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The Orphan Adhesion-GPCR GPR126 Is Required for Embryonic Development in the Mouse  [PDF]
Helen Waller-Evans,Simone Pr?mel,Tobias Langenhan,John Dixon,Dirk Zahn,William H. Colledge,Joanne Doran,Mark B. L. Carlton,Ben Davies,Samuel A. J. R. Aparicio,Johannes Grosse,Andreas P. Russ
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0014047
Abstract: Adhesion-GPCRs provide essential cell-cell and cell-matrix interactions in development, and have been implicated in inherited human diseases like Usher Syndrome and bilateral frontoparietal polymicrogyria. They are the second largest subfamily of seven-transmembrane spanning proteins in vertebrates, but the function of most of these receptors is still not understood. The orphan Adhesion-GPCR GPR126 has recently been shown to play an essential role in the myelination of peripheral nerves in zebrafish. In parallel, whole-genome association studies have implicated variation at the GPR126 locus as a determinant of body height in the human population. The physiological function of GPR126 in mammals is still unknown. We describe a targeted mutation of GPR126 in the mouse, and show that GPR126 is required for embryonic viability and cardiovascular development.
Gαo Is Required for L-Canavanine Detection in Drosophila  [PDF]
Isabelle Devambez, Moutaz Ali Agha, Christian Mitri, Jo?l Bockaert, Marie-Laure Parmentier, Frédéric Marion-Poll, Yves Grau, Laurent Soustelle
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0063484
Abstract: Taste is an essential sense for the survival of most organisms. In insects, taste is particularly important as it allows to detect and avoid ingesting many plant toxins, such as L-canavanine. We previously showed that L-canavanine is toxic for Drosophila melanogaster and that flies are able to detect this toxin in the food. L-canavanine is a ligand of DmXR, a variant G-protein coupled receptor (GPCR) belonging to the metabotropic glutamate receptor subfamily that is expressed in bitter-sensitive taste neurons of Drosophila. To transduce the signal intracellularly, GPCR activate heterotrimeric G proteins constituted of α, β and γ subunits. The aim of this study was to identify which Gα protein was required for L-canavanine detection in Drosophila. By using a pharmacological approach, we first demonstrated that DmXR has the best coupling with Gαo protein subtype. Then, by using genetic, behavioral assays and electrophysiology, we found that Gαo47A is required in bitter-sensitive taste neurons for L-canavanine sensitivity. In conclusion, our study revealed that Gαo47A plays a crucial role in L-canavanine detection.
Contribution to the Creation Of DMX Queries in Mining Student Data  [PDF]
Marija Blagojevic,Zivadin Micic
International Journal of Emerging Sciences , 2012,
Abstract: The paper is a contribution to creating DMX queries for mining student data. The focus is placed on the possibilities of data mining techniques applied in e-learning. DMX queries are created and applied against data mining models. The log files of students from Moodle learning management system at Technical Faculty Cacak, University of Kragujevac (Serbia) have been used in the research. The results point to the possibility of applying DMX queries in student data mining and they also imply the possibility of predicable behavior patterns of the students. In addition, the paper presents the contribution of DMX queries in the evaluation of electronic Moodle courses.
GPCR oligomers in pharmacology and signaling
Javier González-Maeso
Molecular Brain , 2011, DOI: 10.1186/1756-6606-4-20
Abstract: G protein-coupled receptors (GPCRs) [1], also known as seven transmembrane receptors, were initially considered to function as monomeric structural units. In the last decade, however, there has been an increasing number of publications describing GPCR homodimers or even higher order oligomers [2-5]. There is also evidence that GPCR heterocomplexes may exist [6-8]. Two of the main lines of research in structure and function of GPCRs are focused on the residues and domains responsible for GPCR complex formation, as well as the stability and mechanisms of signaling crosstalk between the components of these homo- and heteromers. Another point of interest is the identification of GPCR complexes in native tissues and their functional significance in whole animal models. In this review, we will summarize recent advances in our understanding of GPCR homo- and heteromerization, as well as their potential implication in physiological responses.In the 1980s, two laboratories at the Karolinska Institute in Stockholm and the National Institute for Medical Research in London proposed the existence of receptor mosaics [9,10] and a direct interaction of two receptors with each other [11]. This hypothesis was also supported by previous publications demonstrating negatively cooperative site-site interactions among the β-adrenergic receptors [12]. Similarly, using a photoaffinity labeling approach, Sokolovsky and collaborators proposed that muscarinic receptors exist in interconvertible dimer and tetramer forms [13]. They also suggested a model in which muscarinic receptor monomers formed dimers and tetramers joined by covalent bonds; although this model of covalent bonding has not been confirmed. Immunoaffinity chromatography approaches with the β2-adrenergic receptor in mammalian lung [14], and protocols of radiation inactivation with the α2-adrenergic receptor in human platelets [15] also pointed toward the phenomenon of GPCR oligomerization. Years earlier, it had been introduced t
