bluuebunny/crossref_metadata_2025 huggingface dataset:
Responding to DNA
Authors: Gough Nancy R.
Published: March 2008

The body has multiple mechanisms to mount a response to infection, including pathways activated by lipids, proteins, and nucleic acids. However, the mechanism by which DNA viruses trigger an innate immune response that is independent from pathways that involve the Toll-like receptors (TLRs) has been unclear. Muruve
et al
. found that adenovirus-infected cultured cells stimulated the processing and release of the proinflammatory mediator interleukin-1β (IL-1β) and that this response required the DNA from the virus (delivered by cationic liposomes), but not the capsid, and was independent of TLR signaling. Transfected DNA from bacteria, synthetic DNA, plasmid DNA, or mammalian DNA also triggered IL-1β secretion, although short double-stranded oligonucleotides did not. A minimum size of about 250 base pairs was required to stimulate IL-1β release. IL-1β processing involves the inflammasome, a multiprotein complex that includes a NALP protein (a Nod-like cytosolic receptor), the adaptor protein ASC, and caspase-1. Macrophages from NALP3- or ASC-deficient mice failed to stimulate IL-1β processing and secretion in response to adenovirus infection. However, if the DNA was introduced by cationic liposome delivery, then NALP3 was not required, but ASC and caspase-1 were required, suggesting that DNA delivered by that mechanism may use an inflammasome complex with a different sensor protein. K
+
efflux is known to be involved in inflammasome activation, and blocking K
+
efflux pharmacologically prevented IL-1β release by adenovirus infection or DNA transfection. Mice deficient in NALP3, ASC, or caspase-1 exhibited a reduced innate immune response to infection with adenovirus. The identification of this new DNA sensor pathway for innate immunity has implications not only for understanding and potentially manipulating the response to pathogen infection but also in autoimmune disease, which may also involve aberrant activity of the inflammasome.

D. A. Muruve, V. Pétrilli, A. K. Zaiss, L. R. White, S. A. Clark, P. J. Ross, R. J. Parks, J. Tschopp, The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response.
Nature
452
, 103-107 (2008).
[PubMed]
Saved from Destruction
Authors: Adler Elizabeth M.
Published: March 2008

Survival of naïve B lymphocytes depends on the cytokine BAFF (B cell-activating factor of the tumor necrosis factor family). Although BAFF can signal through several receptors, only one of them (BAFF-R) is essential for survival (see Cancro). Noting that BAFF-R binds TNF receptor-associated factor 3 (TRAF3) and that TRAF3 and TRAF2 have been implicated in B cell survival, Gardam
et al
. examined the effects on lymphocyte survival of lineage-specific inactivation of TRAF2 or TRAF3 or both. Mice lacking B cell TRAF2 (
Traf2ΔB
mice) or B cell TRAF3 (
Traf3ΔB
mice) showed an indistinguishable phenotype, characterized by increased numbers of lymph node and splenic marginal zone B cells, that resembled that of mice overexpressing BAFF (BAFF-tg mice). B cells from
Traf2ΔB
and
Traf3ΔB
mice survived in vitro in the absence of BAFF and, like BAFF-tg B cells, showed increased activation of the alternative (noncanonical) NF-κB (nuclear factor κB) signaling pathway. No further effects on B cell phenotype were seen when both TRAF2 and TRAF3 were absent, and microarray analysis revealed that mature B cells from
Traf2ΔB
and
Traf3ΔB
mice showed nearly identical gene expression profiles, which were similar to those of BAFF-tg B cells. Elimination of TRAF2 from the B cells rescued B cell development in BAFF-deficient mice. The abundance of TRAF3 protein (but not
Traf3
mRNA) was increased in B cells from mice lacking BAFF, BAFF-R, or TRAF-2. The authors thus propose that BAFF acts as a survival factor by stimulating TRAF2-dependent TRAF3 depletion and reversing the cooperative TRAF2- and TRAF3-dependent inhibition of B cell survival.

S. Gardam, F. Sierro, A. Basten, F. Mackay, R. Brink, TRAF2 and TRAF3 signal adapters act cooperatively to control the maturation and survival signals delivered to B cells by the BAFF receptor.
Immunity
28
, 391-401 (2008).
[PubMed]

M. P. Cancro, Living in context with the survival factor BAFF.
Immunity
28
, 300-301 (2008).
[PubMed]
Synaptic Metaplasticity
Authors: Stern Peter
Published: March 2008

N
-methyl-D-aspartate (NMDA) receptor-dependent synaptic strengthening is the most common and best understood form of plasticity in the central nervous system. However, how NMDA receptors influence plasticity after the initiation of synaptic strengthening in vivo has not been well studied. Clem
et al
. (see the Perspective by Brecht and Schmitz) examined the effect of cumulative sensory experience on synaptic strengthening at layer 4-2/3 synapses in the mouse barrel cortex. NMDA receptors opposed synaptic potentiation after single whisker experience, and NMDA receptor blockade restored pairing plasticity via a metabotropic glutamate receptor-dependent mechanism.

R. L. Clem, T. Celikel, A. L. Barth, Ongoing in vivo experience triggers synaptic metaplasticity in the neocortex.
Science
319
, 101-104 (2008).
[Abstract]
[Full Text]

M. Brecht, D. Schmitz, Rules of plasticity.
Science
319
, 39-40 (2008).
[Summary]
[Full Text]
The Ant and the Butterfly
Authors: Zahn Laura M.
Published: March 2008

Complex channels of chemical communication affect both the ecology and evolution of interactions among species. In Denmark, the Alcon blue butterfly larvae are adopted by ants of the genus
Myrmica
, which raise them preferentially to their own young. Nash
et al.
show that similarity in host and parasite surface chemistry explains a significant proportion of the variation in virulence of the parasite. Patterns of host cuticular chemistry are consistent with an ongoing coevolutionary arms race with one of its host ants (
Myrmica rubra
) but not with an alternative host (
Myrmica ruginodis
).

