bluuebunny/crossref_metadata_2025 huggingface dataset:
Enumeration of Circuit Breaker Mechanisms Through Boolean Functions
Authors: Deo Hrishikesh V. , Amarnath C.
Published: June 2008

An attempt has been made to evolve an approach for the synthesis of contact breaker mechanisms used in electrical switchgear. These mechanisms belong to a class of devices in which the input and output links (and other links of interest) occupy only two positions of primary interest and hence the devices could be looked upon as binary mechanical systems. In this paper we demonstrate that application of binary logic greatly simplifies the type synthesis of such binary mechanical systems.
The Variable Rocker-Arm Mechanism
Authors: Raghavan Madhusudan
Published: June 2008

We present an investigation of a novel variable valve-lift mechanism known as the Variable Rocker-Arm mechanism (VR-Arm, for short). This mechanism has simple construction, low friction due to rolling contact, and provides continuously variable lift. Dynamic analysis of the mechanism using ADAMS shows that frictional losses at the intake camshaft are of the order of 1 Newton-meter for a four-cylinder engine.
A Triad-Based Two-DOF Robomech: Architecture and Optimum Synthesis
Authors: Smaili Ahmad , Chaaya Bachir
Published: June 2008

Presented in this paper is a 2-dof robomech that carries two end effectors to perform two functions simultaneously. The robomech has a 7R architecture consisting of two triad wings connected to form two cells. The over-constrained kinematic chain cannot traverse continuous trajectories but may be synthesized to move the end effectors through a set of desired locations. The article presents the architecture of the proposed robomech, establishes its kinematic relations and constraints, and provides dimensional synthesis scheme based on genetic algorithm and gradient search methods. Two case studies are included to demonstrate the applicability of the proposed robomech.
On Detecting Undercutting in Conjugate Pairs
Authors: Ilies¸ Horea T.
Published: June 2008

One significant and common trait of a conjugate pair is the occurrence of geometric singularities in the contacting surfaces, which typically prevents the correct meshing of the two contacting parts. These singularities, which have been naturally linked to the concept of “undercutting” in a conjugate pair, are notoriously difficult to determine both formally and computationally. On the other hand, it is surprising that, although the concept of undercutting has been known for a long time, it has not yet been formally defined or studied except for some very specific applications. Consequently, general purpose algorithms for undercutting detection and quantification remain elusive. We argue that detecting points around a singularity appears to be significantly easier than detecting the singularity itself. Thus, we propose that undercutting be unambiguously defined in terms of points in the neighborhood of geometric singularities, which may lead to general computational algorithms to detect and quantify undercutting in a conjugate pair.
Planar Motion Generation Incorporating a 6-Link Mechanism and Non-Circular Elements
Authors: Rolda´n-Mckinley Javier , Dooner David B. , Crane Carl , Kammath Jean-Francois
Published: June 2008

This work is a specific application of a particular one degree of freedom six-link geared planar mechanism. A procedure to synthesize non-circular gear pitch profiles to generate any prescribed function of position and orientation in a determined range is presented. The geometry of the mechanism, i.e. the link lengths of the six-bar mechanisms, is assumed known. The input parameters are the prescribed path, the orientation angle at each position along the path, and the interval along which the motion is required. A generic function y = f(x) = ax2 + bx + c, in a particular interval of x, was used to define the desired path. The desired orientation of the coupler link was specified as being tangent to the path at each point. An analysis was performed and complete non-circular profiles were successfully synthesized. Numerical examples are presented.
Design and Modelling of a Micro Fluid Filter for Separating Spermatogenic Cells
Authors: Ma Xianghong , Prince Mark , Ward Mike , Docker Peter
Published: June 2008

The small size of microfabricated structures are opening new avenues in the field of biomedical engineering where structures are being developed to process [1] and analyze [2,3] nanolitre quantities of biological fluids, and cellular tissues. This paper outlines the design and manufacture principals of a passive micro-mechatronic device for the filtration and sorting of spermatogenic cells. This device is to be applied in a urological clinical environment where it can be used to semi-automate the spermatozoa selection process from non-obstructive azoospermic testis biopsies. Detailed and discussed herein are the advantages and drawbacks of Micro-Electro-Mechanical Systems (MEMS) as applied to clinical biomedical situations, and requirements for the design methodology and process of a microfluidic system based on MEMS technology with a view to manufacture by Deep Reactive Ion Etching process. The modelling of the micro device using computational fluid dynamic simulation methods is also covered in this paper.
Multivariate Parameter Sets for Optimal Synthesis of Compliant Mechanisms
Authors: Shibakov Alexander , Canfield Stephen L. , Hull Patrick V.
Published: June 2008

This paper will propose the use of control maps along with discretized elements or meshes in the design parameter set for optimizing compliant mechanisms. The use of control maps will be demonstrated to encode the motion of groups of nodes or control points defining the mesh with simple mapping rules. The technique will serve as an alternative to increased mesh size or node wandering techniques that have been proposed to increase the number of alternative design shapes that may be considered. As an alternative approach, the proposed control map parameterization has the significant benefit that it minimizes the number of design parameters necessary (parameters increase linearly with the mesh size) in describing a given design making it computationally efficient. A limited number of tiles can produce a map that has a significant effect on the final shape. If the tiles are chosen appropriately, the problems such as material overlap and non-convex mesh elements are avoided automatically. This paper will describe the implementation of these control maps and provide several examples showing their implementation in the compliant mechanism topology synthesis process.
A Remote Needle Guidance System for Percutaneous Biopsies
Authors: Barrett Steven R. H. , Hanumara Nevan , Walsh Conor J. , Slocum Alexander H. , Gupta Rajiv , Shepard Jo-Anne O.
Published: June 2008