Canavanine-induced longevity in mice may require diets with greater than 15.7% protein
Dan L Brown
Nutrition & Metabolism , 2005, DOI: 10.1186/1743-7075-2-7
Abstract: In order to determine if this effect also obtains at more moderate dietary protein concentrations, 30 female BALB/c mice were fed a basal diet with 14% protein (15.7% dry matter basis) and another 30 were fed the same diet plus 1% canavanine.Neither mean (Control 873.2 d, Canavanine 870.0 d; SEM = 34.2 d; P = 0.949 from ANOVA) nor median (Control 902 d, Canavanine 884.5 d; P = 0.9058 from Mann-Whitney) lifespans differed between groups.Although mean antinuclear antibody (ANA) titers did not differ between control and canavanine-treated mice at 833 days of age (19.84 vs 20.39 respectively; SEM = 2.64; P = 0.889 from ANOVA), one canavanine-treated mouse displayed an outlying ANA value of 50 (next lower value = 30) denoting possible early sign of incipient autoimmune disease in that individual.There may be an interaction between dietary protein level and canavanine with respect to lifespan in mice.L-canavanine is a common non-protein amino acid found naturally in alfalfa sprouts, broad beans, jack beans, and a number of other legume foods and animal feed ingredients [1] at up to 2.4% of food dry matter. This analog of arginine (Figure 1.) can also block NO synthesis [2-5], interfere with normal ammonia disposal [6,7], charge tRNAarg, cause the synthesis of canavanyl proteins [8], as well as prevent normal reproduction in arthropods [9] and rodents [10].Canavanine has also been reported to induce a condition that mimics systemic lupus erythematosus (SLE) in primates [11,12], to increase antibodies to nuclear components and promote SLE-like lesions in auto immune-susceptible (e.g., (NZB X NZW)F1) mice [13].In our previous study [14], eighteen female BALB/c mice were fed a 23.4% protein diet containing 1.56% L-canavanine sulfate (equivalent to 1% L-canavanine base) and eighteen control mice received control diet (23.4% protein) from 84–477 days of age. More canavanine-fed mice (16 of 18) survived to age 477 days than those fed the basal diet (9 of 18) (X 2 with Yates corr
A brief review on the evolution of GPCR: conservation and diversification  [PDF]
Zaichao Zhang, Jiayan Wu, Jun Yu, Jingfa Xiao
Open Journal of Genetics (OJGen) , 2012, DOI: 10.4236/ojgen.2012.24B003
Abstract: G-protein couple receptors (GPCR) possess diversified functions and they comprise a large protein superfamily in cellular signaling. Numerous identification methods for GPCR have been employed and versatile GPCR types are discussed. Although they share conserved transmembrane structural topology, alignment results of all GPCR show no significant sequence similarities. Each GPCR type distributes diversely in different evolutionary hierarchies of eukaryotes, but it has a distinctive boundary in the era of metazoan. The common ancestor of GPCR metabotropic glutamate receptor includes 7-transmembrane structure and venus flytrap module, which is probably evolved from a compound of bacteriorhodopsin and periplasmic binding protein. Many investigations focus on fine structure shaping and GPCR classification. Here, we briefly discuss evolutionary dynamic mechanism of GPCR from the perspective of classification, diversification and conservation.
Orphan Care in China
Meng, Liu,Kai, Zhu
Social Work and Society , 2009,
Abstract: Orphan care in China was once provided by the central government as a means of social control. The centralized welfare delivery guaranteed some of the poorest orphans to be protected by the government. Since the economic reform, the central government started to relinquish its control over social welfare delivery, new forms of orphan care were introduced into China, sharing the responsibilities and burdens for caring the orphans. Yet, many issues and problems exist in social delivery due to a lack of finances, professionals, and policy support. In this chapter, we will discuss the background of social welfare changes in China, as pertains to orphan care, focusing on the different types of orphans as a result of social issues, service delivery, barriers and solutions. It is claimed that during the reform, the burden of orphan care in China may not be reduced in the coming future, and we offer suggestions to cope with that.
