We study in a self-consistent way the impact of the emission of bulk gravitons on the (homogeneous) cosmology of a three-brane embedded in a fivedimensional spacetime. In the low energy regime, we recover the well known result that the bulk affects the Friedmann equation only via a radiation-like term C/a 4 , called dark or Weyl radiation. By contrast, in the high energy regime, we find that the Weyl parameter C is no longer constant but instead grows very rapidly as C ∝ a 4 . As a consequence, the value of C today is not a free parameter as usually considered but is a fixed number, which, generically, depends only on the number of relativistic degrees of freedom at the high/low energy transition. Our estimated amount of Weyl radiation satisfies the present nucleosynthesis bounds.

1 The present study analyses the in¯uence of hypertension and endothelium on the e ect induced by hydrogen peroxide (H 2 O 2 ) on basal tone in aortic segments from normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) of 6-month-old, as well as the possible mechanisms involved. 2 Single (1 mM) or cumulative (100 nM ± 10 mM) concentrations of H 2 O 2 produced a transient contraction or a concentration-dependent increase of basal tone, respectively, in segments from WKY and SHR. In both cases, the contractions were higher in intact segments from hypertensive than from normotensive rats, and increased by endothelium removal in both strains. Catalase (1000 u ml 71 , a H 2 O 2 scavenger) abolished the contraction elicited by 1 mM H 2 O 2 in both strains. 3 Superoxide dismutase (SOD, 150 u ml 71 ) and dimethylsulphoxide (DMSO, 7 mM), scavengers of superoxide anions and hydroxyl radicals, respectively, did not alter H 2 O 2 -induced contractions in intact segments from both strains. However, L-N G -nitroarginine methyl ester (L-NAME, 100 mM, a nitric oxide synthase inhibitor) increased the response to H 2 O 2 in normotensive rats, although the increase was less than that produced by endothelium removal. 4 Incubation of segments with 1 mM H 2 O 2 for 15 min and subsequent washout reduced the contractile responses induced by 75 mM KCl in intact segments from SHR and in endothelium-denuded segments from both strains; this e ect being prevented by catalase (1000 u ml 71 ). 5 Indomethacin (10 mM, a cyclo-oxygenase inhibitor) and SQ 29,548 (10 mM, a prostaglandin H 2 / thromboxane A 2 receptor antagonist) practically abolished the contractions elicited by H 2 O 2 in normotensive and hypertensive rats. 6 We conclude that: (1) the oxidant stress induced by H 2 O 2 produces contractions mediated by generation of a product of the cyclo-oxygenase pathway, prostaglandin H 2 or more probably thromboxane A 2 , in normotensive and hypertensive rats; (2) oxygen-derived free radicals are not involved in the e ect of H 2 O 2 ; (3) in normotensive rats, endothelium protects against H 2 O 2 -mediated injury to contractile machinery, determined by the impairment of KCl-induced contractions; and (4) endothelial nitric oxide has a protective role on the contractile e ect induced by H 2 O 2 , that is lost in hypertension.

Protein kinase D (PKD) controls protein traffic from the transGolgi network (TGN) to the plasma membrane of epithelial cells in an isoform-specific manner. However, whether the different PKD isoforms could be selectively regulating the traffic of their specific substrates remains unexplored. We identified the C terminus of the different PKDs that constitutes a postsynaptic density-95/discs large/zonula occludens-1 (PDZ)-binding motif in PKD1 and PKD2, but not in PKD3, to be responsible for the differential control of kinase D-interacting substrate of 220-kDa (Kidins220) surface localization, a neural membrane protein identified as the first substrate of PKD1. A kinase-inactive mutant of PKD3 is only able to alter the localization of Kidins220 at the plasma membrane when its C terminus has been substituted by the PDZ-binding motif of PKD1 or PKD2. This isoform-specific regulation of Kidins220 transport might not be due to differences among kinase activity or substrate selectivity of the PKD isoenzymes but more to the adaptors bound to their unique C terminus. Furthermore, by mutating the autophosphorylation site Ser 916 , located at the critical position ؊2 of the PDZ-binding domain within PKD1, or by phorbol ester stimulation, we demonstrate that the phosphorylation of this residue is crucial for Kidins220-regulated transport. We also discovered that Ser 916 trans-phosphorylation takes place among PKD1 molecules. Finally, we demonstrate that PKD1 association to intracellular membranes is critical to control Kidins220 traffic. Our findings reveal the molecular mechanism by which PKD localization and activity control the traffic of Kidins220, most likely by modulating the recruitment of PDZ proteins in an isoform-specific and phosphorylationdependent manner. Protein kinase D1 (PKD1)5 (1), also known as PKC (2), belongs to a novel family of diacylglycerol (DAG)-stimulated Ser/Thr kinases, composed of two more members PKD2 (3) and PKD3 (4) (reviewed in Refs. 5-7). PKDs contain several well characterized domains, including two cysteine-rich repeats (C1a and C1b) that constitute a C1 domain (CR), a pleckstrin homology domain, and a catalytic domain at the C terminus. The CR domain binds DAG and phorbol esters with high affinity (1,8) and is involved in the association of PKD1 to cellular membranes such as the plasma membrane and the trans-Golgi network (TGN) (9 -12). The pleckstrin homology domain is an autoinhibitory domain that regulates the activity of this kinase (13). PKD is activated by the phosphorylation of two activation loop sites within the catalytic domain through a protein kinase C (PKC)-dependent pathway, which stabilizes the enzyme in an active conformation (14, 15). Activated PKD1 autophosphorylates at Ser 916 present at the very C terminus, and this phosphorylation event is frequently used to determine the activation state of this kinase (16 -18).PKD has been shown to participate in many cellular processes, such as cell survival, proliferation, and invasion (5-7), but the regulation of protein transpo...

