bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-Lived Giant Number Fluctuations in a Swarming Granular Nematic
Authors: Narayan Vijay , Ramaswamy Sriram , Menon Narayanan
Published: July 2007

Coherently moving flocks of birds, beasts, or bacteria are examples of living matter with spontaneous orientational order. How do these systems differ from thermal equilibrium systems with such liquid crystalline order? Working with a fluidized monolayer of macroscopic rods in the nematic liquid crystalline phase, we find giant number fluctuations consistent with a standard deviation growing linearly with the mean, in contrast to any situation where the central limit theorem applies. These fluctuations are long-lived, decaying only as a logarithmic function of time. This shows that flocking, coherent motion, and large-scale inhomogeneity can appear in a system in which particles do not communicate except by contact.
Host Resistance to Lung Infection Mediated by Major Vault Protein in Epithelial Cells
Authors: Kowalski Michael P. , Dubouix-Bourandy Anne , Bajmoczi Milan , Golan David E. , Zaidi Tanweer , Coutinho-Sledge Yamara S. , Gygi Melanie P. , Gygi Steven P. , Wiemer Erik A. C. , Pier Gerald B.
Published: July 2007

The airway epithelium plays an essential role in innate immunity to lung pathogens. Ribonucleoprotein particles primarily composed of major vault protein (MVP) are highly expressed in cells that encounter xenobiotics. However, a clear biologic function for MVP is not established. We report here that MVP is rapidly recruited to lipid rafts when human lung epithelial cells are infected with
Pseudomonas aeruginosa
, and maximal recruitment is dependent on bacterial binding to the cystic fibrosis transmembrane conductance regulator. MVP was also essential for optimal epithelial cell internalization and clearance of
P. aeruginosa
. These results suggest that MVP makes a substantial contribution to epithelial cell–mediated resistance to infection.
Devoted to Dogs
Authors: Ostrander Elaine A.
Published: July 2007

The Behavioural Biology of Dogs
.
Per Jensen, Ed.
. CABI, Wallingford, UK, 2007. 276 pp. Paper, $70, £35, €55. ISBN 9781845931872.

In a series of short chapters, the contributors survey a range of topics including the evolutionary history and domestication of dogs, breed diversity, behavior, learning, behavioral genetics, and dogs among humans.
Unconventional Roles of the NADPH Oxidase: Signaling, Ion Homeostasis, and Cell Death
Authors: Steinberg Benjamin E. , Grinstein Sergio
Published: July 2007

Although the central role of the phagocytic NADPH oxidase in mediating bacterial killing has long been appreciated, this sophisticated enzyme complex serves various other important functions. This Perspective focuses on these underappreciated roles of phagocytic NADPH oxidase, highlighting recent work implicating reactive oxygen species in triggering an unconventional form of cell death.
Division Decisions
Authors: Simpson Stephen
Published: July 2007

During an immune reaction, T cells divide rapidly and differentiate, producing a variety of T cell types that respond appropriately to the particular threat. Memory T cells also emerge from the same population and remain in the body until such time as a new infection calls once again for their attention. Chang
et al
. now show that single T cells undergo an initial asymmetric cell division in response to a pathogen, producing two daughter cells with alternate fates. After forming an immune synapse with an antigen-presenting cell (APC), various proteins, including some responsible for signaling and asymmetric cell division, were reoriented within the T cells. After division, daughters that were proximal to the APC-T cell synapse became effector cells, whereas their distal sisters became more memory-like and able to confer better protection when transferred to mice.

J. T. Chang, V. R. Palanivel, I. Kinjyo, F. Schambach, A. M. Intlekofer, A. Banerjee, S. A. Longworth, K. E. Vinup, P. Mrass, J. Oliaro, N. Killeen, J. S. Orange, S. M. Russell, W. Weninger, S. L. Reiner, Asymmetric T lymphocyte division in the initiation of adaptive immune responses.
Science
315
, 1687-1691 (2007).
[Abstract]
[Full Text]

D. R. Littman, H. Singh, Asymmetry and immune memory.
Science
315
, 1673-1674 (2007).
[Summary]
[Full Text]
Modeling Competence
Authors: Ray L. Bryan
Published: July 2007

Bacteria undergo a well-studied transient differentiation into a state of competence, during which they can take up DNA from the environment. It is a rare example of a developmental system understood sufficiently well to be analyzed in a rigorous quantitative manner. Süel
et al
. use mathematical models and precise experimental measurements to describe key properties of this developmental system. The frequency and duration of episodes of competence could be independently tuned by simple changes in gene expression, and such variations in gene expression could also give rise to distinct dynamic properties of the system.

G. M. Süel, R. P. Kulkarni, J. Dworkin, J. Garcia-Ojalvo, M. B. Elowitz, Tunability and noise dependence in differentiation dynamics.
Science
315
, 1716-1719 (2007).
[Abstract]
[Full Text]
Staying in Charge
Authors: Chin Gilbert
Published: July 2007

Under normal conditions, the intracellular concentration of adenosine triphosphate (ATP) is on the order of 1 millimolar. Numerous enzymes and regulatory proteins rely on this universal currency of energy for anabolic, catabolic, and general housekeeping processes. One of the primary enzymes that regulates ATP levels is the AMP-activated protein kinase (AMPK), which senses the relative ratio of ATP to AMP. When this ratio falls, AMPK phosphorylates metabolic enzymes, which then consume less ATP and make more of it. Townley and Shapiro have solved the structure of the fission yeast AMPK homolog and demonstrate the competitive binding of ATP and AMP at a single nucleotide site, where the absence of counterions appears to amplify the discrimination between the mono- and triphosphate ligands.