D. R. Nash, T. D. Als, R. Maile, G. R. Jones, J. J. Boomsma, A mosaic of chemical coevolution in a large blue butterfly.
Science
319
, 88-90 (2008).
[Abstract]
[Full Text]
Absence Makes the Wnt Go Stronger
Authors: Foley John F.
Published: March 2008

Wnts are secreted lipoproteins that are important in developmental processes. In the canonical Wnt pathway, Wnt3a signaling stabilizes β-catenin, which enters the nucleus and leads to expression of Wnt-target genes. Cilia are cellular projections that contain a central core of microtubules, and some proteins that are found in cilia, such as Inversin (see the commentary by He), mediate Wnt signaling. Corbit
et al
. investigated a possible role for cilia in the regulation of canonical Wnt signaling by generating mice and mouse embryonic fibroblasts (MEFs) deficient in
Kif3a
, which encodes a protein necessary for the generation of cilia. Reporter assays showed that
Kif3a
–/–
MEFs responded more strongly to Wnt3a than did
Kif3a
+/–
MEFs, whereas both cell types showed similar levels of basal activity. Western blotting assays showed that whereas Wnt3a treatment of
Kif3a
+/–
MEFs resulted in the accumulation of β-catenin,
Kif3a
–/–
MEFs showed a similar abundance of stabilized β-catenin even in the absence of Wnt3a. Wnt activation of Frizzled receptors results in the phosphorylation of Dishevelled (Dvl), which promotes stabilization of β-catenin. The authors showed by Western blotting that Dvl was constitutively phosphorylated in
Kif3a
–/–
MEFs and that this was blocked by inhibition of casein kinase I (CKI), a kinase previously implicated in Dvl phosphorylation. Treatment with the CKI inhibitor also prevented the hyperresponsiveness of
Kif3a
–/–
MEFs to treatment with Wnt3a, as assessed by reporter assays. Immunofluorescence microscopy demonstrated that some Wnt pathway components, including β-catenin, are present in cilia. This study suggests that cilia play a role in inhibiting canonical Wnt signaling, which may have implications for diseases associated with abnormal cilia, such as polycystic kidney disease.

K. C. Corbit, A. E. Shyer, W. E. Dowdle, J. Gaulden, V. Singla, J. F. Reiter, Kif3a constrains β-catenin-dependent Wnt signalling through dual ciliary and non-ciliary mechanisms.
Nat. Cell Biol.
10
, 70-76 (2008).
[PubMed]

X. He, Cilia put a brake on Wnt signalling.
Nat. Cell Biol
.
10
, 11-13 (2008).
[PubMed]
Reduced to Activation
Authors: Adler Elizabeth M.
Published: March 2008

The transient receptor potential (TRP) channels constitute a large and diverse family of multimeric ion channels for which new mechanisms of activation and specific functions continue to emerge. The "canonical" TRP 5 (TRPC5) channel contains two cysteine residues in a predicted extracellular loop near the ion pore, leading Xu
et al
. to investigate the hypothesis that their reduction might modulate channel activity. The reducing agents dithiothreitol (DTT) and Tris (2-carboxyethyl) phosphine hydrochloride (TCEP) activated TRPC5 channels expressed in human embryonic kidney (HEK) 293 cells, whereas mutant channels in which alanine was substituted for cysteine were constitutively active. Moreover, the reduced form of the endogenous redox protein thioredoxin (rTRX) activated TRPC5 or a heteromultimer comprising TRPC5 and TRPC1 (in which the two cysteines are conserved). Noting that high concentrations of thioredoxin have been found in the serum and synovial fluid of individuals with rheumatoid arthritis, the authors showed that rTRX elicited a cation current in fibroblast-like synoviocytes (FLS cells) from people with rheumatoid arthritis. FLS cells expressed TRPC5 and TRPC1 mRNA and protein, and both the current-voltage relationship and pharmacological response of the current evoked by rTRX resembled that of the TRPC5-TRPC1 heteromultimer. Furthermore, both a dominant-negative TRPC5 mutant and antibodies directed against TRPC5 (T5E3) or TRPC1 (T1E3) suppressed rTRX-evoked current in FLS cells. Exposure to T5E3 or T1E3 enhanced matrix metalloproteinase (MMP) secretion by FLS cells (as did TRPC5 and TRPC1 knockdown) and blocked inhibition of MMP secretion by rTRX. Thus, extracellular rTRX appears to activate TRPC5 and the TRPC5-TRPC1 heteromultimer by breaking a disulphide bridge.

S.-Z. Xu, P. Sukumar, F. Zeng, J. Li, A. Jairaman, A. English, J. Naylor, C. Ciurtin, Y. Majeed, C. J. Milligan, Y. M. Bahnasi, E. Al-Shawaf, K. E. Porter, L.-H. Jiang, P. Emery, A. Sivaprasadarao, D. J. Beech, TRPC channel activation by extracellular thioredoxin.
Nature
451
, 69-72 (2008).
[PubMed]
No TNF-α Secretion Without ERK Activation
Authors: Foley John F.
Published: March 2008

