bluuebunny/crossref_metadata_2025 huggingface dataset:
Dueling Regulators
Authors: Adler Elizabeth M.
Published: March 2007

To investigate the mechanisms whereby phosphoinositides (PIs) regulate members of the TRP (transient receptor potential) family of ion channels, Kwon
et al
. focused on TRPC6, a channel modulated both by phosphatidylinositol 3,4,5-trisphosphate (PIP
3
) and by calmodulin. Various PIs bound directly to a fusion protein containing the C-terminal region of TRPC6, and mutational analysis revealed that the PI-binding site overlapped that for calmodulin (PCaM domain). PIs disrupted calmodulin binding to the C-terminal region of TRPC6 in an in vitro assay, with PIP
3
being most potent; mutational analysis indicated that this interaction involved the PCaM domain. When expressed in human embryonic kidney (HEK) 293T cells, a TRPC6 mutant associated with decreased potency of PIs in disrupting calmodulin binding displayed reduced whole-cell currents relative to wild-type after TRPC6 activation, whereas a TRPC6 mutant associated with enhanced potency of PI disruption of calmodulin binding showed larger peak currents. Experiments in which intracellular calcium was buffered or in which calmodulin was overexpressed supported the idea that calcium-calmodulin inhibits TRPC6 activity and that PIs enhance TRPC6 function by disrupting the TRPC6-calmodulin interaction, as did experiments in which an AKT-PH domain was overexpressed to act as a PIP
3
"sponge." Other TRP family channels thought to bind calmodulin also bound PIs; with some of these, PIs reduced calmodulin binding. PIs also reduced calmodulin binding to the KCNQ1 potassium channel and the Ca
v
1.2 calcium channel. Thus, the authors propose that PI regulation of calmodulin binding may represent a common mechanism for modulating ion channel function.

Y. Kwon, T. Hofmann, C. Montell, Integration of phosphoinositide- and calmodulin-mediated regulation of TRPC6.
Mol. Cell
25
, 491-503 (2007).
[Online Journal]
Smelling Their Way to an Early Grave
Authors: Kelner Katrina L.
Published: March 2007

When animals are reared on a near-starvation diet, they live much longer than those that eat freely. Even the fruit fly
Drosophila
has this reaction to a low-glucose diet and lives considerable longer on a 5% than on a 15% sugar-yeast diet. This effect of dietary restriction is easily reversed when flies consume more food. Libert
et al
. report a less expected effect: Just the smell of the flies’ food (yeast) can inhibit some of the effects of dietary restriction and shorten the flies’ life span by 6 to 18%. Flies lacking an essential part of their odor receptors, which have greatly impaired senses of smell, live longer than flies with intact odor sensation.

S. Libert, J. Zwiener, X. Chu, W. VanVoorhies, G. Roman, S. D. Pletcher, Regulation of
Drosophila
life span by olfaction and food-derived odors.
Science
315
, 1133-1137 (2007).
[Abstract]
[Full Text]

M. Leslie, Odor of food hastens dieting flies’ deaths.
Science
315
, 584 (2007).
[Summary]
[Full Text]
The Heart of Metabolic Syndrome?
Authors: Kiberstis Paula A.
Published: March 2007

Patients with coronary artery disease (CAD) often have accompanying hypertension, diabetes, and aberrant levels of cholesterol and triglycerides. This diverse group of risk factors is collectively known as "metabolic syndrome," but the underlying molecular mechanisms that link these disorders are still poorly understood. Mani
et al
. have identified the causative mutation in a family afflicted with a rare, inherited form of early-onset CAD that cosegregates with many features of metabolic syndrome. The culprit gene encodes low-density lipoprotein receptor-related protein 6 (LRP6), a co-receptor in the Wnt cellular signaling pathway.

A. Mani, J. Radhakrishnan, H. Wang, A. Mani, M.-A. Mani, C. Nelson-Williams, K. S. Carew, S. Mane, H. Najmabadi, D. Wu, R. P. Lifton,
LRP6
mutation in a family with early coronary disease and metabolic risk factors.
Science
315
, 1278-1282 (2007).
[Abstract]
[Full Text]
Caspase for Cell Movement
Authors: Gough Nancy R.
Published: March 2007

Caspases are well known for their roles in programmed cell death and for their roles in maturation of inflammatory cytokines. Li
et al
. now show that caspase 11 also has a role in regulating actin dynamics that contributes to cell migration. Leukocytes deficient for caspase 11 were defective in cell migration in culture (transwell assays) and in vivo. When injected into host mice, these cells were defective in homing (leaving the blood and reaching the target organs). Affinity purification experiments identified actin interacting protein 1 (AIP1) as a binding partner for caspase 11. Coimmunoprecipitation experiments with various truncation mutants of AIP1 and caspase 11 showed that the CARD domain of caspase 11 and the C-terminal WD propeller domain of AIP1 were required for the interaction. Notably, the protease domain of caspase 11 was not required. RNA interference experiments confirmed that AIP1 was important for cell migration with membrane ruffling defective in the absence of AIP1 (ruffling was also defective in the caspase 11-deficient cells). Overexpression of a catalytically inactive caspase 11 restored migration to the AIP knockdown cells. In vitro actin polymerization assays showed that caspase 11 synergized with AIP1 to stimulate cofilin-mediated actin depolymerization, whereas caspase 11 in the absence of AIP1 did not affect cofilin-mediated actin depolymerization. In an actin pelleting assay, the addition of caspase 11 with cofilin and AIP1 increased the soluble actin, consistent with enhanced depolymerization. This did not require protease activity, as it was not inhibited by the addition of a pan-caspase inhibitor. The action of caspase 11 did require the presence of AIP1. In the presence of actin alone, caspase 11 was shifted to the pellet, suggesting an interaction with the actin filament; in the presence of cofilin and AIP1, caspase 11 shifted to the supernatant, suggesting an interaction with the actin monomers as well. Thus, caspase 11 now appears to influence multiple inflammatory cell processes: cytokine secretion, apoptosis, and cell migration. The authors propose that caspase 11 may serve early in the inflammatory response by aiding the delivery of cytokine-producing cells to the site of infection and then by terminating cytokine production through stimulation of apoptosis. Bailly discusses the mechanisms of regulation of cofilin in an associated commentary.

