bluuebunny/crossref_metadata_2025 huggingface dataset:
Conception and Dynamic Modeling of an Assisted Passive Snake-Like Robot Using Gibbs-Appell Method
Authors: Vossoughi Golamreza , Pendar Hodjat , Heidari Zoya , Mohammadi Saman
Published: June 2008

In this paper we present a novel planar structure of a snake-like robot. This structure enables passive locomotion in snake-like robots through an auxiliary link in joint and a torsional spring. Dynamic equations are derived, using Gibbs-Appell method. Kinematic model of the robot include numerous non-holonomic constraints, which can be omitted at the beginning by choosing proper coordinates to describe the model in Gibbs-Appell framework. In such a case, dynamic equations will be significantly simplified, resulting in significant reduction of simulation time. Simulation results show that, by proper selecting initial conditions, joint angles operate in a limit cycle and robot can locomote steadily on a passive trajectory. It can be seen that the passive trajectory is approximately a Serpenoid curve.
Kinematic Mapping Based Evaluation of Assembly Modes for Planar Four-Bar Synthesis
Authors: Schro¨cker Hans-Peter , Husty Manfred L. , McCarthy J. Michael
Published: June 2008

This paper presents a new method to determine if two task positions used to design a four-bar linkage lie on separate circuits of a coupler curve, known as a “branch defect.” The approach uses the image space of a kinematic mapping to provide a geometric environment for both the synthesis and analysis of four-bar linkages. In contrast to current methods of solution rectification, this approach guides the modification of the specified task positions, which means it can be used for the complete five position synthesis problem.
An Energy Efficient Manipulator Design Approach: Application to a Leg in Swing Phase
Authors: Agrawal Abhishek , Agrawal Sunil K.
Published: June 2008

The importance of energy efficiency of a robotic manipulator is clearly evident when the manipulator has to use on-board power. With miniature machines, this issue is even more important since the size and the weight guides the performance of the design. In this paper, a design methodology is proposed which may allow a robot to follow desired trajectories approximately without actuator inputs. Actuator inputs can be used to further modify the trajectories. The design philosophy has the following key elements: (i) the inertia matrix of the device is suitably altered using mass distribution, (ii) compliant elements are introduced to take away the gravity terms, and (iii) additional springs are used to create certain periodic gait motion. If the generated motion is the desired motion, then no external inputs are needed. Otherwise, actuators can be added to get the desired motion. The energy efficiency with this design philosophy is compared using an example of a two degree-of-freedom leg executing a swing motion.
Synthesis of Compliant Mechanisms With Specified Equilibrium Positions
Authors: Su Hai-Jun , McCarthy J. Michael
Published: June 2008

This paper presents a synthesis procedure for a compliant four-bar linkage with three specified equilibrium configurations. The finite position synthesis equations are combined with equilibrium constraints at the flexure pivots to form design equations. These equations are simplified by modeling the joint angle variables in the equilibrium equations using sine and cosine functions. Solutions to these design equations were computed using a polynomial homotopy solver. In order to provide a design specification, we first compute the six equilibrium configurations of a known compliant four-bar mechanism. We use these results as design requirements to synthesize a compliant four-bar. The solver obtained eight real solutions which we refined using a Newton-Raphson technique. A numerical example is provided to verify the design methodology.
Dynamics and Control of a Helicopter Carrying a Payload Using a Cable-Suspended Robot
Authors: Oh So-Ryeok , Ryu Ji-Chul , Agrawal Sunil K.
Published: June 2008

This paper presents a study of the dynamics and control of a helicopter carrying a payload through a cable-suspended robot. The helicopter can perform gross motion, while the cable suspended robot underneath the helicopter can modulate a platform in position and orientation. Due to the under-actuated nature of the helicopter, the operation of this dual system consisting of the helicopter and the cable robot is challenging. We propose here a two time scale control method, which makes it possible to control the helicopter and the cable robot independently. In addition, this method provides an effective estimation on the bound of the motion of the helicopter. Therefore, even in the case where the helicopter motion is unknown, the cable robot can be stabilized by implementing a robust controller. Simulation results of the dual system show that the proposed control approach is effective for such a helicopter-robot system.
Analysis for Stiffness of Large-Deformation Flexure Hinge and Its Application
Authors: Jia Ming , Yu Jingjun , Bi Shusheng , Xu Yicun
Published: June 2008

The paper discusses the stiffness of flexure hinge made by rubber material. A revolute compliant joint made by rubber is proposed which offer improvements over existing flexures made by metal in the qualities of large range of motion, long lift, and reduced weight. Based on the theory of nonlinear deformation and the characters of strain-energy functions of Mooney-Rivlin model, the stiffness of rubber flexure hinge is obtained by piece-wise linearization of the stress-strain curve. Some geometric parameters such as t/R ratios affecting the stiffness of rubber hinge are calculated. Thereby, the problem of the relationship between moment and large angle deformation is resolved. The result from the FEA performed on the various flexures to find the angle displacement shows ideal consistency. Finally, the application of rubber flexure hinge using in the compliant thorax of micro air vehicle with flapping wings is given.
A Collision-Free Path Planning Method for an Articulated Mobile Robot in a Free Environment
Authors: Quintero-Alvarez Patricia , Ramirez Gabriel , Zeghloul Sai¨d
Published: June 2008