When stimulated by the microbial product lipopolysaccharide (LPS), macrophages secrete the proinflammatory cytokine, tumor necrosis factor-α (TNF-α). LPS stimulation of macrophages results in the sequential activation of the mitogen-activated protein kinase (MAPK) kinase kinase TPL2; the MAPK kinases MKK1 and MKK2; and the MAPKs extracellular signal-regulated kinase (ERK) 1 and 2. Macrophages from mice deficient in TPL2 fail to secrete TNF-α when stimulated with LPS, which suggests that TPL2 might be targeted in the treatment of inflammatory disorders. Rousseau
et al
. studied LPS-stimulated secretion of TNF-α in a mouse macrophage cell line (RAW24.7 cells). Although inhibition of MKK1 blocked secretion of TNF-α from LPS-stimulated RAW24.7 cells, as measured by enzyme-linked immunosorbent assay, production of the precursor form of TNF-α, as detected by analyses of Western blots of cell lysates, was barely affected. The abundance of pre-TNF-α in lysates of LPS-treated TPL2-deficient macrophages was similar to that detected in LPS-treated wild-type macrophages, consistent with a role for ERK activation in the processing of pre-TNF-α. Immunogold electron microscopy demonstrated that inhibition of ERK activity did not interfere with the intracellular trafficking of pre-TNF-α from the Golgi through the secretory pathway; however, immunofluorescence staining showed that inhibition of ERK activation prevented LPS-induced localization of pre-TNF-α to the cell surface. TNF-α-converting enzyme (TACE) is thought to form a complex with pre-TNF-α that localizes it to the surface of the cell, where TACE processes pre-TNF-α to produce mature TNF-α. Using a phosphospecific antibody, the authors showed that Thr
735
of TACE was phosphorylated by ERK1/2 in LPS-treated wild-type, but not TPL2-deficient, macrophages. This study shows that rather than interfering with TNF-α production at the level of gene expression, as had been previously thought, the TPL2-MKK1-ERK1/2 pathway regulates the processing of pre-TNF-α instead.

S. Rousseau, M. Papoutsopoulou, A. Symons, D. Cook, J. M. Lucocq, A. R. Prescott, A. O’Garra, S. C. Ley, P. Cohen, TPL2-mediated activation of ERK1 and ERK2 regulates the processing of pre-TNFα in LPS-stimulated macrophages.
J. Cell Sci.
121
, 149-154 (2008).
[Abstract]
[Full Text]
Controlling Tremor with Adenosine
Authors: Gough Nancy R.
Published: March 2008

Deep brain stimulation (DBS), in which high-frequency electrical stimuli are continuously delivered into the brain through implanted wires, is an effective treatment for movement disorders characterized by muscle tremors, including Parkinson’s disease and essential tremor (see Asaad and Eskandar). Bekar
et al
. provide evidence that one mechanism by which DBS reduces tremor is through stimulation of nonsynaptic release of adenosine triphosphate (ATP). Conversion of ATP to adenosine by ectoATPases then stimulates the activation of A1 receptors. The authors detected ATP in thalamic slices (and exposed mouse cortex) in response to high-frequency stimulation with a bioluminescence assay. Adenosine was detected in the thalamic slices with an amperometric biosensor, and production by ectoATPases was confirmed by pharmacological inhibition. The release of ATP was deemed to be nonsynaptic, because it did not require calcium and removal of extracellular calcium increased the accumulation of adenosine in response to high-frequency stimulation. The role of the A1 receptor and adenosine was also confirmed by showing that high-frequency stimulation failed to reduce evoked excitatory postsynaptic potentials (eEPSPs) in the presence of an A1 receptor antagonist or an inhibitor of ectoATPase activity. Application of adenosine or an A1 receptor agonist reduced eEPSP amplitude in the absence of high-frequency stimulation. In slices from mice deficient for A1 receptors, high-frequency stimulation failed to reduce eEPSP amplitude. Using a mouse model of essential tremor, the authors showed that administration of an A1 receptor antagonist exacerbated the tremor; delivery of adenosine or an A1 receptor agonist reduced the tremor, as did DBS. As DBS is also under investigation for application in other neurological disorders, such as obsessive-compulsive disorder and depression, understanding the mechanisms by which it exerts its effects may allow for more precise treatments that limit undesirable side effects.

L. Bekar, W. Libionka, G.-F. Tian, Q. Xu, A. Torres, X. Wang, D. Lovatt, E. Williams, T. Takano, J. Schnermann, R. Bakos, M. Nedergaard, Adenosine is crucial for deep brain stimulation-mediated attenuation of tremor.
Nat. Med.
14
, 75-80 (2008).
[PubMed]

W. Asaad, E. Eskandar, The movers and shakers of deep brain stimulation.
Nat. Med.
14
, 17-19 (2008).
[PubMed]
Expressing Estrogen-Responsive Genes
Authors: Purnell Beverly A.
Published: March 2008

Estrogens, upon recruitment of their cognate receptors, govern the expression of target genes. Perillo
et al
. show that transcription of estrogen-responsive genes is driven by hormone-dependent demethylation of a critical lysine in histone H3 to induce a local oxidative burst that modifies the surrounding DNA by guanine oxidation, which is subsequently removed by specific glycosylases. 8-oxo-guanine-DNA glycosylase 1 and the topoisomerase IIβ enzyme are recruited to these loci and bend the intervening DNA-chromatin region to mark the site where transcription begins and drive expression of estrogen-responsive genes.

B. Perillo, M. N. Ombra, A. Bertoni, C. Cuozzo, S. Sacchetti, A. Sasso, L. Chiariotti, A. Malorni, C. Abbondanza, E. V. Avvedimento, DNA oxidation as triggered by H3K9me2 demethylation drives estrogen-induced gene expression.
Science
319
, 202-206 (2008).
[Abstract]
[Full Text]
Pass on the Salt
Authors: Foley John F.
Published: March 2008

Salt is well known to promote hypertension, but the mechanisms involved in regulating the tone of arterial smooth muscle are poorly characterized. This is particularly true with regard to our understanding of whether similar or distinct mechanisms are responsible for regulating both basal blood pressure and salt-induced hypertension. Phosphorylation of myosin light chain (MLC) is critical for the vascular constriction that is associated with hypertension. Many receptors promote the phosphorylation of MLC either by stimulating MLC kinase, through the activation of heterotrimeric GTP-binding proteins (G proteins) of the G
q
and G
11
families, or by inhibiting, through G
12
and G
13
G proteins, the phosphatase that returns MLC to its inactive form. Wirth
et al
. produced mice that could be induced by treatment with tamoxifen to lack both G
q
and G
11
(G
q
-G
11
KO) or both G
12
and G
13
(G
12
-G
13
KO) in smooth muscle cells. Treatment with tamoxifen caused an increase in blood pressure in all mice, but whereas the blood pressure of wild-type and G
12
-G
13
KO mice soon returned to basal levels, that of G
q
-G
11
KO mice became 10 to 15% lower than normal, implicating G
q
and G
11
in the regulation of basal blood pressure. Treatment of wild-type mice with a salt preparation increased their blood pressure, but G
q
-G
11
KO and G
12
-G
13
KO mice were unaffected, showing that both sets of G proteins mediate salt-induced hypertension. Mice deficient in LARG, an effector of G
12
and G
13
found in smooth muscle cells that mediates the inhibition of myosin phosphatase, responded to salt treatment similarly to G
12
-G
13
KO mice. As Schoner discusses in commentary, this study makes possible the development of therapies that could interfere with salt-induced hypertension while leaving basal blood pressure regulation intact.