R. Townley, L. Shapiro, Crystal structures of the adenylate sensor from fission yeast AMP-activated protein kinase.
Science
315
, 1726-1729 (2007).
[Abstract]
[Full Text]

D. G. Hardie, Balancing cellular energy.
Science
315
, 1671-1672 (2007).
[Summary]
[Full Text]
Fat Flies Expanded the Hippo Pathway: A Matter of Size Control
Authors: Yin Feng , Pan Duojia
Published: July 2007

By simultaneously inhibiting cell proliferation while promoting apoptosis, the Hippo signaling pathway provides a robust mechanism to restrict organ size during
Drosophila
development. Despite impressive progress in revealing the key intracellular components of this growth-regulatory pathway, the nature of the signal that regulates Hippo signaling in vivo has remained elusive. Several studies now implicate the atypical cadherin protein Fat as a cell surface receptor for the Hippo signaling pathway, thus potentially linking the Hippo kinase cascade with the extracellular milieu.
Is Suppressor Function in Mouse CD4
+
CD25
+
Tregs Due Wholly to GRAIL?
Authors: Foley John F.
Published: July 2007

The (E3) ubiquitin ligase, GRAIL (gene related to anergy in lymphocytes), is associated with CD4
+
T cell anergy, a state of T cell nonresponsiveness to antigen. MacKenzie
et al
. found that amounts of GRAIL mRNA and protein were greater in mouse CD4
+
CD25
+
Tregs than in CD4
+
CD25
–
naïve cells. Transfer of naïve CD4
+
T cells from TCR-DO11.10/Rag2
–/–
(DO11) mice to BALB/c mice, followed by injection of the mice with OVA peptide, induced tolerized CD4
+
CD25
+
cells detected with the DO11-specific antibody KJ1.26. This is a routinely used method for studying tolerance, because the donor cells express a T cell receptor (TCR) that responds only to OVA peptide, and the donor mice cannot produce any mature T cells because of the lack of the Rag2 gene (recombinase activating gene 2). KJ1.26
+
CD25
+
cells had larger amounts of GRAIL mRNA and Foxp3 mRNA and protein than did the KJ1.26
+
CD25
–
subset, as measured by real-time reverse transcription polymerase chain reaction (RT-PCR) and flow cytometry. A retroviral system was used to generate cell lines producing large amounts of GRAIL (DO11 GRAIL) or GFP (DO11 GFP). Co-culture of naïve CD4
+
CD25
–
T cells with antigen-presenting cells, OVA peptide, and DO GFP cells resulted in proliferation of naïve cells. However, when DO11 GRAIL cells were used instead of DO11 GFP cells, proliferation of naïve CD4
+
CD25
–
T cells was suppressed. DO11 GRAIL cells produced more transforming growth factor-β (TGF-β), a cytokine associated with Treg function, than did DO11 cells. DO11 GRAIL cells also had larger amounts of the surface Treg markers, CD25, GITR, and CTLA4. Surprisingly, DO11 GRAIL cells did not produce the cytokine, IL-10, or the transcription factor, Foxp3, both of which are associated with Treg function. However, this study demonstrates the presence of GRAIL in CD4
+
CD25
+
Tregs and suggests a role for GRAIL in suppressor function.

D. A. MacKenzie, J. Schartner, J. Lin, A. Timmel, M. Jennens-Clough, C. G. Fathman, C. M. Seroogy, GRAIL is up-regulated in CD4
+
CD25
+
T regulatory cells and is sufficient for conversion of T cells to a regulatory phenotype.
J. Biol. Chem.
282
, 9696-9702 (2007).
[Abstract]
[Full Text]
Key to Liver Regeneration
Authors: Ray L. Bryan
Published: July 2007

The liver is one tissue in mammals that can regenerate. Passino
et al
. now find that hepatocyte proliferation is controlled by the neurotrophin receptor p75
NTR
, known primarily for its role in neurons in regulation of survival, apoptosis, and neuronal regeneration. Mice lacking p75
NTR
showed impaired hepatocyte proliferation. p75
NTR
appeared to act on hepatic stellate cells (HSCs), which differentiate in response to p75
NTR
and then make growth factors and extracellular matrix that support proliferation of hepatocytes. Modulation of the effects of p75
NTR
on HSCs could thus provide a therapeutic target for management of liver disease.

M. A. Passino, R. A. Adams, S. L. Sikorski, K. Akassoglou, Regulation of hepatic stellate cell differentiation by the neurotrophin receptor p75
NTR
.
Science
315
, 1853-1856 (2007).
[Abstract]
[Full Text]
Meeting Report: Tumor Biology--How Signaling Processes Translate to TherapyA report on the "Signal Transduction Society (STS) Meeting 2006: Signal Transduction-Receptors, Mediators and Genes," Weimar, Germany, 2 to 4 November 2006.
Authors: Friedrich Karlheinz , Janssen Ottmar , Hass Ralf
Published: July 2007

On the occasion of the 10th Joint Meeting "Signal Transduction—Receptors, Mediators and Genes" in November 2006, the Signal Transduction Society (STS) focused on the holy grail of translational research, that is, how basic signaling research might be transferred into cancer therapy. Participants heard of blockbusters and setbacks and learned of new therapeutic approaches that concentrate on distinct signaling pathways at a more individual level. Thus, the young STS community and the 300 meeting participants left with an optimistic outlook and the notion that the translational task will keep scientists busy all over the world for a while.
Sensing Salt, Sending Signals
Authors: Ray L. Bryan
Published: July 2007