J. Li, W. M. Brieher, M. L. Scimone, S. J. Kang, H. Zhu, H. Yin, U. H. von Andrian, T. Mitchison, J. Yuan, Caspase-11 regulates cell migration by promoting Aip1-cofilin-mediated actin depolymerization.
Nat. Cell Biol.
9
, 276-286 (2007).
[PubMed]

M. Bailly, Moving away from death: When caspase-11 meets cofilin.
Nat. Cell Biol.
9
, 245-246 (2007).
[PubMed]
The Calcium Sensor for Slow Afterhyperpolarization
Authors: Ray L. Bryan
Published: March 2007

Neurons in the brain protect themselves from excessive activity in part by a mechanism through which an influx of calcium ions activates potassium channels, which then cause hyperpolarization of the nerve cell, thus inhibiting further action potentials. The identity of this potassium channel is not known, but the current it conducts is called the slow afterhyperpolarization current (I
sAHP
). Tzingounis
et al
. identified a new key component of the mechanism by which calcium influences the channel: the neuronal calcium sensor family member known as hippocalcin. The authors interpreted results from kinetic analysis of I
sAHP
in the presence of various calcium buffers to indicate that I
sAHP
responded primarily to general changes in calcium concentration within the cell, as opposed to large rapid changes in calcium concentration in the immediate vicinity of calcium channels. The latter is characteristic of other potassium channels that exist together with calcium channels in large complexes in which the calcium sensor is bound to or part of the potassium channel. Instead, the sAHP channels appeared to be regulated by a diffusible calcium sensor, so the authors suspected hippocalcin. They found that, indeed, hippocampal slices from hippocalcin knockout mice lacked I
sAHP
, whereas expression of hippocalcin in cultured neurons enhanced I
sAHP
. Hippocalcin contains a "myristoyl switch," a mechanism by which a conformational change induced by calcium binding causes exposure of a myristoyl moiety that causes hippocalcin to bind to the plasma membrane. A mutant lacking the myristoylation site failed to increase I
sAHP
. The authors therefore propose that hippocalcin senses global changes in the concentration of intracellular free calcium and relays that information back to the plasma membrane. Brown
et al
. point out in commentary that elucidation of the mechanism by which hippocalcin actually regulates the sAHP channel, be it direct or through another messenger molecule (hippocalcin is known to bind phosphatidylinositol 4,5-bisphosphate), may be possible only when the so-far-elusive molecular identity of the sAHP channel itself is resolved.

A. V. Tzingounis, M. Kobayashi, K. Takamatsu, R. A. Nicoll, Hippocalcin gates the calcium activation of the slow afterhyperpolarization in hippocampal pyramidal cells.
Neuron
53
, 487-493 (2007).
[Online Journal]

D. A. Brown, B. Lancaster, M. M. Shah, Hippocalcin: A new solution to an old puzzle.
Neuron
53
, 467-468 (2007).
[Online Journal]
Atypical Antipsychotics Activate Hypothalamic AMPK
Authors: Adler Elizabeth M.
Published: March 2007

Although atypical antipsychotic drugs (AAPDs) are currently the most commonly used treatments for schizophrenia, some of them stimulate a substantial weight gain--largely associated with increased food intake--that can lead to the development of diabetes and cardiovascular disease. Noting that activation of hypothalamic adenosine 5'-monophosphate-activated protein kinase (AMPK) is associated with increased food intake, Kim
et al
. explored the effects of AAPDs on AMPK phosphorylation (and thereby activation). Clozapine and olanzapine, two AAPDs that elicit weight gain, stimulated phosphorylation of AMPK in mouse hypothalamic slices, as did quetiapine, whereas antipsychotic drugs with less effect on appetite did not. Furthermore, clozapine stimulated the phosphorylation and catalytic activity of hypothalamic AMPK in intact mice. After confirming reports that the potency of AAPDs in blocking the histamine H
1
receptor (H1R) correlated with their tendency to stimulate weight gain (determined from the clinical literature), the authors showed that clozapine blocked the ability of histamine to decrease phosphorylation of AMPK in hypothalamic slices. Moreover, clozapine failed to stimulate AMPK phosphorylation in mice lacking the H1R. Thus, the authors conclude that the orexigenic effects of AAPDs likely involve blockade of the H1R and an associated activation of hypothalamic AMPK. In a thoughtful commentary, Meltzer notes that the first modern antipsychotic, chlorpromazine, was initially developed in a search for antihistamines.

S. F. Kim, A. S. Huang, A. M. Snowman, C. Teuscher, S. H. Snyder, Antipsychotic drug-induced weight gain mediated by histamine H
1
receptor-linked activation of hypothalamic AMP-kinase.
Proc. Natl. Acad. Sci. U.S.A.
104
, 3456-3459 (2007).
[Abstract]
[Full Text]

H. Y. Meltzer, Illuminating the molecular basis for some antipsychotic drug-induced metabolic burden.
Proc. Natl. Acad. Sci. U.S.A.
104
, 3019-3020 (2007).
[Full Text]
Drugs, Dopamine, and Disposition
Authors: Stern Peter
Published: March 2007

Individual differences in drug abuse reflect distinct behavioral and physiological traits. Dalley
et al
. found that, compared with controls, spontaneously impulsive rats had decreased dopamine D2/3 receptors in the nucleus accumbens even before exposure to cocaine. Trait impulsivity in rats was predictive of subsequent high rates of intravenous cocaine self-administration. Impulsivity is thus an important mediator of drug abuse vulnerability and not a consequence of chronic drug exposure.