This paper describes a teleoperated needle guidance and insertion tool to assist doctors in performing minimally invasive percutaneous biopsies remotely under computed tomography [CT] guidance. Robopsy is a user-friendly robotic device that grips, positions and inserts a biopsy needle while the patient is imaged to provide the radiologist with simultaneous needle position feedback. Patient care is improved through more precise targeting and shortened procedure times. Robopsy is made primarily of simple, lightweight, snap-together, disposable plastic parts and modular motors; contrasting devices are heavy, complex and expensive. It is designed to be taped onto a patient so as to passively compensate for respiratory chest motion and, additionally, it incorporates a novel feature, which compensates for passive needle oscillation. The design process is outlined and the first prototype presented. Initial results from testing on a cardiac phantom indicate that artifacts from the device in the CT images are negligible and that the device can successfully orientate and insert a needle remotely.
Closed-Form Nonlinear Analysis of Beam-Based Flexure Modules
Authors: Awtar Shorya , Slocum Alexander H.
Published: June 2008

The simple beam acts as a constraint element when used in flexure mechanisms. Non-linearities arising from the force equilibrium conditions in a beam significantly affect its properties as a constraint element. Consequently, beam-based flexure mechanisms typically suffer from performance tradeoffs in terms of motion range, accuracy and stiffness. This paper presents simple yet accurate approximations that capture this non-linearity and allow for the closed-form analysis of flexure mechanisms of moderate complexity. These general analytical tools enable a designer to parametrically predict key performance parameters of a conceived mechanism such as mobility, over-constraint, stiffness variation, and error motions, without resorting to tedious numerical or computational methods. To illustrate their effectiveness, these approximations are used in deriving the closed-form force-displacement characteristics of several important beam-based flexure modules, and the results are validated using Finite Element Analysis. Variations in the beam shape and flexure module geometry are also considered analytically.
Damping Flexure Mechanisms Using Low-Density, Low-Wave-Speed Media
Authors: Varanasi Kripa K. , Nayfeh Samir A. , Slocum Alexander H.
Published: June 2008

Lightly damped poles and zeros in the response of flexure-based servomechanisms often limit their dynamic performance. In this paper, we measure the frequency response of a single-and a double-parallelogram flexure stage coupled to low-density, low-wave-speed foams in various configurations, and find that addition of the foam yields relatively high damping of in-plane, out-of-plane, and higher-order resonances. At frequencies high enough for waves to propagate into the foam, strong interactions between the foam and flexure structure occur, giving rise to a great deal of damping. This is a promising method for improvement of the dynamic performance of positioning and constraint systems that employ flexures.
A Note on Denavit-Hartenberg Notation in Robotics
Authors: Lipkin Harvey
Published: June 2008

The Denavit-Hartenberg conventions model chains of bodies connected by joints. Originally they were applied to single-loop chains but are now almost universally applied to open-loop serial chains such as robotic manipulators. Unfortunately there are several popular variations of the notation: the original, the distal variant, and the proximal variant. These three cases are compared for their application to serial robots. The proximal variate is advanced as the most notationally transparent for the mechanical analysis of serial manipulators.
Smart Portable Rehabilitation Devices
Authors: Mavroidis C. , Nikitczuk J. , Weinberg B. , Arango R. , Danaher G. , Jensen K. , Leahey M. , Pavone R. , Pelletier P. , Provo A. , Prugnarola J. , Stuart R. , Yasevac D.
Published: June 2008

In this paper we present several new advancements in the area of smart rehabilitation devices that have been developed by the Northeastern University Robotics and Mechatronics Laboratory. They are all compact, wearable and portable devices and boast re-programmable, real time computer controlled functions as the central theme behind their operation. The sensory information and computer control of the three described devices make for highly efficient and versatile systems that represent a whole new breed in wearable rehabilitation devices. Their applications range from active-assistive rehabilitation to resistance exercise and even have applications in gait training. The three devices described are: a transportable continuous passive motion elbow device, a wearable electro-rheological fluid based knee resistance device, and a wearable electrical stimulation and biofeedback knee device.
Focus Issue: A Niche of One’s Own
Authors: Adler Elizabeth M. , Foley John F.
Published: June 2008

In this Focus Issue of
Science Signaling
, which complements the
Science
Special Issue on Microbial Ecology (
http://www.sciencemag.org/microbialecology/
), we explore signaling mechanisms whereby microbes—both benign and pathogenic—interact with their hosts.
Algae Present a New Cell Cycle Paradigm
Authors: VanHook Annalisa M.
Published: June 2008