To survive, cells and organisms must regulate concentrations of Na
+
within a range compatible with physiological functions. Shimizu
et al
. show that Na
+
sensing occurs in part through an unusual mechanism in the mammalian brain in which neuronal activity is controlled by associated glial cells. Mammals appear to sense Na
+
concentrations in the blood through special brain structures known as circumventricular organs, in particular the subfornical organ (SFO), where a blood-brain barrier is not present, allowing cells to sense the chemical makeup of the blood. Sodium channels known as Na
x
channels are required for proper behavioral responses to excess Na
+
, but these channels are expressed on astrocytes rather than neurons. The authors used a yeast two-hybrid screen to detect proteins that interacted with the cytoplasmic domain of Na
x
. One of the interacting proteins was identified as the cell membrane sodium pump (Na
+
/K
+
-ATPase). In cultured cells expressing Na
x
, increased concentrations of extracellular Na
+
caused increased activity of the Na
+
/K
+
-ATPase. Suspecting that the association of Na
x
with the Na
+
/K
+
-ATPase might influence cellular energy metabolism, the authors showed that exposure of slices from the SFO of wild-type mice to excessive extracellular Na
+
caused an increase in glucose uptake that was absent in SFO slices from animals lacking Na
x
. This enhanced glucose use led to increased lactate secretion in the slices. The lactate in turn was found to increase the firing frequency of GABAergic neurons in the SFO slices. The effect on the neurons was reduced when activity of the transporter that carries lactate into the neurons was inhibited. Thus, the authors conclude that Na
+
sensing in the SFO results from glial cells that are the key sensors, which then signal to neighboring neurons by secretion of lactate. Commentary by Iadecola places the work in the context of other instances of lactate signaling in neurons and other physiological mechanisms that cooperate to keep Na
+
concentrations in check.

H. Shimizu, E. Watanabe, T. Y. Hiyama, A. Nagakura, A. Fujikawa, H. Okado, Y. Yanagawa, K. Obata, M. Noda, Glial Na
x
channels control lactate signaling to neurons for brain [Na
+
] sensing.
Neuron
54
, 59-72 (2007).
[Online Journal]

C. Iadecola, Astrocytes take center stage in salt sensing.
Neuron
54
, 3-5 (2007).
[Online Journal]
Golgi Releases a Numb Regulator
Authors: Gough Nancy R.
Published: July 2007

Numb is a signaling protein that functions in two different aspects of neuronal specification: Numb promotes progenitor cell fates over neuronal fates, and it is necessary for neuronal differentiation. Numb is segregated during interphase onto one side of the dividing progenitor cell, where dNumb specifies a particular sensory cell fate in
Drosophila
or self-renewal of neuronal progenitors in mice [mNumb or Numb-like (Numbl)]. Shortly after mitosis, Numb appears in the cell from which it was originally excluded, where it contributes to the differentiation of that cell: in
Drosophila
, the formation of the sensory organ hair cell, and in mice, neuronal differentiation. Zhou
et al
. provide insight into how Numb can serve these two different, mitotically regulated functions. They identified the Golgi protein ACBD3 (for acyl-coenzyme A-binding domain protein 3) as an mNumb-interacting protein in a yeast two-hybrid screen, and the interaction was confirmed by coimmunoprecipitation of transfected cells. Deletion of the ACBD3 binding domain from mNumb rendered it incapable of rescuing sensory organ defects caused by dNumb deficiency when expressed in
Drosophila
. Knockout of
ACBD3
in mouse caused the death of embryos, and detailed analysis of the embryos revealed phenotypes similar to those associated with Numb deficiency, such as loss of progenitor cells leading to thinning of the neuroepithelium. Although ACBD3 and mNumb and Numbl were all present in the wild-type mouse neuroprogenitor cells of the neuroepithelium, their subcellular distributions were different: ACBD3 colocalized with Golgi markers in interphase cells, and the Numb proteins were cytosolic and membrane-associated. ACBD3 became more diffuse and cytosolically distributed during mitosis at a time when Numb proteins had already segregated to the apical side of the neuroprogenitor cell. This redistribution of ACBD3 was critical to neuronal differentiation because replacement of the endogenous mouse
ACBD3
gene in neural progenitor cells with a myristoylated form that was uniformly associated with the plasma membrane disrupted neuron formation throughout the nervous system, a phenotype similar to that associated with forcing uniform distribution of Numb. The authors suggest that Golgi fragmentation during mitosis may release ACBD3, allowing it to regulate Numb signaling, which may provide a mechanism to couple cell fate specification with the cell cycle.

Y. Zhou, J. B. Atkins, S. B. Rompani, D. L. Bancescu, P. H. Petersen, H. Tang, K. Zou, S. B. Stewart, W. Zhong, The mammalian Golgi regulates Numb signaling in asymmetric cell division by releasing ACBD3 during mitosis.
Cell
129
, 163-178 (2007).
[Online Journal]
Pancreatic β Cell Proliferation Is Stimulated by Wnt Signaling
Authors: Foley John F.
Published: July 2007