A. Wirth, Z. Benyó, M. Lukasova, B. Leutgeb, N. Wettschureck, S. Gorbey, P. Őrsy, B. Horváth, C. Maser-Gluth, E. Greiner, B. Lemmer, G. Schütz, J. S. Gutkind, S. Offermanns, G
12
-G
13
-LARG-mediated signaling in vascular smooth muscle is required for salt-induced hypertension.
Nat. Med.
14
, 64-68 (2008).
[PubMed]

W. Schoner, Salt abuse: The path to hypertension.
Nat. Med.
14
, 16-17 (2008).
[PubMed]
LMP1 Subverts "TRADDitional" Signals
Authors: Foley John F.
Published: March 2008

Epstein-Barr virus (EBV) is a DNA tumor virus that infects and transforms B lymphocytes. The viral oncoprotein latent membrane protein 1 (LMP1) promotes the proliferation of infected B lymphocytes and is critical for cellular transformation by EBV. LMP1 recruits the tumor necrosis factor-α (TNF-α) receptor 1 (TNFR1)-associated death domain protein (TRADD), which seems counterintuitive given that the major role of TRADD as a TNFR1 adaptor protein is to promote the apoptosis of cells in response to TNF-α. TRADD also leads to the activation of the mitogen-activated protein kinase (MAPK) c-Jun N-terminal kinase (JNK) and the transcription factor nuclear factor κB (NF-κB). LMP1 contains two cytoplasmic C-terminal activating regions (CTARs) that are important for triggering canonical and noncanonical NF-κB signaling and the activation of JNK. To try to understand the role of TRADD in LMP1 signaling, Schneider
et al
. first had to generate human B lymphocytes that were deficient in TRADD. Western blotting analyses showed that, whereas TRADD was necessary for both TNF-α- and LMP1-induced NF-κB activation, it was dispensable for LMP-1-mediated JNK activation. Coimmunoprecipitation studies demonstrated that TRADD mediated the interaction between the LMP1 CTAR2 domain and inhibitor of NF-κB kinase β, which is necessary for NF-κB activation. The authors then showed that amino acid residues 371 to 386 of LMP1 contained the TRADD-binding domain. When this domain was substituted for the death domain of TNFR1 in mouse embryonic fibroblasts, reporter assays showed that the TNFR1-LMP1 chimera activated NF-κB similarly to wild-type TNFR1 but that the chimeric receptor no longer induced apoptosis. This study shows that EBV, through LMP1, alters the functional properties of TRADD to promote cellular transformation.

F. Schneider, J. Neugebauer, J. Griese, N. Liefold, H. Kutz, C. Briseño, A. Kieser, The viral oncoprotein LMP1 exploits TRADD for signaling by masking its apoptotic activity.
PLoS Biol
.
6
, e8 (2008).
[PubMed]
Homering In on T Cell Activation
Authors: Simpson Stephen J.
Published: March 2008

In the immune system, T cells are stimulated by signals that emanate from the T cell receptor (TCR) and costimulatory cell surface receptors, most notably CD28. CD28 signals profoundly influence the ensuing immune response--TCR stimulation in the absence of CD28 results in anergy, a state of permanent inactivation. Huang
et al
. provide evidence that the alternate pathways for a T cell are coordinated by two cytoplasmic scaffolding proteins, Homer2 and Homer3. Absence of these proteins caused unchecked activity of the central cytokine transcriptional regulator NFAT (nuclear factor of activated T cells), up-regulation of cytokine expression, and signs of overt T cell reactivity. Thus, a dynamic decision mechanism dictates whether a T cell will become activated or anergized.

G. N. Huang, D. L. Huso, S. Bouyain, J. Tu, K. A. McCorkell, M. J. May, Y. Zhu, M. Lutz, S. Collins, M. Dehoff, S. Kang, K. Whartenby, J. Powell, D. Leahy, P. F. Worley, NFAT binding and regulation of T cell activation by the cytoplasmic scaffolding Homer proteins.
Science
319
, 476-481 (2008).
[Abstract]
[Full Text]
Metabotropic Glutamate Receptors and Fragile X Mental Retardation Protein: Partners in Translational Regulation at the Synapse
Authors: Ronesi Jennifer A. , Huber Kimberly M.
Published: March 2008

Fragile X syndrome (FXS) mental retardation is caused by loss-of-function mutations in an RNA-binding protein, fragile X mental retardation protein (FMRP). Previous studies in patients or animal models of FXS have identified alterations in dendritic spine structure, as well as synaptic plasticity induced by metabotropic glutamate receptors (mGluRs). The translation of multiple messenger RNA (mRNA) targets of FMRP is regulated by mGluRs at synapses. Here, we incorporate data from several studies into a working model of how FMRP regulates mGluR-stimulated protein synthesis and, in turn, regulates protein synthesis–dependent synaptic plasticity. Understanding the complex functions of FMRP at the synapse will lead to a better understanding of the neurobiological underpinnings of mental retardation.
A BAD Role in Insulin Release
Authors: Gough Nancy R.
Published: March 2008

