scholarly journals VARIATION AND SELECTION IN AXON NAVIGATION THROUGH MICROTUBULE-DEPENDENT STEPWISE GROWTH CONE ADVANCE

2020 ◽  
Author(s):  
Stephen G Turney ◽  
Indra Chandrasekar ◽  
Mostafa Ahmed ◽  
Robert M Rioux ◽  
George M Whitesides ◽  
...  
Keyword(s):  
Growth Cone ◽  
Traction Force ◽  
Leading Edge ◽  
Sensory Axons ◽  
Microtubule Polymerization ◽  
Ngf Signaling ◽  
The Individual ◽  
Substrate Patterning ◽  
Variation And Selection ◽  
Adhesion Site

ABSTRACTMyosin II (MII) activity is required for elongating mammalian sensory axons to change speed and direction in response to Nerve Growth Factor (NGF) and laminin-1 (LN). NGF signaling induces faster outgrowth on LN through regulation of actomyosin restraint of microtubule advance into the growth cone periphery. It remains unclear whether growth cone turning on LN works through the same mechanism and, if it does, how the mechanism produces directed advance. Using a novel method for substrate patterning, we tested how directed advance occurs on LN by creating a gap immediately in front of a growth cone advancing on a narrow LN path. The growth cone stopped until an actin-rich protrusion extended over the gap, adhered to LN, and became stabilized. Stepwise advance over the gap was triggered by microtubule +tip entry up to the adhesion site of the protrusion and was independent of traction force pulling. We found that the probability of microtubule entry is regulated at the level of the individual protrusion and is sensitive to the rate of microtubule polymerization and the rate of rearward actin flow as controlled by adhesion-cytoskeletal coupling and MII. We conclude that growth cone navigation is an iterative process of variation and selection. Growth cones extend leading edge actin-rich protrusions that adhere transiently (variation). Microtubule entry up to an adhesion site stabilizes a protrusion (selection) leading to engorgement, consolidation, protrusive activity distal to the adhesion site, and stepwise growth cone advance. The orientation of the protrusion determines the direction of advance.

scholarly journals The organization of F-actin and microtubules in growth cones exposed to a brain-derived collapsing factor.

1993 ◽  
Vol 121 (4) ◽  
pp. 867-878 ◽  
Author(s):  
J Fan ◽  
S G Mansfield ◽  
T Redmond ◽  
P R Gordon-Weeks ◽  
J A Raper
Keyword(s):  
Growth Cone ◽  
Relative Concentration ◽  
Leading Edge ◽  
Growth Cones ◽  
Rhodamine Phalloidin ◽  
Alpha Tubulin ◽  
Microtubule Polymerization ◽  
Before And After ◽  
General Protein ◽  
The Brain

In previous work we characterized a brain derived collapsing factor that induces the collapse of dorsal root ganglion growth cones in culture (Raper and Kapfhammer, 1990). To determine how the growth cone cytoskeleton is rearranged during collapse, we have compared the distributions of F-actin and microtubules in normal and partially collapsed growth cones. The relative concentration of F-actin as compared to all proteins can be measured in growth cones by rationing the intensity of rhodamine-phalloidin staining of F-actin to the intensity of a general protein stain. The relative concentration of F-actin is decreased by about one half in growth cones exposed to collapsing factor for five minutes, a time at which they are just beginning to collapse. During this period the relative concentration of F-actin in the leading edges of growth cones decreases dramatically while the concentration of F-actin in the centers decreases little. These results suggest that collapse is associated with a net loss of F-actin at the leading edge. The distributions of microtubules in normal and collapsing factor treated growth cones were examined with antibodies to tyrosinated and detyrosinated isoforms of alpha-tubulin. The tyrosinated form is found in newly polymerized microtubules while the detyrosinated form is not. The relative proximal-distal distributions of these isoforms are not altered during collapse, suggesting that rates of microtubule polymerization and depolymerization are not greatly affected by the presence of collapsing factor. An analysis of the distributions of microtubules before and after collapse suggests that microtubules are rearranged, but their polymerization state is unaffected during collapse. These results are consistent with the hypothesis that the brain derived collapsing factor has little effect on microtubule polymerization or depolymerization. Instead it appears to induce a net loss of F-actin at the leading edge of the growth cone.