In our previous work, we have treated the collision-free path-planning problem for a nonholonomic mobile robot in a cluttered environment. The method we have used is based on a representation of the obstacles in the robot’s velocity space, called Feasible Velocities Polygon (FVP). Every obstacle in the robot’s influence zone is represented by a linear constraint over the robot’s velocities such that it could not be collision between the robot and the obstacle. These constraints define a convex subset in the velocity space, the FVP. Every velocity vector of the FVP ensures a safe motion for the given obstacle configuration. The path-planning problem is solved by an optimization approach between the FVP and a reference velocity to reach the goal. In this paper, we have extended our work to an articulated mobile robot. This robot is composed of a differential mobile robot as tractor and a trailer, linked by off-center joints. We have modified the reference velocity in order to consider the constraints imposed by the trailer over the robot’s velocities. The control law is a nonlinear control law, which is asymptotically stable to the goal. We use the virtual robot concept, to solve the stability problem when the robot and its trailer move backwards. An articulated mobile robot is a strongly constrained system. Even in a free environment, under some circumstances, the robot may get blocked by its trailer in its progression towards the goal. To solve these situations, we have developed a heuristic algorithm. This algorithm is based in human experience: when a blocking situation is detected, a forward-backward maneuver is made, in order to increase the distance between the tows until a maximal value. After this maneuver, the robot takes the path to the original goal. Some numerical results show that our method leads the robot and the trailer to the final position in a stable way.
On the Computation of Spatial Angular Orientation From Angular Position Sensor Data
Authors: Jin Zhe , Ge Q. J. , Rastegar J.
Published: June 2008

Recently, it has been discovered that RF waveguides can be used as onboard wireless sensors for the direct measurements of angular positions of a moving object and that a combination of RF waveguides may be used to measure full spatial angular orientation of the object. This paper deals with the computational issues that arise in resolving the spatial orientation from the measurement data of a set of RF waveguide sensors. The paper presents an algorithm that combines a heuristic search method with the least-squares approach for computing the full orientation of an object. The goal is to develop a general and efficient method for computing spatial orientation from the sensor data of a class of angular position sensors that have smooth sensor profiles.
Dynamic Modeling and Controller Design of a Planar Parallel 3-RRR Compliant Micromanipulator
Authors: Yu Jingjun , Zhao Dong , Bi Shusheng , Zong Guanghua
Published: June 2008

This paper presents control system formulations of a planar parallel 3-RRR parallel compliant micromanipulator. The design methodology is illustrated with one of such designs constructed at Beijing University of Aeronautics and Astronautics, China. Compliant joints and motion-amplifying mechanism allow rapid and accurate response as well as larger workspace. The three PZT actuators attached on the linkages produce the bending moments. The sensor is a CCD camera feeding back the tool point position. The plant is the equations of motion which can be formulated using the Lagrangian method and dynamics software. The system dynamic model was developed with ADAMS which can export the nonlinear and linearized control plant to Matlab Simulink. Overall dynamic behavior of the manipulator will be illustrated through simulations with Matlab Simulink Toolbox. After comparison of two different control plans, the controller obtained from LQR method was chosen to achieve the control objectives. Closed-loop performance in response to a step reference was plotted. Bode plots of the sensitivity and complementary sensitivity showed their relation to the step response. Gain and phase margins was computed.
Modeling and Experimental Design for the On-Orbit Inertial Parameter Identification of Free-Flying Space Robots
Authors: Lampariello Roberto , Hirzinger Gerhard
Published: June 2008

A method is proposed for the identification of the inertial parameters of a free-flying robot directly in orbit, using accelerometers. This can serve to improve the path planning and tracking capabilities of the robot, as well as its efficiency in energy consumption. The method is applied to the identification of the base body and of the load on the end-effector, giving emphasis to the experimental design. The problem of the identification of the full system is also addressed in its theoretical aspects. The experience from the Getex Dynamic Motion experiments performed on the ETS-VII satellite have allowed to determine a most suitable model for the identification.
Curve Representation Using Principal Component Analysis for Shape Optimization of Path Generating Mechanisms
Authors: Khaled Nassim , Smaili Ahmad
Published: June 2008

The focus of this paper is on the synthesis of path generation mechanisms based on shape optimization. The principle component analysis (PCA) technique used in image processing is employed to represent the desired coupler curve of the mechanism and simulated annealing is used as the optimization tool. PCA representation is invariant under rotation, translation, scaling, and starting point. Once a shape-optimized mechanism is found, it is translated, rotated, and scaled to its final form. An illustrative example is introduced to demonstrate the proposed method.
Inverse Dynamic Analysis and Linearisation of a High Speed Parallel Mechanism
Authors: Sahinkaya M. Necip , Li Yanzhi
Published: June 2008

Inverse dynamic analysis of a three degree of freedom parallel mechanism driven by three electrical motors is carried out to study the effect of motion speed on the system dynamics and control input requirements. Availability of inverse dynamics models offer many advantages, but controllers based on real-time inverse dynamic simulations are not practical for many applications due to computational limitations. An off-line linearisation of system and error dynamics based on the inverse dynamic analysis is developed. It is shown that accurate linear models can be obtained even at high motion speeds eliminating the need to use computationally intensive inverse dynamics models. A point-to-point motion path for the mechanism platform is formulated by using a third order exponential function. It is shown that the linearised model parameters vary significantly at high motion speeds, hence it is necessary to use adaptive controllers for high performance.
A New Approach to Sonar Based Indoor Mapping Localization
Authors: Meghdari A. , Kobravi K. , Safyallah H. , Moeeni M. , Khatami Y. , Khasteh H.
Published: June 2008

