First description of a histamine receptor of class 2 (HRH2) in a protochordate: expression during blastogenesis and role in regulation of ciliary beat frequency

Histaminergic receptors belong to the family of seven-transmembrane \u3b1-helix domain receptors classified in mammals into four distinct classes. Despite being widely studied in vertebrates, few data are available on the invertebrate receptors, with only predicted H1 and H2 sequences for non-chordate deuterostomes. We report the first transcript evidence of an H2 receptor for histamine in the colonial ascidian Botryllus schlosseri showing a high degree of conservation with HRH2 mammalian and other vertebrate orthologous proteins. The transcript and protein localisation during blastogenic development through in situ hybridisation and immunohistochemistry has been described. The mRNA expression appears first in the ciliary tissues of the alimentary system in filter-feeding adults and the buds, with a particular intensity in the pharynx. Transcription is activated very early, beginning from the inner layer of the disc of the secondary bud. From one generation to the next, the transcript signals become more and more intense at the level of the emergence of primordia of the branchial and peribranchial chambers and, finally, in the cells bordering the stigmata, dorsal lamina, and non-glandular ciliated zones of the endostyle. The translated H2 receptor appears as soon as the primordia of branchial and peribranchial chambers form in the secondary bud, and, in the primary buds, is found mainly in the protostigmata before the two layers of branchial and peribranchial epithelial tissue perforate to form the stigmata. In the adult zooid, the H2 receptor is expressed by ciliated mucous cells involved in food progression throughout the whole length of the alimentary canal. The observation of the effects of histamine and histamine-receptor antagonist (ranitidine) and agonist (dimaprit) drugs on explanted branchial tissue has provided confirmation concerning the receptor class and its role in regulating the ciliary beat frequency. The involvement in the local regulation of ciliary activity is of particular concern for evolutionary considerations because HRH2 seems to have been conserved in the pharynx and its developmental derivatives (e.g. upper respiratory tract and middle ear of mammals) during the evolution of chordates

H3 histamine receptor-mediated activation of protein kinase calpha inhibits the growth of cholangiocarcinoma in vitro and in vivo

Histamine regulates functions via four receptors (HRH1, HRH2, HRH3, and HRH4). The D-myo-inositol 1,4,5-trisphosphate (IP(3))/Ca(2+)/protein kinase C (PKC)/mitogen-activated protein kinase pathway regulates cholangiocarcinoma growth. We evaluated the role of HRH3 in the regulation of cholangiocarcinoma growth. Expression of HRH3 in intrahepatic and extrahepatic cell lines, normal cholangiocytes, and human tissue arrays was measured. In Mz-ChA-1 cells stimulated with (R)-(alpha)-(-)-methylhistamine dihydrobromide (RAMH), we measured (a) cell growth, (b) IP(3) and cyclic AMP levels, and (c) phosphorylation of PKC and mitogen-activated protein kinase isoforms. Localization of PKC alpha was visualized by immunofluorescence in cell smears and immunoblotting for PKC alpha in cytosol and membrane fractions. Following knockdown of PKC alpha, Mz-ChA-1 cells were stimulated with RAMH before evaluating cell growth and extracellular signal-regulated kinase (ERK)-1/2 phosphorylation. In vivo experiments were done in BALB/c nude mice. Mice were treated with saline or RAMH for 44 days and tumor volume was measured. Tumors were excised and evaluated for proliferation, apoptosis, and expression of PKC alpha, vascular endothelial growth factor (VEGF)-A, VEGF-C, VEGF receptor 2, and VEGF receptor 3. HRH3 expression was found in all cells. RAMH inhibited the growth of cholangiocarcinoma cells. RAMH increased IP(3) levels and PKC alpha phosphorylation and decreased ERK1/2 phosphorylation. RAMH induced a shift in the localization of PKC alpha expression from the cytosolic domain into the membrane region of Mz-ChA-1 cells. Silencing of PKC alpha prevented RAMH inhibition of Mz-ChA-1 cell growth and ablated RAMH effects on ERK1/2 phosphorylation. In vivo, RAMH decreased tumor growth and expression of VEGF and its receptors; PKC alpha expression was increased. RAMH inhibits cholangiocarcinoma growth by PKC alpha-dependent ERK1/2 dephosphorylation. Modulation of PKC alpha by histamine receptors may be important in regulating cholangiocarcinoma growth. (Mol Cancer Res 2009;7(10):1704-13

Histamine inhibits adrenocortical cell proliferation but does not affect steroidogenesis.

Histamine (HA) is a neurotransmitter synthesized in most mammalian tissues exclusively by histidine decarboxylase enzyme. Among the plethora of actions mediated by HA, the modulatory effects on steroidogenesis and proliferation in Leydig cells (LCs) have been described recently. To determine whether the effects on LCs reported could be extrapolated to all steroidogenic systems, in this study, we assessed the effect of this amine on adrenal proliferation and steroidogenesis, using two adrenocortical cell lines as experimental models, murine Y1 cells and human NCI-H295R cells. Even when steroidogenesis was not modified by HA in adrenocortical cells, the biogenic amine inhibited the proliferation of H295R cells. This action was mediated by the activation of HRH1 subtype and an increase in the production of inositol phosphates as second messengers, causing cell-cycle arrest in the G2/M phase. These results indicate a new role for HA in the proliferation of human adrenocortical cells that could contribute to a better understanding of tumor pathology as well as to the development of new therapeutic agents.Fil: Pagotto, Romina María del Luján. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Pereyra, Elba Nora. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Monzón, Casandra Margarita. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Mondillo, Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Pignataro, Omar Pedro. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentin

