to decorate microtubules in plant cells. Therefore, we used tobacco BY-2 cells expressing the microtubule reporter GFP-MAP4 to test whether PLD activation affects the organization of plant microtubules. Within 30 min of adding n-butanol, a potent activator of PLD, cortical microtubules were released from the plasma membrane and partially depolymerized, as visualized with four-dimensional confocal imaging. The isomers sec- and tert-butanol, which did not activate PLD, did not affect microtubule organization. The effect of treatment on PLD activation was monitored by the in vivo formation of phosphatidylbutanol, a specific reporter of PLD activity. Tobacco cells also were treated with mastoparan, xylanase, NaCl, and hypoosmotic stress as reported activators of PLD. We confirmed the reports and found that all treatments induced microtubule reorganization and PLD activation within the same time frame. PLD still was activated in microtubule-stabilized (taxol) and microtubule-depolymerized (oryzalin) situations, suggesting that PLD activation triggers microtubular reorganization and not vice versa. Exogenously applied water-soluble synthetic phosphatidic acid did not affect the microtubular cytoskeleton. Cell cycle studies revealed that n-butanol influenced not just interphase cortical microtubules but also those in the preprophase band and phragmoplast, but not those in the spindle structure. Cell growth and division were inhibited in the presence of n-butanol, whereas sec- and tert-butanol had no such effects. Using these novel insights, we propose a model for the mechanism by which PLD activation triggers microtubule reorganization in plant cells.

  7. Dynamical output feedback stabilization for neutral systems with mixed delays

    Institute of Scientific and Technical Information of China (English)

    Wei QIAN; Guo-jiang SHEN; You-xian SUN

    2008-01-01

    This paper is concerned with the issue of stabilization for the linear neutral systems with mixed delays.The attention is focused on the design of output feedback controllers which guarantee the asymptotical stability of the closed-loop systems.Based on the model transformation of neutral type,the Lyapunov-Krasovskii functional method is employed to establish the delay-dependent stability criterion.Then,through the controller parameterization and some matrix transformation techniques,the desired parameters are determined under the delay-dependent design condition in terms of linear matrix inequalities (LMIs),and the desired controller is explicitly formulated.A numerical example is given to illustrate the effectiveness of the proposed method.

  8. Stability and dynamical properties of Cooper-Shepard-Sodano compactons.

    Science.gov (United States)

    Mihaila, Bogdan; Cardenas, Andres; Cooper, Fred; Saxena, Avadh

    2010-12-01

    Extending a Padé approximant method used for studying compactons in the Rosenau-Hyman (RH) equation, we study the numerical stability of single compactons of the Cooper-Shepard-Sodano (CSS) equation and their pairwise interactions. The CSS equation has a conserved Hamiltonian which has allowed various approaches for studying analytically the nonlinear stability of the solutions. We study three different compacton solutions and find they are numerically stable. Similar to the collisions between RH compactons, the CSS compactons re-emerge with same coherent shape when scattered. The time evolution of the small-amplitude ripple resulting after scattering depends on the values of the parameters l and p characterizing the corresponding CSS equation. The simulation of the CSS compacton scattering requires a much smaller artificial viscosity to obtain numerical stability than in the case of RH compacton propagation.

  9. Walking in simulated Martian gravity: influence of the portable life support system's design on dynamic stability.

    Science.gov (United States)

    Scott-Pandorf, Melissa M; O'Connor, Daniel P; Layne, Charles S; Josić, Kresimir; Kurz, Max J

    2009-09-01

    With human exploration of the moon and Mars on the horizon, research considerations for space suit redesign have surfaced. The portable life support system (PLSS) used in conjunction with the space suit during the Apollo missions may have influenced the dynamic balance of the gait pattern. This investigation explored potential issues with the PLSS design that may arise during the Mars exploration. A better understanding of how the location of the PLSS load influences the dynamic stability of the gait pattern may provide insight, such that space missions may have more productive missions with a smaller risk of injury and damaging equipment while falling. We explored the influence the PLSS load position had on the dynamic stability of the walking pattern. While walking, participants wore a device built to simulate possible PLSS load configurations. Floquet and Lyapunov analysis techniques were used to quantify the dynamic stability of the gait pattern. The dynamic stability of the gait pattern was influenced by the position of load. PLSS loads that are placed high and forward on the torso resulted in less dynamically stable walking patterns than loads placed evenly and low on the torso. Furthermore, the kinematic results demonstrated that all joints of the lower extremity may be important for adjusting to different load placements and maintaining dynamic stability. Space scientists and engineers may want to consider PLSS designs that distribute loads evenly and low, and space suit designs that will not limit the sagittal plane range of motion at the lower extremity joints.

  10. Studies of the Stability and Dynamics of Levitated Drops

    Science.gov (United States)

    Anikumar, A.; Lee, Chun Ping; Wang, T. G.