Vehicle localization and environment mapping are the most essential parts of the robot navigation in unknown environments. Since the problem of localization in indoor environments is directly related to the problem of online map generation, in this paper a new and efficient algorithm for simultaneous localization and map generation is proposed and novel results for real environments are achieved. This new algorithm interprets and validates the raw sonar measurements in first step, and applies them to the environment map in the next step. There are various adjustable parameters which make the algorithm flexible for different sonar types. This algorithm is efficient and is robust to sonar failure; if sonar does not work properly data can be discarded. These abilities make the algorithm efficient for sonar navigation in flat environments even by poor sonar and odometers perception data. This algorithm has the ability of matching with various types of sonar and even to be used with laser scanner data, whenever each laser scanner data is treated as multiple sonar detections with narrow beam detection patterns.
An Investigation Into the Use of Springs and Wing Motions to Minimize the Power Expended by a Mechanical Pigeon for Steady Flight
Authors: Issac K. Kurien , Agrawal Sunil K.
Published: June 2008

In this paper, we investigate the effect of using springs and wing motions to minimize the power required by a mechanical bird to fly. Inertia forces as well as aerodynamic forces on the wing are included. The design takes into account different flight speeds in the range from 0 to 20 m/s. Two ways in which springs can be attached, are considered. The frequency of wing beat is kept fixed and both flapping and feathering are assumed to be simple harmonic. Constraints are imposed on the maximum power expended by the two actuators of a wing. The results show that introduction of springs increases the power required at lower speeds, marginally reducing the power at higher speeds. In the manner in which they are used here, springs do not appear to be useful to reduce power. However, the optimal solutions obtained without springs indicate that it is possible to develop pigeon like mechanical birds which can hover and fly steadily up to 20 m/s.
Rough Terrain Rovers Dynamics Analysis and Optimization
Authors: Tavakoli Nia Hadi , Alemohammad Seyed Hamidreza , Bagheri Saeed , Hajiaghaee Khiabani Reza , Meghdari Ali
Published: June 2008

In this paper a new approach to dynamics optimization of rough terrain rovers is introduced. Since rover wheels traction has a significant role in rover mobility, optimization is based on the minimization of traction at rover wheel-ground interfaces. The method of optimization chosen is Genetic Algorithm (GA) which is a directed random search technique along with the usual optimization based on directional derivatives. GA is a suitable and efficient method of optimization for nonlinear problems. The procedure is applied on a specific rough terrain rover called CEDRA-I Shrimp Rover. Dynamical equations are obtained using Kane’s method. Finally, the results are verified by modeling of the rover in ADAMS® software package.
Design of Parallel Kinematic XY Flexure Mechanisms
Authors: Awtar Shorya , Slocum Alexander H.
Published: June 2008

This paper presents parallel kinematic XY mechanism designs that are based on a systematic constraint pattern. The constraint pattern, realized by means of double parallelogram flexure modules, is such that it allows large ranges of motion without over-constraining the mechanism or generating significant error motions. Nonlinear force-displacement characteristics of the double parallelogram flexure are used in analytically predicting the performance measures of the proposed XY mechanisms. Comparisons between closed-form linear and nonlinear analyses are presented to highlight the inadequacy of the former. Fundamental design tradeoffs in flexure mechanism performance are discussed qualitatively and quantitatively. It is shown that geometric symmetry in the constraint arrangement relaxes some of the design tradeoffs, resulting in improved performance. The nonlinear analytical predictions are validated by means of Finite Element Analysis and experimental measurements.
Design of an Adjustable Compensation Mechanism for Use in a Passive Arm Support
Authors: Lucieer Pieter , Herder Just L.
Published: June 2008

People with (neuro-)muscular diseases have problems lifting their arms against gravity because of degeneration of their muscles. Many of them are in need of a device that supports the weight of their arms, so as to regain some independence. Existing solutions do not meet all of the requirements. This paper presents the design of a new type of spring-compensation mechanism which is adjustable to varying load. The most important part of this design is a wrapping cam with variable transmission to compensate for errors, which rolls on a support plane to minimize friction.
Grasping Mechanisms With Self-Centering and Force-Balancing Characteristics
Authors: Brooks Scott H. , Magleby Spencer P. , Howell Larry L.
Published: June 2008

This paper presents grasping mechanism configurations that are self-centering with balanced reaction forces, and develops the design principles, models, and analysis methods of achieving these characteristics in compliant mechanisms. The configurations emulate the self-centering and balanced actuation force characteristics exhibited by hydraulic disc-brake systems. Purely mechanical grasping systems, in which both the mechanism and the object being grasped are rigidly attached to ground, require 2 degrees of freedom in the grasping mechanism. It is shown that compliant configurations can exhibit the balanced-force behavior as well as rigid-link mechanisms.
Optimal Design of the Coring Bit Cutting Edge in Percussive/Vibratory Drilling
Authors: Liu Yinghui , Mavroidis Constantinos , Bar-Cohen Yoseph , Chang Zensheu
Published: June 2008