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We consider "cosmologically symmetric" (i.e. solutions with homogeneity and isotropy along three spatial dimensions) five-dimensional spacetimes with a scalar field and a three-brane representing our universe. We write Einstein's equations in a conformal gauge, using light-cone coordinates. We obtain explicit solutions: a. assuming proportionality between the scalar field and the logarithm of the (bulk) scale factor; b. assuming separable solutions. We then discuss the cosmology in the brane induced by these solutions.

Kidins220 (kinase D-interacting substrate of 220 kDa) is a novel neurospecific protein recently cloned as the first substrate for the Ser/Thr kinase protein kinase D (PKD). Herein we report that Kidins220 is constitutively associated to lipid rafts in PC12 cells, rat primary cortical neurons, and brain synaptosomes. Immunocytochemistry and confocal microscopy together with sucrose gradient fractionation show co-localization of Kidins220 and lipid raft-associated proteins. In addition, cholesterol depletion of cell membranes with methyl-␤-cyclodextrin dramatically alters Kidins220 localization and detergent solubility. By studying the putative involvement of lipid rafts in PKD activation and signaling we have found that active PKD partitions in lipid raft fractions after sucrose gradient centrifugation and that green fluorescent protein-PKD translocates to lipid raft microdomains at the plasma membrane after phorbol ester treatment. Strikingly, lipid rafts disruption by methyl-␤-cyclodextrin delays green fluorescent protein-PKD translocation, as determined by live cell confocal microscopy, and activates PKD, increasing Kidins220 phosphorylation on Ser 919 by a mechanism involving PKC⑀ and the small soluble tyrosine kinase Src. Collectively, these results reveal the importance of lipid rafts on PKD activation, translocation, and downstream signaling to its substrate Kidins220. Kidins220 (kinase D-interacting substrate of 220 kDa) 1 (1), also known as ankyrin repeat-rich membrane spanning or ARMS (2), is a novel integral membrane protein mainly expressed in brain, encoded by a single gene in Drosophila melanogaster, Caenorhabditis elegans, and mammals. Its primary amino acid sequence contains several structural and functional domains and diverse motifs that may link this protein to membranes, cytoskeleton, and different signaling pathways. The N terminus bears 11 ankyrin repeats that are likely to be involved in protein-protein interactions specially with the cytoskeleton (3). Downstream, the sequence presents four transmembrane domains and a proline-rich region that may serve as a binding site for adaptor modules like SH3 domains. Kidins220 C-terminal half is very abundant in phosphorylatable residues, serine, threonine, and tyrosine, that could constitute docking sites for Ser/Thr binding domain-containing proteins or phosphotyrosine binding modules such as SH2 domains. It also bears a sterile-␣ motif or SAM domain (4) and a potential PSD95/SAP90, DGL/ZO-1 (PDZ) binding motif at the very C terminus (5), both candidates for protein-protein interactions.Kidins220 was cloned as the first physiological substrate for protein kinase D (PKD) (1). This kinase, also known as PKD1 or protein kinase C (PKC) (6, 7), belongs to a novel family of diacylglycerol (DAG)-stimulated Ser/Thr kinases distantly related to the PKC family, characterized by unique enzymatic properties and domain architecture (for a recent review, see Refs. 8 and 9). PKD has multiple domains, including two cysteine-rich repeats that constitute a C1 domain...

Current treatments of sporadic Burkitt's lymphoma (sBL) are associated with severe toxicities. A better understanding of sBL formation would facilitate development of less toxic therapies. The etiology of sBL remains, however, largely unknown, C-MYC up-regulation being the only lesion known to occur in all sBL cases. Several studies examining the role of C-MYC in the pathogenesis of BL have concluded that C-MYC translocation is not the only critical event and that additional unidentified factors are expected to be involved in the formation of this tumor. We herein report that a gene distinct from C-MYC, E2F1, is involved in the formation of all or most sBL tumors. We found that E2F1 is highly expressed in Burkitt's lymphoma cell lines and sBL lymphoma specimens. Our data indicate that its elevated expression is not merely the consequence of the presence of more cycling cells in this tumor relative to other cell lines or to other neoplasias. In fact, we show that reduction of its expression in sBL cells inhibits tumor formation and decreases their proliferation rate. We also provide data suggesting that E2F1 collaborates with C-MYC in sBL formation. E2F1 expression downregulation did not affect, however, the proliferation of human primary diploid fibroblasts. Because E2F1 is not needed for cell proliferation of normal cells, our results reveal E2F1 as a promising therapeutic target for sBL. [Cancer Res 2009;69(9):4052-8]

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