Acceleration of the sliding movement of actin filaments with the use of a non-motile mutant myosin in in vitro motility assays driven by skeletal muscle heavy meromyosin.

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Kohei Iwase

Full Text Available We examined the movement of an actin filament sliding on a mixture of normal and genetically modified myosin molecules that were attached to a glass surface. For this purpose, we used a Dictyostelium G680V mutant myosin II whose release rates of Pi and ADP were highly suppressed relative to normal myosin, leading to a significantly extended life-time of the strongly bound state with actin and virtually no motility. When the mixing ratio of G680V mutant myosin II to skeletal muscle HMM (heavy myosin was 0.01%, the actin filaments moved intermittently. When they moved, their sliding velocities were about two-fold faster than the velocity of skeletal HMM alone. Furthermore, sliding movements were also faster when the actin filaments were allowed to slide on skeletal muscle HMM-coated glass surfaces in the motility buffer solution containing G680V HMM. In this case no intermittent movement was observed. When the actin filaments used were copolymerized with a fusion protein consisting of Dictyostelium actin and Dictyostelium G680V myosin II motor domain, similar faster sliding movements were observed on skeletal muscle HMM-coated surfaces. The filament sliding velocities were about two-fold greater than the velocities of normal actin filaments. We found that the velocity of actin filaments sliding on skeletal muscle myosin molecules increased in the presence of a non-motile G680V mutant myosin motor.

Gene transfer, expression, and sarcomeric incorporation of a headless myosin molecule in cardiac myocytes: evidence for a reserve in myofilament motor function

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Vandenboom, Rene; Herron, Todd; Favre, Elizabeth; Albayya, Faris P.

2011-01-01

The purpose of this study was to implement a living myocyte in vitro model system to test whether a motor domain-deleted headless myosin construct could be incorporated into the sarcomere and affect contractility. To this end we used gene transfer to express a “headless” myosin heavy chain (headless-MHC) in complement with the native full-length myosin motors in the cardiac sarcomere. An NH2-terminal Flag epitope was used for unique detection of the motor domain-deleted headless-MHC. Total MHC content (i.e., headless-MHC + endogenous MHC) remained constant, while expression of the headless-MHC in transduced myocytes increased from 24 to 72 h after gene transfer until values leveled off at 96 h after gene transfer, at which time the headless-MHC comprised ∼20% of total MHC. Moreover, immunofluorescence labeling and confocal imaging confirmed expression and demonstrated incorporation of the headless-MHC in the A band of the cardiac sarcomere. Functional measurements in intact myocytes showed that headless-MHC modestly reduced amplitude of dynamic twitch contractions compared with controls (P < 0.05). In chemically permeabilized myocytes, maximum steady-state isometric force and the tension-pCa relationship were unaltered by the headless-MHC. These data suggest that headless-MHC can express to 20% of total myosin and incorporate into the sarcomere yet have modest to no effects on dynamic and steady-state contractile function. This would indicate a degree of functional tolerance in the sarcomere for nonfunctional myosin molecules. PMID:21112946

Harmonic Force Spectroscopy Reveals a Force-Velocity Curve from a Single Human Beta Cardiac Myosin Motor

DEFF Research Database (Denmark)

Sung, Jongmin; Nag, Suman; Vestergaard, Christian L.

2014-01-01

human beta cardiac myosin S1. We also compare load-velocity curves for wild-type motors with load-velocity curves of mutant forms that cause hypertrophic or dilated-cardiomyopathy (HCM or DCM), in order to understand the effects of mutations on the contractile cycle at the single molecule level....

Robust mechanobiological behavior emerges in heterogeneous myosin systems

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Egan, Paul F.; Moore, Jeffrey R.; Ehrlicher, Allen J.; Weitz, David A.; Schunn, Christian; Cagan, Jonathan; LeDuc, Philip

2017-09-01

Biological complexity presents challenges for understanding natural phenomenon and engineering new technologies, particularly in systems with molecular heterogeneity. Such complexity is present in myosin motor protein systems, and computational modeling is essential for determining how collective myosin interactions produce emergent system behavior. We develop a computational approach for altering myosin isoform parameters and their collective organization, and support predictions with in vitro experiments of motility assays with α-actinins as molecular force sensors. The computational approach models variations in single myosin molecular structure, system organization, and force stimuli to predict system behavior for filament velocity, energy consumption, and robustness. Robustness is the range of forces where a filament is expected to have continuous velocity and depends on used myosin system energy. Myosin systems are shown to have highly nonlinear behavior across force conditions that may be exploited at a systems level by combining slow and fast myosin isoforms heterogeneously. Results suggest some heterogeneous systems have lower energy use near stall conditions and greater energy consumption when unloaded, therefore promoting robustness. These heterogeneous system capabilities are unique in comparison with homogenous systems and potentially advantageous for high performance bionanotechnologies. Findings open doors at the intersections of mechanics and biology, particularly for understanding and treating myosin-related diseases and developing approaches for motor molecule-based technologies.

Evolutionary traces decode molecular mechanism behind fast pace of myosin XI

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Syamaladevi Divya P

2011-09-01

Full Text Available Abstract Background Cytoplasmic class XI myosins are the fastest processive motors known. This class functions in high-velocity cytoplasmic streaming in various plant cells from algae to angiosperms. The velocities at which they process are ten times faster than its closest class V homologues. Results To provide sequence determinants and structural rationale for the molecular mechanism of this fast pace myosin, we have compared the sequences from myosin class V and XI through Evolutionary Trace (ET analysis. The current study identifies class-specific residues of myosin XI spread over the actin binding site, ATP binding site and light chain binding neck region. Sequences for ET analysis were accumulated from six plant genomes, using literature based text search and sequence searches, followed by triple validation viz. CDD search, string-based searches and phylogenetic clustering. We have identified nine myosin XI genes in sorghum and seven in grape by sequence searches. Both the plants possess one gene product each belonging to myosin type VIII as well. During this process, we have re-defined the gene boundaries for three sorghum myosin XI genes using fgenesh program. Conclusion Molecular modelling and subsequent analysis of putative interactions involving these class-specific residues suggest a structural basis for the molecular mechanism behind high velocity of plant myosin XI. We propose a model of a more flexible switch I region that contributes to faster ADP release leading to high velocity movement of the algal myosin XI.

A Role for Myosin Va in Human Cytomegalovirus Nuclear Egress.

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Wilkie, Adrian R; Sharma, Mayuri; Pesola, Jean M; Ericsson, Maria; Fernandez, Rosio; Coen, Donald M

2018-03-15

Herpesviruses replicate and package their genomes into capsids in replication compartments within the nuclear interior. Capsids then move to the inner nuclear membrane for envelopment and release into the cytoplasm in a process called nuclear egress. We previously found that nuclear F-actin is induced upon infection with the betaherpesvirus human cytomegalovirus (HCMV) and is important for nuclear egress and capsid localization away from replication compartment-like inclusions toward the nuclear rim. Despite these and related findings, it has not been shown that any specific motor protein is involved in herpesvirus nuclear egress. In this study, we have investigated whether the host motor protein, myosin Va, could be fulfilling this role. Using immunofluorescence microscopy and coimmunoprecipitation, we observed associations between a nuclear population of myosin Va and the viral major capsid protein, with both concentrating at the periphery of replication compartments. Immunoelectron microscopy showed that nearly 40% of assembled nuclear capsids associate with myosin Va. We also found that myosin Va and major capsid protein colocalize with nuclear F-actin. Importantly, antagonism of myosin Va with RNA interference or a dominant negative mutant revealed that myosin Va is important for the efficient production of infectious virus, capsid accumulation in the cytoplasm, and capsid localization away from replication compartment-like inclusions toward the nuclear rim. Our results lead us to suggest a working model whereby human cytomegalovirus capsids associate with myosin Va for movement from replication compartments to the nuclear periphery during nuclear egress. IMPORTANCE Little is known regarding how newly assembled and packaged herpesvirus capsids move from the nuclear interior to the periphery during nuclear egress. While it has been proposed that an actomyosin-based mechanism facilitates intranuclear movement of alphaherpesvirus capsids, a functional role for

Auxotonic to isometric contraction transitioning in a beating heart causes myosin step-size to down shift.

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Thomas P Burghardt

Full Text Available Myosin motors in cardiac ventriculum convert ATP free energy to the work of moving blood volume under pressure. The actin bound motor cyclically rotates its lever-arm/light-chain complex linking motor generated torque to the myosin filament backbone and translating actin against resisting force. Previous research showed that the unloaded in vitro motor is described with high precision by single molecule mechanical characteristics including unitary step-sizes of approximately 3, 5, and 8 nm and their relative step-frequencies of approximately 13, 50, and 37%. The 3 and 8 nm unitary step-sizes are dependent on myosin essential light chain (ELC N-terminus actin binding. Step-size and step-frequency quantitation specifies in vitro motor function including duty-ratio, power, and strain sensitivity metrics. In vivo, motors integrated into the muscle sarcomere form the more complex and hierarchically functioning muscle machine. The goal of the research reported here is to measure single myosin step-size and step-frequency in vivo to assess how tissue integration impacts motor function. A photoactivatable GFP tags the ventriculum myosin lever-arm/light-chain complex in the beating heart of a live zebrafish embryo. Detected single GFP emission reports time-resolved myosin lever-arm orientation interpreted as step-size and step-frequency providing single myosin mechanical characteristics over the active cycle. Following step-frequency of cardiac ventriculum myosin transitioning from low to high force in relaxed to auxotonic to isometric contraction phases indicates that the imposition of resisting force during contraction causes the motor to down-shift to the 3 nm step-size accounting for >80% of all the steps in the near-isometric phase. At peak force, the ATP initiated actomyosin dissociation is the predominant strain inhibited transition in the native myosin contraction cycle. The proposed model for motor down-shifting and strain sensing involves ELC N

Distinct functional interactions between actin isoforms and nonsarcomeric myosins.

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Mirco Müller

Full Text Available Despite their near sequence identity, actin isoforms cannot completely replace each other in vivo and show marked differences in their tissue-specific and subcellular localization. Little is known about isoform-specific differences in their interactions with myosin motors and other actin-binding proteins. Mammalian cytoplasmic β- and γ-actin interact with nonsarcomeric conventional myosins such as the members of the nonmuscle myosin-2 family and myosin-7A. These interactions support a wide range of cellular processes including cytokinesis, maintenance of cell polarity, cell adhesion, migration, and mechano-electrical transduction. To elucidate differences in the ability of isoactins to bind and stimulate the enzymatic activity of individual myosin isoforms, we characterized the interactions of human skeletal muscle α-actin, cytoplasmic β-actin, and cytoplasmic γ-actin with human myosin-7A and nonmuscle myosins-2A, -2B and -2C1. In the case of nonmuscle myosins-2A and -2B, the interaction with either cytoplasmic actin isoform results in 4-fold greater stimulation of myosin ATPase activity than was observed in the presence of α-skeletal muscle actin. Nonmuscle myosin-2C1 is most potently activated by β-actin and myosin-7A by γ-actin. Our results indicate that β- and γ-actin isoforms contribute to the modulation of nonmuscle myosin-2 and myosin-7A activity and thereby to the spatial and temporal regulation of cytoskeletal dynamics. FRET-based analyses show efficient copolymerization abilities for the actin isoforms in vitro. Experiments with hybrid actin filaments show that the extent of actomyosin coupling efficiency can be regulated by the isoform composition of actin filaments.

Non-muscle myosin II in disease: mechanisms and therapeutic opportunities

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Karen A. Newell-Litwa

2015-12-01

Full Text Available The actin motor protein non-muscle myosin II (NMII acts as a master regulator of cell morphology, with a role in several essential cellular processes, including cell migration and post-synaptic dendritic spine plasticity in neurons. NMII also generates forces that alter biochemical signaling, by driving changes in interactions between actin-associated proteins that can ultimately regulate gene transcription. In addition to its roles in normal cellular physiology, NMII has recently emerged as a critical regulator of diverse, genetically complex diseases, including neuronal disorders, cancers and vascular disease. In the context of these disorders, NMII regulatory pathways can be directly mutated or indirectly altered by disease-causing mutations. NMII regulatory pathway genes are also increasingly found in disease-associated copy-number variants, particularly in neuronal disorders such as autism and schizophrenia. Furthermore, manipulation of NMII-mediated contractility regulates stem cell pluripotency and differentiation, thus highlighting the key role of NMII-based pharmaceuticals in the clinical success of stem cell therapies. In this Review, we discuss the emerging role of NMII activity and its regulation by kinases and microRNAs in the pathogenesis and prognosis of a diverse range of diseases, including neuronal disorders, cancer and vascular disease. We also address promising clinical applications and limitations of NMII-based inhibitors in the treatment of these diseases and the development of stem-cell-based therapies.

Myosin phosphatase Fine-tunes Zebrafish Motoneuron Position during Axonogenesis.

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Juliane Bremer

2016-11-01

Full Text Available During embryogenesis the spinal cord shifts position along the anterior-posterior axis relative to adjacent tissues. How motor neurons whose cell bodies are located in the spinal cord while their axons reside in adjacent tissues compensate for such tissue shift is not well understood. Using live cell imaging in zebrafish, we show that as motor axons exit from the spinal cord and extend through extracellular matrix produced by adjacent notochord cells, these cells shift several cell diameters caudally. Despite this pronounced shift, individual motoneuron cell bodies stay aligned with their extending axons. We find that this alignment requires myosin phosphatase activity within motoneurons, and that mutations in the myosin phosphatase subunit mypt1 increase myosin phosphorylation causing a displacement between motoneuron cell bodies and their axons. Thus, we demonstrate that spinal motoneurons fine-tune their position during axonogenesis and we identify the myosin II regulatory network as a key regulator.

Advances in quantum simulations of ATPase catalysis in the myosin motor.

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Kiani, Farooq Ahmad; Fischer, Stefan

2015-04-01

During its contraction cycle, the myosin motor catalyzes the hydrolysis of ATP. Several combined quantum/classical mechanics (QM/MM) studies of this step have been published, which substantially contributed to our thinking about the catalytic mechanism. The methodological difficulties encountered over the years in the simulation of this complex reaction are now understood: (a) Polarization of the protein peptide groups surrounding the highly charged ATP(4-) cannot be neglected. (b) Some unsuspected protein groups need to be treated QM. (c) Interactions with the γ-phosphate versus the β-phosphate favor a concurrent versus a sequential mechanism, respectively. Thus, these practical aspects strongly influence the computed mechanism, and should be considered when studying other catalyzed phosphor-ester hydrolysis reactions, such as in ATPases or GTPases. Copyright © 2015 Elsevier Ltd. All rights reserved.

Formation of contractile networks and fibers in the medial cell cortex through myosin-II turnover, contraction, and stress-stabilization.

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Nie, Wei; Wei, Ming-Tzo; Ou-Yang, H Daniel; Jedlicka, Sabrina S; Vavylonis, Dimitrios

2015-01-01

The morphology of adhered cells depends crucially on the formation of a contractile meshwork of parallel and cross-linked fibers along the contacting surface. The motor activity and minifilament assembly of non-muscle myosin-II is an important component of cortical cytoskeletal remodeling during mechanosensing. We used experiments and computational modeling to study cortical myosin-II dynamics in adhered cells. Confocal microscopy was used to image the medial cell cortex of HeLa cells stably expressing myosin regulatory light chain tagged with GFP (MRLC-GFP). The distribution of MRLC-GFP fibers and focal adhesions was classified into three types of network morphologies. Time-lapse movies show: myosin foci appearance and disappearance; aligning and contraction; stabilization upon alignment. Addition of blebbistatin, which perturbs myosin motor activity, leads to a reorganization of the cortical networks and to a reduction of contractile motions. We quantified the kinetics of contraction, disassembly and reassembly of myosin networks using spatio-temporal image correlation spectroscopy (STICS). Coarse-grained numerical simulations include bipolar minifilaments that contract and align through specified interactions as basic elements. After assuming that minifilament turnover decreases with increasing contractile stress, the simulations reproduce stress-dependent fiber formation in between focal adhesions above a threshold myosin concentration. The STICS correlation function in simulations matches the function measured in experiments. This study provides a framework to help interpret how different cortical myosin remodeling kinetics may contribute to different cell shape and rigidity depending on substrate stiffness. © 2015 Wiley Periodicals, Inc.

Myosin-Powered Membrane Compartment Drives Cytoplasmic Streaming, Cell Expansion and Plant Development.

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Peremyslov, Valera V; Cole, Rex A; Fowler, John E; Dolja, Valerian V

2015-01-01

Using genetic approaches, particle image velocimetry and an inert tracer of cytoplasmic streaming, we have made a mechanistic connection between the motor proteins (myosins XI), cargo transported by these motors (distinct endomembrane compartment defined by membrane-anchored MyoB receptors) and the process of cytoplasmic streaming in plant cells. It is shown that the MyoB compartment in Nicotiana benthamiana is highly dynamic moving with the mean velocity of ~3 μm/sec. In contrast, Golgi, mitochondria, peroxisomes, carrier vesicles and a cytosol flow tracer share distinct velocity profile with mean velocities of 0.6-1.5 μm/sec. Dominant negative inhibition of the myosins XI or MyoB receptors using overexpression of the N. benthamiana myosin cargo-binding domain or MyoB myosin-binding domain, respectively, resulted in velocity reduction for not only the MyoB compartment, but also each of the tested organelles, vesicles and cytoplasmic streaming. Furthermore, the extents of this reduction were similar for each of these compartments suggesting that MyoB compartment plays primary role in cytosol dynamics. Using gene knockout analysis in Arabidopsis thaliana, it is demonstrated that inactivation of MyoB1-4 results in reduced velocity of mitochondria implying slower cytoplasmic streaming. It is also shown that myosins XI and MyoB receptors genetically interact to contribute to cell expansion, plant growth, morphogenesis and proper onset of flowering. These results support a model according to which myosin-dependent, MyoB receptor-mediated transport of a specialized membrane compartment that is conserved in all land plants drives cytoplasmic streaming that carries organelles and vesicles and facilitates cell growth and plant development.

Distribution and evolution of stable single α-helices (SAH domains in myosin motor proteins.

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Dominic Simm

Full Text Available Stable single-alpha helices (SAHs are versatile structural elements in many prokaryotic and eukaryotic proteins acting as semi-flexible linkers and constant force springs. This way SAH-domains function as part of the lever of many different myosins. Canonical myosin levers consist of one or several IQ-motifs to which light chains such as calmodulin bind. SAH-domains provide flexibility in length and stiffness to the myosin levers, and may be particularly suited for myosins working in crowded cellular environments. Although the function of the SAH-domains in human class-6 and class-10 myosins has well been characterised, the distribution of the SAH-domain in all myosin subfamilies and across the eukaryotic tree of life remained elusive. Here, we analysed the largest available myosin sequence dataset consisting of 7919 manually annotated myosin sequences from 938 species representing all major eukaryotic branches using the SAH-prediction algorithm of Waggawagga, a recently developed tool for the identification of SAH-domains. With this approach we identified SAH-domains in more than one third of the supposed 79 myosin subfamilies. Depending on the myosin class, the presence of SAH-domains can range from a few to almost all class members indicating complex patterns of independent and taxon-specific SAH-domain gain and loss.

Phrenic motor unit recruitment during ventilatory and non-ventilatory behaviors.

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Mantilla, Carlos B; Sieck, Gary C

2011-10-15

Phrenic motoneurons are located in the cervical spinal cord and innervate the diaphragm muscle, the main inspiratory muscle in mammals. Similar to other skeletal muscles, phrenic motoneurons and diaphragm muscle fibers form motor units which are the final element of neuromotor control. In addition to their role in sustaining ventilation, phrenic motor units are active in other non-ventilatory behaviors important for airway clearance such as coughing or sneezing. Diaphragm muscle fibers comprise all fiber types and are commonly classified based on expression of contractile proteins including myosin heavy chain isoforms. Although there are differences in contractile and fatigue properties across motor units, there is a matching of properties for the motor neuron and muscle fibers within a motor unit. Motor units are generally recruited in order such that fatigue-resistant motor units are recruited earlier and more often than more fatigable motor units. Thus, in sustaining ventilation, fatigue-resistant motor units are likely required. Based on a series of studies in cats, hamsters and rats, an orderly model of motor unit recruitment was proposed that takes into consideration the maximum forces generated by single type-identified diaphragm muscle fibers as well as the proportion of the different motor unit types. Using this model, eupnea can be accomplished by activation of only slow-twitch diaphragm motor units and only a subset of fast-twitch, fatigue-resistant units. Activation of fast-twitch fatigable motor units only becomes necessary when accomplishing tasks that require greater force generation by the diaphragm muscle, e.g., sneezing and coughing. Copyright © 2011 Elsevier B.V. All rights reserved.

A global, myosin light chain kinase-dependent increase in myosin II contractility accompanies the metaphase-anaphase transition in sea urchin eggs.

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Lucero, Amy; Stack, Christianna; Bresnick, Anne R; Shuster, Charles B

2006-09-01

Myosin II is the force-generating motor for cytokinesis, and although it is accepted that myosin contractility is greatest at the cell equator, the temporal and spatial cues that direct equatorial contractility are not known. Dividing sea urchin eggs were placed under compression to study myosin II-based contractile dynamics, and cells manipulated in this manner underwent an abrupt, global increase in cortical contractility concomitant with the metaphase-anaphase transition, followed by a brief relaxation and the onset of furrowing. Prefurrow cortical contractility both preceded and was independent of astral microtubule elongation, suggesting that the initial activation of myosin II preceded cleavage plane specification. The initial rise in contractility required myosin light chain kinase but not Rho-kinase, but both signaling pathways were required for successful cytokinesis. Last, mobilization of intracellular calcium during metaphase induced a contractile response, suggesting that calcium transients may be partially responsible for the timing of this initial contractile event. Together, these findings suggest that myosin II-based contractility is initiated at the metaphase-anaphase transition by Ca2+-dependent myosin light chain kinase (MLCK) activity and is maintained through cytokinesis by both MLCK- and Rho-dependent signaling. Moreover, the signals that initiate myosin II contractility respond to specific cell cycle transitions independently of the microtubule-dependent cleavage stimulus.

A Global, Myosin Light Chain Kinase-dependent Increase in Myosin II Contractility Accompanies the Metaphase–Anaphase Transition in Sea Urchin Eggs

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Lucero, Amy; Stack, Christianna; Bresnick, Anne R.

2006-01-01

Myosin II is the force-generating motor for cytokinesis, and although it is accepted that myosin contractility is greatest at the cell equator, the temporal and spatial cues that direct equatorial contractility are not known. Dividing sea urchin eggs were placed under compression to study myosin II-based contractile dynamics, and cells manipulated in this manner underwent an abrupt, global increase in cortical contractility concomitant with the metaphase–anaphase transition, followed by a brief relaxation and the onset of furrowing. Prefurrow cortical contractility both preceded and was independent of astral microtubule elongation, suggesting that the initial activation of myosin II preceded cleavage plane specification. The initial rise in contractility required myosin light chain kinase but not Rho-kinase, but both signaling pathways were required for successful cytokinesis. Last, mobilization of intracellular calcium during metaphase induced a contractile response, suggesting that calcium transients may be partially responsible for the timing of this initial contractile event. Together, these findings suggest that myosin II-based contractility is initiated at the metaphase–anaphase transition by Ca2+-dependent myosin light chain kinase (MLCK) activity and is maintained through cytokinesis by both MLCK- and Rho-dependent signaling. Moreover, the signals that initiate myosin II contractility respond to specific cell cycle transitions independently of the microtubule-dependent cleavage stimulus. PMID:16837551

Myosin Va Plays a Role in Nitrergic Smooth Muscle Relaxation in Gastric Fundus and Corpora Cavernosa of Penis

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Carew, Josephine A.; Goyal, Raj K.; Sullivan, Maryrose P.

2014-01-01

The intracellular motor protein myosin Va is involved in nitrergic neurotransmission possibly by trafficking of neuronal nitric oxide synthase (nNOS) within the nerve terminals. In this study, we examined the role of myosin Va in the stomach and penis, proto-typical smooth muscle organs in which nitric oxide (NO) mediated relaxation is critical for function. We used confocal microscopy and co-immunoprecipitation of tissue from the gastric fundus (GF) and penile corpus cavernosum (CCP) to localize myosin Va with nNOS and demonstrate their molecular interaction. We utilized in vitro mechanical studies to test whether smooth muscle relaxations during nitrergic neuromuscular neurotransmission is altered in DBA (dilute, brown, non-agouti) mice which lack functional myosin Va. Myosin Va was localized in nNOS-positive nerve terminals and was co-immunoprecipitated with nNOS in both GF and CCP. In comparison to C57BL/6J wild type (WT) mice, electrical field stimulation (EFS) of precontracted smooth muscles of GF and CCP from DBA animals showed significant impairment of nitrergic relaxation. An NO donor, Sodium nitroprusside (SNP), caused comparable levels of relaxation in smooth muscles of WT and DBA mice. These normal postjunctional responses to SNP in DBA tissues suggest that impairment of smooth muscle relaxation resulted from inhibition of NO synthesis in prejunctional nerve terminals. Our results suggest that normal physiological processes of relaxation of gastric and cavernosal smooth muscles that facilitate food accommodation and penile erection, respectively, may be disrupted under conditions of myosin Va deficiency, resulting in complications like gastroparesis and erectile dysfunction. PMID:24516539

Identification and molecular modelling of a mutation in the motor head domain of myosin VIIA in a family with autosomal dominant hearing impairment (DFNA11)

NARCIS (Netherlands)

Luijendijk, M.W.J.; Wijk, E. van; Bischoff, A.M.L.C.; Krieger, E.; Huygen, P.L.M.; Pennings, R.J.E.; Brunner, H.G.; Cremers, C.W.R.J.; Cremers, F.P.M.; Kremer, J.M.J.

2004-01-01

Myosin VIIA is an unconventional myosin that has been implicated in Usher syndrome type 1B, atypical Usher syndrome, non-syndromic autosomal recessive hearing impairment (DFNB2) and autosomal dominant hearing impairment (DFNA11). Here, we present a family with non-syndromic autosomal dominant

Identification and molecular modelling of a mutation in the motor head domain of myosin VIIA in a family with autosomal dominant hearing impairment (DFNA11).

NARCIS (Netherlands)

Luijendijk, M.W.J.; Wijk, E. van; Bischoff, A.M.L.C.; Krieger, E.; Huygen, P.L.M.; Pennings, R.J.E.; Brunner, H.G.; Cremers, C.W.R.J.; Cremers, F.P.M.; Kremer, J.M.J.

2004-01-01

Myosin VIIA is an unconventional myosin that has been implicated in Usher syndrome type 1B, atypical Usher syndrome, non-syndromic autosomal recessive hearing impairment (DFNB2) and autosomal dominant hearing impairment (DFNA11). Here, we present a family with non-syndromic autosomal dominant

Electron Tomography of Cryofixed, Isometrically Contracting Insect Flight Muscle Reveals Novel Actin-Myosin Interactions

International Nuclear Information System (INIS)

Wu, Shenping; Liu, Jun; Reedy, Mary C.; Tregear, Richard T.; Winkler, Hanspeter; Franzini-Armstrong, Clara; Sasaki, Hiroyuki; Lucaveche, Carmen; Goldman, Yale E.; Reedy, Michael K.; Taylor, Kenneth A.

2010-01-01

Isometric muscle contraction, where force is generated without muscle shortening, is a molecular traffic jam in which the number of actin-attached motors is maximized and all states of motor action are trapped with consequently high heterogeneity. This heterogeneity is a major limitation to deciphering myosin conformational changes in situ. We used multivariate data analysis to group repeat segments in electron tomograms of isometrically contracting insect flight muscle, mechanically monitored, rapidly frozen, freeze substituted, and thin sectioned. Improved resolution reveals the helical arrangement of F-actin subunits in the thin filament enabling an atomic model to be built into the thin filament density independent of the myosin. Actin-myosin attachments can now be assigned as weak or strong by their motor domain orientation relative to actin. Myosin attachments were quantified everywhere along the thin filament including troponin. Strong binding myosin attachments are found on only four F-actin subunits, the 'target zone', situated exactly midway between successive troponin complexes. They show an axial lever arm range of 77 o /12.9 nm. The lever arm azimuthal range of strong binding attachments has a highly skewed, 127 o range compared with X-ray crystallographic structures. Two types of weak actin attachments are described. One type, found exclusively in the target zone, appears to represent pre-working-stroke intermediates. The other, which contacts tropomyosin rather than actin, is positioned M-ward of the target zone, i.e. the position toward which thin filaments slide during shortening. We present a model for the weak to strong transition in the myosin ATPase cycle that incorporates azimuthal movements of the motor domain on actin. Stress/strain in the S2 domain may explain azimuthal lever arm changes in the strong binding attachments. The results support previous conclusions that the weak attachments preceding force generation are very different from

Electron tomography of cryofixed, isometrically contracting insect flight muscle reveals novel actin-myosin interactions.

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Shenping Wu

2010-09-01

Full Text Available Isometric muscle contraction, where force is generated without muscle shortening, is a molecular traffic jam in which the number of actin-attached motors is maximized and all states of motor action are trapped with consequently high heterogeneity. This heterogeneity is a major limitation to deciphering myosin conformational changes in situ.We used multivariate data analysis to group repeat segments in electron tomograms of isometrically contracting insect flight muscle, mechanically monitored, rapidly frozen, freeze substituted, and thin sectioned. Improved resolution reveals the helical arrangement of F-actin subunits in the thin filament enabling an atomic model to be built into the thin filament density independent of the myosin. Actin-myosin attachments can now be assigned as weak or strong by their motor domain orientation relative to actin. Myosin attachments were quantified everywhere along the thin filament including troponin. Strong binding myosin attachments are found on only four F-actin subunits, the "target zone", situated exactly midway between successive troponin complexes. They show an axial lever arm range of 77°/12.9 nm. The lever arm azimuthal range of strong binding attachments has a highly skewed, 127° range compared with X-ray crystallographic structures. Two types of weak actin attachments are described. One type, found exclusively in the target zone, appears to represent pre-working-stroke intermediates. The other, which contacts tropomyosin rather than actin, is positioned M-ward of the target zone, i.e. the position toward which thin filaments slide during shortening.We present a model for the weak to strong transition in the myosin ATPase cycle that incorporates azimuthal movements of the motor domain on actin. Stress/strain in the S2 domain may explain azimuthal lever arm changes in the strong binding attachments. The results support previous conclusions that the weak attachments preceding force generation are very

Multidimensional structure-function relationships in human β-cardiac myosin from population-scale genetic variation

NARCIS (Netherlands)

Homburger, J.R. (Julian R.); Green, E.M. (Eric M.); Caleshu, C. (Colleen); Sunitha, M.S. (Margaret S.); Taylor, R.E. (Rebecca E.); Ruppel, K.M. (Kathleen M.); Metpally, R.P.R. (Raghu Prasad Rao); S.D. Colan (Steven); M. Michels (Michelle); Day, S.M. (Sharlene M.); I. Olivotto (Iacopo); Bustamante, C.D. (Carlos D.); Dewey, F.E. (Frederick E.); Ho, C.Y. (Carolyn Y.); Spudich, J.A. (James A.); Ashley, E.A. (Euan A.)

2016-01-01

textabstractMyosin motors are the fundamental force-generating elements of muscle contraction. Variation in the human β-cardiac myosin heavy chain gene (MYH7) can lead to hypertrophic cardiomyopathy (HCM), a heritable disease characterized by cardiac hypertrophy, heart failure, and sudden cardiac

Effects of TMS on different stages of motor and non-motor verb processing in the primary motor cortex.

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Liuba Papeo

Full Text Available The embodied cognition hypothesis suggests that motor and premotor areas are automatically and necessarily involved in understanding action language, as word conceptual representations are embodied. This transcranial magnetic stimulation (TMS study explores the role of the left primary motor cortex in action-verb processing. TMS-induced motor-evoked potentials from right-hand muscles were recorded as a measure of M1 activity, while participants were asked either to judge explicitly whether a verb was action-related (semantic task or to decide on the number of syllables in a verb (syllabic task. TMS was applied in three different experiments at 170, 350 and 500 ms post-stimulus during both tasks to identify when the enhancement of M1 activity occurred during word processing. The delays between stimulus onset and magnetic stimulation were consistent with electrophysiological studies, suggesting that word recognition can be differentiated into early (within 200 ms and late (within 400 ms lexical-semantic stages, and post-conceptual stages. Reaction times and accuracy were recorded to measure the extent to which the participants' linguistic performance was affected by the interference of TMS with M1 activity. No enhancement of M1 activity specific for action verbs was found at 170 and 350 ms post-stimulus, when lexical-semantic processes are presumed to occur (Experiments 1-2. When TMS was applied at 500 ms post-stimulus (Experiment 3, processing action verbs, compared with non-action verbs, increased the M1-activity in the semantic task and decreased it in the syllabic task. This effect was specific for hand-action verbs and was not observed for action-verbs related to other body parts. Neither accuracy nor RTs were affected by TMS. These findings suggest that the lexical-semantic processing of action verbs does not automatically activate the M1. This area seems to be rather involved in post-conceptual processing that follows the retrieval of motor

Simultaneous nano-tracking of multiple motor proteins via spectral discrimination of quantum dots.

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Kakizuka, Taishi; Ikezaki, Keigo; Kaneshiro, Junichi; Fujita, Hideaki; Watanabe, Tomonobu M; Ichimura, Taro

2016-07-01

Simultaneous nanometric tracking of multiple motor proteins was achieved by combining multicolor fluorescent labeling of target proteins and imaging spectroscopy, revealing dynamic behaviors of multiple motor proteins at the sub-diffraction-limit scale. Using quantum dot probes of distinct colors, we experimentally verified the localization precision to be a few nanometers at temporal resolution of 30 ms or faster. One-dimensional processive movement of two heads of a single myosin molecule and multiple myosin molecules was successfully traced. Furthermore, the system was modified for two-dimensional measurement and applied to tracking of multiple myosin molecules. Our approach is useful for investigating cooperative movement of proteins in supramolecular nanomachinery.

Actin and myosin contribute to mammalian mitochondrial DNA maintenance

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Reyes, A.; He, J.; Mao, C. C.; Bailey, L. J.; Di Re, M.; Sembongi, H.; Kazak, L.; Dzionek, K.; Holmes, J. B.; Cluett, T. J.; Harbour, M. E.; Fearnley, I. M.; Crouch, R. J.; Conti, M. A.; Adelstein, R. S.; Walker, J. E.; Holt, I. J.

2011-01-01

Mitochondrial DNA maintenance and segregation are dependent on the actin cytoskeleton in budding yeast. We found two cytoskeletal proteins among six proteins tightly associated with rat liver mitochondrial DNA: non-muscle myosin heavy chain IIA and β-actin. In human cells, transient gene silencing of MYH9 (encoding non-muscle myosin heavy chain IIA), or the closely related MYH10 gene (encoding non-muscle myosin heavy chain IIB), altered the topology and increased the copy number of mitochondrial DNA; and the latter effect was enhanced when both genes were targeted simultaneously. In contrast, genetic ablation of non-muscle myosin IIB was associated with a 60% decrease in mitochondrial DNA copy number in mouse embryonic fibroblasts, compared to control cells. Gene silencing of β-actin also affected mitochondrial DNA copy number and organization. Protease-protection experiments and iodixanol gradient analysis suggest some β-actin and non-muscle myosin heavy chain IIA reside within human mitochondria and confirm that they are associated with mitochondrial DNA. Collectively, these results strongly implicate the actomyosin cytoskeleton in mammalian mitochondrial DNA maintenance. PMID:21398640

Direct observation of the myosin Va recovery stroke that contributes to unidirectional stepping along actin.

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Katsuyuki Shiroguchi

2011-04-01

Full Text Available Myosins are ATP-driven linear molecular motors that work as cellular force generators, transporters, and force sensors. These functions are driven by large-scale nucleotide-dependent conformational changes, termed "strokes"; the "power stroke" is the force-generating swinging of the myosin light chain-binding "neck" domain relative to the motor domain "head" while bound to actin; the "recovery stroke" is the necessary initial motion that primes, or "cocks," myosin while detached from actin. Myosin Va is a processive dimer that steps unidirectionally along actin following a "hand over hand" mechanism in which the trailing head detaches and steps forward ∼72 nm. Despite large rotational Brownian motion of the detached head about a free joint adjoining the two necks, unidirectional stepping is achieved, in part by the power stroke of the attached head that moves the joint forward. However, the power stroke alone cannot fully account for preferential forward site binding since the orientation and angle stability of the detached head, which is determined by the properties of the recovery stroke, dictate actin binding site accessibility. Here, we directly observe the recovery stroke dynamics and fluctuations of myosin Va using a novel, transient caged ATP-controlling system that maintains constant ATP levels through stepwise UV-pulse sequences of varying intensity. We immobilized the neck of monomeric myosin Va on a surface and observed real time motions of bead(s attached site-specifically to the head. ATP induces a transient swing of the neck to the post-recovery stroke conformation, where it remains for ∼40 s, until ATP hydrolysis products are released. Angle distributions indicate that the post-recovery stroke conformation is stabilized by ≥ 5 k(BT of energy. The high kinetic and energetic stability of the post-recovery stroke conformation favors preferential binding of the detached head to a forward site 72 nm away. Thus, the recovery

Preparation of human cardiac anti-myosin: a review

International Nuclear Information System (INIS)

Okada, H.; Souza, I.T.T.

1990-01-01

The present communication is a review of the physicochemical characterization and immunological properties of myosin isolated from the cardiac muscle, the production of monoclonal antibody anti-myosin, the radiolabeling of this antibody and its applications as radiopharmaceuticals to imaging myocardial infarcts. The classical example of radioimmunologic diagnosis of non malignant tissues is the detection of myocardial infarction by radiolabeled antibodies to myosin. (author)

Flexural Stiffness of Myosin Va Subdomains as Measured from Tethered Particle Motion

Science.gov (United States)

Michalek, Arthur J.; Kennedy, Guy G.; Warshaw, David M.; Ali, M. Yusuf

2015-01-01

Myosin Va (MyoVa) is a processive molecular motor involved in intracellular cargo transport on the actin cytoskeleton. The motor's processivity and ability to navigate actin intersections are believed to be governed by the stiffness of various parts of the motor's structure. Specifically, changes in calcium may regulate motor processivity by altering the motor's lever arm stiffness and thus its interhead communication. In order to measure the flexural stiffness of MyoVa subdomains, we use tethered particle microscopy, which relates the Brownian motion of fluorescent quantum dots, which are attached to various single- and double-headed MyoVa constructs bound to actin in rigor, to the motor's flexural stiffness. Based on these measurements, the MyoVa lever arm and coiled-coil rod domain have comparable flexural stiffness (0.034 pN/nm). Upon addition of calcium, the lever arm stiffness is reduced 40% as a result of calmodulins potentially dissociating from the lever arm. In addition, the flexural stiffness of the full-length MyoVa construct is an order of magnitude less stiff than both a single lever arm and the coiled-coil rod. This suggests that the MyoVa lever arm-rod junction provides a flexible hinge that would allow the motor to maneuver cargo through the complex intracellular actin network. PMID:26770194

Using electrical and optical tweezers to facilitate studies of molecular motors.

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Arsenault, Mark E; Sun, Yujie; Bau, Haim H; Goldman, Yale E

2009-06-28

Dielectrophoresis was used to stretch and suspend actin filaments across a trench etched between two electrodes patterned on a glass slide. Optical tweezers were used to bring a motor protein-coated bead into close proximity to a pre-selected, suspended actin filament, facilitating the attachment of the myosin-coated bead to the filament. The clearance beneath the filament allowed the bead to move freely along and around its filamentous track, unhindered by solid surfaces. Using defocused images, the three-dimensional position of the bead was tracked as a function of time to obtain its trajectory. Experiments were carried out with myosin V and myosin X. Both motor proteins followed left-handed helical paths with the myosin X motor exhibiting a shorter pitch than the myosin V. The combined use of electrostatic and optical tweezers facilitates the preparation of motility assays with suspended tracks. Variants of this technique will enable higher complexity experiments in vitro to better understand the behavior of motors in cells.

The fungal myosin I is essential for Fusarium toxisome formation.

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Guangfei Tang

2018-01-01

Full Text Available Myosin-I molecular motors are proposed to function as linkers between membranes and the actin cytoskeleton in several cellular processes, but their role in the biosynthesis of fungal secondary metabolites remain elusive. Here, we found that the myosin I of Fusarium graminearum (FgMyo1, the causal agent of Fusarium head blight, plays critical roles in mycotoxin biosynthesis. Inhibition of myosin I by the small molecule phenamacril leads to marked reduction in deoxynivalenol (DON biosynthesis. FgMyo1 also governs translation of the DON biosynthetic enzyme Tri1 by interacting with the ribosome-associated protein FgAsc1. Disruption of the ATPase activity of FgMyo1 either by the mutation E420K, down-regulation of FgMyo1 expression or deletion of FgAsc1 results in reduced Tri1 translation. The DON biosynthetic enzymes Tri1 and Tri4 are mainly localized to subcellular structures known as toxisomes in response to mycotoxin induction and the FgMyo1-interacting protein, actin, participates in toxisome formation. The actin polymerization disruptor latrunculin A inhibits toxisome assembly. Consistent with this observation, deletion of the actin-associated proteins FgPrk1 and FgEnd3 also results in reduced toxisome formation. Unexpectedly, the FgMyo1-actin cytoskeleton is not involved in biosynthesis of another secondary metabolite tested. Taken together, this study uncovers a novel function of myosin I in regulating mycotoxin biosynthesis in filamentous fungi.

The fungal myosin I is essential for Fusarium toxisome formation.

Science.gov (United States)

Tang, Guangfei; Chen, Yun; Xu, Jin-Rong; Kistler, H Corby; Ma, Zhonghua

2018-01-01

Myosin-I molecular motors are proposed to function as linkers between membranes and the actin cytoskeleton in several cellular processes, but their role in the biosynthesis of fungal secondary metabolites remain elusive. Here, we found that the myosin I of Fusarium graminearum (FgMyo1), the causal agent of Fusarium head blight, plays critical roles in mycotoxin biosynthesis. Inhibition of myosin I by the small molecule phenamacril leads to marked reduction in deoxynivalenol (DON) biosynthesis. FgMyo1 also governs translation of the DON biosynthetic enzyme Tri1 by interacting with the ribosome-associated protein FgAsc1. Disruption of the ATPase activity of FgMyo1 either by the mutation E420K, down-regulation of FgMyo1 expression or deletion of FgAsc1 results in reduced Tri1 translation. The DON biosynthetic enzymes Tri1 and Tri4 are mainly localized to subcellular structures known as toxisomes in response to mycotoxin induction and the FgMyo1-interacting protein, actin, participates in toxisome formation. The actin polymerization disruptor latrunculin A inhibits toxisome assembly. Consistent with this observation, deletion of the actin-associated proteins FgPrk1 and FgEnd3 also results in reduced toxisome formation. Unexpectedly, the FgMyo1-actin cytoskeleton is not involved in biosynthesis of another secondary metabolite tested. Taken together, this study uncovers a novel function of myosin I in regulating mycotoxin biosynthesis in filamentous fungi.

Two-boundary first exit time of Gauss-Markov processes for stochastic modeling of acto-myosin dynamics.

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D'Onofrio, Giuseppe; Pirozzi, Enrica

2017-05-01

We consider a stochastic differential equation in a strip, with coefficients suitably chosen to describe the acto-myosin interaction subject to time-varying forces. By simulating trajectories of the stochastic dynamics via an Euler discretization-based algorithm, we fit experimental data and determine the values of involved parameters. The steps of the myosin are represented by the exit events from the strip. Motivated by these results, we propose a specific stochastic model based on the corresponding time-inhomogeneous Gauss-Markov and diffusion process evolving between two absorbing boundaries. We specify the mean and covariance functions of the stochastic modeling process taking into account time-dependent forces including the effect of an external load. We accurately determine the probability density function (pdf) of the first exit time (FET) from the strip by solving a system of two non singular second-type Volterra integral equations via a numerical quadrature. We provide numerical estimations of the mean of FET as approximations of the dwell-time of the proteins dynamics. The percentage of backward steps is given in agreement to experimental data. Numerical and simulation results are compared and discussed.

Characterization of f-actin tryptophan phosphorescence in the presence and absence of tryptophan-free myosin motor domain.

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Bódis, Emöke; Strambini, Giovanni B; Gonnelli, Margherita; Málnási-Csizmadia, András; Somogyi, Béla

2004-08-01

The effect of binding the Trp-free motor domain mutant of Dictyostelium discoideum, rabbit skeletal muscle myosin S1, and tropomyosin on the dynamics and conformation of actin filaments was characterized by an analysis of steady-state tryptophan phosphorescence spectra and phosphorescence decay kinetics over a temperature range of 140-293 K. The binding of the Trp-free motor domain mutant of D. discoideum to actin caused red shifts in the phosphorescence spectrum of two internal Trp residues of actin and affected the intrinsic lifetime of each emitter, decreasing by roughly twofold the short phosphorescence lifetime components (tau(1) and tau(2)) and increasing by approximately 20% the longest component (tau(3)). The alteration of actin phosphorescence by the motor protein suggests that i), structural changes occur deep down in the core of actin and that ii), subtle changes in conformation appear also on the surface but in regions distant from the motor domain binding site. When actin formed complexes with skeletal S1, an extra phosphorescence lifetime component appeared (tau(4), twice as long as tau(3)) in the phosphorescence decay that is absent in the isolated proteins. The lack of this extra component in the analogous actin-Trp-free motor domain mutant of D. discoideum complex suggests that it should be assigned to Trps in S1 that in the complex attain a more compact local structure. Our data indicated that the binding of tropomyosin to actin filaments had no effect on the structure or flexibility of actin observable by this technique.

Motor system contributions to verbal and non-verbal working memory

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Diana A Liao

2014-09-01

Full Text Available Working memory (WM involves the ability to maintain and manipulate information held in mind. Neuroimaging studies have shown that secondary motor areas activate during WM for verbal content (e.g., words or letters, in the absence of primary motor area activation. This activation pattern may reflect an inner speech mechanism supporting online phonological rehearsal. Here, we examined the causal relationship between motor system activity and WM processing by using transcranial magnetic stimulation (TMS to manipulate motor system activity during WM rehearsal. We tested WM performance for verbalizable (words and pseudowords and non-verbalizable (Chinese characters visual information. We predicted that disruption of motor circuits would specifically affect WM processing of verbalizable information. We found that TMS targeting motor cortex slowed response times on verbal WM trials with high (pseudoword vs. low (real word phonological load. However, non-verbal WM trials were also significantly slowed with motor TMS. WM performance was unaffected by sham stimulation or TMS over visual cortex. Self-reported use of motor strategy predicted the degree of motor stimulation disruption on WM performance. These results provide evidence of the motor system’s contributions to verbal and non-verbal WM processing. We speculate that the motor system supports WM by creating motor traces consistent with the type of information being rehearsed during maintenance.

Increased expression of Myosin binding protein H in the skeletal muscle of amyotrophic lateral sclerosis patients

KAUST Repository

Conti, Antonio

2014-01-01

Amyotrophic lateral sclerosis (ALS) is a severe and fatal neurodegenerative disease of still unknown pathogenesis. Recent findings suggest that the skeletal muscle may play an active pathogenetic role. To investigate ALS\\'s pathogenesis and to seek diagnostic markers, we analyzed skeletal muscle biopsies with the differential expression proteomic approach. We studied skeletal muscle biopsies from healthy controls (CN), sporadic ALS (sALS), motor neuropathies (MN) and myopathies (M). Pre-eminently among several differentially expressed proteins, Myosin binding protein H (MyBP-H) expression in ALS samples was anomalously high. MyBP-H is a component of the thick filaments of the skeletal muscle and has strong affinity for myosin, but its function is still unclear. High MyBP-H expression level was associated with abnormal expression of Rho kinase 2 (ROCK2), LIM domain kinase 1 (LIMK1) and cofilin2, that might affect the actin-myosin interaction. We propose that MyBP-H expression level serves, as a putative biomarker in the skeletal muscle, to discriminate ALS from motor neuropathies, and that it signals the onset of dysregulation in actin-myosin interaction; this in turn might contribute to the pathogenesis of ALS. © 2013 Elsevier B.V.

Non-motor and motor features in LRRK2 transgenic mice.

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Zoë Bichler

Full Text Available Non-motor symptoms are increasingly recognized as important features of Parkinson's disease (PD. LRRK2 mutations are common causes of familial and sporadic PD. Non-motor features have not been yet comprehensively evaluated in LRRK2 transgenic mouse models.Using a transgenic mouse model overexpressing the R1441G mutation of the human LRRK2 gene, we have investigated the longitudinal correlation between motor and non-motor symptoms and determined if specific non-motor phenotypes precede motor symptoms.We investigated the onset of motor and non-motor phenotypes on the LRRK2(R1441G BAC transgenic mice and their littermate controls from 4 to 21 month-old using a battery of behavioral tests. The transgenic mutant mice displayed mild hypokinesia in the open field from 16 months old, with gastrointestinal dysfunctions beginning at 6 months old. Non-motor features such as depression and anxiety-like behaviors, sensorial functions (pain sensitivity and olfaction, and learning and memory abilities in the passive avoidance test were similar in the transgenic animals compared to littermate controls.LRRK2(R1441G BAC transgenic mice displayed gastrointestinal dysfunction at an early stage but did not have abnormalities in fine behaviors, olfaction, pain sensitivity, mood disorders and learning and memory compared to non-transgenic littermate controls. The observations on olfaction and gastrointestinal dysfunction in this model validate findings in human carriers. These mice did recapitulate mild Parkinsonian motor features at late stages but compensatory mechanisms modulating the progression of PD in these models should be further evaluated.

Cytoskeleton Molecular Motors: Structures and Their Functions in Neuron.

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Xiao, Qingpin; Hu, Xiaohui; Wei, Zhiyi; Tam, Kin Yip

2016-01-01

Cells make use of molecular motors to transport small molecules, macromolecules and cellular organelles to target region to execute biological functions, which is utmost important for polarized cells, such as neurons. In particular, cytoskeleton motors play fundamental roles in neuron polarization, extension, shape and neurotransmission. Cytoskeleton motors comprise of myosin, kinesin and cytoplasmic dynein. F-actin filaments act as myosin track, while kinesin and cytoplasmic dynein move on microtubules. Cytoskeleton motors work together to build a highly polarized and regulated system in neuronal cells via different molecular mechanisms and functional regulations. This review discusses the structures and working mechanisms of the cytoskeleton motors in neurons.

Fast and slow myosins as markers of muscle injury.

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Guerrero, M; Guiu-Comadevall, M; Cadefau, J A; Parra, J; Balius, R; Estruch, A; Rodas, G; Bedini, J L; Cussó, R

2008-07-01

The diagnosis of muscular lesions suffered by athletes is usually made by clinical criteria combined with imaging of the lesion (ultrasonography and/or magnetic resonance) and blood tests to detect the presence of non-specific muscle markers. This study was undertaken to evaluate injury to fast and slow-twitch fibres using specific muscle markers for these fibres. Blood samples were obtained from 51 non-sports people and 38 sportsmen with skeletal muscle injury. Western blood analysis was performed to determine fast and slow myosin and creatine kinase (CK) levels. Skeletal muscle damage was diagnosed by physical examination, ultrasonography and magnetic resonance and biochemical markers. The imaging tests were found to be excellent for detecting and confirming grade II and III lesions. However, grade I lesions were often unconfirmed by these techniques. Grade I lesions have higher levels of fast myosin than slow myosin with a very small increase in CK levels. Grade II and III lesions have high values of both fast and slow myosin. The evaluation of fast and slow myosin in the blood 48 h after the lesion occurs is a useful aid for the detection of type I lesions in particular, since fast myosin is an exclusive skeletal muscle marker. The correct diagnosis of grade I lesions can prevent progression of the injury in athletes undergoing continual training sessions and competitions, thus aiding sports physicians in their decision making.

Cell differentiation through tissue elasticity-coupled, myosin-driven remodeling.

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Zajac, Allison L; Discher, Dennis E

2008-12-01

Cells may lack eyes to see and ears to hear, but cells do seem to have a sense of 'touch' that allows them to feel their microenvironment. This is achieved in part through contractility coupled adhesion to physically flexible 'soft' tissue. Here we summarize some of the known variations in elasticity of solid tissue and review some of the long-term effects of cells 'feeling' this elasticity, focusing on differentiation processes of both committed cell types and stem cells. We then highlight what is known of molecular remodeling in cells under stress on short time scales. Key roles for forces generated by ubiquitous and essential myosin-II motors in feedback remodeling are emphasized throughout.

Random myosin loss along thick-filaments increases myosin attachment time and the proportion of bound myosin heads to mitigate force decline in skeletal muscle

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Tanner, Bertrand C.W.; McNabb, Mark; Palmer, Bradley M.; Toth, Michael J.; Miller, Mark S.

2014-01-01

Diminished skeletal muscle performance with aging, disuse, and disease may be partially attributed to the loss of myofilament proteins. Several laboratories have found a disproportionate loss of myosin protein content relative to other myofilament proteins, but due to methodological limitations, the structural manifestation of this protein loss is unknown. To investigate how variations in myosin content affect ensemble cross-bridge behavior and force production we simulated muscle contraction in the half-sarcomere as myosin was removed either i) uniformly, from the Z-line end of thick-filaments, or ii) randomly, along the length of thick-filaments. Uniform myosin removal decreased force production, showing a slightly steeper force-to-myosin content relationship than the 1:1 relationship that would be expected from the loss of cross-bridges. Random myosin removal also decreased force production, but this decrease was less than observed with uniform myosin loss, largely due to increased myosin attachment time (ton) and fractional cross-bridge binding with random myosin loss. These findings support our prior observations that prolonged ton may augment force production in single fibers with randomly reduced myosin content from chronic heart failure patients. These simulation also illustrate that the pattern of myosin loss along thick-filaments influences ensemble cross-bridge behavior and maintenance of force throughout the sarcomere. PMID:24486373

Increased expression of Myosin binding protein H in the skeletal muscle of amyotrophic lateral sclerosis patients.

Science.gov (United States)

Conti, Antonio; Riva, Nilo; Pesca, Mariasabina; Iannaccone, Sandro; Cannistraci, Carlo V; Corbo, Massimo; Previtali, Stefano C; Quattrini, Angelo; Alessio, Massimo

2014-01-01

Amyotrophic lateral sclerosis (ALS) is a severe and fatal neurodegenerative disease of still unknown pathogenesis. Recent findings suggest that the skeletal muscle may play an active pathogenetic role. To investigate ALS's pathogenesis and to seek diagnostic markers, we analyzed skeletal muscle biopsies with the differential expression proteomic approach. We studied skeletal muscle biopsies from healthy controls (CN), sporadic ALS (sALS), motor neuropathies (MN) and myopathies (M). Pre-eminently among several differentially expressed proteins, Myosin binding protein H (MyBP-H) expression in ALS samples was anomalously high. MyBP-H is a component of the thick filaments of the skeletal muscle and has strong affinity for myosin, but its function is still unclear. High MyBP-H expression level was associated with abnormal expression of Rho kinase 2 (ROCK2), LIM domain kinase 1 (LIMK1) and cofilin2, that might affect the actin-myosin interaction. We propose that MyBP-H expression level serves, as a putative biomarker in the skeletal muscle, to discriminate ALS from motor neuropathies, and that it signals the onset of dysregulation in actin-myosin interaction; this in turn might contribute to the pathogenesis of ALS. © 2013 Elsevier B.V. All rights reserved.

Oxidation of myosin by haem proteins generates myosin radicals and protein cross-links

DEFF Research Database (Denmark)

Lametsch, Marianne Lund; Luxford, Catherine; Skibsted, Leif Horsfelt

2008-01-01

of thiyl and tyrosyl radicals is consistent with the observed consumption of cysteine and tyrosine residues, the detection of di-tyrosine by HPLC and the detection of both reducible (disulfide bond) and non-reducible cross-links between myosin molecules by SDS/PAGE. The time course of radical formation...

Control of non-conventional synchronous motors

CERN Document Server

Louis, Jean-Paul

2013-01-01

Classical synchronous motors are the most effective device to drive industrial production systems and robots with precision and rapidity. However, numerous applications require efficient controls in non-conventional situations. Firstly, this is the case with synchronous motors supplied by thyristor line-commutated inverters, or with synchronous motors with faults on one or several phases. Secondly, many drive systems use non-conventional motors such as polyphase (more than three phases) synchronous motors, synchronous motors with double excitation, permanent magnet linear synchronous motors,

Parkinson's Disease Subtypes Identified from Cluster Analysis of Motor and Non-motor Symptoms.

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Mu, Jesse; Chaudhuri, Kallol R; Bielza, Concha; de Pedro-Cuesta, Jesus; Larrañaga, Pedro; Martinez-Martin, Pablo

2017-01-01

Parkinson's disease is now considered a complex, multi-peptide, central, and peripheral nervous system disorder with considerable clinical heterogeneity. Non-motor symptoms play a key role in the trajectory of Parkinson's disease, from prodromal premotor to end stages. To understand the clinical heterogeneity of Parkinson's disease, this study used cluster analysis to search for subtypes from a large, multi-center, international, and well-characterized cohort of Parkinson's disease patients across all motor stages, using a combination of cardinal motor features (bradykinesia, rigidity, tremor, axial signs) and, for the first time, specific validated rater-based non-motor symptom scales. Two independent international cohort studies were used: (a) the validation study of the Non-Motor Symptoms Scale ( n = 411) and (b) baseline data from the global Non-Motor International Longitudinal Study ( n = 540). k -means cluster analyses were performed on the non-motor and motor domains (domains clustering) and the 30 individual non-motor symptoms alone (symptoms clustering), and hierarchical agglomerative clustering was performed to group symptoms together. Four clusters are identified from the domains clustering supporting previous studies: mild, non-motor dominant, motor-dominant, and severe. In addition, six new smaller clusters are identified from the symptoms clustering, each characterized by clinically-relevant non-motor symptoms. The clusters identified in this study present statistical confirmation of the increasingly important role of non-motor symptoms (NMS) in Parkinson's disease heterogeneity and take steps toward subtype-specific treatment packages.

[Non-motor symptoms of Parkinson's disease

NARCIS (Netherlands)

Weerkamp, N.J.; Nijhof, A.; Tissingh, G.

2012-01-01

Parkinson's disease has traditionally been viewed as a disease with only motor features. Nowadays, a wide variety of non-motor symptoms and signs are also recognised as being characteristic of the disease. Non-motor symptoms, most importantly autonomic dysfunction, neuropsychiatric symptoms and

An isoform of myosin XI is responsible for the translocation of endoplasmic reticulum in tobacco cultured BY-2 cells.

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Yokota, Etsuo; Ueda, Shunpei; Tamura, Kentaro; Orii, Hidefumi; Uchi, Satoko; Sonobe, Seiji; Hara-Nishimura, Ikuko; Shimmen, Teruo

2009-01-01

The involvement of myosin XI in generating the motive force for cytoplasmic streaming in plant cells is becoming evident. For a comprehensive understanding of the physiological roles of myosin XI isoforms, it is necessary to elucidate the properties and functions of each isoform individually. In tobacco cultured BY-2 cells, two types of myosins, one composed of 175 kDa heavy chain (175 kDa myosin) and the other of 170 kDa heavy chain (170 kDa myosin), have been identified biochemically and immunocytochemically. From sequence analyses of cDNA clones encoding heavy chains of 175 kDa and 170 kDa myosin, both myosins have been classified as myosin XI. Immunocytochemical studies using a polyclonal antibody against purified 175 kDa myosin heavy chain showed that the 175 kDa myosin is distributed throughout the cytoplasm as fine dots in interphase BY-2 cells. During mitosis, some parts of 175 kDa myosin were found to accumulate in the pre-prophase band (PPB), spindle, the equatorial plane of a phragmoplast and on the circumference of daughter nuclei. In transgenic BY-2 cells, in which an endoplasmic reticulum (ER)-specific retention signal, HDEL, tagged with green fluorescent protein (GFP) was stably expressed, ER showed a similar behaviour to that of 175 kDa myosin. Furthermore, this myosin was co-fractionated with GFP-ER by sucrose density gradient centrifugation. From these findings, it was suggested that the 175 kDa myosin is a molecular motor responsible for translocating ER in BY-2 cells.

Myosin II dynamics are regulated by tension in intercalating cells.

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Fernandez-Gonzalez, Rodrigo; Simoes, Sérgio de Matos; Röper, Jens-Christian; Eaton, Suzanne; Zallen, Jennifer A

2009-11-01

Axis elongation in Drosophila occurs through polarized cell rearrangements driven by actomyosin contractility. Myosin II promotes neighbor exchange through the contraction of single cell boundaries, while the contraction of myosin II structures spanning multiple pairs of cells leads to rosette formation. Here we show that multicellular actomyosin cables form at a higher frequency than expected by chance, indicating that cable assembly is an active process. Multicellular cables are sites of increased mechanical tension as measured by laser ablation. Fluorescence recovery after photobleaching experiments show that myosin II is stabilized at the cortex in regions of increased tension. Myosin II is recruited in response to an ectopic force and relieving tension leads to a rapid loss of myosin, indicating that tension is necessary and sufficient for cortical myosin localization. These results demonstrate that myosin II dynamics are regulated by tension in a positive feedback loop that leads to multicellular actomyosin cable formation and efficient tissue elongation.

Diverse functions of myosin VI elucidated by an isoform-specific α-helix domain.

Science.gov (United States)

Wollscheid, Hans-Peter; Biancospino, Matteo; He, Fahu; Magistrati, Elisa; Molteni, Erika; Lupia, Michela; Soffientini, Paolo; Rottner, Klemens; Cavallaro, Ugo; Pozzoli, Uberto; Mapelli, Marina; Walters, Kylie J; Polo, Simona

2016-04-01

Myosin VI functions in endocytosis and cell motility. Alternative splicing of myosin VI mRNA generates two distinct isoform types, myosin VI(short) and myosin VI(long), which differ in the C-terminal region. Their physiological and pathological roles remain unknown. Here we identified an isoform-specific regulatory helix, named the α2-linker, that defines specific conformations and hence determines the target selectivity of human myosin VI. The presence of the α2-linker structurally defines a new clathrin-binding domain that is unique to myosin VI(long) and masks the known RRL interaction motif. This finding is relevant to ovarian cancer, in which alternative myosin VI splicing is aberrantly regulated, and exon skipping dictates cell addiction to myosin VI(short) in tumor-cell migration. The RRL interactor optineurin contributes to this process by selectively binding myosin VI(short). Thus, the α2-linker acts like a molecular switch that assigns myosin VI to distinct endocytic (myosin VI(long)) or migratory (myosin VI(short)) functional roles.

Phosphorylated peptides occur in a non-helical portion of the tail of a catch muscle myosin

International Nuclear Information System (INIS)

Castellani, L.; Elliott, B.W. Jr.; Cohen, C.

1987-01-01

Myosin from a molluscan catch muscle (the Anterior Byssus Retractor (ABRM) of Mytilus edulis) is unusual in being phosphorylated in the rod by an endogenous heavy-chain kinase. This phosphorylation enhances myosin solubility at low ionic strength and induces molecular folding of the myosin tail. Papain and chymotryptic cleavage of this myosin, phosphorylated with [γ- 32 P]ATP, indicates that the phosphorylated residues are associated with the carboxy-terminal end of the light meromyosin. Ion-exchange and reverse-phase HPLC of radiolabeled chymotryptic peptides allow the isolation of two different peptides with high specific activity. One of these peptides is rich in lysine and arginine residues, a finding consistent with the observation that basic residues often determine the substrate specificity of protein kinases. The second peptide contains proline residues. Taken together, these results suggest that, as in the case of Acanthamoeba myosin, phosphorylation occurs in a nonhelical portion of the rod that may also control solubility. Identification of the residues that are phosphorylated and their location in the rod may reveal how the phosphorylation-dependent changes observed in the myosin in vitro are related to changes in intermolecular interactions in the thick filaments in vivo

Specific nuclear localizing sequence directs two myosin isoforms to the cell nucleus in calmodulin-sensitive manner.