The objective of this study is to develop an analytical method for the optimization of the design of the coring bits of vibratory drills with cutting teeth that percussively penetrate into brittle material. This optimization is intended to improve the drill rate of the Ultrasonic Driller and Corer (USDC) that was developed by scientists from JPL and engineers from Cybersonics, Inc. The USDC was developed for possible in-situ sample and other extraterrestrial applications in future NASA missions. A theoretical investigation was undertaken to study the rock-bit penetration characteristics and derive the analytical formulation of the specific energy for a coring bit with wedge-shape cutting teeth, based on two analytical models from rock fracture mechanics. It was found that there exists an optimal spacing/depth ratio for the cutting teeth, and the optimal number of cutting teeth on the bottom annulus of the coring bit can be designed to achieve a minimum total coring bit specific energy. Experimental tests were performed to corroborate the analytical results. It was shown that the laboratory drilling tests follow the trend predicted by the theoretical analysis. The methodology developed here can be used for the optimization of any coring/drill bit with a wedge-shape cutting teeth array in percussive/vibratory drills into brittle material.
Compliant Bistable Dielectric Elastomer Actuators for Binary Mechatronic Systems
Authors: Plante Jean-Se´bastien , Santer Matthew , Dubowsky Steven , Pellegrino Sergio
Published: June 2008

In this paper, a new all-polymer actuation approach for binary mechatronic systems is demonstrated. The technology consists of using Dielectric Elastomer actuators in a binary fashion by coupling them with a properly designed compliant structure. Here, a bistable actuator based around the “flip-flop” concept is implemented in which two antagonistic actuators switch a compliant truss between two stable positions. This prototype shows promising performance with output forces ranging from 1 to 3.5 N and displacements of 30% of the actuator dimension.
Antisense Boosts EPO Receptors
Authors: Gough Nancy R.
Published: June 2008

Erythropoetin (EPO) signaling contributes to organ development, as well as to differentiation of erythrocytes. Previously, the abundance of EPO receptor was reported to increase following surgical removal of one lung (pneumonectomy) in postnatal dogs. Zhang
et al
. now report that the abundance of EPO-R appears to be regulated by both transcriptional mechanisms from the sense EPO-R transcript (
sEPO-R
), as well as by either the antisense transcript (
asEPO-R
) itself or proteins encoded within
asEPO-R
. Both sense and antisense transcripts of EPO-R were detected by Northern blot in normal canine lung, as well as other canine tissues and several human tissues. The abundance of
sEPO-R
increased modestly after pneumonectomy (23% above control), whereas the abundance of
asEPO-R
increased substantially (119% above control) as did the abundance of EPO-R (169%). Cloning and characterization of canine lung asEPO-R revealed two putative open reading frames (ORF1 and ORF2). Both EPO-R transcripts, as well as the EPO-R protein, were detected in the same bronchiolar epithelial cells by in situ hybridization and immunofluorescence, whereas antisense transcripts for surfactant-associated protein-A were not detected. Coexpression of
sEPO-R
and
asEPO-R
increased the abundance of the EPO-R produced by transfected human embryonic kidney (HEK) 293 cells compared with those transfected with only
sEPO-R
; the effect of
asEPO-R
increased with increasing dose. When the start codon of ORF1 was mutated, EPO-R abundance was still elevated in the cotransfected cells, which suggests that the putative encoded protein is not important for the enhancing effect of
asEPO-R
. In contrast, the region near ORF2 appeared to play a more complex role in EPO-R regulation. When a long construct that included ORF2 and 300 base pairs of 5′ of the ORF2 start site were cotransfected with
sEPO-R
, then EPO-R production was increased compared with cells only transfected with
sEPO-R
. However, when the 300 extra base pairs were not included, then EPO-R abundance was not enhanced. Further complicating the effect of the ORF2 region, when the start codon of the ORF2 was mutated in the construct lacking the extra 300 base pairs, enhancement of EPO-R abundance was restored. The authors propose that the
asEPO-R
has several regulatory elements: The RNA itself has stimulatory effects, and the protein encoded by ORF2 is a negative regulator of EPO-R synthesis. Thus, when the ORF2 start codon is eliminated, the positive effects of the antisense RNA dominate and EPO-R production is enhanced.

Q. Zhang, J. Zhang, O. W. Moe, C. C. W. Hsia, Synergistic upregulation of erythropoietin receptor (EPO-R) expression by sense and antisense EPO-R transcripts in the canine lung.
Proc. Natl. Acad. Sci. U.S.A.
105
, 7612-7617 (2008).
[Abstract]
[Full Text]
Allies from Within
Authors: Adler Elizabeth M.
Published: June 2008

In general, people coexist peacefully with the innumerable microorganisms that colonize the gut. Some gut microbes, however, are potential pathogens; moreover, inappropriate immune responses directed against gastrointestinal flora may be involved in the pathogenesis of inflammatory bowel diseases (IBDs) such as ulcerative colitis. Mazmanian
et al
. used a mouse model of IBD in which naïve effector T cells were introduced into immunodeficient mice, along with the bacterium
Helicobacter hepaticus
, to investigate the hypothesis that IBDs may involve an imbalance between potentially harmful and potentially beneficial commensal bacteria. Co-colonization with the bacterium
Bacteroides fragilis
protected these mice from colitis, whereas
B. fragilis
lacking the surface polysaccharide PSA (
B. fragilis
ΔPSA) were not protective. Colon cultures revealed increased abundance of pro-inflammatory cytokines like tumor necrosis factor-α (TNF-α) in mice with experimental colitis, an increase blocked by colonization with
B. fragilis
but not
B. fragilis
ΔPSA. Oral PSA protected against this model of colitis as well--and also against a chemically induced model of colitis. PSA increased expression of the transcript encoding the anti-inflammatory cytokine interleukin-10 (IL-10) in mouse colon and also in cocultures of bone marrow-derived dendritic cells and naïve CD4
+
T cells (BMDC-T cell cocultures). PSA decreased production of TNF-α in BMDC-T cell cocultures infected with
H. hepaticus
, an effect blocked by neutralizing antibodies directed against the IL-10 receptor. Furthermore, such antibodies inhibited the protective effect of PSA in the T cell-transfer model of colitis, and PSA failed to protect against colitis when the naïve effector T cells were derived from mice lacking IL-10. The authors thus conclude that
B. fragilis
PSA can modulate the inflammatory response associated with
H. hepaticus
and thereby protect against IBD. Kullberg discusses the results and provides thoughtful commentary.