    1996-01-01

    This is a review of our experimental and theoretical studies relating to equilibrium and stability of liquid drops, typically of low viscosity, levitated in air by a sound field. The major emphasis here is on the physical principles and understanding behind the stability of levitated drops. A comparison with experimental data is also given, along with some fascinating pictures from high-speed photography. One of the aspects we shall deal with is how a drop can suddenly burst in an intense sound field; a phenomenon which can find applications in atomization technology. Also, we are currently investigating the phenomenon of suppression of coalescence between drops levitated in intense acoustic fields.

  11. Metal hydride switchable mirrors: Factors influencing dynamic range and stability

    Energy Technology Data Exchange (ETDEWEB)

    Slack, Jonathan L.; Locke, James C.W.; Song, Seung-Wan; Ona, Jason; Richardson, Thomas J. [Lawrence Berkeley National Laboratory, Building Technologies Department, Environmental Energy Technologies Division, Berkeley, CA 94720 (United States)

    2006-03-06

    Palladium-coated magnesium-manganese-nickel films behave as gasochromic switchable mirrors, becoming transparent on exposure to dilute hydrogen, and reverting to a mirror state on exposure to air. The cycling stability of the optical switching depends upon preservation of the integrity of the Pd catalyst overlayer. Alloying between Mg and Pd causes interdiffusion of the two elements, and leads to degradation in switching speed and eventual deactivation. Incorporation of a thin niobium oxide barrier layer between the active magnesium alloy film and the Pd layer substantially improves the cycling stability of the mirror. (author)

  12. Stability properties of nonlinear dynamical systems and evolutionary stable states

    Energy Technology Data Exchange (ETDEWEB)

    Gleria, Iram, E-mail: iram@fis.ufal.br [Instituto de Física, Universidade Federal de Alagoas, 57072-970 Maceió-AL (Brazil); Brenig, Leon [Faculté des Sciences, Université Libre de Bruxelles, 1050 Brussels (Belgium); Rocha Filho, Tarcísio M.; Figueiredo, Annibal [Instituto de Física and International Center for Condensed Matter Physics, Universidade de Brasília, 70919-970 Brasília-DF (Brazil)

    2017-03-18

    Highlights: • We address the problem of equilibrium stability in a general class of non-linear systems. • We link Evolutionary Stable States (ESS) to stable fixed points of square quasi-polynomial (QP) systems. • We show that an interior ES point may be related to stable interior fixed points of QP systems. - Abstract: In this paper we address the problem of stability in a general class of non-linear systems. We establish a link between the concepts of asymptotic stable interior fixed points of square Quasi-Polynomial systems and evolutionary stable states, a property of some payoff matrices arising from evolutionary games.

  13. Molecular mechanisms of antitumor activity of taxanes. I. Interaction of docetaxel with microtubules

    Directory of Open Access Journals (Sweden)

    Sabina Tabaczar

    2010-11-01

    Full Text Available Docetaxel (Taxotere, a new semisynthetic taxoid, is a mitotic inhibitor, widely used in monotherapy or in combination with other anticancer drugs against many types of cancer. The structure and dynamics of microtubules as the main target for docetaxel activity inside the cell and the taxane-binding site on β-tubulin are discussed. Microtubules are highly dynamic assemblies of α- and β-tubulin. They readily polymerize and depolymerize in cells and these dynamic behaviours are crucial to cell mitosis. Microtubule instability is attributed to their capability to hydrolyze GTP to GDP, which causes their depolymerization. Addition of new α-, β-tubulin heterodimer bound to GTP leads to tubulin polymerization, which increases the length of the microtubule. Docetaxel alters the polymerization dynamics of microtubules, which causes blockage of cell mitosis, and consequently induces apoptotic and non-apoptotic cell death. Docetaxel specifically acts on the S, M and G2 phases of the cell cycle. This paper reviews the current state of knowledge related to the molecular mechanisms of docetaxel action on the cell cycle and microtubule dynamics. In addition, a brief survey of the present state of research on the new generation (2nd and 3rd of taxanes is presented.

  14. The kinesin-13 KLP10A motor regulates oocyte spindle length and affects EB1 binding without altering microtubule growth rates

    Directory of Open Access Journals (Sweden)

    Kevin K. Do

    2014-06-01

    Full Text Available Kinesin-13 motors are unusual in that they do not walk along microtubules, but instead diffuse to the ends, where they remove tubulin dimers, regulating microtubule dynamics. Here we show that Drosophila kinesin-13 klp10A regulates oocyte meiosis I spindle length and is haplo-insufficient – KLP10A, reduced by RNAi or a loss-of-function P element insertion mutant, results in elongated and mispositioned oocyte spindles, and abnormal cortical microtubule asters and aggregates. KLP10A knockdown by RNAi does not significantly affect microtubule growth rates in oocyte spindles, but, unexpectedly, EB1 binding and unbinding are slowed, suggesting a previously unobserved role for kinesin-13 in mediating EB1 binding interactions with microtubules. Kinesin-13 may regulate spindle length both by disassembling subunits from microtubule ends and facilitating EB1 binding to plus ends. We also observe an increased number of paused microtubules in klp10A RNAi knockdown spindles, consistent with a reduced frequency of microtubule catastrophes. Overall, our findings indicate that reduced kinesin-13 decreases microtubule disassembly rates and affects EB1 interactions with microtubules, rather than altering microtubule growth rates, causing spindles to elongate and abnormal cortical microtubule asters and aggregates to form.

