bluuebunny/crossref_metadata_2025 huggingface dataset:
Modelling of Film Thickness and Traction in a Variable Ratio Traction Drive Rig
Authors: Sharif K. J. , Evans H. P. , Snidle R. W. , Newall J. P.
Published: June 2008

The paper describes the application of a full non-Newtonian, thermal elastohydrodynamic lubrication (EHL) model for the prediction of film thickness and viscous traction force in a special high speed rolling traction rig. The primary objective of the work was to identify a suitable lubricant rheological model that would describe the behavior of practical EHL traction drive contacts over their operating range. Experiments were carried out on a special rolling contact rig at temperatures of 60, 90 and 120°C and contact loads giving maximum Hertzian pressures of 1, 2 and 3 GPa. Entrainment speeds of up to 18 m/s were investigated. Corresponding modelling work was carried out using lubricant physical properties obtained for the traction fluid Santotrac 50. Viscosity data for this lubricant were available from the work of Bair and Winer, but a degree of extrapolation was required to this data to cover the range of the experiments. In view of the crucial importance of viscosity/pressure behavior in the prediction of traction attention was therefore focused upon the lower contact loads for which reliable viscosity/pressure data are available. A best-fit exercise was then carried out to establish an appropriate rheological model to account for shear thinning of the lubricant. Different non-Newtonian relationships were investigated including those of Johnson and Tevaarwerk, Bair and Winer, and a model which combined the features of both of these. The most encouraging agreement between experiment and theory over the range of temperatures and speeds considered was obtained with the Johnson and Tevaarwerk (Eyring) model.
Characteristics of Profile-Shifted Straight Bevel Gears With Octoid Form
Authors: Chang Chi-Kang , Tsay Chung-Biau
Published: June 2008

The mathematical model of profile-shifted straight bevel gears with Octoid form is developed based on the gear theory and the gear generation mechanism. The developed mathematical model is then applied to plot computer graphs of this type of gearing. In addition, the geometries, characteristics and tooth undercutting of the profile-shifted straight bevel gears are also studied.
Utilization of Powdered Metal and Shot Peening Residual Stress to Maximize Cost and Performance Benefit of High Load Gearing
Authors: Breuer David J.
Published: June 2008

The primary benefit of powdered metal (PM) gearing is reduced cost of manufacturing making it an obvious choice for lower load applications. The perception that PM gears are only limited to low load classes has been changing with recent developments in higher density PM technology and advanced manufacturing techniques such as powder forging, isostatic pressing, conventional compaction, surface densification, and activated sintering. This paper will focus on bending fatigue strength improvements of PM gearing from recent improvements in PM technology combined with the established technology of shot peening. Factoring in the significant cost savings of PM manufacturing, PM gears with shot peening have the potential to replace higher load applications currently served by wrought gearing. This paper addresses gear applications limited by bending fatigue and not other failure modes.
Effect of Superfinishing on Scuffing Resistance
Authors: Winkelmann Lane W. , Michaud Mark D. , Snidle Ray W. , Alanou Mark P.
Published: June 2008

A fundamental understanding of gear scuffing has been promoted for a number of years by the use of twin disc scuffing rigs. Quantities of interest such as friction and bulk temperature are more easily and less expensively measured than performing actual gear testing. This paper discusses the scuffing test data performed on specimens superfinished using chemically accelerated vibratory finishing. One set of samples was superfinished using a high density non-abrasive ceramic media, while another set of samples was superfinished using a non-abrasive plastic media. This data is compared to other specimens with different surface finishes tested under identical conditions.
Analytical and Test Evaluation of Planetary Gear Train Efficiency (Torque Related Losses) With Multiple Power Flow Arrangements
Authors: Chen Joseph Y. , Borgerson James B.
Published: June 2008

A step-by-step computational procedure for estimating planetary gear train efficiency is presented. This technique is especially useful for complex gear train systems, because it does not require re-arranging the power circuit to perform efficiency calculations for different power paths. A hardware test program validating the computation is also documented. The test results correlate well with the analytical model.
Power Loss of Spur Gear Drive Lubricated With Traction Oil
Authors: Ikejo Kiyotaka , Nagamura Kazuteru
Published: June 2008

This paper describes the effect of traction oil on the power loss of spur gear drive. In this study, we measured the power loss of super gear drive using several traction oils. We separated the power loss into gear friction loss and oil churning loss. Furthermore, we measured the surface temperature on the gear tooth by the dynamic thermocouple method, and observed the lubrication condition between meshing teeth by the electrical resistance method. Then, we investigated the relationships between the power loss of the gear drive lubricated with the traction oil, the surface temperature on the gear tooth, and the lubrication condition.
Nonlinear Dynamic Modelling of Gear-Shaft-Disk-Bearing Systems Using Finite Elements and Describing Functions
Authors: Maliha Rafiq , Dog˘ruer Can U. , O¨zgu¨ven H. Nevzat
Published: June 2008