J. W. Dalley, T. D. Fryer, L. Brichard, E. S. J. Robinson, D. E. H. Theobald, K. Lääne, Y. Peña, E. R. Murphy, Y. Shah, K. Probst, I. Abakumova, F. I. Aigbirhio, H. K. Richards, Y. Hong, J.-C. Baron, B. J. Everitt, T. W. Robbins, Nucleus accumbens D2/3 receptors predict trait impulsivity and cocaine reinforcement.
Science
315
, 1267-1270 (2007).
[Abstract]
[Full Text]
Flux at Focal Adhesions: Slippage Clutch, Mechanical Gauge, or Signal Depot
Authors: Wang Yu-li
Published: March 2007

Focal adhesions provide physical linkages between the interior of an adhesive cell and the extracellular matrix (ECM). They may be involved in mediating such functions as cell migration, anchorage, mechanical interactions with the ECM, and the detection of physical cues in the environment. Cell biologists have long struggled to piece together the complex array of components found at focal adhesions, and the equally complex network of interactions among these components, into a "machine" that performs these putative functions. Two recent studies, however, indicate that focal adhesions may be more amorphous and dynamic than previously envisioned. These studies found different degrees of correlated retrograde movement of various focal adhesion proteins with actin filaments, while integrins remained largely stationary. Such differential movements appear inconsistent with a precisely engineered machine and may reflect a slippage clutch for transmitting a variable amount of contractile force to the substrate for migration, a gauge of physical interactions at adhesive sites, or a mechanism for releasing signals from the adhesive sites to the interior of the cell.
How Smurfs Control Axon Formation
Authors: Ray L. Bryan
Published: March 2007

In the course of development, hippocampal neurons normally produce multiple equivalent neurites, only one of which eventually becomes the axon of a polarized neuron. The small guanosine triphosphatase (GTPase) Rap1B is a necessary and sufficient regulator of this process and is initially present in each of the neurites, but is later present only in the neurite destined to become the axon. Results from Schwamborn
et al
. show that this critical loss of Rap1B is mediated by ubiquitin-dependent degradation of the GTPase. Treatment of cultured hippocampal neurons from rat embryos with various inhibitors of the proteasome caused formation of extra axons. In transfected cells or in vitro binding assays, a catalytically inactive mutant of the ubiquitin ligase Smurf2 could be immunoprecipitated with a dominant-negative mutant of Rap1 and associated with nucleotide-free or GDP-bound Rap1, but not with Rap1 bound to a nonhydrolyzable analog of GTP. These results indicate that the ligase recognizes only inactive Rap1. Depletion of Smurf2 also caused formation of supernumerary axons in the cultured neurons. Thus, the authors propose that the ubiquitination and proteasome-dependent degradation of Rap1B is required for selection of a single neurite that becomes the axon. In their model, through a mechanism not yet revealed, one of the neurites would have higher activity of Rap1. Because the active GTPase is resistant to degradation, the Smurf-induced degradation would occur primarily in the remaining neurites with low Rap1B activity, thus converting the quantitative differences in Rap1B activity to a switchlike mechanism that allows only a single neurite to go on to form the axon.

J. C. Schwamborn, M. Müller, A. H. M. Becker, A. W. Püschel, Ubiquitination of the GTPase Rap1B by the ubiquitin ligase Smurf2 is required for the establishment of neuronal polarity.
EMBO J
.
26
, 1410-1422 (2007).
[Online Journal]
Releasing ErbB4
Authors: Adler Elizabeth M.
Published: March 2007

Early in development, the human zygote undergoes repeated cell divisions to form a blastocyst. Trophoectoderm cells, which form the blastocyst shell, mediate blastocyst attachment to uterine epithelial cells, triggering trophoblast proliferation and uterine invasion. Sugihara
et al
., a group that previously identified trophinin as a homophilic cell adhesion molecule expressed by trophoblasts and endometrial epithelium, found that adhesion to trophinin-expressing cells stimulated tyrosine phosphorylation in trophinin-expressing trophoblastic embryonal carcinoma HT-H cells. Peptides containing a glycine-tryptophan-arginine-glutamine motif (GWRQ, which the authors implicated in trophinin binding) stimulated tyrosine phosphorylation in HT-H cells, as well as actin polymerization and cell proliferation and motility. Western analysis indicated that the major protein phosphorylated in response to GWRQ was of a size consistent with that of ErbB-family epidermal growth factor (EGF) receptors, an identification supported by immunoprecipitation analysis. In vitro binding assays revealed that bystin, a protein known to interact with trophinin, also bound ErbB4. GWRQ reduced coimmunoprecipitation of trophinin with ErbB4 from HT-H cells and reduced their colocalization as assessed with immunofluorescence. In the absence of fetal calf serum in the culture medium, GWRQ failed to stimulate tyrosine phosphorylation in HT-H cells. GWRQ-dependent phosphorylation was restored by EGF or heparin-binding EGF-like growth factor (HB-EGF), neither of which stimulated tyrosine phosphorylation in the absence of GWRQ. When trophinin and bystin were knocked down with small interfering RNA, however, HB-EGF stimulated tyrosine phosphorylation whether or not GWRQ was present. Thus, the authors propose that trophinin inhibits ErbB4, an inhibition that is released by trophinin-mediated cell adhesion (mimicked by GWRQ binding), enabling ErbB4 activation and stimulating trophoblast proliferation and motility.