  15. Impulsive and hybrid dynamical systems stability, dissipativity, and control

    CERN Document Server

    Haddad, Wassim M; Nersesov, Sergey G

    2014-01-01

    This book develops a general analysis and synthesis framework for impulsive and hybrid dynamical systems. Such a framework is imperative for modern complex engineering systems that involve interacting continuous-time and discrete-time dynamics with multiple modes of operation that place stringent demands on controller design and require implementation of increasing complexity--whether advanced high-performance tactical fighter aircraft and space vehicles, variable-cycle gas turbine engines, or air and ground transportation systems. Impulsive and Hybrid Dynamical Systems goes beyond similar

  16. Manipulation and quantification of microtubule lattice integrity

    Directory of Open Access Journals (Sweden)

    Taylor A. Reid

    2017-08-01

    Full Text Available Microtubules are structural polymers that participate in a wide range of cellular functions. The addition and loss of tubulin subunits allows the microtubule to grow and shorten, as well as to develop and repair defects and gaps in its cylindrical lattice. These lattice defects act to modulate the interactions of microtubules with molecular motors and other microtubule-associated proteins. Therefore, tools to control and measure microtubule lattice structure will be invaluable for developing a quantitative understanding of how the structural state of the microtubule lattice may regulate its interactions with other proteins. In this work, we manipulated the lattice integrity of in vitro microtubules to create pools of microtubules with common nucleotide states, but with variations in structural states. We then developed a series of novel semi-automated analysis tools for both fluorescence and electron microscopy experiments to quantify the type and severity of alterations in microtubule lattice integrity. These techniques will enable new investigations that explore the role of microtubule lattice structure in interactions with microtubule-associated proteins.

  17. Qualitative and quantitative analysis of stability and instability dynamics of positive lattice solitons.

    Science.gov (United States)

    Sivan, Y; Fibich, G; Ilan, B; Weinstein, M I

    2008-10-01

    We present a unified approach for qualitative and quantitative analysis of stability and instability dynamics of positive bright solitons in multidimensional focusing nonlinear media with a potential (lattice), which can be periodic, periodic with defects, quasiperiodic, single waveguide, etc. We show that when the soliton is unstable, the type of instability dynamic that develops depends on which of two stability conditions is violated. Specifically, violation of the slope condition leads to a focusing instability, whereas violation of the spectral condition leads to a drift instability. We also present a quantitative approach that allows one to predict the stability and instability strength.

  18. Adaptive Finite-Time Stabilization of High-Order Nonlinear Systems with Dynamic and Parametric Uncertainties

    Directory of Open Access Journals (Sweden)

    Meng-Meng Jiang

    2016-01-01

    Full Text Available Under the weaker assumption on nonlinear functions, the adaptive finite-time stabilization of more general high-order nonlinear systems with dynamic and parametric uncertainties is solved in this paper. To solve this problem, finite-time input-to-state stability (FTISS is used to characterize the unmeasured dynamic uncertainty. By skillfully combining Lyapunov function, sign function, backstepping, and finite-time input-to-state stability approaches, an adaptive state feedback controller is designed to guarantee high-order nonlinear systems are globally finite-time stable.

  19. On the internal dynamics of starless cores: stability of starless cores with internal motions and collapse dynamics

    CERN Document Server

    Seo, Young Min; Shirley, Yancy L

    2013-01-01

    In order to understand the collapse dynamics of observed low-mass starless cores, we revise the conventional stability condition of hydrostatic Bonnor-Ebert spheres to take internal motions into account. Because observed starless cores resemble Bonnor-Ebert density structures, the stability and dynamics of the starless cores are frequently analyzed by comparing to the conventional stability condition of a hydrostatic Bonnor-Ebert sphere. However, starless cores are not hydrostatic but have observed internal motions. In this study, we take gaseous spheres with a homologous internal velocity field and derive stability conditions of the spheres utilizing a virial analysis. We propose two limiting models of spontaneous gravitational collapse: the collapse of critical Bonnor-Ebert spheres and uniform density spheres. The collapse of these two limiting models are intended to provide the lower and the upper limits, respectively, of the infall speeds for a given density structure. The results of our study suggest tha...