This study presents a new nonlinear dynamic model for a gear-shaft-disk-bearing system. A nonlinear dynamic model of a spur gear pair is coupled with linear finite element models of shafts carrying them, and with discrete models of bearings and disks. The nonlinear elasticity term resulting from backlash is expressed by a describing function, and a method developed in previous studies to determine the harmonic responses of nonlinear multi degree of freedom systems is employed for the solution. The code developed, Nonlinear Geared Rotor Dynamics (NLGRD), combines the versatility of modeling a shaft-bearing-disk system that can have any configuration, with the accuracy of an advanced nonlinear gear mesh interface model. Thus any single stage gear mesh configuration can be modeled easily and accurately. NLGRD is capable of calculating dynamic gear loads, dynamic bearing forces, bearing displacements and making modal analysis of the corresponding linear system. Theoretical results obtained by NLGRD are compared with the experimental data available in literature.
The Duality Between Planar Kinematics and Statics
Authors: Shai Offer , Pennock Gordon R.
Published: June 2008

This paper shows that there is a correlation between basic concepts underlying the kinematics of mechanisms and the statics of trusses. The implication of this correlation, referred to here as duality, is that the science of kinematics can be utilized in a systematic manner to yield insight into the statics of mechanical systems. The paper begins by proving the existence of a unique line (referred to as the equimomental line) where the moments, at each point on this line, caused by two arbitrary co-planar forces are equal. The dual concept in kinematics is the instantaneous center of zero velocity and two theorems are presented based on the duality between equimomental lines and instantaneous centers. The first theorem states that the three equimomental lines defined by three co-planar forces must intersect at a unique point. The second theorem states that the equimomental line for two co-planar forces acting in a trusss with two degrees of indeterminacy must pass through a unique point. The paper presents several practical examples to demonstrate how the duality between kinematics and statics provides a better understanding of planar linkages and trusses. The new concepts are used to identify the singular configurations of linkages and the configurations of determinate trusses where they are not rigid. Finally, the paper takes advantage of some important relationships between linkages and trusses to provide a general perspective of the duality between the kinematics of mechanisms and the statics of trusses.
Resolution of Singular Configuration Space of 3/6-SPS Parallel Manipulator Using an Equivalent SC Simulation Mechanism
Authors: Lu Yi , Huang Zhen
Published: June 2008

The determination of the 6-dimensional singular configurations (SC) space of 3/6-SPS Stewart parallel manipulator is a very important and quite complicated problem. For a long time, its developments, however, have been very limited, especially the general-linear complex-SC (GSC). Currently, the Jacobian matrix and the Grassmann line geometry have been used to solve the SC space of the Stewart parallel robot. However, these two approaches are not straightforward. In this paper, a novel computer aided geometric approach is proposed for solving the 6-dimensional SC space of the 3/6-SPS Stewart parallel manipulator. First, a simulation mechanism of the 3/6-SPS parallel manipulator is created. Second, its equivalent SC simulation mechanism is created. Third, from the equivalent SC simulation mechanism, some analytical geometry formulas for solving 6-dimension SC space are derived. Finally, some SC space characteristics are analyzed, and some important developments are achieved.
Obstacle Avoidance Influence Coefficients for Manipulator Motion Planning
Authors: Harden Troy , Kapoor Chetan , Tesar Delbert
Published: June 2008

Motion planning in cluttered environments is a weakness of current robotic technology. While research addressing this issue has been conducted, few efforts have attempted to use minimum distance rates of change in motion planning. Geometric influence coefficients provide extraordinary insight into the interactions between a robot and its environment. They isolate the geometry of distance functions from system inputs and make the higher-order properties of minimum distance magnitudes directly available. Knowledge of the higher order properties of minimum distance magnitudes can be used to predict the future obstacle avoidance, path planning, and/or target acquisition state of a manipulator system and aid in making intelligent motion planning decisions. Here, first and second order geometric influence coefficients for minimum distance magnitudes are rigorously developed for several simple modeling primitives. A general method for similar derivations using new primitives and an evaluation of finite difference approximations versus analytical second order coefficient calculations are presented. Two application examples demonstrate the utility of minimum distance magnitude influence coefficients in motion planning.
A Systematic Formulation of Overconstraint Conditions in Kinematic Chains by Displacement Groups
Authors: Galletti Carlo , Fanghella Pietro , Giannotti Elena
Published: June 2008

The paper describes a systematic approach to define geometrical and dimensional overconstraint conditions for single-loop kinematic chains of both “banal” and “exceptional” types. The approach is an application of the theory of displacement groups. It presents several interesting features: it can be easily integrated with mobility analysis; it makes use of geometric data local to links and does not require a preliminary mechanism assembly nor a given initial congruent position; it is systematic and can be suitably implemented in a computer code; it suggests where geometrical and dimensional tolerances have to be located; it can be embedded in other group-based approaches, like kinematic synthesis or dynamic analysis. After a brief summary of the properties of displacement groups and their operations, the paper shows how they can be used to formulate systematically the overconstraint conditions in kinematic chains. A computer implementation of the approach is also outlined, and several examples with different complexities are given.
A Robotic “Jack Spring”™ for Ankle Gait Assistance
Authors: Hollander Kevin W. , Sugar Thomas G. , Herring Donald E.
Published: June 2008