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Dzijak, Rastislav; Yildirim, Sukriye; Kahle, Michal; Novák, Petr; Hnilicová, Jarmila; Venit, Tomáš; Hozák, Pavel

2012-01-01

Nuclear myosin I (NM1) was the first molecular motor identified in the cell nucleus. Together with nuclear actin, they participate in crucial nuclear events such as transcription, chromatin movements, and chromatin remodeling. NM1 is an isoform of myosin 1c (Myo1c) that was identified earlier and is known to act in the cytoplasm. NM1 differs from the "cytoplasmic" myosin 1c only by additional 16 amino acids at the N-terminus of the molecule. This amino acid stretch was therefore suggested to direct NM1 into the nucleus. We investigated the mechanism of nuclear import of NM1 in detail. Using over-expressed GFP chimeras encoding for truncated NM1 mutants, we identified a specific sequence that is necessary for its import to the nucleus. This novel nuclear localization sequence is placed within calmodulin-binding motif of NM1, thus it is present also in the Myo1c. We confirmed the presence of both isoforms in the nucleus by transfection of tagged NM1 and Myo1c constructs into cultured cells, and also by showing the presence of the endogenous Myo1c in purified nuclei of cells derived from knock-out mice lacking NM1. Using pull-down and co-immunoprecipitation assays we identified importin beta, importin 5 and importin 7 as nuclear transport receptors that bind NM1. Since the NLS sequence of NM1 lies within the region that also binds calmodulin we tested the influence of calmodulin on the localization of NM1. The presence of elevated levels of calmodulin interfered with nuclear localization of tagged NM1. We have shown that the novel specific NLS brings to the cell nucleus not only the "nuclear" isoform of myosin I (NM1 protein) but also its "cytoplasmic" isoform (Myo1c protein). This opens a new field for exploring functions of this molecular motor in nuclear processes, and for exploring the signals between cytoplasm and the nucleus.

Human myosin VIIA responsible for the Usher 1B syndrome: a predicted membrane-associated motor protein expressed in developing sensory epithelia.

Science.gov (United States)

Weil, D; Levy, G; Sahly, I; Levi-Acobas, F; Blanchard, S; El-Amraoui, A; Crozet, F; Philippe, H; Abitbol, M; Petit, C

1996-04-16

The gene encoding human myosin VIIA is responsible for Usher syndrome type III (USH1B), a disease which associates profound congenital sensorineural deafness, vestibular dysfunction, and retinitis pigmentosa. The reconstituted cDNA sequence presented here predicts a 2215 amino acid protein with a typical unconventional myosin structure. This protein is expected to dimerize into a two-headed molecule. The C terminus of its tail shares homology with the membrane-binding domain of the band 4.1 protein superfamily. The gene consists of 48 coding exons. It encodes several alternatively spliced forms. In situ hybridization analysis in human embryos demonstrates that the myosin VIIA gene is expressed in the pigment epithelium and the photoreceptor cells of the retina, thus indicating that both cell types may be involved in the USH1B retinal degenerative process. In addition, the gene is expressed in the human embryonic cochlear and vestibular neuroepithelia. We suggest that deafness and vestibular dysfunction in USH1B patients result from a defect in the morphogenesis of the inner ear sensory cell stereocilia.

Actin-myosin network is required for proper assembly of influenza virus particles

Energy Technology Data Exchange (ETDEWEB)

Kumakura, Michiko; Kawaguchi, Atsushi, E-mail: ats-kawaguchi@md.tsukuba.ac.jp; Nagata, Kyosuke, E-mail: knagata@md.tsukuba.ac.jp

2015-02-15

Actin filaments are known to play a central role in cellular dynamics. After polymerization of actin, various actin-crosslinking proteins including non-muscle myosin II facilitate the formation of spatially organized actin filament networks. The actin-myosin network is highly expanded beneath plasma membrane. The genome of influenza virus (vRNA) replicates in the cell nucleus. Then, newly synthesized vRNAs are nuclear-exported to the cytoplasm as ribonucleoprotein complexes (vRNPs), followed by transport to the beneath plasma membrane where virus particles assemble. Here, we found that, by inhibiting actin-myosin network formation, the virus titer tends to be reduced and HA viral spike protein is aggregated on the plasma membrane. These results indicate that the actin-myosin network plays an important role in the virus formation. - Highlights: • Actin-myosin network is important for the influenza virus production. • HA forms aggregations at the plasma membrane in the presence of blebbistatin. • M1 is recruited to the budding site through the actin-myosin network.

Actin-myosin network is required for proper assembly of influenza virus particles

International Nuclear Information System (INIS)

Kumakura, Michiko; Kawaguchi, Atsushi; Nagata, Kyosuke

2015-01-01

Actin filaments are known to play a central role in cellular dynamics. After polymerization of actin, various actin-crosslinking proteins including non-muscle myosin II facilitate the formation of spatially organized actin filament networks. The actin-myosin network is highly expanded beneath plasma membrane. The genome of influenza virus (vRNA) replicates in the cell nucleus. Then, newly synthesized vRNAs are nuclear-exported to the cytoplasm as ribonucleoprotein complexes (vRNPs), followed by transport to the beneath plasma membrane where virus particles assemble. Here, we found that, by inhibiting actin-myosin network formation, the virus titer tends to be reduced and HA viral spike protein is aggregated on the plasma membrane. These results indicate that the actin-myosin network plays an important role in the virus formation. - Highlights: • Actin-myosin network is important for the influenza virus production. • HA forms aggregations at the plasma membrane in the presence of blebbistatin. • M1 is recruited to the budding site through the actin-myosin network

Myosins and DYNLL1/LC8 in the honey bee (Apis mellifera L.) brain.

Science.gov (United States)

Calábria, Luciana Karen; Peixoto, Pablo Marco Veras; Passos Lima, Andreia Barcelos; Peixoto, Leonardo Gomes; de Moraes, Viviane Rodrigues Alves; Teixeira, Renata Roland; Dos Santos, Claudia Tavares; E Silva, Letícia Oliveira; da Silva, Maria de Fátima Rodrigues; dos Santos, Ana Alice Diniz; Garcia-Cairasco, Norberto; Martins, Antônio Roberto; Espreafico, Enilza Maria; Espindola, Foued Salmen

2011-09-01

Honey bees have brain structures with specialized and developed systems of communication that account for memory, learning capacity and behavioral organization with a set of genes homologous to vertebrate genes. Many microtubule- and actin-based molecular motors are involved in axonal/dendritic transport. Myosin-Va is present in the honey bee Apis mellifera nervous system of the larvae and adult castes and subcastes. DYNLL1/LC8 and myosin-IIb, -VI and -IXb have also been detected in the adult brain. SNARE proteins, such as CaMKII, clathrin, syntaxin, SNAP25, munc18, synaptophysin and synaptotagmin, are also expressed in the honey bee brain. Honey bee myosin-Va displayed ATP-dependent solubility and was associated with DYNLL1/LC8 and SNARE proteins in the membrane vesicle-enriched fraction. Myosin-Va expression was also decreased after the intracerebral injection of melittin and NMDA. The immunolocalization of myosin-Va and -IV, DYNLL1/LC8, and synaptophysin in mushroom bodies, and optical and antennal lobes was compared with the brain morphology based on Neo-Timm histochemistry and revealed a distinct and punctate distribution. This result suggested that the pattern of localization is associated with neuron function. Therefore, our data indicated that the roles of myosins, DYNLL1/LC8, and SNARE proteins in the nervous and visual systems of honey bees should be further studied under different developmental, caste and behavioral conditions. Copyright © 2011 Elsevier Ltd. All rights reserved.

Myosin-II sets the optimal response time scale of chemotactic amoeba

Science.gov (United States)

Hsu, Hsin-Fang; Westendorf, Christian; Tarantola, Marco; Bodenschatz, Eberhard; Beta, Carsten

2014-03-01

The response dynamics of the actin cytoskeleton to external chemical stimuli plays a fundamental role in numerous cellular functions. One of the key players that governs the dynamics of the actin network is the motor protein myosin-II. Here we investigate the role of myosin-II in the response of the actin system to external stimuli. We used a microfluidic device in combination with a photoactivatable chemoattractant to apply stimuli to individual cells with high temporal resolution. We directly compare the actin dynamics in Dictyostelium discodelium wild type (WT) cells to a knockout mutant that is deficient in myosin-II (MNL). Similar to the WT a small population of MNL cells showed self-sustained oscillations even in absence of external stimuli. The actin response of MNL cells to a short pulse of chemoattractant resembles WT during the first 15 sec but is significantly delayed afterward. The amplitude of the dominant peak in the power spectrum from the response time series of MNL cells to periodic stimuli with varying period showed a clear resonance peak at a forcing period of 36 sec, which is significantly delayed as compared to the resonance at 20 sec found for the WT. This shift indicates an important role of myosin-II in setting the response time scale of motile amoeba. Institute of Physics und Astronomy, University of Potsdam, Karl-Liebknecht-Str. 24/25, 14476 Potsdam, Germany.

Characterization of myosin light chain in shrimp hemocytic phagocytosis.

Science.gov (United States)

Han, Fang; Wang, Zhiyong; Wang, Xiaoqing

2010-11-01

Myosin light chain, a well-known cytoskeleton gene, regulates multiple processes that are involved in material transport, muscle shrink and cell division. However, its function in phagocytosis against invading pathogens in crustacean remains unknown. In this investigation, a myosin light chain gene was obtained from Marsupenaeus japonicus shrimp. The full-length cDNA of this gene was of 766 bp and an open reading frame (ORF) of 462 bp encoding a polypeptide of 153 amino acids. The myosin light chain protein was expressed in Escherichia coli and purified. Subsequently the specific antibody was raised using the purified GST fusion protein. As revealed by immuno-electron microscopy, the myosin light chain protein was only expressed in the dark bands of muscle. In the present study, the myosin light chain gene was up-regulated in the WSSV-resistant shrimp as revealed by real-time PCR and western blot. And the phagocytic percentage and phagocytic index using FITC-labeled Vibrio parahemolyticus were remarkably increased in the WSSV-resistant shrimp, suggesting that the myosin light chain protein was essential in hemocytic phagocytosis. On the other hand, RNAi assays indicated that the phagocytic percentage and phagocytic index were significantly decreased when the myosin light chain gene was silenced by sequence-specific siRNA. These findings suggested that myosin light chain protein was involved in the regulation of hemocytic phagocytosis of shrimp. Copyright 2010 Elsevier Ltd. All rights reserved.

Local pulsatile contractions are an intrinsic property of the myosin 2A motor in the cortical cytoskeleton of adherent cells.

Science.gov (United States)

Baird, Michelle A; Billington, Neil; Wang, Aibing; Adelstein, Robert S; Sellers, James R; Fischer, Robert S; Waterman, Clare M

2017-01-15

The role of nonmuscle myosin 2 (NM2) pulsatile dynamics in generating contractile forces required for developmental morphogenesis has been characterized, but whether these pulsatile contractions are an intrinsic property of all actomyosin networks is not known. Here we used live-cell fluorescence imaging to show that transient, local assembly of NM2A "pulses" occurs in the cortical cytoskeleton of single adherent cells of mesenchymal, epithelial, and sarcoma origin, independent of developmental signaling cues and cell-cell or cell-ECM interactions. We show that pulses in the cortical cytoskeleton require Rho-associated kinase- or myosin light chain kinase (MLCK) activity, increases in cytosolic calcium, and NM2 ATPase activity. Surprisingly, we find that cortical cytoskeleton pulses specifically require the head domain of NM2A, as they do not occur with either NM2B or a 2B-head-2A-tail chimera. Our results thus suggest that pulsatile contractions in the cortical cytoskeleton are an intrinsic property of the NM2A motor that may mediate its role in homeostatic maintenance of tension in the cortical cytoskeleton of adherent cells. © 2017 Baird 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).

Drosophila UNC-45 prevents heat-induced aggregation of skeletal muscle myosin and facilitates refolding of citrate synthase

Energy Technology Data Exchange (ETDEWEB)

Melkani, Girish C.; Lee, Chi F.; Cammarato, Anthony [Department of Biology and the Molecular Biology Institute, San Diego State University, San Diego, CA 92182-4614 (United States); Bernstein, Sanford I., E-mail: sbernst@sciences.sdsu.edu [Department of Biology and the Molecular Biology Institute, San Diego State University, San Diego, CA 92182-4614 (United States)

2010-05-28

UNC-45 belongs to the UCS (UNC-45, CRO1, She4p) domain protein family, whose members interact with various classes of myosin. Here we provide structural and biochemical evidence that Escherichia coli-expressed Drosophila UNC-45 (DUNC-45) maintains the integrity of several substrates during heat-induced stress in vitro. DUNC-45 displays chaperone function in suppressing aggregation of the muscle myosin heavy meromyosin fragment, the myosin S-1 motor domain, {alpha}-lactalbumin and citrate synthase. Biochemical evidence is supported by electron microscopy, which reveals the first structural evidence that DUNC-45 prevents inter- or intra-molecular aggregates of skeletal muscle heavy meromyosin caused by elevated temperatures. We also demonstrate for the first time that UNC-45 is able to refold a denatured substrate, urea-unfolded citrate synthase. Overall, this in vitro study provides insight into the fate of muscle myosin under stress conditions and suggests that UNC-45 protects and maintains the contractile machinery during in vivo stress.

Smooth muscle myosin light chain kinase efficiently phosphorylates serine 15 of cardiac myosin regulatory light chain

International Nuclear Information System (INIS)

Josephson, Matthew P.; Sikkink, Laura A.; Penheiter, Alan R.; Burghardt, Thomas P.; Ajtai, Katalin

2011-01-01

Highlights: ► Cardiac myosin regulatory light chain (MYL2) is phosphorylated at S15. ► Smooth muscle myosin light chain kinase (smMLCK) is a ubiquitous kinase. ► It is a widely believed that MYL2 is a poor substrate for smMLCK. ► In fact, smMLCK efficiently and rapidly phosphorylates S15 in MYL2. ► Phosphorylation kinetics measured by novel fluorescence method without radioactivity. -- Abstract: Specific phosphorylation of the human ventricular cardiac myosin regulatory light chain (MYL2) modifies the protein at S15. This modification affects MYL2 secondary structure and modulates the Ca 2+ sensitivity of contraction in cardiac tissue. Smooth muscle myosin light chain kinase (smMLCK) is a ubiquitous kinase prevalent in uterus and present in other contracting tissues including cardiac muscle. The recombinant 130 kDa (short) smMLCK phosphorylated S15 in MYL2 in vitro. Specific modification of S15 was verified using the direct detection of the phospho group on S15 with mass spectrometry. SmMLCK also specifically phosphorylated myosin regulatory light chain S15 in porcine ventricular myosin and chicken gizzard smooth muscle myosin (S20 in smooth muscle) but failed to phosphorylate the myosin regulatory light chain in rabbit skeletal myosin. Phosphorylation kinetics, measured using a novel fluorescence method eliminating the use of radioactive isotopes, indicates similar Michaelis–Menten V max and K M for regulatory light chain S15 phosphorylation rates in MYL2, porcine ventricular myosin, and chicken gizzard myosin. These data demonstrate that smMLCK is a specific and efficient kinase for the in vitro phosphorylation of MYL2, cardiac, and smooth muscle myosin. Whether smMLCK plays a role in cardiac muscle regulation or response to a disease causing stimulus is unclear but it should be considered a potentially significant kinase in cardiac tissue on the basis of its specificity, kinetics, and tissue expression.

Smooth muscle myosin light chain kinase efficiently phosphorylates serine 15 of cardiac myosin regulatory light chain

Energy Technology Data Exchange (ETDEWEB)

Josephson, Matthew P.; Sikkink, Laura A. [Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905 (United States); Penheiter, Alan R. [Molecular Medicine Program, Mayo Clinic, Rochester, MN 55905 (United States); Burghardt, Thomas P., E-mail: burghardt@mayo.edu [Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905 (United States); Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905 (United States); Ajtai, Katalin [Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905 (United States)

2011-12-16

Highlights: Black-Right-Pointing-Pointer Cardiac myosin regulatory light chain (MYL2) is phosphorylated at S15. Black-Right-Pointing-Pointer Smooth muscle myosin light chain kinase (smMLCK) is a ubiquitous kinase. Black-Right-Pointing-Pointer It is a widely believed that MYL2 is a poor substrate for smMLCK. Black-Right-Pointing-Pointer In fact, smMLCK efficiently and rapidly phosphorylates S15 in MYL2. Black-Right-Pointing-Pointer Phosphorylation kinetics measured by novel fluorescence method without radioactivity. -- Abstract: Specific phosphorylation of the human ventricular cardiac myosin regulatory light chain (MYL2) modifies the protein at S15. This modification affects MYL2 secondary structure and modulates the Ca{sup 2+} sensitivity of contraction in cardiac tissue. Smooth muscle myosin light chain kinase (smMLCK) is a ubiquitous kinase prevalent in uterus and present in other contracting tissues including cardiac muscle. The recombinant 130 kDa (short) smMLCK phosphorylated S15 in MYL2 in vitro. Specific modification of S15 was verified using the direct detection of the phospho group on S15 with mass spectrometry. SmMLCK also specifically phosphorylated myosin regulatory light chain S15 in porcine ventricular myosin and chicken gizzard smooth muscle myosin (S20 in smooth muscle) but failed to phosphorylate the myosin regulatory light chain in rabbit skeletal myosin. Phosphorylation kinetics, measured using a novel fluorescence method eliminating the use of radioactive isotopes, indicates similar Michaelis-Menten V{sub max} and K{sub M} for regulatory light chain S15 phosphorylation rates in MYL2, porcine ventricular myosin, and chicken gizzard myosin. These data demonstrate that smMLCK is a specific and efficient kinase for the in vitro phosphorylation of MYL2, cardiac, and smooth muscle myosin. Whether smMLCK plays a role in cardiac muscle regulation or response to a disease causing stimulus is unclear but it should be considered a potentially significant

Implementation of a Non-Metallic Barrier in an Electric Motor

Science.gov (United States)

M?Sadoques, George; Carra, Michael; Beringer, Woody

2012-01-01

Electric motors that run in pure oxygen must be sealed, or "canned," for safety reasons to prevent the oxygen from entering into the electrical portion of the motor. The current canning process involves designing a metallic barrier around the rotor to provide the separation. This metallic barrier reduces the motor efficiency as speed is increased. In higher-speed electric motors, efficiency is greatly improved if a very thin, nonmetallic barrier can be utilized. The barrier thickness needs to be approximately 0.025-in. (.0.6-mm) thick and can be made of a brittle material such as glass. The motors, however, designed for space applications are typically subject to high-vibration environments. A fragile, non-metallic barrier can be utilized in a motor assembly if held in place by a set of standard rubber O-ring seals. The O-rings provide the necessary sealing to keep oxygen away from the electrical portion of the motor and also isolate the fragile barrier from the harsh motor vibration environment. The compliance of the rubber O-rings gently constrains the fragile barrier and isolates it from the harsh external motor environment. The use of a non-metallic barrier greatly improves motor performance, especially at higher speeds, while isolating the electronics from the working fluid with an inert liner.

Alternative S2 Hinge Regions of the Myosin Rod Affect Myofibrillar Structure and Myosin Kinetics

Energy Technology Data Exchange (ETDEWEB)

Miller, Mark S.; Dambacher, Corey M.; Knowles, Aileen F.; Braddock, Joan M.; Farman, Gerrie P.; Irving, Thomas C.; Swank, Douglas M.; Bernstein, Sanford I.; Maughan, David W.; (RPI); (IIT); (SDSU); (Vermont)

2009-07-01

The subfragment 2/light meromyosin 'hinge' region has been proposed to significantly contribute to muscle contraction force and/or speed. Transgenic replacement of the endogenous fast muscle isovariant hinge A (exon 15a) in Drosophila melanogaster indirect flight muscle with the slow muscle hinge B (exon 15b) allows examination of the structural and functional changes when only this region of the myosin molecule is different. Hinge B was previously shown to increase myosin rod length, increase A-band and sarcomere length, and decrease flight performance compared to hinge A. We applied additional measures to these transgenic lines to further evaluate the consequences of modifying this hinge region. Structurally, the longer A-band and sarcomere lengths found in the hinge B myofibrils appear to be due to the longitudinal addition of myosin heads. Functionally, hinge B, although a significant distance from the myosin catalytic domain, alters myosin kinetics in a manner consistent with this region increasing myosin rod length. These structural and functional changes combine to decrease whole fly wing-beat frequency and flight performance. Our results indicate that this hinge region plays an important role in determining myosin kinetics and in regulating thick and thin filament lengths as well as sarcomere length.

36 CFR 292.45 - Use of motorized and non-motorized rivercraft.

Science.gov (United States)

2010-07-01

... practicable, conflicts between motorized and non-motorized rivercraft users and between both types of...-motorized rivercraft may be permitted subject to restrictions on size, type of craft, numbers, duration... Service where such activity may be permitted subject to restrictions on size, type of craft, numbers...

Myosin isoform determines the conformational dynamics and cooperativity of actin filaments in the strongly bound actomyosin complex

Science.gov (United States)

Prochniewicz, Ewa; Chin, Harvey F.; Henn, Arnon; Hannemann, Diane E.; Olivares, Adrian O.; Thomas, David D.; De La Cruz, Enrique M.

2010-01-01

SUMMARY We have used transient phosphorescence anisotropy (TPA) to detect the microsecond rotational dynamics of erythrosin iodoacetamide (ErIA)-labeled actin strongly bound to single-headed fragments of muscle myosin (muscle S1) and non-muscle myosin V (MV). The conformational dynamics of actin filaments in solution are markedly influenced by the isoform of bound myosin. Both myosins increase the final anisotropy of actin at sub-stoichiometric binding densities, indicating long-range, non-nearest neighbor cooperative restriction of filament rotational dynamics amplitude, but the cooperative unit is larger with MV than muscle S1. Both myosin isoforms also cooperatively affect the actin filament rotational correlation time, but with opposite effects; muscle S1 decreases rates of intrafilament torsional motion, while binding of MV increases the rates of motion. The cooperative effects on the rates of intrafilament motions correlate with the kinetics of myosin binding to actin filaments such that MV binds more rapidly, and muscle myosin more slowly, to partially decorated filaments than to bare filaments. The two isoforms also differ in their effects on the phosphorescence lifetime of the actin-bound ErIA; while muscle S1 increases the lifetime, suggesting decreased aqueous exposure of the probe, MV does not induce a significant change. We conclude that the dynamics and structure of actin in the strongly bound actomyosin complex is determined by the isoform of the bound myosin, in a manner likely to accommodate the diverse functional roles of actomyosin in muscle and non-muscle cells. PMID:19962990

Myosin isoform switching during assembly of the Drosophila flight muscle thick filament lattice.

Science.gov (United States)

Orfanos, Zacharias; Sparrow, John C

2013-01-01

During muscle development myosin molecules form symmetrical thick filaments, which integrate with the thin filaments to produce the regular sarcomeric lattice. In Drosophila indirect flight muscles (IFMs) the details of this process can be studied using genetic approaches. The weeP26 transgenic line has a GFP-encoding exon inserted into the single Drosophila muscle myosin heavy chain gene, Mhc. The weeP26 IFM sarcomeres have a unique MHC-GFP-labelling pattern restricted to the sarcomere core, explained by non-translation of the GFP exon following alternative splicing. Characterisation of wild-type IFM MHC mRNA confirmed the presence of an alternately spliced isoform, expressed earlier than the major IFM-specific isoform. The two wild-type IFM-specific MHC isoforms differ by the presence of a C-terminal 'tailpiece' in the minor isoform. The sequential expression and assembly of these two MHCs into developing thick filaments suggest a role for the tailpiece in initiating A-band formation. The restriction of the MHC-GFP sarcomeric pattern in weeP26 is lifted when the IFM lack the IFM-specific myosin binding protein flightin, suggesting that it limits myosin dissociation from thick filaments. Studies of flightin binding to developing thick filaments reveal a progressive binding at the growing thick filament tips and in a retrograde direction to earlier assembled, proximal filament regions. We propose that this flightin binding restricts myosin molecule incorporation/dissociation during thick filament assembly and explains the location of the early MHC isoform pattern in the IFM A-band.

Motor and non-motor symptoms in old-age onset Parkinson's disease patients.

Science.gov (United States)

Mendonça, Marcelo D; Lampreia, Tania; Miguel, Rita; Caetano, André; Barbosa, Raquel; Bugalho, Paulo

2017-07-01

Advancing age is a well-known risk factor for Parkinson's disease (PD). With population ageing it is expected that the total number of patients with PD onset at oldage increases. Information on the motor but particularly on non-motor phenotype of this late-onset population is lacking. We recruited 24 patients with PD onset at or over 75 years. Each patient was matched with 1 control patient with PD onset between the ages of 40 and 65 and matched for disease duration. Both groups were assessed with the UPDRS, the Non-motor symptoms scale (NMSS) and other scales to assess non-motor symptoms. Groups were compared with conditional logistic regression analysis. Old-age onset PD was, on average, 80 years at the time of PD onset while middle-age onset were 59. Disease duration was approximately 5 years in both groups. While no difference was observed in the total UPDRS-III scores, old-age onset PD was associated with higher axial symptoms (7.42 vs. 4.63, p = 0.011) and a higher frequency of dementia (7/24 vs. 0/24, p = 0.009). While no difference in the total number of non-motor symptoms was observed (6.79 vs. 6.22, p = 0.310), old-age onset patients had a higher prevalence of gastrointestinal symptoms (20/24 vs. 12/24, p = 0.037). For the same disease duration, older age onset is associated with worse axial motor dysfunction and dementia in PD patients. Beside gastrointestinal symptoms, non-motor symptoms are not associated with age.

Myosin heavy chain-like localizes at cell contact sites during Drosophila myoblast fusion and interacts in vitro with Rolling pebbles 7

Energy Technology Data Exchange (ETDEWEB)

Bonn, Bettina R.; Rudolf, Anja; Hornbruch-Freitag, Christina; Daum, Gabor; Kuckwa, Jessica; Kastl, Lena; Buttgereit, Detlev [Developmental Biology, Department of Biology, Philipps-Universität Marburg, Karl-von-Frisch-Strasse 8, 35037 Marburg (Germany); Renkawitz-Pohl, Renate, E-mail: renkawit@biologie.uni-marburg.de [Developmental Biology, Department of Biology, Philipps-Universität Marburg, Karl-von-Frisch-Strasse 8, 35037 Marburg (Germany)

2013-02-15

Besides representing the sarcomeric thick filaments, myosins are involved in many cellular transport and motility processes. Myosin heavy chains are grouped into 18 classes. Here we show that in Drosophila, the unconventional group XVIII myosin heavy chain-like (Mhcl) is transcribed in the mesoderm of embryos, most prominently in founder cells (FCs). An ectopically expressed GFP-tagged Mhcl localizes in the growing muscle at cell–cell contacts towards the attached fusion competent myoblast (FCM). We further show that Mhcl interacts in vitro with the essential fusion protein Rolling pebbles 7 (Rols7), which is part of a protein complex established at cell contact sites (Fusion-restricted Myogenic-Adhesive Structure or FuRMAS). Here, branched F-actin is likely needed to widen the fusion pore and to integrate the myoblast into the growing muscle. We show that the localization of Mhcl is dependent on the presence of Rols7, and we postulate that Mhcl acts at the FuRMAS as an actin motor protein. We further show that Mhcl deficient embryos develop a wild-type musculature. We thus propose that Mhcl functions redundantly to other myosin heavy chains in myoblasts. Lastly, we found that the protein is detectable adjacent to the sarcomeric Z-discs, suggesting an additional function in mature muscles. - Highlights: ► The class XVIII myosin encoding gene Mhcl is transcribed in the mesoderm. ► Mhcl localization at contact sites of fusing myoblasts depends on Rols7. ► Mhcl interacts in vitro with Rols7 which is essential for myogenesis. ► Functional redundancy with other myosins is likely as mutants show no muscle defects. ► Mhcl localizes adjacent to Z-discs of sarcomeres and might support muscle integrity.

Myosin heavy chain-like localizes at cell contact sites during Drosophila myoblast fusion and interacts in vitro with Rolling pebbles 7

International Nuclear Information System (INIS)

Bonn, Bettina R.; Rudolf, Anja; Hornbruch-Freitag, Christina; Daum, Gabor; Kuckwa, Jessica; Kastl, Lena; Buttgereit, Detlev; Renkawitz-Pohl, Renate

2013-01-01

Besides representing the sarcomeric thick filaments, myosins are involved in many cellular transport and motility processes. Myosin heavy chains are grouped into 18 classes. Here we show that in Drosophila, the unconventional group XVIII myosin heavy chain-like (Mhcl) is transcribed in the mesoderm of embryos, most prominently in founder cells (FCs). An ectopically expressed GFP-tagged Mhcl localizes in the growing muscle at cell–cell contacts towards the attached fusion competent myoblast (FCM). We further show that Mhcl interacts in vitro with the essential fusion protein Rolling pebbles 7 (Rols7), which is part of a protein complex established at cell contact sites (Fusion-restricted Myogenic-Adhesive Structure or FuRMAS). Here, branched F-actin is likely needed to widen the fusion pore and to integrate the myoblast into the growing muscle. We show that the localization of Mhcl is dependent on the presence of Rols7, and we postulate that Mhcl acts at the FuRMAS as an actin motor protein. We further show that Mhcl deficient embryos develop a wild-type musculature. We thus propose that Mhcl functions redundantly to other myosin heavy chains in myoblasts. Lastly, we found that the protein is detectable adjacent to the sarcomeric Z-discs, suggesting an additional function in mature muscles. - Highlights: ► The class XVIII myosin encoding gene Mhcl is transcribed in the mesoderm. ► Mhcl localization at contact sites of fusing myoblasts depends on Rols7. ► Mhcl interacts in vitro with Rols7 which is essential for myogenesis. ► Functional redundancy with other myosins is likely as mutants show no muscle defects. ► Mhcl localizes adjacent to Z-discs of sarcomeres and might support muscle integrity

Altered cortical processing of motor inhibition in schizophrenia.

Science.gov (United States)

Lindberg, Påvel G; Térémetz, Maxime; Charron, Sylvain; Kebir, Oussama; Saby, Agathe; Bendjemaa, Narjes; Lion, Stéphanie; Crépon, Benoît; Gaillard, Raphaël; Oppenheim, Catherine; Krebs, Marie-Odile; Amado, Isabelle

2016-12-01

Inhibition is considered a key mechanism in schizophrenia. Short-latency intracortical inhibition (SICI) in the motor cortex is reduced in schizophrenia and is considered to reflect locally deficient γ-aminobutyric acid (GABA)-ergic modulation. However, it remains unclear how SICI is modulated during motor inhibition and how it relates to neural processing in other cortical areas. Here we studied motor inhibition Stop signal task (SST) in stabilized patients with schizophrenia (N = 28), healthy siblings (N = 21) and healthy controls (n = 31) matched in general cognitive status and educational level. Transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) were used to investigate neural correlates of motor inhibition. SST performance was similar in patients and controls. SICI was modulated by the task as expected in healthy controls and siblings but was reduced in patients with schizophrenia during inhibition despite equivalent motor inhibition performance. fMRI showed greater prefrontal and premotor activation during motor inhibition in schizophrenia. Task-related modulation of SICI was higher in subjects who showed less inhibition-related activity in pre-supplementary motor area (SMA) and cingulate motor area. An exploratory genetic analysis of selected markers of inhibition (GABRB2, GAD1, GRM1, and GRM3) did not explain task-related differences in SICI or cortical activation. In conclusion, this multimodal study provides direct evidence of a task-related deficiency in SICI modulation in schizophrenia likely reflecting deficient GABA-A related processing in motor cortex. Compensatory activation of premotor areas may explain similar motor inhibition in patients despite local deficits in intracortical processing. Task-related modulation of SICI may serve as a useful non-invasive GABAergic marker in development of therapeutic strategies in schizophrenia. Copyright © 2016 Elsevier Ltd. All rights reserved.

Comparative genomic analysis of the arthropod muscle myosin heavy chain genes allows ancestral gene reconstruction and reveals a new type of 'partially' processed pseudogene

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Kollmar Martin

2008-02-01

Full Text Available Abstract Background Alternative splicing of mutually exclusive exons is an important mechanism for increasing protein diversity in eukaryotes. The insect Mhc (myosin heavy chain gene produces all different muscle myosins as a result of alternative splicing in contrast to most other organisms of the Metazoa lineage, that have a family of muscle genes with each gene coding for a protein specialized for a functional niche. Results The muscle myosin heavy chain genes of 22 species of the Arthropoda ranging from the waterflea to wasp and Drosophila have been annotated. The analysis of the gene structures allowed the reconstruction of an ancient muscle myosin heavy chain gene and showed that during evolution of the arthropods introns have mainly been lost in these genes although intron gain might have happened in a few cases. Surprisingly, the genome of Aedes aegypti contains another and that of Culex pipiens quinquefasciatus two further muscle myosin heavy chain genes, called Mhc3 and Mhc4, that contain only one variant of the corresponding alternative exons of the Mhc1 gene. Mhc3 transcription in Aedes aegypti is documented by EST data. Mhc3 and Mhc4 inserted in the Aedes and Culex genomes either by gene duplication followed by the loss of all but one variant of the alternative exons, or by incorporation of a transcript of which all other variants have been spliced out retaining the exon-intron structure. The second and more likely possibility represents a new type of a 'partially' processed pseudogene. Conclusion Based on the comparative genomic analysis of the alternatively spliced arthropod muscle myosin heavy chain genes we propose that the splicing process operates sequentially on the transcript. The process consists of the splicing of the mutually exclusive exons until one exon out of the cluster remains while retaining surrounding intronic sequence. In a second step splicing of introns takes place. A related mechanism could be responsible for

Premotor and non-motor features of Parkinson’s disease

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Goldman, Jennifer G.; Postuma, Ron

2014-01-01

Purpose of review This review highlights recent advances in premotor and non-motor features in Parkinson’s disease, focusing on these issues in the context of prodromal and early stage Parkinson’s disease. Recent findings While Parkinson’s disease patients experience a wide range of non-motor symptoms throughout the disease course, studies demonstrate that non-motor features are not solely a late manifestation. Indeed, disturbances of smell, sleep, mood, and gastrointestinal function may herald Parkinson’s disease or related synucleinopathies and precede these neurodegenerative conditions by 5 or more years. In addition, other non-motor symptoms such as cognitive impairment are now recognized in incident or de novo Parkinson’s disease cohorts. Many of these non-motor features reflect disturbances in non-dopaminergic systems and early involvement of peripheral and central nervous systems including olfactory, enteric, and brainstem neurons as in Braak’s proposed pathological staging of Parkinson’s disease. Current research focuses on identifying potential biomarkers that may detect persons at risk for Parkinson’s disease and permit early intervention with neuroprotective or disease-modifying therapeutics. Summary Recent studies provide new insights on the frequency, pathophysiology, and importance of non-motor features in Parkinson’s disease as well as the recognition that these non-motor symptoms occur in premotor, early, and later phases of Parkinson’s disease. PMID:24978368

Extracellular matrix-dependent myosin dynamics during G1-S phase cell cycle progression in hepatocytes

International Nuclear Information System (INIS)

Bhadriraju, Kiran; Hansen, Linda K.

2004-01-01

Cell spreading and proliferation are tightly coupled in anchorage-dependent cells. While adhesion-dependent proliferation signals require an intact actin cytoskeleton, and some of these signals such as ERK activation have been characterized, the role of myosin in spreading and cell cycle progression under different extracellular matrix (ECM) conditions is not known. Studies presented here examine changes in myosin activity in freshly isolated hepatocytes under ECM conditions that promote either proliferation (high fibronectin density) or growth arrest (low fibronectin density). Three different measures were obtained and related to both spreading and cell cycle progression: myosin protein levels and association with cytoskeleton, myosin light chain phosphorylation, and its ATPase activity. During the first 48 h in culture, corresponding with transit through G1 phase, there was a six-fold increase in both myosin protein levels and myosin association with actin cytoskeleton. There was also a steady increase in myosin light chain phosphorylation and ATPase activity with spreading, which did not occur in non-spread, growth-arrested cells on low density of fibronectin. Myosin-inhibiting drugs blocked ERK activation, cyclin D1 expression, and S phase entry. Overexpression of the cell cycle protein cyclin D1 overcame both ECM-dependent and actomyosin-dependent inhibition of DNA synthesis, suggesting that cyclin D1 is a key event downstream of myosin-dependent cell cycle regulation

Azidoblebbistatin, a photoreactive myosin inhibitor

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Képiró, Miklós; Várkuti, Boglárka H.; Bodor, Andrea; Hegyi, György; Drahos, László; Kovács, Mihály; Málnási-Csizmadia, András

2012-01-01

Photoreactive compounds are important tools in life sciences that allow precisely timed covalent crosslinking of ligands and targets. Using a unique technique we have synthesized azidoblebbistatin, which is a derivative of blebbistatin, the most widely used myosin inhibitor. Without UV irradiation azidoblebbistatin exhibits identical inhibitory properties to those of blebbistatin. Using UV irradiation, azidoblebbistatin can be covalently crosslinked to myosin, which greatly enhances its in vitro and in vivo effectiveness. Photo-crosslinking also eliminates limitations associated with the relatively low myosin affinity and water solubility of blebbistatin. The wavelength used for photo-crosslinking is not toxic for cells and tissues, which confers a great advantage in in vivo tests. Because the crosslink results in an irreversible association of the inhibitor to myosin and the irradiation eliminates the residual activity of unbound inhibitor molecules, azidoblebbistatin has a great potential to become a highly effective tool in both structural studies of actomyosin contractility and the investigation of cellular and physiological functions of myosin II. We used azidoblebbistatin to identify previously unknown low-affinity targets of the inhibitor (EC50 ≥ 50 μM) in Dictyostelium discoideum, while the strongest interactant was found to be myosin II (EC50 = 5 μM). Our results demonstrate that azidoblebbistatin, and potentially other azidated drugs, can become highly useful tools for the identification of strong- and weak-binding cellular targets and the determination of the apparent binding affinities in in vivo conditions. PMID:22647605

Clinical study on the time courses of serum myosin light chain I levels in patients with acute myocardial infarction

International Nuclear Information System (INIS)

Nakanishi, Masako; Saiki, Yasuhiko; Ui, Kazuyo

1992-01-01

Changes of serum myosin light chain I (Myosin LCI) concentrations and creatine kinase (CK) activities were serially measured in 23 patients with acute myocardial infarction. Intracoronary thrombolysis was performed in 14 patients (ICT group) while the remaining 9 patients were treated in the conventional manner (non ICT group). The relationships between the maximum levels of serum Myosin LCI or CK and a myocardial infarct size index or left ventricular function were evaluated in 18 patients. The myocardial infarct size index was determined by 201 Tl myocardial scintigrams performed in the chronic phase. Multiple peaks of Myosin LCI were observed in 64% (9/14) of the ICT group and the first peak in 6 of these patients appeared much earlier in the same time as CK peak than in the non-ICT group, while multiple peaks were seen only in one case in the non-ICT group. The infarct size index by 201 Tl myocardial SPECT correlated with maximum Myosin LCI levels (r=0.88, p<0.001, n=10) and CK activities (r=0.67, p<0.05, n=10). These results indicate that the measurement of serum Myosin LCI is very useful for estimating the extent of myocardial damage and suggest that myocardial degeneration occurs at a very early phase of myocardial infarction. (author)

Benefit on motor and non-motor behavior in a specialized unit for Parkinson's disease.

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Müller, Thomas; Öhm, Gabi; Eilert, Kathrin; Möhr, Katharina; Rotter, Stephanie; Haas, Thomas; Küchler, Matthias; Lütge, Sven; Marg, Marion; Rothe, Hartmut

2017-06-01

Treatment of patients with Parkinson's disease in specialized units is quite common in Germany. Data on the benefit of this hospitalization of patients with Parkinson's disease on motor and non-motor symptoms in conjunction with standardized tests are rare. Objective was to determine the efficacy of this therapeutic setting. We scored disease severity and performed clinical tests, respectively, instrumental procedures under standardized conditions in consecutively referred in-patients initially and at the end of their hospital stay. There was a decrease of motor and non-motor symptoms. The extent of improvement of non-motor and motor symptoms correlated to each other. Performance of complex movement sequences became better, whereas execution of simple movement series did not ameliorate. The interval for the timed up and go test went down. We demonstrate the effectiveness of an in-patient stay in a specialized unit for Parkinson's disease. Objective standardized testing supplements subjective clinical scoring with established rating scales.

Catch-slip bonds can be dispensable for motor force regulation during skeletal muscle contraction

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Dong, Chenling; Chen, Bin

2015-07-01

It is intriguing how multiple molecular motors can perform coordinated and synchronous functions, which is essential in various cellular processes. Recent studies on skeletal muscle might have shed light on this issue, where rather precise motor force regulation was partly attributed to the specific stochastic features of a single attached myosin motor. Though attached motors can randomly detach from actin filaments either through an adenosine triphosphate (ATP) hydrolysis cycle or through "catch-slip bond" breaking, their respective contribution in motor force regulation has not been clarified. Here, through simulating a mechanical model of sarcomere with a coupled Monte Carlo method and finite element method, we find that the stochastic features of an ATP hydrolysis cycle can be sufficient while those of catch-slip bonds can be dispensable for motor force regulation.

Pigment granule translocation in red ovarian chromatophores from the palaemonid shrimp Macrobrachium olfersi (Weigmann, 1836): functional roles for the cytoskeleton and its molecular motors.

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Milograna, Sarah Ribeiro; Ribeiro, Márcia Regina; Baqui, Munira Muhammad Abdel; McNamara, John Campbell

2014-12-01

The binding of red pigment concentrating hormone (RPCH) to membrane receptors in crustacean chromatophores triggers Ca²⁺/cGMP signaling cascades that activate cytoskeletal motors, driving pigment granule translocation. We investigate the distributions of microfilaments and microtubules and their associated molecular motors, myosin and dynein, by confocal and transmission electron microscopy, evaluating a functional role for the cytoskeleton in pigment translocation using inhibitors of polymer turnover and motor activity in vitro. Microtubules occupy the chromatophore cell extensions whether the pigment granules are aggregated or dispersed. The inhibition of microtubule turnover by taxol induces pigment aggregation and inhibits re-dispersion. Phalloidin-FITC actin labeling, together with tannic acid fixation and ultrastructural analysis, reveals that microfilaments form networks associated with the pigment granules. Actin polymerization induced by jasplaquinolide strongly inhibits RPCH-induced aggregation, causes spontaneous pigment dispersion, and inhibits pigment re-dispersion. Inhibition of actin polymerization by latrunculin-A completely impedes pigment aggregation and re-dispersion. Confocal immunocytochemistry shows that non-muscle myosin II (NMMII) co-localizes mainly with pigment granules while blebbistatin inhibition of NMMII strongly reduces the RPCH response, also inducing spontaneous pigment dispersion. Myosin II and dynein also co-localize with the pigment granules. Inhibition of dynein ATPase by erythro-9-(2-hydroxy-3-nonyl) adenine induces aggregation, inhibits RPCH-triggered aggregation, and inhibits re-dispersion. Granule aggregation and dispersion depend mainly on microfilament integrity although microtubules may be involved. Both cytoskeletal polymers are functional only when subunit turnover is active. Myosin and dynein may be the molecular motors that drive pigment aggregation. These mechanisms of granule translocation in crustacean

Coupling between myosin head conformation and the thick filament backbone structure.

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Hu, Zhongjun; Taylor, Dianne W; Edwards, Robert J; Taylor, Kenneth A

2017-12-01

The recent high-resolution structure of the thick filament from Lethocerus asynchronous flight muscle shows aspects of thick filament structure never before revealed that may shed some light on how striated muscles function. The phenomenon of stretch activation underlies the function of asynchronous flight muscle. It is most highly developed in flight muscle, but is also observed in other striated muscles such as cardiac muscle. Although stretch activation is likely to be complex, involving more than a single structural aspect of striated muscle, the thick filament itself, would be a prime site for regulatory function because it must bear all of the tension produced by both its associated myosin motors and any externally applied force. Here we show the first structural evidence that the arrangement of myosin heads within the interacting heads motif is coupled to the structure of the thick filament backbone. We find that a change in helical angle of 0.16° disorders the blocked head preferentially within the Lethocerus interacting heads motif. This observation suggests a mechanism for how tension affects the dynamics of the myosin heads leading to a detailed hypothesis for stretch activation and shortening deactivation, in which the blocked head preferentially binds the thin filament followed by the free head when force production occurs. Copyright © 2017 Elsevier Inc. All rights reserved.

Motor cortical processing is causally involved in object recognition.

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Decloe, Rebecca; Obhi, Sukhvinder S

2013-12-14

Motor activity during vicarious experience of actions is a widely reported and studied phenomenon, and motor system activity also accompanies observation of graspable objects in the absence of any actions. Such motor activity is thought to reflect simulation of the observed action, or preparation to interact with the object, respectively. Here, in an initial exploratory study, we ask whether motor activity during observation of object directed actions is involved in processes related to recognition of the object after initial exposure. Single pulse Transcranial Magnetic Stimulation (TMS) was applied over the thumb representation of the motor cortex, or over the vertex, during observation of a model thumb typing on a cell-phone, and performance on a phone recognition task at the end of the trial was assessed. Disrupting motor processing over the thumb representation 100 ms after the onset of the typing video impaired the ability to recognize the phone in the recognition test, whereas there was no such effect for TMS applied over the vertex and no TMS trials. Furthermore, this effect only manifested for videos observed from the first person perspective. In an additional control condition, there was no evidence for any effects of TMS to the thumb representation or vertex when observing and recognizing non-action related shape stimuli. Overall, these data provide evidence that motor cortical processing during observation of object-directed actions from a first person perspective is causally linked to the formation of enduring representations of objects-of-action.

Electron microscopic evidence for the myosin head lever arm mechanism in hydrated myosin filaments using the gas environmental chamber

International Nuclear Information System (INIS)

Minoda, Hiroki; Okabe, Tatsuhiro; Inayoshi, Yuhri; Miyakawa, Takuya; Miyauchi, Yumiko; Tanokura, Masaru; Katayama, Eisaku; Wakabayashi, Takeyuki; Akimoto, Tsuyoshi; Sugi, Haruo

2011-01-01

Research highlights: → We succeeded in recording structural changes of hydrated myosin cross-bridges. → We succeeded in position-marking the cross-bridges with site-directed antibodies. → We recorded cross-bridge movement at different regions in individual cross-bridge. → The movement was smallest at the cross-bridge-subfragment two boundary. → The results provide evidence for the cross-bridge lever arm mechanism. -- Abstract: Muscle contraction results from an attachment-detachment cycle between the myosin heads extending from myosin filaments and the sites on actin filaments. The myosin head first attaches to actin together with the products of ATP hydrolysis, performs a power stroke associated with release of hydrolysis products, and detaches from actin upon binding with new ATP. The detached myosin head then hydrolyses ATP, and performs a recovery stroke to restore its initial position. The strokes have been suggested to result from rotation of the lever arm domain around the converter domain, while the catalytic domain remains rigid. To ascertain the validity of the lever arm hypothesis in muscle, we recorded ATP-induced movement at different regions within individual myosin heads in hydrated myosin filaments, using the gas environmental chamber attached to the electron microscope. The myosin head were position-marked with gold particles using three different site-directed antibodies. The amplitude of ATP-induced movement at the actin binding site in the catalytic domain was similar to that at the boundary between the catalytic and converter domains, but was definitely larger than that at the regulatory light chain in the lever arm domain. These results are consistent with the myosin head lever arm mechanism in muscle contraction if some assumptions are made.

Chitin Synthases with a Myosin Motor-Like Domain Control the Resistance of Aspergillus fumigatus to Echinocandins

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Jiménez-Ortigosa, Cristina; Aimanianda, Vishukumar; Muszkieta, Laetitia; Mouyna, Isabelle; Alsteens, David; Pire, Stéphane; Beau, Remi; Krappmann, Sven; Beauvais, Anne; Dufrêne, Yves F.

2012-01-01

Aspergillus fumigatus has two chitin synthases (CSMA and CSMB) with a myosin motor-like domain (MMD) arranged in a head-to-head configuration. To understand the function of these chitin synthases, single and double csm mutant strains were constructed and analyzed. Although there was a slight reduction in mycelial growth of the mutants, the total chitin synthase activity and the cell wall chitin content were similar in the mycelium of all of the mutants and the parental strain. In the conidia, chitin content in the ΔcsmA strain cell wall was less than half the amount found in the parental strain. In contrast, the ΔcsmB mutant strain and, unexpectedly, the ΔcsmA/ΔcsmB mutant strain did not show any modification of chitin content in their conidial cell walls. In contrast to the hydrophobic conidia of the parental strain, conidia of all of the csm mutants were hydrophilic due to the presence of an amorphous material covering the hydrophobic surface-rodlet layer. The deletion of CSM genes also resulted in an increased susceptibility of resting and germinating conidia to echinocandins. These results show that the deletion of the CSMA and CSMB genes induced a significant disorganization of the cell wall structure, even though they contribute only weakly to the overall cell wall chitin synthesis. PMID:22964252

Selective expression of myosin IC Isoform A in mouse and human cell lines and mouse prostate cancer tissues.

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Ivanna Ihnatovych

Full Text Available Myosin IC is a single headed member of the myosin superfamily. We recently identified a novel isoform and showed that the MYOIC gene in mammalian cells encodes three isoforms (isoforms A, B, and C. Furthermore, we demonstrated that myosin IC isoform A but not isoform B exhibits a tissue specific expression pattern. In this study, we extended our analysis of myosin IC isoform expression patterns by analyzing the protein and mRNA expression in various mammalian cell lines and in various prostate specimens and tumor tissues from the transgenic mouse prostate (TRAMP model by immunoblotting, qRT-PCR, and by indirect immunohistochemical staining of paraffin embedded prostate specimen. Analysis of a panel of mammalian cell lines showed an increased mRNA and protein expression of specifically myosin IC isoform A in a panel of human and mouse prostate cancer cell lines but not in non-cancer prostate or other (non-prostate- cancer cell lines. Furthermore, we demonstrate that myosin IC isoform A expression is significantly increased in TRAMP mouse prostate samples with prostatic intraepithelial neoplasia (PIN lesions and in distant site metastases in lung and liver when compared to matched normal tissues. Our observations demonstrate specific changes in the expression of myosin IC isoform A that are concurrent with the occurrence of prostate cancer in the TRAMP mouse prostate cancer model that closely mimics clinical prostate cancer. These data suggest that elevated levels of myosin IC isoform A may be a potential marker for the detection of prostate cancer.

40 CFR 69.52 - Non-motor vehicle diesel fuel.

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2010-07-01

... 40 Protection of Environment 15 2010-07-01 2010-07-01 false Non-motor vehicle diesel fuel. 69.52... (CONTINUED) SPECIAL EXEMPTIONS FROM REQUIREMENTS OF THE CLEAN AIR ACT Alaska § 69.52 Non-motor vehicle diesel... NRLM diesel fuel. (5) Exempt NRLM diesel fuel and heating oil must be segregated from motor vehicle...

Myosin Light Chain Kinase and the Role of Myosin Light Chain Phosphorylation in Skeletal Muscle

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Stull, James T.; Kamm, Kristine E.; Vandenboom, Rene

2011-01-01

Skeletal muscle myosin light chain kinase (skMLCK) is a dedicated Ca2+/calmodulin-dependent serine-threonine protein kinase that phosphorylates the regulatory light chain (RLC) of sarcomeric myosin. It is expressed from the MYLK2 gene specifically in skeletal muscle fibers with most abundance in fast contracting muscles. Biochemically, activation occurs with Ca2+ binding to calmodulin forming a (Ca2+)4•calmodulin complex sufficient for activation with a diffusion limited, stoichiometic binding and displacement of a regulatory segment from skMLCK catalytic core. The N-terminal sequence of RLC then extends through the exposed catalytic cleft for Ser15 phosphorylation. Removal of Ca2+ results in the slow dissociation of calmodulin and inactivation of skMLCK. Combined biochemical properties provide unique features for the physiological responsiveness of RLC phosphorylation, including (1) rapid activation of MLCK by Ca2+/calmodulin, (2) limiting kinase activity so phosphorylation is slower than contraction, (3) slow MLCK inactivation after relaxation and (4) much greater kinase activity relative to myosin light chain phosphatase (MLCP). SkMLCK phosphorylation of myosin RLC modulates mechanical aspects of vertebrate skeletal muscle function. In permeabilized skeletal muscle fibers, phosphorylation-mediated alterations in myosin structure increase the rate of force-generation by myosin cross bridges to increase Ca2+-sensitivity of the contractile apparatus. Stimulation-induced increases in RLC phosphorylation in intact muscle produces isometric and concentric force potentiation to enhance dynamic aspects of muscle work and power in unfatigued or fatigued muscle. Moreover, RLC phosphorylation-mediated enhancements may interact with neural strategies for human skeletal muscle activation to ameliorate either central or peripheral aspects of fatigue. PMID:21284933

Motor cortical processing is causally involved in object recognition

Science.gov (United States)

2013-01-01

Background Motor activity during vicarious experience of actions is a widely reported and studied phenomenon, and motor system activity also accompanies observation of graspable objects in the absence of any actions. Such motor activity is thought to reflect simulation of the observed action, or preparation to interact with the object, respectively. Results Here, in an initial exploratory study, we ask whether motor activity during observation of object directed actions is involved in processes related to recognition of the object after initial exposure. Single pulse Transcranial Magnetic Stimulation (TMS) was applied over the thumb representation of the motor cortex, or over the vertex, during observation of a model thumb typing on a cell-phone, and performance on a phone recognition task at the end of the trial was assessed. Disrupting motor processing over the thumb representation 100 ms after the onset of the typing video impaired the ability to recognize the phone in the recognition test, whereas there was no such effect for TMS applied over the vertex and no TMS trials. Furthermore, this effect only manifested for videos observed from the first person perspective. In an additional control condition, there was no evidence for any effects of TMS to the thumb representation or vertex when observing and recognizing non-action related shape stimuli. Conclusion Overall, these data provide evidence that motor cortical processing during observation of object-directed actions from a first person perspective is causally linked to the formation of enduring representations of objects-of-action. PMID:24330638

Parkinson Disease: The Relationship Between Non-motor Symptoms and Motor Phenotype.

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Ba, Fang; Obaid, Mona; Wieler, Marguerite; Camicioli, Richard; Martin, W R Wayne

2016-03-01

Parkinson disease (PD) presents with motor and non-motor symptoms (NMS). The NMS often precede the onset of motor symptoms, but may progress throughout the disease course. Tremor dominant, postural instability gait difficulty (PIGD), and indeterminate phenotypes can be distinguished using Unified PD Rating scales (UPDRS-III). We hypothesized that the PIGD phenotype would be more likely to develop NMS, and that the non-dopamine-responsive axial signs would correlate with NMS severity. We conducted a retrospective cross-sectional chart review to assess the relationship between NMS and PD motor phenotypes. PD patients were administered the NMS Questionnaire, the UPDRS-III, and the Mini-Mental State Examination score. The relationship between NMS burden and PD subtypes was examined using linear regression models. The prevalence of each NMS among difference PD motor subtypes was analyzed using chi-square test. PD patients with more advanced disease based on their UPDRS-III had higher NMS Questionnaire scores. The axial component of UPDRS-III correlated with higher NMS. There was no correlation between NMS and tremor scores. There was a significant correlation between PIGD score and higher NMS burden. PIGD group had higher prevalence in most NMS domains when compared with tremor dominant and indeterminate groups independent of disease duration and severity. NMS profile and severity vary according to motor phenotype. We conclude that in the PD population, patients with a PIGD phenotype who have more axial involvement, associated with advanced disease and poor motor response, have a higher risk for a higher NMS burden.

Non-Motor Symptoms in Patients Suffering from Motor Neuron Diseases.

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Günther, René; Richter, Nicole; Sauerbier, Anna; Chaudhuri, Kallol Ray; Martinez-Martin, Pablo; Storch, Alexander; Hermann, Andreas

2016-01-01

The recently postulated "disease spreading hypothesis" has gained much attention, especially for Parkinson's disease (PD). The various non-motor symptoms (NMS) in neurodegenerative diseases would be much better explained by this hypothesis than by the degeneration of disease-specific cell populations. Motor neuron disease (MND) is primarily known as a group of diseases with a selective loss of motor function. However, recent evidence suggests disease spreading into non-motor brain regions also in MND. The aim of this study was to comprehensively detect NMS in patients suffering from MND. We used a self-rating questionnaire including 30 different items of gastrointestinal, autonomic, neuropsychiatric, and sleep complaints [NMS questionnaire (NMSQuest)], which is an established tool in PD patients. 90 MND patients were included and compared to 96 controls. In total, MND patients reported significantly higher NMS scores (median: 7 points) in comparison to controls (median: 4 points). Dribbling, impaired taste/smelling, impaired swallowing, weight loss, loss of interest, sad/blues, falling, and insomnia were significantly more prevalent in MND patients compared to controls. Interestingly, excessive sweating was more reported in the MND group. Correlation analysis revealed an increase of total NMS score with disease progression. NMS in MND patients seemed to increase with disease progression, which would fit with the recently postulated "disease spreading hypothesis." The total NMS score in the MND group significantly exceeded the score for the control group, but only 8 of the 30 single complaints of the NMSQuest were significantly more often reported by MND patients. Dribbling, impaired swallowing, weight loss, and falling could primarily be connected to motor neuron degeneration and declared as motor symptoms in MND.

Tai Chi Exercise to Improve Non-Motor Symptoms of Parkinson's Disease.

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Nocera, Joe R; Amano, Shinichi; Vallabhajosula, Srikant; Hass, Chris J

2013-08-20

A substantial number of individuals with Parkinson's disease exhibit debilitating non-motor symptoms that decrease quality of life. To date, few treatment options exist for the non-motor symptomatology related to Parkinson's disease. The goal of this pilot investigation was to determine the effects of Tai Chi exercise on the non-motor symptomology in Parkinson's disease. Twenty-one individuals with Parkinson's disease were enrolled in a Tai Chi intervention (n=15) or a noncontact control group (n=6). Participants assigned to Tai Chi participated in 60-minute Tai Chi sessions three times per week, for 16 weeks. Pre and post measures included indices of cognitive-executive function including visuomotor tracking and attention, selective attention, working memory, inhibition, processing speed and task switching. Additionally, all participants were evaluated on the Parkinson's disease Questionnaire-39 and Tinetti's Falls Efficacy Scale. Results indicated that the Tai Chi training group had significantly better scores following the intervention than the control group on the Parkinson's disease Questionnaire-39 total score as well as the emotional well-being sub score. Trends for improvement were noted for the Tai Chi group on Digits Backwards, Tinetti's Falls Efficacy Scale, and the activities of daily living and communication sub scores of the Parkinson's disease Questionnaire-39. This research provides initial data that supports future studies to definitively establish efficacy of Tai Chi to improve non-motor features of Parkinson's disease.

Markov process of muscle motors

International Nuclear Information System (INIS)

Kondratiev, Yu; Pechersky, E; Pirogov, S

2008-01-01

We study a Markov random process describing muscle molecular motor behaviour. Every motor is either bound up with a thin filament or unbound. In the bound state the motor creates a force proportional to its displacement from the neutral position. In both states the motor spends an exponential time depending on the state. The thin filament moves at a velocity proportional to the average of all displacements of all motors. We assume that the time which a motor stays in the bound state does not depend on its displacement. Then one can find an exact solution of a nonlinear equation appearing in the limit of an infinite number of motors

Current and investigational non-dopaminergic agents for management of motor symptoms (including motor complications) in Parkinson's disease.

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Müller, Thomas

2017-10-01

Parkinson's disease is characterized by a heterogeneous combination of motor and non motor symptoms. The nigrostriatal dopamine deficit is one of its essential pathophysiologic features. Areas covered: This invited narrative review provides an overlook over current available and future promising non dopaminergic therapeutics to modulate altered dopaminergic neurotransmission in Parkinson's disease. Current research strategies aim to proof clinical efficacy by amelioration of motor symptoms and preponderant levodopa related movement fluctuations. These so-called motor complications are characterized by involuntary movements as a result of an overstimulation of the nigrostriatal dopaminergic system or by temporary recurrence of motor symptoms, when beneficial effects of dopamine substituting drugs vane. Expert opinion: Non dopaminergic modulation of dopamine replacement is currently mostly investigated in well defined and selected patients with motor complications to get approval. However, the world of daily maintenance of patients with its individually adapted, so-called personalised, therapy will determine the real value of these therapeutics. Here the clinical experience of the treating neurologists and the courage to use unconventional drug combinations are essential preconditions for successful treatments of motor and associated non motor complications in cooperation with the patients and their care giving surroundings.

Non-motor signs in Parkinson’s disease: a review

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Renato P. Munhoz

2015-05-01

Full Text Available During the past decade the view of Parkinson’s disease (PD as a motor disorder has changed significantly and currently it is recognized as a multisystem process with diverse non-motor signs (NMS. In addition to been extremely common, these NMS play a major role in undermining functionality and quality of life. On the other hand, NMS are under recognized by physicians and neglected by patients. Here, we review the most common NMS in PD, including cognitive, psychiatric, sleep, metabolic, and sensory disturbances, discuss the current knowledge from biological, epidemiological, clinical, and prognostic standpoints, highlighting the need for early recognition and management.

[Use of nondeclarative and automatic memory processes in motor learning: how to mitigate the effects of aging].

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Chauvel, Guillaume; Maquestiaux, François; Didierjean, André; Joubert, Sven; Dieudonné, Bénédicte; Verny, Marc

2011-12-01

Does normal aging inexorably lead to diminished motor learning abilities? This article provides an overview of the literature on the question, with particular emphasis on the functional dissociation between two sets of memory processes: declarative, effortful processes, and non-declarative, automatic processes. There is abundant evidence suggesting that aging does impair learning when past memories of former actions are required (episodic memory) and recollected through controlled processing (working memory). However, other studies have shown that aging does not impair learning when motor actions are performed non verbally and automatically (tapping procedural memory). These findings led us to hypothesize that one can minimize the impact of aging on the ability to learn new motor actions by favouring procedural learning. Recent data validating this hypothesis are presented. Our findings underline the importance of developing new motor learning strategies, which "bypass" declarative, effortful memory processes.

The Effect of Experimental Hyperthyroidism on Characteristics of Actin-Myosin Interaction in Fast and Slow Skeletal Muscles.

Science.gov (United States)

Kopylova, G V; Shchepkin, D V; Bershitsky, S Y

2018-05-01

The molecular mechanism of the failure of contractile function of skeletal muscles caused by oxidative damage to myosin in hyperthyroidism is not fully understood. Using an in vitro motility assay, we studied the effect of myosin damage caused by oxidative stress in experimental hyperthyroidism on the actin-myosin interaction and its regulation by calcium. We found that hyperthyroidism-induced oxidation of myosin is accompanied by a decrease in the sliding velocity of the regulated thin filaments in the in vitro motility assay, and this effect is increased with the duration of the pathological process.

Motor and non-motor features of Parkinson's disease in LRRK2 G2019S carriers versus matched controls.