  20. A Robust Stability and Control Theory for Hybrid Dynamical Systems

    Science.gov (United States)

    2006-09-30

    IEEE Transactions on Automatic Control , to...Dual Linear Differential Inclusions", IEEE Transactions on Automatic Control , Vol. 51, Issue 4, April 2006, pp. 661-666. D. Liberzon and J. Hespanha...34Stabilization of nonlinear systems with limited information feedback", IEEE Transactions on Automatic Control , vol. 50, no. 6, pp. 910-915,

  1. Robust adaptive dynamic programming and feedback stabilization of nonlinear systems.

    Science.gov (United States)

    Jiang, Yu; Jiang, Zhong-Ping

    2014-05-01

    This paper studies the robust optimal control design for a class of uncertain nonlinear systems from a perspective of robust adaptive dynamic programming (RADP). The objective is to fill up a gap in the past literature of adaptive dynamic programming (ADP) where dynamic uncertainties or unmodeled dynamics are not addressed. A key strategy is to integrate tools from modern nonlinear control theory, such as the robust redesign and the backstepping techniques as well as the nonlinear small-gain theorem, with the theory of ADP. The proposed RADP methodology can be viewed as an extension of ADP to uncertain nonlinear systems. Practical learning algorithms are developed in this paper, and have been applied to the controller design problems for a jet engine and a one-machine power system.

  2. A unifying energy-based approach to stability of power grids with market dynamics

    NARCIS (Netherlands)

    Stegink, Tjerk; De Persis, Claudio; van der Schaft, Arjan

    2016-01-01

    In this paper a unifying energy-based approach is provided to the modeling and stability analysis of power systems coupled with market dynamics. We consider a standard model of the power network with a third-order model for the synchronous generators involving voltage dynamics. By applying the prima

  3. Meteorological fluid dynamics asymptotic modelling, stability and chaotic atmospheric motion

    CERN Document Server

    Zeytounian, Radyadour K

    1991-01-01

    The author considers meteorology as a part of fluid dynamics. He tries to derive the properties of atmospheric flows from a rational analysis of the Navier-Stokes equations, at the same time analyzing various types of initial and boundary problems. This approach to simulate nature by models from fluid dynamics will be of interest to both scientists and students of physics and theoretical meteorology.

  4. Dynamic stability during level walking and obstacle crossing in persons with facioscapulohumeral muscular dystrophy.

    Science.gov (United States)

    Rijken, N H M; van Engelen, B G M; Geurts, A C H; Weerdesteyn, V

    2015-09-01

    Patients with FSHD suffer from progressive skeletal muscle weakness, which is associated with an elevated fall risk. To obtain insight into fall mechanisms in this patient group, we aimed to assess dynamic stability during level walking and obstacle crossing in patients at different disease stages. Ten patients with at least some lower extremity weakness were included, of whom six were classified as moderately affected and four as mildly affected. Ten healthy controls were also included. Level walking at comfortable speed was assessed, as well as crossing a 10 cm high wooden obstacle. We assessed forward and lateral dynamic stability, as well as spatiotemporal and kinematics variables. During level walking, the moderately affected group demonstrated a lower walking speed, which was accompanied by longer step times and smaller step lengths, yet dynamic stability was unaffected. When crossing the obstacle, however, the moderately affected patients demonstrated reduced forward stability margins during the trailing step, which was accompanied by an increased toe clearance and greater trunk and hip flexion. This suggests that during level walking, the patients effectively utilized compensatory strategies for maintaining dynamic stability, but that the moderately affected group lacked the capacity to fully compensate for the greater stability demands imposed by obstacle crossing, rendering them unable to maintain optimal stability levels. The present results highlight the difficulties that FSHD patients experience in performing this common activity of daily living and may help explain their propensity to fall in the forward direction.

  5. The microtubule-stabilizing agent discodermolide competitively inhibits the binding of paclitaxel (Taxol) to tubulin polymers, enhances tubulin nucleation reactions more potently than paclitaxel, and inhibits the growth of paclitaxel-resistant cells.

    Science.gov (United States)

    Kowalski, R J; Giannakakou, P; Gunasekera, S P; Longley, R E; Day, B W; Hamel, E

    1997-10-01

    The lactone-bearing polyhydroxylated alkatetraene (+)-discodermolide, which was isolated from the sponge Discodermia dissoluta, induces the polymerization of purified tubulin with and without microtubule-associated proteins or GTP, and the polymers formed are stable to cold and calcium. These effects are similar to those of paclitaxel (Taxol), but discodermolide is more potent. We confirmed that these properties represent hypernucleation phenomena; we obtained lower tubulin critical concentrations and shorter polymers with discodermolide than paclitaxel under a variety of reaction conditions. Furthermore, we demonstrated that discodermolide is a competitive inhibitor with [3H]paclitaxel in binding to tubulin polymer, with an apparent Ki value of 0.4 microM. Multidrug-resistant human colon and ovarian carcinoma cells overexpressing P-glycoprotein, which are 900- and 2800-fold resistant to paclitaxel, respectively, relative to the parental lines, retained significant sensitivity to discodermolide (25- and 89-fold more resistant relative to the parental lines). Ovarian carcinoma cells that are 20-30-fold more resistant to paclitaxel than the parental line on the basis of expression of altered beta-tubulin polypeptides retained nearly complete sensitivity to discodermolide. The effects of discodermolide on the reorganization of the microtubules of Potorous tridactylis kidney epithelial cells were examined at different times. Intracellular microtubules were reorganized into bundles in interphase cells much more rapidly after discodermolide treatment compared with paclitaxel treatment. A variety of spindle aberrations were observed after treatment with both drugs. The proportions of the different types of aberration were different for the two drugs and changed with the length of drug treatment.