A Robotic ‘Jack Spring’™ is a new type of mechanical actuator, which is based upon the concept of structure control. A Jack Spring™ mechanism is used to create an adjustable Robotic Tendon, which is a spring based linear actuator in which the properties of a spring are crucial to its successful use in gait assistance. Like its human analog, the adjustable Robotic Tendon uses its inherent elastic nature to reduce both peak power and energy requirements for its motor. In the ideal example, peak power required of the motor for ankle gait is reduced from 250W to just 81 W. In addition, ideal energy requirements are reduced from nearly 36 Joules to just 25 Joules per step. Using this approach, an initial prototype is expected to provide 100% of the power and energy neccessary for ankle gait in a compact 0.84kg package. This weight is 8 times less than that predicted for an equivalent direct drive approach.
Error Modeling in a Reconfigurable Machine Tool
Authors: Giri Deepak , Moon Yong-Mo
Published: June 2008

This paper proposes a new approach for tool tip error estimation for reconfigurable machine tools by linearly adding the module errors represented by a screw in global coordinate. The presented method is ideal for modular structured reconfigurable machine tools since the errors are represented in modules’ coordinate system in coordinate independent screw representation method. The contribution of each error sources is then estimated by linear combination (AKA parallel combination) after the error screws are transformed into the global coordinate system of the machine tools. The presented method is verified through the comparison with the serial matrix multiplication method proposed by Moon et al. [3] Simulations for the above mentioned methods are run and total tool tip errors are compared to study the feasibility of parallel method. The study shows the errors are smaller for parallel combination and both methods have similar trends over the work volume.
On the Different Actuation’s Ways of the Spherically Actuated Platform Manipulator
Authors: Vakil Mohammad , Pendar Hodjat , Zohoor Hassan
Published: June 2008

In this article kinematic analysis of a 3 Leg-Spherically Actuated (3SA) parallel manipulator will be addressed. Since each leg has a spherical actuator (three inputs for each leg) and manipulator has three legs; totally, there are nine inputs. Due to the fact that the manipulator has six degree of freedom, only six independent inputs are needed. Thus actuation could be done in different ways. If the triangles representing base and platform are equilateral, there are twenty different ways of actuation that should be studied during forward kinematic analysis. Rather than adopting the standard Denavit-Hartenberg approach, a simple method for forward kinematic analysis for all these different ways of twenty ways has been introduced. Considering all these ways, it will be shown that at least two and at most six nonlinear algebraic equations should be solved during forward kinematic analysis, while choosing the standard approach twelve nonlinear equations should be solved for each way of actuation. A unique inverse kinematic method has been presented. The singularly analysis for all these different ways of actuation has also been studied. For two out of the twenty different ways, closed form solutions for the singularity analysis have been obtained, for other ways; conditions which result in singularity configuration has been presented and simulation justified the proposed criteria.
Design of Lead Screw Actuators for Wearable Robotic Applications
Authors: Hollander Kevin W. , Sugar Thomas G.
Published: June 2008

A wearable robot is a controlled and actuated device that is in direct contact with its user. As such, the implied requirements of this device are that it must be portable, lightweight and most importantly safe. To achieve these goals an actuator with a good ‘power to weight’ ratio, good mechanical efficiency, good ‘strength to weight’ ratio and that is safe is desired. The design of the standard lead screw does not normally perform well in any of these categories. The typical lead screw has low pitch angles and large radii, thereby yielding low mechanical efficiencies and high weight. However, using the design procedure outlined in this text both efficiency and weight are improved, thus yielding a lead screw system with performances that rival human muscle. The result of an example problem reveals a feasible lead screw design that has a ‘power to weight’ ratio of 277W/kg, approaching that of the DC motor driving it, at 312W/kg, as well as a mechanical efficiency of 0.74, and a maximum ‘strength to weight’ ratio of 11.3kN/kg(1154kgf/kg).
Kinematics and Force Optimization for Efficient Self-Reconfiguration of Chain-Type Modular Robots
Authors: Nelson Carl A. , Cipra Raymond J.
Published: June 2008

The problem of self-reconfiguration planning for chain-type unit-modular robots is a complex one, with many issues yet to be successfully addressed. This paper describes an approach to several sub-problems associated with self-reconfiguration, namely kinematic modeling and analysis, including kinematic constraint satisfaction, and load analysis and redistribution. These issues are addressed in a unified framework whose primary objective is minimization of the time and mechanical energy expended during reconfiguration. Computer simulation efforts are described and results presented.
Patterned Bootstrap: A New Method Which Gives Efficiency for Precision Position Synthesis of Planar Linkages
Authors: Luo Zhenjun , Dai Jian S.
Published: June 2008