Science.gov (United States)

Gunzler, Steven A; Riley, David E; Chen, Shu G; Tatsuoka, Curtis M; Johnson, William M; Mieyal, John J; Walter, Ellen M; Whitney, Christina M; Feng, I Jung; Owusu-Dapaah, Harry; Mittal, Shivam O; Wilson-Delfosse, Amy L

2018-05-15

LRRK2 G2019S mutation carriers with Parkinson's disease (PD) have been generally indistinguishable from those with idiopathic PD, with the exception of variable differences in some motor and non-motor domains, including cognition, gait, and balance. LRRK2 G2019S is amongst the most common genetic etiologies for PD, particularly in Ashkenazi Jewish (AJ) populations. This cross-sectional data collection study sought to clarify the phenotype of LRRK2 G2019S mutation carriers with PD. Primary endpoints were the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS) and Montreal Cognitive Assessment (MoCA). Other motor and non-motor data were also assessed. The Mann-Whitney U Test was utilized to compare LRRK2 G2019S carriers with PD (LRRK2+) with non-carrier PD controls who were matched for age, gender, education, and PD duration. Survival analyses and log rank tests were utilized to compare interval from onset of PD to development of motor and non-motor complications. We screened 251 subjects and 231 completed the study, of whom 9 were LRRK2+, including 7 AJ subjects. 22.73% of AJ subjects with a family history of PD (FH) and 12.96% of AJ subjects without a FH were LRRK2+. There were no significant differences between the 9 LRRK2+ subjects and 19 matched PD controls in MDS-UPDRS, MoCA, or other motor and non-motor endpoints. Prevalence of the LRRK2 G2019S mutation in AJ and non-AJ subjects in our study population in Cleveland, Ohio was comparable to other clinical studies. There were no significant motor or non-motor differences between LRRK2+ PD and matched PD controls. Copyright © 2018 Elsevier B.V. All rights reserved.

Are we missing non-motor seizures in Parkinson's disease? Two case reports.

Science.gov (United States)

Son, Andre Y; Cucca, Alberto; Agarwal, Shashank; Liu, Anli; Di Rocco, Alessandro; Biagioni, Milton C

2017-01-01

Parkinson's disease (PD) is predominantly recognized for its motor symptoms, but patients struggle from a morbid and heterogeneous collection of non-motor symptoms (NMS-PD) that can affect their quality of life even more. NMS-PD is a rather generalized term and the heterogeneity and non-specific nature of many symptoms poses a clinical challenge when a PD patient presents with non-motor complaints that may not be NMS-PD. We report two patients with idiopathic PD who presented with acute episodes of cognitive changes. Structural brain images, cardiovascular and laboratory assessment were unremarkable. Both patients experienced a considerable delay before receiving an epilepsy-evaluation, at which point electroencephalogram abnormalities supported the diagnosis of focal non-motor seizures with alteration of awareness. Antiepileptic therapy was implemented and was effective in both cases. Diagnosing non-motor seizures can be challenging. However, PD patients pose an even greater challenge given their eclectic non-motor clinical manifestations and other disease-related complications that could confound and mislead adequate clinical interpretation. Our two cases provide examples of non-motor seizures that may mimic non-motor symptoms of PD. Treating physicians should always consider other possible causes of non-motor symptoms that may coexist in PD patients. Epilepsy work-up should be contemplated in the differential of acute changes in cognition, behavior, or alertness.

Myosin light chain kinase regulates synaptic plasticity and fear learning in the lateral amygdala.

Science.gov (United States)

Lamprecht, R; Margulies, D S; Farb, C R; Hou, M; Johnson, L R; LeDoux, J E

2006-01-01

Learning and memory depend on signaling molecules that affect synaptic efficacy. The cytoskeleton has been implicated in regulating synaptic transmission but its role in learning and memory is poorly understood. Fear learning depends on plasticity in the lateral nucleus of the amygdala. We therefore examined whether the cytoskeletal-regulatory protein, myosin light chain kinase, might contribute to fear learning in the rat lateral amygdala. Microinjection of ML-7, a specific inhibitor of myosin light chain kinase, into the lateral nucleus of the amygdala before fear conditioning, but not immediately afterward, enhanced both short-term memory and long-term memory, suggesting that myosin light chain kinase is involved specifically in memory acquisition rather than in posttraining consolidation of memory. Myosin light chain kinase inhibitor had no effect on memory retrieval. Furthermore, ML-7 had no effect on behavior when the training stimuli were presented in a non-associative manner. Anatomical studies showed that myosin light chain kinase is present in cells throughout lateral nucleus of the amygdala and is localized to dendritic shafts and spines that are postsynaptic to the projections from the auditory thalamus to lateral nucleus of the amygdala, a pathway specifically implicated in fear learning. Inhibition of myosin light chain kinase enhanced long-term potentiation, a physiological model of learning, in the auditory thalamic pathway to the lateral nucleus of the amygdala. When ML-7 was applied without associative tetanic stimulation it had no effect on synaptic responses in lateral nucleus of the amygdala. Thus, myosin light chain kinase activity in lateral nucleus of the amygdala appears to normally suppress synaptic plasticity in the circuits underlying fear learning, suggesting that myosin light chain kinase may help prevent the acquisition of irrelevant fears. Impairment of this mechanism could contribute to pathological fear learning.

Improved Classification by Non Iterative and Ensemble Classifiers in Motor Fault Diagnosis

Directory of Open Access Journals (Sweden)

PANIGRAHY, P. S.

2018-02-01

Full Text Available Data driven approach for multi-class fault diagnosis of induction motor using MCSA at steady state condition is a complex pattern classification problem. This investigation has exploited the built-in ensemble process of non-iterative classifiers to resolve the most challenging issues in this area, including bearing and stator fault detection. Non-iterative techniques exhibit with an average 15% of increased fault classification accuracy against their iterative counterparts. Particularly RF has shown outstanding performance even at less number of training samples and noisy feature space because of its distributive feature model. The robustness of the results, backed by the experimental verification shows that the non-iterative individual classifiers like RF is the optimum choice in the area of automatic fault diagnosis of induction motor.

CHARACTERIZATION OF TIGHTLY-ASSOCIATED SMOOTH MUSCLE MYOSIN-MYOSIN LIGHT CHAIN KINASE-CALMODULIN COMPLEXES*

OpenAIRE

Hong, Feng; Haldeman, Brian D.; John, Olivia A.; Brewer, Paul D.; Wu, Yi-Ying; Ni, Shaowei; Wilson, David P.; Walsh, Michael P.; Baker, Jonathan E.; Cremo, Christine R.

2009-01-01

A current popular model to explain phosphorylation of smooth muscle myosin (SMM) by smooth muscle myosin light chain kinase (MLCK) proposes that MLCK is bound tightly to actin but weakly to SMM. We found that MLCK and calmodulin (CaM) co-purify with unphosphorylated SMM (up-SMM) from chicken gizzard, suggesting that they are tightly bound. Although the MLCK:SMM molar ratio in SMM preparations was well below stoichiometric (1:73 ± 9), the ratio was ~ 23–37% of that in gizzard tissue. Fifteen t...

Striatal Dopamine Depletion Patterns and Early Non-Motor Burden in Parkinsons Disease.

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Su Jin Chung

Full Text Available The mechanism underlying non-motor symptoms in Parkinson's disease has not yet been elucidated. In this study, we hypothesized that Parkinson patients with more non-motor symptoms have a different pattern of striatal dopamine depletion, particularly in areas other than the sensorimotor striatum, compared to those with fewer non-motor symptoms.We conducted a prospective survey of the degree of non-motor symptoms (using the Korean version of the Non-Motor Symptoms Scale; K-NMSS in 151 patients with early-stage Parkinson's disease who had undergone a dopamine transporter PET scan as an initial diagnostic procedure. We classified the patients into two groups; high non-motor patients (HNM-PD; K-NMSS score ≥ 41 and low non-motor patients (LNM-PD.Patients in the HNM-PD group (n = 71 were older, had longer symptom duration, exhibited more severe motor deficits, and had been prescribed higher levodopa-equivalent doses at follow-up than those in the LNM-PD group. However, dopamine transporter binding to the striatal sub-regions and inter-sub-regional binding ratios were comparable between the two groups. A general linear model showed that the HNM-PD group had significantly more severe motor deficits than the LNM-PD group after controlling for age, gender, symptom duration, and dopamine transporter binding to the sensorimotor striatum.This study demonstrated that the pattern of striatal dopamine depletion does not contribute to early non-motor burden in Parkinson's disease. Our results suggest that LNM-PD patients may have a more benign course of motor symptom progression than HNM-PD patients.

GBA Variants Influence Motor and Non-Motor Features of Parkinson's Disease.

Science.gov (United States)

Jesús, Silvia; Huertas, Ismael; Bernal-Bernal, Inmaculada; Bonilla-Toribio, Marta; Cáceres-Redondo, María Teresa; Vargas-González, Laura; Gómez-Llamas, Myriam; Carrillo, Fátima; Calderón, Enrique; Carballo, Manuel; Gómez-Garre, Pilar; Mir, Pablo

2016-01-01

The presence of mutations in glucocerebrosidase (GBA) gene is a known factor increasing the risk of developing Parkinson's disease (PD). Mutations carriers have earlier disease onset and are more likely to develop neuropsychiatric symptoms than other sporadic PD cases. These symptoms have primarily been observed in Parkinson's patients carrying the most common pathogenic mutations L444P and N370S. However, recent findings suggest that other variants across the gene may have a different impact on the phenotype as well as on the disease progression. We aimed to explore the influence of variants across GBA gene on the clinical features and treatment related complications in PD. In this study, we screened the GBA gene in a cohort of 532 well-characterised PD patients and 542 controls from southern Spain. The potential pathogeniticy of the identified variants was assessed using in-silico analysis and subsequently classified as benign or deleterious. As a result, we observed a higher frequency of GBA variants in PD patients (12.2% vs. 7.9% in controls, p = 0.021), earlier mean age at disease onset in GBA variant carriers (50.6 vs. 56.6 years; p = 0.013), as well as more prevalent motor and non-motor symptoms in patients carrying deleterious variants. In addition, we found that dopaminergic motor complications are influenced by both benign and deleterious variants. Our results highlight the fact that the impact on the phenotype highly depends on the potential pathogenicity of the carried variants. Therefore, the course of motor and non-motor symptoms as well as treatment-related motor complications could be influenced by GBA variants.

GBA Variants Influence Motor and Non-Motor Features of Parkinson's Disease.

Directory of Open Access Journals (Sweden)

Silvia Jesús

Full Text Available The presence of mutations in glucocerebrosidase (GBA gene is a known factor increasing the risk of developing Parkinson's disease (PD. Mutations carriers have earlier disease onset and are more likely to develop neuropsychiatric symptoms than other sporadic PD cases. These symptoms have primarily been observed in Parkinson's patients carrying the most common pathogenic mutations L444P and N370S. However, recent findings suggest that other variants across the gene may have a different impact on the phenotype as well as on the disease progression. We aimed to explore the influence of variants across GBA gene on the clinical features and treatment related complications in PD. In this study, we screened the GBA gene in a cohort of 532 well-characterised PD patients and 542 controls from southern Spain. The potential pathogeniticy of the identified variants was assessed using in-silico analysis and subsequently classified as benign or deleterious. As a result, we observed a higher frequency of GBA variants in PD patients (12.2% vs. 7.9% in controls, p = 0.021, earlier mean age at disease onset in GBA variant carriers (50.6 vs. 56.6 years; p = 0.013, as well as more prevalent motor and non-motor symptoms in patients carrying deleterious variants. In addition, we found that dopaminergic motor complications are influenced by both benign and deleterious variants. Our results highlight the fact that the impact on the phenotype highly depends on the potential pathogenicity of the carried variants. Therefore, the course of motor and non-motor symptoms as well as treatment-related motor complications could be influenced by GBA variants.

Identification and biochemical analysis of Slac2-c/MyRIP as a Rab27A-, myosin Va/VIIa-, and actin-binding protein.

Science.gov (United States)

Kuroda, Taruho S; Fukuda, Mitsunori

2005-01-01

Slac2-c/MyRIP is a specific Rab27A-binding protein that contains an N-terminal synaptotagmin-like protein (Slp) homology domain (SHD, a newly identified GTP-Rab27A-binding motif), but in contrast to the Slp family proteins, it lacks C-terminal tandem C2 domains. In vitro Slac2-c simultaneously directly interacts with both Rab27A and an actin-based motor protein, myosin Va, via its N-terminal SHD and middle region, respectively, consistent with the fact that the overall structure of Slac2-c is similar to that of Slac2-a/melanophilin, a linker protein between Rab27A and myosin Va in the melanosome transport in melanocytes. Unlike Slac2-a, however, the middle region of Slac2-c interacts with two types of myosins, myosin Va and myosin VIIa. In addition, the most C-terminal part of both Slac2-a and Slac2-c functions as an actin-binding domain: it directly interacts with globular and fibrous actin in vitro, and the actin-binding domain of Slac2-a and Slac2-c colocalizes with actin filaments when it is expressed in living cells (i.e., PC12 cells and mouse melanocytes). In this chapter we describe the methods that have been used to analyze the protein-protein interactions of Slac2-c, specifically with Rab27A, myosin Va/VIIa, and actin.

Localization of Myosin and Actin in the Pelage and Whisker Hair Follicles of Rat

International Nuclear Information System (INIS)

Morioka, Kiyokazu; Matsuzaki, Toshiyuki; Takata, Kuniaki

2006-01-01

The combined effects of myosin II and actin enable muscle and nonmuscle cells to generate forces required for muscle contraction, cell division, cell migration, cellular morphological changes, the maintenance of cellular tension and polarity, and so on. However, except for the case of muscle contraction, the details are poorly understood. We focus on nonmuscle myosin and actin in the formation and maintenance of hair and skin, which include highly active processes in mammalian life with respect to the cellular proliferation, differentiation, and movement. The localization of nonmuscle myosin II and actin in neonatal rat dorsal skin, mystacial pad, hair follicles, and vibrissal follicles was studied by immunohistochemical technique to provide the basis for the elucidation of the roles of these proteins. Specificities of the antibodies were verified by using samples from the relevant tissues and subjecting them to immunoblotting test prior to morphological analyses. The myosin and actin were abundant and colocalized in the spinous and granular layers but scarce in the basal layer of the dorsal and mystacial epidermis. In hair and vibrissal follicles, nonmuscle myosin and actin were colocalized in the outer root sheath and some hair matrix cells adjoining dermal papillae. In contrast, most areas of the inner root sheath and hair matrix appeared to comprise very small amounts of myosin and actin. Hair shaft may comprise significant myosin during the course of its keratinization. These results suggest that the actin-myosin system plays a part in cell movement, differentiation, protection and other key functions of skin and hair cells

Myosin Light Chain Kinase and the Role of Myosin Light Chain Phosphorylation in Skeletal Muscle

OpenAIRE

Stull, James T.; Kamm, Kristine E.; Vandenboom, Rene

2011-01-01

Skeletal muscle myosin light chain kinase (skMLCK) is a dedicated Ca2+/calmodulin-dependent serine-threonine protein kinase that phosphorylates the regulatory light chain (RLC) of sarcomeric myosin. It is expressed from the MYLK2 gene specifically in skeletal muscle fibers with most abundance in fast contracting muscles. Biochemically, activation occurs with Ca2+ binding to calmodulin forming a (Ca2+)4•calmodulin complex sufficient for activation with a diffusion limited, stoichiometic bindin...

Role of medial premotor areas in action language processing in relation to motor skills.

Science.gov (United States)

Courson, Melody; Macoir, Joël; Tremblay, Pascale

2017-10-01

The literature reports that the supplementary motor area (SMA) and pre-supplementary motor area (pre-SMA) are involved in motor planning and execution, and in motor-related cognitive functions such as motor imagery. However, their specific role in action language processing remains unclear. In the present study, we investigated the impact of repetitive transcranial magnetic stimulation (rTMS) over SMA and pre-SMA during an action semantic analogy task (SAT) in relation with fine motor skills (i.e., manual dexterity) and motor imagery abilities in healthy non-expert adults. The impact of rTMS over SMA (but not pre-SMA) on reaction times (RT) during SAT was correlated with manual dexterity. Specifically, results show that rTMS over SMA modulated RT for those with lower dexterity skills. Our results therefore demonstrate a causal involvement of SMA in action language processing, as well as the existence of inter-individual differences in this involvement. We discuss these findings in light of neurolinguistic theories of language processing. Copyright © 2017 Elsevier Ltd. All rights reserved.

The 133-kDa N-terminal domain enables myosin 15 to maintain mechanotransducing stereocilia and is essential for hearing

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Fang, Qing; Indzhykulian, Artur A; Mustapha, Mirna; Riordan, Gavin P; Dolan, David F; Friedman, Thomas B; Belyantseva, Inna A; Frolenkov, Gregory I; Camper, Sally A; Bird, Jonathan E

2015-01-01

The precise assembly of inner ear hair cell stereocilia into rows of increasing height is critical for mechanotransduction and the sense of hearing. Yet, how the lengths of actin-based stereocilia are regulated remains poorly understood. Mutations of the molecular motor myosin 15 stunt stereocilia growth and cause deafness. We found that hair cells express two isoforms of myosin 15 that differ by inclusion of an 133-kDa N-terminal domain, and that these isoforms can selectively traffic to different stereocilia rows. Using an isoform-specific knockout mouse, we show that hair cells expressing only the small isoform remarkably develop normal stereocilia bundles. However, a critical subset of stereocilia with active mechanotransducer channels subsequently retracts. The larger isoform with the 133-kDa N-terminal domain traffics to these specialized stereocilia and prevents disassembly of their actin core. Our results show that myosin 15 isoforms can navigate between functionally distinct classes of stereocilia, and are independently required to assemble and then maintain the intricate hair bundle architecture. DOI: http://dx.doi.org/10.7554/eLife.08627.001 PMID:26302205

[Non-motor symptoms in Parkinson's disease: cognition and behavior].

Science.gov (United States)

Bonnet, Anne Marie; Czernecki, Virginie

2013-09-01

Although the diagnosis of Parkinson disease is based on motor symptoms, it is now well known that non-motor symptoms are an integral part of this pathology, involving in fact multiple systems. These non-motor symptoms affect large population of patients and can appear sometimes before the motor disorders. The non-motor symptoms include mainly neuropsychological difficulties, neuropsychiatric symptoms, and autonomic disorders, but involve also pain and sleep disturbances for example. Depression may occur at any stage of the disease, and consists in major depressive disorder, minor depressive disorder, and dysthymia. During the course of the disease, 50% of patients experience anxiety. Apathy is present in up to 30-40% of patients, due to loss of motivation, appearing in emotional, intellectual and behavioral domains. Dopamine dysregulation syndrome and impulse control disorders are not rare, and in relation with dopaminergic therapies. Impulse control disorders include pathological gambling, hyper sexuality, compulsive shopping, and eating disorder. Visual hallucinations can occur in 30% of patients, mostly induced by dopaminergic therapies. Often, they have deeper impact on the quality of life than the motor symptoms themselves, which stay the focus of attention during consulting. Identifying those can help in providing better care with a positive impact on the quality of life of the patients.

Quad-copter UAV BLDC Motor Control: Linear v/s non-linear control maps

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Deep Parikh

2015-08-01

Full Text Available This paper presents some investigations and comparison of using linear versus non-linear static motor-control maps for the speed control of a BLDC (Brush Less Direct Current motors used in quad-copter UAV (Unmanned Aerial Vehicles. The motor-control map considered here is the inverse of the static map relating motor-speed output to motor-voltage input for a typical out-runner type Brushless DC Motors (BLDCM.  Traditionally, quad-copter BLDC motor speed control uses simple linear motor-control map defined by the motor-constant specification. However, practical BLDC motors show non-linear characteristic, particularly when operated across wide operating speed-range as is commonly required in quad-copter UAV flight operations. In this paper, our investigations to compare performance of linear versus non-linear motor-control maps are presented. The investigations cover simulation-based and experimental study of BLDC motor speed control systems for  quad-copter vehicle available. First the non-linear map relating rotor RPM to motor voltage for quad-copter BLDC motor is obtained experimentally using an optical speed encoder. The performance of the linear versus non-linear motor-control-maps for the speed control are studied. The investigations also cover study of time-responses for various standard test input-signals e.g. step, ramp and pulse inputs, applied as the reference speed-commands. Also, simple 2-degree of freedom test-bed is developed in our laboratory to help test the open-loop and closed-loop experimental investigations. The non-linear motor-control map is found to perform better in BLDC motor speed tracking control performance and thereby helping achieve better quad-copter roll-angle attitude control.

N-terminus of Cardiac Myosin Essential Light Chain Modulates Myosin Step-Size

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Wang, Yihua; Ajtai, Katalin; Kazmierczak, Katarzyna; Szczesna-Cordary, Danuta; Burghardt, Thomas P.

2016-01-01

Muscle myosin cyclically hydrolyzes ATP to translate actin. Ventricular cardiac myosin (βmys) moves actin with three distinct unitary step-sizes resulting from its lever-arm rotation and with step-frequencies that are modulated in a myosin regulation mechanism. The lever-arm associated essential light chain (vELC) binds actin by its 43 residue N-terminal extension. Unitary steps were proposed to involve the vELC N-terminal extension with the 8 nm step engaging the vELC/actin bond facilitating an extra ~19 degrees of lever-arm rotation while the predominant 5 nm step forgoes vELC/actin binding. A minor 3 nm step is the unlikely conversion of the completed 5 to the 8 nm step. This hypothesis was tested using a 17 residue N-terminal truncated vELC in porcine βmys (Δ17βmys) and a 43 residue N-terminal truncated human vELC expressed in transgenic mouse heart (Δ43αmys). Step-size and step-frequency were measured using the Qdot motility assay. Both Δ17βmys and Δ43αmys had significantly increased 5 nm step-frequency and coincident loss in the 8 nm step-frequency compared to native proteins suggesting the vELC/actin interaction drives step-size preference. Step-size and step-frequency probability densities depend on the relative fraction of truncated vELC and relate linearly to pure myosin species concentrations in a mixture containing native vELC homodimer, two truncated vELCs in the modified homodimer, and one native and one truncated vELC in the heterodimer. Step-size and step-frequency, measured for native homodimer and at two or more known relative fractions of truncated vELC, are surmised for each pure species by using a new analytical method. PMID:26671638

Non-Motor Features in Parkinson's Disease Patients Attending ...

African Journals Online (AJOL)

Background: The clinical course of Parkinson's disease (PD) is not limited to motor symptoms (tremor, bradykinesia, rigidity, gait problems and imbalance). A variety of non-motor symptoms (NMS) such as psychiatric, gastrointestinal, cognitive, sudomotor, autonomic, sleep and sensory disorders which occur commonly are ...

Decoding the non-stationary neuron spike trains by dual Monte Carlo point process estimation in motor Brain Machine Interfaces.

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Liao, Yuxi; Li, Hongbao; Zhang, Qiaosheng; Fan, Gong; Wang, Yiwen; Zheng, Xiaoxiang

2014-01-01

Decoding algorithm in motor Brain Machine Interfaces translates the neural signals to movement parameters. They usually assume the connection between the neural firings and movements to be stationary, which is not true according to the recent studies that observe the time-varying neuron tuning property. This property results from the neural plasticity and motor learning etc., which leads to the degeneration of the decoding performance when the model is fixed. To track the non-stationary neuron tuning during decoding, we propose a dual model approach based on Monte Carlo point process filtering method that enables the estimation also on the dynamic tuning parameters. When applied on both simulated neural signal and in vivo BMI data, the proposed adaptive method performs better than the one with static tuning parameters, which raises a promising way to design a long-term-performing model for Brain Machine Interfaces decoder.

TREATMENT AND REHABILITATION IN NON-MOTOR SYMPTOMS OF PARKINSON’S DISEASE

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Gabriela Dogaru

2015-12-01

Full Text Available Parkinson's disease (PD is the second most common neurodegenerative disease. The cardinal clinical features of PD are motor and include bradykinesia, rigidity, and resting tremor with an asymmetric pattern. Apart from these, various nonmotor symptoms (NMS also occur in PD and constitute a major clinical symptoms. NMS can present at any stage of the disease including early and pre-motor phase of PD. Management of PD requires recognition of both motor and nonmotor symptoms as well as an understanding of the relationship between these symptoms and how they can be affected by treatments for PD. Therapy should be individualized for each patient, as treatments for the motor symptoms of PD can improve some nonmotor symptoms while they can worsen others. Some non-motor symptoms, including depression, constipation, pain, genitourinary problems, and sleep disorders, can be improved with antiparkinsonian drugs . Other non-motor symptoms can be more refractory and need the introduction of novel non-dopaminergic drugs in association with rehabilitation programs . In the future, development of treatments that can slow or prevent the progression of Parkinson's disease and its multicentric neurodegeneration are the best hope of ameliorating non-motor symptoms

Topology of interaction between titin and myosin thick filaments.

Science.gov (United States)

Kellermayer, Miklós; Sziklai, Dominik; Papp, Zsombor; Decker, Brennan; Lakatos, Eszter; Mártonfalvi, Zsolt

2018-05-05

Titin is a giant protein spanning between the Z- and M-lines of the sarcomere. In the A-band titin is associated with the myosin thick filament. It has been speculated that titin may serve as a blueprint for thick-filament formation due to the super-repeat structure of its A-band domains. Accordingly, titin might provide a template that determines the length and structural periodicity of the thick filament. Here we tested the titin ruler hypothesis by mixing titin and myosin at in situ stoichiometric ratios (300 myosins per 12 titins) in buffers of different ionic strength (KCl concentration range 100-300 mM). The topology of the filamentous complexes was investigated with atomic force microscopy. We found that the samples contained distinct, segregated populations of titin molecules and myosin thick filaments. We were unable to identify complexes in which myosin molecules were regularly associated to either mono- or oligomeric titin in either relaxed or stretched states of the titin filaments. Thus, the electrostatically driven self-association is stronger in both myosin and titin than their binding to each other, and it is unlikely that titin functions as a geometrical template for thick-filament formation. However, when allowed to equilibrate configurationally, long myosin thick filaments appeared with titin oligomers attached to their surface. The titin meshwork formed on the thick-filament surface may play a role in controlling thick-filament length by regulating the structural dynamics of myosin molecules and placing a mechanical limit on the filament length. Copyright © 2018 Elsevier Inc. All rights reserved.

GBA Variants Influence Motor and Non-Motor Features of Parkinson’s Disease

Science.gov (United States)

Jesús, Silvia; Huertas, Ismael; Cáceres-Redondo, María Teresa; Vargas-González, Laura; Gómez-Llamas, Myriam; Carrillo, Fátima; Calderón, Enrique; Carballo, Manuel; Gómez-Garre, Pilar; Mir, Pablo

2016-01-01

The presence of mutations in glucocerebrosidase (GBA) gene is a known factor increasing the risk of developing Parkinson’s disease (PD). Mutations carriers have earlier disease onset and are more likely to develop neuropsychiatric symptoms than other sporadic PD cases. These symptoms have primarily been observed in Parkinson’s patients carrying the most common pathogenic mutations L444P and N370S. However, recent findings suggest that other variants across the gene may have a different impact on the phenotype as well as on the disease progression. We aimed to explore the influence of variants across GBA gene on the clinical features and treatment related complications in PD. In this study, we screened the GBA gene in a cohort of 532 well-characterised PD patients and 542 controls from southern Spain. The potential pathogeniticy of the identified variants was assessed using in-silico analysis and subsequently classified as benign or deleterious. As a result, we observed a higher frequency of GBA variants in PD patients (12.2% vs. 7.9% in controls, p = 0.021), earlier mean age at disease onset in GBA variant carriers (50.6 vs. 56.6 years; p = 0.013), as well as more prevalent motor and non-motor symptoms in patients carrying deleterious variants. In addition, we found that dopaminergic motor complications are influenced by both benign and deleterious variants. Our results highlight the fact that the impact on the phenotype highly depends on the potential pathogenicity of the carried variants. Therefore, the course of motor and non-motor symptoms as well as treatment-related motor complications could be influenced by GBA variants. PMID:28030538

MDS-UPDRS to assess non-motor symptoms after STN DBS for Parkinson's disease.

Science.gov (United States)

Jafari, Nickey; Pahwa, Rajesh; Nazzaro, Jules M; Arnold, Paul M; Lyons, Kelly E

2016-01-01

To determine if the non-motor sections of the Movement Disorder Society's (MDS) version of the Unified Parkinson's Disease Rating Scale (UPDRS) could supplement the original UPDRS as a patient completed assessment of changes in non-motor symptoms in Parkinson's disease (PD) patients after bilateral subthalamic nucleus (STN) deep brain stimulation (DBS). Thirty PD patients who underwent bilateral STN DBS were assessed using the total UPDRS and the non-motor sections of the MDS-UPDRS prior to surgery and one year following surgery. This study focuses on non-motor symptoms as assessed by Part I of the UPDRS and Part 1A and 1B of the MDS-UPDRS. One year following surgery, no individual non-motor symptoms or the total mentation score of the UPDRS were significantly changed. In comparison, the MDS-UPDRS showed significant improvements in sleep and urinary problems and a trend towards improvement in anxiety, constipation, daytime sleepiness, fatigue and pain. This study provides evidence that the MDS-UPDRS non-motor sections, when completed by the patients, can supplement the original version of the UPDRS as an effective method of measuring changes in non-motor symptoms after DBS. It also reinforces the benefits of bilateral STN DBS on non-motor symptoms of PD.

Effects of proteolysis on the adenosinetriphosphatase activities of thymus myosin

International Nuclear Information System (INIS)

Vu, N.D.; Wagner, P.D.

1987-01-01

Limited proteolysis was used to identify regions on the heavy chains of calf thymus myosin which may be involved in ATP and actin binding. Assignments of the various proteolytic fragments to different parts of the myosin heavy chain were based on solubility, gel filtration, electron microscopy, and binding of 32 P-labeled regulatory light chains. Chymotrypsin rapidly cleaved within the head of thymus myosin to give a 70,000-dalton N-terminal fragment and a 140,000-dalton C-terminal fragment. These two fragments did not dissociate under nondenaturing conditions. Cleavage within the myosin tail to give heavy meromyosin occurred more slowly. Cleavage at the site 70,000 daltons from the N-terminus of the heavy chain caused about a 30-fold decrease in the actin concentration required to achieve half-maximal stimulation of the magnesium-adenosinetriphosphatase (Mg-ATPase) activity of unphosphorylated thymus myosin. The actin-activated ATPase activity of this digested myosin was only slightly affected by light chain phosphorylation. Actin inhibited the cleavage at this site by chymotrypsin. In the presence of ATP, chymotrypsin rapidly cleaved the thymus myosin heavy chain at an additional site about 4000 daltons from the N-terminus. Cleavage at this site caused a 2-fold increase in the ethylenediaminetetraacetic acid-ATPase activity and 3-fold decreases in the Ca 2+ - and Mg-ATPase activities of thymus myosin. Thus, cleavage at the N-terminus of thymus myosin was affected by ATP, and this cleavage altered ATPase activity. Papain cleaved the thymus myosin heavy chain about 94,000 daltons from the N-terminus to give subfragment 1. Although this subfragment 1 contained intact light chains, its actin-activated ATPase activity was not affected by light chain phosphorylation

A novel role for myosin II in insulin-stimulated glucose uptake in 3T3-L1 adipocytes

International Nuclear Information System (INIS)

Steimle, Paul A.; Kent Fulcher, F.; Patel, Yashomati M.

2005-01-01

Insulin-stimulated glucose uptake requires the activation of several signaling pathways to mediate the translocation and fusion of GLUT4 vesicles from an intracellular pool to the plasma membrane. The studies presented here show that inhibition of myosin II activity impairs GLUT4-mediated glucose uptake but not GLUT4 translocation to the plasma membrane. We also show that adipocytes express both myosin IIA and IIB isoforms, and that myosin IIA is recruited to the plasma membrane upon insulin stimulation. Taken together, the data presented here represent the first demonstration that GLUT4-mediated glucose uptake is a myosin II-dependent process in adipocytes. Based on our findings, we hypothesize that myosin II is activated upon insulin stimulation and recruited to the cell cortex to facilitate GLUT4 fusion with the plasma membrane. The identification of myosin II as a key component of GLUT4-mediated glucose uptake represents an important advance in our understanding of the mechanisms regulating glucose homeostasis

Effect of ageing on the myosin heavy chain composition of the human sternocleidomastoid muscle.

Science.gov (United States)

Meznaric, M; Eržen, I; Karen, P; Cvetko, E

2018-03-01

The myosin heavy chain (MyHC) composition of ageing limb muscles is transformed into a slower phenotype and expresses fast-twitch fibre type atrophy, presumably due to age-related motor unit remodelling and a change in the patterns of physical activity. It is not known if ageing affects the sternocleidomastoid muscle (SCM) in a similar way. The goal of the study was to analyze the MyHC composition and the size of muscle fibres in the ageing SCM by immunohistochemical methods and quantitative analysis and stereology using our own software for morphometry. We hypothesize that with ageing the MyHC composition of SCM transforms similarly as in ageing limb muscles, but the size of the muscle fibres is less effected as in limb muscles. The study was performed on the autopsy samples of the SCM in 12 older males. The results were compared with those published in our previous study on 15 young adult males. An ageing SCM transforms into a slower MyHC profile: the percentage of slow-twitch fibres is enhanced (numerical proportion 44.6 vs. 31.5%, Pfibres is diminished (numerical proportion 14.1 vs. 26.8%, Pfast-twitch fibres expressing MyHC-2a and 2x is smaller (50.6 vs. 63.5%, Pfibres expressing the fastest myosin isoform MyHC-2x is smaller too (19.0 vs. 34.5%, Pfibres expressing the fastest MyHC-2x provide circumstantial evidence for: (i) more fast-twitch than slow-twitch motor units being lost; and (ii) reinnervation by the surviving motor units. There appears to be no significant influence on muscle fibre size, which is congruent with relatively unchanged SCM activity during life. Copyright © 2017 Elsevier GmbH. All rights reserved.

Non-Motor Symptoms of Parkinson's Disease: Diagnosis and ...

African Journals Online (AJOL)

Non-motor symptoms (NMS) of Parkinson's disease (PD) are a key determinant of health, quality of life (QoL) and societal cost of PD. They are often less appreciated than motor symptoms but are important sources of disability for manyPDpatients. Literature search was performed using the reference databases Medline, ...

Assessment of Early Stage Non-Motor Symptoms in Parkinson’sDisease

Directory of Open Access Journals (Sweden)

Haluk Gümüş

2013-09-01

Full Text Available OBJECTIVE: In this study, our purpose is, in the early stage of PD, examining the frequency of occurrence of non-motor symptoms and discussing the effects of morbidity of disease. METHODS: Selcuk University, Meram Faculty of Medicine, Neurology outpatient clinic in the study, which is followed by the United Kingdom Brain Bank criteria for Parkinson's Disease Parkinson's Disease diagnosis and clinical staging according to Hoehn Yahr stages 1 and 2 of the 80 patients were studied. RESULTS: Cases, an increase in UPDRS scores were significantly higher non-motor symptoms. CONCLUSION: Non-motor symptoms in Parkinson's disease can often go unnoticed. Symptomatic treatment is an important part of the success. Therefore, PH and the non-motor symptoms, early detection is important to treat them in accordance with

Non-stationary discharge patterns in motor cortex under subthalamic nucleus deep brain stimulation.

Science.gov (United States)

Santaniello, Sabato; Montgomery, Erwin B; Gale, John T; Sarma, Sridevi V

2012-01-01

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) directly modulates the basal ganglia (BG), but how such stimulation impacts the cortex upstream is largely unknown. There is evidence of cortical activation in 6-hydroxydopamine (OHDA)-lesioned rodents and facilitation of motor evoked potentials in Parkinson's disease (PD) patients, but the impact of the DBS settings on the cortical activity in normal vs. Parkinsonian conditions is still debated. We use point process models to analyze non-stationary activation patterns and inter-neuronal dependencies in the motor and sensory cortices of two non-human primates during STN DBS. These features are enhanced after treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which causes a consistent PD-like motor impairment, while high-frequency (HF) DBS (i.e., ≥100 Hz) strongly reduces the short-term patterns (period: 3-7 ms) both before and after MPTP treatment, and elicits a short-latency post-stimulus activation. Low-frequency DBS (i.e., ≤50 Hz), instead, has negligible effects on the non-stationary features. Finally, by using tools from the information theory [i.e., receiver operating characteristic (ROC) curve and information rate (IR)], we show that the predictive power of these models is dependent on the DBS settings, i.e., the probability of spiking of the cortical neurons (which is captured by the point process models) is significantly conditioned on the timely delivery of the DBS input. This dependency increases with the DBS frequency and is significantly larger for high- vs. low-frequency DBS. Overall, the selective suppression of non-stationary features and the increased modulation of the spike probability suggest that HF STN DBS enhances the neuronal activation in motor and sensory cortices, presumably because of reinforcement mechanisms, which perhaps involve the overlap between feedback antidromic and feed-forward orthodromic responses along the BG-thalamo-cortical loop.

Leading-process actomyosin coordinates organelle positioning and adhesion receptor dynamics in radially migrating cerebellar granule neurons.

Science.gov (United States)

Trivedi, Niraj; Ramahi, Joseph S; Karakaya, Mahmut; Howell, Danielle; Kerekes, Ryan A; Solecki, David J

2014-12-02

During brain development, neurons migrate from germinal zones to their final positions to assemble neural circuits. A unique saltatory cadence involving cyclical organelle movement (e.g., centrosome motility) and leading-process actomyosin enrichment prior to nucleokinesis organizes neuronal migration. While functional evidence suggests that leading-process actomyosin is essential for centrosome motility, the role of the actin-enriched leading process in globally organizing organelle transport or traction forces remains unexplored. We show that myosin ii motors and F-actin dynamics are required for Golgi apparatus positioning before nucleokinesis in cerebellar granule neurons (CGNs) migrating along glial fibers. Moreover, we show that primary cilia are motile organelles, localized to the leading-process F-actin-rich domain and immobilized by pharmacological inhibition of myosin ii and F-actin dynamics. Finally, leading process adhesion dynamics are dependent on myosin ii and F-actin. We propose that actomyosin coordinates the overall polarity of migrating CGNs by controlling asymmetric organelle positioning and cell-cell contacts as these cells move along their glial guides.

Motor and non-motor symptoms of Parkinson's disease and their impact on quality of life and on different clinical subgroups.

Science.gov (United States)

Berganzo, K; Tijero, B; González-Eizaguirre, A; Somme, J; Lezcano, E; Gabilondo, I; Fernandez, M; Zarranz, J J; Gómez-Esteban, J C

The aim of the present study is to analyse the influence that motor and non-motor symptoms have on the quality of life (QoL) of patients with Parkinson's disease (PD), and to study the relationship between the two types of symptoms. This cross-sectional study included 103 patients with PD (55 men and 48 women). Quality of life was measured on the PDQ-39 scale. The UPDRS scale (I-IV) was also used, and different items were grouped to analyse the presence of tremor, rigidity, bradykinesia, and axial symptoms. The non-motor symptoms scale (NMSS) was administered to assess non-motor symptoms. We performed correlation analyses between different scales to analyse the influence of motor and non-motor symptoms on QoL. Correlations were observed between the PDQ-39 summary index (PDQ39_SI) and the NMSS (correlation coefficient [cc], 0.56; pde Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

Reciprocal and dynamic polarization of planar cell polarity core components and myosin

Science.gov (United States)

Newman-Smith, Erin; Kourakis, Matthew J; Reeves, Wendy; Veeman, Michael; Smith, William C

2015-01-01

The Ciona notochord displays planar cell polarity (PCP), with anterior localization of Prickle (Pk) and Strabismus (Stbm). We report that a myosin is polarized anteriorly in these cells and strongly colocalizes with Stbm. Disruption of the actin/myosin machinery with cytochalasin or blebbistatin disrupts polarization of Pk and Stbm, but not of myosin complexes, suggesting a PCP-independent aspect of myosin localization. Wash out of cytochalasin restored Pk polarization, but not if done in the presence of blebbistatin, suggesting an active role for myosin in core PCP protein localization. On the other hand, in the pk mutant line, aimless, myosin polarization is disrupted in approximately one third of the cells, indicating a reciprocal action of core PCP signaling on myosin localization. Our results indicate a complex relationship between the actomyosin cytoskeleton and core PCP components in which myosin is not simply a downstream target of PCP signaling, but also required for PCP protein localization. DOI: http://dx.doi.org/10.7554/eLife.05361.001 PMID:25866928

MUSIC CUED EXERCISES FOR MOTOR AND NON-MOTOR SIGNS IN PEOPLE WITH DEMENTIA: PROTOCOL FOR A SYSTEMATIC REVIEW

OpenAIRE

Yasmine S Gomaa; Salah A Sawan; Joanne E Wittwer; Meg E Morris

2017-01-01

Background: Movement disorders and non-motor problems such as cognitive decline, anxiety, depression and behavioural problems, are common in people with dementia and can progress over time. Exercise coupled with music is a promising form of therapy designed to improve both the motor and non-motor manifestations of this debilitating neurological condition. Objectives: To present a protocol for a systematic review and critical analysis of the literature to answer the following questions: ...

The Role of Motor Processes in Three-Dimensional Mental Rotation: Shaping Cognitive Processing via Sensorimotor Experience

Science.gov (United States)

Moreau, David

2012-01-01

An extensive body of literature has explored the involvement of motor processes in mental rotation, yet underlying individual differences are less documented and remain to be fully understood. We propose that sensorimotor experience shapes spatial abilities such as assessed in mental rotation tasks. Elite wrestlers' and non-athletes' mental…

Dual role for myosin II in GLUT4-mediated glucose uptake in 3T3-L1 adipocytes

International Nuclear Information System (INIS)

Fulcher, F. Kent; Smith, Bethany T.; Russ, Misty; Patel, Yashomati M.

2008-01-01

Insulin-stimulated glucose uptake requires the activation of several signaling pathways to mediate the translocation and fusion of GLUT4 vesicles to the plasma membrane. Our previous studies demonstrated that GLUT4-mediated glucose uptake is a myosin II-dependent process in adipocytes. The experiments described in this report are the first to show a dual role for the myosin IIA isoform specifically in regulating insulin-stimulated glucose uptake in adipocytes. We demonstrate that inhibition of MLCK but not RhoK results in impaired insulin-stimulated glucose uptake. Furthermore, our studies show that insulin specifically stimulates the phosphorylation of the RLC associated with the myosin IIA isoform via MLCK. In time course experiments, we determined that GLUT4 translocates to the plasma membrane prior to myosin IIA recruitment. We further show that recruitment of myosin IIA to the plasma membrane requires that myosin IIA be activated via phosphorylation of the RLC by MLCK. Our findings also reveal that myosin II is required for proper GLUT4-vesicle fusion at the plasma membrane. We show that once at the plasma membrane, myosin II is involved in regulating the intrinsic activity of GLUT4 after insulin stimulation. Collectively, our results are the first to reveal that myosin IIA plays a critical role in mediating insulin-stimulated glucose uptake in 3T3-LI adipocytes, via both GLUT4 vesicle fusion at the plasma membrane and GLUT4 activity

Allosteric communication in myosin V: from small conformational changes to large directed movements.

Directory of Open Access Journals (Sweden)

M Cecchini

Full Text Available The rigor to post-rigor transition in myosin, a consequence of ATP binding, plays an essential role in the Lymn-Taylor functional cycle because it results in the dissociation of the actomyosin complex after the powerstroke. On the basis of the X-ray structures of myosin V, we have developed a new normal mode superposition model for the transition path between the two states. Rigid-body motions of the various subdomains and specific residues at the subdomain interfaces are key elements in the transition. The allosteric communication between the nucleotide binding site and the U50/L50 cleft is shown to result from local changes due to ATP binding, which induce large amplitude motions that are encoded in the structure of the protein. The triggering event is the change in the interaction of switch I and the P-loop, which is stabilized by ATP binding. The motion of switch I, which is a relatively rigid element of the U50 subdomain, leads directly to a partial opening of the U50/L50 cleft; the latter is expected to weaken the binding of myosin to actin. The calculated transition path demonstrates the nature of the subdomain coupling and offers an explanation for the mutual exclusion of ATP and actin binding. The mechanism of the uncoupling of the converter from the motor head, an essential part of the transition, is elucidated. The origin of the partial untwisting of the central beta-sheet in the rigor to post-rigor transition is described.

Mouse nuclear myosin I knock-out shows interchangeability and redundancy of myosin isoforms in the cell nucleus

Czech Academy of Sciences Publication Activity Database

Venit, Tomáš; Dzijak, Rastislav; Kalendová, Alžběta; Kahle, Michal; Rohožková, Jana; Schmidt, V.; Rülicke, T.; Rathkolb, B.; Hans, W.; Bohla, A.; Eickelberg, O.; Stoeger, T.; Wolf, E.; Yildirim, A.Ö.; Gailus-Durner, V.; Fuchs, H.; de Angelis, M.H.; Hozák, Pavel

2013-01-01

Roč. 8, č. 4 (2013), e61406 E-ISSN 1932-6203 R&D Projects: GA ČR GAP305/11/2232; GA TA ČR TE01020022; GA MŠk LH12143; GA ČR(CZ) GD204/09/H084 Institutional research plan: CEZ:AV0Z50520514 Institutional support: RVO:68378050 Keywords : nuclear myosin * myosin isoforms * cell nucleus Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.534, year: 2013

Brain infusion of α-synuclein oligomers induces motor and non-motor Parkinson's disease-like symptoms in mice.

Science.gov (United States)

Fortuna, Juliana T S; Gralle, Matthias; Beckman, Danielle; Neves, Fernanda S; Diniz, Luan P; Frost, Paula S; Barros-Aragão, Fernanda; Santos, Luís E; Gonçalves, Rafaella A; Romão, Luciana; Zamberlan, Daniele C; Soares, Felix A A; Braga, Carolina; Foguel, Debora; Gomes, Flávia C A; De Felice, Fernanda G; Ferreira, Sergio T; Clarke, Julia R; Figueiredo, Cláudia P

2017-08-30

Parkinson's disease (PD) is characterized by motor dysfunction, which is preceded by a number of non-motor symptoms including olfactory deficits. Aggregation of α-synuclein (α-syn) gives rise to Lewy bodies in dopaminergic neurons and is thought to play a central role in PD pathology. However, whether amyloid fibrils or soluble oligomers of α-syn are the main neurotoxic species in PD remains controversial. Here, we performed a single intracerebroventricular (i.c.v.) infusion of α-syn oligomers (α-SYOs) in mice and evaluated motor and non-motor symptoms. Familiar bedding and vanillin essence discrimination tasks showed that α-SYOs impaired olfactory performance of mice, and decreased TH and dopamine levels in the olfactory bulb early after infusion. The olfactory deficit persisted until 45days post-infusion (dpi). α- SYO-infused mice behaved normally in the object recognition and forced swim tests, but showed increased anxiety-like behavior in the open field and elevated plus maze tests 20 dpi. Finally, administration of α-SYOs induced late motor impairment in the pole test and rotarod paradigms, along with reduced TH and dopamine content in the caudate putamen, 45 dpi. Reduced number of TH-positive cells was also seen in the substantia nigra of α-SYO-injected mice compared to control. In conclusion, i.c.v. infusion of α-SYOs recapitulated some of PD-associated non-motor symptoms, such as increased anxiety and olfactory dysfunction, but failed to recapitulate memory impairment and depressive-like behavior typical of the disease. Moreover, α-SYOs i.c.v. administration induced motor deficits and loss of TH and dopamine levels, key features of PD. Results point to α-syn oligomers as the proximal neurotoxins responsible for early non-motor and motor deficits in PD and suggest that the i.c.v. infusion model characterized here may comprise a useful tool for identification of PD novel therapeutic targets and drug screening. Copyright © 2017 Elsevier B.V. All

10 CFR 431.383 - Enforcement process for electric motors.

Science.gov (United States)

2010-01-01

... 10 Energy 3 2010-01-01 2010-01-01 false Enforcement process for electric motors. 431.383 Section... COMMERCIAL AND INDUSTRIAL EQUIPMENT Enforcement § 431.383 Enforcement process for electric motors. (a) Test... motor sold by a particular manufacturer or private labeler, which indicates that the electric motor may...

Discoidin Domain Receptor 1 Mediates Myosin-Dependent Collagen Contraction

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Nuno M. Coelho

2017-02-01

Full Text Available Discoidin domain receptor 1 (DDR1 is a tyrosine kinase collagen adhesion receptor that mediates cell migration through association with non-muscle myosin IIA (NMIIA. Because DDR1 is implicated in cancer fibrosis, we hypothesized that DDR1 interacts with NMIIA to enable collagen compaction by traction forces. Mechanical splinting of rat dermal wounds increased DDR1 expression and collagen alignment. In periodontal ligament of DDR1 knockout mice, collagen mechanical reorganization was reduced >30%. Similarly, cultured cells with DDR1 knockdown or expressing kinase-deficient DDR1d showed 50% reduction of aligned collagen. Tractional remodeling of collagen was dependent on DDR1 clustering, activation, and interaction of the DDR1 C-terminal kinase domain with NMIIA filaments. Collagen remodeling by traction forces, DDR1 tyrosine phosphorylation, and myosin light chain phosphorylation were increased on stiff versus soft substrates. Thus, DDR1 clustering, activation, and interaction with NMIIA filaments enhance the collagen tractional remodeling that is important for collagen compaction in fibrosis.

Study of an integrated non-motor symptoms questionnaire for Parkinson's disease

Institute of Scientific and Technical Information of China (English)

YU Bo; XIAO Zhi-ying; LI Jia-zhen; YUAN Jing; LIU Yi-ming

2010-01-01

Background Although the validity of non-motor symptoms screening questionnaire (NMSQuest) for Parkinson's disease has been verified in several recent researches, the specificity of the questionnaire is still in doubt. This study aimed to compare the non-motor symptoms (NMS) in Parkinson's disease (PD) with a medically ill control group.Methods In this study, the first comprehensive clinic-based NMS screening questionnaire for PD developed by the Parkinson's Disease Non-Motor Group (PDNMG) was used. Data from 90 PD patients and 270 sex-and age-matched control subjects, including stroke (n=90), heart disease (n=90) and diabetes (n=90) were analyzed.Results Compared with control group, NMS was more common in PD; on an average, most PD patients reported more than 12 non-motor items. There was a correlation of total NMS score in PD patients with Hoehn & Yahr Staging, but not with age, sex distribution, disease duration, or age at disease onset. Additionally, depression, constipation and impaired olfaction which occurred prior to the motor symptoms of PD were reported in this study.Conclusions NMS are more common in PD patients. There are some NMS that occurred at the preclinical stage of PD and might predict the onset of motor symptoms of PD patients.

Expression of smooth muscle and non-muscle myosin heavy chain isoforms in cultured vascular smooth muscle cells

International Nuclear Information System (INIS)

Rovner, A.S.; Murphy, R.A.; Owens, G.K.

1986-01-01

Immunocytochemical studies of cultured smooth muscle cells (SMCs) have disagreed on the nature of myosin expression. This investigation was undertaken to test for the presence of heterogeneous myosin heavy chain (MHC) isoforms in cell culture as a possible explanation for these results. Previously, Rovner et al. detected two MHCs in intact smooth muscles which differed in molecular weight by ca. 4000 daltons (SM1 and SM2) using a 3-4% acrylamide gradient SDS gel system. When sub-confluent primary cultures of rat aorta SMCs were assayed by this system, SM1 and SM2 were seen, along with large amounts of a third, unique MHC, NM, which closely resembled the MHC from human platelet in size and antigenicity. Data from 35 S-methionine autoradiograms showed that the log growth phase SMC cultures were producing almost exclusively NM, but the growth arrest, post-confluent cultures synthesized increased relative amounts of the SM MHC forms and contained comparable amounts of SM1, SM2, and NM. The same patterns of MHC synthesis were seen in sub-passaged SMCs. The expression of the SM-specific forms of myosin in quiescent, post-confluent cultures parallels that of smooth muscle actin suggesting that density induced growth arrest promotes cytodifferentiation in cultured vascular SMCs

Cross-sectional and longitudinal associations of motor fluctuations and non-motor predominance with cerebrospinal τ and Aβ as well as dementia-risk in Parkinson's disease.

Science.gov (United States)

Modreanu, Raluca; Cerquera, Sonia Catalina; Martí, María José; Ríos, José; Sánchez-Gómez, Almudena; Cámara, Ana; Fernández, Manel; Compta, Yaroslau

2017-02-15

Experimental, neuropathological and cerebrospinal fluid (CSF) studies support τ and amyloid-β (Aβ) relevance in Parkinson's disease (PD) related dementia. Lesser motor fluctuations (MFs) and non-motor features have also been related to PD-dementia. Yet, little is known about the association of MFs and non-motor symptoms with CSF τ and Aβ in PD. We hypothesized that lesser MFs and non-motor predominance are related to these CSF markers and dementia-risk in PD. We studied 58 PD patients (dementia at baseline, n=21; dementia at 18-months, n=35) in whom CSF Aβ and τ had been determined with ELISA techniques. MFs and a number of non-motor symptoms (apathy, anxiety, irritability, depression, visual hallucinations, spatial disorientation, memory complaints) over disease course were dichotomized as absent-mild vs. moderate-severe by retrospective clinical chart review blind to CSF findings. Non-motor predominance was defined as ≥3 non-motor symptoms (after the cohort-median of non-motor symptoms per patient) with ≥2 being moderate-severe and ≥1 having been present from onset, with all these being more disabling overall than motor features. Cross-sectionally, CSF biomarkers were non-parametrically compared according to dichotomized MFs and non-motor predominance. Longitudinally, dementia was the outcome (dependent variable), CSF markers, MFs and non-motor predominance were the predictors (independent variables), and potential modifiers as age, sex, and memory complaints were the covariates in binary regression models. Absent-mild MFs were associated with higher CSF τ markers and shorter time-to-dementia, while non-motor predominance and decreasing CSF Aβ independently increased longitudinal dementia-risk. In summary, absent-mild MFs, non-motor predominance and CSF τ and Aβ might define endophenotypes related to the timing or risk of dementia in PD. Copyright © 2016 Elsevier B.V. All rights reserved.

MOTOR UNIT TERRITORIES AND FIBER TYPES IN RABBIT MASSETER MUSCLE

NARCIS (Netherlands)

WEIJS, WA; JUCH, PJW; KWA, SHS; KORFAGE, JAM

1993-01-01

The myosin heavy chain (MHC) content and spatial distribution of the fibers of 11 motor units (MUs) of the rabbit masseter muscle were determined. The fibers of single MUs were visualized in whole-muscle serial sections by a negative periodic acid/Schiff reaction for glycogen after they had been

Stress generation by myosin minifilaments in actin bundles

International Nuclear Information System (INIS)

Dasanayake, Nilushi L; Carlsson, Anders E

2013-01-01

Forces and stresses generated by the action of myosin minifilaments are analyzed in idealized computer-generated actin bundles, and compared to results for isotropic actin networks. The bundles are generated as random collections of actin filaments in two dimensions with constrained orientations, crosslinked and attached to two fixed walls. Myosin minifilaments are placed on actin filament pairs and allowed to move and deform the network so that it exerts forces on the walls. The vast majority of simulation runs end with contractile minifilament stress, because minifilaments rotate into energetically stable contractile configurations. This process is aided by the bending and stretching of actin filaments, which accomodate minifilament rotation. Stresses for bundles are greater than those for isotropic networks, and antiparallel filaments generate more tension than parallel filaments. The forces transmitted by the actin network to the walls of the simulation cell often exceed the tension in the minifilament itself. (paper)

Phosphorylation of human skeletal muscle myosin

International Nuclear Information System (INIS)

Houston, M.E.; Lingley, M.D.; Stuart, D.S.; Hoffman-Goetz, L.

1986-01-01

Phosphorylation of the P-light chains (phosphorylatable light chains) in human skeletal muscle myosin was studied in vitro and in vivo under resting an d contracted conditions. biopsy samples from rested vastus lateralis muscle of male and female subjects were incubated in oxygenated physiological solution at 30 0 C. Samples frozen following a quiescent period showed the presence of only unphosphorylated P-light chains designated LC2f (light chain two of fast myosin) CL2s and LC2s'(light chains two of slow myosin). Treatment with caffeine (10 mM) or direct electrical stimulation resulted in the appearance of three additional bands which were identified as the phosphorylated forms of the P-light chains i.e. LC2f-P, LC2s-P and LC2s'-P. The presence of phosphate was confirmed by prior incubation with ( 30 P) orthophosphate. Muscle samples rapidly frozen from resting vastus lateralis muscle revealed the presence of unphosphorylated and phosphorylated P-light chains in approximately equal ratios. Muscle samples rapidly frozen following a maximal 10 second isometric contraction showed virtually only phosphorylated fast and slow P-light chains. These results reveal that the P-light chains in human fast and slow myosin may be rapidly phosphorylated, but the basal level of phosphorylation in rested human muscle considerably exceeds that observed in animal muscles studied in vitro or in situ

Non-motor symptoms in Parkinson's disease

NARCIS (Netherlands)

Verbaan, Dagmar

2009-01-01

The thesis “Non-motor symptoms in Parkinson’s disease” is part of the PROPARK study, a longitudinal cohort study of approximately 400 patients with Parkinson’s disease (PD), who are profiled on genotype, phenotype, disability, and global outcomes of health, using valid and reliable assessment

Myosin-1C uses a novel phosphoinositide-dependent pathway for nuclear localization.

Science.gov (United States)

Nevzorov, Ilja; Sidorenko, Ekaterina; Wang, Weihuan; Zhao, Hongxia; Vartiainen, Maria K

2018-02-01

Accurate control of macromolecule transport between nucleus and cytoplasm underlines several essential biological processes, including gene expression. According to the canonical model, nuclear import of soluble proteins is based on nuclear localization signals and transport factors. We challenge this view by showing that nuclear localization of the actin-dependent motor protein Myosin-1C (Myo1C) resembles the diffusion-retention mechanism utilized by inner nuclear membrane proteins. We show that Myo1C constantly shuttles in and out of the nucleus and that its nuclear localization does not require soluble factors, but is dependent on phosphoinositide binding. Nuclear import of Myo1C is preceded by its interaction with the endoplasmic reticulum, and phosphoinositide binding is specifically required for nuclear import, but not nuclear retention, of Myo1C. Our results therefore demonstrate, for the first time, that membrane association and binding to nuclear partners is sufficient to drive nuclear localization of also soluble proteins, opening new perspectives to evolution of cellular protein sorting mechanisms. © 2018 The Authors. Published under the terms of the CC BY NC ND 4.0 license.

Myosin heavy chain expression in rabbit masseter muscle during postnatal development

NARCIS (Netherlands)

Bredman, J. J.; Weijs, W. A.; Korfage, H. A.; Brugman, P.; Moorman, A. F.

1992-01-01

The expression of isoforms of myosin heavy chain (MHC) during postnatal development was studied in the masseter muscle of the rabbit. Evidence is presented that in addition to adult fast and slow myosin, the rabbit masseter contains neonatal and 'cardiac' alpha-MHC. During postnatal growth myosin

Interaction of c-Cbl with myosin IIA regulates Bleb associated macropinocytosis of Kaposi's sarcoma-associated herpesvirus.

Directory of Open Access Journals (Sweden)

Mohanan Valiya Veettil

2010-12-01

Full Text Available KSHV is etiologically associated with Kaposi's sarcoma (KS, an angioproliferative endothelial cell malignancy. Macropinocytosis is the predominant mode of in vitro entry of KSHV into its natural target cells, human dermal microvascular endothelial (HMVEC-d cells. Although macropinocytosis is known to be a major route of entry for many viruses, the molecule(s involved in the recruitment and integration of signaling early during macropinosome formation is less well studied. Here we demonstrate that tyrosine phosphorylation of the adaptor protein c-Cbl is required for KSHV induced membrane blebbing and macropinocytosis. KSHV induced the tyrosine phosphorylation of c-Cbl as early as 1 min post-infection and was recruited to the sites of bleb formation. Infection also led to an increase in the interaction of c-Cbl with PI3-K p85 in a time dependent manner. c-Cbl shRNA decreased the formation of KSHV induced membrane blebs and macropinocytosis as well as virus entry. Immunoprecipitation of c-Cbl followed by mass spectrometry identified the interaction of c-Cbl with a novel molecular partner, non-muscle myosin heavy chain IIA (myosin IIA, in bleb associated macropinocytosis. Phosphorylated c-Cbl colocalized with phospho-myosin light chain II in the interior of blebs of infected cells and this interaction was abolished by c-Cbl shRNA. Studies with the myosin II inhibitor blebbistatin demonstrated that myosin IIA is a biologically significant component of the c-Cbl signaling pathway and c-Cbl plays a new role in the recruitment of myosin IIA to the blebs during KSHV infection. Myosin II associates with actin in KSHV induced blebs and the absence of actin and myosin ubiquitination in c-Cbl ShRNA cells suggested that c-Cbl is also responsible for the ubiquitination of these proteins in the infected cells. This is the first study demonstrating the role of c-Cbl in viral entry as well as macropinocytosis, and provides the evidence that a signaling complex

Identification of signals that facilitate isoform specific nucleolar localization of myosin IC

Energy Technology Data Exchange (ETDEWEB)

Schwab, Ryan S.; Ihnatovych, Ivanna; Yunus, Sharifah Z.S.A.; Domaradzki, Tera [Department of Physiology and Biophysics, University at Buffalo—State University of New York, Buffalo, NY (United States); Hofmann, Wilma A., E-mail: whofmann@buffalo.edu [Department of Physiology and Biophysics, University at Buffalo—State University of New York, Buffalo, NY (United States)

2013-05-01

Myosin IC is a single headed member of the myosin superfamily that localizes to the cytoplasm and the nucleus, where it is involved in transcription by RNA polymerases I and II, intranuclear transport, and nuclear export. In mammalian cells, three isoforms of myosin IC are expressed that differ only in the addition of short isoform-specific N-terminal peptides. Despite the high sequence homology, the isoforms show differences in cellular distribution, in localization to nuclear substructures, and in their interaction with nuclear proteins through yet unknown mechanisms. In this study, we used EGFP-fusion constructs that express truncated or mutated versions of myosin IC isoforms to detect regions that are involved in isoform-specific localization. We identified two nucleolar localization signals (NoLS). One NoLS is located in the myosin IC isoform B specific N-terminal peptide, the second NoLS is located upstream of the neck region within the head domain. We demonstrate that both NoLS are functional and necessary for nucleolar localization of specifically myosin IC isoform B. Our data provide a first mechanistic explanation for the observed functional differences between the myosin IC isoforms and are an important step toward our understanding of the underlying mechanisms that regulate the various and distinct functions of myosin IC isoforms. - Highlights: ► Two NoLS have been identified in the myosin IC isoform B sequence. ► Both NoLS are necessary for myosin IC isoform B specific nucleolar localization. ► First mechanistic explanation of functional differences between the isoforms.

Myosin VIIa as a common component of cilia and microvilli.

Science.gov (United States)

Wolfrum, U; Liu, X; Schmitt, A; Udovichenko, I P; Williams, D S

1998-01-01

The distribution of myosin VIIa, which is defective or absent in Usher syndrome 1B, was studied in a variety of tissues by immunomicroscopy. The primary aim was to determine whether this putative actin-based mechanoenzyme is a common component of cilia. Previously, it has been proposed that defective ciliary function might be the basis of some forms of Usher syndrome. Myosin VIIa was detected in cilia from cochlear hair cells, olfactory neurons, kidney distal tubules, and lung bronchi. It was also found to cofractionate with the axonemal fraction of retinal photoreceptor cells. Immunolabeling appeared most concentrated in the periphery of the transition zone of the cilia. This general presence of a myosin in cilia is surprising, given that cilia are dominated by microtubules, and not actin filaments. In addition to cilia, myosin VIIa was also found in actin-rich microvilli of different types of cell. We conclude that myosin VIIa is a common component of cilia and microvilli.