Classical embryologists long ago demonstrated that sperm entry initiates Ca
2+
waves that trigger important early developmental events such as the cortical reaction, meiotic release (egg activation), establishment of polarity, and passage through the G1/S checkpoint. Zygotic polarity in the brown alga
Fucus serratus
is established by changes in intracellular Ca
2+
concentration ([Ca
2+
]
int
) that occur over a period of several hours and induce growth at the basal pole, ultimately resulting in an asymmetric first mitosis. In yeast, G1/S progression and bud growth are initiated at the same time, but passage through the G2/M transition requires actin localization at the bud collar. Bothwell
et al.
report that polarization and the G1/S transition in
Fucus
are coordinately triggered by a Ca
2+
wave but, unlike yeast, there is no morphogenesis checkpoint at the G2/M transition. Using two-photon microscopy to measure the ratio of fluorescent Ca
2+
-sensitive and Ca
2+
-insensitive dyes, they determined that both cytosolic and nuclear [Ca
2+
] ([Ca
2+
]
cyt
and [Ca
2+
]
nuc
) increased steadily upon fertilization and peaked after about 30 minutes, the same time at which the sperm pronucleus began migrating toward the egg pronucleus. Both [Ca
2+
]
cyt
and [Ca
2+
]
nuc
decreased during the migration, but [Ca
2+
]
nuc
increased again just as the zygote entered S phase about 2.5 hours after fertilization. When zygotes were treated with the high-affinity Ca
2+
chelator BAPTA before S phase, there was no effect on pronuclear migration, but both S phase and asymmetric growth were prevented. BAPTA treatment after S phase had no effect on asymmetric growth, which indicates that polarization was established before S phase. BAPTA also prevented the first mitosis in about half of treated zygotes, regardless of whether it was added before or after S phase. In contrast, only very high concentrations of the lower-affinity Ca
2+
chelator Br
2
BAPTA affected mitosis, but it had no effect on polarization regardless of when it was administered. Treating zygotes with the actin depolymerizing drug lantrunculin B inhibited polarization but did not have any effect on mitosis. These results are consistent with a model in which the [Ca
2+
] wave initiates both polarization and cell cycle progression, but the two processes occur independently. This stands in direct contrast to budding yeast, where polarized growth of the bud is absolutely required for the G2/M transition. In
Fucus
the two events are coordinately regulated, but there is no such morphogenesis checkpoint.

J. H. F. Bothwell, J. Kisielewska, M. J. Genner, M. R. McAinsh, C. Brownlee, Ca
2+
signals coordinate zygotic polarization and cell cycle progression in the brown alga
Fucus serratus
.
Development
135
, 2173-2181 (2008).
[Abstract]
[Full Text]
Micro Managing Translational Repression
Authors: Riddihough Guy
Published: June 2008

MicroRNAs (miRNAs) are small noncoding RNAs that generally repress gene expression. The degree of complementarity between a miRNA and its RNA target is thought to determine the mode of repression. In plants, most characterized miRNAs are highly complementary to their targets, resulting in target cleavage (slicing), whereas those in animals have reduced complementarity and instead down-regulate mRNA translation. Brodersen
et al
. conducted a screen in
Arabidopsis
for factors involved in miRNA-mediated gene regulation and found that, in addition to directing cleavage, highly complementary miRNAs also repressed translation. Furthermore, siRNAs, which are precisely complementary to their mRNA targets and generally thought to repress gene expression by slicing, also have a translational repression component.

P. Brodersen, L. Sakvarelidze-Achard, M. Bruun-Rasmussen, P. Dunoyer, Y. Y. Yamamoto, L. Sieburth, O. Voinnet, Widespread translational inhibition by plant miRNAs and siRNAs.
Science
320
, 1185-1190 (2008).
[Abstract]
[Full Text]
NF-κB Links Immunity to the Hypoxic Response
Authors: Foley John F.
Published: June 2008

Under normal oxygen tension (normoxia), the abundance of mRNA of the α subunit of hypoxia-inducible transcription factor 1 (HIF-1α) is kept low through its degradation by oxygen-dependent enzymes. When oxygen tension is low (hypoxia),
HIF-1α
mRNA accumulates and its target genes, such as that encoding vascular endothelial growth factor (VEGF), are expressed. HIF-1α also affects the expression of genes encoding inflammatory cytokines, which are activated by nuclear factor κB (NF-κB). Rius
et al
. investigated the relationship between HIF-1α and NF-κB in mice inducibly deficient in the inhibitor of κB (IκB) kinase β (IKK-β); cells deficient in IKK-β cannot activate NF-κB. Reverse transcription polymerase chain reaction (RT-PCR) assays showed that exposing wild-type, but not IKK-β-deficient, macrophages to bacteria resulted in the increased expression of
HIF-1α
mRNA and that the induction of HIF-1α -target genes in response to bacteria was lower in IKK-β-deficient than in wild-type macrophages. Basal
HIF-1α
mRNA abundance was also lower in IKK-β-deficient cells. Hypoxic conditions induced the accumulation of HIF-1α in wild-type but not in IKK-β-deficient macrophages, and the induction of HIF-1α-responsive genes was almost completely blocked in the IKK-β-deficient cells. Indeed, the basal abundance of
HIF-1α
mRNA under normoxia was lower in IKK-β-deficient than in wild-type macrophages. Although treatment of a mouse macrophage cell line with bacterial lipopolysaccharide (LPS) induced
HIF-1α
expression under normoxia, HIF-1α protein accumulated only when LPS treatment occurred under hypoxia. Western blotting of samples from wild-type and IKK-β-deficient mice exposed to hypoxia showed that accumulation of HIF-1α in the liver and brain was dependent on IKK-β, as was the appearance of VEGF mRNA and protein. Together, these data suggest that the basal and hypoxia-induced expression of
HIF-1α
mRNA requires activated NF-κB, which thus acts as a link between innate immunity and the hypoxic response.