This paper presents a new method, termed as patterned bootstrap (PB), which is suitable for precision position synthesis of planar linkages. The method solves a determined system of equations using a new bootstrapping strategy. In principle, a randomly generated starting point is advanced to a final solution through solving a number of intermediate systems. The structure and the associated parameters of each intermediate system is defined as a pattern. In practice, a PB procedure generally consists of two levels: an upper level which controls the transition of patterns, and a lower level which solves intermediate systems using globally convergent root-finding algorithms. Besides introducing the new method, tunnelling functions have been added to several systems of polynomials derived by formal researchers in order to exclude degenerated solutions. Our numerical experiments demonstrate that many precision position synthesis problems can be solved efficiently without resorting to time-consuming polynomial homotopy continuation methods or interval methods. Finding over 95 percentages of the complete solutions of the 11 precision position function generation problem of a Stephenson-III linkage has been achieved for the first time.
Static and Dynamic Analysis of the PAMINSA (Parallel Manipulator of the I.N.S.A.)
Authors: Arakelian Vigen , Gue´gan Sylvain , Briot Se´bastien
Published: June 2008

In this paper we present an analytical approach for the static and dynamic analysis of the PAMINSA, a new 4 degrees of freedom parallel manipulator that has been designed at the I.N.S.A. in Rennes. On the base of the developed static model, the input torques due to the static loads are reduced by means of the optimum redistribution of the moving link masses. The analytical dynamic modeling of the PAMINSA by means of Lagrange equations is achieved. A numerical example and a comparison between the suggested analytical model and an ADAMS software simulation are presented.
Optimal Synthesis of Compliant Mechanisms Using a Connectivity Preserving Level Set Method
Authors: Chen Shikui , Wang Michael Yu , Wang Shengyin , Xia Qi
Published: June 2008

We present a level set based method for optimal design of compliant mechanisms. The focus of the investigation is on how to preserve the structural connectivity in the optimization process of the level set method. By introducing an extra constraint using the connected components labeling technique, the structural connectivity of the design is well maintained during the topology optimization process.
Integrated Design and Control of a Biped Robot
Authors: Schmiedeler James P. , Westervelt Eric R. , Dunki-Jacobs Adam R.
Published: June 2008

This paper introduces a methodology for the integration of mechanical and control system design of planar biped robots. The control approach is a procedure for the systematic design, analysis, and performance enhancement of controllers that induce provably stable dynamic walking in planar bipeds. Iterative application of this procedure with variations in the mechanical parameters of the biped model enables a designer to drive design changes based upon analytical metrics of stability and efficiency. The outcomes are a dynamically-informed mechanical design and controllers that maximally exploit the unforced dynamics of that design. This methodology has been applied to the design and construction of the prototype biped BIRT (BIped Robot with Three legs). BIRT is a planar biped whose two outside legs are slaved by means of control to act together. The paper provides a detailed description of BIRT’s mechanical system.
Modeling and Simulation of Flapping Wing Micro Air Vehicles
Authors: Khan Zaeem A. , Agrawal Sunil K.
Published: June 2008

This paper presents modeling and simulation of a flapping wing micro air vehicle. The overall geometry of this vehicle is based on hummingbirds and large insects. The purpose of this study is to understand the mechanics of flight and to achieve a preliminary design based on simulation results. A quasi-unsteady aerodynamic model is used based on in-house experimental investigation of flapping wing aerodynamics. The simulation results reveal important information regarding the behaviour of the system, that could be used in future designs.
Mobility Analysis of Parallel Mechanisms Based on Screw Theory and the Concept of Equivalent Serial Kinematic Chain
Authors: Kong Xianwen , Gosselin Cle´ment M.
Published: June 2008

This paper presents a systematic approach for the mobility analysis of parallel mechanisms. The method is based on screw theory and the concept of equivalent serial chain. An equivalent serial kinematic chain of a k-legged PKC (parallel kinematic chain) is defined as a serial kinematic chain which has the same twist system and the wrench system as the k-legged PKC. Using the proposed approach, the mobility analysis of a PKC is performed in two steps. The first step is the instantaneous mobility analysis, and the second step is the full-cycle mobility inspection. The first step is dealt with based on screw theory. The second step is performed with the aid of the concept of equivalent serial chain and the types of multi-DOF overconstrained single-loop kinematic chains. The proposed approach is illustrated with several examples.
Instabilities in a Class of Dual-Axis MEMS Gyroscopes
Authors: Wang Tianfu , Asokanthan Samuel F.
Published: June 2008

Stability of a dual-axis vibratory MEMS gyroscope that is subject to periodic fluctuations in input angular rates is investigated. For the purpose of acquiring stability conditions, when the angular rate input is subject to small intensity periodic fluctuations, dynamic behavior of periodically perturbed linear gyroscopic systems is studied in detail. An asymptotic approach based on the method of averaging has been employed for this purpose, and closed-form conditions for the onset of instability due to parametric resonances have been obtained for this type of vibrating gyroscope. Furthermore, for characterizing the effect due to change in angular rate input, an in-depth natural frequency analysis has been performed. Stability predictions have been illustrated via plots in the excitation amplitude-frequency space. Based on these results, the dangerous critical frequencies can be avoided in the design to achieve a high performance.
Whole Skin Locomotion Inspired by Amoeboid Motility Mechanisms
Authors: Ingram Mark , Hong Dennis
Published: June 2008