K. Sugihara, D. Sugiyama, J. Byrne, D. P. Wolf, K. P. Lowitz, Y. Kobayashi, M. Kabir-Salmani, D. Nadano, D. Aoki, S. Nozawa, J. Nakayama, T. Mustelin, E. Ruoslahti, N. Yamaguchi, M. N. Fukuda, Trophoblast cell activation by trophinin ligation is implicated in human embryo implantation.
Proc. Natl. Acad. Sci. U.S.A.
104
, 3799-3804 (2007).
[Abstract]
[Full Text]
Hindsight in the Switch from Mitotic Cycle to Endocycle
Authors: Gough Nancy R.
Published: March 2007

Follicle cells of the
Drosophila
egg chamber undergo a switch from mitotic cell divisions to endoreplication in which the DNA is replicated but the cells do not divide. Notch signaling is known to be an important input into the switch. In addition, decreased function of two regulators of the M phase of the cell cycle, Cut and String, is also required for this transition. Sun and Deng show that Notch stimulates the accumulation (based on antibody staining) of a zinc finger transcription factor called Hindsight (Hnt) and that Hnt appears to mediate this switch in cell cycle programs. Cells in which Notch signaling was defective did not show the usual increase in Hnt at the stage that the endoreplication cycle normally occurs. Cells in which Hnt function was decreased or absent showed delayed exit from the mitotic cell cycle and increased abundance of Cut and String compared with adjacent wild-type cells in mosaic egg chambers. Furthermore, premature expression of Hnt caused the cells to enter the endoreplication cycle earlier than did wild-type cells, and misexpression of Hnt also decreased the abundance and activities of Cut and String. Hedgehog signaling is present in the stages when the follicle cells are undergoing mitotic cell divisions, and then signaling through this pathway is decreased as the cells enter the stage of endoreplication. Sun and Deng show that Notch signaling is necessary for this inhibition of Hedgehog signaling and that Hnt appears to mediate this pathway crosstalk. Cells in which Hnt was defective showed elevated levels of Cubitus interruptus (Ci), a marker for Hedgehog signaling, whereas Ci is completely undetected in cells in which Hnt is misexpressed prematurely. Thus, Hnt appears to carry the Notch signal that opposes Hedgehog signaling and allows endoreplication to occur.

J. Sun, W.-M. Deng, Hindsight mediates the role of Notch in suppressing Hedgehog signaling and cell proliferation.
Dev. Cell
12
, 431-442 (2007).
[PubMed]
Eat Up to Meet Up
Authors: Simpson Stephen
Published: March 2007

Different members of the Toll-like receptor (TLR) family have evolved to recognize the distinct signatures left by pathogens, including the single-stranded (ss) and double-stranded nucleic acid genomes of viruses. In the case of plasmacytoid dendritic cells (pDCs), detection by TLRs culminates in a program of gene activation that helps these cells prime antiviral adaptive immune responses. The response to some viruses, such as influenza, is achieved without the need for replication of pDCs, which makes the process of immune activation less dependent on direct infection of pDCs. However, Lee
et al
. (see the Perspective by Reis e Sousa) show that for RNA viruses that generate replication intermediates in the cytosol, a direct indicator of viral replication is needed. In such cases, autophagy--the sequestering of organelles and long-lived proteins for delivery to the lysosome for degradation--helped unite ssRNA and its TLR sensing protein in the lysosome. It is not clear if this link between autophagy and innate recognition represents a broader means of facilitating immunity to pathogens.

H. K. Lee, J. M. Lund, B. Ramanathan, N. Mizushima, A. Iwasaki, Autophagy-dependent viral recognition by plasmacytoid dendritic cells.
Science
315
, 1398-1401 (2007).
[Abstract]
[Full Text]

C. Reis e Sousa, Eating in to avoid infection.
Science
315
, 1376-1377 (2007).
[Summary]
[Full Text]
Regulating Calcium in Plants
Authors: Hines Pamela J.
Published: March 2007

In
Arabidopsis
, the concentration of intracellular calcium fluctuates in a daily cycle, above and beyond other responses to signaling inputs. Tang
et al
. have now analyzed the interactions between intracellular and extracellular calcium concentrations, and various signaling components in between, to arrive at a complex view of calcium physiology in the plant. Not simply a passive reflection of external calcium status, the calcium levels within a resting cell are actively monitored and managed.

R.-H. Tang, S. Han, H. Zheng, C. W. Cook, C. S. Choi, T. E. Woerner, R. B. Jackson, Z.-M. Pei, Coupling diurnal cytosolic Ca
2+
oscillations to the CAS-IP
3
pathway in
Arabidopsis.
Science
315
, 1423-1426 (2007).
[Abstract]
[Full Text]
Changing the Histone Landscape
Authors: Riddihough Guy
Published: March 2007

In eukaryotes, histone proteins help package DNA into chromatin. Marks or covalent modifications on histones play an important role in the epigenetic regulation of gene expression, as well as DNA replication and repair. It has been assumed that the histones within chromatin will be fairly stable. Mito
et al
. and Dion
et al
. instead show that for certain regions of the genome in yeast and in
Drosophila
, there is a dramatic variation in histone H3 turnover rates. Coding regions in the genome were unexpectedly "quiet," and protein binding sites in promoters--and especially boundary elements--showed a very high level of turnover. In regions of high turnover, epigenetic marks must be in a state of constant flux, which provides the potential for their rapid and dynamic regulation.