Artificial muscle-like function from hierarchical supramolecular assembly of photoresponsive molecular motors

NARCIS (Netherlands)

Chen, Jiawen; Leung, Franco King-Chi; Stuart, Marc C A; Kajitani, Takashi; Fukushima, Takanori; van der Giessen, Erik; Feringa, Ben L

A striking feature of living systems is their ability to produce motility by amplification of collective molecular motion from the nanoscale up to macroscopic dimensions. Some of nature's protein motors, such as myosin in muscle tissue, consist of a hierarchical supramolecular assembly of very large

Motor activation in literal and non literal sentences: does time matter?

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Cristina eCacciari

2013-05-01

Full Text Available Despite the impressive amount of evidence showing involvement of the sensorimotor systems in language processing, important questions remain unsolved among which the relationship between non literal uses of language and sensorimotor activation. The literature did not yet provide a univocal answer on whether the comprehension of non literal, abstract motion sentences engages the same neural networks recruited for literal sentences. A previous TMS study using the same experimental materials of the present study showed activation for literal, fictive and metaphoric motion sentences but not for idiomatic ones. To evaluate whether this may depend on insufficient time for elaborating the idiomatic meaning, we conducted a behavioural experiment that used a sensibility judgment task performed by pressing a button either with a hand finger or with a foot. Motor activation is known to be sensitive to the action-congruency of the effector used for responding. Therefore, all other things being equal, significant differences between response emitted with an action-congruent or incongruent effector (foot vs. hand may be attributed to motor activation. Foot-related action verbs were embedded in sentences conveying literal motion, fictive motion, metaphoric motion or idiomatic motion. Mental sentences were employed as a control condition. Foot responses were significantly faster than finger responses but only in literal motion sentences. We hypothesize that motor activation may arise in early phases of comprehension processes (i.e. upon reading the verb for then decaying as a function of the strength of the semantic motion component of the verb.

Mouse nuclear myosin I knock-out shows interchangeability and redundancy of myosin isoforms in the cell nucleus.

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Venit, Tomáš; Dzijak, Rastislav; Kalendová, Alžběta; Kahle, Michal; Rohožková, Jana; Schmidt, Volker; Rülicke, Thomas; Rathkolb, Birgit; Hans, Wolfgang; Bohla, Alexander; Eickelberg, Oliver; Stoeger, Tobias; Wolf, Eckhard; Yildirim, Ali Önder; Gailus-Durner, Valérie; Fuchs, Helmut; de Angelis, Martin Hrabě; Hozák, Pavel

2013-01-01

Nuclear myosin I (NM1) is a nuclear isoform of the well-known "cytoplasmic" Myosin 1c protein (Myo1c). Located on the 11(th) chromosome in mice, NM1 results from an alternative start of transcription of the Myo1c gene adding an extra 16 amino acids at the N-terminus. Previous studies revealed its roles in RNA Polymerase I and RNA Polymerase II transcription, chromatin remodeling, and chromosomal movements. Its nuclear localization signal is localized in the middle of the molecule and therefore directs both Myosin 1c isoforms to the nucleus. In order to trace specific functions of the NM1 isoform, we generated mice lacking the NM1 start codon without affecting the cytoplasmic Myo1c protein. Mutant mice were analyzed in a comprehensive phenotypic screen in cooperation with the German Mouse Clinic. Strikingly, no obvious phenotype related to previously described functions has been observed. However, we found minor changes in bone mineral density and the number and size of red blood cells in knock-out mice, which are most probably not related to previously described functions of NM1 in the nucleus. In Myo1c/NM1 depleted U2OS cells, the level of Pol I transcription was restored by overexpression of shRNA-resistant mouse Myo1c. Moreover, we found Myo1c interacting with Pol II. The ratio between Myo1c and NM1 proteins were similar in the nucleus and deletion of NM1 did not cause any compensatory overexpression of Myo1c protein. We observed that Myo1c can replace NM1 in its nuclear functions. Amount of both proteins is nearly equal and NM1 knock-out does not cause any compensatory overexpression of Myo1c. We therefore suggest that both isoforms can substitute each other in nuclear processes.

Effects of sleep disorders on the non-motor symptoms of Parkinson disease.

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Neikrug, Ariel B; Maglione, Jeanne E; Liu, Lianqi; Natarajan, Loki; Avanzino, Julie A; Corey-Bloom, Jody; Palmer, Barton W; Loredo, Jose S; Ancoli-Israel, Sonia

2013-11-15

To evaluate the impact of sleep disorders on non-motor symptoms in patients with Parkinson disease (PD). This was a cross-sectional study. Patients with PD were evaluated for obstructive sleep apnea (OSA), restless legs syndrome (RLS), periodic limb movement syndrome (PLMS), and REM sleep behavior disorder (RBD). Cognition was assessed with the Montreal Cognitive Assessment and patients completed self-reported questionnaires assessing non-motor symptoms including depressive symptoms, fatigue, sleep complaints, daytime sleepiness, and quality of life. Sleep laboratory. 86 patients with PD (mean age = 67.4 ± 8.8 years; range: 47-89; 29 women). N/A. Having sleep disorders was a predictor of overall non-motor symptoms in PD (R(2) = 0.33, p sleep disorder significantly predicted sleep complaints (ΔR(2) = 0.13, p = 0.006), depressive symptoms (ΔR(2) = 0.01, p = 0.03), fatigue (ΔR(2) = 0.12, p = 0.007), poor quality of life (ΔR(2) = 0.13, p = 0.002), and cognitive decline (ΔR(2) = 0.09, p = 0.036). Additionally, increasing number of sleep disorders (0, 1, or ≥ 2 sleep disorders) was a significant contributor to non-motor symptom impairment (R(2) = 0.28, p sleep disorders predicted more non-motor symptoms including increased sleep complaints, more depressive symptoms, lower quality of life, poorer cognition, and more fatigue. RBD and RLS were factors of overall increased non-motor symptoms, but OSA was not.

The Kinetics of Myosin Light Chain Kinase Activation of Smooth Muscle Myosin in an In Vitro Model System

OpenAIRE

Hong, Feng; Facemyer, Kevin C.; Carter, Michael S.; Jackson, Del R.; Haldeman, Brian D.; Ruana, Nick; Sutherland, Cindy; Walsh, Michael P.; Cremo, Christine R.; Baker, Josh E.

2013-01-01

During activation of smooth muscle contraction, one myosin light chain kinase (MLCK) molecule rapidly phosphorylates many smooth muscle myosin (SMM) molecules, suggesting that muscle activation rates are influenced by the kinetics of MLCK-SMM interactions. To determine the rate-limiting step underlying activation of SMM by MLCK, we measured the kinetics of calcium-calmodulin (Ca2+-CaM)-MLCK-mediated SMM phosphorylation and the corresponding initiation of SMM-based F-actin motility in an in vi...

Amelioration of non-motor dysfunctions after transplantation of human dopamine neurons in a model of Parkinson's disease.

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Lelos, M J; Morgan, R J; Kelly, C M; Torres, E M; Rosser, A E; Dunnett, S B

2016-04-01

Patients suffering from Parkinson's disease (PD) display cognitive and neuropsychiatric dysfunctions, especially with disease progression. Although these impairments have been reported to impact more heavily upon a patient's quality of life than any motor dysfunctions, there are currently no interventions capable of adequately targeting these non-motor deficits. Utilizing a rodent model of PD, we investigated whether cell replacement therapy, using intrastriatal transplants of human-derived ventral mesencephalic (hVM) grafts, could alleviate cognitive and neuropsychiatric, as well as motor, dysfunctions. Rats with unilateral 6-hydroxydopamine lesions to the medial forebrain bundle were tested on a complex operant task that dissociates motivational, visuospatial and motor impairments sensitive to the loss of dopamine. A subset of lesioned rats received intrastriatal hVM grafts of ~9 weeks gestation. Post-graft, rats underwent repeated drug-induced rotation tests and were tested on two versions of the complex operant task, before post-mortem analysis of the hVM tissue grafts. Post-graft behavioural testing revealed that hVM grafts improved non-motor aspects of task performance, specifically visuospatial function and motivational processing, as well as alleviating motor dysfunctions. We report the first evidence of human VM cell grafts alleviating both non-motor and motor dysfunctions in an animal model of PD. This intervention, therefore, is the first to improve cognitive and neuropsychiatric symptoms long-term in a model of PD. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Clinical Significance of REM Sleep Behavior Disorders and Other Non-motor Symptoms of Parkinsonism

Institute of Scientific and Technical Information of China (English)

Hong Jin; Jin-Ru Zhang; Yun Shen; Chun-Feng Liu

2017-01-01

Rapid eye movement sleep behavior disorder (RBD) is one of the most common non-motor symptoms of parkinsonism,and it may serve as a prodromal marker of neurodegenerative disease.The mechanism underlying RBD is unclear.Several prospective studies have reported that specific non-motor symptoms predict a conversion risk of developing a neurodegenerative disease,including olfactory dysfunction,abnormal color vision,autonomic dysfunction,excessive daytime sleepiness,depression,and cognitive impairment.Parkinson's disease (PD) with RBD exhibits clinical heterogeneity with respect to motor and non-motor symptoms compared with PD without RBD.In this review,we describe the main clinical and pathogenic features of RBD,focusing on its association with other non-motor symptoms of parkinsonism.

[Non-speech oral motor treatment efficacy for children with developmental speech sound disorders].

Science.gov (United States)

Ygual-Fernandez, A; Cervera-Merida, J F

2016-01-01

In the treatment of speech disorders by means of speech therapy two antagonistic methodological approaches are applied: non-verbal ones, based on oral motor exercises (OME), and verbal ones, which are based on speech processing tasks with syllables, phonemes and words. In Spain, OME programmes are called 'programas de praxias', and are widely used and valued by speech therapists. To review the studies conducted on the effectiveness of OME-based treatments applied to children with speech disorders and the theoretical arguments that could justify, or not, their usefulness. Over the last few decades evidence has been gathered about the lack of efficacy of this approach to treat developmental speech disorders and pronunciation problems in populations without any neurological alteration of motor functioning. The American Speech-Language-Hearing Association has advised against its use taking into account the principles of evidence-based practice. The knowledge gathered to date on motor control shows that the pattern of mobility and its corresponding organisation in the brain are different in speech and other non-verbal functions linked to nutrition and breathing. Neither the studies on their effectiveness nor the arguments based on motor control studies recommend the use of OME-based programmes for the treatment of pronunciation problems in children with developmental language disorders.

Constraining movement alters the recruitment of motor processes in mental rotation.

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Moreau, David

2013-02-01

Does mental rotation depend on the readiness to act? Recent evidence indicates that the involvement of motor processes in mental rotation is experience-dependent, suggesting that different levels of expertise in sensorimotor interactions lead to different strategies to solve mental rotation problems. Specifically, experts in motor activities perceive spatial material as objects that can be acted upon, triggering covert simulation of rotations. Because action simulation depends on the readiness to act, movement restriction should therefore disrupt mental rotation performance in individuals favoring motor processes. In this experiment, wrestlers and non-athletes judged whether pairs of three-dimensional stimuli were identical or different, with their hands either constrained or unconstrained. Wrestlers showed higher performance than controls in the rotation of geometric stimuli, but this difference disappeared when their hands were constrained. However, movement restriction had similar consequences for both groups in the rotation of hands. These findings suggest that expert's advantage in mental rotation of abstract objects is based on the readiness to act, even when physical manipulation is impossible.

Life-space mobility in Parkinson's disease: Associations with motor and non-motor symptoms.

Science.gov (United States)

Rantakokko, Merja; Iwarsson, Susanne; Slaug, Björn; Nilsson, Maria H

2018-04-10

To describe life-space mobility and explore associations of motor and non-motor symptoms with life-space mobility in people with Parkinson's disease (PD). 164 community-dwelling persons with PD (mean age 71.6 years, 64.6% men) received a postal survey and a subsequent home visit. Motor assessments included perceived walking difficulties (Walk-12G), mobility (Timed Up and Go test), motor symptoms (UPDRS-III) and freezing of gait (item 3, FOG-Qsa). Non-motor symptoms included depressive symptoms (GDS-15), pain, fatigue (NHP-EN) and global cognition (MoCA). Life-space mobility was assessed with the life-space assessment (LSA). Calculations included composite score (range 0-120; higher indicating better life-space mobility), independent life-space (range 0-5), assisted life-space (range 0-5), and maximal life-space (range 0-5). Associations were analyzed with linear regression models, adjusted for age, sex, and PD severity (Hoehn and Yahr). Mean life-space mobility score was 72.3 (SD 28.8). Almost all participants (90 %) reached the highest life-space level (beyond town). Half of these reached this level independently, while one-third were unable to move outside their bedroom without assistive devices or personal help. When adjusted for confounders, depressive symptoms, pain, and perceived walking difficulties was negatively associated with life-space mobility. In the multivariable model, only perceived walking difficulties was associated with life-space mobility. Our findings indicate that perceived walking difficulties should be targeted to maintain or improve life-space mobility in people with PD. Depressive symptoms and pain may also merit consideration. More research is needed to elucidate the role of environmental and personal factors for life-space mobility in PD.

Towards a molecular understanding of the apicomplexan actin motor: on a road to novel targets for malaria remedies?

Energy Technology Data Exchange (ETDEWEB)

Kumpula, Esa-Pekka [University of Oulu, PO Box 3000, 90014 Oulu (Finland); Helmholtz Centre for Infection Research, Notkestrasse 85, 22607 Hamburg (Germany); German Electron Synchrotron, Notkestrasse 85, 22607 Hamburg (Germany); Kursula, Inari, E-mail: inari.kursula@helmholtz-hzi.de [University of Oulu, PO Box 3000, 90014 Oulu (Finland); Helmholtz Centre for Infection Research, Notkestrasse 85, 22607 Hamburg (Germany); German Electron Synchrotron, Notkestrasse 85, 22607 Hamburg (Germany); University of Bergen, Jonas Lies vei 91, 5009 Bergen (Norway)

2015-04-16

In this review, current structural understanding of the apicomplexan glideosome and actin regulation is described. Apicomplexan parasites are the causative agents of notorious human and animal diseases that give rise to considerable human suffering and economic losses worldwide. The most prominent parasites of this phylum are the malaria-causing Plasmodium species, which are widespread in tropical and subtropical regions, and Toxoplasma gondii, which infects one third of the world’s population. These parasites share a common form of gliding motility which relies on an actin–myosin motor. The components of this motor and the actin-regulatory proteins in Apicomplexa have unique features compared with all other eukaryotes. This, together with the crucial roles of these proteins, makes them attractive targets for structure-based drug design. In recent years, several structures of glideosome components, in particular of actins and actin regulators from apicomplexan parasites, have been determined, which will hopefully soon allow the creation of a complete molecular picture of the parasite actin–myosin motor and its regulatory machinery. Here, current knowledge of the function of this motor is reviewed from a structural perspective.

Studies of viral DNA packaging motors with optical tweezers: a comparison of motor function in bacteriophages φ29, λ, and T4

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Smith, Douglas E.; Fuller, Derek N.; Raymer, Dorian M.; Rickgauer, Peter; Grimes, Shelley; Jardine, Paul J.; Anderson, Dwight L.; Catalano, Carlos E.; Kottadiel, Vishal; Rao, Venigalla B.

2007-09-01

A key step in the assembly of many viruses is the packaging of double-stranded DNA into a viral procapsid (an empty protein shell) by the action of an ATP-powered portal motor complex. We have developed methods to measure the packaging of single DNA molecules into single viral proheads in real time using optical tweezers. We can measure DNA binding and initiation of translocation, the DNA translocation dynamics, and the filling of the capsid against resisting forces. In addition to studying bacteriophage φ29, we have recently extended these methods to study the E. coli bacteriophages λ and T4, two important model systems in molecular biology. The three systems have different capsid sizes/shapes, genome lengths, and biochemical and structural differences in their packaging motors. Here, we compare and contrast these three systems. We find that all three motors translocate DNA processively and generate very large forces, each exceeding 50 piconewtons, ~20x higher force than generated by the skeletal muscle myosin 2 motor. This high force generation is required to overcome the forces resisting the confinement of the stiff, highly charged DNA at high density within the viral capsids. However, there are also striking differences between the three motors: they exhibit different DNA translocation rates, degrees of static and dynamic disorder, responses to load, and pausing and slipping dynamics.

Myosin 1g Contributes to CD44 Adhesion Protein and Lipid Rafts Recycling and Controls CD44 Capping and Cell Migration in B Lymphocytes

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Orestes López-Ortega

2017-12-01

Full Text Available Cell migration and adhesion are critical for immune system function and involve many proteins, which must be continuously transported and recycled in the cell. Recycling of adhesion molecules requires the participation of several proteins, including actin, tubulin, and GTPases, and of membrane components such as sphingolipids and cholesterol. However, roles of actin motor proteins in adhesion molecule recycling are poorly understood. In this study, we identified myosin 1g as one of the important motor proteins that drives recycling of the adhesion protein CD44 in B lymphocytes. We demonstrate that the lack of Myo1g decreases the cell-surface levels of CD44 and of the lipid raft surrogate GM1. In cells depleted of Myo1g, the recycling of CD44 was delayed, the delay seems to be caused at the level of formation of recycling complex and entry into recycling endosomes. Moreover, a defective lipid raft recycling in Myo1g-deficient cells had an impact both on the capping of CD44 and on cell migration. Both processes required the transportation of lipid rafts to the cell surface to deliver signaling components. Furthermore, the extramembrane was essential for cell expansion and remodeling of the plasma membrane topology. Therefore, Myo1g is important during the recycling of lipid rafts to the membrane and to the accompanied proteins that regulate plasma membrane plasticity. Thus, Myosin 1g contributes to cell adhesion and cell migration through CD44 recycling in B lymphocytes.

Myosin light chain kinase phosphorylation in tracheal smooth muscle

International Nuclear Information System (INIS)

Stull, J.T.; Hsu, L.C.; Tansey, M.G.; Kamm, K.E.

1990-01-01

Purified myosin light chain kinase from smooth muscle is phosphorylated by cyclic AMP-dependent protein kinase, protein kinase C, and the multifunctional calmodulin-dependent protein kinase II. Because phosphorylation in a specific site (site A) by any one of these kinases desensitizes myosin light chain kinase to activation by Ca2+/calmodulin, kinase phosphorylation could play an important role in regulating smooth muscle contractility. This possibility was investigated in 32 P-labeled bovine tracheal smooth muscle. Treatment of tissues with carbachol, KCl, isoproterenol, or phorbol 12,13-dibutyrate increased the extent of kinase phosphorylation. Six primary phosphopeptides (A-F) of myosin light chain kinase were identified. Site A was phosphorylated to an appreciable extent only with carbachol or KCl, agents which contract tracheal smooth muscle. The extent of site A phosphorylation correlated to increases in the concentration of Ca2+/calmodulin required for activation. These results show that cyclic AMP-dependent protein kinase and protein kinase C do not affect smooth muscle contractility by phosphorylating site A in myosin light chain kinase. It is proposed that phosphorylation of myosin light chain kinase in site A in contracting tracheal smooth muscle may play a role in the reported desensitization of contractile elements to activation by Ca2+

Covalent and non-covalent chemical engineering of actin for biotechnological applications.

Science.gov (United States)

Kumar, Saroj; Mansson, Alf

2017-11-15

The cytoskeletal filaments are self-assembled protein polymers with 8-25nm diameters and up to several tens of micrometres length. They have a range of pivotal roles in eukaryotic cells, including transportation of intracellular cargoes (primarily microtubules with dynein and kinesin motors) and cell motility (primarily actin and myosin) where muscle contraction is one example. For two decades, the cytoskeletal filaments and their associated motor systems have been explored for nanotechnological applications including miniaturized sensor systems and lab-on-a-chip devices. Several developments have also revolved around possible exploitation of the filaments alone without their motor partners. Efforts to use the cytoskeletal filaments for applications often require chemical or genetic engineering of the filaments such as specific conjugation with fluorophores, antibodies, oligonucleotides or various macromolecular complexes e.g. nanoparticles. Similar conjugation methods are also instrumental for a range of fundamental biophysical studies. Here we review methods for non-covalent and covalent chemical modifications of actin filaments with focus on critical advantages and challenges of different methods as well as critical steps in the conjugation procedures. We also review potential uses of the engineered actin filaments in nanotechnological applications and in some key fundamental studies of actin and myosin function. Finally, we consider possible future lines of investigation that may be addressed by applying chemical conjugation of actin in new ways. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

The "handwriting brain": a meta-analysis of neuroimaging studies of motor versus orthographic processes.

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Planton, Samuel; Jucla, Mélanie; Roux, Franck-Emmanuel; Démonet, Jean-François

2013-01-01

Handwriting is a modality of language production whose cerebral substrates remain poorly known although the existence of specific regions is postulated. The description of brain damaged patients with agraphia and, more recently, several neuroimaging studies suggest the involvement of different brain regions. However, results vary with the methodological choices made and may not always discriminate between "writing-specific" and motor or linguistic processes shared with other abilities. We used the "Activation Likelihood Estimate" (ALE) meta-analytical method to identify the cerebral network of areas commonly activated during handwriting in 18 neuroimaging studies published in the literature. Included contrasts were also classified according to the control tasks used, whether non-specific motor/output-control or linguistic/input-control. These data were included in two secondary meta-analyses in order to reveal the functional role of the different areas of this network. An extensive, mainly left-hemisphere network of 12 cortical and sub-cortical areas was obtained; three of which were considered as primarily writing-specific (left superior frontal sulcus/middle frontal gyrus area, left intraparietal sulcus/superior parietal area, right cerebellum) while others related rather to non-specific motor (primary motor and sensorimotor cortex, supplementary motor area, thalamus and putamen) or linguistic processes (ventral premotor cortex, posterior/inferior temporal cortex). This meta-analysis provides a description of the cerebral network of handwriting as revealed by various types of neuroimaging experiments and confirms the crucial involvement of the left frontal and superior parietal regions. These findings provide new insights into cognitive processes involved in handwriting and their cerebral substrates. Copyright © 2013 Elsevier Ltd. All rights reserved.

Myosin content of individual human muscle fibers isolated by laser capture microdissection.

Science.gov (United States)

Stuart, Charles A; Stone, William L; Howell, Mary E A; Brannon, Marianne F; Hall, H Kenton; Gibson, Andrew L; Stone, Michael H

2016-03-01

Muscle fiber composition correlates with insulin resistance, and exercise training can increase slow-twitch (type I) fibers and, thereby, mitigate diabetes risk. Human skeletal muscle is made up of three distinct fiber types, but muscle contains many more isoforms of myosin heavy and light chains, which are coded by 15 and 11 different genes, respectively. Laser capture microdissection techniques allow assessment of mRNA and protein content in individual fibers. We found that specific human fiber types contain different mixtures of myosin heavy and light chains. Fast-twitch (type IIx) fibers consistently contained myosin heavy chains 1, 2, and 4 and myosin light chain 1. Type I fibers always contained myosin heavy chains 6 and 7 (MYH6 and MYH7) and myosin light chain 3 (MYL3), whereas MYH6, MYH7, and MYL3 were nearly absent from type IIx fibers. In contrast to cardiomyocytes, where MYH6 (also known as α-myosin heavy chain) is seen solely in fast-twitch cells, only slow-twitch fibers of skeletal muscle contained MYH6. Classical fast myosin heavy chains (MHC1, MHC2, and MHC4) were present in variable proportions in all fiber types, but significant MYH6 and MYH7 expression indicated slow-twitch phenotype, and the absence of these two isoforms determined a fast-twitch phenotype. The mixed myosin heavy and light chain content of type IIa fibers was consistent with its role as a transition between fast and slow phenotypes. These new observations suggest that the presence or absence of MYH6 and MYH7 proteins dictates the slow- or fast-twitch phenotype in skeletal muscle. Copyright © 2016 the American Physiological Society.

RUNX1-induced silencing of non-muscle myosin heavy chain IIB contributes to megakaryocyte polyploidization.

Science.gov (United States)

Lordier, Larissa; Bluteau, Dominique; Jalil, Abdelali; Legrand, Céline; Pan, Jiajia; Rameau, Philippe; Jouni, Dima; Bluteau, Olivier; Mercher, Thomas; Leon, Catherine; Gachet, Christian; Debili, Najet; Vainchenker, William; Raslova, Hana; Chang, Yunhua

2012-03-06

Megakaryocytes are unique mammalian cells that undergo polyploidization (endomitosis) during differentiation, leading to an increase in cell size and protein production that precedes platelet production. Recent evidence demonstrates that endomitosis is a consequence of a late failure in cytokinesis associated with a contractile ring defect. Here we show that the non-muscle myosin IIB heavy chain (MYH10) is expressed in immature megakaryocytes and specifically localizes in the contractile ring. MYH10 downmodulation by short hairpin RNA increases polyploidization by inhibiting the return of 4N cells to 2N, but other regulators, such as of the G1/S transition, might regulate further polyploidization of the 4N cells. Conversely, re-expression of MYH10 in the megakaryocytes prevents polyploidization and the transition of 2N to 4N cells. During polyploidization, MYH10 expression is repressed by the major megakaryocyte transcription factor RUNX1. Thus, RUNX1-mediated silencing of MYH10 is required for the switch from mitosis to endomitosis, linking polyploidization with megakaryocyte differentiation.

Myosin VIII regulates protonemal patterning and developmental timing in the moss Physcomitrella patens.

Science.gov (United States)

Wu, Shu-Zon; Ritchie, Julie A; Pan, Ai-Hong; Quatrano, Ralph S; Bezanilla, Magdalena

2011-09-01

Plants have two classes of myosins. While recent work has focused on class XI myosins showing that myosin XI is responsible for organelle motility and cytoplasmic streaming, much less is known about the role of myosin VIII in plant growth and development. We have used a combination of RNAi and insertional knockouts to probe myosin VIII function in the moss Physcomitrella patens. We isolated Δmyo8ABCDE plants demonstrating that myosin VIII is not required for plant viability. However, myosin VIII mutants are smaller than wild-type plants in part due to a defect in cell size. Additionally, Δmyo8ABCDE plants produce more side branches and form gametophores much earlier than wild-type plants. In the absence of nutrient media, Δmyo8ABCDE plants exhibit significant protonemal patterning defects, including highly curved protonemal filaments, morphologically defective side branches, as well as an increase in the number of branches. Exogenous auxin partially rescues protonemal defects in Δmyo8ABCDE plants grown in the absence of nutrients. This result, together with defects in protonemal branching, smaller caulonemal cells, and accelerated development in the Δmyo8ABCDE plants, suggests that myosin VIII is involved in hormone homeostasis in P. patens.

Sentence processing: linking language to motor chains

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Fabian Chersi

2010-05-01

Full Text Available A growing body of evidence in cognitive science and neuroscience is pointing towards the existence of a deep interconnection between cognition, perception and action. According to this embodied perspective language understanding is based on a mental simulation process involving a sensory-motor matching system known as the mirror neuron system. However, the precise dynamics underling the relation between language and action are not yet well understood. In fact, experimental studies are not always coherent as some report that language processing interferes with action execution while others find facilitation. In this work we present a detailed neural network model capable of reproducing experimentally observed influences of the processing of action-related sentences on the execution of motor sequences. The proposed model is based on three main points. The first is that the processing of action-related sentences causes the resonance of motor and mirror neurons encoding the corresponding actions. The second is that there exists a varying degree of crosstalk between neuronal populations depending on whether they encode the same motor act, the same effector or the same action-goal. The third is the fact that neuronal populations’ internal dynamics, which results from the combination of multiple processes taking place at different time scales, can facilitate or interfere with successive activations of the same or of partially overlapping pools.

Structural insight into the UNC-45–myosin complex

DEFF Research Database (Denmark)

Fratev, Filip; Jonsdottir, Svava Osk; Pajeva, Ilza

2013-01-01

The UNC-45 chaperone protein interacts with and affects the folding, stability, and the ATPase activity of myosins. It plays a critical role in the cardiomyopathy development and in the breast cancer tumor growth. Here we propose the first structural model of the UNC-45–myosin complex using various...... is mainly stabilized by electrostatic interactions. Remarkably, the contact surface area is similar to that of the myosinactin complex. A significant interspecies difference in the myosin binding epitope is observed. Our results reveal the structural basis of MYH7 exons 15–16 hypertrophic cardiomyopathy...... mutations and provide directions for drug targeting. © 2013 Wiley Periodicals, Inc....

Non-viral gene therapy that targets motor neurons in vivo

Directory of Open Access Journals (Sweden)

Mary-Louise eRogers

2014-10-01

Full Text Available A major challenge in neurological gene therapy is safe delivery of transgenes to sufficient cell numbers from the circulation or periphery. This is particularly difficult for diseases involving spinal cord motor neurons such as amyotrophic lateral sclerosis (ALS. We have examined the feasibility of non-viral gene delivery to spinal motor neurons from intraperitoneal injections of plasmids carried by ‘immunogene’ nanoparticles targeted for axonal retrograde transport using antibodies. PEGylated polyethylenimine (PEI-PEG12 as DNA carrier was conjugated to an antibody (MLR2 to the neurotrophin receptor p75 (p75NTR. We used a plasmid (pVIVO2 designed for in vivo gene delivery that produces minimal immune responses, has improved nuclear entry into post mitotic cells and also expresses green fluorescent protein (GFP. MLR2-PEI-PEG12 carried pVIVO2 and was specific for mouse motor neurons in mixed cultures containing astrocytes. While only 8% of motor neurons expressed GFP 72 h post transfection in vitro, when the immunogene was given intraperitonealy to neonatal C57BL/6J mice GFP specific motor neuron expression was observed in 25.4% of lumbar, 18.3% of thoracic and 17.0 % of cervical motor neurons, 72 h post transfection. PEI-PEG12 carrying pVIVO2 by itself did not transfect motor neurons in vivo, demonstrating the need for specificity via the p75NTR antibody MLR2. This is the first time that specific transfection of spinal motor neurons has been achieved from peripheral delivery of plasmid DNA as part of a non-viral gene delivery agent. These results stress the specificity and feasibility of immunogene delivery targeted for p75NTR expressing motor neurons, but suggests that further improvements are required to increase the transfection efficiency of motor neurons in vivo.

Three-dimensional stochastic model of actin–myosin binding in the sarcomere lattice

Energy Technology Data Exchange (ETDEWEB)

Mijailovich, Srboljub M.; Kayser-Herold, Oliver; Stojanovic, Boban; Nedic, Djordje; Irving, Thomas C.; Geeves, MA (Harvard); (IIT); (U. Kent); (Kragujevac)

2016-11-18

The effect of molecule tethering in three-dimensional (3-D) space on bimolecular binding kinetics is rarely addressed and only occasionally incorporated into models of cell motility. The simplest system that can quantitatively determine this effect is the 3-D sarcomere lattice of the striated muscle, where tethered myosin in thick filaments can only bind to a relatively small number of available sites on the actin filament, positioned within a limited range of thermal movement of the myosin head. Here we implement spatially explicit actomyosin interactions into the multiscale Monte Carlo platform MUSICO, specifically defining how geometrical constraints on tethered myosins can modulate state transition rates in the actomyosin cycle. The simulations provide the distribution of myosin bound to sites on actin, ensure conservation of the number of interacting myosins and actin monomers, and most importantly, the departure in behavior of tethered myosin molecules from unconstrained myosin interactions with actin. In addition, MUSICO determines the number of cross-bridges in each actomyosin cycle state, the force and number of attached cross-bridges per myosin filament, the range of cross-bridge forces and accounts for energy consumption. At the macroscopic scale, MUSICO simulations show large differences in predicted force-velocity curves and in the response during early force recovery phase after a step change in length comparing to the two simplest mass action kinetic models. The origin of these differences is rooted in the different fluxes of myosin binding and corresponding instantaneous cross-bridge distributions and quantitatively reflects a major flaw of the mathematical description in all mass action kinetic models. Consequently, this new approach shows that accurate recapitulation of experimental data requires significantly different binding rates, number of actomyosin states, and cross-bridge elasticity than typically used in mass action kinetic models to

The expression of myosin genes in developing skeletal muscle in the mouse embryo

International Nuclear Information System (INIS)

Lyons, G.E.; Ontell, M.; Cox, R.; Sassoon, D.; Buckingham, M.

1990-01-01

Using in situ hybridization, we have investigated the temporal sequence of myosin gene expression in the developing skeletal muscle masses of mouse embryos. The probes used were isoform-specific, 35S-labeled antisense cRNAs to the known sarcomeric myosin heavy chain and myosin alkali light chain gene transcripts. Results showed that both cardiac and skeletal myosin heavy chain and myosin light chain mRNAs were first detected between 9 and 10 d post coitum (p.c.) in the myotomes of the most rostral somites. Myosin transcripts appeared in more caudal somites at later stages in a developmental gradient. The earliest myosin heavy chain transcripts detected code for the embryonic skeletal (MHCemb) and beta-cardiac (MHC beta) isoforms. Perinatal myosin heavy chain (MHCpn) transcripts begin to accumulate at 10.5 d p.c., which is much earlier than previously reported. At this stage, MHCemb is the major MHC transcript. By 12.5 d p.c., MHCpn and MHCemb mRNAs are present to an equal extent, and by 15.5 d p.c. the MHCpn transcript is the major MHC mRNA detected. Cardiac MHC beta transcripts are always present as a minor component. In contrast, the cardiac MLC1A mRNA is initially more abundant than that encoding the skeletal MLC1F isoform. By 12.5 d p.c. the two MLC mRNAs are present at similar levels, and by 15.5 d p.c., MLC1F is the predominant MLC transcript detected. Transcripts for the ventricular/slow (MLC1V) and another fast skeletal myosin light chain (MLC3F) are not detected in skeletal muscle before 15 d p.c., which marks the beginning of the fetal stage of muscle development. This is the first stage at which we can detect differences in expression of myosin genes between developing muscle fibers. We conclude that, during the development of the myotome and body wall muscles, different myosin genes follow independent patterns of activation and acculumation

BMP-2 Overexpression Augments Vascular Smooth Muscle Cell Motility by Upregulating Myosin Va via Erk Signaling

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Ming Zhang

2014-01-01

Full Text Available Background. The disruption of physiologic vascular smooth muscle cell (VSMC migration initiates atherosclerosis development. The biochemical mechanisms leading to dysfunctional VSMC motility remain unknown. Recently, cytokine BMP-2 has been implicated in various vascular physiologic and pathologic processes. However, whether BMP-2 has any effect upon VSMC motility, or by what manner, has never been investigated. Methods. VSMCs were adenovirally transfected to genetically overexpress BMP-2. VSMC motility was detected by modified Boyden chamber assay, confocal time-lapse video assay, and a colony wounding assay. Gene chip array and RT-PCR were employed to identify genes potentially regulated by BMP-2. Western blot and real-time PCR detected the expression of myosin Va and the phosphorylation of extracellular signal-regulated kinases 1/2 (Erk1/2. Immunofluorescence analysis revealed myosin Va expression locale. Intracellular Ca2+ oscillations were recorded. Results. VSMC migration was augmented in VSMCs overexpressing BMP-2 in a dose-dependent manner. siRNA-mediated knockdown of myosin Va inhibited VSMC motility. Both myosin Va mRNA and protein expression significantly increased after BMP-2 administration and were inhibited by Erk1/2 inhibitor U0126. BMP-2 induced Ca2+ oscillations, generated largely by a “cytosolic oscillator”. Conclusion. BMP-2 significantly increased VSMCs migration and myosin Va expression, via the Erk signaling pathway and intracellular Ca2+ oscillations. We provide additional insight into the pathophysiology of atherosclerosis, and inhibition of BMP-2-induced myosin Va expression may represent a potential therapeutic strategy.

Porters versus rowers: a unified stochastic model of motor proteins.

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Leibler, S; Huse, D A

1993-06-01

We present a general phenomenological theory for chemical to mechanical energy transduction by motor enzymes which is based on the classical "tight-coupling" mechanism. The associated minimal stochastic model takes explicitly into account both ATP hydrolysis and thermal noise effects. It provides expressions for the hydrolysis rate and the sliding velocity, as functions of the ATP concentration and the number of motor enzymes. It explains in a unified way many results of recent in vitro motility assays. More importantly, the theory provides a natural classification scheme for the motors: it correlates the biochemical and mechanical differences between "porters" such as cellular kinesins or dyneins, and "rowers" such as muscular myosins or flagellar dyneins.

Carboxyl-terminal-dependent recruitment of nonmuscle myosin II to megakaryocyte contractile ring during polyploidization.

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Badirou, Idinath; Pan, Jiajia; Legrand, Céline; Wang, Aibing; Lordier, Larissa; Boukour, Siham; Roy, Anita; Vainchenker, William; Chang, Yunhua

2014-10-16

Endomitosis is a unique megakaryocyte (MK) differentiation process that is the consequence of a late cytokinesis failure associated with a contractile ring defect. Evidence from in vitro studies has revealed the distinct roles of 2 nonmuscle myosin IIs (NMIIs) on MK endomitosis: only NMII-B (MYH10), but not NMII-A (MYH9), is localized in the MK contractile ring and implicated in mitosis/endomitosis transition. Here, we studied 2 transgenic mouse models in which nonmuscle myosin heavy chain (NMHC) II-A was genetically replaced either by II-B or by a chimeric NMHCII that combined the head domain of II-A with the rod and tail domains of II-B. This study provides in vivo evidence on the specific role of NMII-B on MK polyploidization. It demonstrates that the carboxyl-terminal domain of the heavy chains determines myosin II localization to the MK contractile ring and is responsible for the specific role of NMII-B in MK polyploidization.

Non-Muscle Myosin II Isoforms Have Different Functions in Matrix Rearrangement by MDA-MB-231 Cells.

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Bridget Hindman

Full Text Available The role of a stiffening extra-cellular matrix (ECM in cancer progression is documented but poorly understood. Here we use a conditioning protocol to test the role of nonmuscle myosin II isoforms in cell mediated ECM arrangement using collagen constructs seeded with breast cancer cells expressing shRNA targeted to either the IIA or IIB heavy chain isoform. While there are several methods available to measure changes in the biophysical characteristics of the ECM, we wanted to use a method which allows for the measurement of global stiffness changes as well as a dynamic response from the sample over time. The conditioning protocol used allows the direct measurement of ECM stiffness. Using various treatments, it is possible to determine the contribution of various construct and cellular components to the overall construct stiffness. Using this assay, we show that both the IIA and IIB isoforms are necessary for efficient matrix remodeling by MDA-MB-231 breast cancer cells, as loss of either isoform changes the stiffness of the collagen constructs as measured using our conditioning protocol. Constructs containing only collagen had an elastic modulus of 0.40 Pascals (Pa, parental MDA-MB-231 constructs had an elastic modulus of 9.22 Pa, while IIA and IIB KD constructs had moduli of 3.42 and 7.20 Pa, respectively. We also calculated the cell and matrix contributions to the overall sample elastic modulus. Loss of either myosin isoform resulted in decreased cell stiffness, as well as a decrease in the stiffness of the cell-altered collagen matrices. While the total construct modulus for the IIB KD cells was lower than that of the parental cells, the IIB KD cell-altered matrices actually had a higher elastic modulus than the parental cell-altered matrices (4.73 versus 4.38 Pa. These results indicate that the IIA and IIB heavy chains play distinct and non-redundant roles in matrix remodeling.

Compositional and expression analyses of the glideosome during the Plasmodium life cycle reveal an additional myosin light chain required for maximum motility.

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Green, Judith L; Wall, Richard J; Vahokoski, Juha; Yusuf, Noor A; Ridzuan, Mohd A Mohd; Stanway, Rebecca R; Stock, Jessica; Knuepfer, Ellen; Brady, Declan; Martin, Stephen R; Howell, Steven A; Pires, Isa P; Moon, Robert W; Molloy, Justin E; Kursula, Inari; Tewari, Rita; Holder, Anthony A

2017-10-27

Myosin A (MyoA) is a Class XIV myosin implicated in gliding motility and host cell and tissue invasion by malaria parasites. MyoA is part of a membrane-associated protein complex called the glideosome, which is essential for parasite motility and includes the MyoA light chain myosin tail domain-interacting protein (MTIP) and several glideosome-associated proteins (GAPs). However, most studies of MyoA have focused on single stages of the parasite life cycle. We examined MyoA expression throughout the Plasmodium berghei life cycle in both mammalian and insect hosts. In extracellular ookinetes, sporozoites, and merozoites, MyoA was located at the parasite periphery. In the sexual stages, zygote formation and initial ookinete differentiation precede MyoA synthesis and deposition, which occurred only in the developing protuberance. In developing intracellular asexual blood stages, MyoA was synthesized in mature schizonts and was located at the periphery of segmenting merozoites, where it remained throughout maturation, merozoite egress, and host cell invasion. Besides the known GAPs in the malaria parasite, the complex included GAP40, an additional myosin light chain designated essential light chain (ELC), and several other candidate components. This ELC bound the MyoA neck region adjacent to the MTIP-binding site, and both myosin light chains co-located to the glideosome. Co-expression of MyoA with its two light chains revealed that the presence of both light chains enhances MyoA-dependent actin motility. In conclusion, we have established a system to study the interplay and function of the three glideosome components, enabling the assessment of inhibitors that target this motor complex to block host cell invasion. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Ala397Asp mutation of myosin VIIA gene segregating in a Spanish family with type-Ib Usher syndrome.

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Espinós, C; Millán, J M; Sánchez, F; Beneyto, M; Nájera, C

1998-06-01

In the current study, 12 Spanish families affected by type-I Usher syndrome, that was previously linked to chromosome 11q, were screened for the presence of mutations in the N-terminal coding portion of the motor domain of the myosin VIIA gene by single-strand conformation polymorphism analysis of the first 14 exons. A mutation (Ala397Asp) segregating with the disease was identified, and several polymorphisms were also detected. It is presumed that the other USHIB mutations in these families could be located in the unscreened regions of the gene.

The Non-motor Features of Essential Tremor: A Primary Disease Feature or Just a Secondary Phenomenon?

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Ketan Jhunjhunwala

2014-08-01

Full Text Available Essential tremor (ET is a pathologically heterogeneous neurodegenerative disorder with both motor and increasingly recognized non-motor features. It is debated whether the non-motor manifestations in ET result from widespread neurodegeneration or are merely secondary to impaired motor functions and decreased quality of life due to tremor. It is important to review these features to determine how to best treat the non-motor symptoms of patients and to understand the basic pathophysiology of the disease and develop appropriate pharmacotherapies. In this review, retrospective and prospective clinical studies were critically analyzed to identify possible correlations between the severities of non-motor features and tremor. We speculated that if such a correlation existed, the non-motor features were likely to be secondary to tremor. According to the current literature, the deficits in executive function, attention, concentration, and memory often observed in ET are likely to be a primary manifestation of the disease. It has also been documented that patients with ET often exhibit characteristic personality traits. However, it remains to be determined whether the other non-motor features often seen in ET, such as anxiety, depression, and sleep disturbances are primary or secondary to motor manifestations of ET and subsequent poor quality of life. Finally, there is evidence that patients with ET can also have impaired color vision, disturbances of olfaction, and hearing impairments, though there are few studies in these areas. Further investigations of large cohorts of patients with ET are required to understand the prevalence, nature, and true significance of the non-motor features in ET.

Nonmuscle myosin IIB as a therapeutic target for the prevention of relapse to methamphetamine use

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Young, Erica J.; Blouin, Ashley M.; Briggs, Sherri B.; Sillivan, Stephanie E.; Lin, Li; Cameron, Michael D.; Rumbaugh, Gavin; Miller, Courtney A.

2015-01-01

Memories associated with drug use increase vulnerability to relapse in substance use disorder (SUD) and there are no pharmacotherapies for the prevention of relapse. Previously, we reported a promising finding that storage of memories associated with methamphetamine (METH), but not memories for fear or food reward, is vulnerable to disruption by actin depolymerization in the basolateral amygdala complex (BLC). However, actin is not a viable therapeutic target because of its numerous functions throughout the body. Here we report the discovery of a viable therapeutic target, nonmuscle myosin II (NMIIB), a molecular motor that supports memory by directly driving synaptic actin polymerization. A single intra-BLC treatment with Blebbistatin, a small molecule inhibitor of class II myosin isoforms, including NMIIB, produced a long-lasting disruption of context-induced drug seeking (at least 30 days). Further, post-consolidation genetic knockdown of Myh10, the heavy chain of the most highly expressed NMII in the BLC, was sufficient to produce METH-associated memory loss. Blebbistatin was found to be highly brain penetrant. A single systemic injection of the compound selectively disrupted the storage of METH-associated memory and reversed the accompanying increase in BLC spine density. This effect was specific to METH-associated memory, as it had no effect on an auditory fear memory. The effect was also independent of retrieval, as METH-associated memory was disrupted twenty-four hours after a single systemic injection of Blebbistatin delivered in the home cage. Together, these results argue for the further development of small molecule inhibitors of nonmuscle myosin II as potential therapeutics for the prevention of SUD relapse triggered by drug associations. PMID:26239291

Adult fast myosin pattern and Ca2+-induced slow myosin pattern in primary skeletal muscle culture

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Kubis, Hans-Peter; Haller, Ernst-August; Wetzel, Petra; Gros, Gerolf

1997-01-01

A primary muscle cell culture derived from newborn rabbit muscle and growing on microcarriers in suspension was established. When cultured for several weeks, the myotubes in this model develop the completely adult pattern of fast myosin light and heavy chains. When Ca2+ ionophore is added to the culture medium on day 11, raising intracellular [Ca2+] about 10-fold, the myotubes develop to exhibit properties of an adult slow muscle by day 30, expressing slow myosin light as well as heavy chains, elevated citrate synthase, and reduced lactate dehydrogenase. The remarkable plasticity of these myotubes becomes apparent, when 8 days after withdrawal of the ionophore a marked slow-to-fast transition, as judged from the expression of isomyosins and metabolic enzymes, occurs. PMID:9108130

Relationship between pain and motor and non-motor symptoms in Parkinson's disease.

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Defazio, G; Antonini, A; Tinazzi, M; Gigante, A F; Pietracupa, S; Pellicciari, R; Bloise, M; Bacchin, R; Marcante, A; Fabbrini, G; Berardelli, A

2017-07-01

Although female gender, depressive symptoms and medical conditions predisposing to pain are more common in patients with Parkinson's disease (PD) with pain, no study has yet explored the relationship between pain and other non-motor symptoms (NMS). A total of 321 consecutive patients with PD [190 men/131 women aged 68.3 (SD 9.2) years] attending four Italian movement disorder clinics were studied. Demographic/clinical data were obtained by a standardized interview and the NMS scale. The association of pain with motor and NMS was assessed by multivariable logistic regression models. At the time of the study, 180 patients with PD (56%) reported chronic pain that, in most cases, was described as being muscular or arthralgic pain. Pain preceded the onset of motor signs in 36/180 patients. In the main-effect model, factors independently associated with pain were female sex [odds ratio (OR), 2.1; P = 0.01], medical conditions predisposing to pain (OR, 2.9; P motor complications (OR, 4.7; P = 0.04) and NMS belonging to the sleep/fatigue (OR, 1.6; P = 0.04) and mood/cognition (OR, 1.6; P = 0.03) domains. Most explanatory variables in the multivariable analysis were similarly distributed in patients in whom pain may have been related to PD or to a cause other than PD. We confirm that pain in PD is more frequent in women and in subjects with medical conditions predisposing to painful symptoms. Moreover, this strengthens the association between pain and motor severity measures and NMS domains, particularly sleep and mood disturbances. © 2017 EAN.

System of business-processes management at motor-transport enterprise

OpenAIRE

Коgut, Y.

2010-01-01

The place of the system of business-processes management at motor-transport enterprise in the general system of management of the enterprise has been substantiated. The subsystems of strategic management, business-processes management of strategic orientation and current activity, processes of enterprise functioning management have been marked out. The system of motor-transport enterprise business-processes management has been formed, which, unlike the existing ones, is based on the system-cy...

The role of the myosin ATPase activity in adaptive thermogenesis by skeletal muscle.

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Cooke, Roger

2011-03-01

Resting skeletal muscle is a major contributor to adaptive thermogenesis, i.e., the thermogenesis that changes in response to exposure to cold or to overfeeding. The identification of the "furnace" that is responsible for increased heat generation in resting muscle has been the subject of a number of investigations. A new state of myosin, the super relaxed state (SRX), with a very slow ATP turnover rate has recently been observed in skeletal muscle (Stewart et al. in Proc Natl Acad Sci USA 107:430-435, 2010). Inhibition of the myosin ATPase activity in the SRX was suggested to be caused by binding of the myosin head to the core of the thick filament in a structural motif identified earlier by electron microscopy. To be compatible with the basal metabolic rate observed in vivo for resting muscle, most myosin heads would have to be in the SRX. Modulation of the population of this state, relative to the normal relaxed state, was proposed to be a major contributor to adaptive thermogenesis in resting muscle. Transfer of only 20% of myosin heads from the SRX into the normal relaxed state would cause muscle thermogenesis to double. Phosphorylation of the myosin regulatory light chain was shown to transfer myosin heads from the SRX into the relaxed state, which would increase thermogenesis. In particular, thermogenesis by myosin has been proposed to play a role in the dissipation of calories during overfeeding. Up-regulation of muscle thermogenesis by pharmaceuticals that target the SRX would provide new approaches to the treatment of obesity or high blood sugar levels.

Non-retinotopic motor-visual recalibration to temporal lag

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Masaki eTsujita

2012-11-01

Full Text Available Temporal order judgment between the voluntary motor action and its perceptual feedback is important in distinguishing between a sensory feedback which is caused by observer’s own action and other stimulus, which are irrelevant to that action. Prolonged exposure to fixed temporal lag between motor action and visual feedback recalibrates motor-visual temporal relationship, and consequently shifts the point of subjective simultaneity (PSS. Previous studies on the audio-visual temporal recalibration without voluntary action revealed that both low and high level processing are involved. However, it is not clear how the low and high level processings affect the recalibration to constant temporal lag between voluntary action and visual feedback. This study examined retinotopic specificity of the motor-visual temporal recalibration. During the adaptation phase, observers repeatedly pressed a key, and visual stimulus was presented in left or right visual field with a fixed temporal lag (0 or 200 ms. In the test phase, observers performed a temporal order judgment for observer’s voluntary keypress and test stimulus, which was presented in the same as or opposite to the visual field in which the stimulus was presented in the adaptation phase. We found that the PSS was shifted toward the exposed lag in both visual fields. These results suggest that the low visual processing, which is retinotopically specific, has minor contribution to the multimodal adaptation, and that the adaptation to shift the PSS mainly depends upon the high level processing such as attention to specific properties of the stimulus.

Effects of BTS (N-benzyl-p-toluene sulphonamide), an inhibitor for myosin-actin interaction, on myofibrillogenesis in skeletal muscle cells in culture.

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Kagawa, Maiko; Sato, Naruki; Obinata, Takashi

2006-11-01

Actin filaments align around myosin filaments in the correct polarity and in a hexagonal arrangement to form cross-striated structures. It has been postulated that this myosin-actin interaction is important in the initial phase of myofibrillogenesis. It was previously demonstrated that an inhibitor of actin-myosin interaction, BDM (2,3-butanedione monoxime), suppresses myofibril formation in muscle cells in culture. However, further study showed that BDM also exerts several additional effects on living cells. In this study, we further examined the role of actin-myosin interaction in myofibril assembly in primary cultures of chick embryonic skeletal muscle by applying a more specific inhibitor, BTS (N-benzyl-p-toluene sulphonamide), of myosin ATPase and actin-myosin interaction. The assembly of sarcomeric structures from myofibrillar proteins was examined by immunocytochemical methods with the application of BTS to myotubes just after fusion. Addition of BTS (10-50 microM) significantly suppressed the organization of actin and myosin into cross-striated structures. BTS also interfered in the organization of alpha-actinin, C-protein (or MyBP-C), and connectin (or titin) into ordered striated structures, though the sensitivity was less. Moreover, when myotubes cultured in the presence of BTS were transferred to a control medium, sarcomeric structures were formed in 2-3 days, indicating that the inhibitory effect of BTS on myotubes is reversible. These results show that actin-myosin interaction plays a critical role in the process of myofibrillogenesis.

Demagnetization diagnosis in permanent magnet synchronous motors under non-stationary speed conditions

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Ruiz, Jordi-Roger Riba [EUETII, Dept. d' Enginyeria Electrica, Universitat Politecnica de Catalunya, Placa del Rei 15, 08700 Igualada, Barcelona (Spain); Garcia Espinosa, Antonio [Dept. d' Enginyeria Electrica, Universitat Politecnica de Catalunya C/Colom 1, 08222 Terrassa (Spain); Romeral, Luis; Cusido, Jordi [Dept. d' Enginyeria Electronica, Universitat Politecnica de Catalunya C/Colom 1, 08222 Terrassa (Spain)

2010-10-15

Permanent magnet synchronous motors (PMSMs) are applied in high performance positioning and variable speed applications because of their enhanced features with respect to other AC motor types. Fault detection and diagnosis of electrical motors for critical applications is an active field of research. However, much research remains to be done in the field of PMSM demagnetization faults, especially when running under non-stationary conditions. This paper presents a time-frequency method specifically focused to detect and diagnose demagnetization faults in PMSMs running under non-stationary speed conditions, based on the Hilbert Huang transform. The effectiveness of the proposed method is proven by means of experimental results. (author)

A parameter estimation for DC servo motor by using optimization process

International Nuclear Information System (INIS)

Arjoni Amir

2010-01-01

Modeling and simulation parameters of DC servo motor using Matlab Simulink software have been done. The objective to define the DC servo motor parameter estimation is to get DC servo motor parameter values (B, La, Ra, Km, J) which are significant value that can be used for actuation process of control systems. In the analysis of control systems DC the servo motor expressed by transfer function equation to make faster to be analyzed as a component of the actuator. To obtain the data model parameters and initial conditions of the DC servo motors is then carried out the processor modeling and simulation in which the DC servo motor combined with other components. To obtain preliminary data of the DC servo motor parameters as estimated venue, it is obtained from the data factory of the DC servo motor. The initial data parameters of the DC servo motor are applied for the optimization process by using nonlinear least square algorithm and minimize the cost function value so that the DC servo motors parameter values are obtained significantly. The result of the optimization process of the DC servo motor parameter values are B = 0.039881, J= 1.2608e-007, Km = 0.069648, La = 2.3242e-006 and Ra = 1.8837. (author)

Motor and non-motor circuitry activation induced by subthalamic nucleus deep brain stimulation (STN DBS) in Parkinson’s disease patients: Intraoperative fMRI for DBS

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Knight, Emily J.; Testini, Paola; Min, Hoon-Ki; Gibson, William S.; Gorny, Krzysztof R.; Favazza, Christopher P.; Felmlee, Joel P.; Kim, Inyong; Welker, Kirk M.; Clayton, Daniel A.; Klassen, Bryan T.; Chang, Su-youne; Lee, Kendall H.

2015-01-01

Objective To test the hypothesis suggested by previous studies that subthalamic nucleus (STN) deep brain stimulation (DBS) in patients with PD would affect the activity of both motor and non-motor networks, we applied intraoperative fMRI to patients receiving DBS. Patients and Methods Ten patients receiving STN DBS for PD underwent intraoperative 1.5T fMRI during high frequency stimulation delivered via an external pulse generator. The study was conducted between the dates of January 1, 2013 and September 30, 2014. Results We observed blood oxygen level dependent (BOLD) signal changes (FDR<.001) in the motor circuitry, including primary motor, premotor, and supplementary motor cortices, thalamus, pedunculopontine nucleus (PPN), and cerebellum, as well as in the limbic circuitry, including cingulate and insular cortices. Activation of the motor network was observed also after applying a Bonferroni correction (p<.001) to our dataset, suggesting that, across subjects, BOLD changes in the motor circuitry are more consistent compared to those occurring in the non-motor network. Conclusions These findings support the modulatory role of STN DBS on the activity of motor and non-motor networks, and suggest complex mechanisms at the basis of the efficacy of this treatment modality. Furthermore, these results suggest that, across subjects, BOLD changes in the motor circuitry are more consistent compared to those occurring in the non-motor network. With further studies combining the use of real time intraoperative fMRI with clinical outcomes in patients treated with DBS, functional imaging techniques have the potential not only to elucidate the mechanisms of DBS functioning, but also to guide and assist in the surgical treatment of patients affected by movement and neuropsychiatric disorders. PMID:26046412

Integrated motor drive and non-isolated battery charger based on the split-phase PM motors for plug-in vehicles

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Saeid Haghbin

2014-06-01

Full Text Available A novel integrated motor drive and non-isolated battery charger based on a split-phase permanent magnet (PM motor is presented and described for a plug-in vehicle. The motor windings are reconfigured by a relay for the traction and charging operation. In traction mode, the motor is like a normal three-phase motor, whereas in the charging mode, after windings reconnection, the system is a three-phase Boost rectifier. One important challenge to use the motor as three inductors in charger circuit is to have it in standstill during the battery charging. Based on the presented mathematical model of a split-phase PM motor, the zero-torque condition of the motor is explained which led to a proper windings reconnection for the charging. Simulation and experimental results of two separate practical systems are provided to verify the proposed integrated battery charger. Some practical limitations and design recommendations are provided to achieve a more realistic practical system.

Genetic deficiency of GABA differentially regulates respiratory and non-respiratory motor neuron development.

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Matthew J Fogarty

Full Text Available Central nervous system GABAergic and glycinergic synaptic activity switches from postsynaptic excitation to inhibition during the stage when motor neuron numbers are being reduced, and when synaptic connections are being established onto and by motor neurons. In mice this occurs between embryonic (E day 13 and birth (postnatal day 0. Our previous work on mice lacking glycinergic transmission suggested that altered motor neuron activity levels correspondingly regulated motor neuron survival and muscle innervation for all respiratory and non respiratory motor neuron pools, during this period of development [1]. To determine if GABAergic transmission plays a similar role, we quantified motor neuron number and the extent of muscle innervation in four distinct regions of the brain stem and spinal cord; hypoglossal, phrenic, brachial and lumbar motor pools, in mice lacking the enzyme GAD67. These mice display a 90% drop in CNS GABA levels ( [2]; this study. For respiratory-based motor neurons (hypoglossal and phrenic motor pools, we have observed significant drops in motor neuron number (17% decline for hypoglossal and 23% decline for phrenic and muscle innervations (55% decrease. By contrast for non-respiratory motor neurons of the brachial lateral motor column, we have observed an increase in motor neuron number (43% increase and muscle innervations (99% increase; however for more caudally located motor neurons within the lumbar lateral motor column, we observed no change in either neuron number or muscle innervation. These results show in mice lacking physiological levels of GABA, there are distinct regional changes in motor neuron number and muscle innervation, which appear to be linked to their physiological function and to their rostral-caudal position within the developing spinal cord. Our results also suggest that for more caudal (lumbar regions of the spinal cord, the effect of GABA is less influential on motor neuron development compared to

Impacts of dance on non-motor symptoms, participation, and quality of life in Parkinson disease and healthy older adults

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McNeely, ME; Duncan, RP; Earhart, GM

2015-01-01

Evidence indicates exercise is beneficial for motor and non-motor function in older adults and people with chronic diseases including Parkinson disease (PD). Dance may be a relevant form of exercise in PD and older adults due to social factors and accessibility. People with PD experience motor and non-motor symptoms, but treatments, interventions, and assessments often focus more on motor symptoms. Similar non-motor symptoms also occur in older adults. While it is well-known that dance may improve motor outcomes, it is less clear how dance affects non-motor symptoms. This review aims to describe the effects of dance interventions on non-motor symptoms in older adults and PD, highlights limitations of the literature, and identifies opportunities for future research. Overall, intervention parameters, study designs, and outcome measures differ widely, limiting comparisons across studies. Results are mixed in both populations, but evidence supports the potential for dance to improve mood, cognition, and quality of life in PD and healthy older adults. Participation and non-motor symptoms like sleep disturbances, pain, and fatigue have not been measured in older adults. Additional well-designed studies comparing dance and exercise interventions are needed to clarify the effects of dance on non-motor function and establish recommendations for these populations. PMID:26318265

Genes influenced by the non-muscle isoform of Myosin light chain kinase impact human cancer prognosis.

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Tong Zhou

Full Text Available The multifunctional non-muscle isoform of myosin light chain kinase (nmMLCK is critical to the rapid dynamic coordination of the cytoskeleton involved in cancer cell proliferation and migration. We identified 45 nmMLCK-influenced genes by bioinformatic filtering of genome-wide expression in wild type and nmMLCK knockout (KO mice exposed to preclinical models of murine acute inflammatory lung injury, pathologies that are well established to include nmMLCK as an essential participant. To determine whether these nmMLCK-influenced genes were relevant to human cancers, the 45 mouse genes were matched to 38 distinct human orthologs (M38 signature (GeneCards definition and underwent Kaplan-Meier survival analysis in training and validation cohorts. These studies revealed that in training cohorts, the M38 signature successfully identified cancer patients with poor overall survival in breast cancer (P<0.001, colon cancer (P<0.001, glioma (P<0.001, and lung cancer (P<0.001. In validation cohorts, the M38 signature demonstrated significantly reduced overall survival for high-score patients of breast cancer (P = 0.002, colon cancer (P = 0.035, glioma (P = 0.023, and lung cancer (P = 0.023. The association between M38 risk score and overall survival was confirmed by univariate Cox proportional hazard analysis of overall survival in the both training and validation cohorts. This study, providing a novel prognostic cancer gene signature derived from a murine model of nmMLCK-associated lung inflammation, strongly supports nmMLCK-involved pathways in tumor growth and progression in human cancers and nmMLCK as an attractive candidate molecular target in both inflammatory and neoplastic processes.

Non-primary motor areas in the human frontal lobe are connected directly to hand muscles.

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Teitti, S; Määttä, S; Säisänen, L; Könönen, M; Vanninen, R; Hannula, H; Mervaala, E; Karhu, J

2008-04-15

Structural studies in primates have shown that, in addition to the primary motor cortex (M1), premotor areas are a source of corticospinal tracts. The function of these putative corticospinal neuronal tracts in humans is still unclear. We found frontal non-primary motor areas (NPMAs), which react to targeted non-invasive magnetic pulses and activate peripheral muscles as fast as or even faster than those in M1. Hand muscle movements were observed in all our subjects about 20 ms after transcranial stimulation of the superior frontal gyrus (Brodmann areas 6 and 8). Stimulation of NPMA could activate both proximal and distal upper limb muscles with the same delay as a stimulation of the M1, indicating converging motor representations with direct functional connections to the hand. We suggest that these non-primary cortical motor representations provide additional capacity for the fast execution of movements. Such a capacity may play a role in motor learning and in recovery from motor deficits.

Non-Motor Symptoms of Parkinson's Disease: Diagnosis and ...

African Journals Online (AJOL)

AFRICAN JOURNALS ONLINE (AJOL) · Journals · Advanced Search · USING AJOL · RESOURCES ... Log in or Register to get access to full text downloads. ... Abstract. Non-motor symptoms (NMS) of Parkinson's disease (PD) are a key ... Papers discovered by this search were. reviewed, as were references cited therein.

Reduction in beta-myosin heavy chains in stunned myocardium as assessed by nondenaturing gel electrophoresis.

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Garcia, S C; Pomblum, V J; Gams, E; Rupp, H; Schipke, J D

2007-09-01

Myosin plays a key role in the structure and function of cardiac muscle. Three myosin isoenzymes (V(1), V(2), and V(3)) with different ATPase activities have been identified in mammalian ventricles based on their heavy chain constituents. The relative amount of myosin isoenzymes changes under physiological and pathological conditions. Until now, myosin isoenzymes have frequently been determined using either tube gel (nondenaturing) polyacrylamide gel electrophoresis (PAGE), or gradient or uniform sodium dodecyl sulfate (denaturing) PAGE. Both methods have disadvantages, e.g., a long running time. We developed, therefore, a uniform, nondenaturing PAGE with slab minigel format for analyzing the myosin isoenzymes in normoxic and stunned rabbit hearts. In normoxic hearts of adult rabbits, V(3) predominated over V(1) (46 vs 41%). In turn, in the stunned hearts, V(1) predominated over V(3) (70 vs 30%), and the heterodimeric V(2) was not anymore detectable. This alteration appears to result from a selective loss of myosin heavy chain (MHC)-beta. In parallel, the biochemical markers troponin I and creatine kinase were increased in the stunned hearts. We suggest that alterations of myosin isoenzymes in stunned myocardium can be monitored with native PAGE. The present analysis of myosin isoenzyme appears thus as a new tool for evaluating defects in MHC dimer formation in postischemic hearts.