J. Rius, M. Guma, C. Schachtrup, K. Akassoglou, A. S. Zinkernagel, V. Nizet, R. S. Johnson, G. G. Haddad, M. Karin, NF-κB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1α.
Nature
453
, 807-811 (2008).
[PubMed]
Separate and Equal?
Authors: VanHook Annalisa M.
Published: June 2008

Signaling by the CLE small peptide family member CLAVATA 3 (CLV3) restricts stem cell proliferation in the apical meristem of
Arabidopsis
. CLV3 signals through the transmembrane receptors CLV1 and CLV2 to repress transcription of
wuschel
(
wus
), which encodes a homeodomain transcription factor that promotes stem cell proliferation. Müller
et al.
have identified a new member of this signaling pathway, CORYNE (CRN). A loss-of-function mutation in
crn
was isolated from a screen for suppressors of a weak meristem-arrest phenotype induced by
clv3
overexpression.
crn
mutants displayed a set of phenotypes shared with
clv1
and
clv2
loss-of-function mutants, including meristem enlargement due to overproliferation of stem cells, extra carpels, and an increase in the number of meristem cells expressing
clv3
and
wus
. The phenotype of plants carrying loss-of-function mutations in both
crn
and
clv2
was indistinguishable from that of plants carrying either mutation alone. In contrast, plants carrying both
crn
and
clv1
mutations had an exacerbated phenotype that was more severe than with either mutation alone. These genetic interaction experiments indicated that CRN and CLV2 functioned together, whereas CRN and CLV1 acted in parallel. The authors identified the gene affected in the
crn
mutant and found that it encoded a membrane-associated Ser-Thr kinase expressed in meristems and young organs but not in fully differentiated tissues. The authors propose a model in which CLV signaling is transduced separately through two receptor complexes, one of CLV1 homodimers and one of CRN-CLV2 heterodimers. Whereas CLV1 has both ligand-binding and kinase domains, CLV2 has only a ligand-binding domain, and CRN has only a kinase domain. Together, CRN and CLV2 could thus create a fully functional transmembrane receptor kinase. Consistent with this hypothesis, the
crn
allele identified through the screen for suppressors of the
clv
overexpression phenotype had a point mutation that could potentially disrupt dimerization in the transmembrane domain. Both CLV1 and CLV2/CRN transduced the CLV3 signal to WUS through the phosphatases POLTERGEIST (POL) and POLTERGEIST-LIKE 1 (PLL1). Although CLV3 signaling through CLV1 and CLV2/CRN appears to be equivalent in the apical meristem, it is possible that these receptors might differ in their ability to transduce signals from other CLE peptides or confer tissue- or stage-specificity to signaling.

R. Müller, A. Bleckmann, R. Simon, The receptor kinase CORYNE of
Arabidopsis
transmits the stem cell-limiting signal CLAVATA3 independently of CLAVATA1.
Plant Cell
20
, 934-946 (2008).
[Abstract]
[Full Text]
Signaling in Space
Authors: Ray L. Bryan
Published: June 2008

Shen
et al
. explored the role of spacing of receptor ligands for activation of T cells. Regions of interaction of T cells with antigen-presenting cells have a distinct spatial organization of membrane components known as the immunological synapse. Shen
et al.
devised a way to control the spatial distribution of antibodies to the T cell receptor (anti-CD3) and antibodies to the costimulatory receptor CD28 (anti-CD28) on a surface that allowed them to explore the importance of such spatial properties. They used microcontact printing to create a surface in which either anti-CD3 and anti-CD28 were presented together, or anti-CD28 was segregated in dots 1 μm in diameter surrounding anti-CD3 regions. Thus, in the segregated conformation, a 6-μm cell contacted about four of these locations containing anti-CD28. T cells exposed to the surface localized to the antibody-coated regions of the surface regardless of antibody segregation, but secretion of interleukin-2 by mouse CD4
+
T cells was increased if anti-CD28 was segregated at the periphery of a central locus of anti-CD3 rather than uniformly distributed with the anti-CD3. Activation of the kinase Akt was also greater in cells exposed to the segregated signals, but protein kinase C-θ colocalized with anti-CD3 in either spatial presentation. The dynamics of cell interaction with the receptors was measured by interference reflection microscopy and revealed that cells transiently contacted and released patches containing segregated anti-CD28 but--because anti-CD3 is not as readily released--remained associated with surfaces where the ligands were mixed. The experimental system may allow further insight into the mechanisms by which the geometry of immunological synapses influences intracellular signaling.

K. Shen, V. K. Thomas, M. L. Dustin, L. C. Kam, Micropatterning of costimulatory ligands enhances CD4
+
T cell function.
Proc. Natl. Acad. Sci. U.S.A.
105
, 7791-7796 (2008).
[Abstract]
[Full Text]
ROCO Kinase Activity Is Controlled by Internal GTPase Function
Authors: Weiss Bertram
Published: June 2008

Small guanosine triphosphatases (GTPases) have long been known to control the activities of downstream protein kinases. Some members of a rather new multidomain protein family contain not only a GTPase domain of the ROC (Ras of complex protein) subtype but also a protein kinase domain, and both domains seem to cooperate with each other in the same polypeptide. Data now show that the kinase activity of one of these ROCO proteins depends on whether guanosine diphosphate or guanosine triphosphate (GTP) is bound and that the activity is controlled by the adjacent GTPase, which suggests a novel mechanism of intrinsic control. This ROCO family member, leucine-rich repeat kinase 2 (LRRK2), is of special interest because mutations within both its protein kinase and its GTPase domains are associated with Parkinson’s disease (PD). These mutations lead to abnormally enhanced protein kinase activity, which is believed to cause or at least contribute to neuronal damage. The crystal structure of the GTPase domain of LRRK2 has now been resolved and shows that the ROC GTPase domain is responsible for LRRK2 homodimerization in a surprising way. The structure not only offers insights into the molecular effects of some of the PD-associated mutations of LRRK2, but may also help to improve our understanding of the intrinsic control mechanism between a GTPase and a protein kinase within the same protein.
Linking Light to Development and Metabolism
Authors: VanHook Annalisa M.
Published: June 2008