The Orbit of the Orphan Stream  [PDF]
Heidi Jo Newberg,Benjamin A. Willett,Brian Yanny,Yan Xu
Physics , 2010, DOI: 10.1088/0004-637X/711/1/32
Abstract: We use recent SEGUE spectroscopy and SDSS and SEGUE imaging data to measure the sky position, distance, and radial velocities of stars in the tidal debris stream that is commonly referred to as the "Orphan Stream." We fit orbital parameters to the data, and find a prograde orbit with an apogalacticon, perigalacticon, and eccentricity of 90 kpc, 16.4 kpc and 0.7, respectively. Neither the dwarf galaxy UMa II nor the Complex A gas cloud have velocities consistent with a kinematic association with the Orphan Stream. It is possible that Segue-1 is associated with the Orphan Stream, but no other known Galactic clusters or dwarf galaxies in the Milky Way lie along its orbit. The detected portion of the stream ranges from 19 to 47 kpc from the Sun and is an indicator of the mass interior to these distances. There is a marked increase in the density of Orphan Stream stars near (l,b)=(253,49) deg., which could indicate the presence of the progenitor at the edge of the SDSS data. If this is the progenitor, then the detected portion of the Orphan Stream is a leading tidal tail. We find blue horizontal branch (BHB) stars and F turnoff stars associated with the Orphan Stream. The turnoff color is (g-r)_0=0.22. The BHB stars have a low metallicity of [Fe/H]=-2.1. The orbit is best fit to a halo potential with a halo plus disk mass of about 2.6x10^11 Solar masses, integrated to 60 kpc from the Galactic center. Our best fit is found with a logarithmic halo speed of v_halo=73+/-24 km/s, a disk+bulge mass of M(R< 60 kpc) = 1.3x10^11 Solar masses, and a halo mass of M(R< 60 kpc) = 1.4x10^11 Solar masses. The Orphan Stream is projected to extend to 90 kpc from the Galactic center, and measurements of these distant parts of the stream would be a powerful probe of the mass of the Milky Way (truncated).
The Detectability of Orphan Afterglows  [PDF]
Ehud Nakar,Tsvi Piran,Jonathan Granot
Physics , 2002, DOI: 10.1086/342791
Abstract: The realization that GRBs release a constant amount of energy implies that the post jet-break afterglow evolution would be largely universal. For a given redshift all afterglows should be detected up to a fixed observer angle. We estimate the observed magnitude and the implied detectability of orphan afterglows. We show that for reasonable limiting magnitudes ($m_{lim}=25$) orphan afterglows would typically be detected from small ($\sim 10^\circ$) angles away from the GRB jet axis. A detected orphan afterglow would generally correspond to a "near-miss" of the GRB whose jet was pointing just slightly away from us. With our most optimistic parameters we expect that 15 orphan afterglows will be recorded in the SDSS and 35 transients will be recorded in a dedicated 2m class telescope operating full time for a year in an orphan afterglow search. The rate is smaller by a factor of 15 for our "canonical" parameters. We show that for a given facility an optimal survey should be shallower, covering larger area rather than deeper. The limiting magnitude should not be, however, lower than $\sim$ 23rd as in this case more transients from on-axis GRBs will be discovered than orphan afterglows. About 15% of the transients could be discovered with a second exposure of the same area provided that it follows after 3, 4 and 8 days for $m_{lim}=23$, 25 and 27.
Orphan drug: Development trends and strategies  [cached]
Sharma Aarti,Jacob Abraham,Tandon Manas,Kumar Dushyant
Journal of Pharmacy and Bioallied Sciences , 2010,
Abstract: The growth of pharma industries has slowed in recent years because of various reasons such as patent expiries, generic competition, drying pipelines, and increasingly stringent regulatory guidelines. Many blockbuster drugs will loose their exclusivity in next 5 years. Therefore, the current economic situation plus the huge generic competition shifted the focus of pharmaceutical companies from the essential medicines to the new business model - niche busters, also called orphan drugs. Orphan drugs may help pharma companies to reduce the impact of revenue loss caused by patent expiries of blockbuster drugs. The new business model of orphan drugs could offer an integrated healthcare solution that enables pharma companies to develop newer areas of therapeutics, diagnosis, treatment, monitoring, and patient support. Incentives for drug development provided by governments, as well as support from the FDA and EU Commission in special protocols, are a further boost for the companies developing orphan drugs. Although there may still be challenges ahead for the pharmaceutical industry, orphan drugs seem to offer the key to recovery and stability within the market. In our study, we have compared the policies and orphan drug incentives worldwide alongwith the challenges faced by the pharmaceutical companies. Recent developments are seen in orphan drug approval, the various drugs in orphan drug pipeline, and the future prospectives for orphan drugs and diseases.
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