  6. A review of dynamic stability of repulsive-force maglev suspension systems

    Energy Technology Data Exchange (ETDEWEB)

    Cai, Y.; Rote, D.M.

    1998-07-01

    Vehicle dynamics and the need to satisfy ride quality requirements have long been recognized as crucial to the commercial success of passenger-carrying transportation systems. Design concepts for maglev systems are no exception. Early maglev investigators and designers were well aware of the importance of ride quality and took care to ensure that their designs would meet acceptable ride quality standards. In contrast, the dynamic stability of electrodynamic suspension (EDS) systems, which has obvious implications for system safety and cost as well as for ride quality, has not received nearly as much attention. Because of the well-known under-damped nature of EDS suspension systems and the observation of instabilities in laboratory-scale model systems, it is prudent to develop a better understanding of vehicle stability characteristics. The work reported in this was undertaken with the intention of summarizing information that has been accumulated worldwide and that is relevant to dynamic stability of repulsive-force maglev suspension systems, assimilating that information, and gaining an understanding of the factors that influence that stability. Included in the paper is a discussion and comparison of results acquired from some representative tests of large-scale vehicles on linear test tracks, together with analytical and laboratory-scale investigations of stability and dynamics of EDS systems. This paper will also summarize the R and D activities at Argonne National Laboratory (ANL) since 1991 to study the nature of the forces that are operative in an EDS system and the dynamic stability of such systems.

  7. Research on Dynamics and Stability in the Stairs-Climbing of a Tracked Mobile Robot

    Directory of Open Access Journals (Sweden)

    Weijun Tao

    2012-10-01

    Full Text Available Aiming at the functional requirement of climbing up the stairs, the dynamics and stability during a tracked mobile robot's climbing of stairs is studied. First, from the analysis of its cross-country performance, the mechanical structure of the tracked mobile robot is designed and the hardware composition of its control system is given. Second, based on the analysis to its stairs-climbing process, the dynamical model of stairs-climbing is established by using the classical mechanics method. Next, the stability conditions for its stairs-climbing are determined and an evaluation method of its stairs-climbing stability is proposed, based on a mechanics analysis on the robot's backwards tumbling during the stairs-climbing process. Through simulation and experiments, the effectiveness of the dynamical model and the stability evaluation method of the tracked mobile robot in stairs-climbing is verified, which can provide design and analysis foundations for the tracked mobile robots' stairs-climbing.

  8. Microtubule-microtubule sliding by kinesin-1 is essential for normal cytoplasmic streaming in Drosophila oocytes.

    Science.gov (United States)

    Lu, Wen; Winding, Michael; Lakonishok, Margot; Wildonger, Jill; Gelfand, Vladimir I

    2016-08-23

    Cytoplasmic streaming in Drosophila oocytes is a microtubule-based bulk cytoplasmic movement. Streaming efficiently circulates and localizes mRNAs and proteins deposited by the nurse cells across the oocyte. This movement is driven by kinesin-1, a major microtubule motor. Recently, we have shown that kinesin-1 heavy chain (KHC) can transport one microtubule on another microtubule, thus driving microtubule-microtubule sliding in multiple cell types. To study the role of microtubule sliding in oocyte cytoplasmic streaming, we used a Khc mutant that is deficient in microtubule sliding but able to transport a majority of cargoes. We demonstrated that streaming is reduced by genomic replacement of wild-type Khc with this sliding-deficient mutant. Streaming can be fully rescued by wild-type KHC and partially rescued by a chimeric motor that cannot move organelles but is active in microtubule sliding. Consistent with these data, we identified two populations of microtubules in fast-streaming oocytes: a network of stable microtubules anchored to the actin cortex and free cytoplasmic microtubules that moved in the ooplasm. We further demonstrated that the reduced streaming in sliding-deficient oocytes resulted in posterior determination defects. Together, we propose that kinesin-1 slides free cytoplasmic microtubules against cortically immobilized microtubules, generating forces that contribute to cytoplasmic streaming and are essential for the refinement of posterior determinants.

  9. Stability of limit cycles in a pluripotent stem cell dynamics model

    Energy Technology Data Exchange (ETDEWEB)

    Adimy, Mostafa [Laboratoire de Mathematiques Appliquees UMR 5142, Universite de Pau et des Pays de l' Adour, Avenue de l' universite, 64000 Pau (France)] e-mail: mostafa.adimy@univ-pau.fr; Crauste, Fabien [Laboratoire de Mathematiques Appliquees UMR 5142, Universite de Pau et des Pays de l' Adour, Avenue de l' universite, 64000 Pau (France)] e-mail: fabien.crauste@univ-pau.fr; Halanay, Andrei [Department of Mathematics 1, University Politehnica of Bucharest, Splaiul Independentei 313, RO-060042, Bucharest (Romania)] e-mail: halanay@vectron.mathem.pub.ro; Neamtu, Mihaela [Faculty of Economics, I.N. Pestalozzi 16, West University of Timisoara, RO-300115, Timisoara (Romania)] e-mail: mihaela.neamtu@fse.uvt.ro; Opris, Dumitru [Department of Applied Mathematics, Faculty of Mathematics, Bd. V. Parvan 4, West University of Timisoara, RO-300223, Timisoara (Romania)] e-mail: opris@math.uvt.ro