Y. Mito, J. G. Henikoff, S. Henikoff, Histone replacement marks the boundaries of cis-regulatory domains.
Science
315
, 1408-1411 (2007).
[Abstract]
[Full Text]

M. F. Dion, T. Kaplan, M. Kim, S. Buratowski, N. Friedman, O. J. Rando, Dynamics of replication-independent histone turnover in budding yeast.
Science
315
, 1405-1408 (2007).
[Abstract]
[Full Text]
To Turn On or Turn Off: One Molecule’s Dilemma?
Authors: Foley John F.
Published: March 2007

Steroid receptor coactivator-3 (SRC-3) is a member of the SRC family of nuclear receptor coactivators and is known for its function as an enhancer of gene transcription. Although knockout studies show roles for SRC-3 in development, oncogenesis, and tumor suppression, little is known about its contribution to immune responses. In this study, Yu
et al
. first demonstrated that
SRC-3
−/−
mice were more susceptible to lipopolysaccharide (LPS)-induced endotoxic shock than were wild-type mice. The authors found increased concentrations of the proinflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1β in the sera of
SRC-3
−/−
animals. Peritoneal macrophages from
SRC-3
−/−
mice secreted more of these cytokines after treatment with LPS than did macrophages from wild-type mice. These effects were not observed in macrophages from
SRC-1
−/−
or
SRC-2
−/−
mice. Electrophoretic mobility shift assays revealed that LPS-induced activation of the transcription factor NF-κB was comparable in wild-type and
SRC-3
−/−
cells, ruling out a role for SRC-3 in repressing NF-κB activation. There were no differences in the abundance or half-lives of proinflammatory cytokine mRNAs when comparing wild-type and
SRC-3
−/−
macrophages, nor were there any differences in the secretion or stability of TNF-α. Polysomal profile analysis, which estimates the proportion of actively translating cytoplasmic mRNAs, revealed that the increased production of TNF-α and IL-1β by
SRC-3
−/−
macrophages was due to enhanced translation. SRC-3, which does not contain RNA-binding motifs, associated with the translational repressors TIA-1 and TIAR, providing a mechanism by which SRC-3 may repress mRNA translation. This study suggests that a coregulator protein can act as a transcriptional coactivator or a translational corepressor, depending on the cellular context.

C. Yu, B. York, S. Wang, Q. Feng, J. Xu, B. W. O’Malley, An essential function of the SRC-3 coactivator in suppression of cytokine mRNA translation and inflammatory response.
Mol. Cell
25
, 765-778 (2007).
[PubMed]
Maintaining the Integrity of the Intestinal Epithelial Cell Barrier
Authors: Foley John F.
Published: March 2007

The cytokine IL-6 (interleukin-6), which has both pro- and antiinflammatory properties, helps to maintain epithelial barrier function in the intestine. Members of a family of structural proteins called keratins form the intermediate filaments in the cytoskeleton of epithelial cells and have been shown to protect cells from injury. A mutation in keratin-8 is found in some patients with inflammatory bowel disease, and mice deficient in keratin-8 develop colonic problems. Wang
et al
. uncovered a connection between IL-6 and keratins, particularly keratin-8, in studies performed using a human colonic epithelial cell line and IL-6 knockout mice. Treatment of Caco2-BBE cells with IL-6 increased both keratin-8 and keratin-18 at the level of mRNA and protein. The authors used confocal microscopy to show that IL-6 increased these keratins in the subapical region of Caco2-BBE epithelia. Analysis with phosphospecific antibodies showed that IL-6 treatment increased keratin-8 phosphorylation, which is important for the regulation of keratin organization and function. By monitoring the permeability of Caco2-BBE epithelia to fluorescein isothiocyanate-dextran, the authors showed that IL-6 treatment resulted in decreased permeability of the epithelial barrier. Experiments using RNA interference showed that this decreased permeability was mediated by keratin-8, although loss of keratin-8 had no effect on epithelial permeability in the absence of IL-6. IL-6-deficient mice treated with dextran sodium sulfate showed increased intestinal permeability in comparison with wild-type mice. Together, these data implicate keratin-8 in mediating the protective effects of IL-6 on the integrity of the intestinal epithelial layer.

L. Wang, S. Srinivasan, A. L. Theiss, D. Merlin, S. V. Sitaraman, Interleukin-6 induces keratin expression in intestinal epithelial cells.
J. Biol. Chem.
282
, 8219-8227 (2007).
[PubMed]
Using the TIR Domain to Recognize Pathogens
Authors: Gough Nancy R.
Published: March 2007

Plants respond to pathogens with a response called the hypersensitive response that involves necrotic cell death of the infected tissue to prevent further infection. Mounting this response involves the recognition of pathogen elicitor proteins and the plant products of the
Resistance
(
R
) genes, but the exact mechanism remains unclear. Burch-Smith
et al
. used the p50 helicase domain of the Tobacco mosaic virus replicase protein to study in plants the interaction between this p50 protein elicitor and the product of the
N
gene, which encodes an R protein with a leucine-rich repeat (LRR), a nucleotide-binding (NB) site, and a Toll-interleukin-1 receptor (TIR) homolog domain. Plant tissue in which a tagged version of p50 and a tagged version of N were coexpressed exhibited the hypersensitive response. Biochemical fractionation indicated that both proteins were soluble, and fluorescence analysis indicated that both proteins could be found in the cytoplasm and the nucleus of infected leaf cells. Inhibition of the nuclear localization of the N protein through the addition of a nuclear export sequence prevented the hypersensitive response, whereas blocking nuclear localization of p50 did not. This suggests that N and p50 interact in the cytoplasm but that N has nuclear functions that are required for activation of the immune response. Coimmunoprecipitation studies with the tagged proteins, as well as bimolecular fluorescence complementation studies, indicated that the two proteins interacted. However, purified proteins did not interact in vitro, which suggests that the interaction is indirect and that there is another molecule required for p50 and N interaction. Although the LRR domain is best known for recognition of pathogen sequences, the TIR domain of N appeared to be necessary and sufficient for the interaction of p50 with N. Deletion or point mutation of the TIR domain blocked the interaction between the two proteins. The isolated TIR domain of N, but not that of other R proteins, interacted with p50. The authors propose that the TIR domain of N (through an unknown adaptor) recognizes p50, which leads to a change in the N protein, and that the "activated" N protein then engages the defense response through a process that requires the nuclear localization or activation of a nuclear pool of N.