Photoresponsive fungi modulate their development and metabolism in response to light, with many species reproducing sexually and synthesizing secondary metabolites such as toxins and antibiotics only in the dark. In the mold
Aspergillis nidulans
, light inhibits the nuclear accumulation of Velvet (VeA), a negative regulator of asexual reproduction and antibiotic synthesis. Bayram
et al.
report that VeA contributes to this light-regulated switch through its interactions with the closely related velvet-like protein VelB, the secondary metabolism master regulator LaeA, and the nuclear importin KapA. VeA and VelB, both of which were required for sexual development, associated with one another in the nucleus and in the cytoplasm. The association between VeA and VelB was independent of light input, but the abundance of VeA greatly decreased in the light. In the dark, VeA and VelB formed a heterotrimeric nuclear complex with the methyltransferase LaeA. VelB and LaeA did not interact with one another directly, but both bound directly to VeA. The authors suggest a model in which, in the dark, VelB/VeA heterodimers form in the cytoplasm and translocate into the nucleus with the help of KapA. In the nucleus, the VelB/VeA heterodimers associate with LaeA to form a heterotrimeric complex that regulates the expression of secondary metabolite genes. It is not clear how light reduces the abundance of VeA, but the formation of the nuclear VelB/VeA/LaeA heterotrimeric complex provides the first clues as to how sexual development and metabolism are coordinated by light. Commentary by Fischer places this study in the greater context of fungal biology.

Ö. Bayram, S. Krappmann, M. Ni, J. W. Bok, K. Helmstaedt, O. Valerius, S. Braus-Stromeyer, N.-J. Kwon, N. P. Keller, J.-H. Yu, G. H. Braus, VelB/VeA/LaeA complex coordinates light signal with fungal development and secondary metabolism.
Science
320
, 1504-1506 (2008).
[Abstract]
[Full Text]

R. Fischer, Sex and poison in the dark.
Science
320
, 1430-1431 (2008).
[Summary]
[Full Text]
Src Family Kinase for Wnt5 Signaling
Authors: Gough Nancy R.
Published: June 2008

Although most members of the Wnt [Wingless (Wg) in flies] family of ligands signal through seven-transmembrane receptors of the Frizzled family, Wnt5 binds to receptor tyrosine kinase-like proteins called RYKs [ROR in mammals and Derailed (Drl) in flies]. RYKs lack conserved residues that are important for kinase activity and so are likely not catalytically active kinases. Wouda
et al
. identified the Src family tyrosine kinase (SFK) Src64B as a protein that interacted with Drl in a directed yeast two-hybrid screen. Genetic interactions supported a role for Src64B and the related protein Src42A in Wnt5-mediated axonal repulsion of neurons that cross the midline during embryonic development of the
Drosophila
nervous system. Flies deficient in both Src64B and Src42A showed the most penetrant phenotype of abnormal commissural axonal projections, a phenotype similar to the
Wnt5
-null flies. The Wnt5A overexpression phenotype was suppressed in flies heterozygous for a null allele of
Src64B
, whereas the phenotype was not suppressed in flies heterozygous for
Src42A
. Thus, although the two SFKs are partially redundant, Src64B appears to be the primary SFK that participates in Wnt5 signaling. Flies overexpressing Src64B and mildly overexpressing Drl showed higher numbers of neurons crossing the midline than did flies in which either was expressed alone. (No effect of overexpression of Src64B was observed in the absence of overexpressed Drl, which suggests that Drl abundance may be limiting.) Transcripts for Src64B and Drl were detected in the same neurons. Drl and Src64B or the mammalian homologs (ROR and Src) were coimmunoprecipitated from transfected cultured cells. The interaction in the transfected cells did not require Wnt5. In a mammalian two-hybrid assay, only catalytically active Src64B interacted with a fusion protein containing the Drl intracellular domain. Even in the absence of Wnt5, the interaction between Drl and Src64B in the transfected cells resulted in tyrosine phosphorylation of Src64B, which is required for its activity, and tyrosine phosphorylation of Drl. Cells transfected with Wnt5, Drl, and Src64B did not activate a reporter gene responsive to the transcription factor known as TCF/LEF, which is an indicator of canonical Wnt pathway activation. How Wnt5 influences the activity of the Drl-Src64B complex remains unclear, and the authors speculate that Wnt5 may direct the receptor-bound SFK to specific substrates.

R. R. Wouda, M. R. K. S. Bansraj, A. W. M. de Johng, J. N. Noordermeer, L. G. Fradkin, Src family kinases are required for WNT5 signaling through the Derailed/RYK receptor in the
Drosophila
embryonic central nervous system.
Development
135
, 2277-2287 (2008).
[Abstract]
[Full Text]
Location Matters
Authors: Ray L. Bryan
Published: June 2008

The signaling pathway through which cells modulate protein synthesis and cell growth in response to amino acids has been tricky to unravel. Sancak
et al
. add a key piece to the puzzle with experiments that reveal a role for a group of small guanosine triphosphatases (GTPases) known as Rag proteins. RagC associates with the mTORC1 protein kinase complex, a key regulator of cell growth. This interaction of Rag proteins with mTORC1 appears to be necessary and sufficient to convey nutrient availability signals when cells are exposed to amino acids. The physical interaction of Rag proteins with mTORC1 appears not to regulate activity of mTOR but to influence its localization within the endomembrane system of the cell.