Genetic Analysis of Histamine Signaling in Larval Zebrafish Sleep

Pharmacological studies in mammals and zebrafish suggest that histamine plays an important role in promoting arousal. However, genetic studies using rodents with disrupted histamine synthesis or signaling have revealed only subtle or no sleep/wake phenotypes. Studies of histamine function in mammalian arousal are complicated by its production in cells of the immune system and its roles in humoral and cellular immunity, which can have profound effects on sleep/wake states. To avoid this potential confound, we used genetics to explore the role of histamine in regulating sleep in zebrafish, a diurnal vertebrate in which histamine production is restricted to neurons in the brain. Similar to rodent genetic studies, we found that zebrafish that lack histamine due to mutation of histidine decarboxylase (hdc) exhibit largely normal sleep/wake behaviors. Zebrafish containing predicted null mutations in several histamine receptors also lack robust sleep/wake phenotypes, although we are unable to verify that these mutants are completely nonfunctional. Consistent with some rodent studies, we found that arousal induced by overexpression of the neuropeptide hypocretin (Hcrt) or by stimulation of hcrt-expressing neurons is not blocked in hdc or hrh1 mutants. We also found that the number of hcrt-expressing or histaminergic neurons is unaffected in animals that lack histamine or Hcrt signaling, respectively. Thus, while acute pharmacological manipulation of histamine signaling has been shown to have profound effects on zebrafish and mammalian sleep, our results suggest that chronic loss of histamine signaling due to genetic mutations has only subtle effects on sleep in zebrafish, similar to rodents

Two-way multiple relays channel: achievable rate region and optimal resources

This paper considers a communication model containing two users that exchange their information with the help of multiple parallel relay nodes. To avoid interference at these common nodes, two users are required to transmit over the different frequency bands. Based on this scenario, the achievable rate region is initially derived. Next, an optimization scheme is described to choose the best relays that can be used by each user. Then, two power allocation optimization schemes are investigated to allocate the proper average power value to each node. Finally, comparisons between these two optimization schemes are carried out through some numerical examples

On Linear Models with Restrictions on Parameters

7 pages, 1 article*On Linear Models with Restrictions on Parameters* (Searle, Shayle R.) 7 page

Prediction of gene–phenotype associations in humans, mice, and plants using phenologs

All authors are with the Center for Systems and Synthetic Biology, Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712, USA. -- Ulf Martin Singh-Blom is with the Program in Computational and Applied Mathematics, The University of Texas at Austin, Austin, TX 78712, USA, and th Unit of Computational Medicine, Department of Medicine, Karolinska Institutet, Stockholm 171 76, Sweden. -- Kriston L. McGary is with the Department of Biological Sciences, Vanderbilt University, Nashville, TN 37235, USA.Background: Phenotypes and diseases may be related to seemingly dissimilar phenotypes in other species by means of the orthology of underlying genes. Such “orthologous phenotypes,” or “phenologs,” are examples of deep homology, and may be used to predict additional candidate disease genes. Results: In this work, we develop an unsupervised algorithm for ranking phenolog-based candidate disease genes through the integration of predictions from the k nearest neighbor phenologs, comparing classifiers and weighting functions by cross-validation. We also improve upon the original method by extending the theory to paralogous phenotypes. Our algorithm makes use of additional phenotype data — from chicken, zebrafish, and E. coli, as well as new datasets for C. elegans — establishing that several types of annotations may be treated as phenotypes. We demonstrate the use of our algorithm to predict novel candidate genes for human atrial fibrillation (such as HRH2, ATP4A, ATP4B, and HOPX) and epilepsy (e.g., PAX6 and NKX2-1). We suggest gene candidates for pharmacologically-induced seizures in mouse, solely based on orthologous phenotypes from E. coli. We also explore the prediction of plant gene–phenotype associations, as for the Arabidopsis response to vernalization phenotype. Conclusions: We are able to rank gene predictions for a significant portion of the diseases in the Online Mendelian Inheritance in Man database. Additionally, our method suggests candidate genes for mammalian seizures based only on bacterial phenotypes and gene orthology. We demonstrate that phenotype information may come from diverse sources, including drug sensitivities, gene ontology biological processes, and in situ hybridization annotations. Finally, we offer testable candidates for a variety of human diseases, plant traits, and other classes of phenotypes across a wide array of species.Center for Systems and Synthetic BiologyInstitute for Cellular and Molecular [email protected]

Multi-service Signal Multiplexing and Isolation for Physical-Layer Network Slicing (PNS)

Network slicing has been identified as one of the most important features for 5G and beyond to enable operators to utilize networks on an as-a-service basis and meet the wide range of use cases. In physical layer, the frequency and time resources are split into slices to cater for the services with individual optimal designs, resulting in services/slices having different baseband numerologies (e.g., subcarrier spacing) and / or radio frequency (RF) front-end configurations. In such a system, the multi-service signal multiplexing and isolation among the service/slices are critical for the Physical-Layer Network Slicing (PNS) since orthogonality is destroyed and significant inter-service/ slice-band-interference (ISBI) may be generated. In this paper, we first categorize four PNS cases according to the baseband and RF configurations among the slices. The system model is established by considering a low out of band emission (OoBE) waveform operating in the service/slice frequency band to mitigate the ISBI. The desired signal and interference for the two slices are derived. Consequently, one-tap channel equalization algorithms are proposed based on the derived model. The developed system models establish a framework for further interference analysis, ISBI cancelation algorithms, system design and parameter selection (e.g., guard band), to enable spectrum efficient network slicing