T. M. Burch-Smith, M. Schiff, J. F. Caplan, J. Tsao, K. Czymmek, S. P. Dinesh-Kumar, A novel role for the TIR domain in association with pathogen-derived elicitors.
PLoS Biol.
5
, e68 (2007).
[PubMed]
Vital Nonapoptotic Functions for Caspase-8 in B Cells
Authors: Foley John F.
Published: March 2007

Clinical data have suggested both apoptotic and nonapoptotic roles for caspase-8 in human disease. Caspase-8 is a cysteine protease best known for mediating signals downstream of death receptors leading to apoptosis. Its mutation is associated with immunodeficiency in humans. Caspase-8 is known to be important in regulating T cells. To study B cell-specific roles for caspase-8, Lemmers
et al
. generated mice with B cell-specific inactivation of caspase-8 (

bcasp8
−/−

). Although caspase-8 was not necessary for B cell development, B cells from

bcasp8
−/−

mice were more resistant to apoptosis stimulated by the death receptor CD95 than were cells from wild-type mice. After infection with vesicular stomatitis virus (VSV),

bcasp8
−/−

mice exhibited lower production of VSV-neutralizing immunoglobulin G (IgG). This is similar to the situation observed in patients with a mutation in caspase-8, who have decreased concentrations of circulating antibodies after antigenic stimulation. Deletion of caspase-8 inhibited the increase in B cell numbers elicited by agonists for the Toll-like receptors (TLRs), TLR2, -3, and -4. Although

bcasp8
−/−

B cells were resistant to apoptosis induced by CD95, the lack of

bcasp8
−/−

B cell expansion in response to the TLR4 agonist lipopolysaccharide (LPS) was due to increased cell death mediated by caspase-3. Coimmunoprecipitation studies revealed that caspase-8 was recruited to the complex that activated nuclear factor κB (NF-κB), the IKKαβ complex, after LPS stimulation. Consistent with these findings, real-time polymerase chain reaction (PCR) analysis of the abundance of transcripts of NF-κB target genes showed that deletion of caspase-8 decreased the LPS-induced expression of these genes. Nuclear translocation of NF-κB in response to LPS was found to be substantially slower in B cells from

bcasp8
−/−

mice than in wild-type B cells. These data may provide a mechanism to explain the immunodeficiency in patients with a mutation in caspase-8.

B. Lemmers, L. Salmena, N. Bidère, H. Su, E. Matysiak-Zablocki, K. Murakami, P. S. Ohashi, A. Jurisicova, M. Lenardo, R. Hakem, A. Hakem, Essential role for caspase-8 in Toll-like receptors and NFκB signaling.
J. Biol. Chem.
282
, 7416-7423 (2007).
[Abstract]
[Full Text]
Keeping Things Quiet
Authors: Simpson Stephen
Published: March 2007

Among its many functions, RNA silencing provides broad cellular defense against viruses in many plant and animal species. To perform defense functions, microRNAs (miRNAs) arm an RNA-induced silencing complex (RISC), which either degrades messenger RNA or inhibits its translation. Triboulet
et al
. show that proteins responsible for generating miRNA potently inhibit human immunodeficiency virus-type 1 (HIV-1) in naturally infected cells and that HIV-1 counters this by down-modulating the expression of selected cellular miRNAs to favor replication. Targeting the miRNA processing pathway may offer a strategy for activating latent viral reservoirs, which remain barriers to eliminating chronic HIV-1 infection.

R. Triboulet, B. Mari, Y.-L. Lin, C. Chable-Bessia, Y. Bennasser, K. Lebrigand, B. Cardinaud, T. Maurin, P. Barbry, V. Baillat, J. Reynes, P. Corbeau, K.-T. Jeang, M. Benkirane, Suppression of microRNA-silencing pathway by HIV-1 during virus replication.
Science
315
, 1579-1582 (2007).
[Abstract]
[Full Text]
From MicroRNA to Carcinogenesis
Authors: Riddihough Guy
Published: March 2007

Misregulation of microRNA (miRNA) function has been implicated in cancer. However, the precise role of miRNAs in tumorigenesis has been unclear. High mobility group A2 protein (Hmga2) is a small, non-histone, chromatin-associated protein found in a number of benign and malignant tumors, where the gene is often truncated at the 3′ end. Mayr
et al
. now show that it is the loss of the noncoding 3′ untranslated region of the
Hmga2
messenger RNA, and specifically of regulator sites for the
let-7
miRNA, that causes the overexpression of Hmga2, and that this overexpression contributes to the progression of carcinogenesis both in a tissue culture assay and in nude mice.