Dlc1 interaction with non-muscle myosin heavy chain II-A (Myh9 and Rac1 activation

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Mohammad G. Sabbir

2016-04-01

Full Text Available The Deleted in liver cancer 1 (Dlc1 gene codes for a Rho GTPase-activating protein that also acts as a tumour suppressor gene. Several studies have consistently found that overexpression leads to excessive cell elongation, cytoskeleton changes and subsequent cell death. However, none of these studies have been able to satisfactorily explain the Dlc1-induced cell morphological phenotypes and the function of the different Dlc1 isoforms. Therefore, we have studied the interacting proteins associated with the three major Dlc1 transcriptional isoforms using a mass spectrometric approach in Dlc1 overexpressing cells. We have found and validated novel interacting partners in constitutive Dlc1-expressing cells. Our study has shown that Dlc1 interacts with non-muscle myosin heavy chain II-A (Myh9, plectin and spectrin proteins in different multiprotein complexes. Overexpression of Dlc1 led to increased phosphorylation of Myh9 protein and activation of Rac1 GTPase. These data support a role for Dlc1 in induced cell elongation morphology and provide some molecular targets for further analysis of this phenotype.

A shared resource between declarative memory and motor memory

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Keisler, Aysha; Shadmehr, Reza

2010-01-01

The neural systems that support motor adaptation in humans are thought to be distinct from those that support the declarative system. Yet, during motor adaptation changes in motor commands are supported by a fast adaptive process that has important properties (rapid learning, fast decay) that are usually associated with the declarative system. The fast process can be contrasted to a slow adaptive process that also supports motor memory, but learns gradually and shows resistance to forgetting. Here we show that after people stop performing a motor task, the fast motor memory can be disrupted by a task that engages declarative memory, but the slow motor memory is immune from this interference. Furthermore, we find that the fast/declarative component plays a major role in the consolidation of the slow motor memory. Because of the competitive nature of declarative and non-declarative memory during consolidation, impairment of the fast/declarative component leads to improvements in the slow/non-declarative component. Therefore, the fast process that supports formation of motor memory is not only neurally distinct from the slow process, but it shares critical resources with the declarative memory system. PMID:21048140

Myosins 1 and 6, myosin light chain kinase, actin and microtubules cooperate during antibody-mediated internalisation and trafficking of membrane-expressed viral antigens in feline infectious peritonitis virus infected monocytes.

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Dewerchin, Hannah L; Desmarets, Lowiese M; Noppe, Ytse; Nauwynck, Hans J

2014-02-12

Monocytes infected with feline infectious peritonitis virus, a coronavirus, express viral proteins in their plasma membranes. Upon binding of antibodies, these proteins are quickly internalised through a new clathrin- and caveolae-independent internalisation pathway. By doing so, the infected monocytes can escape antibody-dependent cell lysis. In the present study, we investigated which kinases and cytoskeletal proteins are of importance during internalisation and subsequent intracellular transport. The experiments showed that myosin light chain kinase (MLCK) and myosin 1 are crucial for the initiation of the internalisation. With co-localisation stainings, it was found that MLCK and myosin 1 co-localise with antigens even before internalisation started. Myosin 6 co-localised with the internalising complexes during passage through the cortical actin, were it might play a role in moving or disintegrating actin filaments, to overcome the actin barrier. One minute after internalisation started, vesicles had passed the cortical actin, co-localised with microtubules and association with myosin 6 was lost. The vesicles were further transported over the microtubules and accumulated at the microtubule organising centre after 10 to 30 min. Intracellular trafficking over microtubules was mediated by MLCK, myosin 1 and a small actin tail. Since inhibiting MLCK with ML-7 was so efficient in blocking the internalisation pathway, this target can be used for the development of a new treatment for FIPV.

Actin-myosin contractility is responsible for the reduced viability of dissociated human embryonic stem cells.

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Chen, Guokai; Hou, Zhonggang; Gulbranson, Daniel R; Thomson, James A

2010-08-06

Human ESCs are the pluripotent precursor of the three embryonic germ layers. Human ESCs exhibit basal-apical polarity, junctional complexes, integrin-dependent matrix adhesion, and E-cadherin-dependent cell-cell adhesion, all characteristics shared by the epiblast epithelium of the intact mammalian embryo. After disruption of epithelial structures, programmed cell death is commonly observed. If individualized human ESCs are prevented from reattaching and forming colonies, their viability is significantly reduced. Here, we show that actin-myosin contraction is a critical effector of the cell death response to human ESC dissociation. Inhibition of myosin heavy chain ATPase, downregulation of myosin heavy chain, and downregulation of myosin light chain all increase survival and cloning efficiency of individualized human ESCs. ROCK inhibition decreases phosphorylation of myosin light chain, suggesting that inhibition of actin-myosin contraction is also the mechanism through which ROCK inhibitors increase cloning efficiency of human ESCs. Copyright 2010 Elsevier Inc. All rights reserved.

Non-motor symptoms in patients with Parkinson's disease - correlations with inflammatory cytokines in serum.

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Daniel Lindqvist

Full Text Available BACKGROUND: Parkinson's Disease (PD is the second most common neurodegenerative disorder of the central nervous system. Motor symptoms are the focus of pharmacotherapy, yet non-motor features of the disease (e.g. fatigue, mood disturbances, sleep disturbances and symptoms of anxiety are both common and disabling for the patient. The pathophysiological mechanisms behind the non-motor symptoms in PD are yet to be untangled. The main objective of this study was to investigate associations between pro-inflammatory substances and non-motor symptoms in patients with PD. METHODS AND MATERIALS: We measured C-reactive protein, interleukin (IL-6, soluble IL-2 receptor (sIL-2R and tumor necrosis factor-α (TNF-α in blood samples from PD patients (n=86 and healthy controls (n=40. Symptoms of fatigue, depression, anxiety and sleeping difficulties were assessed using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT, the Hospital Anxiety and Depression Scale (HAD, and the Scales for Outcome in PD-Sleep Scale respectively. RESULTS: IL-6 was significantly higher in PD patients than in healthy controls. Compared to healthy controls, PD patients displayed significantly higher mean scores on HAD and lower scores on FACIT, thus indicating more severe symptoms as measured with these scales. Within the PD sample, high levels of both sIL-2R and TNF-α were significantly associated with more severe symptoms assessed by means of FACIT and HAD (depression and anxiety subscales. SIL-2-R levels were able to significantly predict FACIT and HAD scores after the effects of age, gender, anti-parkinsonian medications, and severity of motor symptoms were controlled for. DISCUSSION: We suggest that non-motor symptoms in PD patients, such as fatigue and depressive symptoms, might be generated via inflammatory mechanisms. This knowledge might contribute to the development of novel treatment options in PD, specifically targeting non-motor symptoms.

C0 and C1 N-terminal Ig domains of myosin binding protein C exert different effects on thin filament activation.

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Harris, Samantha P; Belknap, Betty; Van Sciver, Robert E; White, Howard D; Galkin, Vitold E

2016-02-09

Mutations in genes encoding myosin, the molecular motor that powers cardiac muscle contraction, and its accessory protein, cardiac myosin binding protein C (cMyBP-C), are the two most common causes of hypertrophic cardiomyopathy (HCM). Recent studies established that the N-terminal domains (NTDs) of cMyBP-C (e.g., C0, C1, M, and C2) can bind to and activate or inhibit the thin filament (TF). However, the molecular mechanism(s) by which NTDs modulate interaction of myosin with the TF remains unknown and the contribution of each individual NTD to TF activation/inhibition is unclear. Here we used an integrated structure-function approach using cryoelectron microscopy, biochemical kinetics, and force measurements to reveal how the first two Ig-like domains of cMyPB-C (C0 and C1) interact with the TF. Results demonstrate that despite being structural homologs, C0 and C1 exhibit different patterns of binding on the surface of F-actin. Importantly, C1 but not C0 binds in a position to activate the TF by shifting tropomyosin (Tm) to the "open" structural state. We further show that C1 directly interacts with Tm and traps Tm in the open position on the surface of F-actin. Both C0 and C1 compete with myosin subfragment 1 for binding to F-actin and effectively inhibit actomyosin interactions when present at high ratios of NTDs to F-actin. Finally, we show that in contracting sarcomeres, the activating effect of C1 is apparent only once low levels of Ca(2+) have been achieved. We suggest that Ca(2+) modulates the interaction of cMyBP-C with the TF in the sarcomere.

Exploration of flexible phenylpropylurea scaffold as novel cardiac myosin activators for the treatment of systolic heart failure.

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Manickam, Manoj; Jalani, Hitesh B; Pillaiyar, Thanigaimalai; Sharma, Niti; Boggu, Pulla Reddy; Venkateswararao, Eeda; Lee, You-Jung; Jeon, Eun-Seok; Jung, Sang-Hun

2017-07-07

A series of flexible urea derivatives have been synthesized and demonstrated as selective cardiac myosin ATPase activator. Among them 1-phenethyl-3-(3-phenylpropyl)urea (1, cardiac myosin ATPase activation at 10 μM = 51.1%; FS = 18.90; EF = 12.15) and 1-benzyl-3-(3-phenylpropyl)urea (9, cardiac myosin ATPase activation = 53.3%; FS = 30.04; EF = 18.27) showed significant activity in vitro and in vivo. The change of phenyl ring with tetrahydropyran-4-yl moiety viz., 1-(3-phenylpropyl)-3-((tetrahydro-2H-pyran-4-yl)methyl)urea (14, cardiac myosin ATPase activation = 81.4%; FS = 20.50; EF = 13.10), and morpholine moiety viz., 1-(2-morpholinoethyl)-3-(3-phenylpropyl)urea (21, cardiac myosin ATPase activation = 44.0%; FS = 24.79; EF = 15.65), proved to be efficient to activate the cardiac myosin. The potent compounds 1, 9, 14 and 21 were found to be selective for cardiac myosin over skeletal and smooth myosins. Thus, these urea derivatives are potent scaffold to develop as a newer cardiac myosin activator for the treatment of systolic heart failure. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Research on the Method of Setting Waiting Area for Non-motor Vehicle at Signal Control Intersection

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Wang Yun Xia

2018-01-01

Full Text Available Electric bicycle has become an indispensable important component of the transportation system. The fact is that traffic organization and channelizing design of signal control intersection is not intensive, which cannot adapt to the current traffic demand of non-motor vehicle, such as unclear traffic rules and poor visibility, thus the traffic safety of non-motor vehicle is not optimistic. Therefore, it is necessary to study on traffic organization method based on the demand of non-motor vehicle, which can provide certain theoretical basis for traffic administrative department to make policy and traffic design. This article focuses on the method of setting waiting area for non-motor vehicle at signal control intersection, including the advantages, disadvantages and the applicable conditions.

The effects of transdermal rotigotine on non-motor symptoms of Parkinson's disease: a multicentre, observational, retrospective, post-marketing study.

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Valldeoriola, Francesc; Salvador, Antonio; Gómez-Arguelles, José Maria; Marey, José; Moya, Miguel; Ayuga, Ángel; Ramírez, Francisco

2018-04-01

This study evaluated the effect of ≥6 months of transdermal rotigotine on non-motor and motor symptoms of patients with advanced Parkinson's disease. The study was conducted in Spain between September 2011 and December 2012 (ClinicalTrials.gov: NCT01504529). The primary efficacy variable was the change from baseline in non-motor symptoms, as assessed by changes in Parkinson's Disease Non-Motor Symptoms Questionnaire total scores at 6 months. Secondary endpoints included the assessment of motor symptoms by Unified Parkinson's Disease Rating Scale III scores. Data from 378 patients (mean age: 70.2 years; 56.9% male) with Parkinson's disease receiving rotigotine from were collected. Mean disease duration was 6.1 years, and mean rotigotine treatment duration was 45.6 months. Rotigotine reduced non-motor symptoms by 14.6% (mean change from baseline in Parkinson's Disease Non-Motor Symptoms Questionnaire: -1.5 ± 3.4; p < 0.0001). The majority of patients (58.2%) had improved non-motor symptoms at 6 months. Comparing the baseline versus study end, fewer patients experienced events in the urinary (78.6% vs. 73.3%; p = 0.0066), sleep (82.8% vs. 72.8%; p < 0.0001) and mood/cognition (77.3% vs. 66.4%; p < 0.0001) domains of the Parkinson's Disease Non-Motor Symptoms Questionnaire. Mean motor symptoms were reduced from baseline by 8.0% (mean change from baseline in Unified Parkinson's Disease Rating Scale III: -2.6 ± 8.0; p < 0.0001). In clinical practice in Spain, rotigotine may be an effective treatment to reduce the non-motor and motor symptoms in patients with advanced Parkinson's disease.

Qualification Status of Non-Asbestos Internal Insulation in the Reusable Solid Rocket Motor Program

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Clayton, Louie

2011-01-01

This paper provides a status of the qualification efforts associated with NASA's RSRMV non-asbestos internal insulation program. For many years, NASA has been actively engaged in removal of asbestos from the shuttle RSRM motors due to occupation health concerns where technicians are working with an EPA banned material. Careful laboratory and subscale testing has lead to the downselect of a organic fiber known as Polybenzimidazol to replace the asbestos fiber filler in the existing synthetic rubber copolymer Nitrile Butadiene - now named PBI/NBR. Manufacturing, processing, and layup of the new material has been a challenge due to the differences in the baseline shuttle RSRM internal insulator properties and PBI/NBR material properties. For this study, data gathering and reduction procedures for thermal and chemical property characterization for the new candidate material are discussed. Difficulties with test procedures, implementation of properties into the Charring Material Ablator (CMA) codes, and results correlation with static motor fire data are provided. After two successful five segment motor firings using the PBI/NBR insulator, performance results for the new material look good and the material should eventually be qualified for man rated use in large solid rocket motor applications.

Native myosin from adult rabbit skeletal muscle: isoenzymes and states of aggregation.

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Morel, J E; D'hahan, N; Taouil, K; Francin, M; Aguilar, A; Dalbiez, J P; Merah, Z; Grussaute, H; Hilbert, B; Ollagnon, F; Selva, G; Piot, F

1998-04-21

The globular heads of skeletal muscle myosin have been shown to exist as isoenzymes S1 (A1) and S1 (A2), and there are also isoforms of the heavy chains. Using capillary electrophoresis, we found two dominant isoenzymes of the whole native myosin molecule, in agreement with what has previously been found by various techniques for native and nondenatured myosin from adult rabbits. Findings about possible states of aggregation of myosin and its heads are contradictory. By analytical ultracentrifugation, we confirmed the existence of a tail-tail dimer. By laser light scattering, we found a head-head dimer in the presence of MgATP. Capillary electrophoresis coupled with analytical ultracentrifugation and laser light scattering led us to refine these results. We found tail-tail dimers in a conventional buffer. We found tail-tail and head-head dimers in the presence of 0.5 mM MgATP and pure head-head dimers in the presence of 6 mM MgATP. All the dimers were homodimers. Naming the dominant isoenzymes of myosin a and b, we observed tail-tail dimers with isoenzyme a (TaTa) and with isoenzyme b (TbTb) and also head-head dimers with isoenzyme a (HaHa) and with isoenzyme b (HbHb).

Excessive Myosin Activity in Mbs Mutants Causes Photoreceptor Movement Out of the Drosophila Eye Disc Epithelium

OpenAIRE

Lee, Arnold; Treisman, Jessica E.

2004-01-01

Neuronal cells must extend a motile growth cone while maintaining the cell body in its original position. In migrating cells, myosin contraction provides the driving force that pulls the rear of the cell toward the leading edge. We have characterized the function of myosin light chain phosphatase, which down-regulates myosin activity, in Drosophila photoreceptor neurons. Mutations in the gene encoding the myosin binding subunit of this enzyme cause photoreceptors to drop out of the eye disc e...

Motor proteins and molecular motors: how to operate machines at the nanoscale

International Nuclear Information System (INIS)

Kolomeisky, Anatoly B

2013-01-01

Several classes of biological molecules that transform chemical energy into mechanical work are known as motor proteins or molecular motors. These nanometer-sized machines operate in noisy stochastic isothermal environments, strongly supporting fundamental cellular processes such as the transfer of genetic information, transport, organization and functioning. In the past two decades motor proteins have become a subject of intense research efforts, aimed at uncovering the fundamental principles and mechanisms of molecular motor dynamics. In this review, we critically discuss recent progress in experimental and theoretical studies on motor proteins. Our focus is on analyzing fundamental concepts and ideas that have been utilized to explain the non-equilibrium nature and mechanisms of molecular motors. (topical review)

Non-stationarity and power spectral shifts in EMG activity reflect motor unit recruitment in rat diaphragm muscle.

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Seven, Yasin B; Mantilla, Carlos B; Zhan, Wen-Zhi; Sieck, Gary C

2013-01-15

We hypothesized that a shift in diaphragm muscle (DIAm) EMG power spectral density (PSD) to higher frequencies reflects recruitment of more fatigable fast-twitch motor units and motor unit recruitment is reflected by EMG non-stationarity. DIAm EMG was recorded in anesthetized rats during eupnea, hypoxia-hypercapnia (10% O(2)-5% CO(2)), airway occlusion, and sneezing (maximal DIAm force). Although power in all frequency bands increased progressively across motor behaviors, PSD centroid frequency increased only during sneezing (pmotor units were recruited during different motor behaviors. Motor units augmented their discharge frequencies progressively beyond the non-stationary period; yet, EMG signal became stationary. In conclusion, non-stationarity of DIAm EMG reflects the period of motor unit recruitment, while a shift in the PSD towards higher frequencies reflects recruitment of more fatigable fast-twitch motor units. Copyright © 2012 Elsevier B.V. All rights reserved.

Smitin, a novel smooth muscle titin-like protein, interacts with myosin filaments in vivo and in vitro.

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Kim, Kyoungtae; Keller, Thomas C S

2002-01-07

Smooth muscle cells use an actin-myosin II-based contractile apparatus to produce force for a variety of physiological functions, including blood pressure regulation and gut peristalsis. The organization of the smooth muscle contractile apparatus resembles that of striated skeletal and cardiac muscle, but remains much more poorly understood. We have found that avian vascular and visceral smooth muscles contain a novel, megadalton protein, smitin, that is similar to striated muscle titin in molecular morphology, localization in a contractile apparatus, and ability to interact with myosin filaments. Smitin, like titin, is a long fibrous molecule with a globular domain on one end. Specific reactivities of an anti-smitin polyclonal antibody and an anti-titin monoclonal antibody suggest that smitin and titin are distinct proteins rather than differentially spliced isoforms encoded by the same gene. Smitin immunofluorescently colocalizes with myosin in chicken gizzard smooth muscle, and interacts with two configurations of smooth muscle myosin filaments in vitro. In physiological ionic strength conditions, smitin and smooth muscle myosin coassemble into irregular aggregates containing large sidepolar myosin filaments. In low ionic strength conditions, smitin and smooth muscle myosin form highly ordered structures containing linear and polygonal end-to-end and side-by-side arrays of small bipolar myosin filaments. We have used immunogold localization and sucrose density gradient cosedimentation analyses to confirm association of smitin with both the sidepolar and bipolar smooth muscle myosin filaments. These findings suggest that the titin-like protein smitin may play a central role in organizing myosin filaments in the contractile apparatus and perhaps in other structures in smooth muscle cells.

Interaction of Myosin Phosphatase Target Subunit (MYPT1) with Myosin Phosphatase-RhoA Interacting Protein (MRIP): A Role of Glutamic Acids in the Interaction.

Science.gov (United States)

Lee, Eunhee; Stafford, Walter F

2015-01-01

Scaffold proteins bind to and functionally link protein members of signaling pathways. Interaction of the scaffold proteins, myosin phosphatase target subunit (MYPT1) and myosin phosphatase-RhoA interacting protein (MRIP), causes co-localization of myosin phosphatase and RhoA to actomyosin. To examine biophysical properties of interaction of MYPT1 with MRIP, we employed analytical ultracentrifugation and surface plasmon resonance. In regard to MRIP, its residues 724-837 are sufficient for the MYPT1/MRIP interaction. Moreover, MRIP binds to MYPT1 as either a monomer or a dimer. With respect to MYPT1, its leucine repeat region, LR (residues 991-1030) is sufficient to account for the MYPT1/MRIP interaction. Furthermore, point mutations that replace glutamic acids 998-1000 within LR reduced the binding affinity toward MRIP. This suggests that the glutamic acids of MYPT1 play an important role in the interaction.

Myosin Va associates with mRNA in ribonucleoprotein particles present in myelinated peripheral axons and in the central nervous system.

Science.gov (United States)

Calliari, Aldo; Farías, Joaquina; Puppo, Agostina; Canclini, Lucía; Mercer, John A; Munroe, David; Sotelo, José R; Sotelo-Silveira, José R

2014-03-01

Sorting of specific mRNAs to particular cellular locations and regulation of their translation is an essential mechanism underlying cell polarization. The transport of RNAs by kinesins and dyneins has been clearly established in several cell models, including neurons in culture. A similar role appears to exist in higher eukaryotes for the myosins. Myosin Va (Myo5a) has been described as a component of ribonucleoprotein particles (RNPs) in the adult rat nervous system and associated to ZBP1 and ribosomes in ribosomal periaxoplasmic plaques (PARPs), making it a likely candidate for mediating some aspects of RNA transport in neurons. To test this hypothesis, we have characterized RNPs containing Myo5a in adult brains of rats and mice. Microarray analysis of RNAs co-immunoprecipitated with Myo5a indicates that this motor may associate with a specific subpopulation of neuronal mRNAs. We found mRNAs encoding α-synuclein and several proteins with functions in translation in these RNPs. Immunofluorescence analyses of RNPs showed apparent co-localization of Myo5a with ribosomes, mRNA and RNA-binding proteins in discrete structures present both in axons of neurons in culture and in myelinated fibers of medullary roots. Our data suggest that PARPs include RNPs bearing the mRNA coding for Myo5a and are equipped with kinesin and Myo5a molecular motors. In conclusion, we suggest that Myo5a is involved in mRNA trafficking both in the central and peripheral nervous systems. Copyright © 2013 Wiley Periodicals, Inc.

Transportation of drug–gold nanocomposites by actinomyosin motor system

International Nuclear Information System (INIS)

Kaur, Harsimran; Chaudhary, Archana; Kaur, Inderpreet; Singh, Kashmir; Bharadwaj, Lalit M.

2011-01-01

Nanotechnology is playing an important role in drug delivery to overcome limitations of conventional drug delivery systems in terms of solubility, in vivo stability, pharmacokinetics, and bio-distribution. The controlled transportation of drug into the cell and within the cell is a major challenge to be addressed. Cellular molecular motors have been exploited for their cargo carrying capacity for various applications including engineering and health care. Combination of nanotechnology and biomolecular motors can address some of the challenges in drug delivery. In the present study, transportation of drug nanocomposites has been demonstrated. Nanocomposites of 6-mercaptopurine and levodopa drugs (cancer and Parkinson’s disease, respectively) were prepared with gold nanoparticles (GNPs) by covalent attachment and these nanocomposites were attached to actin filaments. These nanocomposites were in-turn transported by actin filaments on myosin tracks. Characterization of drug nanocomposites formation was done by UV–Vis spectroscopy, field emission scanning electron microscopy, transmission electron microscopy, and confocal microscopy. GNP composites of 6-mercaptopurine and levodopa were formed by sulfide and amide bond formation, respectively. Average velocity of actin filament attached to nanocomposites was found to be 3.17 and 3.89 μm/s for levodopa and 6-mercaptopurine, respectively, as compared to actin filaments with velocity of 4.0–6.0 μm/s. Three concepts have been proposed for the study of drug transportation into the cell based on polycationic complex formation, interaction of actin with cellular myosin and Biomolecular Adaptor for Retrograde Transport (BART) technology. The aspects of this study heads toward the development of an approach to utilize molecular motors for nanoscale transportation endogenously.

Transportation of drug-gold nanocomposites by actinomyosin motor system

Science.gov (United States)

Kaur, Harsimran; Chaudhary, Archana; Kaur, Inderpreet; Singh, Kashmir; Bharadwaj, Lalit M.

2011-06-01

Nanotechnology is playing an important role in drug delivery to overcome limitations of conventional drug delivery systems in terms of solubility, in vivo stability, pharmacokinetics, and bio-distribution. The controlled transportation of drug into the cell and within the cell is a major challenge to be addressed. Cellular molecular motors have been exploited for their cargo carrying capacity for various applications including engineering and health care. Combination of nanotechnology and biomolecular motors can address some of the challenges in drug delivery. In the present study, transportation of drug nanocomposites has been demonstrated. Nanocomposites of 6-mercaptopurine and levodopa drugs (cancer and Parkinson's disease, respectively) were prepared with gold nanoparticles (GNPs) by covalent attachment and these nanocomposites were attached to actin filaments. These nanocomposites were in-turn transported by actin filaments on myosin tracks. Characterization of drug nanocomposites formation was done by UV-Vis spectroscopy, field emission scanning electron microscopy, transmission electron microscopy, and confocal microscopy. GNP composites of 6-mercaptopurine and levodopa were formed by sulfide and amide bond formation, respectively. Average velocity of actin filament attached to nanocomposites was found to be 3.17 and 3.89 μm/s for levodopa and 6-mercaptopurine, respectively, as compared to actin filaments with velocity of 4.0-6.0 μm/s. Three concepts have been proposed for the study of drug transportation into the cell based on polycationic complex formation, interaction of actin with cellular myosin and Biomolecular Adaptor for Retrograde Transport (BART) technology. The aspects of this study heads toward the development of an approach to utilize molecular motors for nanoscale transportation endogenously.

Transportation of drug-gold nanocomposites by actinomyosin motor system

Energy Technology Data Exchange (ETDEWEB)

Kaur, Harsimran, E-mail: microsimbac@gmail.com; Chaudhary, Archana; Kaur, Inderpreet [Council of Scientific and Industrial Research (CSIR), Biomolecular Electronics and Nanotechnology Division (BEND), Central Scientific Instruments Organization - CSIO (India); Singh, Kashmir [Panjab University, Department of Biotechnology (India); Bharadwaj, Lalit M. [Council of Scientific and Industrial Research (CSIR), Biomolecular Electronics and Nanotechnology Division (BEND), Central Scientific Instruments Organization - CSIO (India)

2011-06-15

Nanotechnology is playing an important role in drug delivery to overcome limitations of conventional drug delivery systems in terms of solubility, in vivo stability, pharmacokinetics, and bio-distribution. The controlled transportation of drug into the cell and within the cell is a major challenge to be addressed. Cellular molecular motors have been exploited for their cargo carrying capacity for various applications including engineering and health care. Combination of nanotechnology and biomolecular motors can address some of the challenges in drug delivery. In the present study, transportation of drug nanocomposites has been demonstrated. Nanocomposites of 6-mercaptopurine and levodopa drugs (cancer and Parkinson's disease, respectively) were prepared with gold nanoparticles (GNPs) by covalent attachment and these nanocomposites were attached to actin filaments. These nanocomposites were in-turn transported by actin filaments on myosin tracks. Characterization of drug nanocomposites formation was done by UV-Vis spectroscopy, field emission scanning electron microscopy, transmission electron microscopy, and confocal microscopy. GNP composites of 6-mercaptopurine and levodopa were formed by sulfide and amide bond formation, respectively. Average velocity of actin filament attached to nanocomposites was found to be 3.17 and 3.89 {mu}m/s for levodopa and 6-mercaptopurine, respectively, as compared to actin filaments with velocity of 4.0-6.0 {mu}m/s. Three concepts have been proposed for the study of drug transportation into the cell based on polycationic complex formation, interaction of actin with cellular myosin and Biomolecular Adaptor for Retrograde Transport (BART) technology. The aspects of this study heads toward the development of an approach to utilize molecular motors for nanoscale transportation endogenously.

Lyapunov exponent for aging process in induction motor

Science.gov (United States)

Bayram, Duygu; Ünnü, Sezen Yıdırım; Şeker, Serhat

2012-09-01

Nonlinear systems like electrical circuits and systems, mechanics, optics and even incidents in nature may pass through various bifurcations and steady states like equilibrium point, periodic, quasi-periodic, chaotic states. Although chaotic phenomena are widely observed in physical systems, it can not be predicted because of the nature of the system. On the other hand, it is known that, chaos is strictly dependent on initial conditions of the system [1-3]. There are several methods in order to define the chaos. Phase portraits, Poincaré maps, Lyapunov Exponents are the most common techniques. Lyapunov Exponents are the theoretical indicator of the chaos, named after the Russian mathematician Aleksandr Lyapunov (1857-1918). Lyapunov Exponents stand for the average exponential divergence or convergence of nearby system states, meaning estimating the quantitive measure of the chaotic attractor. Negative numbers of the exponents stand for a stable system whereas zero stands for quasi-periodic systems. On the other hand, at least if one of the exponents is positive, this situation is an indicator of the chaos. For estimating the exponents, the system should be modeled by differential equation but even in that case mathematical calculation of Lyapunov Exponents are not very practical and evaluation of these values requires a long signal duration [4-7]. For experimental data sets, it is not always possible to acquire the differential equations. There are several different methods in literature for determining the Lyapunov Exponents of the system [4, 5]. Induction motors are the most important tools for many industrial processes because they are cheap, robust, efficient and reliable. In order to have healthy processes in industrial applications, the conditions of the machines should be monitored and the different working conditions should be addressed correctly. To the best of our knowledge, researches related to Lyapunov exponents and electrical motors are mostly

Compromised Motor Dexterity Confounds Processing Speed Task Outcomes in Stroke Patients

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Essie Low

2017-09-01

Full Text Available Most conventional measures of information processing speed require motor responses to facilitate performance. However, although not often addressed clinically, motor impairment, whether due to age or acquired brain injury, would be expected to confound the outcome measure of such tasks. The current study recruited 29 patients (20 stroke and 9 transient ischemic attack with documented reduction in dexterity of the dominant hand, and 29 controls, to investigate the extent to which 3 commonly used processing speed measures with varying motor demands (a Visuo-Motor Reaction Time task, and the Wechsler Adult Intelligence Scale-IV Symbol Search and Coding subtests may be measuring motor-related speed more so than cognitive speed. Analyses include correlations between indices of cognitive and motor speed obtained from two other tasks (Inspection Time and Pegboard task, respectively with the three speed measures, followed by hierarchical regressions to determine the relative contribution of cognitive and motor speed indices toward task performance. Results revealed that speed outcomes on tasks with relatively high motor demands, such as Coding, were largely reflecting motor speed in individuals with reduced dominant hand dexterity. Thus, findings indicate the importance of employing measures with minimal motor requirements, especially when the assessment of speed is aimed at understanding cognitive rather than physical function.

Electron Microscopic Recording of the Power and Recovery Strokes of Individual Myosin Heads Coupled with ATP Hydrolysis: Facts and Implications

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Haruo Sugi

2018-05-01

Full Text Available The most straightforward way to get information on the performance of individual myosin heads producing muscle contraction may be to record their movement, coupled with ATP hydrolysis, electron-microscopically using the gas environmental chamber (EC. The EC enables us to visualize and record ATP-induced myosin head movement in hydrated skeletal muscle myosin filaments. When actin filaments are absent, myosin heads fluctuate around a definite neutral position, so that their time-averaged mean position remains unchanged. On application of ATP, myosin heads are found to move away from, but not towards, the bare region, indicating that myosin heads perform a recovery stroke (average amplitude, 6 nm. After exhaustion of ATP, myosin heads return to their neutral position. In the actin–myosin filament mixture, myosin heads form rigor actin myosin linkages, and on application of ATP, they perform a power stroke by stretching adjacent elastic structures because of a limited amount of applied ATP ≤ 10 µM. The average amplitude of the power stroke is 3.3 nm and 2.5 nm at the distal and the proximal regions of the myosin head catalytic domain (CAD, respectively. The power stroke amplitude increases appreciably at low ionic strength, which is known to enhance Ca2+-activated force in muscle. In both the power and recovery strokes, myosin heads return to their neutral position after exhaustion of ATP.

Visual but not motor processes predict simple visuomotor reaction time of badminton players.

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Hülsdünker, Thorben; Strüder, Heiko K; Mierau, Andreas

2018-03-01

The athlete's brain exhibits significant functional adaptations that facilitate visuomotor reaction performance. However, it is currently unclear if the same neurophysiological processes that differentiate athletes from non-athletes also determine performance within a homogeneous group of athletes. This information can provide valuable help for athletes and coaches aiming to optimize existing training regimes. Therefore, this study aimed to identify the neurophysiological correlates of visuomotor reaction performance in a group of skilled athletes. In 36 skilled badminton athletes, electroencephalography (EEG) was used to investigate pattern reversal and motion onset visual-evoked potentials (VEPs) as well as visuomotor reaction time (VMRT) during a simple reaction task. Stimulus-locked and response-locked event-related potentials (ERPs) in visual and motor regions as well as the onset of muscle activation (EMG onset) were determined. Correlation and multiple regression analyses identified the neurophysiological parameters predicting EMG onset and VMRT. For pattern reversal stimuli, the P100 latency and age best predicted EMG onset (r = 0.43; p = .003) and VMRT (r = 0.62; p = .001). In the motion onset experiment, EMG onset (r = 0.80; p badminton players while motor-related processes, although differentiating athletes from non-athletes, are not associated simple with visuomotor reaction performance.

Maintenance of muscle myosin levels in adult C. elegans requires both the double bromodomain protein BET-1 and sumoylation

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Kate Fisher

2013-10-01

Attenuation of RAS-mediated signalling is a conserved process essential to control cell proliferation, differentiation, and apoptosis. Cooperative interactions between histone modifications such as acetylation, methylation and sumoylation are crucial for proper attenuation in C. elegans, implying that the proteins recognising these histone modifications could also play an important role in attenuation of RAS-mediated signalling. We sought to systematically identify these proteins and found BET-1. BET-1 is a conserved double bromodomain protein that recognises acetyl-lysines on histone tails and maintains the stable fate of various lineages. Unexpectedly, adults lacking both BET-1 and SUMO-1 are depleted of muscle myosin, an essential component of myofibrils. We also show that this muscle myosin depletion does not occur in all animals at a specific time, but rather that the penetrance of the phenotype increases with age. To gain mechanistic insights into this process, we sought to delay the occurrence of the muscle myosin depletion phenotype and found that it requires caspase activity and MEK-dependent signalling. We also performed transcription profiling on these mutants and found an up-regulation of the FGF receptor, egl-15, a tyrosine kinase receptor acting upstream of MEK. Consistent with a MEK requirement, we could delay the muscle phenotype by systemic or hypodermal knock down of egl-15. Thus, this work uncovered a caspase- and MEK-dependent mechanism that acts specifically on ageing adults to maintain the appropriate net level of muscle myosin.

[Myosin B ATPase activity of the intestinal smooth muscle in intestinal obstruction].

Science.gov (United States)

Takamatsu, H

1983-06-01

Intestinal smooth myosin B was prepared from muscle layers around the lesion in dogs with experimental colonic stenosis and in patients with congenital intestinal obstruction. Mg2+-ATPase activity of the myosin B was compared between the proximal dilated segment and distal segment to obstruction. Experimental colonic stenosis: In early period after surgery, proximal colons showed higher activity of myosin B ATPase than distal colons, decreasing to less than distal colon as time passed. Congenital intestinal obstruction: In three cases, whose atresia might have occurred at earlier period of gestation, proximal bowels showed less activity of myosin B ATPase than distal bowels. However, in two cases, whose atresia might have occurred at later period of gestation, and two cases with intestinal stenosis, proximal bowels indicated higher activity of myosin B ATPase than distal bowels. These data suggested that the contractibility of the proximal intestine was depending on the duration of obstruction, and it was depressed in the former patients and was accelerated in the latter patients. These results suggested that the extensive resection of dilated proximal bowel in the congenital atresia is not always necessary to obtain good postoperative intestinal dynamics at the operation of the atresial lesions which may be induced at later period of gestation. They also suggested that surgery for intestinal obstruction should be performed before the depression of intestinal contractibility to get good bowel function.

Preparation and Characterization of Myosin Proteins.

Science.gov (United States)

Caldwell, Elizabeth; Eftink, Maurice R.

1985-01-01

Students complete five experimental projects at the end of a senior-level biochemistry course which involves the isolation and characterization of myosin and its water-soluble subfragments. Procedures used and results obtained are provided for such projects as viscosity and ATPase measurements and gel electrophoresis experiments. (JN)

The Role of a Novel Myosin Isoform in Prostate Cancer Metastasis

Science.gov (United States)

2013-10-01

2013 Accepted 14 February 2013 Available online 21 February 2013 Keywords: Myosin IC Isoforms Nucleolar localization signal Nucleolus Nucleus RNA...polymerase I Fibrillarinnt matter & 2013 Elsevier 1016/j.yexcr.2013.02.008 S, nucleolar localization ; No, nucleolus ; N, nucle bovine serum albumin; S...the nucleus, and the nucleolus . In the cytoplasm, myosin IC associ- ates with membranes and is involved in vesicle transport of membrane proteins [2

Response of slow and fast muscle to hypothyroidism: maximal shortening velocity and myosin isoforms

Science.gov (United States)

Caiozzo, V. J.; Herrick, R. E.; Baldwin, K. M.

1992-01-01

This study examined both the shortening velocity and myosin isoform distribution of slow- (soleus) and fast-twitch (plantaris) skeletal muscles under hypothyroid conditions. Adult female Sprague-Dawley rats were randomly assigned to one of two groups: control (n = 7) or hypothyroid (n = 7). In both muscles, the relative contents of native slow myosin (SM) and type I myosin heavy chain (MHC) increased in response to the hypothyroid treatment. The effects were such that the hypothyroid soleus muscle expressed only the native SM and type I MHC isoforms while repressing native intermediate myosin and type IIA MHC. In the plantaris, the relative content of native SM and type I MHC isoforms increased from 5 to 13% and from 4 to 10% of the total myosin pool, respectively. Maximal shortening velocity of the soleus and plantaris as measured by the slack test decreased by 32 and 19%, respectively, in response to hypothyroidism. In contrast, maximal shortening velocity as estimated by force-velocity data decreased only in the soleus (-19%). No significant change was observed for the plantaris.

Preparation of monoclonal antibodies against cardiac myosin and some radiolabelling studies

International Nuclear Information System (INIS)

Bapat, K.; Venkatesh, M.; Pillai, M.R.A.; Sarma, H.D.; Sainis, K.B.

1998-01-01

Monoclonal antibodies were raised against myosin, a specific indicator of myocardial infarction and labelled with 125 I and 99m Tc. Human cardiac myosin was isolated from normal human heart and was used for raising the monoclonal antibodies by the hybridoma technique. Antibody producing clones were identified by ELISA and cloning was done by the limiting dilution technique. Of the 13 clones obtained, 4 were deemed suitable for further studies. The antibodies were grown in ascites, purified, isotyped and their cross reactions with other forms of myosin were estimated. All the clones showed negligible cross reaction with rabbit myosin, but reacted to different extents with bovine skeletal myosin. The most avid antibody Mab-4G4 was chosen for further labelling studies. Mab-4G4 was labelled with 125 I using different oxidising agents such as iodogen, chloramine-T and lactoperoxidase. Purified radioiodinated antibody with radiochemical purity >95% could be obtained by gel filtration. Immunoreactivity was retained as tested by binding to myosin immobilised on a solid support. Mab-4G4 was also labelled with 99m Tc using stannous tartrate as the reducing agent. Radiolabelling yield was ∼60%, the purity was >95% and the immunoreactivity was retained. Both the labelled preparations were tested for bio-distribution in normal and infarcted rats. The activity accumulation in the infarcted region was ∼ 1.5 and 3.5 times as that in normal heart muscle for 125 I and 99m Tc labelled Mab-4G4 respectively. The major problem with the iodinated antibody was the in vivo deiodination resulting in very high percentage of activity in the thyroid. Although the fraction of the total activity associated with the infarcted heart is not very impressive, the fact that the activities with the infarcted and normal hearths are significantly different is heartening. With further optimisation of labelling and use of F(ab)'2 fragments, better delineation of the infarct sites is aspired. (author)

Thermodynamics and kinetics of molecular motors.

Science.gov (United States)

Astumian, R Dean

2010-06-02

Molecular motors are first and foremost molecules, governed by the laws of chemistry rather than of mechanics. The dynamical behavior of motors based on chemical principles can be described as a random walk on a network of states. A key insight is that any molecular motor in solution explores all possible motions and configurations at thermodynamic equilibrium. By using input energy and chemical design to prevent motion that is not wanted, what is left behind is the motion that is desired. This review is focused on two-headed motors such as kinesin and Myosin V that move on a polymeric track. By use of microscopic reversibility, it is shown that the ratio between the number of forward steps and the number of backward steps in any sufficiently long time period does not directly depend on the mechanical properties of the linker between the two heads. Instead, this ratio is governed by the relative chemical specificity of the heads in the front-versus-rear position for the fuel, adenosine triphosphate and its products, adenosine diphosphate and inorganic phosphate. These insights have been key factors in the design of biologically inspired synthetic molecular walkers constructed out of DNA or out of small organic molecules. Copyright (c) 2010 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Metal cation controls phosphate release in the myosin ATPase.

Science.gov (United States)

Ge, Jinghua; Huang, Furong; Nesmelov, Yuri E

2017-11-01

Myosin is an enzyme that utilizes ATP to produce a conformational change generating a force. The kinetics of the myosin reverse recovery stroke depends on the metal cation complexed with ATP. The reverse recovery stroke is slow for MgATP and fast for MnATP. The metal ion coordinates the γ phosphate of ATP in the myosin active site. It is accepted that the reverse recovery stroke is correlated with the phosphate release; therefore, magnesium "holds" phosphate tighter than manganese. Magnesium and manganese are similar ions in terms of their chemical properties and the shell complexation; hence, we propose to use these ions to study the mechanism of the phosphate release. Analysis of octahedral complexes of magnesium and manganese show that the partial charge of magnesium is higher than that of manganese and the slightly larger size of manganese ion makes its ionic potential smaller. We hypothesize that electrostatics play a role in keeping and releasing the abstracted γ phosphate in the active site, and the stronger electric charge of magnesium ion holds γ phosphate tighter. We used stable myosin-nucleotide analog complex and Raman spectroscopy to examine the effect of the metal cation on the relative position of γ phosphate analog in the active site. We found that in the manganese complex, the γ phosphate analog is 0.01 nm further away from ADP than in the magnesium complex. We conclude that the ionic potential of the metal cation plays a role in the retention of the abstracted phosphate. © 2017 The Protein Society.

K-252a, a novel microbial product, inhibits smooth muscle myosin light chain kinase

International Nuclear Information System (INIS)

Nakanishi, S.; Yamada, K.; Kase, H.; Nakamura, S.; Nonomura, Y.

1988-01-01

Effects of K-252a, purified from the culture broth of Nocardiopsis sp., on the activity of myosin (light chain kinase were investigated. 1) K-252a affected three characteristic properties of chicken gizzard myosin-B, natural actomyosin, to a similar degree: the Ca 2+ -dependent activity of ATPase, superprecipitation, and the phosphorylation of the myosin light chain. 2) K-252a inhibited the activities of the purified myosin light chain kinase and a Ca 2+ -independent form of the enzyme which was constructed by cross-linking of myosin light chain kinase and calmodulin using glutaraldehyde. The degrees of inhibition by 3 x 10 -6 M K-252a were 69 and 48% of the control activities with the purified enzyme and the cross-linked complex, respectively. Chlorpromazine (3 x 10 -4 M), a calmodulin antagonist, inhibited the native enzyme, but not the cross-linked one. These results suggested that K-252a inhibited myosin light chain kinase by direct interaction with the enzyme, whereas chlorpromazine suppressed the enzyme activation by interacting with calmodulin. 3) The inhibition by K-252a of the cross-linked kinase was affected by the concentration of ATP, a phosphate donor. The concentration causing 50% inhibition was two orders magnitude lowere in the presence of 100 μM ATP than in the presence of 2 mM ATP. 4) Kinetic analyses using [γ- 32 P]ATP indicated that the inhibitory mode of K-252a was competitive with respect to ATP. These results suggest that K-252a interacts at the ATP-binding domain of myosin light chain kinase

The Effects of Hsp90α1 Mutations on Myosin Thick Filament Organization.

Science.gov (United States)

He, Qiuxia; Liu, Kechun; Tian, Zhenjun; Du, Shao Jun

2015-01-01

Heat shock protein 90α plays a key role in myosin folding and thick filament assembly in muscle cells. To assess the structure and function of Hsp90α and its potential regulation by post-translational modification, we developed a combined knockdown and rescue assay in zebrafish embryos to systematically analyze the effects of various mutations on Hsp90α function in myosin thick filament organization. DNA constructs expressing the Hsp90α1 mutants with altered putative ATP binding, phosphorylation, acetylation or methylation sites were co-injected with Hsp90α1 specific morpholino into zebrafish embryos. Myosin thick filament organization was analyzed in skeletal muscles of the injected embryos by immunostaining. The results showed that mutating the conserved D90 residue in the Hsp90α1 ATP binding domain abolished its function in thick filament organization. In addition, phosphorylation mimicking mutations of T33D, T33E and T87E compromised Hsp90α1 function in myosin thick filament organization. Similarly, K287Q acetylation mimicking mutation repressed Hsp90α1 function in myosin thick filament organization. In contrast, K206R and K608R hypomethylation mimicking mutations had not effect on Hsp90α1 function in thick filament organization. Given that T33 and T87 are highly conserved residues involved post-translational modification (PTM) in yeast, mouse and human Hsp90 proteins, data from this study could indicate that Hsp90α1 function in myosin thick filament organization is potentially regulated by PTMs involving phosphorylation and acetylation.

The Mechanical Transient Process at Asynchronous Motor Oscillating Mode

Science.gov (United States)

Antonovičs, Uldis; Bražis, Viesturs; Greivulis, Jānis

2009-01-01

The research object is squirrel-cage asynchronous motor connected to single-phase sinusoidal. There are shown, that by connecting to the stator windings a certain sequence of half-period positive and negative voltage, a motor rotor is rotated, but three times slower than in the three-phase mode. Changing the connecting sequence of positive and negative half-period voltage to stator windings, motor can work in various oscillating modes. It is tested experimentally. The mechanical transient processes had been researched in rotation and oscillating modes.

Stretch activates myosin light chain kinase in arterial smooth muscle

International Nuclear Information System (INIS)

Barany, K.; Rokolya, A.; Barany, M.

1990-01-01

Stretching of porcine carotid arterial muscle increased the phosphorylation of the 20 kDa myosin light chain from 0.23 to 0.68 mol [32P]phosphate/mol light chain, whereas stretching of phorbol dibutyrate treated muscle increased the phosphorylation from 0.30 to 0.91 mol/mol. Two-dimensional gel electrophoresis followed by two-dimensional tryptic phosphopeptide mapping was used to identify the enzyme involved in the stretch-induced phosphorylation. Quantitation of the [32P]phosphate content of the peptides revealed considerable light chain phosphorylation by protein kinase C only in the phorbol dibutyrate treated arterial muscle, whereas most of the light chain phosphorylation was attributable to myosin light chain kinase. Upon stretch of either the untreated or treated muscle, the total increment in [32P]phosphate incorporation into the light chain could be accounted for by peptides characteristic for myosin light chain kinase catalyzed phosphorylation, demonstrating that the stretch-induced phosphorylation is caused by this enzyme exclusively

Head-head interactions of resting myosin crossbridges in intact frog skeletal muscles, revealed by synchrotron x-ray fiber diffraction.

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Kanji Oshima

Full Text Available The intensities of the myosin-based layer lines in the x-ray diffraction patterns from live resting frog skeletal muscles with full thick-thin filament overlap from which partial lattice sampling effects had been removed were analyzed to elucidate the configurations of myosin crossbridges around the thick filament backbone to nanometer resolution. The repeat of myosin binding protein C (C-protein molecules on the thick filaments was determined to be 45.33 nm, slightly longer than that of myosin crossbridges. With the inclusion of structural information for C-proteins and a pre-powerstroke head shape, modeling in terms of a mixed population of regular and perturbed regions of myosin crown repeats along the filament revealed that the myosin filament had azimuthal perturbations of crossbridges in addition to axial perturbations in the perturbed region, producing pseudo-six-fold rotational symmetry in the structure projected down the filament axis. Myosin crossbridges had a different organization about the filament axis in each of the regular and perturbed regions. In the regular region that lacks C-proteins, there were inter-molecular interactions between the myosin heads in axially adjacent crown levels. In the perturbed region that contains C-proteins, in addition to inter-molecular interactions between the myosin heads in the closest adjacent crown levels, there were also intra-molecular interactions between the paired heads on the same crown level. Common features of the interactions in both regions were interactions between a portion of the 50-kDa-domain and part of the converter domain of the myosin heads, similar to those found in the phosphorylation-regulated invertebrate myosin. These interactions are primarily electrostatic and the converter domain is responsible for the head-head interactions. Thus multiple head-head interactions of myosin crossbridges also characterize the switched-off state and have an important role in the regulation

Multisensory integration in non-human primates during a sensory-motor task

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Florian eLanz

2013-11-01

Full Text Available Daily our central nervous system receives inputs via several sensory modalities, processes them and integrates information in order to produce a suitable behaviour. The amazing part is that such a multisensory integration brings all information into a unified percept. An approach to start investigating this property is to show that perception is better and faster when multimodal stimuli are used as compared to unimodal stimuli. This forms the first part of the present study conducted in a non-human primate’s model (n=2 engaged in a detection sensory-motor task where visual and auditory stimuli were displayed individually or simultaneously. The measured parameters were the reaction time (RT between stimulus and onset of arm movement, successes and errors percentages, as well as the evolution as a function of time of these parameters with training. As expected, RTs were shorter when the subjects were exposed to combined stimuli. The gains for both subjects were around 20 and 40 msec, as compared with the auditory and visual stimulus alone, respectively. Moreover the number of correct responses increased in response to bimodal stimuli. We interpreted such multisensory advantage through redundant signal effect which decreases perceptual ambiguity, increases speed of stimulus detection and improves performance accuracy.The second part of the study presents single unit recordings derived from the premotor cortex (PM of the same subjects during the sensory-motor task. Response patterns to sensory/multisensory stimulation are documented and specific type proportions are reported. Characterization of bimodal neurons indicates a mechanism of audio-visual integration possibly through a decrease of inhibition. Nevertheless the neural processing leading to faster motor response from PM as a polysensory association cortical area remains still unclear.

Parkinson’s disease motor disorganization and temporal processing

OpenAIRE

Florio, Tiziana M.

2017-01-01

Motor control is essential for everyday life and highly contributes to the development and organisation of higher cognitive functions. Embodied cognition endemically approaches cognitive activities, grounding on sensory-motor processes and the ability to switch from each other in response to specific context and situations. In this view, it is possible to deliberate higher functions such as “expertise” and “decision making” as the ability to reactivate, deconstruct and reconstruct different m...

Increasing Mud Pump Motor Reliability against Malfunctions of DC Motor Excitation System

Science.gov (United States)

Nikulin, O. V.; Shabanov, V. A.

2017-10-01

The most widely used drilling machinery, such as mud pumps, draw-works, and rotors, use direct-current (DC) motors with independent excitation as the electric drive. Drilling machinery drives operate in harsh ambient conditions, including those with the presence of moisture, dust and vibration, which increases the malfunction rate of both drilling equipment and their electric drives. One of the frequently encountered malfunctions are DC motor excitation coil faults, which disrupt the normal functioning of electric drives, often leading to shutdown of the drilling process. In a four-pole DC motor, the malfunction of one coil leads to lack of excitation current in just one coil pair, while the other pair remains functional. In this case, DC motors and drilling equipment can remain operational, which would allow for continuing the drilling process. This paper considers the possibility of operation of a DC motor on a drilling rig in those cases when one pair of excitation coils is non-functional, and describes the device for switching between the excitation coils and the auxiliary winding in a DC motor with independent excitation.

Probing intracellular motor protein activity using an inducible cargo trafficking assay.

Science.gov (United States)

Kapitein, Lukas C; Schlager, Max A; van der Zwan, Wouter A; Wulf, Phebe S; Keijzer, Nanda; Hoogenraad, Casper C

2010-10-06

Although purified cytoskeletal motor proteins have been studied extensively with the use of in vitro approaches, a generic approach to selectively probe actin and microtubule-based motor protein activity inside living cells is lacking. To examine specific motor activity inside living cells, we utilized the FKBP-rapalog-FRB heterodimerization system to develop an in vivo peroxisomal trafficking assay that allows inducible recruitment of exogenous and endogenous kinesin, dynein, and myosin motors to drive specific cargo transport. We demonstrate that cargo rapidly redistributes with distinct dynamics for each respective motor, and that combined (antagonistic) actions of more complex motor combinations can also be probed. Of importance, robust cargo redistribution is readily achieved by one type of motor protein and does not require the presence of opposite-polarity motors. Simultaneous live-cell imaging of microtubules and kinesin or dynein-propelled peroxisomes, combined with high-resolution particle tracking, revealed that peroxisomes frequently pause at microtubule intersections. Titration and washout experiments furthermore revealed that motor recruitment by rapalog-induced heterodimerization is dose-dependent but irreversible. Our assay directly demonstrates that robust cargo motility does not require the presence of opposite-polarity motors, and can therefore be used to characterize the motile properties of specific types of motor proteins. Copyright © 2010 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Myosin X is recruited to nascent focal adhesions at the leading edge and induces multi-cycle filopodial elongation.

Science.gov (United States)

He, Kangmin; Sakai, Tsuyoshi; Tsukasaki, Yoshikazu; Watanabe, Tomonobu M; Ikebe, Mitsuo

2017-10-20

Filopodia protrude from the leading edge of cells and play important roles in cell motility. Here we report the mechanism of myosin X (encoded by Myo10)-induced multi-cycle filopodia extension. We found that actin, Arp2/3, vinculin and integrin-β first accumulated at the cell's leading edge. Myosin X was then gathered at these sites, gradually clustered by lateral movement, and subsequently initiated filopodia formation. During filopodia extension, we found the translocation of Arp2/3 and integrin-β along filopodia. Arp2/3 and integrin-β then became localized at the tip of filopodia, from where myosin X initiated the second extension of filopodia with a change in extension direction, thus producing long filopodia. Elimination of integrin-β, Arp2/3 and vinculin by siRNA significantly attenuated the myosin-X-induced long filopodia formation. We propose the following mechanism. Myosin X accumulates at nascent focal adhesions at the cell's leading edge, where myosin X promotes actin convergence to create the base of filopodia. Then myosin X moves to the filopodia tip and attracts integrin-β and Arp2/3 for further actin nucleation. The tip-located myosin X then initiates the second cycle of filopodia elongation to produce the long filopodia.

Reduced NAA in motor and non-motor brain regions in amyotrophic lateral sclerosis: a cross-sectional and longitudinal study.

Science.gov (United States)

Rule, R R; Suhy, J; Schuff, N; Gelinas, D F; Miller, R G; Weiner, M W

2004-09-01

After replication of previous findings we aimed to: 1) determine if previously reported (1)H MRSI differences between ALS patients and control subjects are limited to the motor cortex; and 2) determine the longitudinal metabolic changes corresponding to varying levels of diagnostic certainty. Twenty-one patients with possible/suspected ALS, 24 patients with probable/definite ALS and 17 control subjects underwent multislice (1)H MRSI co-registered with tissue-segmented MRI to obtain concentrations of the brain metabolites N-acetylaspartate (NAA), creatine, and choline in the left and right motor cortex and in gray matter and white matter of non-motor regions in the brain. In the more affected hemisphere, reductions in the ratios, NAA/Cho and NAA/Cre+Cho were observed both within (12.6% and 9.5% respectively) and outside (9.2% and 7.3% respectively) the motor cortex in probable/definite ALS. However, these reductions were significantly greater within the motor cortex (PNAA/Cho and PNAA/Cre+Cho). Longitudinal changes in NAA were observed at three months within the motor cortex of both possible/suspected ALS patients (PNAA ratios are reduced in the motor cortex and outside the motor cortex in ALS, suggesting widespread neuronal injury. Longitudinal changes of NAA are not reliable, suggesting that NAA may not be a useful surrogate marker for treatment trials.

Direct photoaffinity labeling by nucleotides of the apparent catalytic site on the heavy chains of smooth muscle and Acanthamoeba myosins

International Nuclear Information System (INIS)

Maruta, H.; Korn, E.D.

1981-01-01

The heavy chains of Acanthamoeba myosins, IA, IB and II, turkey gizzard myosin, and rabbit skeletal muscle myosin subfragment-1 were specifically labeled by radioactive ATP, ADP, and UTP, each of which is a substrate or product of myosin ATPase activity, when irradiated with uv light at 0 0 C. With UTP, as much as 0.45 mol/mol of Acanthamoeba myosin IA heavy chain and 1 mol/mol of turkey gizzard myosin heavy chain was incorporated. Evidence that the ligands were associated with the catalytic site included the observations that reaction occurred only with nucleotides that are substrates or products of the ATPase activity; that the reaction was blocked by pyrophosphate which is an inhibitor of the ATPase activity; that ATP was bound as ADP; and that label was probably restricted to a single peptide following limited subtilisin proteolysis of labeled Acanthamoeba myosin IA heavy chain and extensive cleavage with CNBr and trypsin of labeled turkey gizzard myosin heavy chain

Molecular cloning and complete nucleotide sequence of a human ventricular myosin light chain 1

Energy Technology Data Exchange (ETDEWEB)

Hoffmann, E; Shi, Q W; Floroff, M; Mickle, D A.G.; Wu, T W; Olley, P M; Jackowski, G

1988-03-25

Human ventricular plasmid library was constructed. The library was screened with the oligonucleotide probe (17-mer) corresponding to a conserve region of myosin light chain 1 near the carboxy terminal. Full length cDNA recombinant plasmid containing 1100 bp insert was isolated. RNA blot hybridization with this insert detected a message of approximately 1500 bp corresponding to the size of VLCl and mRNA. Complete nucleotide sequence of the coding region was determined in M13 subclones using dideoxy chain termination method. With the isolation of this clone (pCD HLVCl), the publication of the complete nucleotide sequence of HVLCl and the predicted secondary structure of this protein will aid in understanding of the biochemistry of myosin and its function in contraction, the evolution of myosin light genes and the genetic, developmental and physiological regulation of myosin genes.

Assessing the Impact of Electrostatic Drag on Processive Molecular Motor Transport.

Science.gov (United States)

Smith, J Darby; McKinley, Scott A

2018-06-04

The bidirectional movement of intracellular cargo is usually described as a tug-of-war among opposite-directed families of molecular motors. While tug-of-war models have enjoyed some success, recent evidence suggests underlying motor interactions are more complex than previously understood. For example, these tug-of-war models fail to predict the counterintuitive phenomenon that inhibiting one family of motors can decrease the functionality of opposite-directed transport. In this paper, we use a stochastic differential equations modeling framework to explore one proposed physical mechanism, called microtubule tethering, that could play a role in this "co-dependence" among antagonistic motors. This hypothesis includes the possibility of a trade-off: weakly bound trailing molecular motors can serve as tethers for cargoes and processing motors, thereby enhancing motor-cargo run lengths along microtubules; however, this introduces a cost of processing at a lower mean velocity. By computing the small- and large-time mean-squared displacement of our theoretical model and comparing our results to experimental observations of dynein and its "helper protein" dynactin, we find some supporting evidence for microtubule tethering interactions. We extrapolate these findings to predict how dynein-dynactin might interact with the opposite-directed kinesin motors and introduce a criterion for when the trade-off is beneficial in simple systems.

Human Usher 1B/mouse shaker-1: the retinal phenotype discrepancy explained by the presence/absence of myosin VIIA in the photoreceptor cells.

Science.gov (United States)

el-Amraoui, A; Sahly, I; Picaud, S; Sahel, J; Abitbol, M; Petit, C

1996-08-01

Usher syndrome type 1 (USH1) associates severe congenital deafness, vestibular dysfunction and progressive retinitis pigmentosa leading to blindness. The gene encoding myosin VIIA is responsible for USH1B. Mutations in the murine orthologous gene lead to the shaker-1 phenotype, which manifests cochlear and vestibular dysfunction, without any retinal defect. To address this phenotypic discrepancy, the expression of myosin VIIA in retinal cells was analyzed in human and mouse during embryonic development and adult life. In the human embryo, myosin VIIA was present first in the pigment epithelium cells, and later in these cells as well as in the photoreceptor cells. In the adult human retina, myosin VIIA was present in both cell types. In contrast, in mouse, only pigment epithelium cells expressed the protein throughout development and adult life. Myosin VIIA was also found to be absent in the photoreceptor cells of other rodents (rat and guinea-pig), whereas these cells expressed the protein in amphibians, avians and primates. These observations suggest that retinitis pigmentosa of USH1B results from a primary rod and cone defect. The USH1B/shaker-1 paradigm illustrates a species-specific cell pattern of gene expression as a possible cause for the discrepancy between phenotypes involving defective orthologous genes in man and mouse. Interestingly, in the photoreceptor cells, myosin VIIA is mainly localized in the inner and base of outer segments as well as in the synaptic ending region where it is co-localized with the synaptic vesicles. Therefore, we suggest that myosin VIIA might play a role in the trafficking of ribbon-synaptic vesicle complexes and the renewal processes of the outer photoreceptor disks.

CONTRACTION CHARACTERISTICS AND MYOSIN HEAVY-CHAIN COMPOSITION OF RABBIT MASSETER MOTOR UNITS

NARCIS (Netherlands)

KWA, SHS; WEIJS, WA; JUCH, PJW

1. We studied isometric twitch peak force (TPF) and twitch contraction time (TCT) of 249 motor units of the masseter muscle in 41 rabbits after extracellular electrical stimulation of single trigeminal motoneurons in the brain stem. In 41 of these units we determined the amount of tension decrease

Using non-invasive brain stimulation to augment motor training-induced plasticity

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Pascual-Leone Alvaro

2009-03-01

Full Text Available Abstract Therapies for motor recovery after stroke or traumatic brain injury are still not satisfactory. To date the best approach seems to be the intensive physical therapy. However the results are limited and functional gains are often minimal. The goal of motor training is to minimize functional disability and optimize functional motor recovery. This is thought to be achieved by modulation of plastic changes in the brain. Therefore, adjunct interventions that can augment the response of the motor system to the behavioural training might be useful to enhance the therapy-induced recovery in neurological populations. In this context, noninvasive brain stimulation appears to be an interesting option as an add-on intervention to standard physical therapies. Two non-invasive methods of inducing electrical currents into the brain have proved to be promising for inducing long-lasting plastic changes in motor systems: transcranial magnetic stimulation (TMS and transcranial direct current stimulation (tDCS. These techniques represent powerful methods for priming cortical excitability for a subsequent motor task, demand, or stimulation. Thus, their mutual use can optimize the plastic changes induced by motor practice, leading to more remarkable and outlasting clinical gains in rehabilitation. In this review we discuss how these techniques can enhance the effects of a behavioural intervention and the clinical evidence to date.

Artificial muscle-like function from hierarchical supramolecular assembly of photoresponsive molecular motors.