Because both loss-of-function (
Bad
−/−
) and gain-of-function (
Bad
3SA
) mutations in the apoptotic function of BAD produce the same metabolic defects in mice, Danial
et al
. investigated the role of the Bcl-2 proapoptotic family member BAD in insulin secretion from pancreatic β cells.
Bad
−/−
mice and isolated islets from these mice exhibited decreased insulin secretion in response to either hyperglycemia (in vivo) or exogenous glucose despite having similar total intracellular pools of releasable insulin (in culture). Application of secretagogues that stimulated insulin secretion at different points in the pathway suggested that the defect in secretion occurred at the level of glucose and glucokinase (upstream of activation of mitochondrial respiration). BAD interacted with glucokinase and, compared with wild-type islets,
Bad
−/−
islets showed decreased glucokinase activity and required greater concentrations of glucose to stimulate the same amount of insulin release. The defective secretion appeared to be due to decreased mitochondrial respiration in response to glucose, which is required to produce the increase in the ATP/ADP ratio that regulates the K
ATP
channel. The secretion defect was not corrected by reconstituting the knockout cells with either a BAD mutant that failed to interact with its antiapoptotic target proteins or with a mutant that constitutively interacts with these same target proteins. Thus, the secretory function of BAD does not appear to involve its role in regulating the activity of antiapoptotic proteins directly. Application of cell-permeable helix-stabilized BH3 domains based on BAD, or phosphorylated or phosphorylation mimics of this domain, to
Bad
−/−
islet cells restored glucose-stimulated insulin secretion. (Note that when the BH3 domain of BAD is phosphorylated, it does not interact with the antiapoptotic proteins Bcl-2 and Bcl-X
L
.) Application of these cell-permeable BAD BH3 peptides to INS-1 cells stimulated glucokinase activity, and the peptides could be crosslinked to glucokinase, suggesting a direct interaction. Mutation of the residues that were necessary for BAD to restore glucose-stimulated insulin secretion in the
Bad
−/−
cells in the BAD BH3 cell-permeable peptides resulted in peptides that failed to bind glucokinase. Thus, signals that stimulate the phosphorylation of BAD, which frequently also stimulate cell survival, appear to trigger a shift in the function of BAD from a mediator of apoptosis to a stimulator of cellular metabolism, which has important implications for both the increase in islet cell mass and insulin secretion in response to demand.

N. N. Danial, L. D. Walensky, C.-Y. Zhang, C. S. Choi, J. K. Fisher, A. J. A. Molina, S. R. Datta, K. L. Pitter, G. H. Bird, J. D. Wikstrom, J. T. Deeney, K. Robertson, J. Morash, A. Kulkarni, S. Neschen, S. Kim, M. E. Greenberg, B. E. Corkey, O. S. Shirihai, G. I. Shulman, B. B. Lowell, S. J. Korsmeyer, Dual role of proapoptotic BAD in insulin secretion and beta cell survival.
Nat. Med.
14
, 144-153 (2008).
[PubMed]
Capturing Kinase Substrates
Authors: Gough Nancy R.
Published: March 2008

Combining chemistry and molecular biology allowed the development of kinases that use an ATP analog to phosphorylate their targets (so-called as-kinases, for kinases with an analog-sensitizing mutation). However, application of this technique to identify kinase substrates in systems where the substrates are low-abundance proteins has proven challenging. Blethrow
et al
. describe a selective chemistry-based purification method for identifying low-abundance substrates. The purification process involves phosphorylation of the substrates in cell lysates by an as-kinase that can use the radiolabeled ATP analog [N
6
-(benzyl)ATP-γ-
35
S] to generate thiophosphopeptides, hydrolysis of the cell lysates to generate peptide fragments, and then two-step purification of the thiophosphopeptides. In the first step, the peptide fragments are mixed with iodoacetyl-agarose resin, which binds to the thiophosphorylated peptides and peptides containing cysteine. In the second step, the thiophosphorylated peptides are selectively released from the resin by oxidation and are then identified by mass spectrometry. The method was applied to HeLa cell lysates phosphorylated by as-cyclin-dependent kinase 1/cyclin B (as-Cdk1-cyclin B). Many known substrates as well as several new substrates and new phosphorylation sites were identified. Analysis of the sequences surrounding the phosphorylation sites revealed that ~30% of the sites did not match the consensus sequence, suggesting that sequence analysis underestimates the number of targets. The method was also applied to a subcellular fraction, the nuclear envelope of rat liver nuclei, and known and new candidate targets that may be regulated by phosphorylation during mitosis. The main limitation of the method is that substrates with cysteine residues will be excluded from the purification.

J. D. Blethrow, J. S. Glavy, D. O. Morgan, K. M. Shokat, Covalent capture of kinase-specific phosphopeptides reveals Cdk1-cyclin B substrates.
Proc. Natl. Acad. Sci. U.S.A.
105
, 1442-1447 (2008).
[Abstract]
[Full Text]
No Role for HIF?
Authors: Foley John F.
Published: March 2008

Ischemia, the combined lack of oxygen (hypoxia) and nutrients, triggers the production of vascular endothelial growth factor (VEGF) and other angiogenic factors that contribute to neovascularization in the affected tissue, which leads to protection from further damage. Arany
et al
. investigated a role for the transcriptional coactivator PGC-1α [peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α] in the ischemic response. Real-time quantitative polymerase chain reaction assays and Western blotting analysis showed that the abundance of PGC-1α mRNA and protein was increased in C2C12 myotubes cultured under conditions of ischemia. Ischemia-induced
VEGF
expression was lower in skeletal muscle cells from
PGC-1α
–/–
mice than in wild-type mice, whereas cells from PGC-1α transgenic mice showed increased expression of
VEGF
. Ligation of the femoral artery in PGC-1α transgenic mice resulted in neovascularization at a rate higher than that in wild-type mice, which in turn was accelerated compared to the rate in
PGC-1α
–/–
mice. Although the transcription factor hypoxia-inducible factor 1α (HIF-1α) is known to induce increased expression of
VEGF
under hypoxic conditions, reporter assays showed that PGC-1α-induced
VEGF
expression was HIF-1α-independent, as was expression of
PGC-1α
. Instead, the authors showed that PGC-1α increased
VEGF
expression by coactivating the orphan nuclear receptor, estrogen receptor-related α (ERRα). Adenoviral expression of PGC-1α in embryonic fibroblasts from
ERR-α
–/–
mice failed to increase expression of
VEGF
. Together, these data suggest an important role for PGC-1α in the HIF-1α-independent, ERR-α-dependent induction of genes encoding angiogenic factors in response to ischemia, which provides a new potential therapeutic target in the treatment of ischemia.

