The P2X 7 receptor is a ligand-gated cation-selective channel that mediates ATP-induced apoptosis of cells of the immune system. We and others have shown that P2X 7 is nonfunctional both in lymphocytes and monocytes from some subjects. To study a possible genetic basis we sequenced DNA coding for the carboxyl-terminal tail of P2X 7 . In 9 of 45 normal subjects a heterozygous nucleotide substitution (1513A3 C) was found, whereas 1 subject carried the homozygous substitution that codes for glutamic acid to alanine at amino acid position 496. Surface expression of P2X 7 on lymphocytes was not affected by this E496A polymorphism, demonstrated both by confocal microscopy and immunofluorescent staining. Monocytes and lymphocytes from the E496A homozygote subject expressed nonfunctional receptor, whereas heterozygotes showed P2X 7 function that was half that of germline P2X 7 . Results of transfection experiments showed that the mutant P2X 7 receptor was nonfunctional when expressed at low receptor density but regained function at a high receptor density. This density dependence of mutant P2X 7 function was also seen on differentiation of fresh monocytes to macrophages with interferon-␥, which up-regulated mutant P2X 7 and partially restored its function. P2X 7 -mediated apoptosis of lymphocytes was impaired in homozygous mutant P2X 7 compared with germline (8.6 versus 35.2%). The data suggest that the glutamic acid at position 496 is required for optimal assembly of the P2X 7 receptor.Purinergic P2X 7 receptors are ligand-gated cation channels, present on cells of the immune and hemopoietic system, that have been shown to mediate the ATP-induced apoptotic death of monocytes (1), macrophages (2), and lymphocytes (3, 4). The P2X 7 receptor family has two transmembrane domains with intracellular amino and carboxyl termini and an oligomeric structure in the plasma membrane based on trimeric or larger complexes of identical subunits (5). Moreover, the P2X7 receptor does not appear to form heteropolymers with other P2X subtypes (6). The genes for both the rat and human P2X 7 receptors have now been cloned and show extensive homology (30 -40%) with the other members of the P2X receptor family, although P2X 7 differs in having a long carboxyl terminus of 240 amino acids from the inner membrane face (7). The genomic structure of P2X 7 consists of 13 exons, with exon 12 and exon 13 coding for the C-terminal tail of this molecule. There is strong evidence that this long carboxyl terminus is necessary for the permeability properties of the P2X 7 receptor, because truncation of this tail abolishes ATP-induced uptake of the fluorescent dye YoPro-1 (8). Studies of P2X 7 of macrophages or lymphocytes as well as of human embryonic kidney cells (HEK-293) expressing the cDNA for P2X 7 have shown features that are most unusual for a channel. These include the slow further dilatation following channel opening (9) and the activation of various proteases including membrane metalloproteases (10) and intracellular caspases (2, 11). The fully ...

Olfactory receptors (ORs) are expressed not only in the sensory neurons of the olfactory epithelium, where they detect volatile substances, but also in various other tissues where their potential functions are largely unknown. Here, we report the physiological characterization of human OR51E2, also named prostate-specific G-protein-coupled receptor (PSGR) due to its reported up-regulation in prostate cancer. We identified androstenone derivatives as ligands for the recombinant receptor. PSGR can also be activated with the odorant ␤-ionone. Activation of the endogenous receptor in prostate cancer cells by the identified ligands evoked an intracellular Ca 2؉ increase. Exposure to ␤-ionone resulted in the activation of members of the MAPK family and inhibition of cell proliferation. Our data give support to the hypothesis that because PSGR signaling could reduce growth of prostate cancer cells, specific receptor ligands might therefore be potential candidates for prostate cancer treatment.Excessive signaling by G-protein-coupled receptors (GPCRs) 3 such as endothelin A receptor (1), bradykinin 1 receptor (2), follicle-stimulating hormone receptor (3), and thrombin receptor (4, 5) is known to occur in prostate cancers due to strong overexpression of the respective receptors. Activation of some of these GPCRs results in androgen-independent androgen receptor activation, thus promoting the transition of prostate cancer cells from an androgen-dependent to an androgen-independent state (6, 7).The prostate-specific G-protein-coupled receptor (PSGR) is a class A GPCR that was initially identified as a prostate-specific tumor biomarker (8 -10). It is specifically expressed in prostate epithelial cells, and its expression increases significantly in human prostate intraepithelial neoplasia and prostate tumors, suggesting that PSGR may play an important role in early prostate cancer development and progression (9, 11). Although expression of the human PSGR was found to be prostate-specific (10, 12), mRNA can also be detected in the olfactory zone and the medulla oblongata of the human brain (12). Human PSGR shares 93% amino acid homology to the respective mouse and rat homologues, which are also expressed in the brain (12). Interestingly, PSGR has numerous sequence motifs in common with the large superfamily of olfactory receptors (ORs), which build the largest class of human GPCRs and allow the recognition of a wide range of structurally diverse molecules in the nasal epithelium (13-15). Recently, also the steroid hormones androstenone and androstadienone were identified as OR ligands (16). In addition to their role in the sensory neurons of the nose, ORs have been found in different tissues throughout the body (17,18). Their function(s) in these extranasal locations are questionable except for in a few cases where functional studies have been performed in spermatozoa (19,20) and in enterochromaffin cells of the gastrointestinal tract (21).Here, we report the identification of steroid ligands of heterologously expressed PSGR...