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Chen, Jiawen; Leung, Franco King-Chi; Stuart, Marc C A; Kajitani, Takashi; Fukushima, Takanori; van der Giessen, Erik; Feringa, Ben L

2018-02-01

A striking feature of living systems is their ability to produce motility by amplification of collective molecular motion from the nanoscale up to macroscopic dimensions. Some of nature's protein motors, such as myosin in muscle tissue, consist of a hierarchical supramolecular assembly of very large proteins, in which mechanical stress induces a coordinated movement. However, artificial molecular muscles have often relied on covalent polymer-based actuators. Here, we describe the macroscopic contractile muscle-like motion of a supramolecular system (comprising 95% water) formed by the hierarchical self-assembly of a photoresponsive amphiphilic molecular motor. The molecular motor first assembles into nanofibres, which further assemble into aligned bundles that make up centimetre-long strings. Irradiation induces rotary motion of the molecular motors, and propagation and accumulation of this motion lead to contraction of the fibres towards the light source. This system supports large-amplitude motion, fast response, precise control over shape, as well as weight-lifting experiments in water and air.

Artificial muscle-like function from hierarchical supramolecular assembly of photoresponsive molecular motors

Science.gov (United States)

Chen, Jiawen; Leung, Franco King-Chi; Stuart, Marc C. A.; Kajitani, Takashi; Fukushima, Takanori; van der Giessen, Erik; Feringa, Ben L.

2018-02-01

A striking feature of living systems is their ability to produce motility by amplification of collective molecular motion from the nanoscale up to macroscopic dimensions. Some of nature's protein motors, such as myosin in muscle tissue, consist of a hierarchical supramolecular assembly of very large proteins, in which mechanical stress induces a coordinated movement. However, artificial molecular muscles have often relied on covalent polymer-based actuators. Here, we describe the macroscopic contractile muscle-like motion of a supramolecular system (comprising 95% water) formed by the hierarchical self-assembly of a photoresponsive amphiphilic molecular motor. The molecular motor first assembles into nanofibres, which further assemble into aligned bundles that make up centimetre-long strings. Irradiation induces rotary motion of the molecular motors, and propagation and accumulation of this motion lead to contraction of the fibres towards the light source. This system supports large-amplitude motion, fast response, precise control over shape, as well as weight-lifting experiments in water and air.

How to Measure Load-Dependent Kinetics of Individual Motor Molecules Without a Force-Clamp

DEFF Research Database (Denmark)

Sung, Jongmin; Mortensen, Kim; Spudich, James A.

Molecular motors are responsible for numerous cellular processes from cargo transport to heart contraction. Their interactions with other cellular components are often transient and exhibit kinetics that depend on load. Here, we measure such interactions using a new method, Harmonic Force...... and efficient. The protocol accumulates statistics fast enough to deliver single-molecule results from single-molecule experiments. We demonstrate the method's performance by measuring the force-dependent kinetics of individual human beta-cardiac myosin molecules interacting with an actin filament...... at physiological ATP concentration. We show that a molecule's ADP release rate depends exponentially on the applied load. This points to Kramer's Brownian diffusion model of chemical reactions as explanation why muscle contracts with a velocity inversely proportional to external load....

The impact of physical activity on non-motor symptoms in Parkinson’s disease: a systematic review

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Melanie Elizabeth Cusso

2016-08-01

Full Text Available Parkinson’s disease (PD is a neurological disorder that is associated with both motor and non-motor symptoms. The management of PD is primarily via pharmaceutical treatment, however non-pharmaceutical interventions have become increasingly recognised in the management of motor and non-motor symptoms (NMS. In this review, the efficacy of physical activity, including physiotherapy and occupational therapy, as an intervention in NMS will be assessed. The papers were extracted between the 20th to 22th of June 2016 from Pubmed, Web of Science, Medline, Ovid, SportsDiscuss and Scopus using the MeSH search terms ‘Parkinson’s’, ‘Parkinson’ and ‘Parkinsonism’ in conjunction with ‘exercise’, ‘physical activity’, ‘physiotherapy’, ‘occupational therapy’, ‘physical therapy’, ‘rehabilitation’, ‘dance’ and ‘martial arts’. Twenty studies matched inclusion criteria of having ten or more participants with diagnosed idiopathic PD participating in the intervention as well as having to evaluate the effects of physical activity on NMS in PD as controlled, randomized intervention studies. The outcomes of interest were NMS, including depression, cognition, fatigue, apathy, anxiety and sleep. Risk of bias in the studies was evaluated using the Cochrane Collaboration’s tool for assessing risk of bias. Comparability of the various intervention methods however was challenging due to demographic variability and methodological differences. Nevertheless, physical activity can positively impact the global NMS burden including depression, apathy, fatigue, day time sleepiness, sleep and cognition, thus supporting its therapeutic potential in neurodegenerative conditions such as PD. It is recommended that further adequately powered studies are conducted to assess the therapeutic role of physical activity on both motor and non-motor aspects of PD. These studies should be optimally designed to assess non-motor elements of disease

Somato-motor haptic processing in posterior inner perisylvian region (SII/pIC of the macaque monkey.

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Hiroaki Ishida

Full Text Available The posterior inner perisylvian region including the secondary somatosensory cortex (area SII and the adjacent region of posterior insular cortex (pIC has been implicated in haptic processing by integrating somato-motor information during hand-manipulation, both in humans and in non-human primates. However, motor-related properties during hand-manipulation are still largely unknown. To investigate a motor-related activity in the hand region of SII/pIC, two macaque monkeys were trained to perform a hand-manipulation task, requiring 3 different grip types (precision grip, finger exploration, side grip both in light and in dark conditions. Our results showed that 70% (n = 33/48 of task related neurons within SII/pIC were only activated during monkeys' active hand-manipulation. Of those 33 neurons, 15 (45% began to discharge before hand-target contact, while the remaining neurons were tonically active after contact. Thirty-percent (n = 15/48 of studied neurons responded to both passive somatosensory stimulation and to the motor task. A consistent percentage of task-related neurons in SII/pIC was selectively activated during finger exploration (FE and precision grasping (PG execution, suggesting they play a pivotal role in control skilled finger movements. Furthermore, hand-manipulation-related neurons also responded when visual feedback was absent in the dark. Altogether, our results suggest that somato-motor neurons in SII/pIC likely contribute to haptic processing from the initial to the final phase of grasping and object manipulation. Such motor-related activity could also provide the somato-motor binding principle enabling the translation of diachronic somatosensory inputs into a coherent image of the explored object.

Adaptation and psychometric properties of the Italian version of the Non-Motor Symptoms Questionnaire for Parkinson's disease.

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Cova, I; Di Battista, M E; Vanacore, N; Papi, C P; Alampi, G; Rubino, A; Valente, M; Meco, G; Contri, P; Di Pucchio, A; Lacorte, E; Priori, A; Mariani, C; Pomati, S

2017-04-01

Although non-motor symptoms (NMS) of Parkinson's disease (PD) are very common also in early stages of the disease, they are still under-recognized. Screening tools for non-motor symptoms, such as non-motor symptoms questionnaire (NMSQuest), help clinicians to recognize NMS and to evaluate if patients could require further assessment or specific treatments. To validate an adapted Italian version of NMSQuest and study its psychometric properties, Italian PD patients self-completed Italian NMSQuest, and then underwent a standard clinical evaluation including motor assessment (by Hoehn and Yahr staging, unified Parkinson's disease rating scale part III) and non-motor assessment (by Montreal cognitive assessment, Beck depression inventory, neuropsychiatric inventory, Epworth sleepiness scale, scale for outcomes in Parkinson's disease-Autonomic and movement disorder society-sponsored revision of the unified Parkinson's disease rating scale part I). Somatic comorbidities were quantified using the modified cumulative illness rating scale (CIRS). Seventy-one subjects were assessed (mean age years 69.8 ± 9.6 SD; 31% women; mean duration of disease 6.3 ± 4.6 years; H&Y median 2). Italian NMSQuest showed adequate satisfactory clinimetrics in terms of data quality, precision, acceptability, internal consistency and reliability. A significant correlation was found between NMSQuest and most of non-motor assessment scales, while no significant correlation appeared with motor severity as well as with age of patients, disease duration, levodopa equivalent daily dose, L-DOPA/dopamine agonists assumption and CIRS total score. The Italian version of the NMSQuest resulted as a reliable instrument for screening NMS in Italian PD patients.

High frequency electromagnetic processes in induction motors supplied from PWM inverters

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Ioan Ţilea

2010-12-01

Full Text Available The paper presents the electromagnetic interference between induction motors and inverters when at high frequency electromagnetic process appears in induction motors having a parallel resonant effect because of parasitic capacitive coupling between windings and ground, using a numerical model in simulink and a high frequency induction motor equivalent circuit model this effect is shown.

Contractile properties of motor units and expression of myosin heavy chain isoforms in rat fast-type muscle after volitional weight-lifting training.

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Łochyński, Dawid; Kaczmarek, Dominik; Mrówczyński, Włodzimierz; Warchoł, Wojciech; Majerczak, Joanna; Karasiński, Janusz; Korostyński, Michał; Zoladz, Jerzy A; Celichowski, Jan

2016-10-01

Dynamic resistance training increases the force and speed of muscle contraction, but little is known about modifications to the contractile properties of the main physiological types of motor units (MUs) that contribute to these muscle adaptations. Although the contractile profile of MU muscle fibers is tightly coupled to myosin heavy chain (MyHC) protein expression, it is not well understood if MyHC transition is a prerequisite for modifications to the contractile characteristics of MUs. In this study, we examined MU contractile properties, the mRNA expression of MyHC, parvalbumin, and sarcoendoplasmic reticulum Ca 2+ pump isoforms, as well as the MyHC protein content after 5 wk of volitional progressive weight-lifting training in the medial gastrocnemius muscle in rats. The training had no effect on MyHC profiling or Ca 2+ -handling protein gene expression. Maximum force increased in slow (by 49%) and fast (by 21%) MUs. Within fast MUs, the maximum force increased in most fatigue-resistant and intermediate but not most fatigable MUs. Twitch contraction time was shortened in slow and fast fatigue-resistant MUs. Twitch half-relaxation was shortened in fast most fatigue-resistant and intermediate MUs. The force-frequency curve shifted rightward in fast fatigue-resistant MUs. Fast fatigable MUs fatigued less within the initial 15 s while fast fatigue-resistant units increased the ability to potentiate the force within the first minute of the standard fatigue test. In conclusion, at the early stage of resistance training, modifications to the contractile characteristics of MUs appear in the absence of MyHC transition and the upregulation of Ca 2+ -handling genes. Copyright © 2016 the American Physiological Society.

Regulation of nonmuscle myosin II during 3-methylcholanthrene induced dedifferentiation of C2C12 myotubes

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Dey, Sumit K.; Saha, Shekhar; Das, Provas; Das, Mahua R.; Jana, Siddhartha S., E-mail: bcssj@iacs.res.in

2014-08-01

3-Methylcholanthrene (3MC) induces tumor formation at the site of injection in the hind leg of mice within 110 days. Recent reports reveal that the transformation of normal muscle cells to atypical cells is one of the causes for tumor formation, however the molecular mechanism behind this process is not well understood. Here, we show in an in vitro study that 3MC induces fragmentation of multinucleate myotubes into viable mononucleates. These mononucleates form colonies when they are seeded into soft agar, indicative of cellular transformation. Immunoblot analysis reveals that phosphorylation of myosin regulatory light chain (RLC{sub 20}) is 5.6±0.5 fold reduced in 3MC treated myotubes in comparison to vehicle treated myotubes during the fragmentation of myotubes. In contrast, levels of myogenic factors such as MyoD, Myogenin and cell cycle regulators such as Cyclin D, Cyclin E1 remain unchanged as assessed by real-time PCR array and reverse transcriptase PCR analysis, respectively. Interestingly, addition of the myosin light chain kinase inhibitor, ML-7, enhances the fragmentation, whereas phosphatase inhibitor perturbs the 3MC induced fragmentation of myotubes. These results suggest that decrease in RLC{sub 20} phosphorylation may be associated with the fragmentation step of dedifferentiation. - Highlights: • 3-Methylcholanthrene induces fragmentation of C2C12-myotubes. • Dedifferentiation can be divided into two steps – fragmentation and proliferation. • Fragmentation is associated with rearrangement of nonmuscle myosin II. • Genes associated with differentiation and proliferation are not altered during fragmentation. • Phosphorylation of myosin regulatory light chain is reduced during fragmentation.

Cytoskeletal dynamics

DEFF Research Database (Denmark)

Bendix, Pól Martin

2015-01-01

I worked with reconstitutted contractile acto-myosin systems containing mainly actin, actin cross-linkers and myosin motors. Contractility and rheology of such systems was studied using confocal microscopy and rheology.......I worked with reconstitutted contractile acto-myosin systems containing mainly actin, actin cross-linkers and myosin motors. Contractility and rheology of such systems was studied using confocal microscopy and rheology....

Supplementation with 0.1% and 2% vitamin e in diabetic rats: analysis of myenteric neurons immunostained for myosin-V and nNOS in the jejunum

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Eleandro Aparecido Tronchini

2012-12-01

Full Text Available CONTEXT: Diabetes mellitus is a disease characterized by hyperglycemia that, when allowed to progress long-term untreated, develops vascular and neurological complications, which are responsible for the development of alterations in the enteric nervous system in diabetic patients. In the gastrointestinal tract, diabetes mellitus promotes motor and sensory changes, and in the reflex function of this system, causing gastroparesis, diarrhea, constipation, megacolon, slow gastrointestinal transit, gastric stasis and dilation with decreased or increased peristaltic contractions. Several studies have shown that oxidative stress is the main responsible for the vascular and neurological complications affecting the enteric nervous system of diabetics. OBJECTIVE: The effects of 0.1% and 2% vitamin E on myosin-V- and nNOS-immunoreactive neurons in the jejunum of diabetic rats were investigated. METHODS: Thirty rats were divided into the groups: normoglycemic, normoglycemic treated with 0.1% vitamin E, normoglycemic treated with 2% vitamin E, diabetic, diabetic treated with 0.1% vitamin E, and diabetic treated with 2% vitamin E. The neuronal density and areas of neuron cell bodies were determined. RESULTS: Diabetes (diabetic group significantly reduced the number of myosin-V-immunoreactive neurons compared with the normoglycemic group. The diabetic treated with 0.1% vitamin E and diabetic treated with 2% vitamin E groups did not exhibit a greater density than the D group (P>0.05. Nitrergic density did not change with diabetes (P>0.05. The areas of myosin-V- and nNOS-immunoreactive neurons significantly increased in the normoglycemic treated with 2% vitamin E and diabetic groups compared with the normoglycemic group. CONCLUSION: Supplementation with 2% vitamin E had a neurotrophic effect only in the area of myosin-V-immunoreactive neurons compared with the diabetic group.

Cannabis (medical marijuana) treatment for motor and non-motor symptoms of Parkinson disease: an open-label observational study.

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Lotan, Itay; Treves, Therese A; Roditi, Yaniv; Djaldetti, Ruth

2014-01-01

The use of cannabis as a therapeutic agent for various medical conditions has been well documented. However, clinical trials in patients with Parkinson disease (PD) have yielded conflicting results. The aim of the present open-label observational study was to assess the clinical effect of cannabis on motor and non-motor symptoms of PD. Twenty-two patients with PD attending the motor disorder clinic of a tertiary medical center in 2011 to 2012 were evaluated at baseline and 30 minutes after smoking cannabis using the following battery: Unified Parkinson Disease Rating Scale, visual analog scale, present pain intensity scale, Short-Form McGill Pain Questionnaire, as well as Medical Cannabis Survey National Drug and Alcohol Research Center Questionnaire. Mean (SD) total score on the motor Unified Parkinson Disease Rating Scale score improved significantly from 33.1 (13.8) at baseline to 23.2 (10.5) after cannabis consumption (t = 5.9; P effects of the drug were observed. The study suggests that cannabis might have a place in the therapeutic armamentarium of PD. Larger, controlled studies are needed to verify the results.

Myosin-1A Targets to Microvilli Using Multiple Membrane Binding Motifs in the Tail Homology 1 (TH1) Domain*

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Mazerik, Jessica N.; Tyska, Matthew J.

2012-01-01

One of the most abundant components of the enterocyte brush border is the actin-based monomeric motor, myosin-1a (Myo1a). Within brush border microvilli, Myo1a carries out a number of critical functions at the interface between membrane and actin cytoskeleton. Proper physiological function of Myo1a depends on its ability to bind to microvillar membrane, an interaction mediated by a C-terminal tail homology 1 (TH1) domain. However, little is known about the mechanistic details of the Myo1a-TH1/membrane interaction. Structure-function analysis of Myo1a-TH1 targeting in epithelial cells revealed that an N-terminal motif conserved among class I myosins and a C-terminal motif unique to Myo1a-TH1 are both required for steady state microvillar enrichment. Purified Myo1a bound to liposomes composed of phosphatidylserine and phosphoinositol 4,5-bisphosphate, with moderate affinity in a charge-dependent manner. Additionally, peptides of the N- and C-terminal regions required for targeting were able to compete with Myo1a for binding to highly charged liposomes in vitro. Single molecule total internal reflection fluorescence microscopy showed that these motifs are also necessary for slowing the membrane detachment rate in cells. Finally, Myo1a-TH1 co-localized with both lactadherin-C2 (a phosphatidylserine-binding protein) and PLCδ1-PH (a phosphoinositol 4,5-bisphosphate-binding protein) in microvilli, but only lactaderin-C2 expression reduced brush border targeting of Myo1a-TH1. Together, our results suggest that Myo1a targeting to microvilli is driven by membrane binding potential that is distributed throughout TH1 rather than localized to a single motif. These data highlight the diversity of mechanisms that enable different class I myosins to target membranes in distinct biological contexts. PMID:22367206

Fast But Fleeting: Adaptive Motor Learning Processes Associated with Aging and Cognitive Decline

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Trewartha, Kevin M.; Garcia, Angeles; Wolpert, Daniel M.

2014-01-01

Motor learning has been shown to depend on multiple interacting learning processes. For example, learning to adapt when moving grasped objects with novel dynamics involves a fast process that adapts and decays quickly—and that has been linked to explicit memory—and a slower process that adapts and decays more gradually. Each process is characterized by a learning rate that controls how strongly motor memory is updated based on experienced errors and a retention factor determining the movement-to-movement decay in motor memory. Here we examined whether fast and slow motor learning processes involved in learning novel dynamics differ between younger and older adults. In addition, we investigated how age-related decline in explicit memory performance influences learning and retention parameters. Although the groups adapted equally well, they did so with markedly different underlying processes. Whereas the groups had similar fast processes, they had different slow processes. Specifically, the older adults exhibited decreased retention in their slow process compared with younger adults. Within the older group, who exhibited considerable variation in explicit memory performance, we found that poor explicit memory was associated with reduced retention in the fast process, as well as the slow process. These findings suggest that explicit memory resources are a determining factor in impairments in the both the fast and slow processes for motor learning but that aging effects on the slow process are independent of explicit memory declines. PMID:25274819

Fast but fleeting: adaptive motor learning processes associated with aging and cognitive decline.

Science.gov (United States)

Trewartha, Kevin M; Garcia, Angeles; Wolpert, Daniel M; Flanagan, J Randall

2014-10-01

Motor learning has been shown to depend on multiple interacting learning processes. For example, learning to adapt when moving grasped objects with novel dynamics involves a fast process that adapts and decays quickly-and that has been linked to explicit memory-and a slower process that adapts and decays more gradually. Each process is characterized by a learning rate that controls how strongly motor memory is updated based on experienced errors and a retention factor determining the movement-to-movement decay in motor memory. Here we examined whether fast and slow motor learning processes involved in learning novel dynamics differ between younger and older adults. In addition, we investigated how age-related decline in explicit memory performance influences learning and retention parameters. Although the groups adapted equally well, they did so with markedly different underlying processes. Whereas the groups had similar fast processes, they had different slow processes. Specifically, the older adults exhibited decreased retention in their slow process compared with younger adults. Within the older group, who exhibited considerable variation in explicit memory performance, we found that poor explicit memory was associated with reduced retention in the fast process, as well as the slow process. These findings suggest that explicit memory resources are a determining factor in impairments in the both the fast and slow processes for motor learning but that aging effects on the slow process are independent of explicit memory declines. Copyright © 2014 the authors 0270-6474/14/3413411-11$15.00/0.

Body-part specific interactions of action verb processing with motor behaviour.

Science.gov (United States)

Klepp, Anne; Niccolai, Valentina; Sieksmeyer, Jan; Arnzen, Stephanie; Indefrey, Peter; Schnitzler, Alfons; Biermann-Ruben, Katja

2017-06-15

The interaction of action-related language processing with actual movement is an indicator of the functional role of motor cortical involvement in language understanding. This paper describes two experiments using single action verb stimuli. Motor responses were performed with the hand or the foot. To test the double dissociation of language-motor facilitation effects within subjects, Experiments 1 and 2 used a priming procedure where both hand and foot reactions had to be performed in response to different geometrical shapes, which were preceded by action verbs. In Experiment 1, the semantics of the verbs could be ignored whereas Experiment 2 included semantic decisions. Only Experiment 2 revealed a clear double dissociation in reaction times: reactions were facilitated when preceded by verbs describing actions with the matching effector. In Experiment 1, by contrast, there was an interaction between verb-response congruence and a semantic variable related to motor features of the verbs. Thus, the double dissociation paradigm of semantic motor priming was effective, corroborating the role of the motor system in action-related language processing. Importantly, this effect was body part specific. Copyright © 2017 Elsevier B.V. All rights reserved.

Myosin II activity is required for functional leading-edge cells and closure of epidermal sheets in fish skin ex vivo.

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Morita, Toshiyuki; Tsuchiya, Akiko; Sugimoto, Masazumi

2011-09-01

Re-epithelialization in skin wound healing is a process in which epidermal sheets grow and close the wound. Although the actin-myosin system is thought to have a pivotal role in re-epithelialization, its role is not clear. In fish skin, re-epithelialization occurs around 500 μm/h and is 50 times faster than in mammalian skin. We had previously reported that leading-edge cells of the epidermal outgrowth have both polarized large lamellipodia and "purse string"-like actin filament cables in the scale-skin culture system of medaka fish, Oryzias latipes (Cell Tissue Res, 2007). The actin purse-string (APS) is a supracellular contractile machinery in which adherens junctions (AJs) link intracellular myosin II-including actin cables between neighboring cells. In this study, we developed a modified "face-to-face" scale-skin culture system as an ex vivo model to study epidermal wound healing, and examined the role of the actin-myosin system in the rapid re-epithelialization using a myosin II ATPase inhibitor, blebbistatin. A low level of blebbistatin suppressed the formation of APS and induced the dissociation of keratocytes from the leading edge without attenuating the growth of the epidermal sheet or the migration rate of solitary keratocytes. AJs in the superficial layer showed no obvious changes elicited by blebbistatin. However, two epidermal sheets without APSs did not make a closure with each other, which was confirmed by inhibiting the connecting AJs between the superficial layers. These results suggest that myosin II activity is required for functional leading-edge cells and for epidermal closure.

Association of Myosin Va and Schwann cells-derived RNA in mammal myelinated axons, analyzed by immunocytochemistry and confocal FRET microscopy.

Science.gov (United States)

Canclini, Lucía; Wallrabe, Horst; Di Paolo, Andrés; Kun, Alejandra; Calliari, Aldo; Sotelo-Silveira, José Roberto; Sotelo, José Roberto

2014-03-15

Evidence from multiple sources supports the hypothesis that Schwann cells in the peripheral nervous system transfer messenger RNA and ribosomes to the axons they ensheath. Several technical and methodological difficulties exist for investigators to unravel this process in myelinated axons - a complex two-cell unit. We present an experimental design to demonstrate that newly synthesized RNA is transferred from Schwann cells to axons in association with Myosin Va. The use of quantitative confocal FRET microscopy to track newly-synthesized RNA and determine the molecular association with Myosin Va, is described in detail. Copyright © 2013 Elsevier Inc. All rights reserved.

Parathyroid hormone promotes the disassembly of cytoskeletal actin and myosin in cultured osteoblastic cells: Mediation by cyclic AMP

International Nuclear Information System (INIS)

Egan, J.J.; Gronowicz, G.; Rodan, G.A.

1991-01-01

Parathyroid hormone (PTH) alters the shape of osteoblastic cells both in vivo and in vitro. In this study, we examined the effect of PTH on cytoskeletal actin and myosin, estimated by polyacrylamide gel electrophoresis of Triton X-100 (1%) nonextractable proteins. After 2-5 minutes, PTH caused a rapid and transient decrease of 50-60% in polymerized actin and myosin associated with the Triton X-100 nonextractable cytoskeleton. Polymerized actin returned to control levels by 30 min. The PTH effect was dose-dependent with an IC50 of about 1 nM, and was partially inhibited by the (3-34) PTH antagonist. PTH caused a rapid transient rise in cyclic AMP (cAMP) in these cells that peaked at 4 min, while the nadir in cytoskeletal actin and myosin was recorded around 5 min. The intracellular calcium chelator Quin-2/AM (10 microM) also decreased cytoskeletal actin and myosin, to the same extent as did PTH (100 nM). To distinguish between cAMP elevation and Ca++ reduction as mediators of PTH action, we measured the phosphorylation of the 20 kD (PI 4.9) myosin light chain in cells preincubated with [32P]-orthophosphate. The phosphorylation of this protein decreased within 2-3 min after PTH addition and returned to control levels after 5 min. The calcium ionophore A-23187 did not antagonize this PTH effect. Visualization of microfilaments with rhodamine-conjugated phalloidin showed that PTH altered the cytoskeleton by decreasing the number of stress fibers. These changes in the cytoskeleton paralleled changes in the shape of the cells from a spread configuration to a stellate form with retracting processes. The above findings indicate that the alteration in osteoblast shape produced by PTH involve relatively rapid and transient changes in cytoskeletal organization that appear to be mediated by cAMP

Zinc-induced cardiomyocyte relaxation in a rat model of hyperglycemia is independent of myosin isoform

Directory of Open Access Journals (Sweden)

Yi Ting

2012-11-01

Full Text Available Abstract It has been reported previously that diabetic cardiomyopathy can be inhibited or reverted with chronic zinc supplementation. In the current study, we hypothesized that total cardiac calcium and zinc content is altered in early onset diabetes mellitus characterized in part as hyperglycemia (HG and that exposure of zinc ion (Zn2+ to isolated cardiomyocytes would enhance contraction-relaxation function in HG more so than in nonHG controls. To better control for differential cardiac myosin isoform expression as occurs in rodents after β-islet cell necrosis, hypothyroidism was induced in 16 rats resulting in 100% β-myosin heavy chain expression in the heart. β-Islet cell necrosis was induced in half of the rats by streptozocin administration. After 6 wks of HG, both HG and nonHG controls rats demonstrated similar myofilament performance measured as thin filament calcium sensitivity, native thin filament velocity in the myosin motility assay and contractile velocity and power. Extracellular Zn2+ reduced cardiomyocyte contractile function in both groups, but enhanced relaxation function significantly in the HG group compared to controls. Most notably, a reduction in diastolic sarcomere length with increasing pacing frequencies, i.e., incomplete relaxation, was more pronounced in the HG compared to controls, but was normalized with extracellular Zn2+ application. This is a novel finding implicating that the detrimental effect of HG on cardiomyocyte Ca2+ regulation can be amelioration by Zn2+. Among the many post-translational modifications examined, only phosphorylation of ryanodine receptor (RyR at S-2808 was significantly higher in HG compared to nonHG. We did not find in our hypothyroid rats any differentiating effects of HG on myofibrillar protein phosphorylation, lysine acetylation, O-linked N-acetylglucosamine and advanced glycated end-products, which are often implicated as complicating factors in cardiac performance due to HG. Our

Motor-cognitive dual-task performance: effects of a concurrent motor task on distinct components of visual processing capacity.

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Künstler, E C S; Finke, K; Günther, A; Klingner, C; Witte, O; Bublak, P

2018-01-01

Dual tasking, or the simultaneous execution of two continuous tasks, is frequently associated with a performance decline that can be explained within a capacity sharing framework. In this study, we assessed the effects of a concurrent motor task on the efficiency of visual information uptake based on the 'theory of visual attention' (TVA). TVA provides parameter estimates reflecting distinct components of visual processing capacity: perceptual threshold, visual processing speed, and visual short-term memory (VSTM) storage capacity. Moreover, goodness-of-fit values and bootstrapping estimates were derived to test whether the TVA-model is validly applicable also under dual task conditions, and whether the robustness of parameter estimates is comparable in single- and dual-task conditions. 24 subjects of middle to higher age performed a continuous tapping task, and a visual processing task (whole report of briefly presented letter arrays) under both single- and dual-task conditions. Results suggest a decline of both visual processing capacity and VSTM storage capacity under dual-task conditions, while the perceptual threshold remained unaffected by a concurrent motor task. In addition, goodness-of-fit values and bootstrapping estimates support the notion that participants processed the visual task in a qualitatively comparable, although quantitatively less efficient way under dual-task conditions. The results support a capacity sharing account of motor-cognitive dual tasking and suggest that even performing a relatively simple motor task relies on central attentional capacity that is necessary for efficient visual information uptake.

Short-term quality of life after subthalamic stimulation depends on non-motor symptoms in Parkinson's disease.

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Dafsari, Haidar Salimi; Weiß, Luisa; Silverdale, Monty; Rizos, Alexandra; Reddy, Prashanth; Ashkan, Keyoumars; Evans, Julian; Reker, Paul; Petry-Schmelzer, Jan Niklas; Samuel, Michael; Visser-Vandewalle, Veerle; Antonini, Angelo; Martinez-Martin, Pablo; Ray-Chaudhuri, K; Timmermann, Lars

2018-02-24

Subthalamic nucleus (STN) deep brain stimulation (DBS) improves quality of life (QoL), motor, and non-motor symptoms (NMS) in advanced Parkinson's disease (PD). However, considerable inter-individual variability has been observed for QoL outcome. We hypothesized that demographic and preoperative NMS characteristics can predict postoperative QoL outcome. In this ongoing, prospective, multicenter study (Cologne, Manchester, London) including 88 patients, we collected the following scales preoperatively and on follow-up 6 months postoperatively: PDQuestionnaire-8 (PDQ-8), NMSScale (NMSS), NMSQuestionnaire (NMSQ), Scales for Outcomes in PD (SCOPA)-motor examination, -complications, and -activities of daily living, levodopa equivalent daily dose. We dichotomized patients into "QoL responders"/"non-responders" and screened for factors associated with QoL improvement with (1) Spearman-correlations between baseline test scores and QoL improvement, (2) step-wise linear regressions with baseline test scores as independent and QoL improvement as dependent variables, (3) logistic regressions using aforementioned "responders/non-responders" as dependent variable. All outcomes improved significantly on follow-up. However, approximately 44% of patients were categorized as "QoL non-responders". Spearman-correlations, linear and logistic regression analyses were significant for NMSS and NMSQ but not for SCOPA-motor examination. Post-hoc, we identified specific NMS (flat moods, difficulties experiencing pleasure, pain, bladder voiding) as significant contributors to QoL outcome. Our results provide evidence that QoL improvement after STN-DBS depends on preoperative NMS characteristics. These findings are important in the advising and selection of individuals for DBS therapy. Future studies investigating motor and non-motor PD clusters may enable stratifying QoL outcomes and help predict patients' individual prospects of benefiting from DBS. Copyright © 2018. Published by Elsevier

The impact of high intensity physical training on motor and non-motor symptoms in patients with Parkinson's disease (PIP)

DEFF Research Database (Denmark)

Morberg, Bo M; Jensen, Joakim; Bode, Matthias

2014-01-01

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disease caused by loss of dopaminergic nigrostriatal neurons. Several studies have investigated various physical interventions on PD. The effects of a high intensity exercise program with focus on resistance; cardio; equilibrium......; and flexibility training have not been evaluated previously. OBJECTIVE: The aim of this study was to investigate the effects of a complex, high intensity physical training program, with a long duration, on motor and non-motor symptoms in patients with PD. METHOD: 24 patients with PD Hoehn and Yahr stage 1-3 were...... non-randomly allocated to an intervention group (n = 12) and a control group (n = 12). The intervention group underwent 32 weeks of high intensity personalized physical training twice a week, with an optional extra training session once a week. The control group received general recommendations...

Learning-performance distinction and memory processes for motor skills: a focused review and perspective.

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Kantak, Shailesh S; Winstein, Carolee J

2012-03-01

Behavioral research in cognitive psychology provides evidence for an important distinction between immediate performance that accompanies practice and long-term performance that reflects the relative permanence in the capability for the practiced skill (i.e. learning). This learning-performance distinction is strikingly evident when challenging practice conditions may impair practice performance, but enhance long-term retention of motor skills. A review of motor learning studies with a specific focus on comparing differences in performance between that at the end of practice and at delayed retention suggests that the delayed retention or transfer performance is a better indicator of motor learning than the performance at (or end of) practice. This provides objective evidence for the learning-performance distinction. This behavioral evidence coupled with an understanding of the motor memory processes of encoding, consolidation and retrieval may provide insight into the putative mechanism that implements the learning-performance distinction. Here, we propose a simplistic empirically-based framework--motor behavior-memory framework--that integrates the temporal evolution of motor memory processes with the time course of practice and delayed retention frequently used in behavioral motor learning paradigms. In the context of the proposed framework, recent research has used noninvasive brain stimulation to decipher the role of each motor memory process, and specific cortical brain regions engaged in motor performance and learning. Such findings provide beginning insights into the relationship between the time course of practice-induced performance changes and motor memory processes. This in turn has promising implications for future research and practical applications. Copyright © 2011 Elsevier B.V. All rights reserved.

Differential Effects of Motor Efference Copies and Proprioceptive Information on Response Evaluation Processes

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Stock, Ann-Kathrin; Wascher, Edmund; Beste, Christian

2013-01-01

It is well-kown that sensory information influences the way we execute motor responses. However, less is known about if and how sensory and motor information are integrated in the subsequent process of response evaluation. We used a modified Simon Task to investigate how these streams of information are integrated in response evaluation processes, applying an in-depth neurophysiological analysis of event-related potentials (ERPs), time-frequency decomposition and sLORETA. The results show that response evaluation processes are differentially modulated by afferent proprioceptive information and efference copies. While the influence of proprioceptive information is mediated via oscillations in different frequency bands, efference copy based information about the motor execution is specifically mediated via oscillations in the theta frequency band. Stages of visual perception and attention were not modulated by the interaction of proprioception and motor efference copies. Brain areas modulated by the interactive effects of proprioceptive and efference copy based information included the middle frontal gyrus and the supplementary motor area (SMA), suggesting that these areas integrate sensory information for the purpose of response evaluation. The results show how motor response evaluation processes are modulated by information about both the execution and the location of a response. PMID:23658624

Thick filament length and isoform composition determine self-organized contractile units in actomyosin bundles.

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Thoresen, Todd; Lenz, Martin; Gardel, Margaret L

2013-02-05

Diverse myosin II isoforms regulate contractility of actomyosin bundles in disparate physiological processes by variations in both motor mechanochemistry and the extent to which motors are clustered into thick filaments. Although the role of mechanochemistry is well appreciated, the extent to which thick filament length regulates actomyosin contractility is unknown. Here, we study the contractility of minimal actomyosin bundles formed in vitro by mixtures of F-actin and thick filaments of nonmuscle, smooth, and skeletal muscle myosin isoforms with varied length. Diverse myosin II isoforms guide the self-organization of distinct contractile units within in vitro bundles with shortening rates similar to those of in vivo myofibrils and stress fibers. The tendency to form contractile units increases with the thick filament length, resulting in a bundle shortening rate proportional to the length of constituent myosin thick filament. We develop a model that describes our data, providing a framework in which to understand how diverse myosin II isoforms regulate the contractile behaviors of disordered actomyosin bundles found in muscle and nonmuscle cells. These experiments provide insight into physiological processes that use dynamic regulation of thick filament length, such as smooth muscle contraction. Copyright © 2013 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Myosin phosphorylation improves contractile economy of mouse fast skeletal muscle during staircase potentiation.

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Bunda, Jordan; Gittings, William; Vandenboom, Rene

2018-01-30

Phosphorylation of the myosin regulatory light chain (RLC) by skeletal myosin light chain kinase (skMLCK) potentiates rodent fast twitch muscle but is an ATP-requiring process. Our objective was to investigate the effect of skMLCK-catalyzed RLC phosphorylation on the energetic cost of contraction and the contractile economy (ratio of mechanical output to metabolic input) of mouse fast twitch muscle in vitro (25°C). To this end, extensor digitorum longus (EDL) muscles from wild-type (WT) and from skMLCK-devoid (skMLCK -/- ) mice were subjected to repetitive low-frequency stimulation (10 Hz for 15 s) to produce staircase potentiation of isometric twitch force, after which muscles were quick frozen for determination of high-energy phosphate consumption (HEPC). During stimulation, WT muscles displayed significant potentiation of isometric twitch force while skMLCK -/- muscles did not (i.e. 23% versus 5% change, respectively). Consistent with this, RLC phosphorylation was increased ∼3.5-fold from the unstimulated control value in WT but not in skMLCK -/- muscles. Despite these differences, the HEPC of WT muscles was not greater than that of skMLCK -/- muscles. As a result of the increased contractile output relative to HEPC, the calculated contractile economy of WT muscles was greater than that of skMLCK -/- muscles. Thus, our results suggest that skMLCK-catalyzed phosphorylation of the myosin RLC increases the contractile economy of WT mouse EDL muscle compared with skMLCK -/- muscles without RLC phosphorylation. © 2018. Published by The Company of Biologists Ltd.

Planning-related motor processes underlie mental practice and imitation learning.

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Bach, Patric; Allami, Bassem Khalaf; Tucker, Mike; Ellis, Rob

2014-06-01

It is still controversial whether mental practice-the internal rehearsal of movements to improve later performance-relies on processes engaged during physical motor performance and, if so, which processes these are. We report data from 5 experiments, in which participants mentally practiced complex rhythms with either feet or hands while using the same or different body parts to respond to unrelated sounds. We found that responses were impaired for those body parts that were concurrently used in mental practice, suggesting a binding of body-part-specific motor processes to action plans. This result was found when participants mentally trained to memorize the rhythms, to merely improve their performance, when mental practice and execution directly followed one another and when separated by a different task. Finally, it was found irrespective of whether participants practiced on the basis of a symbolic rhythm description and when they practiced by watching somebody perform the rhythms (imitation learning). The effect was eliminated only when the requirement for mental practice was eliminated from the task while keeping visual stimulation identical. These data link mental practice not to execution but planning related motor processes and reveal that these planning processes underlie both mental practice and imitation learning. PsycINFO Database Record (c) 2014 APA, all rights reserved.

Non-invasive brain stimulation for fine motor improvement after stroke: a meta-analysis.

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O'Brien, A T; Bertolucci, F; Torrealba-Acosta, G; Huerta, R; Fregni, F; Thibaut, A

2018-05-09

The aim of this study was to determine whether non-invasive brain stimulation (NIBS) techniques improve fine motor performance in stroke. We searched PubMed, EMBASE, Web of Science, SciELO and OpenGrey for randomized clinical trials on NIBS for fine motor performance in stroke patients and healthy participants. We computed Hedges' g for active and sham groups, pooled data as random-effects models and performed sensitivity analysis on chronicity, montage, frequency of stimulation and risk of bias. Twenty-nine studies (351 patients and 152 healthy subjects) were reviewed. Effect sizes in stroke populations for transcranial direct current stimulation and repeated transcranial magnetic stimulation were 0.31 [95% confidence interval (CI), 0.08-0.55; P = 0.010; Tau 2 , 0.09; I 2 , 34%; Q, 18.23; P = 0.110] and 0.46 (95% CI, 0.00-0.92; P = 0.05; Tau 2 , 0.38; I 2 , 67%; Q, 30.45; P = 0.007). The effect size of non-dominant healthy hemisphere transcranial direct current stimulation on non-dominant hand function was 1.25 (95% CI, 0.09-2.41; P = 0.04; Tau 2 , 1.26; I 2 , 93%; Q, 40.27; P < 0.001). Our results show that NIBS is associated with gains in fine motor performance in chronic stroke patients and healthy subjects. This supports the effects of NIBS on motor learning and encourages investigation to optimize their effects in clinical and research settings. © 2018 EAN.

The study of transient processes in the asynchronous starting of the synchronous motor

OpenAIRE

Alexandru Bârlea; Olivian Chiver

2012-01-01

Starting synchronous motors can be achieved by several ethods: starting with an auxiliary motor launch, starting in asynchronous regim, by feeding from a variable frequency source, auto-synchronization with the network.. In our case we study the transient processes in a asynchronous regim . In this case the synchronous motor is started like a squirrel cage induction motor . To start, the synchronous motor is equipped with a starting winding cage placed in the pole pieces of polar inducers; la...

Drosophila PINK1 and parkin loss-of-function mutants display a range of non-motor Parkinson's disease phenotypes.

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Julienne, Hannah; Buhl, Edgar; Leslie, David S; Hodge, James J L

2017-08-01

Parkinson's disease (PD) is more commonly associated with its motor symptoms and the related degeneration of dopamine (DA) neurons. However, it is becoming increasingly clear that PD patients also display a wide range of non-motor symptoms, including memory deficits and disruptions of their sleep-wake cycles. These have a large impact on their quality of life, and often precede the onset of motor symptoms, but their etiology is poorly understood. The fruit fly Drosophila has already been successfully used to model PD, and has been used extensively to study relevant non-motor behaviours in other contexts, but little attention has yet been paid to modelling non-motor symptoms of PD in this genetically tractable organism. We examined memory performance and circadian rhythms in flies with loss-of-function mutations in two PD genes: PINK1 and parkin. We found learning and memory abnormalities in both mutant genotypes, as well as a weakening of circadian rhythms that is underpinned by electrophysiological changes in clock neurons. Our study paves the way for further work that may help us understand the mechanisms underlying these neglected aspects of PD, thus identifying new targets for treatments to address these non-motor problems specifically and perhaps even to halt disease progression in its prodromal phase. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

THE TRANSFORMATIONAL PROCESSES INVOLVING MOTOR SKILLS THAT OCCUR UNDER THE INFLUENCE OF BASIC PRELIMINARY TRAINING IN YOUNG HANDBALL PLAYERS

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Markovic Sasa

2011-06-01

Full Text Available The population from which we extracted a sample of 76 subjects consisted of elementary school students in Kursumlija, all male, aged 12-13, who were divided into a sub-sample consisting of 38 young handball players who took part in the training sessions of a school of handball and another sub-sample consisting of 38 non-athletes, who only took part in their regular physical education classes. The aim of the research was to determine the transformation processes involving motor skills, which occur under the influence of basic preliminary training in young handball players. The subject matter of the study was to examine whether a statistically significant increase in the level of motor skills would occur under the influence of physical exercise as part of basic preliminary training in the final as compared to the initial state. Six motor tests which define the dimensions of explosive and repetitive strength were used. The results of the research indicate that significant transformational processes involving the motor skills of young handball players occurred in the final as compared to the initial measuring, under the influence of basic preliminary training.

The relationships between gross motor coordination and sport-specific skills in adolescent non-athletes

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Chagas Daniel V

2017-12-01

Full Text Available Purpose. While the usefulness of gross motor coordination score as predictor of sports performance in young athletes has been demonstrated, practical applications in the settings where the focus is not on elite performance is limited. Further, little is known about the extent to which gross motor coordination score is associated with sport-specific skills among adolescent nonathletes. The aim of this study was to analyse the relationship between the degree of gross motor coordination and execution in specific volleyball tests among adolescent non-athletes. Methods. The total of 34 students (27 females and 7 males aged 13-14 years who regularly participated in volleyball during physical education classes were randomly recruited. Gross motor coordination was assessed with the Körperkoordinationstest für Kinder. Motor performance on volley-specific skills was indicated by two product-oriented tasks: volleyball under service and service reception. Correlation and linear regression analyses were applied to examine the associations between motor coordination scores and motor performance in volley-specific skills. Results. Motor coordination score was positively correlated with motor performance on specific skills (r = 0.503, p = 0.02. Linear regression analysis revealed that motor coordination score accounted for 23% of the variance in the motor performance on volleyball skills (R2 = 0.253, R2 adjusted = 0.230, F = 10.836, p = 0.02. Conclusions. The degree of gross motor coordination seems to play a significant role in the execution of specific volleyball tasks.

Myosin IIA interacts with the spectrin-actin membrane skeleton to control red blood cell membrane curvature and deformability.

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Smith, Alyson S; Nowak, Roberta B; Zhou, Sitong; Giannetto, Michael; Gokhin, David S; Papoin, Julien; Ghiran, Ionita C; Blanc, Lionel; Wan, Jiandi; Fowler, Velia M

2018-05-08

The biconcave disk shape and deformability of mammalian RBCs rely on the membrane skeleton, a viscoelastic network of short, membrane-associated actin filaments (F-actin) cross-linked by long, flexible spectrin tetramers. Nonmuscle myosin II (NMII) motors exert force on diverse F-actin networks to control cell shapes, but a function for NMII contractility in the 2D spectrin-F-actin network of RBCs has not been tested. Here, we show that RBCs contain membrane skeleton-associated NMIIA puncta, identified as bipolar filaments by superresolution fluorescence microscopy. MgATP disrupts NMIIA association with the membrane skeleton, consistent with NMIIA motor domains binding to membrane skeleton F-actin and contributing to membrane mechanical properties. In addition, the phosphorylation of the RBC NMIIA heavy and light chains in vivo indicates active regulation of NMIIA motor activity and filament assembly, while reduced heavy chain phosphorylation of membrane skeleton-associated NMIIA indicates assembly of stable filaments at the membrane. Treatment of RBCs with blebbistatin, an inhibitor of NMII motor activity, decreases the number of NMIIA filaments associated with the membrane and enhances local, nanoscale membrane oscillations, suggesting decreased membrane tension. Blebbistatin-treated RBCs also exhibit elongated shapes, loss of membrane curvature, and enhanced deformability, indicating a role for NMIIA contractility in promoting membrane stiffness and maintaining RBC biconcave disk cell shape. As structures similar to the RBC membrane skeleton exist in many metazoan cell types, these data demonstrate a general function for NMII in controlling specialized membrane morphology and mechanical properties through contractile interactions with short F-actin in spectrin-F-actin networks.

Differences of Fundamental Motor Skills Stunting and Non Stunting Preschool Children in Kindergarten in North Padang

Science.gov (United States)

Komaini, A.; Mardela, R.

2018-04-01

The problem that emerged is based on the result of research done by the writer in kindergarten in North Padang Sub-district which concluded that: there were kindergarten students in this sub-district who were still lack of motor ability, research data shows that 59 people (37,34%) and then 34 people (21, 52%) were in very good category, 35 people (22.15%), were in moderate category, 22 people (13.92%) were in the poor category, and 5 (5,06%) were in the very poor category. Based on this data, the authors thought that the dominant factors that affect the above situation was a nutritional factor. It could be seen from the physical appearance of kindergarten children who tend to slow growth. The purpose of this study is to explain the description and differences in stunting and non stunting Fundamental motor skills capabilities in early childhood (preschool) children. This research is comparative study with cross sectional approach. The population in this study was the students of Kindergarten of Perwari II which consisted of 60 people consisting of 37 children of stunting and 23 non stunting children in Kindergarten of North Padang Sub district, the sample was taken as a whole. The data were collected with Fundamental motor skills tests including jumping, walking, running, balance exercises, throwing and catching the ball. Technique of data analysis in this research was descriptive statistic. The result of data analysis shows that there is difference of Fundamental motor skills between stunting and non stunting children. Fundamental motor skills of non stunting or normal children are better than those who were stunting or short. While the results of Fundamental motor skills of kindergarten children in North Padang District as a whole is at a good level.

Comparative analysis of two immunohistochemical methods for antigen retrieval in the optical lobe of the honeybee Apis mellifera: Myosin-v assay

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LUCIANA KAREN CALÁBRIA

2010-01-01

Full Text Available The present study compared two heating methods currently used for antigen retrieval (AR immunostaining: the microwave oven and the steam cooker. Myosin-V, a molecular motor involved in vesicle transport, was used as a neuronal marker in honeybee Apis mellifera brains fixed in formalin. Overall, the steam cooker showed the most satisfactory AR results. At 100 ºC, tissue morphology was maintained and revealed epitope recovery, while evaporation of the AR solution was markedly reduced; this is important for stabilizing the sodium citrate molarity of the AR buffer and reducing background effects. Standardization of heat-mediated AR of formalin-fixed and paraffin-embedded tissue sections results in more reliable immunostaining of the honeybee brain.

Phosphorylation of Tropomyosin Extends Cooperative Binding of Myosin Beyond a Single Regulatory Unit

OpenAIRE

Rao, Vijay S.; Marongelli, Ellisha N.; Guilford, William H.

2009-01-01

Tropomyosin (Tm) is one of the major phosphoproteins comprising the thin filament of muscle. However, the specific role of Tm phosphorylation in modulating the mechanics of actomyosin interaction has not been determined. Here we show that Tm phosphorylation is necessary for long-range cooperative activation of myosin binding. We used a novel optical trapping assay to measure the isometric stall force of an ensemble of myosin molecules moving actin filaments reconstituted with either natively ...

Motoric subtypes of delirium in geriatric patients

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Sandeep Grover

2014-01-01

Results: On amended DMSS, hyperactive subtype (N = 45; 45.9% was the most common motoric subtype of delirium, followed by hypoactive subtype (N = 23; 23.5%, and mixed subtype (N = 21; 21.4%. On DRS-R-98, all patients fulfilled the criteria of ′acute (temporal onset of symptoms′, ′presence of an underlying physical disorder′ and ′difficulty in attention′. In the total sample, >90% of the patients had disturbances in sleep-wake cycle, orientation and fluctuation of symptoms. The least common symptoms were delusions, visuospatial disturbances and motor retardation. When compared to hypoactive group, significantly higher proportion of patients with hyperactive subtype had delusions, perceptual disturbances, and motor agitation. Whereas, compared to hyperactive subtype, significantly higher proportion of patients with hypoactive subtype had thought process abnormality and motor retardation. When the hyperactive and mixed motoric subtype groups were compared, patients with mixed subtype group had significantly higher prevalence of thought process abnormality and motor retardation. Comparison of hypoactive and mixed subtype revealed significant differences in the frequency of perceptual disturbances, delusions and motor agitation and all these symptoms being found more commonly in patients with the mixed subtype. Severity of symptoms were found to be significantly different across the various motoric subtypes for some of the non-cognitive symptoms, but significant differences were not seen for the cognitive symptoms as assessed on DRS-R-98. Conclusion: In elderly patients, motor subtypes of delirium differ from each other on non-cognitive symptom profile in terms of frequency and severity.

HSPB1 mutations causing hereditary neuropathy in humans disrupt non-cell autonomous protection of motor neurons.

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Heilman, Patrick L; Song, SungWon; Miranda, Carlos J; Meyer, Kathrin; Srivastava, Amit K; Knapp, Amy; Wier, Christopher G; Kaspar, Brian K; Kolb, Stephen J

2017-11-01

Heat shock protein beta-1 (HSPB1), is a ubiquitously expressed, multifunctional protein chaperone. Mutations in HSPB1 result in the development of a late-onset, distal hereditary motor neuropathy type II (dHMN) and axonal Charcot-Marie Tooth disease with sensory involvement (CMT2F). The functional consequences of HSPB1 mutations associated with hereditary neuropathy are unknown. HSPB1 also displays neuroprotective properties in many neuronal disease models, including the motor neuron disease amyotrophic lateral sclerosis (ALS). HSPB1 is upregulated in SOD1-ALS animal models during disease progression, predominately in glial cells. Glial cells are known to contribute to motor neuron loss in ALS through a non-cell autonomous mechanism. In this study, we examined the non-cell autonomous role of wild type and mutant HSPB1 in an astrocyte-motor neuron co-culture model system of ALS. Astrocyte-specific overexpression of wild type HSPB1 was sufficient to attenuate SOD1(G93A) astrocyte-mediated toxicity in motor neurons, whereas, overexpression of mutHSPB1 failed to ameliorate motor neuron toxicity. Expression of a phosphomimetic HSPB1 mutant in SOD1(G93A) astrocytes also reduced toxicity to motor neurons, suggesting that phosphorylation may contribute to HSPB1 mediated-neuroprotection. These data provide evidence that astrocytic HSPB1 expression may play a central role in motor neuron health and maintenance. Copyright © 2017 Elsevier Inc. All rights reserved.

An adhesome comprising laminin, dystroglycan and myosin IIA is required during notochord development in Xenopus laevis.

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Buisson, Nicolas; Sirour, Cathy; Moreau, Nicole; Denker, Elsa; Le Bouffant, Ronan; Goullancourt, Aline; Darribère, Thierry; Bello, Valérie

2014-12-01

Dystroglycan (Dg) is a transmembrane receptor for laminin that must be expressed at the right time and place in order to be involved in notochord morphogenesis. The function of Dg was examined in Xenopus laevis embryos by knockdown of Dg and overexpression and replacement of the endogenous Dg with a mutated form of the protein. This analysis revealed that Dg is required for correct laminin assembly, for cell polarization during mediolateral intercalation and for proper differentiation of vacuoles. Using mutations in the cytoplasmic domain, we identified two sites that are involved in cell polarization and are required for mediolateral cell intercalation, and a site that is required for vacuolation. Furthermore, using a proteomic analysis, the cytoskeletal non-muscle myosin IIA has been identified for the first time as a molecular link between the Dg-cytoplasmic domain and cortical actin. The data allowed us to identify the adhesome laminin-Dg-myosin IIA as being required to maintain the cortical actin cytoskeleton network during vacuolation, which is crucial to maintain the shape of notochordal cells. © 2014. Published by The Company of Biologists Ltd.

Neurons other than motor neurons in motor neuron disease.

Science.gov (United States)

Ruffoli, Riccardo; Biagioni, Francesca; Busceti, Carla L; Gaglione, Anderson; Ryskalin, Larisa; Gambardella, Stefano; Frati, Alessandro; Fornai, Francesco

2017-11-01

Amyotrophic lateral sclerosis (ALS) is typically defined by a loss of motor neurons in the central nervous system. Accordingly, morphological analysis for decades considered motor neurons (in the cortex, brainstem and spinal cord) as the neuronal population selectively involved in ALS. Similarly, this was considered the pathological marker to score disease severity ex vivo both in patients and experimental models. However, the concept of non-autonomous motor neuron death was used recently to indicate the need for additional cell types to produce motor neuron death in ALS. This means that motor neuron loss occurs only when they are connected with other cell types. This concept originally emphasized the need for resident glia as well as non-resident inflammatory cells. Nowadays, the additional role of neurons other than motor neurons emerged in the scenario to induce non-autonomous motor neuron death. In fact, in ALS neurons diverse from motor neurons are involved. These cells play multiple roles in ALS: (i) they participate in the chain of events to produce motor neuron loss; (ii) they may even degenerate more than and before motor neurons. In the present manuscript evidence about multi-neuronal involvement in ALS patients and experimental models is discussed. Specific sub-classes of neurons in the whole spinal cord are reported either to degenerate or to trigger neuronal degeneration, thus portraying ALS as a whole spinal cord disorder rather than a disease affecting motor neurons solely. This is associated with a novel concept in motor neuron disease which recruits abnormal mechanisms of cell to cell communication.

Changes in neural circuitry associated with depression at pre-clinical, pre-motor and early motor phases of Parkinson's disease.

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Borgonovo, Janina; Allende-Castro, Camilo; Laliena, Almudena; Guerrero, Néstor; Silva, Hernán; Concha, Miguel L

2017-02-01

Although Parkinson's Disease (PD) is mostly considered a motor disorder, it can present at early stages as a non-motor pathology. Among the non-motor clinical manifestations, depression shows a high prevalence and can be one of the first clinical signs to appear, even a decade before the onset of motor symptoms. Here, we review the evidence of early dysfunction in neural circuitry associated with depression in the context of PD, focusing on pre-clinical, pre-motor and early motor phases of the disease. In the pre-clinical phase, structural and functional changes in the substantia nigra, basal ganglia and limbic structures are already observed. Some of these changes are linked to motor compensation mechanisms while others correspond to pathological processes common to PD and depression and thus could underlie the appearance of depressive symptoms during the pre-motor phase. Studies of the early motor phase (less than five years post diagnosis) reveal an association between the extent of damage in different monoaminergic systems and the appearance of emotional disorders. We propose that the limbic loop of the basal ganglia and the lateral habenula play key roles in the early genesis of depression in PD. Alterations in the neural circuitry linked with emotional control might be sensitive markers of the ongoing neurodegenerative process and thus may serve to facilitate an early diagnosis of this disease. To take advantage of this, we need to improve the clinical criteria and develop biomarkers to identify depression, which could be used to determine individuals at risk to develop PD. Copyright © 2016 Elsevier Ltd. All rights reserved.

Processing of metaphors in transcortical motor aphasia

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Renata Mancopes

Full Text Available Abstract Great emphasis has been placed on the right hemisphere, due to its possible selective contribution, in the processing of metaphorical statements. Objectives: To describe the processing of metaphors in the case of a patient with transcortical motor aphasia, using specific tests for patients with encephalic injuries of the right hemisphere, and to contribute to the discussion on the inter-hemispheric relationships associated with this function. Methods: A 54 year-old man with transcortical motor aphasia was evaluated three years after a left hemisphere stroke. The tasks of comprehension of metaphors were based on the subtest Metaphor Comprehension Task of the Montreal Evaluation of Communications Scale (MEC. Two metaphor comprehension tests were applied, in 45-minute sessions with a 48 hour interval between each. Test 1 involved comprehension of the metaphors according to the options offered, and Test 2 the comprehension of metaphors measured by response time and visual field. Results: Although the right hemisphere was not affected by the stroke in this case, difficulties were observed in the processing of metaphors. Conclusions: This study suggests that the left hemisphere participates in the processing of figurative meanings. The adaptability of the brain can also re-accommodate the uninjured areas of the brain, causing the dynamic of the brain to be modified. As a result, deducing cerebral functions based on clinical data can be problematic. The value of this study is that it can contribute to clinical aspects of language rehabilitation.

Using electrical and optical tweezers to facilitate studies of molecular motors†

Science.gov (United States)

Arsenault, Mark E.; Sun, Yujie; Bau, Haim H.; Goldman, Yale E.

2013-01-01

Dielectrophoresis was used to stretch and suspend actin filaments across a trench etched between two electrodes patterned on a glass slide. Optical tweezers were used to bring a motor protein-coated bead into close proximity to a pre-selected, suspended actin filament, facilitating the attachment of the myosin-coated bead to the filament. The clearance beneath the filament allowed the bead to move freely along and around its filamentous track, unhindered by solid surfaces. Using defocused images, the three-dimensional position of the bead was tracked as a function of time to obtain its trajectory. Experiments were carried out with myosin V and myosin X. Both motor proteins followed left-handed helical paths with the myosin X motor exhibiting a shorter pitch than the myosin V. The combined use of electrostatic and optical tweezers facilitates the preparation of motility assays with suspended tracks. Variants of this technique will enable higher complexity experiments in vitro to better understand the behavior of motors in cells. PMID:19506758

Pesquisa de marcadores para os genes da cadeia pesada da beta-miosina cardíaca e da proteína C de ligação à miosina em familiares de pacientes com cardiomiopatia hipertrófica Research of markers for the genes of the heavy chain of cardiac beta-myosin and myosin binding protein C in relatives of patients with hypertrophic cardiomyopathy

Directory of Open Access Journals (Sweden)

Adriana Paula Tirone

2005-06-01

families, the connections with the two genes were excluded; in two, the connection with the gene of the myosin-binding protein C, but for the b-myosin gene the results were non-conclusive; in two families, the results were non-conclusive for both genes and in one the connection for the b-myosin gene was excluded. The results were non-conclusive for the gene of the myosin-binding protein C. CONCLUSION: In our environment, other genes, different from those described in the literature, may prevail, or there are other genetic differences related to the origin of our population and/or environmental factors.

Myosin light chain phosphorylation is critical for adaptation to cardiac stress.

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Warren, Sonisha A; Briggs, Laura E; Zeng, Huadong; Chuang, Joyce; Chang, Eileen I; Terada, Ryota; Li, Moyi; Swanson, Maurice S; Lecker, Stewart H; Willis, Monte S; Spinale, Francis G; Maupin-Furlowe, Julie; McMullen, Julie R; Moss, Richard L; Kasahara, Hideko

2012-11-27

Cardiac hypertrophy is a common response to circulatory or neurohumoral stressors as a mechanism to augment contractility. When the heart is under sustained stress, the hypertrophic response can evolve into decompensated heart failure, although the mechanism(s) underlying this transition remain largely unknown. Because phosphorylation of cardiac myosin light chain 2 (MLC2v), bound to myosin at the head-rod junction, facilitates actin-myosin interactions and enhances contractility, we hypothesized that phosphorylation of MLC2v plays a role in the adaptation of the heart to stress. We previously identified an enzyme that predominantly phosphorylates MLC2v in cardiomyocytes, cardiac myosin light-chain kinase (cMLCK), yet the role(s) played by cMLCK in regulating cardiac function in health and disease remain to be determined. We found that pressure overload induced by transaortic constriction in wild-type mice reduced phosphorylated MLC2v levels by ≈40% and cMLCK levels by ≈85%. To examine how a reduction in cMLCK and the corresponding reduction in phosphorylated MLC2v affect function, we generated Mylk3 gene-targeted mice and transgenic mice overexpressing cMLCK specifically in cardiomyocytes. Pressure overload led to severe heart failure in cMLCK knockout mice but not in mice with cMLCK overexpression in which cMLCK protein synthesis exceeded degradation. The reduction in cMLCK protein during pressure overload was attenuated by inhibition of ubiquitin-proteasome protein degradation systems. Our results suggest the novel idea that accelerated cMLCK protein turnover by the ubiquitin-proteasome system underlies the transition from compensated hypertrophy to decompensated heart failure as a result of reduced phosphorylation of MLC2v.

Myosin XI-dependent formation of tubular structures from endoplasmic reticulum isolated from tobacco cultured BY-2 cells.

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Yokota, Etsuo; Ueda, Haruko; Hashimoto, Kohsuke; Orii, Hidefumi; Shimada, Tomoo; Hara-Nishimura, Ikuko; Shimmen, Teruo

2011-05-01

The reticular network of the endoplasmic reticulum (ER) consists of tubular and lamellar elements and is arranged in the cortical region of plant cells. This network constantly shows shape change and remodeling motion. Tubular ER structures were formed when GTP was added to the ER vesicles isolated from tobacco (Nicotiana tabacum) cultured BY-2 cells expressing ER-localized green fluorescent protein. The hydrolysis of GTP during ER tubule formation was higher than that under conditions in which ER tubule formation was not induced. Furthermore, a shearing force, such as the flow of liquid, was needed for the elongation/extension of the ER tubule. The shearing force was assumed to correspond to the force generated by the actomyosin system in vivo. To confirm this hypothesis, the S12 fraction was prepared, which contained both cytosol and microsome fractions, including two classes of myosins, XI (175-kD myosin) and VIII (BY-2 myosin VIII-1), and ER-localized green fluorescent protein vesicles. The ER tubules and their mesh-like structures were arranged in the S12 fraction efficiently by the addition of ATP, GTP, and exogenous filamentous actin. The tubule formation was significantly inhibited by the depletion of 175-kD myosin from the S12 fraction but not BY-2 myosin VIII-1. Furthermore, a recombinant carboxyl-terminal tail region of 175-kD myosin also suppressed ER tubule formation. The tips of tubules moved along filamentous actin during tubule elongation. These results indicated that the motive force generated by the actomyosin system contributes to the formation of ER tubules, suggesting that myosin XI is responsible not only for the transport of ER in cytoplasm but also for the reticular organization of cortical ER.