S. K. Mazmanian, J. L. Round, D. L. Kasper, A microbial symbiosis factor prevents intestinal inflammatory disease.
Nature
453
, 620-625 (2008).
[PubMed]

M. C. Kullberg, Immunology: Soothing intestinal sugars.
Nature
453
, 602-604 (2008).
[PubMed]
Right Time, Right Place
Authors: Simpson Stephen J.
Published: June 2008

Regulatory T cells are highly immunosuppressive lymphocytes that help the body avoid autoimmunity and overzealous immune reactions. However, their existence also presents a dilemma for the immune system, because they might inadvertently shut down useful pathogen-specific immune responses. Lund
et al

.

(see the Perspective by Kassiotis and O'Garra) present evidence that suggests that regulatory T cells can in fact optimize immune responses during the early stages of infection. Using a mouse model of herpes simplex virus infection, depleting regulatory T cells delayed the arrival of the relevant immune cells at the site of infection. At the same time, inflammatory chemokines became elevated in the lymph nodes. Thus, under normal circumstances, regulatory T cells may minimize the expression of these soluble factors in the lymph nodes so as to redirect immune cells for a timely arrival at the site of infection.

J. M. Lund, L. Hsing, T. T. Pham, A. Y. Rudensky, Coordination of early protective immunity to viral infection by regulatory T cells.
Science
320
, 1220-1224 (2008).
[Abstract]
[Full Text]

G. Kassiotis, A. O'Garra, Immunity benefits from a little suppression
.
Science
320
, 1168-1169 (2008).
[Summary]
[Full Text]
More Than One Way to Skin a Kinase
Authors: Foley John F.
Published: June 2008

The abundance and activity of the membrane-associated nonreceptor tyrosine kinase c-Src are higher in malignant than in nonmalignant cells. Phosphorylation of c-Src by the cytosolic C-terminal Src kinase (Csk) inhibits its activity, thus preventing cellular transformation. In some cancers, however, even an increased abundance of Csk is not sufficient to prevent c-Src-mediated tumorigenesis. Csk is recruited to the plasma membrane by the transmembrane, lipid raft-associated adaptor protein Csk-binding protein (Cbp), which is itself a target of c-Src. Oneyama
et al
. examined the function of Cbp in c-Src-transformed
Csk
–/–
mouse embryo fibroblasts (MEFs). Retroviral-mediated overexpression of c-Src caused the transformation of
Csk
–/–
MEFs, which was accompanied by a decrease in the abundance of Cbp mRNA and protein. Overexpression of Cbp dose-dependently inhibited c-Src-mediated cellular transformation without inhibiting the activation of c-Src, as measured by Western blotting. Whereas c-Src was distributed in raft and nonraft fractions of transformed cells, overexpression of Cbp resulted in the complete recruitment of c-Src to rafts. Coimmunoprecipitation assays showed a direct association between c-Src and Cbp. Analysis of mutant Cbp proteins showed that its Src homology 2 (SH2) domain-binding sites, but not its Csk-binding site, were needed for Cbp to bind to c-Src and inhibit cellular transformation. Western blotting analysis revealed an inverse correlation between Cbp abundance and the activity of c-Src in various human cancer cell lines. Finally, tumorigenesis in nude mice that received human colon cancer cells expressing Cbp was suppressed compared with that in mice that received the parental cells. In summary, this study suggests that Cbp inhibits the tumorigenic potential of c-Src independently of Csk and that Cbp may serve as a potential anticancer therapeutic target.

C. Oneyama, T. Hikita, K. Enya, M.-W. Dobenecker, K. Saito, S. Nada, A. Tarakhovsky, M. Okada, The lipid raft-anchored adaptor protein Cbp controls the oncogenic potential of c-Src.
Mol
.
Cell
30
, 426-436 (2008).
[PubMed]
Steering in Quadruplet: The Complex Signaling Pathways Directing Chemotaxis
Authors: Rericha Erin C. , Parent Carole A.
Published: June 2008

Studies in the social amoebaDictyostelium discoideumreveal that signaling cascades coordinating chemotactic directional sensing and migration are complex, with redundant pathways emerging as cells differentiate. Lack of accumulation of the leading-edge marker phosphatidylinositol-3,4,5-trisphosphate can be compensated by a pathway containing phospholipase A2(PLA2) in early developed cells and guanylyl cyclase (GC) in later developed, polarized cells. Because numerous signaling networks operational duringDictyosteliumchemotaxis are conserved in mammalian cells, PLA2and GC pathways may also be effective in higher eukaryotes, providing avenues for future research.
Pharmacological PKA Inhibition: All May Not Be What It Seems
Authors: Murray Andrew J.
Published: June 2008