Y. Sancak, T. R. Peterson, Y. D. Shaul, R. A. Lindquist, C. C. Thoreen, L. Bar-Peled, D. M. Sabatini, The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1.
Science
320
, 1496-1501 (2008).
[Abstract]
[Full Text]
Mapping the Yeast Protein Interaction Network
Authors: Jasny Barbara R.
Published: June 2008

To move beyond genes to an understanding of networks, it is necessary to track protein-protein interactions in vivo. Tarassov
et al
. have used protein-fragment complementation assays, which are based on reassembly of two domains of the enzyme dihydrofolate reductase that have been fused to the proteins of interest, to look at the protein interaction network, the interactome, in yeast. In addition to confirming known interactions within complexes, insights were obtained into the network underlying autophagy, a conserved process by which cells digest their own constituents in response to starvation, and a network underlying cellular polarization during the cell cycle.

K. Tarassov, V. Messier, C. R. Landry, S. Radinovic, M. M. Serna Molina, I. Shames, Y. Malitskaya, J. Vogel, H. Bussey, S. W. Michnick, An in vivo map of the yeast protein interactome.
Science
320
(5882), 1465-1470 (2008).
[Abstract]
[Full Text]
Damage Detection
Authors: Riddihough Guy
Published: June 2008

A break in both strands of the DNA double helix is potentially very dangerous for organisms because the free ends can recombine inappropriately with other parts of the genome and cause substantial damage. Eukaryotic cells sense and attempt to repair such breaks very rapidly, through the recruitment of DNA repair proteins to the sites of damage, forming nuclear repair foci. Soutoglou and Misteli have tethered various repair factors individually to unbroken DNA in human tissue culture cells and find that, surprisingly, even in the absence of DNA damage, repair foci form at the tether site. The DNA damage response may thus involve amplification of the damage signaling cascade, and the damage-sensing proteins may detect alterations in the higher-order structure of chromatin around the break.

E. Soutoglou, T. Misteli, Activation of the cellular DNA damage response in the absence of DNA lesions.
Science
320
, 1507-1510 (2008).
[Abstract]
[Full Text]
Fat Controller
Authors: Simpson Stephen J.
Published: June 2008

The synthesis of lipids in the liver depends on transcriptional pathways under the influence of carbohydrate intake. Lee
et al.
(see also commentary by Horton) provide evidence for a rather unexpected addition to the list of transcription factors involved in lipid metabolism, XBP1. XBP1 is already known to regulate the unfolded protein response (UPR) in the endoplasmic reticulum, influencing the secretory capacity of a variety of cell types. Mice lacking
Xbp1
expression in the liver after birth showed reduced levels of cholesterol and triglycerides as a result of attenuated lipid synthesis in the liver. In wild-type mice, the abundance of XBP1 was increased by feeding of carbohydrates and corresponded with the expression of several other genes associated with fatty acid synthesis. It remains unclear exactly how XBP1 helps regulate the complex lipogenic transcriptional network in response to carbohydrate intake.

A.-H. Lee, E. F. Scapa, D. E. Cohen, L. H. Glimcher, Regulation of hepatic lipogenesis by the transcription factor XBP1.
Science
320
, 1492-1496 (2008).
[Abstract]
[Full Text]

J. D. Horton, Unfolding lipid metabolism.
Science
320
, 1433-1434 (2008).
[Summary]
[Full Text]
Glutamate at the Clot
Authors: Ray L. Bryan
Published: June 2008

Glutamate is best known as a neurotransmitter, but glutamate is also present in the blood, and various glutamate receptors are found in tissues that include pancreatic β cells and bone cells. Morrell
et al
. add an important new target for glutamate regulation--platelets. Platelets store glutamate and have glutamate transporters, and Morrell
et al
. used a real-time enzymatic assay to show that glutamate was released during aggregation of human platelets induced in vitro with thrombin. Immunoblotting showed that platelets express AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors. Glutamate alone did not cause platelet activation, but it did enhance activation in response to thrombin receptor-activating peptide (TRAP-6), and pharmacological studies indicated that glutamate acted through AMPA receptors. The authors used studies with Na
+
-sensitive dye and electrophysiological experiments to determine that AMPA receptor activation increased Na
+
influx and promoted depolarization of the plasma membrane. Platelets respond to many regulators, and AMPA receptor activation enhanced the response of platelets to agonists that act through heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors. The authors also provided evidence from intravital microscopy to show that platelets from mice lacking the GluR1 subunit of the AMPA receptor had delayed thrombosis of experimentally damaged mesenteric arteries in vivo. Occlusion of arteries by thrombosis is a key mechanism in the deadly effects of cardiovascular disease and stroke. Thus, the authors suggest that AMPA receptors might provide a valuable new target for therapeutic inhibition of thrombosis.