C. Mayr, M. T. Hemann, D. P. Bartel, Disrupting the pairing between
let-7
and
Hmga2
enhances oncogenic transformation.
Science
315
, 1576-1579 (2007).
[Abstract]
[Full Text]
DUALIZABLE BUT NOT FULLY DUALIZABLE ALGEBRAS
Authors: NIVEN TODD
Published: March 2007

We give an infinite family of finite dualizable unary algebras that are not fully κ-dualizable, for all cardinals κ.
A FINITELY PRESENTED GROUP WITH TWO NON-HOMEOMORPHIC ASYMPTOTIC CONES
Authors: YU. OL'SHANSKII ALEXANDER , SAPIR MARK V.
Published: March 2007

We give an example of a finitely presented group G with two non-π1-equivalent asymptotic cones.
LAMELLIPODIAL AND AMOEBOID CELL LOCOMOTION: THE ROLE OF ACTIN-CYCLING AND BLEB FORMATION
Authors: MANNHERZ HANS GEORG , MACH MONIKA , NOWAK DOROTA , MALICKA-BLASZKIEWICZ MARIA , MAZUR ANTONINA
Published: March 2007

Cell migration depends on the rapid changes of the organization of actin filaments and generation of force by motor proteins. Vertebrate cells use two different mechanisms: mesenchymal or amoeboid migration. Cells migrating in mesenchymal mode are elongated and move over a two-dimensional substratum. They extend thin veil-like extensions at their leading face — lamellipodia, whose protrusion depend on polymerization and depolymerization processes of actin. During mesenchymal migration actin filaments are firmly connected by integrins to the extracellular matrix (ECM) at focal contacts, which serve as points of fixation for subsequent cell body traction by force producing actomyosin interactions. Cells migrating in amoeboid fashion are rounded and move through a three-dimensional ECM-network undergoing considerable shape changes and generating vesicle-like surface extensions — so-called blebs. These blebs and the migrating cells exhibit no or strongly reduced affinity to the ECM. Bleb formation depends on a transient decrease of plasma membrane stiffness and locally increased hydrostatic pressure, which is generated by actin-myosin interactions. Formation of numerous surface blebs is also typical of cells that undergo apoptotic cell death. Since these share a number of properties to blebs of amoeboid cells, an analysis is given of the distribution of some cytoskeletal components in apoptotic blebs.
CAN SINGLE ELECTRONS INITIATE FUSION OF BIOLOGICAL MEMBRANES?
Authors: KOCH MARTIN , OTTO ANGELA M. , WIEST JOACHIM , WOLF BERNHARD
Published: March 2007

Animal cells export the content of vesicles by exocytosis, a process in which a vesicle and the plasma membrane fuse and ultimately form a pore. The initial event leading to the breakthrough of the membranes for pore formation is not well understood. Here we present a mathematical approach which suggests that this process is initiated by single electrons which could be present in the immediate proximity of the fusing membranes in aromatic amino acids. The electron can be regarded as non-classical; it takes up energy and transfers it to the membrane barrier, thereby eliciting conformational changes in the proteo-lipid complex leading to membrane fusion and thus initiating the opening of the fusion pore.
VISUALIZING SOFT MATTER: MESOSCOPIC SIMULATIONS OF MEMBRANES, VESICLES AND NANOPARTICLES
Authors: SHILLCOCK JULIAN , LIPOWSKY REINHARD
Published: March 2007

Biological membranes have properties and behavior that emerge from the propagation of the molecular characteristics of their components across many scales. Artificial smart materials, such as drug delivery vehicles and nanoparticles, often rely on modifying naturally-occurring soft matter, such as polymers and lipid vesicles, so that they possess useful behavior. Mesoscopic simulations allow in silico experiments to be easily and cheaply performed on complex, soft materials requiring as input only the molecular structure of the constituents at a coarse-grained level. They can therefore act as a guide to experimenters prior to performing costly assays. Additionally, mesoscopic simulations provide the only currently feasible window on the length and time scales relevant to important biophysical processes such as vesicle fusion. We describe here recent work using Dissipative Particle Dynamics simulations to explore the structure and behavior of amphiphilic membranes, the fusion of vesicles, and the interactions between rigid nanoparticles and soft surfaces.
ON THE ACTION POTENTIAL AS A PROPAGATING DENSITY PULSE AND THE ROLE OF ANESTHETICS
Authors: HEIMBURG THOMAS , JACKSON ANDREW D.
Published: March 2007

The Hodgkin-Huxley model of nerve pulse propagation relies on ion currents through specific resistors called ion channels. We discuss a number of classical thermodynamic findings on nerves that are not contained within this classical theory. In particular striking is the finding of reversible heat changes, thickness and phase changes of the membrane during the action potential. Data on various nerves rather suggest that a reversible density pulse accompanies the action potential of nerves. Here, we attempted to explain these phenomena by propagating solitons that depend on the presence of cooperative phase transitions in the nerve membrane. The transitions, however, are strongly influenced by the presence of anesthetics. Therefore, the thermodynamic theory of nerve pulses suggests an explanation for the famous Meyer-Overton rule that states that the critical anesthetic dose is linearly related to the solubility of the drug in the membranes.
ON THE ORIGIN AND PROPERTIES OF TWO-POPULATION NEURAL FIELD MODELS - A TUTORIAL INTRODUCTION
Authors: WYLLER JOHN , BLOMQUIST PATRICK , EINEVOLL GAUTE T.
Published: March 2007

Neural field models have a long tradition in mathematical neuroscience, and in the present tutorial paper we outline the neurobiological and biophysical origin of such models, in particular two-population field models describing excitatory and inhibitory neurons interacting via nonlocal spatial connections. Results from investigations of such models on the existence and stability of stationary localized activity pulses ('bumps') and generation of stationary spatial and spatiotemporal oscillations through Turing-type instabilities are described.
Expressed Emotion and Relapse of Psychopathology
Authors: Hooley Jill M.
Published: March 2007