In this paper, we present a novel locomotion mechanism for mobile robots inspired by the motility mechanisms of single celled organisms that use cytoplasmic streaming to generate pseudopods for locomotion. The Whole Skin Locomotion, as we call it, works by way of an elongated toroid which turns itself inside out in a single continuous motion, effectively generating the overall motion of the cytoplasmic streaming ectoplasmic tube in amoebae. With an elastic membrane or a mesh of links acting as its outer skin, the robot can easily squeeze between obstacles or under a collapsed ceiling and move forward using all of its contact surfaces for traction, or even squeeze itself through holes with diameters smaller than its nominal width by actively changing its cross section diameter making this the ideal locomotion method for search and rescue robots that need to traverse over or under rubble, or for applications where a robot needs to move in and maneuver itself into tight spaces such as for robotic endoscopes. This paper summarizes the many existing theories of amoeboid motility mechanisms, and examines how these can be applied on a macro scale as a novel mobile robot locomotion concept. Four locomotion mechanism models are presented with preliminary experiments and their results, demonstrating the feasibility of the whole skin locomotion strategy.
The Synthesis of Planar 4R Linkages With Three Task Positions and Two Specified Velocities
Authors: Robson Nina P. , McCarthy J. Michael
Published: June 2008

In this paper, we consider the complete synthesis of planar 2R chains, in which the five design parameters of the chain are determined using kinematic specifications on the movement of the floating link. We use three positions and two velocities to define algebraic design equations which are solved to obtain multiple solutions. Our primary concern is how to ensure that a 4R chain constructed from two of these solutions moves smoothly through the given task. This is achieved by mapping the design data to an image space of planar displacements and comparing it to the curve traced by the movement of the coupler of the resulting design. Examples show that a designer can work in this image space to adjust the task specification to obtain an effective linkage design.
Effective Teaching of Computer Integrated Mechanism Analysis and Design
Authors: Cheng Harry H. , Campbell Matt
Published: June 2008

An effective teaching strategy that integrates computer aided design and programming into a course on mechanism analysis and design is presented. Mechanism analysis is enhanced when coupled with basic programming that allows students to find solutions to more complex systems than would otherwise be possible. Web-based distance learning is part of the class and students also learn how to create these kinds of materials themselves. Students can better understand the course material through an integrated computing environment. By solving mechanism design problems in C/C++, the programming skills gained in the course are widely applicable in other areas of engineering. Ch, a C/C++ interpreter, is used to incorporate programming and mechanism design because of its high-level numerical and graphical plotting capabilities, scripting capability, and a mechanism toolkit with easy and quick animation. A student project is given as an example to show how computers are integrated for effective learning. This teaching strategy has been actively used at UC Davis for several years in an undergraduate course in computer-aided mechanism design.
Another Way to Die
Authors: Gough Nancy R.
Published: June 2008

Although p53-deficiency is a common factor in many cancers and loss of p53 activity contributes to the inappropriate survival of cells that have DNA damage, in vitro studies suggest that there are p53-independent cell death pathways. To facilitate the discovery of such p53-independent pathways, Sidi
et al
. targeted kinases involved in the DNA damage response with morpholino antisense oligonucleotides in zebrafish embryos defective for p53 activity and found that when the kinase Chk1 was knocked down, cell death (detected with acridine orange) due to irradiation was restored to that of wild-type embryos exposed to irradiation. A specific inhibitor of Chk1 (Gö6976), but not inhibitors for the DNA damage checkpoint kinases ATM or Chk2, also restored irradiation-induced cell death in p53-deficient zebrafish embryos. Although the morphological and ultrastructural characteristics of apoptosis were present in the irradiated

p53
e7/e7

;

chk1
MO

embryos (DNA fragmentation, chromatin compaction, and cytoplasmic condensation), activated caspase-3 was not detectable with an activation-specific antibody. Knockdown of either ATM or ATR in the

p53
e7/e7

;

chk1
MO

embryos severely impaired cell death induced by irradiation. Depletion of Puma, Bcl-X
L
, or caspase-9 failed to prevent irradiation-induced cell death in the

p53
e7/e7

;

chk1
MO

embryos, which suggests that the mitochondrial pathway of cell death was not involved. Depletion or inhibition of components of the extrinsic cell death pathway (caspase-9 or death receptor signaling) also did not interfere with cell death in the

p53
e7/e7

;

chk1
MO

embryos. Instead, irradiation-induced cell death was decreased if caspase-2 was knocked down in the

p53
e7/e7

;

chk1
MO

embryos. This caspase-2-dependent pathway was present in human cancer cells and was detected after irradiation in cells deficient for p53 activity and in which Chk1 was inhibited with Gö6976. Inhibition of Chk1 may be an attractive target for sensitizing human cancers to irradiation because each of the human cancer cell lines tested, regardless of p53 genotype, exhibited enhanced apoptosis in response to irradiation when exposed to the Chk1 inhibitor Gö6976.