Signaling through the cyclic adenosine monophosphate–dependent protein kinase [protein kinase A (PKA)] is an important and widely studied area of signal transduction research. This signaling pathway is commonly investigated through the use of the pharmacological PKA inhibitors H89 and KT 5720. Both of these compounds are thought to block PKA actions through competitive inhibition of the adenosine triphosphate site on the PKA catalytic subunit. Recently, a number of studies have identified actions of H89 and KT 5720 that are independent of their effects on PKA. These nonspecific effects are widespread; they include actions on other protein kinases and signaling molecules and also on basic cellular functions, such as transcription. Here, I summarize the nonspecific effects of these two compounds and compare their actions with those of other PKA inhibitors.
A SUMOylated Energy Switch
Authors: Adler Elizabeth M.
Published: June 2008

Energy homeostasis--and maintenance of body weight--depends on balancing energy intake and expenditure. Indeed, dysregulation of skeletal muscle energy metabolism may play a role in obesity and metabolic syndrome. Oishi
et al
. found that mice heterozygous for Krüppel-like transcription factor 5 (KLF5) fed a high-fat diet gained less weight--despite eating more food--than did wild-type littermates.

Klf5
+/–

mice were also resistant to high fat-induced glucose intolerance and had lower serum cholesterol. Their O
2
consumption and body temperature were higher and, in skeletal muscle, the expression of genes encoding proteins involved in lipid oxidation and energy uncoupling was increased. KLF5 inhibited C/EBP-β-dependent transactivation of the promoters of carnitine-palmitoyl transferase-1b (CPT1b, a rate-limiting enzyme in fatty enzyme oxidation) and uncoupling proteins 2 and 3 (UCP2 and UCP3) in C2C12 myotubes. KLF5 was subject to posttranslational modification by small ubiquitin-related modifier (SUMO) proteins, and a SUMOylation-deficient KLF5 mutant failed to inhibit C/EBP-β-dependent transactivation of the
Cpt1b
,
Ucp2
, and
Ucp3
promoters; moreover, SUMOylation enhanced KLF5 interaction with the transcriptional corepressors NCoR and SMRT. The phenotype of the

Klf5
+/–

mice resembled that of mice treated with agonists of the metabolic regulator peroxisome proliferator-activated receptor-δ (PPAR-δ), and KLF5 coimmunoprecipitated with PPAR-δ. Chromatin immunoprecipitation analysis indicated that KLF5, PPAR-δ, NCoR, and SMRT all associated with the
Cpt1b
,
Ucp2
, and
Ucp3
promoters. The PPAR-δ agonist GW501516 stimulated recruitment of the SUMO protease SENP1 to these promoters, followed by local deSUMOylation, loss of NCoR and SMRT, and recruitment of the coactivator CBP. Experiments in which various combinations of KLF5, the SUMOylation-deficient KLF5 mutant, PPAR-δ, CBP, and SENP1 were coexpressed with a
Ucp3
reporter indicated that GW501516 stimulated the
Ucp3
promoter, a response that required SUMOylatable KLF5. Thus, ligand stimulation of PPAR-δ seems to trigger KLF5 deSUMOylation, thereby flipping a "switch" from a complex that inhibits the transcription of genes involved in energy expenditure to one that stimulates it. Jain provides thoughtful commentary.

Y. Oishi, I. Manabe, K. Tobe, M. Ohsugi, T. Kubota, K. Fujiu, K. Maemura, N. Kubota, T. Kadowaki, R. Nagai, SUMOylation of Krüppel-like transcription factor 5 acts as a molecular switch in transcriptional programs of lipid metabolism involving PPAR-δ.
Nat. Med
.
14
, 656-666 (2008).
[PubMed]

M. K. Jain, Multiple layers of metabolism.
Nat. Med
.
14
, 603-604 (2008).
[PubMed]
Sumoylating TGF-β Receptors
Authors: Gough Nancy R.
Published: June 2008

Signaling by the transforming growth factor-β (TGF-β) superfamily is important in development and in adult tissues, and alterations in this pathway may contribute to some types of cancers and metastasis. Kang
et al
. provide evidence from in vitro experiments and from transfected cells that the type I subunit of the TGF-β receptor (TβRI) is modified by addition of the small molecule SUMO (see commentary by Miyazono
et al
.). Mutation analysis suggested that Lys
389
was the target for sumoylation. Phosphorylation of the TβRI, which is stimulated in response to ligand binding to the dimeric TβRI and TβRII complex, was necessary for SUMO modification because kinase-inactivated forms of a TβRI and TβRII chimera were not sumoylated in vitro or in transfected cells, and sumoylation was not detected in vitro if the reaction was carried out in the presence of a phosphatase. SUMO modification was detected most readily with an activated mutant of TβRI (caTβRI); moreover, in cells coexpressing caTβRI, SUMO-conjugating enzymes, tagged SUMO, and a mutant Smad3, the interaction between the receptor and Smad3 was enhanced (based on coimmunoprecipitation) compared to that in cells only expressing caTβRI and the mutant Smad3. Expression in

Tgfbr1
–

/–
cells of a Lys
389
mutant TβRI that was not sumoylated resulted in less activation of Smads and less activation of TGF-β target genes (either endogenous targets or reporter genes) than did expression of the wild-type receptor, suggesting that sumoylation enhances TGF-β signaling. Ras-transformed mouse embryo fibroblasts from

Tgfbr1
–

/–
animals showed decreased invasiveness in a cell migration assay and formed smaller and fewer metastatic tumor nodules when injected into mice when expressing the Lys
389
mutant TβRI than when expressing the wild-type receptor. Introduction of a mutation (Ser
387
Tyr) found in some human cancers resulted in a sumoylation-defective form of the receptor; however, in the tumor-metastasis model with Ras-transformed cells expressing this mutant form of the receptor, these cells formed fewer and smaller metastatic nodules than did cells expressing wild-type receptors. Thus, mechanisms by which TGF-β signaling contributes to cancer are complex.