scholarly journals Grip and slip of L1-CAM on adhesive substrates direct growth cone haptotaxis

2018 ◽  
Vol 115 (11) ◽  
pp. 2764-2769 ◽  
Author(s):  
Kouki Abe ◽  
Hiroko Katsuno ◽  
Michinori Toriyama ◽  
Kentarou Baba ◽  
Tomoyuki Mori ◽  
...  
Keyword(s):  
Cell Migration ◽  
Growth Cone ◽  
Cell Adhesion Molecule ◽  
Chemical Cues ◽  
Traction Force ◽  
Human Patient ◽  
Direct Growth ◽  
Direct Cell ◽  
Conventional Cell ◽  
Directional Cell Migration

Chemical cues presented on the adhesive substrate direct cell migration, a process termed haptotaxis. To migrate, cells must generate traction forces upon the substrate. However, how cells probe substrate-bound cues and generate directional forces for migration remains unclear. Here, we show that the cell adhesion molecule (CAM) L1-CAM is involved in laminin-induced haptotaxis of axonal growth cones. L1-CAM underwent grip and slip on the substrate. The ratio of the grip state was higher on laminin than on the control substrate polylysine; this was accompanied by an increase in the traction force upon laminin. Our data suggest that the directional force for laminin-induced growth cone haptotaxis is generated by the grip and slip of L1-CAM on the substrates, which occur asymmetrically under the growth cone. This mechanism is distinct from the conventional cell signaling models for directional cell migration. We further show that this mechanism is disrupted in a human patient with L1-CAM syndrome, suffering corpus callosum agenesis and corticospinal tract hypoplasia.

MAKING AN ALGORITHM FOR CONTROLLING THE INDIVIDUAL DRIVE OF THE DRIVING WHEELS OF A TRANSPORT AND TECHNOLOGICAL MODULE

2020 ◽  
pp. 10-15
Author(s):  
SHUTENKO VLADIMIR V. ◽  
Keyword(s):  
Power Distribution ◽  
Rotation Speed ◽  
Traction Force ◽  
Microprocessor System ◽  
Movement Trajectory ◽  
Microprocessor Control ◽  
Microprocessor Control System ◽  
The Individual ◽  
Mathematical Relationships ◽  
Technological Module

Improving the traction properties of mobile power tools is one of the most important tasks of modern tractor construction. The use of transport-technological modules (TTM) helps to solve this problem, but to ensure the best indicators of fuel economy and stabilization of a machine-and-tractor unit (MTU), the TTM driving wheels should be driven individually, which can be ensured by a microprocessor control system. Therefore, the study goal is to make an algorithm for controlling the driving wheels of the TTM, which will ensure the best characteristics of a MTU. To achieve this goal, the authors used mathematical modeling and graph-analytical methods. They are necessary for stating the main relationships and setting algorithm conditions that will optimize a tractor’s traction force and power consumption, as well as stabilize its movement trajectory. The operation of the microprocessor system consists in obtaining data from external sensors and determining the actual speed, skidding and direction of travel. The microprocessor system compares these parameters with ideal conditions, described with mathematical relationships, and based on the developed algorithm, corrects the rotation speed and power distribution between the driving wheels of a TTM.

scholarly journals Transmission of growth cone traction force through apCAM–cytoskeletal linkages is regulated by Src family tyrosine kinase activity

2001 ◽  
Vol 155 (3) ◽  
pp. 427-438 ◽  
Author(s):  
Daniel M. Suter ◽  
Paul Forscher
Keyword(s):  
Tyrosine Kinase ◽  
Growth Cone ◽  
Kinase Activity ◽  
Kinase Inhibitors ◽  
Traction Force ◽  
Tyrosine Kinase Activity ◽  
Cellular Mechanisms ◽  
Traction Forces ◽  
Kinase Activation ◽  
Neuronal Growth Cone