C. N. Morrell, H. Sun, M. Ikeda, J.-C. Beique, A. M. Swaim, E. Mason, T. V. Martin, L. E. Thompson, O. Gozen, D. Ampagoomian, R. Sprengel, J. Rothstein, N. Faraday, R. Huganir, C. J. Lowenstein, Glutamate mediates platelet activation through the AMPA receptor.
J. Exp. Med.
205
, 575-584 (2008).
[Abstract]
[Full Text]
Hear It, Watch It, Read It
Authors: Gough Nancy R.
Published: June 2008

With the launch of four new sections,
Science Signaling
continues to leverage online media to maximize scientific communication and discovery. The editors explain exciting recent discoveries in Podcasts, allowing users to tune-in for a portable and understandable summary of cell signaling research. Meeting Reports and Presentations join the Events calendar in the Community section to bring cell signaling highlights beyond the doors of the auditorium. Through collaboration with GrantsNet,
Science Signaling
brings a list of Funding Sources for cell signaling researchers.
Watching Molecules Talking to Each OtherHighlights of the 11th Joint Meeting of the Signal Transduction Society (STS), Signal Transduction: Receptors, Mediators and Genes, Weimar, Germany, 1 to 3 November 2007.
Authors: Friedrich Karlheinz , Janssen Ottmar , Hass Ralf
Published: June 2008

Not long ago, molecular processes underlying intracellular signal transduction could only be made accessible to the eye by means of cartoons and artwork. Due to enormous technical processes within recent times, the dream of researchers of faithfully visualizing intracellular signal transduction events has now become a reality. While covering a wide range of basic and applied disciplines, the 2007 Signal Transduction Society’s annual meeting focused on results obtained using state-of-the-art imaging methodologies.
Science Signaling
Podcast: 18 January 2008
Authors: Adler Elizabeth M. , Gough Nancy R.
Published: June 2008

This conversation is about research highlighted in Editors' Choice titled "Looking After Polysialic Acid". The highlighted article is G. Di Cristo, B. Chattopadhyaya, S. J. Kuhlman, Y. Fu, M.-C. Bélanger, C. Z. Wu, U. Rutishauser, L. Maffei, Z. J. Huang, Activity-dependent PSA expression regulates inhibitory maturation and onset of critical period plasticity.
Nat. Neurosci.
10
, 1569-1577 (2007). (Length: 9 min; file size: 4.22 MB; file format: mp3; location:

http://stke.sciencemag.org/rss/podcast.xml
)
Science Signaling
Podcast: 22 February 2008
Authors: Gough Nancy R. , Foley John F.
Published: June 2008

This conversation is about research highlighted in Editors' Choice titled "Glucose Fattens Up Muscle". The highlighted article is P. Aguiari, S. Leo, B. Zavan, V. Vindigni, A. Rimessi, K. Bianchi, C. Franzin, R. Cortivo, M. Rossato, R. Vettor, G. Abatangelo, T. Pozzan, P. Pinton, R. Rizzuto, High glucose induces adipogenic differentiation of muscle-derived stem cells.
Proc. Natl. Acad. Sci. U.S.A
105
, 1226-1231 (2008). (Length: 7 min; file size: 3.4 MB; file format: mp3; location:
http://podcasts.aaas.org/science_signaling/ScienceSignaling_080222.mp3
)
Akt Connects Interferon to Translation
Authors: Gough Nancy R.
Published: June 2008

Interferons (IFNs), including the type I IFN-α and IFN-β and the type II IFN-γ, signal through a well-characterized pathway involving the Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) to stimulate genes involved in inflammatory and antiviral responses. Previous reports had suggested that IFNs can also signal through the kinase Akt, but the effect of signaling through this pathway has been controversial. Kaur
et al
. add to this story by providing evidence that Akt signaling connects both type I and type II IFN signaling to regulation of translation through the mTOR pathway. By comparing wild-type mouse embryo fibroblasts (MEFs) with those in which both Akt1 and Akt2 were knocked out, the authors showed that Akt activation (phosphorylation) occurred in response to IFNs. Furthermore, phosphorylation and activation of the kinase p70S6K in response to IFNs was impaired in the Akt double-knockout MEFs, as was the phosphorylation of the translational repressor 4E-BP1. The abundance of ISG15, which is encoded by a gene stimulated by type I IFN signaling, and CXCL10, which is encoded by a gene stimulated by type II IFN signaling, was decreased in the Akt double-knockout MEFs. This was not due to impaired JAK/STAT signaling, because the transcripts were elevated; instead, this appeared to be due to inhibition of translation in the Akt double-knockout cells. This interpretation was supported by analysis of the amount of
Isg15
mRNA in the polysomal fraction in response to IFN-α, which was decreased in the Akt double-knockout MEFs. Finally, the importance of this Akt-mediated regulation of translation for antiviral response was demonstrated by challenging wild-type and double-knockout cells with encephalomyocarditis virus and showing that IFN-α did not protect the knockout cells from the cytopathic effects of the virus as effectively as it did the wild-type cells.

S. Kaur, A. Sassano, B. Dolniak, S. Joshi, B. Majchrzak-Kita, D. P. Baker, N. Hay, E. N. Fish, L. C. Platanias, Role of the Akt pathway in mRNA translation of interferon-stimulated genes.
Proc. Natl. Acad. Sci. U.S.A.
105
, 4808-4813 (2008).
[Abstract]
[Full Text]
NFAT Is Well Placed to Direct Both Enhancer Looping and Domain-Wide Models of Enhancer Function
Authors: Cockerill Peter N.
Published: June 2008