Z. Arany, S.-Y. Foo, Y. Ma, J. L. Ruas, A. Bommi-Reddy, G. Girnun, M. Cooper, D. Laznik, J. Chinsomboon, S. M. Rangwala, K. H. Baek, A. Rosenzweig, B. M. Spiegelman, HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1α.
Nature
451
, 1008-1012 (2008).
[PubMed]
Regulating the Regulon
Authors: Riddihough Guy
Published: March 2008

In the presence of galactose, the yeast
Saccharomyces cerevisiae
transports the sugar into its cytoplasm, where the galactose binds the Gal3 protein, which in turn sequesters the Gal80 repressor away from the transcriptional activator Gal4, resulting in the induction of galactose-metabolizing enzymes. The induction is so rapid that it has been suggested that another unknown factor must somehow be involved in this "galactose regulon." Kumar
et al.
have identified this factor as nicotinamide adenine dinucleotide (NAD) and its phosphate (NADP). In the Gal4:Gal80 complex, NAD is sandwiched between the two proteins. NADP, on the other hand, inhibits the interaction between Gal4 and Gal80. Mutations that have the potential to affect the NAD-binding site in Gal80 result in even faster induction, which suggests that Gal80 is sensing the balance between NAD and NADP and thus the metabolic state of the cell.

P. R. Kumar, Y. Yu, R. Sternglanz, S. A. Johnston, L. Joshua-Tor, NADP regulates the yeast
GAL
induction system.
Science
319
, 1090-1092 (2008).
[Abstract]
[Full Text]
Translating GAGs to Regulate Morphogens
Authors: Adler Elizabeth M.
Published: March 2008

Heparan sulfate proteoglycans [HSPGs, widely distributed extracellular macromolecules that consist of a core protein modified by covalently linked glycosaminoglycan (GAG) chains] interact with and influence the signaling of Hedgehog, Wingless, and bone morphogenetic proteins (BMPs), all of which are critical to
Drosophila
embryonic development. Noting that HSPGs have been directly implicated in regulating Hedgehog and Wingless signaling in
Drosophila
embryos, Bornemann
et al
. investigated their role in BMP signaling. Surprisingly, embryos with mutations that interfered with GAG synthesis showed normal dorsal patterning, a process that depends on the establishment of a BMP signaling gradient. In contrast, exposure to exogenous heparin (which replaces some functions of endogenous HSPGs) disrupted dorsal patterning and inhibited expression of a reporter of signaling by the
Drosophila
BMP decapentaplegic (Dpp). Sequelae of Dpp signaling are evident earlier (2.5 hours after fertilization) than are sequelae of Hedgehog and Wingless signaling (more than 3 hours after fertilization), and Western analysis indicated that GAG modifications were not apparent in embryos less than 3 hours old. The glypican core proteins Dally and Dlp were present in early embryos, as were maternally derived transcripts encoding the GAG synthetic enzymes Ttv and Sfl. Substantial amounts of Ttv and Sfl proteins, however, were not apparent at these very early developmental stages. The
ttv
5′ UTR contained an internal ribosomal entry site (IRES); analysis of the expression of proteins derived from various constructs implicated this IRES in blocking Ttv translation during early embryogenesis and indicated that the
ttv
3′ UTR cooperated with the 5′ UTR to block translation. Thus, BMP signaling early in embryogenesis is independent of HSPGs because of a translational block of GAG synthesis.

D. J. Bornemann, S. Park, S. Phin, R. Warrior, A translational block to HSPG synthesis permits BMP signaling in the early
Drosophila
embryo.
Development
135
, 1039-1047 (2008).
[Abstract]
[Full Text]
Memory Breakdown
Authors: Stern Peter R.
Published: March 2008

The phenomenon of memory reconsolidation has made people question the traditional view that long-term memories become more stable and resistant to perturbation with time. Reconsolidation indicates that memory change is a continuous process and that change is initiated by retrieval experiences themselves. However, the cellular events and mechanisms underlying this phenomenon have not been clear. Lee
et al
. provide evidence for degradation of postsynaptic proteins in hippocampal synapses thought to participate in the formation of contextual fear memories. Blockade of this degradation is accompanied by blockade of the retrieval-induced reorganization of the original memories. Thus, reconsolidation is like a breakdown of original memories while new elements are incorporated by new protein synthesis.

S.-H. Lee, J.-H. Choi, N. Lee, H.-R. Lee, J.-I. Kim, N.-K. Yu, S.-L. Choi, S.-H. Lee, H. Kim, B.-K. Kaang, Synaptic protein degradation underlies destabilization of retrieved fear memory.
Science
319
, 1253-1256 (2008).
[Abstract]
[Full Text]
NANOELECTRONIC DEVICE SIMULATION BASED ON THE WIGNER FUNCTION FORMALISM
Authors: KOSINA HANS
Published: March 2008