J. S. Kang, E. F. Saunier, R. J. Akhurst, R. Derynck, The type I TGF-β receptor is covalently modified and regulated by sumoylation.
Nat. Cell Biol.
10
, 654-664 (2008).
[PubMed]

K. Miyazono, Y. Kamiya, K. Miyazawa, SUMO amplifies TGF-β signalling.
Nat. Cell Biol.
10
, 635-637 (2008).
[PubMed]
Pathway Evolution
Authors: VanHook Annalisa M.
Published: June 2008

Pathways that control complex biological phenomena must be robust enough to function reliably yet retain flexibility if they are to evolve. The ability of bacteria to form spores or move toward food clearly confers a fitness advantage, but it is unclear how the complex networks that control such capabilities evolve. Singh
et al.
performed a large-scale phylogenetic analysis of three microbial stress response gene networks--those involved in chemotaxis, sporulation, and competence to take up DNA--and found, across various species, that some networks are composed of distinct groups of genes that share similarities in function, phenotype, and sequence evolution rate, groups that they termed "modules." Components of the chemotaxis network clustered into five modules, which evolved independently from one another and often occurred in different combinations that did not correlate with species relatedness. The sporulation network comprised three modules that were very tightly linked to one another, so they were far more likely to be found in an all-or-none manner. In both the chemotaxis and sporulation networks, the combination of modules present in a species did not correlate with its phylogeny but did correlate with its phenotype. The authors also identified several previously undescribed genes in chemotaxis and sporulation modules and suggested that their inclusion in a particular module might be used to predict the function of these genes. Components of the competence network, however, did not form modules. For example, a gene that is present in two competent species may be required for conferring competence in one species but have no function in competence in the other. The authors hypothesize that differences in how these three networks have evolved are a consequence of how the network components are reused in other processes. Organization into modules may simplify repurposing of the components but also limits the points at which new inputs and outputs can feed into the system.

A. H. Singh, D. M. Wolf, P. Wang, A. P. Arkin, Modularity of stress response evolution.
Proc. Natl. Acad. Sci.
U
.
S
.
A
.
105
, 7500-7505 (2008).
[Abstract]
[Full Text]
Foresight Among
E. coli
Authors: Ash Caroline
Published: June 2008

Many natural signals progress in a readily predictable sequence. For instance, after being eaten, a bacterium will perceive a sudden temperature rise followed by a drop in oxygen levels. Tagkopoulos
et al
. (see the Perspective by Baliga) investigated
Escherichia coli
’s

predictive powers

in a combination of in silico

and chemostat experiments. On exposure to a large temperature change,
E. coli
can shift from aerobiosis to anaerobiosis even in the presence of 18% oxygen. This might seem maladaptive, but it means that the organism will have a competitive edge as soon as it encounters the zoo of microorganisms in the oxygen-starved lower gut. Furthermore, the authors were able to "train" the organisms to adapt metabolically to "unnatural" sequences of events, e.g., elevated temperature followed by high oxygen.

I. Tagkopoulos, Y.-C. Liu, S. Tavazoie, Predictive behavior within microbial genetic networks.
Science
320
, 1313-1317 (2008).
[Abstract]
[Full Text]

N. S. Baliga, The scale of prediction.
Science
320
, 1297-1298 (2008).
[Summary]
[Full Text]
Dual Functions of the KNOTTED1 Homeodomain: Sequence-Specific DNA Binding and Regulation of Cell-to-Cell Transport
Authors: Bolduc Nathalie , Hake Sarah , Jackson David
Published: June 2008

Homeodomain proteins are well-characterized developmental regulators that control expression of target genes through sequence-specific DNA binding. The homeodomain forms a trihelical structure, with the third helix conferring specific interactions with the DNA major groove. A specific class of plant homeodomain proteins, called KNOX [KNOTTED1 (KN1)-like homeobox], also has the ability to signal between cells by directly trafficking through intercellular channels called plasmodesmata. Trafficking is mediated by a signal that is also contained within the homeodomain. Movement protein binding protein 2C was identified as a protein that interacts with the KN1 homeodomain and regulates the cell-to-cell trafficking of KN1 by sequestering the protein on microtubules. Therefore, KN1 has multiple potential cellular addresses, each of which is conferred by its homeodomain.
Macrophages Go Back to School
Authors: Foley John F.
Published: June 2008