Myosin IIA participates in docking of Glut4 storage vesicles with the plasma membrane in 3T3-L1 adipocytes

International Nuclear Information System (INIS)

Chung, Le Thi Kim; Hosaka, Toshio; Harada, Nagakatsu; Jambaldorj, Bayasgalan; Fukunaga, Keiko; Nishiwaki, Yuka; Teshigawara, Kiyoshi; Sakai, Tohru; Nakaya, Yutaka; Funaki, Makoto

2010-01-01

In adipocytes and myocytes, insulin stimulation translocates glucose transporter 4 (Glut4) storage vesicles (GSVs) from their intracellular storage sites to the plasma membrane (PM) where they dock with the PM. Then, Glut4 is inserted into the PM and initiates glucose uptake into these cells. Previous studies using chemical inhibitors demonstrated that myosin II participates in fusion of GSVs and the PM and increase in the intrinsic activity of Glut4. In this study, the effect of myosin IIA on GSV trafficking was examined by knocking down myosin IIA expression. Myosin IIA knockdown decreased both glucose uptake and exposures of myc-tagged Glut4 to the cell surface in insulin-stimulated cells, but did not affect insulin signal transduction. Interestingly, myosin IIA knockdown failed to decrease insulin-dependent trafficking of Glut4 to the PM. Moreover, in myosin IIA knockdown cells, insulin-stimulated binding of GSV SNARE protein, vesicle-associated membrane protein 2 (VAMP2) to PM SNARE protein, syntaxin 4 was inhibited. These data suggest that myosin IIA plays a role in insulin-stimulated docking of GSVs to the PM in 3T3-L1 adipocytes through SNARE complex formation.

Consequences of Molecular-Scale Non-Equilibrium Activity on the Dynamics and Mechanics of Self-Assembled Actin-Based Structures and Materials

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Marshall Mccall, Patrick

Living cells are hierarchically self-organized forms of active soft matter: molecules on the nanometer scale form functional structures and organelles on the micron scale, which then compose cells on the scale of 10s of microns. While the biological functions of intracellular organelles are defined by the composition and properties of the structures themselves, how those bulk properties emerge from the properties and interactions of individual molecules remains poorly understood. Actin, a globular protein which self-assembles into dynamic semi-flexible polymers, is the basic structural material of cells and the major component of many functional organelles. In this thesis, I have used purified actin as a model system to explore the interplay between molecular-scale dynamics and organelle-scale functionality, with particular focus on the role of molecular-scale non-equilibrium activity. One of the most canonical forms of molecular-scale non-equilibrium activity is that of mechanoenzymes, also called motor proteins. These proteins utilized the free energy liberated by hydrolysis of ATP to perform mechanical work, thereby introducing non-equilibrium "active" stresses on the molecular scale. Combining experiments with mathematical modeling, we demonstrate in this thesis that non-equilibrium motor activity is sufficient to drive self-organization and pattern formation of the multimeric actin-binding motor protein Myosin II on 1D reconstituted actomyosin bundles. Like myosin, actin is itself an ATPase. However, nono-equilibrium ATP hydrolysis on actin is known to regulate the stability and assembly kinetics of actin filaments rather than generate active stresses per se. At the level of single actin filaments, the inhomogeneous nucleotide composition generated along the filament length by hydrolysis directs binding of regulatory proteins like cofilin, which mediate filament disassembly and thereby accelerate actin filament turnover. The concequences of this non

Increased Reliance on Value-based Decision Processes Following Motor Cortex Disruption.

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Zénon, Alexandre; Klein, Pierre-Alexandre; Alamia, Andrea; Boursoit, François; Wilhelm, Emmanuelle; Duque, Julie

2015-01-01

During motor decision making, the neural activity in primary motor cortex (M1) encodes dynamically the competition occurring between potential action plans. A common view is that M1 represents the unfolding of the outcome of a decision process taking place upstream. Yet, M1 could also be directly involved in the decision process. Here we tested this hypothesis by assessing the effect of M1 disruption on a motor decision-making task. We applied continuous theta burst stimulation (cTBS) to inhibit either left or right M1 in different groups of subjects and included a third control group with no stimulation. Following cTBS, participants performed a task that required them to choose between two finger key-presses with the right hand according to both perceptual and value-based information. Effects were assessed by means of generalized linear mixed models and computational simulations. In all three groups, subjects relied both on perceptual (P < 0.0001) and value-based information (P = 0.003) to reach a decision. Yet, left M1 disruption led to an increased reliance on value-based information (P = 0.03). This result was confirmed by a computational model showing an increased weight of the valued-based process on the right hand finger choices following left M1 cTBS (P < 0.01). These results indicate that M1 is involved in motor decision making, possibly by weighting the final integration of multiple sources of evidence driving motor behaviors. Copyright © 2015 Elsevier Inc. All rights reserved.

Do active video games benefit the motor skill development of non-typically developing children and adolescents: A systematic review.

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Page, Zoey E; Barrington, Stephanie; Edwards, Jacqueline; Barnett, Lisa M

2017-12-01

The use of interactive video gaming, known as 'exergames' or 'active video games (AVG)' may provide an opportunity for motor skill development. Youth with non-typical patterns of development may have deficits in gross motor skill capacities and are therefore an intervention target. The aim was to determine the effectiveness of AVG use on motor skill development in non-typically developing children and adolescents. Review article. The PRISMA protocol was used to conduct a systematic review of EBSCOhost, Embase, Gale Cengage, Informit, Ovid, ProQuest, PubMed, Scopus and Web of Science databases. A total of 19 articles met inclusion criteria (non-typically developing participants such as those with a learning or developmental delay aged 3-18, use of an AVG console, assessed one or more gross motor skills). Studies were excluded if gross motor skill outcomes encompassed fine motor skills or reflected mobility related to daily living. Interventions included children and adolescents with eight different conditions. The Nintendo Wii was the most utilised gaming platform (14/19 studies). Studies examined a combination of skills, with most examining balance (15/19), five studies examining ball skills, and other gross motor skills such as coordination (3 studies), running (3 studies) and jumping (3 studies). There was strong evidence that AVG's improved balance. AVG's also appeared to benefit participants with Cerebral Palsy. AVG's could be a valuable tool to improve gross motor skills of non-typically developing children. There is scope for further exploration, particularly of ball, coordination and locomotor skills and varying platforms to draw more conclusive evaluations. Copyright © 2017 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.

The local expression of adult chicken heart myosins during development. I. The three days embryonic chicken heart

NARCIS (Netherlands)

Sanders, E.; Moorman, A. F.; Los, J. A.

1984-01-01

Immunofluorescence studies were performed on serial sections of three days embryonic chicken hearts using antibodies specific for adult atrial and ventricular myosin heavy chains respectively. The anti-ventricular myosin serum reacted with the entire myocardium showing a decreasing intensity going

CALIX[4]ARENE C-99 INHIBITS MYOSIN ATPase ACTIVITY AND CHANGES THE ORGANIZATION OF CONTRACTILE FILAMENTS OF MYOMETRIUM.

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Labyntseva, R D; Bevza, A A; Lul'ko, A O; Cherenok, S O; Kalchenko, V I; Kosterin, S O

2015-01-01

Calix[4]arenes are cup-like macrocyclic (polyphenolic) compounds, they are regarded as promising molecular "platforms" for the design of new physiologically active compounds. We have earlier found that calix[4]arene C-99 inhibits the ATPase activity of actomyosin and myosin subfragment-1 of pig uterus in vitro. The aim of this study was to investigate the interaction of calix[4]arene C-99 with myosin from rat uterine myocytes. It was found that the ATPase activity of myosin prepared from pre-incubated with 100 mM of calix[4]arene C-99 myocytes was almost 50% lower than in control. Additionally, we have revealed the effect of calix[4]arene C-99 on the subcellular distribution of actin and myosin in uterus myocytes by the method of confocal microscopy. This effect can be caused by reorganization of the structure of the contractile smooth muscle cell proteins due to their interaction with calix[4]arene. The obtained results demonstrate the ability of calix[4]arene C-99 to penetrate into the uterus muscle cells and affect not only the myosin ATPase activity, but also the structure of the actin and myosin filaments in the myometrial cells. Demonstrated ability of calix[4]arene C-99 can be used for development of new pharmacological agents for efficient normalization of myometrial contractile hyperfunction.

Calix[4]arene C-99 inhibits myosin ATPase activity and changes the organization of contractile filaments of myometrium

Directory of Open Access Journals (Sweden)

R. D. Labyntseva,

2015-12-01

Full Text Available Calix[4]arenes are cup-like macrocyclic (polyphenolic compounds, they are regarded as promising molecular “platforms” for the design of new physiologically active compounds. We have earlier found that сalix[4]arenе C-99 inhibits the ATPase activity of actomyosin and myosin subfragment-1 of pig uterus іn vitro. The aim of this study was to investigate the interaction of calix[4]arene C-99 with myosin from rat uterine myocytes. It was found that the ATPase activity of myosin prepared from pre-incubated with 100 mM of calix[4]arene C-99 myocytes was almost 50% lower than in control. Additionally, we have revealed the effect of calix[4]arene C-99 on the subcellular distribution of actin and myosin in uterus myocytes by the method of confocal microscopy. This effect can be caused by reorganization of the structure of the contractile smooth muscle cell proteins due to their interaction with calix[4]arene. The obtained results demonstrate the ability of calix[4]arene C-99 to penetrate into the uterus muscle cells and affect not only the myosin ATPase activity, but also the structure of the actin and myosin filaments in the myometrial cells. Demonstrated ability of calix[4]arene C-99 can be used for development of new pharmacological agents for efficient normalization of myometrial contractile hyperfunction.

Management of non-motor complications in Parkinson's disease.

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Fujimoto, Ken-ichi

2009-08-01

This paper summarizes the methods we devised for the treatment of psychosis, orthostatic hypotension, and mood disorders among the various non-motor complications of Parkinson's disease. Psychosis may not manifest when a patient believes in his/her delusions. If left untreated over a prolonged period, however, the delusions progress to paranoia that is very difficult to cure. Accordingly, enquiries should be made during routine examinations to detect the presence of psychosis and facilitate early discovery. Atypical antipsychotics are used when psychosis does not improve after reducing the doses of antiparkinson drugs. We achieved favorable results by using mianserin hydrochloride prior to this step, with efficacy being observed for hallucinations and mild delusions that often manifested at night. This drug does not act as a dopamine receptor blocker, so it has the advantage of not aggravating motor symptoms. With this therapy, it is also possible to improve motor symptoms without inducing psychosis by reducing the doses of antiparkinson drugs and locally stimulating the motor loop by deep brain stimulation of the subthalamic nucleus. We previously introduced leg-holding exercises for the treatment of orthostatic hypotension, through which blood pooled in the veins is returned to the systemic circulation by holding the knees. This can be done easily and is free of adverse reactions. Mood disorders are difficult to cope with in patients with Parkinson's disease, but may be treated by selecting an appropriate dopamine agonist while giving consideration to affinity for the dopamine D3 receptor. However, treatment becomes complicated when the dopamine receptor is overstimulated. Here we report on cases of successfully treated pathological gambling and dopamine dysregulation syndrome, which are considered difficult to manage. The solution may differ depending on a patient's environment, and it is not easy to prescribe therapy based on evidence-based medicine. The best

The influence of age and gender on motor and non-motor features of early Parkinson's disease: initial findings from the Oxford Parkinson Disease Center (OPDC) discovery cohort.

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Szewczyk-Krolikowski, Konrad; Tomlinson, Paul; Nithi, Kannan; Wade-Martins, Richard; Talbot, Kevin; Ben-Shlomo, Yoav; Hu, Michele T M

2014-01-01

Identifying factors influencing phenotypic heterogeneity in Parkinson's Disease is crucial for understanding variability in disease severity and progression. Age and gender are two most basic epidemiological characteristics, yet their effect on expression of PD symptoms is not fully defined. We aimed to delineate effects of age and gender on the phenotype in an incident cohort of PD patients and healthy controls from the Oxford Parkinson Disease Centre (OPDC). Clinical features, including demographic and medical characteristics and non-motor and motor symptoms, were analyzed in a group of PD patients within 3 years of diagnosis and a group of healthy controls from the OPDC cohort. Disease features were stratified according to age and compared between genders, controlling for effects of common covariates. 490 PD patients and 176 healthy controls were analyzed. Stratification by age showed increased disease severity with age on motor scales. Some non-motor features showed similar trend, including cognition and autonomic features. Comparison across genders highlighted a pattern of increased severity and greater symptom symmetricality in the face, neck and arms in men with women having more postural problems. Amongst the non-motor symptoms, men had more cognitive impairment, greater rate of REM behavior disorder (RBD), more orthostatic hypotension and sexual dysfunction. Age in PD is a strong factor contributing to disease severity even after controlling for the effect of disease duration. Gender-related motor phenotype can be defined by a vertical split into more symmetrical upper-body disease in men and disease dominated by postural symptoms in women. Copyright © 2013 Elsevier Ltd. All rights reserved.

Diverging effects of nicotine on motor learning performance: Improvement in deprived smokers and attenuation in non-smokers.

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Grundey, J; Amu, R; Batsikadze, G; Paulus, W; Nitsche, M A

2017-11-01

Nicotine modulates cognition and neuroplasticity in smokers and non-smokers. A possible mechanism for its effect on learning and memory performance is its impact on long-term potentiation (LTP) and long-term depression (LTD). As neuroplasticity is closely connected to learning processes, we aimed to explore the effect of nicotine in healthy, young smokers and non-smokers on performance of the serial reaction time task (SRTT), a sequential motor learning paradigm. 20 nicotine-deprived smokers and 20 non-smokers participated in the study and were exposed to nicotine or placebo medication. Deprived smokers under placebo medication displayed reduced performance in terms of reaction time and error rates compared to the non-smoking group. After application of nicotine, performance in smokers improved while it deteriorated in non-smokers. These results indicate a restituting effect of nicotine in smokers in terms of cognitive parameters. This sheds further light on the proposed mechanism of nicotine on learning processes, which might be linked to the addictive component of nicotine, the probability of relapse and thus needs also be addressed in cessation treatment. Copyright © 2017 Elsevier Ltd. All rights reserved.

Critical role of non-muscle myosin light chain kinase in thrombin-induced endothelial cell inflammation and lung PMN infiltration.

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Fazal, Fabeha; Bijli, Kaiser M; Murrill, Matthew; Leonard, Antony; Minhajuddin, Mohammad; Anwar, Khandaker N; Finkelstein, Jacob N; Watterson, D Martin; Rahman, Arshad

2013-01-01

The pathogenesis of acute lung injury (ALI) involves bidirectional cooperation and close interaction between inflammatory and coagulation pathways. A key molecule linking coagulation and inflammation is the procoagulant thrombin, a serine protease whose concentration is elevated in plasma and lavage fluids of patients with ALI and acute respiratory distress syndrome (ARDS). However, little is known about the mechanism by which thrombin contributes to lung inflammatory response. In this study, we developed a new mouse model that permits investigation of lung inflammation associated with intravascular coagulation. Using this mouse model and in vitro approaches, we addressed the role of non-muscle myosin light chain kinase (nmMLCK) in thrombin-induced endothelial cell (EC) inflammation and lung neutrophil (PMN) infiltration. Our in vitro experiments revealed a key role of nmMLCK in ICAM-1 expression by its ability to control nuclear translocation and transcriptional capacity of RelA/p65 in EC. When subjected to intraperitoneal thrombin challenge, wild type mice showed a marked increase in lung PMN infiltration via expression of ICAM-1. However, these responses were markedly attenuated in mice deficient in nmMLCK. These results provide mechanistic insight into lung inflammatory response associated with intravascular coagulation and identify nmMLCK as a critical target for modulation of lung inflammation.

Solid propellant processing factor in rocket motor design

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1971-01-01

The ways are described by which propellant processing is affected by choices made in designing rocket engines. Tradeoff studies, design proof or scaleup studies, and special design features are presented that are required to obtain high product quality, and optimum processing costs. Processing is considered to include the operational steps involved with the lining and preparation of the motor case for the grain; the procurement of propellant raw materials; and propellant mixing, casting or extrusion, curing, machining, and finishing. The design criteria, recommended practices, and propellant formulations are included.

Plasticity and alterations of trunk motor cortex following spinal cord injury and non-stepping robot and treadmill training.

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Oza, Chintan S; Giszter, Simon F

2014-06-01

Spinal cord injury (SCI) induces significant reorganization in the sensorimotor cortex. Trunk motor control is crucial for postural stability and propulsion after low thoracic SCI and several rehabilitative strategies are aimed at trunk stability and control. However little is known about the effect of SCI and rehabilitation training on trunk motor representations and their plasticity in the cortex. Here, we used intracortical microstimulation to examine the motor cortex representations of the trunk in relation to other representations in three groups of chronic adult complete low thoracic SCI rats: chronic untrained, treadmill trained (but 'non-stepping') and robot assisted treadmill trained (but 'non-stepping') and compared with a group of normal rats. Our results demonstrate extensive and significant reorganization of the trunk motor cortex after chronic adult SCI which includes (1) expansion and rostral displacement of trunk motor representations in the cortex, with the greatest significant increase observed for rostral (to injury) trunk, and slight but significant increase of motor representation for caudal (to injury) trunk at low thoracic levels in all spinalized rats; (2) significant changes in coactivation and the synergy representation (or map overlap) between different trunk muscles and between trunk and forelimb. No significant differences were observed between the groups of transected rats for the majority of the comparisons. However, (3) the treadmill and robot-treadmill trained groups of rats showed a further small but significant rostral migration of the trunk representations, beyond the shift caused by transection alone. We conclude that SCI induces a significant reorganization of the trunk motor cortex, which is not qualitatively altered by non-stepping treadmill training or non-stepping robot assisted treadmill training, but is shifted further from normal topography by the training. This shift may potentially make subsequent rehabilitation with

Non-invasive brain stimulation of motor cortex induces embodiment when integrated with virtual reality feedback.

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Bassolino, M; Franza, M; Bello Ruiz, J; Pinardi, M; Schmidlin, T; Stephan, M A; Solcà, M; Serino, A; Blanke, O

2018-04-01

Previous evidence highlighted the multisensory-motor origin of embodiment - that is, the experience of having a body and of being in control of it - and the possibility of experimentally manipulating it. For instance, an illusory feeling of embodiment towards a fake hand can be triggered by providing synchronous visuo-tactile stimulation to the hand of participants and to a fake hand or by asking participants to move their hand and observe a fake hand moving accordingly (rubber hand illusion). Here, we tested whether it is possible to manipulate embodiment not through stimulation of the participant's hand, but by directly tapping into the brain's hand representation via non-invasive brain stimulation. To this aim, we combined transcranial magnetic stimulation (TMS), to activate the hand corticospinal representation, with virtual reality (VR), to provide matching (as contrasted to non-matching) visual feedback, mimicking involuntary hand movements evoked by TMS. We show that the illusory embodiment occurred when TMS pulses were temporally matched with VR feedback, but not when TMS was administered outside primary motor cortex, (over the vertex) or when stimulating motor cortex at a lower intensity (that did not activate peripheral muscles). Behavioural (questionnaires) and neurophysiological (motor-evoked-potentials, TMS-evoked-movements) measures further indicated that embodiment was not explained by stimulation per se, but depended on the temporal coherence between TMS-induced activation of hand corticospinal representation and the virtual bodily feedback. This reveals that non-invasive brain stimulation may replace the application of external tactile hand cues and motor components related to volition, planning and anticipation. © 2018 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Nonmuscle Myosin II Is Required for Internalization of the Epidermal Growth Factor Receptor and Modulation of Downstream Signaling*

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Kim, Jong Hyun; Wang, Aibing; Conti, Mary Anne; Adelstein, Robert S.

2012-01-01

Ligand-induced internalization of the epidermal growth factor receptor (EGFR) is an important process for regulating signal transduction, cellular dynamics, and cell-cell communication. Here, we demonstrate that nonmuscle myosin II (NM II) is required for the internalization of the EGFR and to trigger the EGFR-dependent activation of ERK and AKT. The EGFR was identified as a protein that interacts with NM II by co-immunoprecipitation and mass spectrometry analysis. This interaction requires both the regulatory light chain 20 (RLC20) of NM II and the kinase domain of the EGFR. Two paralogs of NM II, NM II-A, and NM II-B can act to internalize the EGFR, depending on the cell type and paralog content of the cell line. Loss (siRNA) or inhibition (25 μm blebbistatin) of NM II attenuates the internalization of the EGFR and impairs EGFR-dependent activation of ERK and AKT. Both internalization of the EGFR and downstream signaling to ERK and AKT can be partially restored in siRNA-treated cells by introduction of wild type (WT) GFP-NM II, but cannot be restored by motor mutant NM II. Taken together, these results suggest that NM II plays a role in the internalization of the EGFR and EGFR-mediated signaling pathways. PMID:22718763

Final Progress Report for FG02-89ER14030

Energy Technology Data Exchange (ETDEWEB)

Hanson, Maureen R

2011-10-26

Intracellular Dynamics of Energy-Transducing Organelles. The location and interaction of intracellular organelles is important for exchange of substrate and product between compartments for optimum functioning of biochemical pathways and energy transduction. Plastids and stromules, tubular plastid extensions, are highly dynamic in many plant tissues. Stromules can connect two or more plastids and proteins and macromolecular complexes can be transferred between them. Stromules have been observed to form close contacts with other organelles, the plasma membrane, and can pass through channels in the nucleus. Chloroplasts move in response to light and mechanical stimulus. Especially in non-green cells, plastids change shape and position, and stromules extend and retract. Stromules appear to be involved in recycling of chloroplast proteins when photosynthesis is limited, through an autophagic process that results in degradation of portions of the stromal contents without complete destruction of the chloroplast. Mutations in several genes known to mediate chloroplast division result in altered stromule morphology in some cells. Plastid and stromule motility is mediated by the actin cytoskeleton. The possible role of myosins in chloroplast movement was investigated by labeling the cargo-binding tails of six Arabidopsis myosin XI proteins with yellow fluorescent protein (YFP). The fluorescent proteins were found to localize to vesicles and peroxisomes. The portion of the myosin tail domain fused to YFP affected whether specific or non-specific localization was observed. In contrast to experiments in animal cells, movement of labeled organelles was not entirely inhibited by expression of defective myosin in which the motor domain was replaced with a fluorescent protein. None of the six myosin proteins tested labeled plastids or chloroplasts. However, the Arabidopsis myosin XI gene family expresses an additional seven myosins that await further examination. These experiments

Outcome and Process in Motor Performance: A Comparison of Jumping by Typically Developing Children and Those with Low Motor Proficiency

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Williams, Morgan D.; Saunders, John E.; Maschette, Wayne E.; Wilson, Cameron J.

2013-01-01

The motivation for this study was to explore a conceptual framework to understand the outcomes and processes of motor performance in children. Vertical jumping, a fundamental movement skill, was used to compare children (ages 6-12 years) who were typically developing (TD) and those identified as having low motor proficiency (LMP). Jumps were…

Relationship between the non-motor items of the MDS-UPDRS and Quality of Life in patients with Parkinson's disease.

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Skorvanek, Matej; Rosenberger, Jaroslav; Minar, Michal; Grofik, Milan; Han, Vladimir; Groothoff, Johan W; Valkovic, Peter; Gdovinova, Zuzana; van Dijk, Jitse P

2015-01-01

The Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is a newly developed comprehensive tool to assess Parkinson's disease (PD), which covers a wider range of non-motor PD manifestations than the original UPDRS scale. The aim of this study was to assess the relationship between the MDS-UPDRS and Quality of Life (QoL) and to analyze the relationship between individual MDS-UPDRS non-motor items and QoL. A total of 291 PD patients were examined in a multicenter Slovak study. Patients were assessed by the MDS-UPDRS, HY scale and PDQ39. Data were analyzed using the multiple regression analyses. The mean participant age was 68.0 ± 9.0 years, 53.5% were men, mean disease duration was 8.3 ± 5.3 years and mean HY was 2.7 ± 1.0. In a multiple regression analysis model the PDQ39 summary index was related to MDS-UPDRS parts II, I and IV respectively, but not to part III. Individual MDS-UPDRS non-motor items related to the PDQ39 summary index in the summary group and in the non-fluctuating patients subgroup were pain, fatigue and features of dopamine dysregulation syndrome (DDS). In the fluctuating PD patient subgroup, PDQ39 was related to pain and Depressed mood items. Other MDS-UPDRS non-motor items e.g. Anxious mood, Apathy, Cognitive impairment, Hallucinations and psychosis, Sleep problems, Daytime sleepiness and Urinary problems were related to some PDQ39 domains. The overall burden of NMS in PD is more important in terms of QoL than motor symptoms. Individual MDS-UPDRS non-motor items related to worse QoL are especially pain and other sensations, fatigue and features of DDS. Copyright © 2015 Elsevier B.V. All rights reserved.

Non-physical practice improves task performance in an unstable, perturbed environment: Motor imagery and observational balance training

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Wolfgang eTaube

2014-12-01

Full Text Available For consciously performed motor tasks executed in a defined and constant way, both motor imagery (MI and action observation (AO have been shown to promote motor learning. It is not known whether these forms of non-physical training also improve motor actions when these actions have to be variably applied in an unstable and unpredictable environment. The present study therefore investigated the influence of MI balance training (MI_BT and a balance training combining AO and MI (AO+MI_BT on postural control of undisturbed and disturbed upright stance on unstable ground. As spinal reflex excitability after classical (i.e., physical balance training (BT is generally decreased, we tested whether non-physical BT also has an impact on spinal reflex circuits. Thirty-six participants were randomly allocated into an MI_BT group, in which participants imagined postural exercises, an AO+MI_BT group, in which participants observed videos of other people performing balance exercises and imagined being the person in the video, and a non-active control group (CON. Before and after 4 weeks of non-physical training, balance performance was assessed on a free-moving platform during stance without perturbation and during perturbed stance. Soleus H-reflexes were recorded during stable and unstable stance. The post measurement revealed significantly decreased postural sway during undisturbed and disturbed stance after both MI_BT and AO+MI_BT. Spinal reflex excitability remained unchanged. This is the first study showing that non-physical training (MI_BT and AO+MI_BT not only promotes motor learning of ‘rigid’ postural tasks but also improves performance of highly variable and unpredictable balance actions. These findings may be relevant to improve postural control and thus reduce the risk of falls in temporarily immobilized patients.

Sexual affordances, perceptual-motor invariance extraction and intentional nonlinear dynamics: sexually deviant and non-deviant patterns in male subjects.

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Renaud, Patrice; Goyette, Mathieu; Chartier, Sylvain; Zhornitski, Simon; Trottier, Dominique; Rouleau, Joanne-L; Proulx, Jean; Fedoroff, Paul; Bradford, John-P; Dassylva, Benoit; Bouchard, Stephane

2010-10-01

Sexual arousal and gaze behavior dynamics are used to characterize deviant sexual interests in male subjects. Pedophile patients and non-deviant subjects are immersed with virtual characters depicting relevant sexual features. Gaze behavior dynamics as indexed from correlation dimensions (D2) appears to be fractal in nature and significantly different from colored noise (surrogate data tests and recurrence plot analyses were performed). This perceptual-motor fractal dynamics parallels sexual arousal and differs from pedophiles to non-deviant subjects when critical sexual information is processed. Results are interpreted in terms of sexual affordance, perceptual invariance extraction and intentional nonlinear dynamics.

Blebbistatin, a myosin II inhibitor, suppresses Ca(2+)-induced and "sensitized"-contraction of skinned tracheal muscles from guinea pig.

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Yumoto, Masatoshi; Watanabe, Masaru

2013-01-01

Blebbistatin, a potent inhibitor of myosin II, has inhibiting effects on Ca(2+)-induced contraction and contractile filament organization without affecting the Ca(2+)-sensitivity to the force and phosphorylation level of myosin regulatory light chain (MLC20) in skinned (cell membrane permeabilized) taenia cecum from the guinea pig (Watanabe et al., Am J Physiol Cell Physiol. 2010; 298: C1118-26). In the present study, we investigated blebbistatin effects on the contractile force of skinned tracheal muscle, in which myosin filaments organization is more labile than that in the taenia cecum. Blebbistatin at 10 μM or higher suppressed Ca(2+)-induced tension development at any given Ca(2+) concentration, but had little effects on the Ca(2+)- induced myosin light chain phosphorylation. Also blebbistatin at 10 μM and higher significantly suppressed GTP-γS-induced "sensitized" force development. Since the force inhibiting effects of blebbistatin on the skinned trachea were much stronger than those in skinned taenia cecum, blebbistatin might directly affect myosin filaments organization.

INSIGHTS INTO THE MECHANICS OF CYTOKINETIC RING ASSEMBLY USING 3D MODELING.

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Bidone, Tamara Carla; Tang, Haosu; Vavylonis, Dimitrios

During fission yeast cytokinesis, actin filaments nucleated by cortical formin Cdc12 are captured by myosin motors bound to a band of cortical nodes. The myosin motors exert forces that pull nodes together into a contractile ring. Cross-linking interactions help align actin filaments and nodes into a single bundle. Mutations in the myosin motor domain and changes in the concentration of cross-linkers alpha-actinin and fimbrin alter the morphology of the condensing network, leading to clumps, rings or extended meshworks. How the contractile tension developing during ring formation depends on the interplay between network morphology, myosin motor activity, cross-linking and actin filament turnover remains to be elucidated. We addressed this question using a 3D computational model in which semiflexible actin filaments (represented as beads connected by springs) grow from formins, can be captured by myosin in neighboring nodes, and get cross-linked with one another through an attractive interaction. We identify regimes of tension generation between connected nodes under a wide set of conditions regarding myosin dynamics and strength of cross-linking between actin filaments. We find conditions that maximize circumferential tension, correlate them with network morphology and propose experiments to test these predictions. This work addresses "Morphogenesis of soft and living matter" using computational modeling to simulate cytokinetic ring assembly from the key molecular mechanisms of viscoelastic cross-linked actin networks that include active molecular motors.

The Rho kinases I and II regulate different aspects of myosin II activity

DEFF Research Database (Denmark)

Yoneda, Atsuko; Multhaupt, Hinke A B; Couchman, John R

2005-01-01

The homologous mammalian rho kinases (ROCK I and II) are assumed to be functionally redundant, based largely on kinase construct overexpression. As downstream effectors of Rho GTPases, their major substrates are myosin light chain and myosin phosphatase. Both kinases are implicated in microfilament...... bundle assembly and smooth muscle contractility. Here, analysis of fibroblast adhesion to fibronectin revealed that although ROCK II was more abundant, its activity was always lower than ROCK I. Specific reduction of ROCK I by siRNA resulted in loss of stress fibers and focal adhesions, despite...

Non-motor outcomes of subthalamic stimulation in Parkinson's disease depend on location of active contacts.

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Dafsari, Haidar Salimi; Petry-Schmelzer, Jan Niklas; Ray-Chaudhuri, K; Ashkan, Keyoumars; Weis, Luca; Dembek, Till A; Samuel, Michael; Rizos, Alexandra; Silverdale, Monty; Barbe, Michael T; Fink, Gereon R; Evans, Julian; Martinez-Martin, Pablo; Antonini, Angelo; Visser-Vandewalle, Veerle; Timmermann, Lars

2018-03-16

Subthalamic nucleus (STN) deep brain stimulation (DBS) improves quality of life (QoL), motor, and non-motor symptoms (NMS) in Parkinson's disease (PD). Few studies have investigated the influence of the location of neurostimulation on NMS. To investigate the impact of active contact location on NMS in STN-DBS in PD. In this prospective, open-label, multicenter study including 50 PD patients undergoing bilateral STN-DBS, we collected NMSScale (NMSS), NMSQuestionnaire (NMSQ), Hospital Anxiety and Depression Scale (anxiety/depression, HADS-A/-D), PDQuestionnaire-8 (PDQ-8), Scales for Outcomes in PD-motor examination, motor complications, activities of daily living (ADL), and levodopa equivalent daily dose (LEDD) preoperatively and at 6 months follow-up. Changes were analyzed with Wilcoxon signed-rank/t-test and Bonferroni-correction for multiple comparisons. Although the STN was targeted visually, we employed an atlas-based approach to explore the relationship between active contact locations and DBS outcomes. Based on fused MRI/CT-images, we identified Cartesian coordinates of active contacts with patient-specific Mai-atlas standardization. We computed linear mixed-effects models with x-/y-/z-coordinates as independent, hemispheres as within-subject, and test change scores as dependent variables. NMSS, NMSQ, PDQ-8, motor examination, complications, and LEDD significantly improved at follow-up. Linear mixed-effect models showed that NMS and QoL improvement significantly depended on more medial (HADS-D, NMSS), anterior (HADS-D, NMSQ, PDQ-8), and ventral (HADS-A/-D, NMSS, PDQ-8) neurostimulation. ADL improved more in posterior, LEDD in lateral neurostimulation locations. No relationship was observed for motor examination and complications scores. Our study provides evidence that more anterior, medial, and ventral STN-DBS is significantly related to more beneficial non-motor outcomes. Copyright © 2018. Published by Elsevier Inc.

Influence of fast and slow alkali myosin light chain isoforms on the kinetics of stretch-induced force transients of fast-twitch type IIA fibres of rat.

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Andruchov, Oleg; Galler, Stefan

2008-03-01

This study contributes to understand the physiological role of slow myosin light chain isoforms in fast-twitch type IIA fibres of skeletal muscle. These isoforms are often attached to the myosin necks of rat type IIA fibres, whereby the slow alkali myosin light chain isoform MLC1s is much more frequent and abundant than the slow regulatory myosin light chain isoform MLC2s. In the present study, single-skinned rat type IIA fibres were maximally Ca(2+) activated and subjected to stepwise stretches for causing a perturbation of myosin head pulling cycles. From the time course of the resulting force transients, myosin head kinetics was deduced. Fibres containing MLC1s exhibited slower kinetics independently of the presence or absence of MLC2s. At the maximal MLC1s concentration of about 75%, the slowing was about 40%. The slowing effect of MLC1s is possibly due to differences in the myosin heavy chain binding sites of the fast and slow alkali MLC isoforms, which changes the rigidity of the myosin neck. Compared with the impact of myosin heavy chain isoforms in various fast-twitch fibre types, the influence of MLC1s on myosin head kinetics of type IIA fibres is much smaller. In conclusion, the physiological role of fast and slow MLC isoforms in type IIA fibres is a fine-tuning of the myosin head kinetics.

Intact Acquisition and Short-Term Retention of Non-Motor Procedural Learning in Parkinson's Disease.

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Muriel T N Panouillères

Full Text Available Procedural learning is a form of memory where people implicitly acquire a skill through repeated practice. People with Parkinson's disease (PD have been found to acquire motor adaptation, a form of motor procedural learning, similarly to healthy older adults but they have deficits in long-term retention. A similar pattern of normal learning on initial exposure with a deficit in retention seen on subsequent days has also been seen in mirror-reading, a form of non-motor procedural learning. It is a well-studied fact that disrupting sleep will impair the consolidation of procedural memories. Given the prevalence of sleep disturbances in PD, the lack of retention on following days seen in these studies could simply be a side effect of this well-known symptom of PD. Because of this, we wondered whether people with PD would present with deficits in the short-term retention of a non-motor procedural learning task, when the test of retention was done the same day as the initial exposure. The aim of the present study was then to investigate acquisition and retention in the immediate short term of cognitive procedural learning using the mirror-reading task in people with PD. This task involved two conditions: one where triads of mirror-inverted words were always new that allowed assessing the learning of mirror-reading skill and another one where some of the triads were presented repeatedly during the experiment that allowed assessing the word-specific learning. People with PD both ON and OFF their normal medication were compared to healthy older adults and young adults. Participants were re-tested 50 minutes break after initial exposure to probe for short-term retention. The results of this study show that all groups of participants acquired and retained the two skills (mirror-reading and word-specific similarly. These results suggest that neither healthy ageing nor the degeneration within the basal ganglia that occurs in PD does affect the mechanisms

How molecular motors are arranged on a cargo is important for vesicular transport.

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Robert P Erickson

2011-05-01

Full Text Available The spatial organization of the cell depends upon intracellular trafficking of cargos hauled along microtubules and actin filaments by the molecular motor proteins kinesin, dynein, and myosin. Although much is known about how single motors function, there is significant evidence that cargos in vivo are carried by multiple motors. While some aspects of multiple motor function have received attention, how the cargo itself--and motor organization on the cargo--affects transport has not been considered. To address this, we have developed a three-dimensional Monte Carlo simulation of motors transporting a spherical cargo, subject to thermal fluctuations that produce both rotational and translational diffusion. We found that these fluctuations could exert a load on the motor(s, significantly decreasing the mean travel distance and velocity of large cargos, especially at large viscosities. In addition, the presence of the cargo could dramatically help the motor to bind productively to the microtubule: the relatively slow translational and rotational diffusion of moderately sized cargos gave the motors ample opportunity to bind to a microtubule before the motor/cargo ensemble diffuses out of range of that microtubule. For rapidly diffusing cargos, the probability of their binding to a microtubule was high if there were nearby microtubules that they could easily reach by translational diffusion. Our simulations found that one reason why motors may be approximately 100 nm long is to improve their 'on' rates when attached to comparably sized cargos. Finally, our results suggested that to efficiently regulate the number of active motors, motors should be clustered together rather than spread randomly over the surface of the cargo. While our simulation uses the specific parameters for kinesin, these effects result from generic properties of the motors, cargos, and filaments, so they should apply to other motors as well.

MEDYAN: Mechanochemical Simulations of Contraction and Polarity Alignment in Actomyosin Networks.

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Konstantin Popov

2016-04-01

Full Text Available Active matter systems, and in particular the cell cytoskeleton, exhibit complex mechanochemical dynamics that are still not well understood. While prior computational models of cytoskeletal dynamics have lead to many conceptual insights, an important niche still needs to be filled with a high-resolution structural modeling framework, which includes a minimally-complete set of cytoskeletal chemistries, stochastically treats reaction and diffusion processes in three spatial dimensions, accurately and efficiently describes mechanical deformations of the filamentous network under stresses generated by molecular motors, and deeply couples mechanics and chemistry at high spatial resolution. To address this need, we propose a novel reactive coarse-grained force field, as well as a publicly available software package, named the Mechanochemical Dynamics of Active Networks (MEDYAN, for simulating active network evolution and dynamics (available at www.medyan.org. This model can be used to study the non-linear, far from equilibrium processes in active matter systems, in particular, comprised of interacting semi-flexible polymers embedded in a solution with complex reaction-diffusion processes. In this work, we applied MEDYAN to investigate a contractile actomyosin network consisting of actin filaments, alpha-actinin cross-linking proteins, and non-muscle myosin IIA mini-filaments. We found that these systems undergo a switch-like transition in simulations from a random network to ordered, bundled structures when cross-linker concentration is increased above a threshold value, inducing contraction driven by myosin II mini-filaments. Our simulations also show how myosin II mini-filaments, in tandem with cross-linkers, can produce a range of actin filament polarity distributions and alignment, which is crucially dependent on the rate of actin filament turnover and the actin filament's resulting super-diffusive behavior in the actomyosin-cross-linker system

Age- and Activity-Related Differences in the Abundance of Myosin Essential and Regulatory Light Chains in Human Muscle

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James N. Cobley

2016-04-01

Full Text Available Traditional methods for phenotyping skeletal muscle (e.g., immunohistochemistry are labor-intensive and ill-suited to multixplex analysis, i.e., assays must be performed in a series. Addressing these concerns represents a largely unmet research need but more comprehensive parallel analysis of myofibrillar proteins could advance knowledge regarding age- and activity-dependent changes in human muscle. We report a label-free, semi-automated and time efficient LC-MS proteomic workflow for phenotyping the myofibrillar proteome. Application of this workflow in old and young as well as trained and untrained human skeletal muscle yielded several novel observations that were subsequently verified by multiple reaction monitoring (MRM. We report novel data demonstrating that human ageing is associated with lesser myosin light chain 1 content and greater myosin light chain 3 content, consistent with an age-related reduction in type II muscle fibers. We also disambiguate conflicting data regarding myosin regulatory light chain, revealing that age-related changes in this protein more closely reflect physical activity status than ageing per se. This finding reinforces the need to control for physical activity levels when investigating the natural process of ageing. Taken together, our data confirm and extend knowledge regarding age- and activity-related phenotypes. In addition, the MRM transitions described here provide a methodological platform that can be fine-tuned to suite multiple research needs and thus advance myofibrillar phenotyping.

Position of nonmuscle myosin heavy chain IIA (NMMHC-IIA) mutations predicts the natural history of MYH9-related disease

DEFF Research Database (Denmark)

Pecci, A.; Panza, E.; Pujol-Moix, N.

2008-01-01

MYH9-related disease (MYH9-RD) is a rare autosomal-dominant disorder caused by mutations in MYH9, the gene for the heavy chain of nonmuscle myosin IIA (NMMHC-IIA). All patients present from birth with macrothrombocytopenia, but in infancy or adult life, some of them develop sensorineural deafness...... to 50 unrelated pedigrees. The risk of noncongenital manifestations associated with different genotypes was estimated over time by event-free survival analysis. We demonstrated that all subjects with mutations in the motor domain of NMMHC-IIA present with severe thrombocytopenia and develop nephritis...... and deafness before the age of 40 years, while those with mutations in the tail domain have a much lower risk of noncongenital complications and significantly higher platelet counts. We also evaluated the clinical course of patients with mutations in the four most frequently affected residues of NMMHC...

Decision-Making under Ambiguity Is Modulated by Visual Framing, but Not by Motor vs. Non-Motor Context. Experiments and an Information-Theoretic Ambiguity Model.

Science.gov (United States)

Grau-Moya, Jordi; Ortega, Pedro A; Braun, Daniel A

2016-01-01

A number of recent studies have investigated differences in human choice behavior depending on task framing, especially comparing economic decision-making to choice behavior in equivalent sensorimotor tasks. Here we test whether decision-making under ambiguity exhibits effects of task framing in motor vs. non-motor context. In a first experiment, we designed an experience-based urn task with varying degrees of ambiguity and an equivalent motor task where subjects chose between hitting partially occluded targets. In a second experiment, we controlled for the different stimulus design in the two tasks by introducing an urn task with bar stimuli matching those in the motor task. We found ambiguity attitudes to be mainly influenced by stimulus design. In particular, we found that the same subjects tended to be ambiguity-preferring when choosing between ambiguous bar stimuli, but ambiguity-avoiding when choosing between ambiguous urn sample stimuli. In contrast, subjects' choice pattern was not affected by changing from a target hitting task to a non-motor context when keeping the stimulus design unchanged. In both tasks subjects' choice behavior was continuously modulated by the degree of ambiguity. We show that this modulation of behavior can be explained by an information-theoretic model of ambiguity that generalizes Bayes-optimal decision-making by combining Bayesian inference with robust decision-making under model uncertainty. Our results demonstrate the benefits of information-theoretic models of decision-making under varying degrees of ambiguity for a given context, but also demonstrate the sensitivity of ambiguity attitudes across contexts that theoretical models struggle to explain.

Decision-Making under Ambiguity Is Modulated by Visual Framing, but Not by Motor vs. Non-Motor Context. Experiments and an Information-Theoretic Ambiguity Model.

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Jordi Grau-Moya

Full Text Available A number of recent studies have investigated differences in human choice behavior depending on task framing, especially comparing economic decision-making to choice behavior in equivalent sensorimotor tasks. Here we test whether decision-making under ambiguity exhibits effects of task framing in motor vs. non-motor context. In a first experiment, we designed an experience-based urn task with varying degrees of ambiguity and an equivalent motor task where subjects chose between hitting partially occluded targets. In a second experiment, we controlled for the different stimulus design in the two tasks by introducing an urn task with bar stimuli matching those in the motor task. We found ambiguity attitudes to be mainly influenced by stimulus design. In particular, we found that the same subjects tended to be ambiguity-preferring when choosing between ambiguous bar stimuli, but ambiguity-avoiding when choosing between ambiguous urn sample stimuli. In contrast, subjects' choice pattern was not affected by changing from a target hitting task to a non-motor context when keeping the stimulus design unchanged. In both tasks subjects' choice behavior was continuously modulated by the degree of ambiguity. We show that this modulation of behavior can be explained by an information-theoretic model of ambiguity that generalizes Bayes-optimal decision-making by combining Bayesian inference with robust decision-making under model uncertainty. Our results demonstrate the benefits of information-theoretic models of decision-making under varying degrees of ambiguity for a given context, but also demonstrate the sensitivity of ambiguity attitudes across contexts that theoretical models struggle to explain.

Decision-Making under Ambiguity Is Modulated by Visual Framing, but Not by Motor vs. Non-Motor Context. Experiments and an Information-Theoretic Ambiguity Model

Science.gov (United States)

Grau-Moya, Jordi; Ortega, Pedro A.; Braun, Daniel A.

2016-01-01

A number of recent studies have investigated differences in human choice behavior depending on task framing, especially comparing economic decision-making to choice behavior in equivalent sensorimotor tasks. Here we test whether decision-making under ambiguity exhibits effects of task framing in motor vs. non-motor context. In a first experiment, we designed an experience-based urn task with varying degrees of ambiguity and an equivalent motor task where subjects chose between hitting partially occluded targets. In a second experiment, we controlled for the different stimulus design in the two tasks by introducing an urn task with bar stimuli matching those in the motor task. We found ambiguity attitudes to be mainly influenced by stimulus design. In particular, we found that the same subjects tended to be ambiguity-preferring when choosing between ambiguous bar stimuli, but ambiguity-avoiding when choosing between ambiguous urn sample stimuli. In contrast, subjects’ choice pattern was not affected by changing from a target hitting task to a non-motor context when keeping the stimulus design unchanged. In both tasks subjects’ choice behavior was continuously modulated by the degree of ambiguity. We show that this modulation of behavior can be explained by an information-theoretic model of ambiguity that generalizes Bayes-optimal decision-making by combining Bayesian inference with robust decision-making under model uncertainty. Our results demonstrate the benefits of information-theoretic models of decision-making under varying degrees of ambiguity for a given context, but also demonstrate the sensitivity of ambiguity attitudes across contexts that theoretical models struggle to explain. PMID:27124723

Corticospinal excitability during the processing of handwritten and typed words and non-words.

Science.gov (United States)

Gordon, Chelsea L; Spivey, Michael J; Balasubramaniam, Ramesh

2017-06-09

A number of studies have suggested that perception of actions is accompanied by motor simulation of those actions. To further explore this proposal, we applied Transcranial magnetic stimulation (TMS) to the left primary motor cortex during the observation of handwritten and typed language stimuli, including words and non-word consonant clusters. We recorded motor-evoked potentials (MEPs) from the right first dorsal interosseous (FDI) muscle to measure cortico-spinal excitability during written text perception. We observed a facilitation in MEPs for handwritten stimuli, regardless of whether the stimuli were words or non-words, suggesting potential motor simulation during observation. We did not observe a similar facilitation for the typed stimuli, suggesting that motor simulation was not occurring during observation of typed text. By demonstrating potential simulation of written language text during observation, these findings add to a growing literature suggesting that the motor system plays a strong role in the perception of written language. Copyright © 2017 Elsevier B.V. All rights reserved.

Alterations in rat cardiac myosin isozymes induced by whole-body irradiation are prevented by 3,5,3'-L-triiodothyronine

International Nuclear Information System (INIS)

Litten, R.Z.; Fein, H.G.; Gainey, G.T.; Walden, T.L.; Smallridge, R.C.

1990-01-01

Changes in cardiac myosin isozymes and serum thyroid hormone levels were investigated in rats following 10 Gy whole-body gamma irradiation. The percent beta-myosin heavy chain increased from 21.3 ± 1.8 to 28.1 ± 6.8 (NS) at 3-day postirradiation, 37.7 ± 1.9 (P less than .001) at 6-day postirradiation, and 43.8 ± 3.3 (P less than .001) at 9-day postirradiation. Along with the change in myosin isozymes was a significant 53% decrease (P less than .001) in the serum thyroxine (T4) level by day 3 postirradiation, remaining depressed through day 9 postirradiation. The serum 3,5,3'-triiodothyronine (T3) level, however, was normal until day 9, when significant depression was also observed. In contrast, the thyroid-stimulating hormone (TSH) level was significantly increased by fourfold at day 3, returning to near normal values by day 9 postirradiation. Daily injections of physiological doses of T3 (0.3 microgram/100 g body weight) prevented the change in the myosin isozymes following whole-body irradiation. Daily pharmacological injections of T3 (3.0 micrograms/100 g body weight) to the irradiated rats produced a further decrease in the percent beta-myosin heavy chain (below control values) indicating tissue hyperthyroidism. Thus, this study suggests that the change in myosin isozymes following whole-body irradiation is caused by an alteration in thyroid hormone activity

Myosin VIIa, harmonin and cadherin 23, three Usher I gene products that cooperate to shape the sensory hair cell bundle

Science.gov (United States)

Boëda, Batiste; El-Amraoui, Aziz; Bahloul, Amel; Goodyear, Richard; Daviet, Laurent; Blanchard, Stéphane; Perfettini, Isabelle; Fath, Karl R.; Shorte, Spencer; Reiners, Jan; Houdusse, Anne; Legrain, Pierre; Wolfrum, Uwe; Richardson, Guy; Petit, Christine

2002-01-01

Deaf-blindness in three distinct genetic forms of Usher type I syndrome (USH1) is caused by defects in myosin VIIa, harmonin and cadherin 23. Despite being critical for hearing, the functions of these proteins in the inner ear remain elusive. Here we show that harmonin, a PDZ domain-containing protein, and cadherin 23 are both present in the growing stereocilia and that they bind to each other. Moreover, we demonstrate that harmonin b is an F-actin-bundling protein, which is thus likely to anchor cadherin 23 to the stereocilia microfilaments, thereby identifying a novel anchorage mode of the cadherins to the actin cytoskeleton. Moreover, harmonin b interacts directly with myosin VIIa, and is absent from the disorganized hair bundles of myosin VIIa mutant mice, suggesting that myosin VIIa conveys harmonin b along the actin core of the developing stereocilia. We propose that the shaping of the hair bundle relies on a functional unit composed of myosin VIIa, harmonin b and cadherin 23 that is essential to ensure the cohesion of the stereocilia. PMID:12485990

Flux modeling and analysis of a linear induction motor for steel mill non-contacting conveyance system application

International Nuclear Information System (INIS)

Liu, C.-T.; Lin, S.-Y.; Yang, Y.-Y.

2005-01-01

A detailed mathematical approach for analyzing static/dynamic characteristics of a linear induction motor for steel mill non-contacting conveyance system application will be provided. The dependent reluctances among the motor secondary steel plate and primary poles have been systematically formulated; hence, the operational performance of the system can be derived conveniently. Results showed that not only the motor structure is suitable for the design objective, but also the proposed magnetic equivalent circuit can provide appropriate and convenient modeling for relative analytical investigations

Automated processing of data on the use of motor vehicles in the Serbian Armed Forces

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Nikola S. Osmokrović

2012-10-01

Full Text Available The main aim of introducing information technology into the armed forces is the automation of the management process. The management in movement and transport (M&T in our armed forces has been included in the process of automation from the beginning. For that reason, today we can speak about the automated processing of data on road traffic safety and on the use of motor vehicles. With regard to the overall development of the information system of the movement and transport service, the paper presents an information system of the M&T service for the processing of data on the use of motor vehicles. The main features, components and functions of the 'Vozila' application, which was specially developed for the automated processing of data on motor vehicle use, are explained in particular.

Non-intentional motor vehicle-related carbon monoxide deaths-revisited

Energy Technology Data Exchange (ETDEWEB)

Copeland, A.R.

1986-01-01

A study of non-intentional, motor vehicle-related, carbon monoxide-related deaths was performed on the case files of the Office of the Medical Examiner of Metropolitan Dade Country in Miami, FL (USA) during the years 1980-1984. A total of 15 cases were collected during that time period. These are presented in some detail. A discussion ensues that compares the similar circumstances of these cases, notably running the engine of an automobile in an enclosed space, with older reports in the literature which emphasized defective vehicle exhaust systems as the leading etiology for these deaths.

Actin Filaments and Myosin I Alpha Cooperate with Microtubules for the Movement of LysosomesV⃞

OpenAIRE

Cordonnier, Marie-Neige; Dauzonne, Daniel; Louvard, Daniel; Coudrier, Evelyne

2001-01-01

An earlier report suggested that actin and myosin I alpha (MMIα), a myosin associated with endosomes and lysosomes, were involved in the delivery of internalized molecules to lysosomes. To determine whether actin and MMIα were involved in the movement of lysosomes, we analyzed by time-lapse video microscopy the dynamic of lysosomes in living mouse hepatoma cells (BWTG3 cells), producing green fluorescent protein actin or a nonfunctional domain of MMIα. In GFP-actin cells, lysosomes displayed ...

A comparative study of myosin and its subunits in adult and neonatal-rat hearts and in rat heart cells from young and old cultures.

OpenAIRE

Ghanbari, H A; McCarl, R L

1980-01-01

A possible explanation for the decrease in myosin Ca2+-dependent ATPase activity as rat heart cells age in culture is presented. The subunit structure and enzyme kinetics of myosin from adult and neonatal rat hearts and from rat heart cells of young and old cultures are compared. These studies indicate that the loss in Ca-ATPase activity of myosin from older cultures was an intrinsic property of the myosin itself. Myofibrillar fractions from the indicated four sources showed no qualitative or...

Temporary Nerve Block at Selected Digits Revealed Hand Motor Deficits in Grasping Tasks

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Aude Carteron

2016-11-01

Full Text Available Peripheral sensory feedback plays a crucial role in ensuring correct motor execution throughout hand grasp control. Previous studies utilized local anesthesia to deprive somatosensory feedback in the digits or hand, observations included sensorimotor deficits at both corticospinal and peripheral levels. However, the questions of how the disturbed and intact sensory input integrate and interact with each other to assist the motor program execution, and whether the motor coordination based on motor output variability between affected and non-affected elements (e.g., digits becomes interfered by the local sensory deficiency, have not been answered. The current study aims to investigate the effect of peripheral deafferentation through digital nerve blocks at selective digits on motor performance and motor coordination in grasp control. Our results suggested that the absence of somatosensory information induced motor deficits in hand grasp control, as evidenced by reduced maximal force production ability in both local and non-local digits, impairment of force and moment control during object lift and hold, and attenuated motor synergies in stabilizing task performance variables, namely the tangential force and moment of force. These findings implied that individual sensory input is shared across all the digits and the disturbed signal from local sensory channel(s has a more comprehensive impact on the process of the motor output execution in the sensorimotor integration process. Additionally, a feedback control mechanism with a sensation-based component resides in the formation process for the motor covariation structure.

The emergence of sarcomeric, graded-polarity and spindle-like patterns in bundles of short cytoskeletal polymers and two opposite molecular motors

International Nuclear Information System (INIS)

Craig, E M; Dey, S; Mogilner, A

2011-01-01

We use linear stability analysis and numerical solutions of partial differential equations to investigate pattern formation in the one-dimensional system of short dynamic polymers and one (plus-end directed) or two (one is plus-end, another minus-end directed) molecular motors. If polymer sliding and motor gliding rates are slow and/or the polymer turnover rate is fast, then the polymer-motor bundle has mixed polarity and homogeneous motor distribution. However, if motor gliding is fast, a sarcomeric pattern with periodic bands of alternating polymer polarity separated by motor aggregates evolves. On the other hand, if polymer sliding is fast, a graded-polarity bundle with motors at the center emerges. In the presence of the second, minus-end directed motor, the sarcomeric pattern is more ubiquitous, while the graded-polarity pattern is destabilized. However, if the minus-end motor is weaker than the plus-end directed one, and/or polymer nucleation is autocatalytic, and/or long polymers are present in the bundle, then a spindle-like architecture with a sorted-out polarity emerges with the plus-end motors at the center and minus-end motors at the edges. We discuss modeling implications for actin-myosin fibers and in vitro and meiotic spindles.

The fungal myosin I is essential for Fusarium toxisome formation

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The mycotoxin deoxynivalenol (DON) is the most frequently detected secondary metabolite produced by Fusarium graminearum and other Fusarium spp. To date, relatively few studies have addressed how mycotoxin biosynthesis occurs in fungal cells. Here we found that myosin I governs translation of DON bi...

A Drosophila model of dominant inclusion body myopathy type 3 shows diminished myosin kinetics that reduce muscle power and yield myofibrillar defects.

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Suggs, Jennifer A; Melkani, Girish C; Glasheen, Bernadette M; Detor, Mia M; Melkani, Anju; Marsan, Nathan P; Swank, Douglas M; Bernstein, Sanford I

2017-06-01

Individuals with inclusion body myopathy type 3 (IBM3) display congenital joint contractures with early-onset muscle weakness that becomes more severe in adulthood. The disease arises from an autosomal dominant point mutation causing an E706K substitution in myosin heavy chain type IIa. We have previously expressed the corresponding myosin mutation (E701K) in homozygous Drosophila indirect flight muscles and recapitulated the myofibrillar degeneration and inclusion bodies observed in the human disease. We have also found that purified E701K myosin has dramatically reduced actin-sliding velocity and ATPase levels. Since IBM3 is a dominant condition, we now examine the disease state in heterozygote Drosophila in order to gain a mechanistic understanding of E701K pathogenicity. Myosin ATPase activities in heterozygotes suggest that approximately equimolar levels of myosin accumulate from each allele. In vitro actin sliding velocity rates for myosin isolated from the heterozygotes were lower than the control, but higher than for the pure mutant isoform. Although sarcomeric ultrastructure was nearly wild type in young adults, mechanical analysis of skinned indirect flight muscle fibers revealed a 59% decrease in maximum oscillatory power generation and an approximately 20% reduction in the frequency at which maximum power was produced. Rate constant analyses suggest a decrease in the rate of myosin attachment to actin, with myosin spending decreased time in the strongly bound state. These mechanical alterations result in a one-third decrease in wing beat frequency and marginal flight ability. With aging, muscle ultrastructure and function progressively declined. Aged myofibrils showed Z-line streaming, consistent with the human heterozygote phenotype. Based upon the mechanical studies, we hypothesize that the mutation decreases the probability of the power stroke occurring and/or alters the degree of movement of the myosin lever arm, resulting in decreased in vitro

A Drosophila model of dominant inclusion body myopathy type 3 shows diminished myosin kinetics that reduce muscle power and yield myofibrillar defects

Directory of Open Access Journals (Sweden)

Jennifer A. Suggs

2017-06-01

Full Text Available Individuals with inclusion body myopathy type 3 (IBM3 display congenital joint contractures with early-onset muscle weakness that becomes more severe in adulthood. The disease arises from an autosomal dominant point mutation causing an E706K substitution in myosin heavy chain type IIa. We have previously expressed the corresponding myosin mutation (E701K in homozygous Drosophila indirect flight muscles and recapitulated the myofibrillar degeneration and inclusion bodies observed in the human disease. We have also found that purified E701K myosin has dramatically reduced actin-sliding velocity and ATPase levels. Since IBM3 is a dominant condition, we now examine the disease state in heterozygote Drosophila in order to gain a mechanistic understanding of E701K pathogenicity. Myosin ATPase activities in heterozygotes suggest that approximately equimolar levels of myosin accumulate from each allele. In vitro actin sliding velocity rates for myosin isolated from the heterozygotes were lower than the control, but higher than for the pure mutant isoform. Although sarcomeric ultrastructure was nearly wild type in young adults, mechanical analysis of skinned indirect flight muscle fibers revealed a 59% decrease in maximum oscillatory power generation and an approximately 20% reduction in the frequency at which maximum power was produced. Rate constant analyses suggest a decrease in the rate of myosin attachment to actin, with myosin spending decreased time in the strongly bound state. These mechanical alterations result in a one-third decrease in wing beat frequency and marginal flight ability. With aging, muscle ultrastructure and function progressively declined. Aged myofibrils showed Z-line streaming, consistent with the human heterozygote phenotype. Based upon the mechanical studies, we hypothesize that the mutation decreases the probability of the power stroke occurring and/or alters the degree of movement of the myosin lever arm, resulting in

Developing a Rubric and Best Practices for Conducting Counts of Non-Motorized Transportation Users

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2016-01-01

Over the past five years non-motorized modes of transportation have become ever more prevalent on Utahs roadways. Historically, these modes have not been included in traffic counts nor are they accurately represented in the long range planning mod...

Synthesis of total protein (TP) and myosin heavy chain (HC) isozymes in pressure overloaded rabbit hearts

International Nuclear Information System (INIS)

Nagai, R.; Martin, B.J.; Pritzl, N.; Zak, R.; Low, R.B.; Stirewalt, W.S.; Alpert, N.R.; Litten, R.Z.

1986-01-01

Pulmonary artery banding (PO) leads to a rapid increase in right ventricular (RV) weight as well as a shift toward β myosin isozyme. They determined: (1) the contributions of changes in the capacity (RNA content) and efficiency of total protein synthesis to the increase in RV weight; and (2) the relative contributions of translational and pretranslational mechanisms to the shift in myosin HC isotypes. The rates of synthesis in vivo of TP, α- and β-HC were measured by a constant infusion technique using 3 H-leucine. TP synthesis was 7 +/- 2(SD) mg/day in control (RV:367 +/- 70 mg) and was increased by 2.6 fold at day 2 and 2.9 fold at day 4 following PO (p < 0.01). RV RNA content was increased by 83% at day 2 and 103% at day 4 PO (p < 0.05). The efficiency of synthesis (rate/RNA) was also significantly higher at these time points (1.4- and 1.3-fold). β-HC synthesis was 0.6 +/- 0.2 mg/day in control and increased by 2.6 fold at day 2 and 3.5 fold at day 4 following PO. In contrast, the rate of synthesis of α-HC was unchanged. The relative rates of β-HC to total HC synthesis was correlated linearly with the relative levels of β-myosin mRNA as measured by S1 nuclease mapping. They conclude that increases in the proportion of β-HC myosin following PO is due to increases in the relative amount of β-myosin mRNA and therefore involves modulation of a pretranslational mechanism

Myosin XI-Dependent Formation of Tubular Structures from Endoplasmic Reticulum Isolated from Tobacco Cultured BY-2 Cells1[W][OA

Science.gov (United States)

Yokota, Etsuo; Ueda, Haruko; Hashimoto, Kohsuke; Orii, Hidefumi; Shimada, Tomoo; Hara-Nishimura, Ikuko; Shimmen, Teruo

2011-01-01

The reticular network of the endoplasmic reticulum (ER) consists of tubular and lamellar elements and is arranged in the cortical region of plant cells. This network constantly shows shape change and remodeling motion. Tubular ER structures were formed when GTP was added to the ER vesicles isolated from tobacco (Nicotiana tabacum) cultured BY-2 cells expressing ER-localized green fluorescent protein. The hydrolysis of GTP during ER tubule formation was higher than that under conditions in which ER tubule formation was not induced. Furthermore, a shearing force, such as the flow of liquid, was needed for the elongation/extension of the ER tubule. The shearing force was assumed to correspond to the force generated by the actomyosin system in vivo. To confirm this hypothesis, the S12 fraction was prepared, which contained both cytosol and microsome fractions, including two classes of myosins, XI (175-kD myosin) and VIII (BY-2 myosin VIII-1), and ER-localized green fluorescent protein vesicles. The ER tubules and their mesh-like structures were arranged in the S12 fraction efficiently by the addition of ATP, GTP, and exogenous filamentous actin. The tubule formation was significantly inhibited by the depletion of 175-kD myosin from the S12 fraction but not BY-2 myosin VIII-1. Furthermore, a recombinant carboxyl-terminal tail region of 175-kD myosin also suppressed ER tubule formation. The tips of tubules moved along filamentous actin during tubule elongation. These results indicated that the motive force generated by the actomyosin system contributes to the formation of ER tubules, suggesting that myosin XI is responsible not only for the transport of ER in cytoplasm but also for the reticular organization of cortical ER. PMID:21427277

Alterations in rat cardiac myosin isozymes induced by whole-body irradiation are prevented by 3,5,3'-L-triiodothyronine

Energy Technology Data Exchange (ETDEWEB)

Litten, R.Z.; Fein, H.G.; Gainey, G.T.; Walden, T.L.; Smallridge, R.C. (Armed Forces Radiobiology Research Institute, Bethesda, MD (USA))

1990-01-01

Changes in cardiac myosin isozymes and serum thyroid hormone levels were investigated in rats following 10 Gy whole-body gamma irradiation. The percent beta-myosin heavy chain increased from 21.3 {plus minus} 1.8 to 28.1 {plus minus} 6.8 (NS) at 3-day postirradiation, 37.7 {plus minus} 1.9 (P less than .001) at 6-day postirradiation, and 43.8 {plus minus} 3.3 (P less than .001) at 9-day postirradiation. Along with the change in myosin isozymes was a significant 53% decrease (P less than .001) in the serum thyroxine (T4) level by day 3 postirradiation, remaining depressed through day 9 postirradiation. The serum 3,5,3'-triiodothyronine (T3) level, however, was normal until day 9, when significant depression was also observed. In contrast, the thyroid-stimulating hormone (TSH) level was significantly increased by fourfold at day 3, returning to near normal values by day 9 postirradiation. Daily injections of physiological doses of T3 (0.3 microgram/100 g body weight) prevented the change in the myosin isozymes following whole-body irradiation. Daily pharmacological injections of T3 (3.0 micrograms/100 g body weight) to the irradiated rats produced a further decrease in the percent beta-myosin heavy chain (below control values) indicating tissue hyperthyroidism. Thus, this study suggests that the change in myosin isozymes following whole-body irradiation is caused by an alteration in thyroid hormone activity.