    2006-02-01

    This paper is devoted to the study of the stability of limit cycles of a nonlinear delay differential equation with a distributed delay. The equation arises from a model of population dynamics describing the evolution of a pluripotent stem cells population. We study the local asymptotic stability of the unique nontrivial equilibrium of the delay equation and we show that its stability can be lost through a Hopf bifurcation. We then investigate the stability of the limit cycles yielded by the bifurcation using the normal form theory and the center manifold theorem. We illustrate our results with some numerics.

  10. Atomic-resolution structure of the CAP-Gly domain of dynactin on polymeric microtubules determined by magic angle spinning NMR spectroscopy

    Science.gov (United States)

    Yan, Si; Guo, Changmiao; Hou, Guangjin; Zhang, Huilan; Lu, Xingyu; Williams, John Charles; Polenova, Tatyana

    2015-01-01

    Microtubules and their associated proteins perform a broad array of essential physiological functions, including mitosis, polarization and differentiation, cell migration, and vesicle and organelle transport. As such, they have been extensively studied at multiple levels of resolution (e.g., from structural biology to cell biology). Despite these efforts, there remain significant gaps in our knowledge concerning how microtubule-binding proteins bind to microtubules, how dynamics connect different conformational states, and how these interactions and dynamics affect cellular processes. Structures of microtubule-associated proteins assembled on polymeric microtubules are not known at atomic resolution. Here, we report a structure of the cytoskeleton-associated protein glycine-rich (CAP-Gly) domain of dynactin motor on polymeric microtubules, solved by magic angle spinning NMR spectroscopy. We present the intermolecular interface of CAP-Gly with microtubules, derived by recording direct dipolar contacts between CAP-Gly and tubulin using double rotational echo double resonance (dREDOR)-filtered experiments. Our results indicate that the structure adopted by CAP-Gly varies, particularly around its loop regions, permitting its interaction with multiple binding partners and with the microtubules. To our knowledge, this study reports the first atomic-resolution structure of a microtubule-associated protein on polymeric microtubules. Our approach lays the foundation for atomic-resolution structural analysis of other microtubule-associated motors. PMID:26604305

  11. Atomic-resolution structure of the CAP-Gly domain of dynactin on polymeric microtubules determined by magic angle spinning NMR spectroscopy.

    Science.gov (United States)

    Yan, Si; Guo, Changmiao; Hou, Guangjin; Zhang, Huilan; Lu, Xingyu; Williams, John Charles; Polenova, Tatyana

    2015-11-24

    Microtubules and their associated proteins perform a broad array of essential physiological functions, including mitosis, polarization and differentiation, cell migration, and vesicle and organelle transport. As such, they have been extensively studied at multiple levels of resolution (e.g., from structural biology to cell biology). Despite these efforts, there remain significant gaps in our knowledge concerning how microtubule-binding proteins bind to microtubules, how dynamics connect different conformational states, and how these interactions and dynamics affect cellular processes. Structures of microtubule-associated proteins assembled on polymeric microtubules are not known at atomic resolution. Here, we report a structure of the cytoskeleton-associated protein glycine-rich (CAP-Gly) domain of dynactin motor on polymeric microtubules, solved by magic angle spinning NMR spectroscopy. We present the intermolecular interface of CAP-Gly with microtubules, derived by recording direct dipolar contacts between CAP-Gly and tubulin using double rotational echo double resonance (dREDOR)-filtered experiments. Our results indicate that the structure adopted by CAP-Gly varies, particularly around its loop regions, permitting its interaction with multiple binding partners and with the microtubules. To our knowledge, this study reports the first atomic-resolution structure of a microtubule-associated protein on polymeric microtubules. Our approach lays the foundation for atomic-resolution structural analysis of other microtubule-associated motors.

  12. STUDY ON DYNAMICS, STABILITY AND CONTROL OF MULTI-BODY FLEXIBLE STRUCTURE SYSTEM IN FUNCTIONAL SPACE

    Institute of Scientific and Technical Information of China (English)

    徐建国; 贾军国

    2001-01-01

    The dynamics, stability and control problem of a kind of infinite dimensional system are studied in the functional space with the method of modern mathematics. First,the dynamical control model of the distributed parameter system with multi-body flexible and multi-topological structure was established which has damping, gyroscopic parts and constrained damping. Secondly, the necessary and sufficient condition of controllability and observability, the stability theory and asymptotic property of the system were obtained.These results expand the theory of the field about the dynamics and control of the system with multi-body flexible structure, and have important engineering significance.