Coherent transport in mesoscopic devices is well described by the Schrödinger equation supplemented by open boundary conditions. When electronic devices are operated at room temperature, however, a realistic transport model needs to include carrier scattering. In this work the kinetic equation for the Wigner function is employed as a model for dissipative quantum transport. Carrier scattering is treated in an approximate manner through a Boltzmann collision operator. A Monte Carlo technique for the solution of this kinetic equation has been developed, based on an interpretation of the Wigner potential operator as a generation term for numerical particles. Including a multi-valley semiconductor model and a self-consistent iteration scheme, the described Monte Carlo simulator can be used for routine device simulations. Applications to single barrier and double barrier structures are presented. The limitations of the numerical Wigner function approach are discussed.
QUANTUM SIMULATIONS OF DUAL GATE MOSFET DEVICES: BUILDING AND DEPLOYING COMMUNITY NANOTECHNOLOGY SOFTWARE TOOLS ON NANOHUB.ORG
Authors: AHMED SHAIKH , KLIMECK GERHARD , KEARNEY DERRICK , MCLENNAN MICHAEL , ANANTRAM M. P.
Published: March 2008

Undesirable short-channel effects associated with the relentless downscaling of conventional CMOS devices have led to the emergence of new classes of MOSFETs. This has led to new and unprecedented challenges in computational nanoelectronics. The device sizes have already reached the level of tens of nanometers where quantum nature of charge-carriers dominates the device operation and performance. The goal of this paper is to describe an on-going initiative on nanoHUB.org to provide new models, algorithms, approaches, and a comprehensive suite of freely-available web-based simulation tools for nanoscale devices with capabilities not yet available commercially. Three software packages nanoFET, nanoMOS and QuaMC are benchmarked in the simulation of a widely-studied high-performance novel MOSFET device. The impact of quantum mechanical effects on the device properties is elucidated and key design issues are suggested.
TERAHERTZ POLARIZATION CONTROLLER BASED ON ELECTRONIC DISPERSION CONTROL OF 2D PLASMONS
Authors: Nishimura Takuya , Otsuji Taiichi
Published: March 2008

We numerically investigated the possibility of terahertz polarization controller based on electronic dispersion control of two dimensional (2D) plasmon gratings in semiconductor heterostructure material systems. Taking account of the Mikhailov's dispersive plasmonic conductivity model, the electromagnetic field emission properties of the gated 2D plasmon gratings were numerically analyzed with respect to the density (n) of electrons by using in-house Maxwell's FDTD (finite difference time domain method) simulator. When n is low under a constant drift-velocity condition, the fundamental plasmon mode is excited, being coupled with the radiative zeroth mode of transverse electric (TE) waves. When n exceeds a threshold level, the second harmonic mode of plasmon is predominantly excited, being coupled with the non-radiative first mode of TE waves. We numerically demonstrated that if a grating mesh of 2D plasmons is formed where two independent 2D plasmon gratings are combined orthogonally, the structure can act as a polarization controller by electronically controlling the two axial plasmonic dispersions.
INFRARED QUANTUM-DOT DETECTORS WITH DIFFUSION-LIMITED CAPTURE
Authors: VAGIDOV N. , SERGEEV A. , MITIN V.
Published: March 2008

Employing Monte-Carlo simulations we investigate parameters and optimize geometry of IR quantum-dot detectors with diffusion-limited capture into the dots surrounded by potential barriers. Our results show that structures with modulation doping of interdot matrix provide an effective separation of the localized and conducting electron states. In these structures, the capture time is mainly determined by the quantum dot concentration and the height of potential barriers around dots. The capture is not sensitive to the dot positions. It also weakly depends on the electric field up to the characteristic value, at which significant electron heating allows hot electrons to overcome the barriers. Optimizing the carrier capture and transit times, we show that quantum-dot structures have a lot of potentials for increasing the photoconductive gain and for the development of IR room-temperature detectors.
MULTI-AGENT SIMULATIONS OF THE IMMUNE RESPONSE TO HIV DURING THE ACUTE STAGE OF INFECTION
Authors: WALSHE R. , RUSKIN H. J. , CALLAGHAN A.
Published: March 2008

Results of multi-agent based simulations of the immune response to HIV during the acute phase of infection are presented here. The model successfully recreates the viral dynamics associated with the acute phase of infection, i.e., a rapid rise in viral load followed by a sharp decline to what is often referred to as a "set point", a result of T-cell response and emergence of HIV neutralizing antibodies. The results indicate that sufficient T Killer cell response is the key factor in controlling viral growth during this phase with antibody levels of critical importance only in the absence of a sufficient T Killer response.
MODELS OF OPINION FORMATION: INFLUENCE OF OPINION LEADERS
Authors: BOCCARA NINO
Published: March 2008

This paper studies the evolution of the distribution of opinions in a population of individuals in which there exist two distinct subgroups of highly-committed, well-connected opinion leaders endowed with a strong convincing power. Each individual, located at a vertex of a directed graph, is characterized by her name, the list of people she is interacting with, her level of awareness, and her opinion. Various temporal evolutions according to different local rules are compared in order to find under which conditions the formation of strongly polarized subgroups, each adopting the opinion of one of the two groups of opinion leaders, is favored.
PRISONER'S DILEMMA IN ONE-DIMENSIONAL CELLULAR AUTOMATA: VISUALIZATION OF EVOLUTIONARY PATTERNS
Authors: PEREIRA MARCELO ALVES , MARTINEZ ALEXANDRE SOUTO , ESPÍNDOLA AQUINO LAURI
Published: March 2008

The spatial Prisoner's Dilemma is a prototype model to show the emergence of cooperation in very competitive environments. It considers players, at sites of lattices, that can either cooperate or defect when playing the Prisoner's Dilemma with z other players. This model presents a rich phase diagram. Here we consider players in cells of one-dimensional cellular automata. Each player interacts with z other players. This geometry allows us to vary, in a simple manner, the number of neighbors ranging from one up to the lattice size, including self-interaction. This approach has multiple advantages. It is simple to implement numerically and we are able to retrieve all the results found in the previously considered lattices, with a faster convergence to stationary values. More remarkable, it permits us to keep track of the spatio-temporal evolution of each player of the automaton, giving rise to interesting patterns. These patterns allow the interpretation of cooperation/defection clusters as particles, which can be absorbed and collided among themselves. The presented approach represents a new paradigm to study the emergence and maintenance of cooperation in the spatial Prisoner's Dilemma.
INVERSELY UNSTABLE SOLUTIONS OF TWO-DIMENSIONAL SYSTEMS ON GENUS-p SURFACES AND THE TOPOLOGY OF KNOTTED ATTRACTORS
Authors: SONG YI , BANKS STEPHEN P.
Published: March 2008