No abstract

Despite increasing knowledge about dimerization of G-protein-coupled receptors, nothing is known about dimerization in the largest subfamily, odorant receptors. Using a combination of biochemical and electrophysiological approaches, we demonstrate here that odorant receptors can dimerize. DOR83b, an odorant receptor that is ubiquitously expressed in olfactory neurons from Drosophila melanogaster and highly conserved among insect species, forms heterodimeric complexes with other odorant-receptor proteins, which strongly increases their functionality.

We introduce certain homology and cohomology subgroups for any almost complex structure and study their pureness, fullness and duality properties. Motivated by a question of Donaldson, we use these groups to relate J-tamed symplectic cones and Jcompatible symplectic cones over a large class of almost complex manifolds, including all Kähler manifolds, almost Kähler 4-manifolds and complex surfaces.

Different horticultural types of lettuce exhibit tremendous morphological variation. However, the molecular basis for domestication and divergence among the different horticultural types of lettuce remains unknown. Here, we report the RNA sequencing of 240 lettuce accessions sampled from the major horticultural types and wild relatives, generating 1.1 million single-nucleotide polymorphisms (SNPs). Demographic modeling indicates that there was a single domestication event for lettuce. We identify a list of regions as putative selective sweeps that occurred during domestication and divergence, respectively. Genome-wide association studies (GWAS) identify 5311 expression quantitative trait loci (eQTL) regulating the expression of 4105 genes, including nine eQTLs regulating genes associated with flavonoid biosynthesis. GWAS for leaf color detects six candidate loci responsible for the variation of anthocyanins in lettuce leaves. Our study provides a comprehensive understanding of the domestication and the accumulation of anthocyanins in lettuce, and will facilitate the breeding of cultivars with improved nutritional value.

For any compact almost complex manifold (M, J), the last two authors [8] defined two subgroups H + J (M ), H − J (M ) of the degree 2 real de Rham cohomology group H 2 (M, R). These are the sets of cohomology classes which can be represented by J-invariant, respectively, Janti-invariant real 2−forms. In this note, it is shown that in dimension 4 these subgroups induce a cohomology decomposition of H 2 (M, R). This is a specifically 4-dimensional result, as it follows from a recent work of Fino and Tomassini [6]. Some estimates for the dimensions of these groups are also established when the almost complex structure is tamed by a symplectic form and an equivalent formulation for a question of Donaldson is given. 1 TEDI DRAGHICI, TIAN-JUN LI, AND WEIYI ZHANG is not C ∞ -pure (the intersection of H + J (M ) and H − J (M ) is non-empty). 1 Taking products of this example with arbitrary almost complex manifolds, one obtains examples in all dimensions ≥ 6 of almost complex structures which are not C ∞ -pure. Also in section 2, for a compact 4-manifold with an integrable J, we show that subgroups H + J (M ) and H − J (M ) relate naturally with the (complex) Dolbeault cohomology groups. We also show that a complex type decomposition for cohomology does not hold for non-integrable almost complex structures (see Lemma 2.12 and Corollary 2.14).In section 3 we focus on almost complex structures J which admit compatible or tame symplectic forms and we give estimates for the dimensions h ± J in this case. If there are J-compatible symplectic forms, then the collection of cohomology classes of all such forms, the so-called J−compatible cone, K c J (M ), is a subcone of H 2 (M ; R). In fact,is the collection of cohomology classes of J−tamed symplectic forms. Thus it is also important to understand the group H − J (M ). Our investigation of almost complex structures which are tamed by symplectic forms is also motivated by the following question of Donaldson ([4]).Question 1.1. If J is an almost complex structure on a compact 4-manifold M which is tamed by a symplectic form ω, is there a symplectic form compatible with J?In [8] it was shown that the question has an affirmative answer when J is integrable. For progress on a related problem proposed by Donaldson, the symplectic Calabi-Yau equation, and its relation to Question 1.1, the reader is referred to [4], [13], [12], [11].We observe in Theorem 3.3 that an estimate on h + J which is immediate for compatible J's can be carried over to the case of tamed J's as well. Section 3 ends with an equivalent formulation of Donaldson's Question 1.1.In a later paper [5] we will further study the group H − J . We appreciate V. Apostolov for his very useful comments, R. Hind, T. Perutz for their interest, A. Fino and A. Tomassini for sending us their paper [6], and NSF for the partial support. We also thank the referees for their careful reading of the manuscript and useful remarks. 1 We learned of the preprint [6] while putting together the final form of our paper. There are further interes...

Modern communication networks have become very complicated and highly dynamic, which makes them hard to model, predict and control. In this paper, we develop a novel experience-driven approach that can learn to well control a communication network from its own experience rather than an accurate mathematical model, just as a human learns a new skill (such as driving, swimming, etc). Specifically, we, for the first time, propose to leverage emerging Deep Reinforcement Learning (DRL) for enabling model-free control in communication networks; and present a novel and highly effective DRL-based control framework, DRL-TE, for a fundamental networking problem: Traffic Engineering (TE). The proposed framework maximizes a widely-used utility function by jointly learning network environment and its dynamics, and making decisions under the guidance of powerful Deep Neural Networks (DNNs). We propose two new techniques, TE-aware exploration and actor-critic-based prioritized experience replay, to optimize the general DRL framework particularly for TE. To validate and evaluate the proposed framework, we implemented it in ns-3, and tested it comprehensively with both representative and randomly generated network topologies. Extensive packet-level simulation results show that 1) compared to several widely-used baseline methods, DRL-TE significantly reduces end-to-end delay and consistently improves the network utility, while offering better or comparable throughput; 2) DRL-TE is robust to network changes; and 3) DRL-TE consistently outperforms a state-ofthe-art DRL method (for continuous control), Deep Deterministic Policy Gradient (DDPG), which, however, does not offer satisfying performance.