Tyrosine kinase activity is known to be important in neuronal growth cone guidance. However, underlying cellular mechanisms are largely unclear. Here, we report how Src family tyrosine kinase activity controls apCAM-mediated growth cone steering by regulating the transmission of traction forces through receptor–cytoskeletal linkages. Increased levels of tyrosine phosphorylation were detected at sites where beads coated with apCAM ligands were physically restrained to induce growth cone steering, but not at unrestrained bead binding sites. Interestingly, the rate and level of phosphotyrosine buildup near restrained beads were decreased by the myosin inhibitor 2,3-butanedione-2-monoxime, suggesting that tension promotes tyrosine kinase activation. While not affecting retrograde F-actin flow rates, genistein and the Src family selective tyrosine kinase inhibitors PP1 and PP2 strongly reduced the growth cone's ability to apply traction forces through apCAM–cytoskeletal linkages, assessed using the restrained bead interaction assay. Furthermore, increased levels of an activated Src family kinase were detected at restrained bead sites during growth cone steering events. Our results suggest a mechanism by which growth cones select pathways by sampling both the molecular nature of the substrate and its ability to withstand the application of traction forces.

A Comparison of Two Fan Stage Designs With Different Rotor Leading Edge Sweep

2014 ◽  
Author(s):  
John Gunaraj ◽  
David Hanson ◽  
Jeffrey Hayes ◽  
Heath Lorzel ◽  
Nick Nolcheff ◽  
...  
Keyword(s):  
Pressure Ratio ◽  
Stability Margin ◽  
Leading Edge ◽  
Flow Capacity ◽  
Numerical Predictions ◽  
Performance Trends ◽  
Ansys Cfx ◽  
Significant Difference ◽  
Total Temperature ◽  
The Individual

Two modern single-stage fans have been designed to meet the same set of performance objectives. The most significant difference between the two designs is the fan rotor leading edge sweep. The baseline rotor has a moderately aft swept leading edge while the redesigned rotor has a more complex sweep distribution, including moderate forward sweep in the tip region. Each stage consists of the fan rotor, full span stator, and split mid-frame, and is designed for a medium bypass ratio turbofan application. The stator and the mid-frame are identical for the two configurations. The primary purpose of this study is to validate the CFD methodology, in this case a steady ANSYS-CFX approach, to predict the fan stage performance at the operating point at two tested speeds and also to predict the stalling throttle condition. Numerical predictions and engine test results are presented and show good agreement. These predicted results are compared with high quality test data including thorough measurements of total pressure and total temperature at both the rotor and stator exits allowing for a detailed understanding and comparison of the individual blade row performance. The analytical model identifies the key performance trends, including an increase in flow capacity and stability margin with equivalent stage pressure ratio and efficiency for the redesigned fan relative to the baseline.

scholarly journals Stages in axon formation: observations of growth of Aplysia axons in culture using video-enhanced contrast-differential interference contrast microscopy.

1986 ◽  
Vol 103 (5) ◽  
pp. 1921-1931 ◽  
Author(s):  
D J Goldberg ◽  
D W Burmeister
Keyword(s):  
Axonal Transport ◽  
Growth Cone ◽  
Axon Growth ◽  
Leading Edge ◽  
Main Body ◽  
Differential Interference Contrast ◽  
Differential Interference Contrast Microscopy ◽  
Fast Axonal Transport ◽  
Contrast Microscopy ◽  
Interference Contrast Microscopy

The regenerative growth in culture of the axons of two giant identified neurons from the central nervous system of Aplysia californica was observed using video-enhanced contrast-differential interference contrast microscopy. This technique allowed the visualization in living cells of the membranous organelles of the growth cone. Elongation of axonal branches always occurred through the same sequence of events: A flat organelle-free veil protruded from the front of the growth cone, gradually filled with vesicles that entered by fast axonal transport and Brownian motion from the main body of the growth cone, became more voluminous and engorged with organelles (vesicles, mitochondria, and one or two large, irregular, refractile bodies), and, finally, assumed the cylindrical shape of the axon branch with the organelles predominantly moving by bidirectional fast axonal transport. The veil is thus the nascent axon. Because veils appear to be initially free of membranous organelles, addition of membrane to the plasmalemma by exocytosis is likely to occur in the main body of the growth cone rather than at the leading edge. Veils almost always formed with filopodial borders, protruding between either fully extended or growing filopodia. Therefore, one function of the filopodia is to direct elongation by demarcating the pathway along which axolemma flows. Models of axon growth in which the body of the growth cone is pulled forward, or in which advance of the leading edge is achieved by filopodial shortening or contraction against an adhesion to the substrate, are inconsistent with our observations. We suggest that, during the elongation phase of growth, filopodia may act as structural supports.