  13. THE STABILIZATION SYSTEM ON PAYLOAD BUILT ON A DYNAMICALLY TUNED GYROSCOPE

    Directory of Open Access Journals (Sweden)

    D. M. Malyutin

    2016-01-01

    Full Text Available It is now widely distributed systems stabilization based on gyroscopes with three-degree-freedom and based on gyroscopes with ball suspension. The accuracy and resource of operation of such systems requires an increase. The problem of improving the accuracy and increasing the service life of information – measuring systems of stabilization can be solved by using as a sensitive element of a dynamically tuned gyroscope. Today the issue of achieving the potential of the metrological characteristics of information-measuring systems stabilization on dynamically tuned gyroscope is not fully resolved. It requires the development of mathematical models, different from the known, detailed description of the perturbations acting on a device. In addition, it is necessary to develop structures amplifying-transforming paths of the contours stabilization of information-measuring systems of stabilization on dynamically tuned gyroscopes, assuring higher accuracy and noise immunity of the system, what is the purpose of the work. In using the Euler equations obtained a complete mathematical model of functioning system with three motion bases, in detail taking into account the disturbances acting on the device. Considered are the peculiarities of mathematical description of dynamically tuned gyroscope. Dominant frequencies of components noise is identified in the output signal of the gyroscope. The original scheme of the contours stabilization is presented, that help increase the accuracy of stabilization at low frequencies and of providing the absence of systematic drift of the gyrostabilizer from the action of the permanent disturbing moment along the axis of stabilization. The dynamic calculations show the possibility of providing error of stabilization on payload not more than 0,0042 degree. 

  14. Localized Aurora B activity spatially controls non-kinetochore microtubules during spindle assembly.

    Science.gov (United States)

    Tanenbaum, Marvin E; Medema, René H

    2011-12-01

    Efficient spindle assembly involves the generation of spatial cues around chromosomes that locally stabilize microtubule (MT) plus-ends. In addition to the small GTPase Ran, there is evidence that Aurora B kinase might also generate a spatial cue around chromosomes but direct proof for this is still lacking. Here, we find that the Aurora B substrate MCAK localizes to MT plus-ends throughout the mitotic spindle, but its accumulation is strongly reduced on MT plus-ends near chromatin, suggesting that a signal emanating from chromosomes negatively regulates MCAK plus-end binding. Indeed, we show that Aurora B is the kinase responsible for producing this chromosome-derived signal. These results are the first to visualize spatially restricted Aurora B kinase activity around chromosomes on an endogenous substrate and explain how Aurora B could spatially control the dynamics of non-kinetochore MTs during spindle assembly.

  15. A Stochastic Multiscale Model That Explains the Segregation of Axonal Microtubules and Neurofilaments in Neurological Diseases.

    Directory of Open Access Journals (Sweden)

    Chuan Xue

    2015-08-01

    Full Text Available The organization of the axonal cytoskeleton is a key determinant of the normal function of an axon, which is a long thin projection of a neuron. Under normal conditions two axonal cytoskeletal polymers, microtubules and neurofilaments, align longitudinally in axons and are interspersed in axonal cross-sections. However, in many neurotoxic and neurodegenerative disorders, microtubules and neurofilaments segregate apart from each other, with microtubules and membranous organelles clustered centrally and neurofilaments displaced to the periphery. This striking segregation precedes the abnormal and excessive neurofilament accumulation in these diseases, which in turn leads to focal axonal swellings. While neurofilament accumulation suggests an impairment of neurofilament transport along axons, the underlying mechanism of their segregation from microtubules remains poorly understood for over 30 years. To address this question, we developed a stochastic multiscale model for the cross-sectional distribution of microtubules and neurofilaments in axons. The model describes microtubules, neurofilaments and organelles as interacting particles in a 2D cross-section, and is built upon molecular processes that occur on a time scale of seconds or shorter. It incorporates the longitudinal transport of neurofilaments and organelles through this domain by allowing stochastic arrival and departure of these cargoes, and integrates the dynamic interactions of these cargoes with microtubules mediated by molecular motors. Simulations of the model demonstrate that organelles can pull nearby microtubules together, and in the absence of neurofilament transport, this mechanism gradually segregates microtubules from neurofilaments on a time scale of hours, similar to that observed in toxic neuropathies. This suggests that the microtubule-neurofilament segregation can be a consequence of the selective impairment of neurofilament transport. The model generates the

  16. Distributed-Order Dynamic Systems Stability, Simulation, Applications and Perspectives

    CERN Document Server

    Jiao, Zhuang; Podlubny, Igor

    2012-01-01

    Distributed-order differential equations, a generalization of fractional calculus, are of increasing importance in many fields of science and engineering from the behaviour of complex dielectric media to the modelling of nonlinear systems. This Brief will broaden the toolbox available to researchers interested in modeling, analysis, control and filtering. It contains contextual material outlining the progression from integer-order, through fractional-order to distributed-order systems. Stability issues are addressed with graphical and numerical results highlighting the fundamental differences between constant-, integer-, and distributed-order treatments. The power of the distributed-order model is demonstrated with work on the stability of noncommensurate-order linear time-invariant systems. Generic applications of the distributed-order operator follow: signal processing and viscoelastic damping of a mass–spring set up. A new general approach to discretization of distributed-order derivatives and integrals ...