Nuclear factor of activated T cells (NFAT) plays a central role in activating gene expression at the level of chromatin structure. A study now reveals that NFAT may also help to organize chromatin domains and enable enhancer-promoter communication. In activated T cells, inducible intrachromosomal looping occurs between the tumor necrosis factor–α (TNF-α) gene promoter and two NFAT-dependent enhancers located at –9 kb and +3 kb. This topology places the TNF-α gene and the adjacent lymphotoxin (LT) genes in separate loops, thereby allowing independent regulation of the TNF-α gene within a multigene locus. These findings build on other studies that indicate that NFAT is intimately associated with activities that disrupt nucleosomes within enhancers and mobilize nucleosomes across extensive chromatin domains linking enhancers and promoters. Taken together, these studies highlight NFAT as a factor that creates a chromatin environment that is permissive for both the recruitment and the clustering of factors that control transcription at promoters and enhancers.
SRC-3 Transcription-Coupled Activation, Degradation, and the Ubiquitin Clock: Is There Enough Coactivator to Go Around in Cells?
Authors: Lonard David M. , O’Malley Bert W.
Published: June 2008

Overexpression of nuclear receptor coactivators is a frequent event in breast cancer cells and is recognized as a key mechanism for these cells to maximize their oncogenic growth state. Steroid receptor coactivator–3 [(SRC-3), also known as amplified in breast cancer–1 or AIB1] is foremost among these overexpressed oncogenic coactivators, being overexpressed in most breast cancers. Because of its oncogenic potential, normal cells must carefully control its cellular concentration. We discuss how SRC-3 quantitatively influences estrogen-regulated gene transcription when it is at limiting concentrations in normal breast cells and at nonlimiting concentrations in breast cancer cells. Precise control of the cellular concentration of SRC-3 may thus serve as a mechanism for defining growth responses to estrogen receptors and other growth-promoting transcription factors.
Bacterial TIR Domains
Authors: Gough Nancy R.
Published: June 2008

Bacteria need to evade the first line of immune defense, the innate immune response, to survive in their hosts. Signaling in response to foreign molecules by Toll-like receptors (TLRs) is an important part of the innate immune response, so pathogens have evolved mechanisms to disrupt this pathway (see O’Neill). Cirl
et al
. identified proteins containing the Toll/interleukin-1 receptor (TIR) domains in several human bacterial pathogens, including
Escherichia coli
strain CFT073, which causes urinary tract infections, and
Brucella melitensis
, which causes brucellosis, a disease with symptoms similar to those associated with flu. The authors named these proteins Tcps, for TIR domain-containing proteins; the
E. coli
protein was named TcpC, and the
B. melitensis
protein was named TcpB. Cells infected with a TcpC-deficient mutant of CFT073 showed greater production of the proinflammatory cytokines tumor necrosis factor (TNF) and interleukin-6 (IL-6) and increased bacterial load compared to cells infected with wild-type CFT073. Cells transfected with plasmids encoding TLR signaling components and the TcpC or TcpB proteins, along with reporter plasmids, exhibited decreased signaling through TLRs that are coupled to the adaptor MyD88--TLR4 and TLR2--but not those coupled to other adaptors. CFT073 infection of MyD88-deficient cells did not show a decrease in TNF secretion. Thus, TcpC and TcpB appear to selectively interfere with MyD88-dependent TLR pathways. The TIR domain of TcpC or full-length TcpB bound to MyD88 in pull-down assays. TcpC was secreted from the bacteria and was detectable inside bone marrow-derived macrophages even when the macrophages were separated from the bacteria in a transwell system. Uptake of a purified peptide of the TIR domain of TcpC was inhibited if cholesterol was depleted from the membranes of the host cells, which suggests that lipid rafts may be important for uptake. Finally, the importance of TcpC in disease was determined by infecting mice with the wild-type CFT073 or the TcpC-deficient strain, and those with the wild-type strain had more aggressive disease. In human urinary tract isolates, more severe disease (acute pyelonephritis) was associated with a higher frequency of the presence of the TcpC-positive strains, whereas TcpC-positive strains were less frequently detected in samples from patients with less serious (cystitis) or asymptomatic infection. Thus, as with some viral pathogens, bacteria also appear to target TLR signaling to enhance virulence.

C. Cirl, A. Wieser, M. Yadav, S. Duerr, S. Schubert, H. Fischer, D. Stappert, N. Wantia, N. Rodriguez, H. Wagner, C. Svanborg, T. Miethke, Subversion of Toll-like receptor signaling by a unique family of bacterial Toll/interleukin-1 receptor domain-containing proteins.
Nat. Med.
14
, 399-406 (2008).
[PubMed]

L. A. J. O’Neill, Bacteria fight back against Toll-like receptors.
Nat. Med.
14
, 370-372 (2008).
[PubMed]
Keeping Axons on Track
Authors: Hines Pamela J.
Published: June 2008

Like cars on a highway, neuronal signaling routes merge and diverge between origin and destination. By identifying developing motor and sensory neurons in the mouse embryo with distinguishable labels, Gallarda
et al
. (see the Perspective by Murai and Pasquale) have visualized how the growing axons keep entanglement at bay. The axons grew into parallel but separated bundles. Signaling through the ephrin A receptors and ligands present on the growing axons served to keep like axons bundled with like.

B. W. Gallarda, D. Bonanomi, D. Müller, A. Brown, W. A. Alaynick, S. E. Andrews, G. Lemke, S. L. Pfaff, T. Marquardt, Segregation of axial motor and sensory pathways via heterotypic trans-axonal signaling.
Science
320
, 233-236 (2008).
[Abstract]
[Full Text]

K. K. Murai, E. B. Pasquale, Axons seek neighborly advice.
Science
320
, 185-186 (2008).
[Summary]
[Full Text]