Aerodynamic Performance of Turbine Center Frames With Purge Flows—Part I: The Influence of Turbine Purge Flow Rates

2018 ◽  
Vol 140 (6) ◽  
Author(s):  
Stefan Zerobin ◽  
Andreas Peters ◽  
Sabine Bauinger ◽  
Ashwini Bhadravati Ramesh ◽  
Michael Steiner ◽  
...  
Keyword(s):  
Measurement Data ◽  
Leading Edge ◽  
Aerodynamic Performance ◽  
Flow Structures ◽  
Flow Rates ◽  
Purge Flow ◽  
Mass Flows ◽  
The Individual ◽  
The Impact ◽  
First Time

This two-part paper deals with the influence of high-pressure turbine (HPT) purge flows on the aerodynamic performance of turbine center frames (TCF). Measurements were carried out in a product-representative one and a half-stage turbine test setup. Four individual purge mass flows differing in flow rate, pressure, and temperature were injected through the hub and tip, forward and aft cavities of the unshrouded HPT rotor. Two TCF designs, equipped with nonturning struts, were tested and compared. In this first part of the paper, the influence of different purge flow rates (PFR) is discussed, while in the second part of the paper, the impact of the individual hub and tip purge flows on the TCF aerodynamics is investigated. The acquired measurement data illustrate that the interaction of the ejected purge flow with the main flow enhances the secondary flow structures through the TCF duct. Depending on the PFR, the radial migration of purge air onto the strut surfaces directly impacts the loss behavior of the duct. The losses associated with the flow close to the struts and in the strut wakes are highly dependent on the relative position between the HPT vane and the strut leading edge (LE), as well as the interaction between vane wake and ejected purge flow. This first-time experimental assessment demonstrates that a reduction in the purge air requirement benefits the engine system performance by lowering the TCF total pressure loss.

scholarly journals Growth cone behavior and production of traction force.

1990 ◽  
Vol 111 (5) ◽  
pp. 1949-1957 ◽  
Author(s):  
S R Heidemann ◽  
P Lamoureux ◽  
R E Buxbaum
Keyword(s):  
Growth Cone ◽  
Contractile Activity ◽  
Glass Fibers ◽  
Force Production ◽  
Traction Force ◽  
Dorsal Surface ◽  
Growth Cones ◽  
Retrograde Flow ◽  
Cortical Actin ◽  
Over The Top

The growth cone must push its substrate rearward via some traction force in order to propel itself forward. To determine which growth cone behaviors produce traction force, we observed chick sensory growth cones under conditions in which force production was accommodated by movement of obstacles in the environment, namely, neurites of other sensory neurons or glass fibers. The movements of these obstacles occurred via three, different, stereotyped growth cone behaviors: (a) filopodial contractions, (b) smooth rearward movement on the dorsal surface of the growth cone, and (c) interactions with ruffling lamellipodia. More than 70% of the obstacle movements were caused by filopodial contractions in which the obstacle attached at the extreme distal end of a filopodium and moved only as the filopodium changed its extension. Filopodial contractions were characterized by frequent changes of obstacle velocity and direction. Contraction of a single filopodium is estimated to exert 50-90 microdyn of force, which can account for the pull exerted by chick sensory growth cones. Importantly, all five cases of growth cones growing over the top of obstacle neurites (i.e., geometry that mimics the usual growth cone/substrate interaction), were of the filopodial contraction type. Some 25% of obstacle movements occurred by a smooth backward movement along the top surface of growth cones. Both the appearance and rate of movements were similar to that reported for retrograde flow of cortical actin near the dorsal growth cone surface. Although these retrograde flow movements also exerted enough force to account for growth cone pulling, we did not observe such movements on ventral growth cone surfaces. Occasionally obstacles were moved by interaction with ruffling lamellipodia. However, we obtained no evidence for attachment of the obstacles to ruffling lamellipodia or for directed obstacle movements by this mechanism. These data suggest that chick sensory growth cones move forward by contractile activity of filopodia, i.e., isometric contraction on a rigid substrate. Our data argue against retrograde flow of actin producing traction force.