S. Sidi, T. Sanda, R. D. Kennedy, A. T. Hagen, C. A. Jette, R. Hoffmans, J. Pascual, S. Imamura, S. Kishi, J. F. Amatruda, J. P. Kanki, D. R. Green, A. A. D’Andrea, A. T. Look, Chk1 suppresses a caspase-2 apoptotic response to DNA damage that bypasses p53, Bcl-2, and caspase-3.
Cell
133
, 864-877 (2008).
[PubMed]
Activate or Repress?
Authors: Foley John F.
Published: June 2008

Canonical Wnt signaling results in the stabilization of β-catenin, which translocates to the nucleus and binds to members of the T cell factor (TCF) family of DNA binding proteins. This interaction displaces a corepressor protein from TCF and recruits a coactivator protein to activate gene transcription. However, β-catenin is also known to directly repress the transcription of a small number of genes in a TCF-dependent manner, but how this occurs is unclear. Blauwkamp
et al
. investigated the mechanism by which the
Drosophila
β-catenin protein Armadillo (Arm) represses transcription. The authors performed microarray analyses and identified a number of genes in
Drosophila
Kc167 cells whose decreased expression was dependent on TCF and on signals that stabilized Arm. However, real-time reverse transcription polymerase chain reaction (RT-PCR) assays showed that, in the absence of Wnt signaling, transcription of these genes was activated in a TCF-dependent manner. The authors focused on the gene
Ugt36Bc
and identified a 178-base pair fragment that contained the Wnt responsive element (WRE) required for repressed transcriptional activity in reporter assays. Although the WRE did not contain the consensus TCF-binding site, chromatin immunoprecipitation (ChIP) assays showed that TCF bound to the
Ugt36Bc
WRE in Kc167 cells. A mutant TCF protein that cannot bind to Arm inhibited Arm-dependent repression in a reporter assay. DNAseI protection assays identified the TCF-binding sites, which contained a novel consensus sequence, mutation of which blocked reporter activity in the absence of Wnt signaling. A mutant Arm protein (DisArmed) defective for gene activation was still able to repress target gene transcription in transfected Kc167 cells, which suggests that different Arm domains repress or activate transcription. The authors suggest that distinct TCF-binding sites allosterically determine whether TCF-Arm will activate or repress transcription.

T. A. Blauwkamp, M. V. Chang, K. M. Cadigan, Novel TCF-binding sites specify transcriptional repression by Wnt signalling.
EMBO
J
.
27
, 1436-1446 (2008).
[PubMed]
Lyn for Growth Hormone Receptor
Authors: Gough Nancy R.
Published: June 2008

Growth hormone (GH) signals through its receptor GHR to stimulate proliferation. Receptor-associated kinases of the Jak family are well known for their role in coupling the GHR to activation of members of the transcription factor family known as STATs. Rowlinson
et al
. compared the crystal structures of the extracellular portion of the GHR bound to GH or an antagonist and noticed that the region called the F-G loop was in a different position. They analyzed cells expressing various mutations in the F-G loop and found that proliferation of transfected cells in response to GH was only partially reduced when compared with cells expressing wild-type GHR. Signaling through the Jak-STAT pathway was not altered in the cells expressing the F-G mutant receptors, but activation of the mitogen-activated protein kinase known as ERK in response to GH was decreased. A Src family kinase (SFK) was phosphorylated in response to GH in cells expressing the wild-type receptor, but not those expressing the F-G mutant receptors. The SFK Lyn was coimmunoprecipitated with the wild-type GHR and with the F-G mutant receptors in the presence or absence of agonist; however, only in cells expressing the wild-type receptor was Lyn phosphorylated in response to GH and thus activated. Thus, Lyn constitutively associated with the transfected wild-type or mutant receptors, but only wild-type receptors activated the kinase in response to agonist. Activation of ERK did not require Jak signaling, but instead appeared to proceed through a Lyn to phospholipase C pathway, because pharmacological inhibition of phospholipase C or SFK blocked ERK activation by GH in cells transfected with the wild-type receptor. Modeling of receptors with mutations predicted to alter the transmembrane domain alignment and then analysis of the activation of STAT or ERK in cells transfected with these receptors suggested that transmembrane domain alignment may influence the efficiency of signaling through one pathway or the other. These studies provide insight into the mechanism by which GH-stimulated Lyn-ERK and Jak-STAT signaling may be decoupled, which may have clinical relevance in the development of therapeutics to alter one pathway specifically.

S. W. Rowlinson, H. Yoshizato, J. L. Barclay, A. J. Brooks, S. N. Behncken, L. M. Kerr, K. Millard, K. Palethorpe, K. Nielsen, J. Clyde-Smith, J. F. Hancock, M. J. Waters, An agonist-induced conformational change in the growth hormone receptor determines the choice of signalling pathway.
Nat. Cell Biol.
10
, 740-747 (2008).
[PubMed]
Modular Morphology
Authors: VanHook Annalisa M.
Published: June 2008

Developmental genetics data from invertebrate model systems have enabled the description of gene regulatory networks that control cell fate determination during development. It is less clear how these developmental regulatory networks modulate the processes through which specified cells generate morphological form, such as migration and shape change. The primitive chordate
Ciona intestinalis
has emerged as a model for studying complex morphogenetic events in a system that is similar to vertebrates but morphologically simpler and more experimentally manipulable. Christiaen
et al.
identified transcriptionally regulated targets of the forkhead box transcription factor FoxF and fibroblast growth factor (FGF) signaling, two components involved in heart development in
Ciona
. The genetic network involved in heart specification regulated the expression of a subset of genes whose products promote or coordinate cellular processes, such as filipodial extension and adhesion, required for migration of the heart precursor cells. In contrast, many genes encoding other proteins involved in the mechanics of migration appeared to be constitutively expressed. The encoded proteins regulated by the heart genetic network functioned at key points to regulate migration processes independently from one another and from other cellular inputs. This implies a mechanism whereby developmental regulatory networks act as modules that can be added, removed, and shuffled to generate many different combinations of cell behaviors and, therefore, many different morphologies.