Macrophages, phagocytic cells whose functions are often determined by their environment, are generally divided into two main classes: Classically activated (M1) macrophages are proinflammatory and kill pathogens, and alternatively activated (M2) macrophages produce anti-inflammatory factors. Two groups investigated the involvement of the transcription factor NF-κB in determining whether a macrophage develops an M1 or M2 phenotype. Hagemann
et al
. inhibited signaling of the inhibitor of κB (IκB) kinase β (IKKβ) in mouse bone marrow-derived macrophages (BMDMs) or tumor-associated macrophages (TAMs) through gene deletion or the expression of a dominant-negative IKKβ mutant; inhibition of IKKβ activity resulted in inhibition of NF-κB signaling. Whereas coculture of wild-type BMDMs with ovarian cancer cells resulted in the expected generation of M2 macrophages, as assessed by cytokine production, coculture of ovarian cancer cells with IKKβ-deficient BMDMs or TAMs generated M1 cells. Western blotting analyses showed that the activity of the transcription factor signal transducer and activator of transcription 1 (STAT1) was higher in IKKβ-deficient macrophages than in wild-type macrophages. Transfer of IKKβ-deficient TAMs to mice that contained preestablished tumors resulted in a decrease in tumor burden compared with that in mice that received wild-type cells. This effect was associated with a change in the cytokine profile of the tumors, from anti-inflammatory in mice that received wild-type macrophages to proinflammatory in mice that received IKKβ-deficient macrophages. Fong
et
al
. investigated IKKβ function in the context of a mouse model of lung infection by
Streptococcus pneumoniae
. Whereas specific deletion of
Ikkβ
in airway epithelial cells resulted in both reduced inflammation and clearance of bacteria compared with that in wild-type mice, deletion of
Ikkβ
in macrophages resulted in enhanced bacterial clearance and prolonged inflammation. Consistent with the other study, the effects seen in mice with macrophage-specific
Ikkβ
deficiency were associated with the increased production of proinflammatory cytokines and the activation of STAT1. As Timmer and Nizet discuss, although therapeutically inhibiting IKKβ activity could be of benefit in the fight against tumors, doing so in the context of bacterial infection would be potentially more complicated.

T. Hagemann, T. Lawrence, I. McNeish, K. A. Charles, H. Kulbe, R. G. Thompson, S. C. Robinson, F. R. Balkwill, "Re-educating" tumor-associated macrophages by targeting NF-κB.
J
.
Exp
.
Med
.
205
, 1261-1268 (2008).
[Abstract]
[Full Text]

C. H. Y. Fong, M. Bebien, A. Didierlaurent, R. Nebauer, T. Hussell, D. Broide, M. Karin, T. Lawrence, An antiinflammatory role for IKKβ through the inhibition of "classical" macrophage activation.
J
.
Exp
.
Med
.
205
, 1269-1276 (2008).
[Abstract]
[Full Text]

A. M. Timmer, V. Nizet, IKKβ/NF-κB and the miscreant macrophage.
J
.
Exp
.
Med
.
205
, 1255-1259 (2008).
[Abstract]
[Full Text]
Cold Turkey and MAP Kinase
Authors: Ray L. Bryan
Published: June 2008

Glial cell line-derived neurotrophic factor (GDNF) acts in the ventral tegmental area (VTA) of the brain, a brain region associated with drug-seeking behavior, to decrease self-administration of ethanol in mice. Its receptor is a complex that includes a glycosyl-phosphatidylinositol-linked GDNF family receptor and the receptor tyrosine kinase Ret. Carnicella
et al
. further explored the signaling mechanisms of GDNF and its effects on ethanol-drinking behavior. Administration of GDNF into the VTA, but not other nearby brain areas, reduced the frequency with which mice activated a lever that administered a dose of ethanol. After treatment of animals with GDNF or saline solution, initial rates of lever pressing for an ethanol reward were similar, but GDNF-treated animals repeated the ethanol-seeking behavior less often and terminated sessions of drinking earlier than did control animals. These effects were evident within 10 minutes after administration of GDNF and were associated with increased activity of the mitogen-activated protein kinases (MAPKs) ERK1 and 2 (ERK1/2). Pharmacological inhibition of the MAPK pathway prevented the effects of GDNF. Administration of GDNF also was effective in a mouse model of relapse of drinking behavior after a period of extinction of the behavior. The authors conclude that GDNF appears to reduce the incentive value of alcohol and the strength of behavioral reinforcement associated with alcohol consumption. Interestingly, GDNF did not alter self-administration of a "natural" reward such as sucrose. The effect in the relapse model suggests that GDNF’s effects extend to modification of ethanol-seeking behavior, as well as limiting ethanol consumption. Thus, the authors propose that GDNF signaling in the VTA might be a useful target for therapeutic intervention in alcoholism in humans.

S. Carnicella, V. Kharazia, J. Jeanblanc, P. H. Janak, D. Ron, GDNF is a fast-acting potent inhibitor of alcohol consumption and relapse.
Proc. Natl. Acad. Sci. U.S.A.
105
, 8114-8119 (2008).
[Abstract]
[Full Text]
Science Signaling
Podcast: 17 June 2008
Authors: Adler Elizabeth M. , VanHook Annalisa M.
Published: June 2008

This conversation is about research highlighted in the Editors' Choice summary titled, "A Deadly Gift." The highlighted article is K. Al-Nedawi, B. Meehan, J. Micallef, V. Lhotak, L. May, A. Guha, J. Rak, Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumor cells.
Nat
.
Cell Biol
.
10
, 619-624 (2008). (Length: 8 min; file size: 3.72 MB; file format: mp3; location:
http://podcasts.aaas.org/science_signaling/ScienceSignaling_080617.mp3
)
Intracellular Signaling by Akt: Bound to Be Specific
Authors: Franke Thomas F.
Published: June 2008

Over the past decade, the serine/threonine kinase Akt (also known as protein kinase B) has emerged as a critical signaling molecule within eukaryotic cells. In addition to the research required for the clarification of its regulation by upstream kinases and phosphatases, progress has been made in the identification of Akt-binding partners that modulate its activation, regulate its kinase activity, and define its impact on downstream biological responses. Studies of Akt-binding molecules have highlighted novel mechanisms involved in the regulation of signaling downstream of activated phosphoinositide 3-kinase. Akt-interacting molecules may have important roles in Akt signal transduction both under physiological and pathological conditions.