Both type 1 and type 2 diabetes result from a loss of pancreatic β cell mass. There is considerable interest, therefore, in understanding the mechanisms responsible for β cell proliferation. Previous studies have shown that various components of the Wnt signaling pathway are found in the pancreas and that dysregulation of this pathway can result in reduced islet mass, but the exact mechanisms involved are unknown. Wnts are small proteins that signal though cell surface receptors called Frizzleds, leading to the stabilization and accumulation of β-catenin. This protein then translocates to the nucleus, where it interacts with transcription factors to control the transcription of target genes. Rulifson
et al
. investigated this link between the Wnt pathway and β cell proliferation by treating cultured mouse pancreatic islets with purified Wnt3a. Immunohistochemical analysis demonstrated increased amounts of Ki67, a marker of cell proliferation. Treatment of islets with Wnt3a also increased the abundance of the mRNAs for the transcription factor Pitx2, a known downstream target of β-catenin, and cyclin D2, a protein involved in control of the cell cycle. Chromatin immunoprecipitation assays revealed that Wnt3a directed the association of Pitx2 with the
cyclin D2
gene. Mice with pancreas-specific expression of a constitutively active form of β-catenin had increased β cell proliferation and higher serum insulin levels than did wild-type mice. In contrast, transgenic mice with pancreas-specific inducible expression of Axin, a negative regulator of β-catenin, had reduced islet mass, lower insulin production, and lower abundance of Pitx2 and cyclin D2 than did wild-type mice. This study provides mechanistic evidence of the importance of Wnt signaling for β cell proliferation.

I. C. Rulifson, S. K. Karnik, P. W. Heiser, D. ten Berge, H. Chen, X. Gu, M. M. Taketo, R. Nusse, M. Hebrok, S. K. Kim, Wnt signaling regulates pancreatic β cell proliferation. Proc. Natl. Acad. Sci.
USA
104
, 6247-6252 (2007).
[Abstract]
[Full Text]
Enabling Endocrine Action of Fibroblast Growth Factors
Authors: Ray L. Bryan
Published: July 2007

There are 18 members of the fibroblast growth factor family. Most of these growth factors act in a paracrine manner, mediating signals between epithelial and mesenchymal cell layers that are critical for development. Three members of the fibroblast growth factor family, FGFs 19, 21, and 23, are unusual in that they function in an endocrine manner and regulate physiological processes distinct from those controlled by other family members, including glucose and lipid metabolism, energy and bile acid homeostasis, and regulation of phosphate and vitamin D concentrations. Goetz
et al
. solved the crystal structures of FGF19 and FGF23 alone or in complex with sucrose octasulfate, a disaccharide used to approximate binding of the receptors to heparin sulfate. Binding of most FGF proteins to their receptors is enhanced through interaction with heparin sulfate. However, the authors found that heparin binding appeared to be disrupted in FGF19 and FGF23, and they went on to confirm this in surface plasmon spectroscopy experiments. The authors propose that this failure to bind strongly to heparin sulfate allows these growth factors to avoid being retained by the pericellular heparin sulfate in the location where they are produced and to instead serve their endocrine signaling function. FGF19- and FGF23-receptor complexes have recently been shown to interact with Klotho or βKlotho proteins. Thus, the authors propose that Klotho proteins, rather than heparin sulfate, may serve to enhance receptor binding by FGF19 and FGF23, thereby restricting the endocrine actions of these factors to tissues where Klotho proteins are available.

R. Goetz, A. Beenken, O. A. Ibrahimi, J. Kalinina, S. K. Olsen, A. V. Eliseenkova, C. Xu, T. A. Neubert, F. Zhang, R. J. Linhardt, X. Yu, K. E. White, T. Inagaki, S. A. Kliewer, M. Yamamoto, H. Kurosu, Y. Ogawa, M. Kuro-o, B. Lanske, M. S. Razzaque, M. Mohammadi, Molecular insights into the Klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members.
Mol. Cell. Biol.
27
, 3417-3428 (2007).
[Abstract]
[Full Text]
Double Source for S1P
Authors: Simpson Stephen
Published: July 2007

Sphingosine 1-phosphate (S1P) is a circulating lipid mediator that induces the egress of lymphocytes from lymphoid organs. The immunomodulatory effects of S1P are made apparent by the absence of circulating lymphocytes in mice that are unable to support its production and by the encouraging results of clinical trials aimed at targeting this pathway to suppress transplant rejection and autoimmunity. Pappu
et al
. use a combination of conditional gene deletion and bone marrow chimerism to illuminate two sources of S1P in the blood and lymphatic circulation. By sustaining S1P levels outside the lymphoid organs, these supplies allow lymphocytes to follow a gradient between the lymphoid tissue--where S1P is catabolized to low levels--and the two circulatory systems. This insight may help refine approaches of immune suppression and activation via the S1P pathway.

R. Pappu, S. R. Schwab, I. Cornelissen, J. P. Pereira, J. B. Regard, Y. Xu, E. Camerer, Y.-W. Zheng, Y. Huang, J. G. Cyster, S. R. Coughlin, Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate.
Science
316
, 295-298 (2007).
[Abstract]
[Full Text]

J. Chun, The sources of a lipid conundrum.
Science
316
, 208-210 (2007).
[Summary]
[Full Text]
Pollen-Pistil Signaling in Self-Incompatible Poppy: Does It Allow More Efficient Resource Allocation in the Pistil?
Authors: McClure Bruce
Published: July 2007