L. Christiaen, B. Davidson, T. Kawashima, W. Powell, H. Nolla, K. Vranizan, M. Levine, The transcription/migration interface in heart precursors of
Ciona intestinalis
.
Science
320
, 1349-1352 (2008).
[Abstract]
[Full Text]
Physiological and Pathological Actions of Calpains in Glutamatergic Neurons
Authors: Liu Jing , Liu Ming Cheng , Wang Kevin K. W.
Published: June 2008

These animations show the activation and actions of neuronal calpains under physiological and pathophysiological conditions. They emphasize how physiological events involved in excitatory neurotransmission and synaptic plasticity—such as glutamate release, calcium influx, and activation of postsynaptic calpains—can become destructive under pathological conditions. These animations would be useful in a neurobiology or neuroscience course, where they could be used to illustrate proteolytic mechanisms underling activity-dependent synaptic plasticity, and how excessive activation of these signaling mechanisms can lead to excitotoxic neuronal death.
Receptor Rendezvous
Authors: Ray L. Bryan
Published: June 2008

B cell systems that protect organisms from viral infection walk a fine line because the molecules they detect--such as unmethylated DNA--can also be derived from host cells, and an overzealous defense results in autoimmune disease. Chaturvedi
et al
. describe new insight into how components of the adaptive and innate immune systems--B cell receptors (BCRs) and Toll-like receptor 9 (TLR9), respectively--act together to sense DNA-containing antigens. The answer was not obvious because the BCR is thought to act primarily on the cell surface, whereas TLR9 is normally present on endocytic vesicles. The authors used confocal fluorescence microscopy and immunoelectron microscopy to show that in mouse B cells in which the BCR was activated, TLR9 was relocated into autophagosomes. When cells were stimulated just through TLR9 with unmethylated DNA, phosphorylated (thus, activated) p38 mitogen-activated protein kinase (MAPK) was detected only in endosomes. However, if the BCR was activated with an antibody to immunoglobulin M (IgM) (alone or with DNA to activate TLR9), p38 was detected in large autophagosome-like structures. The recruitment of TLR9 to this compartment appeared to depend on physical internalization of the BCR because treatment of cells with an inhibitor of BCR internalization that still allowed early signaling events prevented relocalization of TLR9. Pharmacological inhibition of phospholipase D (PLD) revealed that activation of the lipase in response to the BCR was necessary for the recruitment of TLR9 to the autophagosomes. In commentary, Monroe and Keir discuss how the cooperation of BCR and TLR appears to be spatially restricted to vesicles where TLRs can interact with unmethylated DNA in the antigen cargo carried by the BCR. They emphasize that the paper opens new areas for further exploration, including the spatial organization of signaling by immune receptors and the continued signaling of internalized BCR after its movement away from the plasma membrane.

A. Chaturvedi, D. Dorward, S. K. Pierce, The B cell receptor governs the subcellular location of Toll-like receptor 9 leading to hyperresponses to DNA-containing antigens.
Immunity
28
, 799-809 (2008).
[PubMed]

J. G. Monroe, M. E. Keir, Bridging Toll-like- and B cell-receptor signaling: Meet me at the autophagosome.
Immunity
28
, 729-731 (2008).
[PubMed]
The SKNy on Old Worms
Authors: Foley John F.
Published: June 2008

A number of studies have established a correlation between increased resistance to cell stress and extended life span. The interplay between cell metabolism and signaling pathways involved in stress responses is an important area of research into the causes of aging. For example, a reduction in insulin-like signaling mediated by DAF-16, a homolog of the transcription factor FOXO, is associated with increased life span in
Caenorhabditis
elegans
. DAF-16-responsive genes include those involved in the response to oxidative stress. Tullet
et
al
. examined the role of insulin-like signaling in the regulation of another transcription factor, SKN-1, which activates genes involved in the detoxification response. A transgenic fusion protein of green fluorescent protein (GFP) and SKN-1 was detectable in the intestinal nuclei of
C
.
elegans
with mutant
daf-2
, the worm homolog of the insulin receptor, which was not the case in wild-type transgenic animals. Animals with mutant
daf-2
also had longer life spans than did control animals. RNAi-mediated knockdown of AKT and SGK kinases, which are activated following DAF-2 stimulation, resulted in increased nuclear localization of SKN-1:GFP compared with that in control animals. Western blotting analysis showed the direct phosphorylation of SKN-1 by these kinases, and quantitative polymerase chain reaction assays demonstrated DAF-2-dependent inhibition of the expression of SKN-1 target genes. Whereas mutation of
skn-1
decreased the extended life spans observed in
daf-2
mutant worms, worms in which
skn-1
was overexpressed had increased life spans compared with wild-type worms, which was independent of DAF-16. Together, these data suggest that SKN-1 makes a critical, DAF-16-independent contribution to stress responses and longevity that are associated with decreased insulin-like signaling. As Jasper discusses in commentary, establishing whether insulin signaling interacts similarly with the SKN-1 homolog Nrf2 in humans is an important next step in understanding the mechanisms of aging.