In this paper, we will show that a periodic nonlinear, time-varying dissipative system that is defined on a genus-p surface contains one or more invariant sets which act as attractors. Moreover, we shall generalize a result in [Martins, 2004] and give conditions under which these invariant sets are not homeomorphic to a circle individually, which implies the existence of chaotic behavior. This is achieved by studying the appearance of inversely unstable solutions within each invariant set.
EVIDENCE CONSISTENT WITH DETERMINISTIC CHAOS IN HUMAN CARDIAC DATA: SURROGATE AND NONLINEAR DYNAMICAL MODELING
Authors: ZHAO YI , SUN JUNFENG , SMALL MICHAEL
Published: March 2008

Whether or not the human cardiac system is chaotic has long been a subject of interest in the application of nonlinear time series analysis. The surrogate data method, which identifies an observed time series against three common kinds of hypotheses, does not provide sufficient evidence to confirm the existence of deterministic chaotic dynamics in cardiac time series, such as electrocardiogram data and pulse pressure propagation data. Moreover, these methods fail to exclude all but the most trivial hypothesis of linear noise. We present a recently suggested fourth algorithm for testing the hypotheses of a noise driven periodic orbit to decide whether these signals are consistent with deterministic chaos. Of course, we cannot exclude all other alternatives but our test is certainly stronger than the those applied previously. The algorithmic complexity is used as the discriminating statistic of the surrogate data method. We then perform nonlinear modeling for the short-term prediction between ECG and pulse data to provide further evidence that they conform to deterministic processes. We demonstrate the application of these methods to human electrocardiogram recordings and blood pressure propagation in the fingertip of seven healthy subjects. Our results indicate that bounded aperiodic determinism exists in both ECG and pulse time series. The addition of (the inevitable) dynamic noise means that it is not possible to conclude the underlying system is chaotic.
A NEW COMPARISON METHOD FOR STABILITY THEORY OF DIFFERENTIAL SYSTEMS WITH TIME-VARYING DELAYS
Authors: ZENG ZHIGANG , YU PEI , LIAO XIAOXIN
Published: March 2008

In this paper, a new comparison method is developed by using increasing and decreasing mechanisms, which are inherent in time-delay systems, to decompose systems. Based on the new method, whose expected performance is compared with the state of the original system, some new conditions are obtained to guarantee that the original system tracks the expected values. The locally exponential convergence rate and the convergence region of the polynomial differential equations with time-varying delays are also investigated. In particular, the comparison method is used to improve the 3/2 stability theorems of differential systems with pure delays. Moreover, the comparison method is applied to identify a threshold, and to consider the disease-free equilibrium points of an HIV endemic model with stages of progress to AIDs and time-varying delay. It is shown that if the threshold is smaller than 1, the equilibrium point of the model is globally, exponentially stable. Another application of the comparison method is to investigate the global, exponential stability of neural networks, and some new theoretical results are obtained. Numerical simulations are presented to verify the theoretical results.
STABILITY OF STEADY STATE AND TRAVELING WAVES SOLUTIONS IN COUPLED MAP LATTICES
Authors: TURZÍK DANIEL , DUBCOVÁ MIROSLAVA
Published: March 2008

We determine the essential spectrum of certain types of linear operators which arise in the study of the stability of steady state or traveling wave solutions in coupled map lattices. The basic tool is the Gelfand transformation which enables us to determine the essential spectrum completely.
CHAOTIC SYNCHRONIZATION AND SECURE COMMUNICATION VIA SLIDING-MODE OBSERVER
Authors: MARTINEZ-GUERRA RAFAEL , YU WEN
Published: March 2008

Information signal embedded in a chaotic transmitter can be recovered by a receiver if it is a replica of the transmitter. In this paper, a new aspect of chaotic communication is introduced. A sliding-mode observer replaces the conventional chaotic system at the receiver side, which does not need information from the transmitter. So the uncertainties in the transmitter and the transmission line do not affect the synchronization, the proposed communication scheme is robust with respect to some disturbances and uncertainties. Three chaotic systems, Duffing equation, Van der Pol oscillator and Chua's circuit, are provided to illustrate the effectiveness of the chaotic communication.
CHAOTIC CONTROL AND CHAOTIFICATION USING FUZZY APPROACH
Authors: LIAN KUANG-YOW , HUANG CHENG-SEA , FANG WEN-HSIEN , SU CHIEN-HSING
Published: March 2008

In this paper, we propose a fuzzy model-based methodology to deal with various control objectives for discrete-time chaotic systems from a unified viewpoint. With intent to unify the design process, we introduce a new design concept called virtual-desired-variable synthesis. Then, both the chaotic control and chaotification are eventually treated as a stabilization problem. Consequently, the conditions concerning the stability of the closed-loop system are formulated into LMIs. A feasible solution of the LMI problem guarantees the quadratical stability and gives the state feedback gains as well. The well-known Hénon map is used to demonstrate the unified approach.
HOPF BIFURCATION ANALYSIS FOR A MATHEMATICAL MODEL OF P53-MDM2 INTERACTION
Authors: NEAMŢU MIHAELA , HORHAT RAUL FLORIN , OPRIŞ DUMITRU
Published: March 2008

In this paper we analyze a simple mathematical model which describes the interaction between proteins P53 and Mdm2. For the stationary state we discuss the local stability and the existence of a Hopf bifurcation. We study the direction and stability of the bifurcating periodic solutions by choosing the delay as a bifurcation parameter. Finally, we will offer some numerical simulations and present our conclusions.