Stable and dynamic microtubules coordinately shape the myosin activation zone during cytokinetic furrow formation

Science.gov (United States)

Foe, Victoria E.; von Dassow, George

2008-01-01

The cytokinetic furrow arises from spatial and temporal regulation of cortical contractility. To test the role microtubules play in furrow specification, we studied myosin II activation in echinoderm zygotes by assessing serine19-phosphorylated regulatory light chain (pRLC) localization after precisely timed drug treatments. Cortical pRLC was globally depressed before cytokinesis, then elevated only at the equator. We implicated cell cycle biochemistry (not microtubules) in pRLC depression, and differential microtubule stability in localizing the subsequent myosin activation. With no microtubules, pRLC accumulation occurred globally instead of equatorially, and loss of just dynamic microtubules increased equatorial pRLC recruitment. Nocodazole treatment revealed a population of stable astral microtubules that formed during anaphase; among these, those aimed toward the equator grew longer, and their tips coincided with cortical pRLC accumulation. Shrinking the mitotic apparatus with colchicine revealed pRLC suppression near dynamic microtubule arrays. We conclude that opposite effects of stable versus dynamic microtubules focuses myosin activation to the cell equator during cytokinesis. PMID:18955555

Alternatives for providing a safe passage for non-motorized traffic across an existing highway bridge.

Science.gov (United States)

2015-08-31

Non-motorized transportation increases mobility choices, relieves congestion, promotes local economy, reduces greenhouse gas emission, promotes a healthy lifestyle, and improves quality of life. Recently, there is an emphasis on developing integrated...

Reversal of long-term potentiation-like plasticity processes after motor learning disrupts skill retention.

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Cantarero, Gabriela; Lloyd, Ashley; Celnik, Pablo

2013-07-31

Plasticity of synaptic connections in the primary motor cortex (M1) is thought to play an essential role in learning and memory. Human and animal studies have shown that motor learning results in long-term potentiation (LTP)-like plasticity processes, namely potentiation of M1 and a temporary occlusion of additional LTP-like plasticity. Moreover, biochemical processes essential for LTP are also crucial for certain types of motor learning and memory. Thus, it has been speculated that the occlusion of LTP-like plasticity after learning, indicative of how much LTP was used to learn, is essential for retention. Here we provide supporting evidence of it in humans. Induction of LTP-like plasticity can be abolished using a depotentiation protocol (DePo) consisting of brief continuous theta burst stimulation. We used transcranial magnetic stimulation to assess whether application of DePo over M1 after motor learning affected (1) occlusion of LTP-like plasticity and (2) retention of motor skill learning. We found that the magnitude of motor memory retention is proportional to the magnitude of occlusion of LTP-like plasticity. Moreover, DePo stimulation over M1, but not over a control site, reversed the occlusion of LTP-like plasticity induced by motor learning and disrupted skill retention relative to control subjects. Altogether, these results provide evidence of a link between occlusion of LTP-like plasticity and retention and that this measure could be used as a biomarker to predict retention. Importantly, attempts to reverse the occlusion of LTP-like plasticity after motor learning comes with the cost of reducing retention of motor learning.

NON-TRADITIONAL SPORTS AT SCHOOL. BENEFITS FOR PHYSICAL AND MOTOR DEVELOPMENT

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AMADOR J. LARA-SÁNCHEZ

2010-12-01

Full Text Available Physical Education teachers have been using some very classic team sports, like football, basketball, handball, volleyball, etc. for many years in order to develop their education work at school. As a consequence of this, the benefits of this kind of activities on Physical Education lessons have not been as notable as we mighthave expected, since, even if they are increasing, their development and application are still low. There are many and very varied new non-traditional sports that have emerged and extended across Spain in recent years. To mention an example, we could refer to a newly created non-traditional sport such as kin-ball. This sport wascreated for the purpose of achieving a way to combine several factors such as health, team-work and competitiveness. Three teams of four players each participate. This way, every player can participate to a great extent in all the moves of the match, for each of them must defend one area of their half in order to achieve a common objective. Besides, kin-ball helps to develop motor skills at school in an easy way; that is, coordination, balance and perception. There is a large variety of non-traditional games and sports that are similar to kin-ball, such as floorball, intercrosse, mazaball, tchoukball, ultimate, indiaca, shuttleball... All of them show many physical, psychic and social advantages, and can help us to make the Physical Education teaching-learning process more motivating, acquiring the recreational component that it showed some years ago and which hasnow disappeared

Functions of nonmuscle myosin II in assembly of the cellular contractile system.

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Maria Shutova

Full Text Available The contractile system of nonmuscle cells consists of interconnected actomyosin networks and bundles anchored to focal adhesions. The initiation of the contractile system assembly is poorly understood structurally and mechanistically, whereas system's maturation heavily depends on nonmuscle myosin II (NMII. Using platinum replica electron microscopy in combination with fluorescence microscopy, we characterized the structural mechanisms of the contractile system assembly and roles of NMII at early stages of this process. We show that inhibition of NMII by a specific inhibitor, blebbistatin, in addition to known effects, such as disassembly of stress fibers and mature focal adhesions, also causes transformation of lamellipodia into unattached ruffles, loss of immature focal complexes, loss of cytoskeleton-associated NMII filaments and peripheral accumulation of activated, but unpolymerized NMII. After blebbistatin washout, assembly of the contractile system begins with quick and coordinated recovery of lamellipodia and focal complexes that occurs before reappearance of NMII bipolar filaments. The initial formation of focal complexes and subsequent assembly of NMII filaments preferentially occurred in association with filopodial bundles and concave actin bundles formed by filopodial roots at the lamellipodial base. Over time, accumulating NMII filaments help to transform the precursor structures, focal complexes and associated thin bundles, into stress fibers and mature focal adhesions. However, semi-sarcomeric organization of stress fibers develops at much slower rate. Together, our data suggest that activation of NMII motor activity by light chain phosphorylation occurs at the cell edge and is uncoupled from NMII assembly into bipolar filaments. We propose that activated, but unpolymerized NMII initiates focal complexes, thus providing traction for lamellipodial protrusion. Subsequently, the mechanical resistance of focal complexes activates a

Non-linear Relationship between BOLD Activation and Amplitude of Beta Oscillations in the Supplementary Motor Area during Rhythmic Finger Tapping and Internal Timing

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Gompf, Florian; Pflug, Anja; Laufs, Helmut; Kell, Christian A.

2017-01-01

Functional imaging studies using BOLD contrasts have consistently reported activation of the supplementary motor area (SMA) both during motor and internal timing tasks. Opposing findings, however, have been shown for the modulation of beta oscillations in the SMA. While movement suppresses beta oscillations in the SMA, motor and non-motor tasks that rely on internal timing increase the amplitude of beta oscillations in the SMA. These independent observations suggest that the relationship between beta oscillations and BOLD activation is more complex than previously thought. Here we set out to investigate this rapport by examining beta oscillations in the SMA during movement with varying degrees of internal timing demands. In a simultaneous EEG-fMRI experiment, 20 healthy right-handed subjects performed an auditory-paced finger-tapping task. Internal timing was operationalized by including conditions with taps on every fourth auditory beat, which necessitates generation of a slow internal rhythm, while tapping to every auditory beat reflected simple auditory-motor synchronization. In the SMA, BOLD activity increased and power in both the low and the high beta band decreased expectedly during each condition compared to baseline. Internal timing was associated with a reduced desynchronization of low beta oscillations compared to conditions without internal timing demands. In parallel with this relative beta power increase, internal timing activated the SMA more strongly in terms of BOLD. This documents a task-dependent non-linear relationship between BOLD and beta-oscillations in the SMA. We discuss different roles of beta synchronization and desynchronization in active processing within the same cortical region. PMID:29249950

Non-linear Relationship between BOLD Activation and Amplitude of Beta Oscillations in the Supplementary Motor Area during Rhythmic Finger Tapping and Internal Timing.

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Gompf, Florian; Pflug, Anja; Laufs, Helmut; Kell, Christian A

2017-01-01

Functional imaging studies using BOLD contrasts have consistently reported activation of the supplementary motor area (SMA) both during motor and internal timing tasks. Opposing findings, however, have been shown for the modulation of beta oscillations in the SMA. While movement suppresses beta oscillations in the SMA, motor and non-motor tasks that rely on internal timing increase the amplitude of beta oscillations in the SMA. These independent observations suggest that the relationship between beta oscillations and BOLD activation is more complex than previously thought. Here we set out to investigate this rapport by examining beta oscillations in the SMA during movement with varying degrees of internal timing demands. In a simultaneous EEG-fMRI experiment, 20 healthy right-handed subjects performed an auditory-paced finger-tapping task. Internal timing was operationalized by including conditions with taps on every fourth auditory beat, which necessitates generation of a slow internal rhythm, while tapping to every auditory beat reflected simple auditory-motor synchronization. In the SMA, BOLD activity increased and power in both the low and the high beta band decreased expectedly during each condition compared to baseline. Internal timing was associated with a reduced desynchronization of low beta oscillations compared to conditions without internal timing demands. In parallel with this relative beta power increase, internal timing activated the SMA more strongly in terms of BOLD. This documents a task-dependent non-linear relationship between BOLD and beta-oscillations in the SMA. We discuss different roles of beta synchronization and desynchronization in active processing within the same cortical region.

Botulinum Toxin Type A Inhibits α-Smooth Muscle Actin and Myosin II Expression in Fibroblasts Derived From Scar Contracture.

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Chen, Minliang; Yan, Tongtong; Ma, Kui; Lai, Linying; Liu, Chang; Liang, Liming; Fu, Xiaobing

2016-09-01

Scar contracture (SC) is one of the most common complications resulting from major burn injuries. Numerous treatments are currently available but they do not always yield excellent therapeutic results. Recent reports suggest that botulinum toxin type A (BTXA) is effective at reducing SC clinically, but the molecular mechanism for this action is unknown. α-Smooth muscle actin (α-SMA) and myosin II are the main components of stress fibers, which are the contractile structures of fibroblasts. The effects of BTXA on α-SMA and myosin II in SC are still unknown. This study aimed to explore the effect of BTXA on α-SMA and myosin II expression in fibroblasts derived from SC and to elucidate its actual mechanism further. Fibroblasts were isolated from tissue specimens of SC. Fibroblasts were cultured in Dulbecco modified Eagle medium with different concentrations of BTXA and their proliferation was analyzed through the tetrazolium-based colorimetric method at 1, 4, and 7 days. Proteins of α-SMA and myosin II were checked using Western blot in fibroblasts treated with different concentrations of BTXA at 1, 4, and 7 days. Fibroblasts without BTXA treatment had a higher proliferation than that in other groups, which indicated that the proliferation of fibroblasts was significantly inhibited by BTXA (P < 0.05). Proteins of α-SMA and myosin II between fibroblasts with BTXA and fibroblasts without BTXA are statistically significant (P < 0.05). These results suggest that BTXA effectively inhibited the growth of fibroblasts derived from SC and reduced the expression of α-SMA and myosin II, which provided theoretical support for the application of BTXA to control SC.

The influence of scopolamine on motor control and attentional processes

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Emma Bestaven

2016-05-01

Full Text Available Background: Motion sickness may be caused by a sensory conflict between the visual and the vestibular systems. Scopolamine, known to be the most effective therapy to control the vegetative symptoms of motion sickness, acts on the vestibular nucleus and potentially the vestibulospinal pathway, which may affect balance and motor tasks requiring both attentional process and motor balance. The aim of this study was to explore the effect of scopolamine on motor control and attentional processes. Methods: Seven subjects were evaluated on four different tasks before and after a subcutaneous injection of scopolamine (0.2 mg: a one-minute balance test, a subjective visual vertical test, a pointing task and a galvanic vestibular stimulation with EMG recordings. Results: The results showed that the reaction time and the movement duration were not modified after the injection of scopolamine. However, there was an increase in the center of pressure displacement during the balance test, a decrease in EMG muscle response after galvanic vestibular stimulation and an alteration in the perception of verticality. Discussion: These results confirm that low doses of scopolamine such as those prescribed to avoid motion sickness have no effect on attentional processes, but that it is essential to consider the responsiveness of each subject. However, scopolamine did affect postural control and the perception of verticality. In conclusion, the use of scopolamine to prevent motion sickness must be considered carefully because it could increase imbalances in situations when individuals are already at risk of falling (e.g., sailing, parabolic flight.

Metastasis-associated protein Mts1 (S100A4) inhibits CK2-mediated phosphorylation and self-assembly of the heavy chain of nonmuscle myosin

DEFF Research Database (Denmark)

Kriajevska, M; Bronstein, I B; Scott, D J

2000-01-01

a regulatory role in the myosin assembly. In the presence of calcium, Mts1 binds at the C-terminal end of the myosin heavy chain close to the site of phosphorylation by protein kinase CK2 (Ser1944). In the present study, we have shown that interaction of Mts1 with the human platelet myosin or C...

Orientation of spin-labeled light chain 2 of myosin heads in muscle fibers.

Science.gov (United States)

Arata, T

1990-07-20

Electron paramagnetic resonance (e.p.r.) spectroscopy has been used to monitor the orientation of spin labels attached rigidly to a reactive SH residue on the light chain 2 (LC2) of myosin heads in muscle fibers. e.p.r. spectra from spin-labeled myosin subfragment-1 (S1), allowed to diffuse into unlabeled rigor (ATP-free) fibers, were roughly approximated by a narrow angular distribution of spin labels centered at 66 degrees relative to the fiber axis, indicating a uniform orientation of S1 bound to actin. On the other hand, spectra from spin-labeled heavy meromyosin (HMM) were roughly approximated by two narrow angular distributions centered at 42 degrees and 66 degrees, suggesting that the LC2 domains of the two HMM heads have different orientations. In contrast to S1 or HMM, the spectra from rigor fibers, in which LC2 of endogenous myosin heads was labeled, showed a random orientation which may be due to distortion imposed by the structure of the filament lattice and the mismatch of the helical periodicities of the thick and thin filaments. However, spectra from the fibers in the presence of ATP analog 5'-adenylyl imidodiphosphate (AMPPNP) were approximated by two narrow angular distributions similar to those obtained with HMM. Thus, AMPPNP may cause the LC2 domain to be less flexible and/or the S2 portion to be more flexible, so as to release the distortion of the LC2 domain and make it return to its natural position. At high ionic strength, AMPPNP disoriented the spin labels as ATP did under relaxing conditions, suggesting that the myosin head is detached from and/or weakly (flexibly) attached to a thin filament.

POSITION CONTROL OF BRUSHLESS DC MOTOR BASED ON DIGITAL SIGNAL PROCESSING

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Çetin GENÇER

2006-01-01

Full Text Available Brushless DC Motors (BLDC have been used widely high performance control systems which are depended on to development of power electronic and control technology. In these motors to fed commutated supply, the control of position without oscilation has been required. In this study, position control of BLDC with digital signal processing has been implemented by a proportional-derivative (PD controller because of its simple structure. It has been seen that the controller which is proposed from simulation and experimental studies, has a quick dynamic responce with nonoscillation.

Differential activation of brain regions involved with error-feedback and imitation based motor simulation when observing self and an expert's actions in pilots and non-pilots on a complex glider landing task.

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Callan, Daniel E; Terzibas, Cengiz; Cassel, Daniel B; Callan, Akiko; Kawato, Mitsuo; Sato, Masa-Aki

2013-05-15

In this fMRI study we investigate neural processes related to the action observation network using a complex perceptual-motor task in pilots and non-pilots. The task involved landing a glider (using aileron, elevator, rudder, and dive brake) as close to a target as possible, passively observing a replay of one's own previous trial, passively observing a replay of an expert's trial, and a baseline do nothing condition. The objective of this study is to investigate two types of motor simulation processes used during observation of action: imitation based motor simulation and error-feedback based motor simulation. It has been proposed that the computational neurocircuitry of the cortex is well suited for unsupervised imitation based learning, whereas, the cerebellum is well suited for error-feedback based learning. Consistent with predictions, pilots (to a greater extent than non-pilots) showed significant differential activity when observing an expert landing the glider in brain regions involved with imitation based motor simulation (including premotor cortex PMC, inferior frontal gyrus IFG, anterior insula, parietal cortex, superior temporal gyrus, and middle temporal MT area) than when observing one's own previous trial which showed significant differential activity in the cerebellum (only for pilots) thought to be concerned with error-feedback based motor simulation. While there was some differential brain activity for pilots in regions involved with both Execution and Observation of the flying task (potential Mirror System sites including IFG, PMC, superior parietal lobule) the majority was adjacent to these areas (Observation Only Sites) (predominantly in PMC, IFG, and inferior parietal loblule). These regions showing greater activity for observation than for action may be involved with processes related to motor-based representational transforms that are not necessary when actually carrying out the task. Copyright © 2013 Elsevier Inc. All rights reserved.

Role of association cortices and cerebellum during motor consolidation process

International Nuclear Information System (INIS)

Nagata, Ken; Wright, David K.; Box, Georgia A.

2008-01-01

Positron emission tomography (PET) studies of cerebral circulation activated during the first (naive) and second (learned) visual-motor tasks were performed to confirm the hypothesis that activated brain regions are different before and after the motor work. Subjects were 30 normal healthy right-handed volunteers (av. age 21 y), who had the first 10 tasks of cursor tracing (regular tracing, rt), as rapidly and accurately as possible, along the given star features and then second 15 tasks of tracing with the cursor with inverse polarity (mirror tracing, mt). During the tasks, PET images were obtained at 7th and 9th rt, and 10 times (1st-15th) during mt, with the high-resolution positron camera (HEADTOME V) to measure the cerebral blood flow after intravenous 15 O-water and were processed into 3D for statistics. At the 1st mt (under the most unfamiliar condition), stimulated were the right frontal and supplementary motor areas and temporal lobe, bilateral centriciput lobe, anterior cingulated gyrus, and left cerebellum hemisphere. Under the learned condition (at 15th mt), the primary motor area, lingual gyrus, cuneus, anterior cuneus, occipital lobe involving posterior cingulated gyrus and left cerebellum hemisphere were activated. Thus the hypothesis above was confirmed: reconfirmation of the brain plasticity. (R.T.)

Virtual process of product development for electric motors; Virtueller Produktentwicklungsprozess fuer Elektromotoren

Energy Technology Data Exchange (ETDEWEB)

Schoening, Marc Christian

2008-07-01

In order to consider all relevant design aspects and their mutual interdependences, current design practice uses a selection of different software packages. The design tools as a rule specialize in a single design criterion, so that tools must be combined in order to consider the mutual interaction of electromagnetic, thermal, and acoustic effects. So far, this has been done individually and manually, with a new model of the motor under investigation generated in every single program. This means that the parameters of a motor must be managed several times. The publication presents a novel simulation tool which provides a comprehensive methodology in which all design aspects of electric motors are considered by a standardised and uniform virtual development process. Further, the virtual reality method is used for representing 3D motor models in their natural dimensions, thus providing better understanding of the numeric simulation results. (orig.)

Kinesin-73 is a processive motor that localizes to Rab5-containing organelles.

Science.gov (United States)

Huckaba, Thomas M; Gennerich, Arne; Wilhelm, James E; Chishti, Athar H; Vale, Ronald D

2011-03-04

Drosophila Kinesin-73 (Khc-73), which plays a role in mitotic spindle polarity in neuroblasts, is a metazoan-specific member of the Kinesin-3 family of motors, which includes mammalian KIF1A and Caenorhabditis elegans Unc-104. The mechanism of Kinesin-3 motors has been controversial because some studies have reported that they transport cargo as monomers whereas other studies have suggested a dimer mechanism. Here, we have performed single-molecule motility and cell biological studies of Khc-73. We find that constructs containing the motor and the conserved short stretches of putative coiled-coil-forming regions are predominantly monomeric in vitro, but that dimerization allows for fast, processive movement and high force production (7 piconewtons). In Drosophila cell lines, we present evidence that Khc-73 can dimerize in vivo. We also show that Khc-73 is recruited specifically to Rab5-containing endosomes through its "tail" domain. Our results suggest that the N-terminal half of Khc-73 can undergo a monomer-dimer transition to produce a fast processive motor and that its C-terminal half possesses a specific Rab5-vesicle binding domain.

How does the interaction between spelling and motor processes build up during writing acquisition?

Science.gov (United States)

Kandel, Sonia; Perret, Cyril

2015-03-01

How do we recall a word's spelling? How do we produce the movements to form the letters of a word? Writing involves several processing levels. Surprisingly, researchers have focused either on spelling or motor production. However, these processes interact and cannot be studied separately. Spelling processes cascade into movement production. For example, in French, producing letters PAR in the orthographically irregular word PARFUM (perfume) delays motor production with respect to the same letters in the regular word PARDON (pardon). Orthographic regularity refers to the possibility of spelling a word correctly by applying the most frequent sound-letter conversion rules. The present study examined how the interaction between spelling and motor processing builds up during writing acquisition. French 8-10 year old children participated in the experiment. This is the age handwriting skills start to become automatic. The children wrote regular and irregular words that could be frequent or infrequent. They wrote on a digitizer so we could collect data on latency, movement duration and fluency. The results revealed that the interaction between spelling and motor processing was present already at age 8. It became more adult-like at ages 9 and 10. Before starting to write, processing irregular words took longer than regular words. This processing load spread into movement production. It increased writing duration and rendered the movements more dysfluent. Word frequency affected latencies and cascaded into production. It modulated writing duration but not movement fluency. Writing infrequent words took longer than frequent words. The data suggests that orthographic regularity has a stronger impact on writing than word frequency. They do not cascade in the same extent. Copyright © 2014 Elsevier B.V. All rights reserved.

Sexual motivation is reflected by stimulus-dependent motor cortex excitability.

Science.gov (United States)

Schecklmann, Martin; Engelhardt, Kristina; Konzok, Julian; Rupprecht, Rainer; Greenlee, Mark W; Mokros, Andreas; Langguth, Berthold; Poeppl, Timm B

2015-08-01

Sexual behavior involves motivational processes. Findings from both animal models and neuroimaging in humans suggest that the recruitment of neural motor networks is an integral part of the sexual response. However, no study so far has directly linked sexual motivation to physiologically measurable changes in cerebral motor systems in humans. Using transcranial magnetic stimulation in hetero- and homosexual men, we here show that sexual motivation modulates cortical excitability. More specifically, our results demonstrate that visual sexual stimuli corresponding with one's sexual orientation, compared with non-corresponding visual sexual stimuli, increase the excitability of the motor cortex. The reflection of sexual motivation in motor cortex excitability provides evidence for motor preparation processes in sexual behavior in humans. Moreover, such interrelationship links theoretical models and previous neuroimaging findings of sexual behavior. © The Author (2015). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Characteristics of myosin profile in human vastus lateralis muscle in relation to training background.

Science.gov (United States)

Zawadowska, B; Majerczak, J; Semik, D; Karasinski, J; Kolodziejski, L; Kilarski, W M; Duda, K; Zoladz, J A

2004-01-01

Twenty-four male volunteers (mean +/- SD: age 25.4+/-5.8 years, height 178.6+/-5.5 cm, body mass 72.1+/-7.7 kg) of different training background were investigated and classified into three groups according to their physical activity and sport discipline: untrained students (group A), national and sub-national level endurance athletes (group B, 7.8+/-2.9 years of specialised training) and sprint-power athletes (group C, 12.8+/-8.7 years of specialised training). Muscle biopsies of vastus lateralis were analysed histochemically for mATPase and SDH activities, immunohistochemically for fast and slow myosin, and electrophoretically followed by Western immunoblotting for myosin heavy chain (MyHC) composition. Significant differences (Pski-jumping, volleyball, soccer and modern dance. Furthermore, the relative amount of the fastest MyHCIIX isoform in vastus lateralis muscle was significantly lower in the athletes from group C than in students (group A). We conclude that the myosin profile in the athletes belonging to group C was unfavourable for their sport disciplines. This could be the reason why those athletes did not reach international level despite of several years of training.

Non-invasive brain stimulation to promote motor and functional recovery following spinal cord injury

Directory of Open Access Journals (Sweden)

Aysegul Gunduz

2017-01-01

Full Text Available We conducted a systematic review of studies using non-invasive brain stimulation (NIBS: repetitive transcranial magnetic stimulation (rTMS and transcranial direct current stimulation (tDCS as a research and clinical tool aimed at improving motor and functional recovery or spasticity in patients following spinal cord injury (SCI under the assumption that if the residual corticospinal circuits could be stimulated appropriately, the changes might be accompanied by functional recovery or an improvement in spasticity. This review summarizes the literature on the changes induced by NIBS in the motor and functional recovery and spasticity control of the upper and lower extremities following SCI.

Comparing Life Quality Strategies and Emotion Regulation in People with Congenital and Non-Congenital Motor Disability

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Seyedeh Zeynab Miraghaei

2017-10-01

Full Text Available Objective: The purpose of the present study was to compare emotion regulation strategies and life quality of people with congenital and non-congenital motor disabilities. Method: This study is a casual-comparative study and its population consisted of all people with congenital and non-congenital motor disability in Kahrizak Charity Foundation in Tehran in 2016. To conduct the study, available sampling method was used, and congenital and non-congenital disabled people were selected (200 people. To collect data, Cognitive Emotion Regulation Scale by Granovsky and life quality questionnaire were used. Research hypotheses were tested using multivariate analysis of variance. Results: The findings of this study showed that there is a significant difference between emotion regulation components in people with congenital and non-congenital disabilities (p<0.05. Also, according to the findings, a significant difference was observed between life quality dimensions (physical and mental health in people with congenital and non-congenital disabilities (p<0.05. Conclusion: According to the significant difference between two groups of subjects, necessary measures regarding consultation and psychotherapy should be taken into consideration to let people benefit from desirable mental health level.

Myosin content of single muscle fibers following short-term disuse and active recovery in young and old healthy men

DEFF Research Database (Denmark)

Hvid, Lars G; Brocca, Lorenza; Ørtenblad, Niels

2017-01-01

healthy men. Following disuse, myosin content decreased (p... young and old in both fiber types, with MHC 2a fibers demonstrating an overshooting in young (+31%, pStrong correlations were observed between myosin content and single fiber SF in both young and old, with greater slope steepness in MHC 2a vs 1 fibers indicating an enhanced intrinsic...

Handbook on linear motor application

International Nuclear Information System (INIS)

1988-10-01

This book guides the application for Linear motor. It lists classification and speciality of Linear Motor, terms of linear-induction motor, principle of the Motor, types on one-side linear-induction motor, bilateral linear-induction motor, linear-DC Motor on basic of the motor, linear-DC Motor for moving-coil type, linear-DC motor for permanent-magnet moving type, linear-DC motor for electricity non-utility type, linear-pulse motor for variable motor, linear-pulse motor for permanent magneto type, linear-vibration actuator, linear-vibration actuator for moving-coil type, linear synchronous motor, linear electromagnetic motor, linear electromagnetic solenoid, technical organization and magnetic levitation and linear motor and sensor.

Context-dependent memory decay is evidence of effort minimization in motor learning: a computational study.

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Takiyama, Ken

2015-01-01

Recent theoretical models suggest that motor learning includes at least two processes: error minimization and memory decay. While learning a novel movement, a motor memory of the movement is gradually formed to minimize the movement error between the desired and actual movements in each training trial, but the memory is slightly forgotten in each trial. The learning effects of error minimization trained with a certain movement are partially available in other non-trained movements, and this transfer of the learning effect can be reproduced by certain theoretical frameworks. Although most theoretical frameworks have assumed that a motor memory trained with a certain movement decays at the same speed during performing the trained movement as non-trained movements, a recent study reported that the motor memory decays faster during performing the trained movement than non-trained movements, i.e., the decay rate of motor memory is movement or context dependent. Although motor learning has been successfully modeled based on an optimization framework, e.g., movement error minimization, the type of optimization that can lead to context-dependent memory decay is unclear. Thus, context-dependent memory decay raises the question of what is optimized in motor learning. To reproduce context-dependent memory decay, I extend a motor primitive framework. Specifically, I introduce motor effort optimization into the framework because some previous studies have reported the existence of effort optimization in motor learning processes and no conventional motor primitive model has yet considered the optimization. Here, I analytically and numerically revealed that context-dependent decay is a result of motor effort optimization. My analyses suggest that context-dependent decay is not merely memory decay but is evidence of motor effort optimization in motor learning.

Context-dependent memory decay is evidence of effort minimization in motor learning: A computational study

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Ken eTakiyama

2015-02-01

Full Text Available Recent theoretical models suggest that motor learning includes at least two processes: error minimization and memory decay. While learning a novel movement, a motor memory of the movement is gradually formed to minimize the movement error between the desired and actual movements in each training trial, but the memory is slightly forgotten in each trial. The learning effects of error minimization trained with a certain movement are partially available in other non-trained movements, and this transfer of the learning effect can be reproduced by certain theoretical frameworks. Although most theoretical frameworks have assumed that a motor memory trained with a certain movement decays at the same speed during performing the trained movement as non-trained movements, a recent study reported that the motor memory decays faster during performing the trained movement than non-trained movements, i.e., the decay rate of motor memory is movement or context dependent. Although motor learning has been successfully modeled based on an optimization framework, e.g., movement error minimization, the type of optimization that can lead to context-dependent memory decay is unclear. Thus, context-dependent memory decay raises the question of what is optimized in motor learning. To reproduce context-dependent memory decay, I extend a motor primitive framework. Specifically, I introduce motor effort optimization into the framework because some previous studies have reported the existence of effort optimization in motor learning processes and no conventional motor primitive model has yet considered the optimization. Here, I analytically and numerically revealed that context-dependent decay is a result of motor effort optimization. My analyses suggest that context-dependent decay is not merely memory decay but is evidence of motor effort optimization in motor learning.

Sub-processes of motor learning revealed by a robotic manipulandum for rodents.

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Lambercy, O; Schubring-Giese, M; Vigaru, B; Gassert, R; Luft, A R; Hosp, J A

2015-02-01

Rodent models are widely used to investigate neural changes in response to motor learning. Usually, the behavioral readout of motor learning tasks used for this purpose is restricted to a binary measure of performance (i.e. "successful" movement vs. "failure"). Thus, the assignability of research in rodents to concepts gained in human research - implying diverse internal models that constitute motor learning - is still limited. To solve this problem, we recently introduced a three-degree-of-freedom robotic platform designed for rats (the ETH-Pattus) that combines an accurate behavioral readout (in the form of kinematics) with the possibility to invasively assess learning related changes within the brain (e.g. by performing immunohistochemistry or electrophysiology in acute slice preparations). Here, we validate this platform as a tool to study motor learning by establishing two forelimb-reaching paradigms that differ in degree of skill. Both conditions can be precisely differentiated in terms of their temporal pattern and performance levels. Based on behavioral data, we hypothesize the presence of several sub-processes contributing to motor learning. These share close similarities with concepts gained in humans or primates. Copyright © 2014 Elsevier B.V. All rights reserved.

Characterization of the minimum domain required for targeting budding yeast myosin II to the site of cell division

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Tolliday Nicola J

2006-06-01

Full Text Available Abstract Background All eukaryotes with the exception of plants use an actomyosin ring to generate a constriction force at the site of cell division (cleavage furrow during mitosis and meiosis. The structure and filament forming abilities located in the C-terminal or tail region of one of the main components, myosin II, are important for localising the molecule to the contractile ring (CR during cytokinesis. However, it remains poorly understood how myosin II is recruited to the site of cell division and how this recruitment relates to myosin filament assembly. Significant conservation between species of the components involved in cytokinesis, including those of the CR, allows the use of easily genetically manipulated organisms, such as budding yeast (Saccharomyces cerevisiae, in the study of cytokinesis. Budding yeast has a single myosin II protein, named Myo1. Unlike most other class II myosins, the tail of Myo1 has an irregular coiled coil. In this report we use molecular genetics, biochemistry and live cell imaging to characterize the minimum localisation domain (MLD of budding yeast Myo1. Results We show that the MLD is a small region in the centre of the tail of Myo1 and that it is both necessary and sufficient for localisation of Myo1 to the yeast bud neck, the pre-determined site of cell division. Hydrodynamic measurements of the MLD, purified from bacteria or yeast, show that it is likely to exist as a trimer. We also examine the importance of a small region of low coiled coil forming probability within the MLD, which we call the hinge region. Removal of the hinge region prevents contraction of the CR. Using fluorescence recovery after photobleaching (FRAP, we show that GFP-tagged MLD is slightly more dynamic than the GFP-tagged full length molecule but less dynamic than the GFP-tagged Myo1 construct lacking the hinge region. Conclusion Our results define the intrinsic determinant for the localization of budding yeast myosin II and show

Motor cortex hand area and speech: implications for the development of language.

Science.gov (United States)

Meister, Ingo Gerrit; Boroojerdi, Babak; Foltys, Henrik; Sparing, Roland; Huber, Walter; Töpper, Rudolf

2003-01-01

Recently a growing body of evidence has suggested that a functional link exists between the hand motor area of the language dominant hemisphere and the regions subserving language processing. We examined the excitability of the hand motor area and the leg motor area during reading aloud and during non-verbal oral movements using transcranial magnetic stimulation (TMS). During reading aloud, but not before or afterwards, excitability was increased in the hand motor area of the dominant hemisphere. This reading effect was found to be independent of the duration of speech. No such effect could be found in the contralateral hemisphere. The excitability of the leg area of the motor cortex remained unchanged during reading aloud. The excitability during non-verbal oral movements was slightly increased in both hemispheres. Our results are consistent with previous findings and may indicate a specific functional connection between the hand motor area and the cortical language network.

Transmodal comparison of auditory, motor, and visual post-processing with and without intentional short-term memory maintenance.

Science.gov (United States)

Bender, Stephan; Behringer, Stephanie; Freitag, Christine M; Resch, Franz; Weisbrod, Matthias

2010-12-01

To elucidate the contributions of modality-dependent post-processing in auditory, motor and visual cortical areas to short-term memory. We compared late negative waves (N700) during the post-processing of single lateralized stimuli which were separated by long intertrial intervals across the auditory, motor and visual modalities. Tasks either required or competed with attention to post-processing of preceding events, i.e. active short-term memory maintenance. N700 indicated that cortical post-processing exceeded short movements as well as short auditory or visual stimuli for over half a second without intentional short-term memory maintenance. Modality-specific topographies pointed towards sensory (respectively motor) generators with comparable time-courses across the different modalities. Lateralization and amplitude of auditory/motor/visual N700 were enhanced by active short-term memory maintenance compared to attention to current perceptions or passive stimulation. The memory-related N700 increase followed the characteristic time-course and modality-specific topography of the N700 without intentional memory-maintenance. Memory-maintenance-related lateralized negative potentials may be related to a less lateralised modality-dependent post-processing N700 component which occurs also without intentional memory maintenance (automatic memory trace or effortless attraction of attention). Encoding to short-term memory may involve controlled attention to modality-dependent post-processing. Similar short-term memory processes may exist in the auditory, motor and visual systems. Copyright © 2010 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Association of coffee consumption and non-motor symptoms in drug-naïve, early-stage Parkinson's disease.

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Cho, Bang-Hoon; Choi, Seong-Min; Kim, Joon-Tae; Kim, Byeong C

2018-02-09

Coffee consumption has an inverse association with the risk of Parkinson's disease (PD). The aim of this study was to investigate the association between coffee consumption and non-motor symptoms (NMSs) in patients with PD. In this cross-sectional study, we included 196 early-stage, treatment-naïve PD patients. Coffee consumption history was obtained via semi-structured interviews. NMSs were assessed using the Non-Motor Symptom assessment scale (NMSS). Of the 196 patients with PD, 136 (69.3%) were categorized as coffee drinkers and 60 (30.6%) were non-drinkers. Coffee drinkers were younger, predominantly male, were younger in age at symptom onset, had lower Unified Parkinson's Disease Rating Scale motor and Beck Depression Inventory scores, and higher Mini-Mental State Examination scores than non-coffee drinkers. After adjustment, coffee drinking was significantly inversely associated with the prevalence of lack of motivation, anhedonia, and lack of pleasure, which were less frequent in coffee drinkers. Total NMSS scores were lower in coffee drinkers than in non-drinkers (p = 0.047). In particular, coffee drinking was significantly associated with a reduced severity of the mood/cognition domain of NMSS (p = 0.003). After correcting for multiple testing, there were no significant differences in the prevalence of NMSs, but there were significant differences in the severity of NMSs between coffee drinkers and non-drinkers. There is a negative association between coffee consumption and the severity of the mood/cognition domain of NMSS in patients with PD. Clinicians should consider the history of coffee consumption in the assessment of NMSs in PD. Copyright © 2018 Elsevier Ltd. All rights reserved.

Non-Motor Correlates of Smoking Habits in de Novo Parkinson's Disease.

Science.gov (United States)

Moccia, Marcello; Mollenhauer, Brit; Erro, Roberto; Picillo, Marina; Palladino, Raffaele; Barone, Paolo

2015-01-01

Parkinson's disease (PD) subjects are less likely to ever smoke and are more prone to quit smoking, as compared to controls. Therefore, smoking habits can be considered part of the non-motor phenotype, preceding the onset of motor PD by several years. To explore non-motor symptom (NMS) correlates of smoking habits in de novo PD. This cross-sectional study included 281 newly diagnosed, drug-naïve PD subjects, recruited in Naples (Italy) and in Kassel (Germany). All subjects completed the NMS Questionnaire (NMSQ), and were investigated for smoking status (never, current and former smokers) and intensity (pack-years). 140 PD subjects never smoked, 20 currently smoked, and 121 had quit smoking before PD diagnosis. NMSQ total score did not associate with smoking status, but with smoking intensity (p = 0.028; coefficient = 0.088). A multinomial logistic regression stepwise model presenting never smoking as reference, selected as NMSQ correlates of current smoking: sex difficulties (p = 0.002; OR = 5.254), daytime sleepiness (p = 0.046; OR = 0.085), insomnia (p = 0.025; OR = 0.135), and vivid dreams (p = 0.040; OR = 3.110); and of former smoking: swallowing (p = 0.013; OR = 0.311), nausea (p = 0.027; OR = 7.157), unexplained pains (p = 0.002; OR = 3.409), forgetfulness (p = 0.005; OR = 2.592), sex interest (p = 0.007; OR = 0.221), sex difficulties (p = 0.038; OR = 4.215), and daytime sleepiness (p = 0.05; OR = 0.372). An ordinal logistic regression stepwise model selected as NMSQ correlates of smoking intensity: nocturnal restlessness (p = 0.027; coefficient = 0.974), and leg swelling (p = 0.004; coefficient = 1.305). Certain NMSs are associated with different smoking status and intensity, suggesting a variety of adaptive mechanisms to cigarette smoking.

How Kinesthetic Motor Imagery works: A predictive-processing theory of visualization in sports and motor expertise

NARCIS (Netherlands)

Ridderinkhof, K.R.; Brass, M.

2015-01-01

Kinesthetic Motor Imagery (KMI) is an important technique to acquire and refine motor skills. KMI is widely used by professional athletes as an effective way to improve motor performance without overt motor output. Despite this obvious relevance, the functional mechanisms and neural circuits

Comparison of the Efficacy of Different Drugs on Non-Motor Symptoms of Parkinson's Disease: a Network Meta-Analysis.

Science.gov (United States)

Li, Bao-Dong; Cui, Jing-Jun; Song, Jia; Qi, Ce; Ma, Pei-Feng; Wang, Ya-Rong; Bai, Jing

2018-01-01

A network meta-analysis is used to compare the efficacy of ropinirole, rasagiline, rotigotine, entacapone, apomorphine, pramipexole, sumanirole, bromocriptine, piribedil and levodopa, with placebo as a control, for non-motor symptoms in Parkinson's disease (PD). PubMed, Embase and the Cochrane Library were searched from their establishment dates up to January 2017 for randomized controlled trials (RCTs) investigating the efficacy of the above ten drugs on the non-motor symptoms of PD. A network meta-analysis combined the evidence from direct comparisons and indirect comparisons and evaluated the pooled weighted mean difference (WMD) values and surfaces under the cumulative ranking curves (SUCRA). The network meta-analysis included 21 RCTs. The analysis results indicated that, using the United Parkinson's Disease Rating Scale (UPDRS) III, the efficacies of placebo, ropinirole, rasagiline, rotigotine, entacapone, pramipexole, sumanirole and levodopa in treating PD were lower than that of apomorphine (WMD = -10.90, 95% CI = -16.12∼-5.48; WMD = -11.85, 95% CI = -17.31∼-6.16; WMD = -11.15, 95% CI = -16.64∼-5.04; WMD = -11.70, 95% CI = -16.98∼-5.60; WMD = -11.04, 95% CI = -16.97∼-5.34; WMD = -13.27, 95% CI = -19.22∼-7.40; WMD = -10.25, 95% CI = -15.66∼-4.32; and WMD = -11.60, 95% CI = -17.89∼-5.57, respectively). Treatment with ropinirole, rasagiline, rotigotine, entacapone, pramipexole, sumanirole, bromocriptine, piribedil or levodopa, with placebo as a control, on PD exhibited no significant differences on PD symptoms when the UPDRS II was used for evaluation. Moreover, using the UPDRS III, the SUCRA values indicated that a pomorphine had the best efficacy on the non-motor symptoms of PD (99.0%). Using the UPDRS II, the SUCRA values for ropinirole, rasagiline, rotigotine, entacapone, pramipexole, sumanirole, bromocriptine, piribedil and levodopa treatments, with placebo as a control, indicated that bromocriptine showed the best efficacy on the non-motor

Motor-cognitive dual-task performance: effects of a concurrent motor task on distinct components of visual processing capacity

OpenAIRE

Künstler, E. C. S.; Finke, K.; Günther, A.; Klingner, C.; Witte, O.; Bublak, P.

2017-01-01

Dual tasking, or the simultaneous execution of two continuous tasks, is frequently associated with a performance decline that can be explained within a capacity sharing framework. In this study, we assessed the effects of a concurrent motor task on the efficiency of visual information uptake based on the ‘theory of visual attention’ (TVA). TVA provides parameter estimates reflecting distinct components of visual processing capacity: perceptual threshold, visual processing speed, and visual sh...

Confinement Sensing and Signal Optimization via Piezo1/PKA and Myosin II Pathways

Directory of Open Access Journals (Sweden)

Wei-Chien Hung

2016-05-01

Full Text Available Summary: Cells adopt distinct signaling pathways to optimize cell locomotion in different physical microenvironments. However, the underlying mechanism that enables cells to sense and respond to physical confinement is unknown. Using microfabricated devices and substrate-printing methods along with FRET-based biosensors, we report that, as cells transition from unconfined to confined spaces, intracellular Ca2+ level is increased, leading to phosphodiesterase 1 (PDE1-dependent suppression of PKA activity. This Ca2+ elevation requires Piezo1, a stretch-activated cation channel. Moreover, differential regulation of PKA and cell stiffness in unconfined versus confined cells is abrogated by dual, but not individual, inhibition of Piezo1 and myosin II, indicating that these proteins can independently mediate confinement sensing. Signals activated by Piezo1 and myosin II in response to confinement both feed into a signaling circuit that optimizes cell motility. This study provides a mechanism by which confinement-induced signaling enables cells to sense and adapt to different physical microenvironments. : Hung et al. demonstrate that a Piezo1-dependent intracellular calcium increase negatively regulates protein kinase A (PKA as cells transit from unconfined to confined spaces. The Piezo1/PKA and myosin II signaling modules constitute two confinement-sensing mechanisms. This study provides a paradigm by which signaling enables cells to sense and adapt to different microenvironments.

Cognitive alterations in motor imagery process after left hemispheric ischemic stroke.

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Jing Yan

Full Text Available BACKGROUND: Motor imagery training is a promising rehabilitation strategy for stroke patients. However, few studies had focused on the neural mechanisms in time course of its cognitive process. This study investigated the cognitive alterations after left hemispheric ischemic stroke during motor imagery task. METHODOLOGY/PRINCIPAL FINDINGS: Eleven patients with ischemic stroke in left hemisphere and eleven age-matched control subjects participated in mental rotation task (MRT of hand pictures. Behavior performance, event-related potential (ERP and event-related (desynchronization (ERD/ERS in beta band were analyzed to investigate the cortical activation. We found that: (1 The response time increased with orientation angles in both groups, called "angle effect", however, stoke patients' responses were impaired with significantly longer response time and lower accuracy rate; (2 In early visual perceptual cognitive process, stroke patients showed hypo-activations in frontal and central brain areas in aspects of both P200 and ERD; (3 During mental rotation process, P300 amplitude in control subjects decreased while angle increased, called "amplitude modulation effect", which was not observed in stroke patients. Spatially, patients showed significant lateralization of P300 with activation only in contralesional (right parietal cortex while control subjects showed P300 in both parietal lobes. Stroke patients also showed an overall cortical hypo-activation of ERD during this sub-stage; (4 In the response sub-stage, control subjects showed higher ERD values with more activated cortical areas particularly in the right hemisphere while angle increased, named "angle effect", which was not observed in stroke patients. In addition, stroke patients showed significant lower ERD for affected hand (right response than that for unaffected hand. CONCLUSIONS/SIGNIFICANCE: Cortical activation was altered differently in each cognitive sub-stage of motor imagery after

Auditory-Motor Interactions in Pediatric Motor Speech Disorders: Neurocomputational Modeling of Disordered Development

Science.gov (United States)

Terband, H.; Maassen, B.; Guenther, F.H.; Brumberg, J.

2014-01-01

Background/Purpose Differentiating the symptom complex due to phonological-level disorders, speech delay and pediatric motor speech disorders is a controversial issue in the field of pediatric speech and language pathology. The present study investigated the developmental interaction between neurological deficits in auditory and motor processes using computational modeling with the DIVA model. Method In a series of computer simulations, we investigated the effect of a motor processing deficit alone (MPD), and the effect of a motor processing deficit in combination with an auditory processing deficit (MPD+APD) on the trajectory and endpoint of speech motor development in the DIVA model. Results Simulation results showed that a motor programming deficit predominantly leads to deterioration on the phonological level (phonemic mappings) when auditory self-monitoring is intact, and on the systemic level (systemic mapping) if auditory self-monitoring is impaired. Conclusions These findings suggest a close relation between quality of auditory self-monitoring and the involvement of phonological vs. motor processes in children with pediatric motor speech disorders. It is suggested that MPD+APD might be involved in typically apraxic speech output disorders and MPD in pediatric motor speech disorders that also have a phonological component. Possibilities to verify these hypotheses using empirical data collected from human subjects are discussed. PMID:24491630

Comparison of performance on process- and product-oriented assessments of fundamental motor skills across childhood.

Science.gov (United States)

Logan, Samuel W; Barnett, Lisa M; Goodway, Jacqueline D; Stodden, David F

2017-04-01

Process-oriented motor competence (MC) assessments evaluate how a movement is performed. Product-oriented assessments evaluate the outcome of a movement. Determining the concurrent validity of process and product assessments is important to address the predictive utility of motor competence for health. The current study aimed to: (1) compare process and product assessments of the standing long jump, hop and throw across age groups and (2) determine the capacity of process assessments to classify levels of MC. Participants included 170 children classified into three age groups: 4-5, 7-8 and 10-11 years old. Participants' skills were examined concurrently using three process assessments ((Test of Gross Motor Development-2nd edition [TGMD-2]), Get Skilled; Get Active, and developmental sequences) and one product measure (throw speed, jump and hop distance). Results indicate moderate to strong correlations between (1) process assessments across skills and age groups (r range = .37-70) and (2) process and product assessments across skills and age groups (r range = .26-.88). In general, sensitivity to detect advanced skill level is lowest for TGMD-2 and highest for developmental sequences for all three skills. The use of process and product assessments is suggested to comprehensively capture levels of MC in human movement.

Conscious motor processing and movement self-consciousness: two dimensions of personality that influence laparoscopic training.

Science.gov (United States)

Malhotra, Neha; Poolton, Jamie M; Wilson, Mark R; Fan, Joe K M; Masters, Rich S W

2014-01-01

Identifying personality factors that account for individual differences in surgical training and performance has practical implications for surgical education. Movement-specific reinvestment is a potentially relevant personality factor that has a moderating effect on laparoscopic performance under time pressure. Movement-specific reinvestment has 2 dimensions, which represent an individual's propensity to consciously control movements (conscious motor processing) or to consciously monitor their 'style' of movement (movement self-consciousness). This study aimed at investigating the moderating effects of the 2 dimensions of movement-specific reinvestment in the learning and updating (cross-handed technique) of laparoscopic skills. Medical students completed the Movement-Specific Reinvestment Scale, a psychometric assessment tool that evaluates the conscious motor processing and movement self-consciousness dimensions of movement-specific reinvestment. They were then trained to a criterion level of proficiency on a fundamental laparoscopic skills task and were tested on a novel cross-handed technique. Completion times were recorded for early-learning, late-learning, and cross-handed trials. Propensity for movement self-consciousness but not conscious motor processing was a significant predictor of task completion times both early (p = 0.036) and late (p = 0.002) in learning, but completion times during the cross-handed trials were predicted by the propensity for conscious motor processing (p = 0.04) rather than movement self-consciousness (p = 0.21). Higher propensity for movement self-consciousness is associated with slower performance times on novel and well-practiced laparoscopic tasks. For complex surgical techniques, however, conscious motor processing plays a more influential role in performance than movement self-consciousness. The findings imply that these 2 dimensions of movement-specific reinvestment have a differential influence in the learning and updating

Cortical mechanics and myosin-II abnormalities associated with post-ovulatory aging: implications for functional defects in aged eggs

Science.gov (United States)

Mackenzie, Amelia C.L.; Kyle, Diane D.; McGinnis, Lauren A.; Lee, Hyo J.; Aldana, Nathalia; Robinson, Douglas N.; Evans, Janice P.

2016-01-01

STUDY HYPOTHESIS Cellular aging of the egg following ovulation, also known as post-ovulatory aging, is associated with aberrant cortical mechanics and actomyosin cytoskeleton functions. STUDY FINDING Post-ovulatory aging is associated with dysfunction of non-muscle myosin-II, and pharmacologically induced myosin-II dysfunction produces some of the same deficiencies observed in aged eggs. WHAT IS KNOWN ALREADY Reproductive success is reduced with delayed fertilization and when copulation or insemination occurs at increased times after ovulation. Post-ovulatory aged eggs have several abnormalities in the plasma membrane and cortex, including reduced egg membrane receptivity to sperm, aberrant sperm-induced cortical remodeling and formation of fertilization cones at the site of sperm entry, and reduced ability to establish a membrane block to prevent polyspermic fertilization. STUDY DESIGN, SAMPLES/MATERIALS, METHODS Ovulated mouse eggs were collected at 21–22 h post-human chorionic gonadotrophin (hCG) (aged eggs) or at 13–14 h post-hCG (young eggs), or young eggs were treated with the myosin light chain kinase (MLCK) inhibitor ML-7, to test the hypothesis that disruption of myosin-II function could mimic some of the effects of post-ovulatory aging. Eggs were subjected to various analyses. Cytoskeletal proteins in eggs and parthenogenesis were assessed using fluorescence microscopy, with further analysis of cytoskeletal proteins in immunoblotting experiments. Cortical tension was measured through micropipette aspiration assays. Egg membrane receptivity to sperm was assessed in in vitro fertilization (IVF) assays. Membrane topography was examined by low-vacuum scanning electron microscopy (SEM). MAIN RESULTS AND THE ROLE OF CHANCE Aged eggs have decreased levels and abnormal localizations of phosphorylated myosin-II regulatory light chain (pMRLC; P = 0.0062). Cortical tension, which is mediated in part by myosin-II, is reduced in aged mouse eggs when compared with

Structural insights into the globular tails of the human type v myosins Myo5a, Myo5b, And Myo5c.

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Hana Velvarska

Full Text Available Vertebrate type V myosins (MyoV Myo5a, Myo5b, and Myo5c mediate transport of several different cargoes. All MyoV paralogs bind to cargo complexes mainly by their C-terminal globular domains. In absence of cargo, the globular domain of Myo5a inhibits its motor domain. Here, we report low-resolution SAXS models for the globular domains from human Myo5a, Myo5b, and Myo5c, which suggest very similar overall shapes of all three paralogs. We determined the crystal structures of globular domains from Myo5a and Myo5b, and provide a homology model for human Myo5c. When we docked the Myo5a crystal structure into a previously published electron microscopy density of the autoinhibited full-length Myo5a, only one domain orientation resulted in a good fit. This structural arrangement suggests the participation of additional region of the globular domain in autoinhibition. Quantification of the interaction of the Myo5a globular domain with its motor complex revealed a tight binding with dissociation half-life in the order of minutes, suggesting a rather slow transition between the active and inactive states.

Lack of replication for the myosin-18B association with mathematical ability in independent cohorts

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Pettigrew, K A; Fajutrao Valles, S F; Moll, K; Northstone, K; Ring, S; Pennell, C; Wang, C; Leavett, R; Hayiou-Thomas, M E; Thompson, P; Simpson, N H; Fisher, S E; Whitehouse, A J O; Snowling, M J; Newbury, D F; Paracchini, S

2015-01-01

Twin studies indicate that dyscalculia (or mathematical disability) is caused partly by a genetic component, which is yet to be understood at the molecular level. Recently, a coding variant (rs133885) in the myosin-18B gene was shown to be associated with mathematical abilities with a specific effect among children with dyslexia. This association represents one of the most significant genetic associations reported to date for mathematical abilities and the only one reaching genome-wide statistical significance. We conducted a replication study in different cohorts to assess the effect of rs133885 maths-related measures. The study was conducted primarily using the Avon Longitudinal Study of Parents and Children (ALSPAC), (N = 3819). We tested additional cohorts including the York Cohort, the Specific Language Impairment Consortium (SLIC) cohort and the Raine Cohort, and stratified them for a definition of dyslexia whenever possible. We did not observe any associations between rs133885 in myosin-18B and mathematical abilities among individuals with dyslexia or in the general population. Our results suggest that the myosin-18B variant is unlikely to be a main factor contributing to mathematical abilities. PMID:25778778

The effect of the substitution of D{sub 2}O for H{sub 2}O on the degradation of myosin {beta} in solution by heat and by {sup 60}Co {gamma} radiation (1962); Effet de la substitution de D{sub 2}O a H{sub 2}O sur l'alteration de la Myosine B en solution par la chaleur et par les rayons {gamma} du {sup 60}CO (1962)

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Pinset-Harstrom, I.; Fritsch, A. [Commissariat a l' Energie Atomique, Saclay (France). Centre d' Etudes Nucleaires

1962-07-01

(1) Alterations of myosin B produced by heat or irradiation are shown to be qualitatively identical as demonstrated by analytical centrifugation. (2) A considerable isotope effect was demonstrated using 75 per cent D{sub 2}O in the solvent. The sensitivity of myosin B to heat and irradiation is discussed in the light of this isotope effect. (3) Polymers appearing upon heat treatment of myosin B seem to be of a very different nature than the polymers occurring alter a similar treatment upon myosin A. Polymers obtained from myosin B can be depolymerized by ATP and they appear in a much narrower temperature range than myosin A polymers. This fact indicates a considerable difference in the activation enthalpies in the two reactions. (authors) [French] (1) Cette etude montre que les alterations de la myosine B provoquees par la chaleur et par l'irradiation aux rayons {gamma} sont - telles qu'elles apparaissent a l'ultracentrifugation analytique - qualitativement semblables. (2) Nous avons observe un effet isotopique considerable de la presence de 75 pour cent de D{sub 2}O dans le solvant sur la sensibilite de la myosine B envers ces deux agents, et nous avons presente une tentative d'explication de ce fait. (3) Les polymeres qui apparaissent apres un traitement par la chaleur de la myosine semblent etre d'une nature tres differente des polymeres que l'on voit apparaitre apres un traitement identique de la myosine A. Ceux obtenus a partir de le myosine B sont depolymerisables par l'intermediaire de l'ATP et apparaissent dans une zone de temperature beaucoup plus etroite que celles de la myosine A. Ce dernier fait indique une difference considerable de l'enthalpie d'activation des deux reactions. (auteurs)

The effect of the substitution of D{sub 2}O for H{sub 2}O on the degradation of myosin {beta} in solution by heat and by {sup 60}Co {gamma} radiation (1962); Effet de la substitution de D{sub 2}O a H{sub 2}O sur l'alteration de la Myosine B en solution par la chaleur et par les rayons {gamma} du {sup 60}CO (1962)

Energy Technology Data Exchange (ETDEWEB)

Pinset-Harstrom, I; Fritsch, A [Commissariat a l' Energie Atomique, Saclay (France). Centre d' Etudes Nucleaires

1962-07-01

(1) Alterations of myosin B produced by heat or irradiation are shown to be qualitatively identical as demonstrated by analytical centrifugation. (2) A considerable isotope effect was demonstrated using 75 per cent D{sub 2}O in the solvent. The sensitivity of myosin B to heat and irradiation is discussed in the light of this isotope effect. (3) Polymers appearing upon heat treatment of myosin B seem to be of a very different nature than the polymers occurring alter a similar treatment upon myosin A. Polymers obtained from myosin B can be depolymerized by ATP and they appear in a much narrower temperature range than myosin A polymers. This fact indicates a considerable difference in the activation enthalpies in the two reactions. (authors) [French] (1) Cette etude montre que les alterations de la myosine B provoquees par la chaleur et par l'irradiation aux rayons {gamma} sont - telles qu'elles apparaissent a l'ultracentrifugation analytique - qualitativement semblables. (2) Nous avons observe un effet isotopique considerable de la presence de 75 pour cent de D{sub 2}O dans le solvant sur la sensibilite de la myosine B envers ces deux agents, et nous avons presente une tentative d'explication de ce fait. (3) Les polymeres qui apparaissent apres un traitement par la chaleur de la myosine semblent etre d'une nature tres differente des polymeres que l'on voit apparaitre apres un traitement identique de la myosine A. Ceux obtenus a partir de le myosine B sont depolymerisables par l'intermediaire de l'ATP et apparaissent dans une zone de temperature beaucoup plus etroite que celles de la myosine A. Ce dernier fait indique une difference considerable de l'enthalpie d'activation des deux reactions. (auteurs)

Interaction of attentional and motor control processes in handwriting.

Science.gov (United States)

Brown, T L; Donnenwirth, E E

1990-01-01

The interaction between attentional capacity, motor control processes, and strategic adaptations to changing task demands was investigated in handwriting, a continuous (rather than discrete) skilled performance. Twenty-four subjects completed 12 two-minute handwriting samples under instructions stressing speeded handwriting, normal handwriting, or highly legible handwriting. For half of the writing samples, a concurrent auditory monitoring task was imposed. Subjects copied either familiar (English) or unfamiliar (Latin) passages. Writing speed, legibility ratings, errors in writing and in the secondary auditory task, and a derived measure of the average number of characters held in short-term memory during each sample ("planning unit size") were the dependent variables. The results indicated that the ability to adapt to instructions stressing speed or legibility was substantially constrained by the concurrent listening task and by text familiarity. Interactions between instructions, task concurrence, and text familiarity in the legibility ratings, combined with further analyses of planning unit size, indicated that information throughput from temporary storage mechanisms to motor processes mediated the loss of flexibility effect. Overall, the results suggest that strategic adaptations of a skilled performance to changing task circumstances are sensitive to concurrent attentional demands and that departures from "normal" or "modal" performance require attention.

In patient's with Parkinson disease, autonomic symptoms are frequent and associated with other non-motor symptoms.

Science.gov (United States)

Arnao, Valentina; Cinturino, Antonio; Valentino, Francesca; Perini, Valentina; Mastrilli, Sergio; Bellavia, Gabriele; Savettieri, Giovanni; Realmuto, Sabrina; D'Amelio, Marco

2015-10-01

Autonomic symptoms and sleep disorders are common non-motor symptoms of Parkinson disease (PD), which are correlated with poor quality of life for patients. To assess the frequency of autonomic symptoms in a consecutive series of PD patients and to correlate them with other motor and non-motor symptoms. All consecutive non-demented PD patients who underwent an extensive evaluation including Hoehn and Yahr staging, Unified Parkinson's Disease Rating Scale, Beck's Depression Inventory, Neuropsychiatric Inventory, PDQ-39 Scale, the Parkinson's diseases Sleep Scale, the Epworth Sleepiness Scale and SCOPA-AUT scale were enrolled. Comorbidity has been also considered. Supine to standing position blood pressure and cardiac frequency changes were also measured. 135 PD patients were included (mean age at interview 67.7; mean disease duration: 5.3 years). Patients were stratified according to mean SCOPA-AUT scale score (13.1). Those with higher SCOPA-AUT scale score were significantly older, had longer disease duration, worse disease stage, worse quality of sleep, were more severely affected, and were also taking a higher dosage of levodopa. At multivariate analysis, older age, longer disease duration, and worse quality of sleep were independently associated with higher SCOPA-AUT scale scores. Our results remark the role of autonomic symptoms in PD. In our patient population, characterized by mild to moderate disease severity, most of the patients complained of autonomic nervous system involvement (84%). A significant association between autonomic symptoms and sleep disorders was also observed.

The force dependence of isometric and concentric potentiation in mouse muscle with and without skeletal myosin light chain kinase.

Science.gov (United States)

Gittings, William; Aggarwal, Harish; Stull, James T; Vandenboom, Rene

2015-01-01

The isometric potentiation associated with myosin phosphorylation is force dependent. The purpose of this study was to assess the influence of a pre-existing period of isometric force on the concentric force potentiation displayed by mouse muscles with and without the ability to phosphorylate myosin. We tested isometric (ISO) and concentric (CON) potentiation, as well as concentric potentiation after isometric force (ISO-CON), in muscles from wild-type (WT) and skeletal myosin light chain kinase-deficient (skMLCK(-/-)) mice. A conditioning stimulus increased (i.e., potentiated) mean concentric force in the ISO-CON and CON conditions to 1.31 ± 0.02 and 1.35 ± 0.02 (WT) and to 1.19 ± 0.02 and 1.21 ± 0.01 (skMLCK(-/-)) of prestimulus levels, respectively (data n = 6-8, p muscles.

[Motor capacities involved in the psychomotor skills of the cardiopulmonary resuscitation technique: recommendations for the teaching-learning process].