J. M. A. Tullet, M. Hertweck, J. H. An, J. Baker, J. Y. Hwang, S. Liu, R. P. Oliveira, R. Baumeister, T. K. Blackwell, Direct inhibition of the longevity-promoting factor SKN-1 by insulin-like signaling in
C
.
elegans
.
Cell
132
, 1025-1038 (2008).
[PubMed]

H. Jasper, SKNy worms and long life.
Cell
132
, 915-916 (2008).
[PubMed]
Hh and BMP Converge on Atoh1
Authors: VanHook Annalisa
Published: June 2008

Hedgehog (Hh) signaling plays an integral role in promoting proliferation in cerebellar granule cell precursors, which multiply in an external layer before differentiating and migrating deeper into the cerebellum. Overactivation of the Hh pathway is associated with medulloblastoma, a pediatric brain tumor that arises when granule cells continue to proliferate rather than differentiate. Genetic lesions commonly associated with human medulloblastoma include mutations in
patched 1
(
Ptch1
), which encodes a Hh receptor, and loss of heterozygosity of
hypermethylated in cancer 1
(
Hic1
), which encodes a transcriptional repressor. Briggs
et
al
. propose that Hic1 attenuates the Hh proliferation signal by repressing expression of Atonal homolog 1 (Atoh1), a proneural transcription factor. Compound heterozygous mice carrying one deletion allele each of
Ptch1
and
Hic1
had an

increased incidence of medulloblastoma as compared with animals carrying only one allele. Microarray analysis identified many potential targets of Hic1 regulation, one of which was
Atoh1
, a putative target of Hh signaling expressed in granule cell precursors and medulloblastomas. Chromatin immunoprecipitation experiments showed a direct interaction between Hic1 and the
Atoh1
enhancer, and experiments in cell culture demonstrated that Hic1-mediated repression of
Atoh1
expression overcomes its activation by Shh. Taken together, these data suggest a model in which Hh signaling induces proliferation of granule cells by activating
Atoh1
expression, and differentiation is initiated when Hic1 represses
Atoh1
expression. In the context of neural development, signaling through bone morphogenetic protein (BMP) pathways antagonizes Hh signaling to induce differentiation. In a related article, Zhao
et
al
. (see commentary by Grimmer and Weiss) report that BMP signaling stimulated proteolytic degradation of Atoh1 in medulloblastoma and granule cells. Redundant mechanisms for reducing the abundance of Atoh1 may ensure that granule cells are insensitive to proliferation signals during terminal differentiation and identify
Atoh1
as a potentially important target for medulloblastoma therapies.

K. J. Briggs, I. M. Corcoran-Schwartz, W. Zhang, T. Harcke, W. L. Devereux, S. B. Baylin, C. G. Eberhart, D. N. Watkins, Cooperation between the
Hic1
and
Ptch1
tumor suppressors in medulloblastoma.
Genes & Dev.
22
, 770-785 (2008).
[Abstract]
[Full Text]

H. Zhao, O. Ayrault, F. Zindy, J.-H. Kim, M. F. Roussel, Post-transcriptional down-regulation of Atoh1/Math1 by bone morphogenic proteins suppresses medulloblastoma development.
Genes & Dev.
22
, 722-727 (2008).
[Abstract]
[Full Text]

M. R. Grimmer, W. A. Weiss, BMPs oppose Math1 in cerebellar development and in medulloblastoma.
Genes & Dev.
22
, 693-699 (2008).
[Full Text]
BDNF + Protein Synthesis = Synaptic Plasticity
Authors: Stern Peter
Published: June 2008

Protein synthesis is required for consolidation of memory and has been used to characterize memory systems. However, it is not clear whether protein synthesis can regulate synaptic plasticity at the level of single synapses and how protein synthesis affects synaptic structures, such as dendritic spines. Tanaka
et al.
(see the Perspective by Korte) discovered that repetitive synaptic stimulation in synchrony with postsynaptic spike induces rapid and long-term spine enlargement, which occurs at the level of single spines and is associated with increases in glutamate sensitivity. This associative paradigm specifically produces long-term and protein synthesis-dependent changes. Brain-derived neurotrophic factor (BDNF) mimics the effects of postsynaptic spiking and occludes the effects of associative stimulation. Thus, protein synthesis and BDNF are required for the alterations in spine morphology associated with synaptic plasticity.

J.-i. Tanaka, Y. Horiike, M. Matsuzaki, T. Miyazaki, G. C. R. Ellis-Davies, H. Kasai, Protein synthesis and neurotrophin-dependent structural plasticity of single dendritic spines.
Science
319
, 1683-1687 (2008).
[Abstract]
[Full Text]

M. Korte, A protoplasmic kiss to remember.
Science
319
, 1627-1628 (2008).
[Summary]
[Full Text]