Expressed emotion (EE) is a measure of the family environment that predicts worse clinical outcomes for patients with a range of disorders. This article describes the assessment of EE and the evidence linking EE to clinical relapse in patients with psychopathology. This is followed by consideration of the possible explanatory models that might account for the EE-relapse link and a review of the evidence suggesting that EE may play a causal role in the relapse process. The results of studies describing the effect of EE on patients, as well as cross-cultural aspects of the construct, are highlighted. Finally, the possibility that high levels of EE may stress patients by perturbing activity in neural circuits that underlie psychopathology is considered and new directions for EE research are outlined.
Evidence-Based Assessment
Authors: Hunsley John , Mash Eric J.
Published: March 2007

Evidence-based assessment (EBA) emphasizes the use of research and theory to inform the selection of assessment targets, the methods and measures used in the assessment, and the assessment process itself. Our review focuses on efforts to develop and promote EBA within clinical psychology. We begin by highlighting some weaknesses in current assessment practices and then present recent efforts to develop EBA guidelines for commonly encountered clinical conditions. Next, we address the need to attend to several critical factors in developing such guidelines, including defining psychometric adequacy, ensuring appropriate attention is paid to the influence of comorbidity and diversity, and disseminating accurate and up-to-date information on EBAs. Examples are provided of how data on incremental validity and clinical utility can inform EBA. Given the central role that assessment should play in evidence-based practice, there is a pressing need for clinically relevant research that can inform EBAs.
Internet Methods for Delivering Behavioral and Health-Related Interventions (eHealth)
Authors: Strecher Victor
Published: March 2007

Emerging communications technologies allow us to potentially reach more individuals with effective health-related advice and information at a very low cost. As we begin a new era of “personalized medicine,” advances in consumer health informatics will parallel and eventually merge with those being made in bioinformatics (e.g., genomic information), medical informatics (e.g., electronic medical records), and public health informatics (e.g., disease surveillance). This article discusses access, use, quality, and types of eHealth programming with a focus on the Internet as the initial instantiation of this programming. Also discussed are criteria relevant to the dissemination of eHealth programming in real-world settings. Finally, possible directions for future eHealth research are presented.
Sexual Dysfunctions in Women
Authors: Meston Cindy M. , Bradford Andrea
Published: March 2007

In this article, we summarize the definition, etiology, assessment, and treatment of sexual dysfunctions in women. Although the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV-TR) is our guiding framework for classifying and defining women's sexual dysfunctions, we draw special attention to recent discussion in the literature criticizing the DSM-IV-TR diagnostic criteria and their underlying assumptions. Our review of clinical research on sexual dysfunction summarizes psychosocial and biomedical management approaches, with a critical examination of the empirical support for commonly prescribed therapies and limitations of recent clinical trials.
Stimulating the Development of Drug Treatments to Improve Cognition in Schizophrenia
Authors: Green Michael F.
Published: March 2007

Cognitive impairment in schizophrenia is a core feature of the illness (i.e., not a result of clinical symptoms or drug treatments) that is related to the daily functioning of patients. Because schizophrenia is associated with poor community functioning, there is considerable interest in finding treatments to improve cognition in schizophrenia in the hopes that such improvement will yield functional benefits. Before the U.S. Food and Drug Administration could consider granting approval to any new drug for improving cognition in schizophrenia, it was first necessary to achieve consensus on the measurements and methods that would be used in clinical trials, as well as neuropharmacological targets. The U.S. National Institute of Mental Health launched an initiative to help address these obstacles to drug approval (MATRICS). This initiative has generated several additional follow-up initiatives including a clinical trial network and consensus projects for other clinical targets, such as negative symptoms. This review describes how an area that was primarily of academic interest (cognition in schizophrenia) became a focus of public health concerns and drug-development policy.
Development of Neural Systems for Reading
Authors: Schlaggar Bradley L. , McCandliss Bruce D.
Published: March 2007

Functional and structural neuroimaging studies of adult readers have provided a deeper understanding of the neural basis of reading, yet such findings also elicit new questions about how developing neural systems come to support this learned ability. A developmental cognitive neuroscience approach provides insights into how skilled reading emerges in the developing brain, yet also raises new methodological challenges. This review focuses on functional changes that occur during reading acquisition in cortical regions associated with both the perception of visual words and spoken language, and it examines how such functional changes differ within developmental reading disabilities. We integrate these findings within an interactive specialization framework of functional development and propose that such a framework may provide insights into how individual differences at several levels of observation (genetics, white matter tract structure, functional organization of language, cultural organization of writing systems) impact the emergence of neural systems involved in reading ability and disability.
Multiple Dopamine Functions at Different Time Courses
Authors: Schultz Wolfram
Published: March 2007

Many lesion studies report an amazing variety of deficits in behavioral functions that cannot possibly be encoded in great detail by the relatively small number of midbrain dopamine neurons. Although hoping to unravel a single dopamine function underlying these phenomena, electrophysiological and neurochemical studies still give a confusing, mutually exclusive, and partly contradictory account of dopamine's role in behavior. However, the speed of observed phasic dopamine changes varies several thousand fold, which offers a means to differentiate the behavioral relationships according to their time courses. Thus dopamine is involved in mediating the reactivity of the organism to the environment at different time scales, from fast impulse responses related to reward via slower changes with uncertainty, punishment, and possibly movement to the tonic enabling of postsynaptic motor, cognitive, and motivational systems deficient in Parkinson's disease.