In the process of pollination, haploid pollen germinates on the stigma surface and a pollen tube grows through the diploid tissues of the pistil toward the ovary. The pistil has two basic functions: to prevent unwanted pollen from gaining access to the ovary and to support the growth of desirable pollen. Pollen-pistil signaling allows these different types of pollen to be distinguished. Self-incompatibility (SI) systems, controlled by the
S
locus, are the best-understood pollen-pistil signaling systems. Other SI systems have been investigated at the molecular level, but the physiology of pollen tube rejection is best understood in the field poppy,
Papaver rhoeas
. This species has a gametophytic SI system: Pollen is rejected when its
S
haplotype is the same as either of the two
S
haplotypes expressed in the diploid pistil. Recent advances reveal new ways that SI controls pollen tube metabolism. A soluble pyrophosphatase is down-regulated as part of the rapid SI response, and, over the long term, perturbations of the actin cytoskeleton lead to programmed cell death in incompatible pollen tubes. Manipulating incompatible pollen tube metabolism in this way may leave more resources available for supporting the growth of compatible pollen tubes, the complementary function of the pistil.
Focus Issue: Keeping the Immune Response in Check
Authors: Foley John F. , Adler Elizabeth M. , Gough Nancy R.
Published: July 2007

When exploring control of a biological system such as the inflammatory response, we often think first of mechanisms that promote activation of the system. But just as important are the signals that that modulate and terminate these processes. Unchecked recruitment and infiltration of leukocytes into tissues and the unrestrained production of pro-inflammatory cytokines and chemokines can lead to tissue damage and even cancer. This issue of
Science’s
STKE highlights studies that enhance our understanding of how pro-inflammatory signals are switched on, and--equally important--how they are switched off.
Professional and Part-Time Chemokine Decoys in the Resolution of Inflammation
Authors: Hansell Chris , Nibbs Robert
Published: July 2007

Inflammation is essential for protection from infection and for the repair of damaged tissue. Much is now known about how inflammation is induced and maintained, but the processes underlying the resolution of inflammation are often overlooked. However, resolution is an essential component of all successful inflammatory responses because it ensures the restoration of tissue homeostasis and prevents immunopathology of the type seen in chronic inflammatory diseases and autoimmunity. Small secreted proteins called chemokines, acting through chemokine receptors, are known to be critical regulators of leukocyte recruitment and function during the initiation and maintenance of inflammation. Thus, their efficient removal would seem to be a prerequisite for successful resolution. In recent years, it has emerged that specialized chemokine "decoy" receptors exist that actively participate in this process. Moreover, other chemokine receptors have been proposed to lead a double life and perform opposing roles during inflammation: leukocyte recruitment (by signaling) and resolution (by chemokine sequestration). A recent study provides further support for this theory by showing that apoptotic inflammatory leukocytes increase the number of surface chemokine receptors and that these receptors can remove chemokines from inflamed tissue. Leukocyte apoptosis is already known to aid resolution, not just because it eliminates leukocytes from inflamed tissues, but also because their consumption by macrophages leads to the production of anti-inflammatory cytokines. The new work indicates that chemokine sequestration may be another mechanism exploited by dying cells to assist in the resolution of inflammation.
Striking Back at the Activator: How IκB Kinase Terminates Antigen Receptor Responses
Authors: Hinz Michael , Scheidereit Claus
Published: July 2007

Antigen recognition by the T cell receptor (TCR) elicits several intracellular signaling cascades, one of which activates the transcription factor NF-κB through IκB kinases (IKK). NF-κB regulates lymphocyte differentiation, proliferation, and apoptosis; thus, tight temporal control of its activation is required to prevent harmful immune cell dysregulation. Although considerable insight into the IKK and NF-κB activation process has emerged, less is known about the temporal regulation and termination of immunoreceptor signaling. Two recent studies have revealed that the scaffold protein Bcl10—which, together with CARMA1 and Malt1, forms the TCR-induced IKK-activating CBM complex—is a negative feedback substrate for IKK. IKKβ initially contributes to CBM formation—which is required for full IKK activation—and then, through carboxyl-terminal Bcl10 phosphorylation, disrupts this structure to terminate signaling. IKK triggers Bcl10 degradation by the ubiquitin-proteasome system through phosphorylation of Bcl10 at other sites. Thus, inactivation through negative feedback mechanisms is an intrinsic property of the TCR-induced NF-κB pathway.
Serotonin’s Axon Guidance Switch
Authors: Ray L. Bryan
Published: July 2007

Alterations in signaling by the neurotransmitter serotonin (also called 5-hydroxytryptamine or 5-HT) are associated with psychiatric illnesses, including anxiety disorders and depression. Such effects may reflect abnormal signaling at synapses in adult brain or changes in brain development, during which serotonin is also present and influences pathfinding by thalamocortical neurons. Bonnin
et al
. provide mechanistic insight into how changes in serotonin signals can disrupt axon migration. In cultured explants from the dorsal thalamus of mice, axons are normally attracted to HEK-293 cells in the same culture that are engineered to express the axon guidance protein netrin-1. But when the authors treated the explants with serotonin, the axons reversed their response to netrin-1 and were repelled from the cells producing the netrin-1. This response was caused by decreased synthesis of the second messenger cAMP (adenosine 3′,5′-monophosphate) in the serotonin-stimulated dorsal thalamus neurons. Pharmacological inhibition of the cAMP-dependent protein kinase could reproduce the effect of serotonin, and activation of the kinase blocked the serotonin effect. To show the importance of this effect in vivo, the authors used targeted electroporation of the developing brain in mouse embryos in the mother’s uterus, thereby causing the cells of the dorsal thalamus to express more serotonin receptors (to enhance signaling) or to express small interfering RNA to the receptors (to limit serotonin signaling). At the same time, the authors introduced a plasmid encoding a fluorescent marker protein that allowed them to trace the growth of the transfected axons. Increasing and decreasing serotonin signaling produced opposite effects, and both caused abnormal migration trajectories of the thalamus axons. Thus the authors propose that developmental abnormalities in serotonin signaling--either too much or too little--may alter the circuitry of thalamocortical axons and thus alter brain functions that later contribute to mental health disorders.