  17. Static-dynamic stability of the body gymnasts qualifications

    Directory of Open Access Journals (Sweden)

    Litvinenko Y.V.

    2015-01-01

    Full Text Available Purpose: evaluation of individual ways of postural control gymnasts skilled in solving problems on the stability of the body in the motor tests. Material : The study involved engaged in gymnastics (n = 9. The measurements were carried out on the platform stabilographic Kistler. Tests used: handstand, Biryuk sample, sample Romberg. Results: set individual ways microvibrations parts of the body and makrokolebany in the sagittal and frontal planes. Joined symmetry and asymmetry postural control of the body, the various indicators of energy expenditure. The quality of postural control in the performance of motor tests were deterministic complex conditions of body position on the support, limited visual orientation. Also corresponds to the test specificity of the sport. Conclusions : The method microvibrations in solving problems on the stability of the body in the motor tests gymnasts is the most strategically important for the effective development and management of a system of regulation poses athlete. Confirmation rates are economical expenditure of energy during motor tests.

  18. Nonlinear dynamics of human locomotion: effects of rhythmic auditory cueing on local dynamic stability

    Directory of Open Access Journals (Sweden)

    Philippe eTerrier

    2013-09-01

    Full Text Available It has been observed that times series of gait parameters (stride length (SL, stride time (ST and stride speed (SS, exhibit long-term persistence and fractal-like properties. Synchronizing steps with rhythmic auditory stimuli modifies the persistent fluctuation pattern to anti-persistence. Another nonlinear method estimates the degree of resilience of gait control to small perturbations, i.e. the local dynamic stability (LDS. The method makes use of the maximal Lyapunov exponent, which estimates how fast a nonlinear system embedded in a reconstructed state space (attractor diverges after an infinitesimal perturbation. We propose to use an instrumented treadmill to simultaneously measure basic gait parameters (time series of SL, ST and SS from which the statistical persistence among consecutive strides can be assessed, and the trajectory of the center of pressure (from which the LDS can be estimated. In 20 healthy participants, the response to rhythmic auditory cueing (RAC of LDS and of statistical persistence (assessed with detrended fluctuation analysis (DFA was compared. By analyzing the divergence curves, we observed that long-term LDS (computed as the reverse of the average logarithmic rate of divergence between the 4th and the 10th strides downstream from nearest neighbors in the reconstructed attractor was strongly enhanced (relative change +47%. That is likely the indication of a more dampened dynamics. The change in short-term LDS (divergence over one step was smaller (+3%. DFA results (scaling exponents confirmed an anti-persistent pattern in ST, SL and SS. Long-term LDS (but not short-term LDS and scaling exponents exhibited a significant correlation between them (r=0.7. Both phenomena probably result from the more conscious/voluntary gait control that is required by RAC. We suggest that LDS and statistical persistence should be used to evaluate the efficiency of cueing therapy in patients with neurological gait disorders.

  19. α-Synuclein Fibrils Exhibit Gain of Toxic Function, Promoting Tau Aggregation and Inhibiting Microtubule Assembly*

    Science.gov (United States)

    Oikawa, Takayuki; Nonaka, Takashi; Terada, Makoto; Tamaoka, Akira; Hisanaga, Shin-ichi; Hasegawa, Masato

    2016-01-01

    α-Synuclein is the major component of Lewy bodies and Lewy neurites in Parkinson disease and dementia with Lewy bodies and of glial cytoplasmic inclusions in multiple system atrophy. It has been suggested that α-synuclein fibrils or intermediate protofibrils in the process of fibril formation may have a toxic effect on neuronal cells. In this study, we investigated the ability of soluble monomeric α-synuclein to promote microtubule assembly and the effects of conformational changes of α-synuclein on Tau-promoted microtubule assembly. In marked contrast to previous findings, monomeric α-synuclein had no effect on microtubule polymerization. However, both α-synuclein fibrils and protofibrils inhibited Tau-promoted microtubule assembly. The inhibitory effect of α-synuclein fibrils was greater than that of the protofibrils. Dot blot overlay assay and spin-down techniques revealed that α-synuclein fibrils bind to Tau and inhibit microtubule assembly by depleting the Tau available for microtubule polymerization. Using various deletion mutants of α-synuclein and Tau, the acidic C-terminal region of α-synuclein and the basic central region of Tau were identified as regions involved in the binding. Furthermore, introduction of α-synuclein fibrils into cultured cells overexpressing Tau protein induced Tau aggregation. These results raise the possibility that α-synuclein fibrils interact with Tau, inhibit its function to stabilize microtubules, and also promote Tau aggregation, leading to dysfunction of neuronal cells. PMID:27226637