scholarly journals CFD DEM Analysis of a Dry Powder Inhaler

2019 ◽  
Author(s):  
Antara Badhan ◽  
V. M. Krushnarao Kotteda ◽  
Vinod Kumar
Keyword(s):  
Sensitivity Analysis ◽  
High Performance ◽  
Dry Powder Inhaler ◽  
Leading Edge ◽  
Active Pharmaceutical Ingredient ◽  
Department Of Energy ◽  
Discrete Element Modeling ◽  
Dry Powder ◽  
Throat Region ◽  
The Individual

Abstract Dry powder inhalers (DPIs), used as a means for pulmonary drug delivery, typically contain a combination of active pharmaceutical ingredient (API) and significantly larger carrier particles. The micro-sized drug particles — which have a strong propensity to aggregate and poor aerosolization performance — mixed with significantly large carrier particles that are unable to penetrate the mouth-throat region to deagglomerate and entrain the smaller API particles in the inhaled airflow. The performance of a DPI, therefore, depends on entrainment the carrier-API combination particles and the time and thoroughness of the deagglomeration of the individual API particles from the carrier particles. Since DPI particle transport is significantly affected by particle-particle interactions, very different particles sizes and shapes, various forces including electrostatic and van der Waals forces, they present significant challenges to Computational Fluid Dynamics (CFD) modelers to model regional lung deposition from a DPI. In the current work, we present a novel high fidelity CFD discrete element modeling (CFD-DEM) and sensitivity analysis framework for predicting the transport of DPI carrier and API particles. The work integrates exascale capable CFD-DEM and sensitivity analysis capabilities by leveraging the Department of Energy (DOE) laboratories libraries: Multiphase Flow Interface Flow Exchange (MFiX) for CFD-DEM, and Trilinos for leading-edge portable/scalable linear algebra. We carried out a sensitivity analysis of various formulation properties and their effects on particle size distribution with Dakota, an open source software designed to exploit High-Performance Computing (HPC) capabilities of a massively parallel supercomputer. We developed wrappers to exchange information among these state-of-the-art tools for DPI.

scholarly journals A cryptic tubulin-binding domain links MEKK1 to curved tubulin protomers

2020 ◽  
Vol 117 (35) ◽  
pp. 21308-21318 ◽  
Author(s):  
Pavel Filipčík ◽  
Sharissa L. Latham ◽  
Antonia L. Cadell ◽  
Catherine L. Day ◽  
David R. Croucher ◽  
...  
Keyword(s):  
Cell Migration ◽  
Map Kinases ◽  
Leading Edge ◽  
Structural Features ◽  
Selective Enrichment ◽  
Microtubule Polymerization ◽  
Binding Interface ◽  
Protein Map ◽  
Tubulin Binding ◽  
Mitogen Activated Protein

The MEKK1 protein is a pivotal kinase activator of responses to cellular stress. Activation of MEKK1 can trigger various responses, including mitogen-activated protein (MAP) kinases, NF-κB signaling, or cell migration. Notably, MEKK1 activity is triggered by microtubule-targeting chemotherapies, among other stressors. Here we show that MEKK1 contains a previously unidentified tumor overexpressed gene (TOG) domain. The MEKK1 TOG domain binds to tubulin heterodimers—a canonical function of TOG domains—but is unusual in that it appears alone rather than as part of a multi-TOG array, and has structural features distinct from previously characterized TOG domains. MEKK1 TOG demonstrates a clear preference for binding curved tubulin heterodimers, which exist in soluble tubulin and at sites of microtubule polymerization and depolymerization. Mutations disrupting tubulin binding decrease microtubule density at the leading edge of polarized cells, suggesting that tubulin binding may play a role in MEKK1 activity at the cellular periphery. We also show that MEKK1 mutations at the tubulin-binding interface of the TOG domain recur in patient-derived tumor sequences, suggesting selective enrichment of tumor cells with disrupted MEKK1–microtubule association. Together, these findings provide a direct link between the MEKK1 protein and tubulin, which is likely to be relevant to cancer cell migration and response to microtubule-modulating therapies.

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