A. Bonnin, M. Torii, L. Wang, P. Rakic, P. Levitt, Serotonin modulates the response of embryonic thalamocortical axons to netrin-1.
Nat. Neurosci.
10
, 588-597 (2007).
[PubMed]
Target the Bridges in Signaling Networks
Authors: Gough Nancy R.
Published: July 2007

The ability to identify essential components in signaling networks may allow for targeted disruption of the processes controlled by these networks. Yu
et al
. wanted to determine whether it was more important that a protein be highly connected (a hub) or that it have a high degree of "betweenness" (a bottleneck), a protein through which many nonredundant paths through the network proceed. They defined four types of nodes in a pathway--hub-bottleneck node, nonhub-bottleneck node, hub-nonbottleneck node, or nonhub-nonbottleneck node--and then analyzed signaling networks, metabolic networks, and protein interaction networks to determine what types of nodes correlated best with essential genes in each type of network. In signaling networks, hub-bottlenecks and nonhub-bottlenecks were likely to be encoded by essential genes, whereas hub-nonbottlenecks were not. Thus, for signaling networks, "betweenness" may be a better indicator of essentialness than is connectedness alone, perhaps because signaling pathways have directed information flow through the network. A further refinement of the nonhub-bottleneck nodes was based on dividing the nodes into those that participate in "permanent" interactions, such as those that hold protein complexes together, versus those that are "transient," mediating temporary protein interactions. Not surprisingly, those nonhub-bottleneck nodes defined as permanent were more likely to be encoded by an essential gene than were the transient nonhub-bottlenecks. Based on their analysis, the authors suggest that nonhub-bottlenecks may represent the points of pathway crosstalk. Cak1p, which is encoded by an essential gene in yeast and is a cyclin-dependent protein kinase-activating kinase, is presented as an example of a nonhub-bottleneck that connects two signaling pathways: regulation of the cell cycle and the sporulation pathway.

H. Yu, P. M. Kim, E. Sprecher, V. Trifonov, M. Gerstein, The importance of bottlenecks in protein networks: Correlation with gene essentiality and expression dynamics.
PLoS Comput. Biol.
3
, e59 (2007).
[PubMed]
Pulling the Trigger for Apoptosis
Authors: Ray L. Bryan
Published: July 2007

No signaling system is more important to the cell than the elaborate ones that switch cells from survival mode to the process of cell death or apoptosis. The so-called "death receptor"--known alternatively as CD95, Fas, or APO-1--activates one such apoptosis pathway. To better understand the multiple components that influence the cell’s response to activation of CD95, Lavrik
et al
. used a combination of mathematical modeling and quantitative experiments to decipher the key factors that produce a cell committed to undergo apoptosis. The authors used a cultured cell line derived from human B lymphoblastoid cells (SKW6.4) to further explore their earlier model, which showed that the cells undergo apoptosis only if subjected to a certain threshold of CD95 activation. The activated receptor forms a complex with multiple other proteins, including procaspase 8 (which, when activated, promotes apoptosis) and also an inhibitor of caspase 8 called c-FLIP. The threshold response might mean that low doses of ligand (the authors use an activating antibody, anti-CD95) activate a small amount of caspase 8 that is insufficient to cause apoptosis or, as predicted in the authors’ mathematical model, no activation of caspase 8 until the appropriate threshold is reached. The authors’ experiments, including quantitative Western blotting to estimate the binding affinities of procaspase 8 and c-FLIP at the receptor complex, confirmed that under conditions of subthreshold stimulation of CD95, the binding affinity of c-FLIP for the receptor complex was higher than that of procaspase 8, leading to a suppression of activation of caspase 8. In fact, under these conditions of subthreshold stimulation, CD-95 actually produced a prosurvival signal through activation of the mitogen-activated protein kinases ERK1 and p38, a signal that apparently predominates over the restrained cell death signal. According to the authors’ model, if CD95 does become sufficiently activated, then enough procaspase 8 accumulates in the receptor complex, and becomes activated, to tip the balance and overcome the survival signal. The authors point out that, to develop appropriate therapeutic strategies for diseases in which apoptosis is a factor, it is essential to understand the detailed molecular mechanisms by which such life and death switches are controlled.

I. N. Lavrik, A. Golks, D. Riess, M. Bentele, R. Eils, P. H. Krammer, Analysis of CD95 threshold signaling: Triggering of CD95 (FAS/APO-1) at low concentrations primarily results in survival signaling.
J. Biol. Chem.
282
, 13664-13671 (2007).
[Abstract]
[Full Text]
When One Leaf Is Eaten, Do the Other Leaves Feel It?
Authors: Foley John F.
Published: July 2007

Plants have developed a number of defense mechanisms against attacks by herbivores. In the case of
Nicotiana attenuata
(coyote tobacco), these mechanisms include the production of jasmonic acid (JA) and ethylene, two compounds with well-characterized roles in host defense. The oral secretions (OS) from larvae of the herbivore
Manduca sexta
(the tobacco hornworm) contain factors that are important in eliciting these defense responses; however, the signal transduction pathways involved are not well understood. Mitogen-activated protein kinase (MAPK) signaling is known to be involved in mediating the response of plants to various forms of stress, and two members of this family, salicylic acid-induced protein kinase (SIPK) and wound-induced protein kinase (WIPK), are rapidly activated after leaf wounding. Wu
et al
. investigated the response of
N. attenuata
to puncture wounds of the leaves that were treated either with water, as a control, or with the OS of
M. sexta
. Real-time polymerase chain reaction and Western blotting analyses demonstrated that, whereas wounding resulted in the production of SIPK and WIPK mRNAs and proteins, as expected, the addition of OS resulted in much higher amounts of these kinases being produced. Other responses to OS included the production and activation of transcription factors and other MAPKs, as well as the synthesis of JA. Notably, these responses to OS were much reduced in plants that had been modified by virus-induced gene silencing to block production of either SIPK or WIPK. SIPK, but not WIPK, was necessary to mediate the production of ethylene. By selectively wounding and testing different parts of a given leaf, the authors found that OS elicited SIPK and WIPK activation in both wounded and unwounded locations. Other leaves on the same plant showed evidence of increased transcription of other genes (downstream of JA signaling) that are involved in host defense, but without the activation of MAPKs. These data suggest that attack by an herbivore results in the acute localized activation of SIPK, WIPK, and the MAPK cascade, resulting in the production of JA and ethylene, which then prime other leaves to be ready to respond in case one leaf is not enough of a meal for the larva.

J. Wu, C. Hettenhausen, S. Meldau, I. T. Baldwin, Herbivory rapidly activates MAPK signaling in attacked and unattacked leaf regions but not between leaves of
Nicotiana attenuata
.
Plant Cell
19
, 1096-1122 (2007).
[Abstract]
[Full Text]
Plastid Distress Signal
Authors: Hines Pamela J.
Published: July 2007

Plastids, including plant chloroplasts, are built and operated largely under the control of the nuclear genome. Largely, but not exclusively: plastids carry their own residual genome and can talk back when things go awry. Koussevitzky
et al
. now show that several signaling pathways that carry news of disaster from the plastid to the nucleus actually converge into one signaling pathway before the news emerges from the chloroplast. Thus, the nucleus receives a coherent report that integrates several aspects of chloroplast function. Gun1 protein is identified as a key integrator within the chloroplast, and ABI4 as a key transcription factor within the nucleus that responds to the news by altering gene transcription.

S. Koussevitzky, A. Nott, T. C. Mockler, F. Hong, G. Sachetto-Martins, M. Surpin, J. Lim, R. Mittler, J. Chory, Signals from chloroplasts converge to regulate nuclear gene expression.
Science
316
, 715-719 (2007).
[Abstract]
[Full Text]

D.-P. Zhang, Signaling to the nucleus with a loaded GUN.
Science
316
, 700-701 (2007).
[Summary]
[Full Text]
Synaptic Communication
Authors: Stern Peter
Published: July 2007

The traditional view of pyramidal neurons, which are excitatory, is that they can only excite their downstream target cells. However, Ren
et al
. report that cortical pyramidal neurons can elicit an inhibitory synaptic current in another neighboring pyramidal neuron. These unusual responses were caused by axo-axonic disynaptic connections onto γ-aminobutyric acid (GABA)-releasing terminals located on or near the soma of the postsynaptic pyramidal cell. These so-called interpyramidal inhibitory postsynaptic currents were remarkably large and frequent, which suggests that they play an important role.

M. Ren, Y. Yoshimura, N. Takada, S. Horibe, Y. Komatsu, Specialized inhibitory synaptic actions between nearby neocortical pyramidal neurons.
Science
316
, 758-761 (2007).
[Abstract]
[Full Text]
Tau Reduction and Cognitive Decline
Authors: Hurtley Stella M.
Published: July 2007

The brain pathology in Alzheimer’s disease involves both neurofibrillary tangles rich in the protein tau and plaques containing amyloid-β peptide (Aβ), but the relative contribution of each to cognitive impairment is unclear. Roberson
et al
. found that cognitive and neuronal deficits in two transgenic mouse models of Alzheimer’s disease are prevented when endogenous tau production is eliminated or reduced by 50%. The effect of tau reduction was robust, despite the absence of tau mutations, hyperphosphorylation, overexpression, or aggregation into neurofibrillary tangles in these models. Tau reduction did not block plaque-associated neuritic dystrophy, indicating that neuritic dystrophy can be dissociated both from tau and from Aβ-induced cognitive impairments.

E. D. Roberson, K. Scearce-Levie, J. J. Palop, F. Yan, I. H. Cheng, T. Wu, H. Gerstein, G.-Q. Yu, L. Mucke, Reducing endogenous tau ameliorates amyloid β-induced deficits in an Alzheimer’s disease mouse model.
Science
316
, 750-754 (2007).
[Abstract]
[Full Text]
Linking Inflammation and Metabolism
Authors: Ray L. Bryan
Published: July 2007

Food is good for you--but only up to a point. In fact, the complications of excess nutrients and consequent obesity represent major factors influencing human health. Obesity, metabolic diseases like diabetes, and exposure to excess nutrients are all associated with inflammatory responses. Wellen
et al
. suspected that there might be natural regulatory factors that limit inflammation during fluctuations in nutrient load. They therefore conducted gene expression screens and identified STAMP2 [six-transmembrane protein of prostate 2, also known as TNF-induced adipose-related protein (TIARP) or six-transmembrane epithelial antigen of prostate 4 (STEAP)] as a protein whose mRNA was decreased in adipose tissue of obese animals lacking proinflammatory signaling by tumor necrosis factor-α (TNFα). Expression of STAMP2 mRNA and protein in adipose tissue was increased after feeding of normal, but not obese, mice. When expression of STAMP2 was decreased with RNAi in cultured 3T3-L1 adipocytes, the cells showed an increased inflammatory response (cytokine production) in response to excess glucose or stimulation with TNFα, which correlated with impaired responses of the cells to insulin. In
STAMP2
–/–
mice, the authors observed increased inflammatory responses when they intraperitoneally administered glucose and lipid. Even when fed on a normal diet, the
STAMP2
–/–
mice showed changes in body weight, glucose metabolism, and lipid metabolism characteristic of metabolic disease, including fat accumulation, glucose intolerance, and insulin resistance. The molecular mechanisms by which STAMP2 functions remain to be determined. The protein has metalloreductase activity and appears to function in cellular uptake of iron and copper. Whatever its mechanism of action, the authors argue that STAMP2 appears to have a central role in coordination of nutrient balance and metabolism with inflammatory responses.

K. E. Wellen, R. Fucho, M. F. Gregor, M. Furuhashi, C. Morgan, T. Lindstad, E. Vaillancourt, C. Z. Gorgun, F. Saatcioglu, G. S. Hotamisligil, Coordinated regulation of nutrient and inflammatory responses by STAMP2 is essential for metabolic homeostasis.
Cell
129
, 537-548 (2007).
[Online Journal]
Pseudopodial Proteome
Authors: Gough Nancy R.
Published: July 2007

There is abundant evidence for polarity of moving cells. Certain signaling pathways are critical for cell movement, some key signaling molecules are inhomogeneously distributed in the cell, and dramatic reorganization of the cytoskeleton occurs primarily at the front of the cell. Wang
et al
. provide new insights into these phenomena through the global analysis of the proteome and phosphoproteome in the cell body versus the pseudopod at the front of a moving cell. Cos-7 cells were grown on microporous filters and then exposed to a chemotactic agent. The pseudopods were manually separated from the cell bodies, and the two fractions were subjected to liquid-chromatography-coupled tandem mass spectrometry (LC-MS/MS) or phosphoprotein analysis by immobilized metal affinity chromatography of isotopically labeled samples. About 3500 proteins were identified by LC-MS/MS; ~1300 were evenly distributed between the cell body and the pseudopod, and approximately equal numbers (~1100) were selectively enriched in either the cell body or the pseudopod. Not surprisingly, the cell body was enriched in proteins involved in nuclear receptor signaling, cell cycle regulation, and DNA and RNA metabolism, whereas the pseudopod was enriched in proteins that regulate the actin cytoskeleton, integrin signaling, and axon guidance. Phosphoproteome analysis identified 228 peptides, one-third of which were enriched in the pseudopod and ~40% of which were enriched in the cell body. The phosphorylated proteins fell into four categories: (i) Those for which high phosphorylation correlated with high abundance within a particular compartment, (ii) those for which abundance and phosphorylation were inversely correlated, (iii) those for which abundance was relatively uniform but phosphorylation was enriched in one compartment, and (iv) those for which the phosphorylated proteins were uniformly distributed but site-specific phosphorylation was enriched in one compartment. The proteins that activate or inhibit mitogen-activated protein kinase ERK, which is known to function in chemotaxis, were analyzed in greater detail, and the authors constructed three pathways by which ERK could be activated in chemotaxing cells: one from the G protein-coupled receptor activated by lysophosphatidic acid, one from transactivation of epidermal growth factor receptors, and one from integrins. Negative influences were also noted.

Y. Wang, S.-J. Ding, W. Wang, J. M. Jacobs, W.-J. Qian, R. J. Moore, F. Yang, D. G. Camp, II, R. D. Smith, R. L. Klemke, Profiling signaling polarity in chemotactic cells.
Proc. Natl. Acad. Sci. U.S.A.
104
, 8328-8333 (2007).
[Abstract]
[Full Text]
Real-Life Transcription Factor Dynamics
Authors: Vinson Valda
Published: July 2007

Transcription factors bind to specific sites on chromosomal DNA to regulate gene expression. It is generally thought that transcription factors find their target DNA through a combination of diffusion through the cytoplasm and diffusion along DNA segments. Elf
et al.
use single-molecule techniques to study the specific and nonspecific binding of a model transcription factor, the
lac
repressor, in living
Escherichia coli
.
Lac
repressor searching for an operator spends 90% of its time diffusing along DNA. If the repressor does not find an operator within 5 milliseconds, it falls off the DNA and diffuses through the cytoplasm to bind to another DNA segment. Such single-molecule approaches will move us toward a quantitative understanding of biochemical processes as they occur in living cells.

J. Elf, G.-W. Li, X. S. Xie, Probing transcription factor dynamics at the single-molecule level in a living cell.
Science
316
, 1191-1194 (2007).
[Abstract]
[Full Text]
Marijuana and Developmental Damage
Authors: Stern Peter
Published: July 2007

The effects of marijuana are mediated by cannabinoid receptors on neurons in the brain, and a causal relation between marijuana use during pregnancy and permanent cognitive deficits in the offspring has been identified. Berghuis
et al
. now define the molecular hierarchy that controls marijuana actions within single neurons and show that activation of cannabinoid receptors by their natural ligands controls the establishment of functional connections between neurons in the brain. These findings define the cellular context through which prenatal marijuana use perturbs brain development.

P. Berghuis, A. M. Rajnicek, Y. M. Morozov, R. A. Ross, J. Mulder, G. M. Urbán, K. Monory, G. Marsicano, M. Matteoli, A. Canty, A. J. Irving, I. Katona, Y. Yanagawa, P. Rakic, B. Lutz, K. Mackie, T. Harkany, Hardwiring the brain: Endocannabinoids shape neuronal connectivity.
Science
316
, 1212-1216 (2007).
[Abstract]
[Full Text]